Detection of oral transglutaminases and their relevance in celiac disease

Thesis (MSD) --Boston University, Henry M. Goldman School of Dental Medicine, 2015 (Department of Molecular and Cell Biology).Includes bibliography: leaves 46-50.Celiac disease (CD) is an autoimmune disorder characterized by enteropathy caused by ingested gluten. Human transglutaminase 2 (TG 2) localized in the lamina propria of the small intestine modifies gluten by deamidating glutamine residues, which enhances gluten binding to T-cell receptors and downstream inflammatory immune responses. Many other human TGs and microbial transglutaminases (MTGs) share a similar catalytic activity with TG2. This study aimed to investigate the presence and activities of oral TGs from both human and microbial origins in whole saliva (WS) and dental plaque of healthy individuals. It also aimed to establish a method and positive control to detect MTG activity from oral bacteria. [TRUNCATED

Anti-inflammatory Effects of α7-nicotinic ACh Receptors are Exerted Through Interactions with Adenylyl Cyclase-6

Background and purpose Alpha 7 nicotinic acetylcholine receptors (CHRNA7) suppress inflammation through diverse pathways in immune cells, so is potentially involved in a number of inflammatory diseases. However, the detailed mechanisms underlying CHRNA7’s anti‐inflammatory effects remain elusive. Experimental approach The anti‐inflammatory effects of CHRNA7 agonists in both murine macrophages (RAW 264.7) and bone marrow‐derived macrophages (BMDM) stimulated with LPS were examined. The role of adenylyl cyclase 6 (AC6) in Toll‐like Receptor 4 (TLR4) degradation was explored via overexpression and knockdown. A mouse model of chronic obstructive pulmonary disease was used to confirm key findings. Results Anti‐inflammatory effects of CHRNA7 were largely dependent on AC6 activation, as knockdown of AC6 considerably abnegated the effects of CHRNA7 agonists while AC6 overexpression promoted them. We found that CHRNA7 and AC6 are co‐localized in lipid rafts of macrophages and directly interact. Activation of AC6 led to the promotion of TLR4 degradation. Administration of CHRNA7 agonist PNU‐282987 attenuated pathological and inflammatory end points in a mouse model of chronic obstructive pulmonary disease (COPD). Conclusion and implications CHRNA7 inhibits inflammation through activating AC6 and promoting degradation of TLR4. The use of CHRNA7 agonists may represent a novel therapeutic approach for treating COPD and likely other inflammatory diseases

Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo

Regulatory T (T reg) cells exert powerful down-modulatory effects on immune responses, but it is not known how they act in vivo. Using intravital two-photon laser scanning microscopy we determined that, in the absence of T reg cells, the locomotion of autoantigen-specific T cells inside lymph nodes is decreased, and the contacts between T cells and antigen-loaded dendritic cells (DCs) are of longer duration. Thus, T reg cells can exert an early effect on immune responses by attenuating the establishment of stable contacts during priming of naive T cells by DCs

TCR-dependent differentiation of thymic Foxp3+ cells is limited to small clonal sizes

Numerous studies have highlighted the importance of high-affinity interactions between T cell receptors (TCRs) and their ligands in the selection of Foxp3+ regulatory T cells (T reg cells). To determine the role of the TCR in directing T cells into the Foxp3+ lineage, we generated transgenic (Tg) mice expressing TCRs from Foxp3+ cells. Initial analyses of the TCR Tg mice crossed with RAG-deficient mice showed that the percentage of Foxp3+ cells was very low. However, intrathymic injection and bone marrow chimera experiments showed a saturable increase of the Foxp3+ population when T reg TCR Tg cells were present in low numbers. Furthermore, when analyzing whole thymi of T reg TCR Tg RAG-deficient mice, we found significantly more Foxp3+ cells than in conventional T cell TCR Tg mice. Our results indicate that although the TCR has an instructive role in determining Foxp3 expression, selection of Foxp3+ individual clones in the thymus is limited by a very small niche

Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia.

The Notch pathway is highly active in almost all patients with T-cell acute lymphoblastic leukemia (T-ALL), but the implication of Notch ligands in T-ALL remains underexplored. Methods: We used a genetic mouse model of Notch ligand delta like 4 (DLL4)-driven T-ALL and performed thymectomies and splenectomies in those animals. We also used several patient-derived T-ALL (PDTALL) models, including one with DLL4 expression on the membrane and we treated PDTALL cells in vitro and in vivo with demcizumab, a blocking antibody against human DLL4 currently being tested in clinical trials in patients with solid cancer. Results: We show that surgical removal of the spleen abrogated T-ALL development in our preclinical DLL4-driven T-ALL mouse model. Mechanistically, we found that the spleen, and not the thymus, promoted the accumulation of circulating CD4+CD8+ T cells before T-ALL onset, suggesting that DLL4-driven T-ALL derives from these cells. Then, we identified a small subset of T-ALL patients showing higher levels of DLL4 expression. Moreover, in mice xenografted with a DLL4-positive PDTALL model, treatment with demcizumab had the same therapeutic effect as global Notch pathway inhibition using the potent γ-secretase inhibitor dibenzazepine. This result demonstrates that, in this PDTALL model, Notch pathway activity depends on DLL4 signaling, thus validating our preclinical mouse model. Conclusion: DLL4 expression in human leukemic cells can be a source of Notch activity in T-ALL, and the spleen plays a major role in a genetic mouse model of DLL4-driven T-ALL.We thank Drs. Susan Schwab, Dan Littman, Sherif Ibrahim, Angel Pellicer, Susanne Tranguch and Adolfo Ferrando for helpful discussions and/or critically comments on the manuscript. Elisabetta Andermarcher professionally edited the manuscript. We are indebted to Dr. M. Yan (Genentech) for the anti-DLL4 antibody for cytometry. We are also in debt with Christopher Murriel from Oncomed who provided the therapeutic murine anti-DLL4 antibody and demcizumab (anti-human DLL4 antibody). We thank the NYU School of Medicine Flow Cytometry Core facility, particularly Dr. Peter Lopez, Keith Kobylarz and Michael Gregory, and also the NYU School of Medicine Confocal imaging facility, particularly Yan Deng. We also thank Henry Alexandre Michaud for his great help with the FACS analysis of PDTALL cells. We thank Nelly Pirot and the rest of members of the IRCM IHC platform for their fantastic work. M.M. is supported by a contract from Fondation ARC. The NYU Cancer Institute Center Support Grant partially funded this core through grant NIH/NCI 5 P30CA16087-31. Work in JJL's laboratory is supported by the NIH/NIAID, National Multiple Sclerosis Society, and the Helmsley Charitable Trust. Work in AM's laboratory is supported by the Fondation ARC (PJA 20131200405), the European Commission (CIG631431), the Institute de Cancer de Montpellier Fondation, and the Institut National du Cancer (INCa_9257 and INCa-DGOS-Inserm 12553).S

Doubly Regularized Portfolio with Risk Minimization

Due to recent empirical success, machine learning algorithms have drawn sufficient attention and are becoming important analysis tools in financial industry. In particular, as the core engine of many financial services such as private wealth and pension fund management, portfolio management calls for the application of those novel algorithms. Most of portfolio allocation strategies do not account for costs from market frictions such as transaction costs and capital gain taxes, as the complexity of sensible cost models often causes the induced problem intractable. In this paper, we propose a doubly regularized portfolio that provides a modest but effective solution to the above difficulty. Specifically, as all kinds of trading costs primarily root in large transaction volumes, to reduce volumes we synergistically combine two penalty terms with classic risk minimization models to ensure: (1) only a small set of assets are selected to invest in each period; (2) portfolios in consecutive trading periods are similar. To assess the new portfolio, we apply standard evaluation criteria and conduct extensive experiments on well-known benchmarks and market datasets. Compared with various state-of-the-art portfolios, the proposed portfolio demonstrates a superior performance of having both higher risk-adjusted returns and dramatically decreased transaction volumes

Anaesthesia for chest wall reconstruction in a patient with Poland syndrome: CARE-compliant case report and literature review

Background: Poland syndrome is a rare congenital disease, characterized by agenesis/hypoplasia of the pectoralis major muscle, usually associated with variable thoracic anomalies that needed chest wall reconstruction under general anesthesia. Anaesthetic management in Poland syndrome has scarcely been described. Case presentation: Here, we present our anaesthetic management of Nuss procedure for chest wall correction in a 5 years old patient with Poland syndrome. We also reviewed the reports of anaesthetic management of Poland syndrome by searching Pubmed, and summarize the perioperative procedures that may warrant a safe surgery. Conclusions: Examinations before surgery, intraoperative monitoring, choice of general anesthetics and pain management after surgery should all be contemplated

FRACTURE ANALYSIS AND IMPROVEMENT OF EGR COOLER WITH ECCENTRIC INTAKE STRUCTURE

Aiming at welding fracture problem of EGR cooler with eccentric intake structure,numerical simulation based on sequential fluid-solid coupling was presented and the improvement of eccentric intake structure was taken. Flow field mesh and solid finite element mesh were set up based on 3 D modeling. The sequential fluid-solid coupling with flow field analysis,heat conduction analysis and thermal stress analysis was taken to study the relation among intake structure,gas side streamline,solid temperature,thermal stress range and the fracture. An improvement scheme with increasing a hump was proposed to improve gas uniformity and reduce local thermal stress range. The results indicate that the sequential fluid-solid coupling is feasible in engineering practice,the partial fracture of EGR cooler will caused by unreasonable eccentric intake structure and will be solved by optimization of flow passage

Regional industrial redistribution and carbon emissions: a dynamic analysis for China

To facilitate and balance regional economic development and to reduce carbon emissions, China has implemented a series of policies to promote the redistribution of industries and economic activities across regions since 2000. This paper employs a logarithmic mean Divisia index (LMDI) to analyse the dynamic net effect on carbon emissions of Chinese policies promoting economic redistribution across sub-national regions, using a panel data of five sectors in 30 provinces during 1995–2017. The results of our analysis show that the redistribution of industry in particular, but also business and construction activities, leads to an increase in CO2 emissions, while the relocation of agriculture and transportation activities reduces emissions. We also find that the emission increase effect of the transfer of carbon intensive industries to new (host) regions is higher than the emission reduction effect induced by the agglomeration of clean industries in the original (home) regions. However, from 2014–2017, alongside the gradual industrial redistribution, China has also reduced aggregate CO2 emissions by 58.6 MT. In addition, the results show that population migration, which is due to redistribution of industry and other economic activity, has caused higher emission increases than emission reductions due to redistribution policies. We further calculate the marginal effect of industrial redistribution on CO2 emissions and draw out relevant policy implications. Industrial (and other economic activity) redistribution within a county can be not only an economic policy, but also an important policy instrument to mitigate CO2 emissions. This is the case in China.In the process of regional industrial redistribution, policymakers should aim to reduce the emission increase effect of transfer of carbon-intensive industries to host regions and to raise the emission reduction effect induced by an agglomeration of clean industries in home regions.Industrial redistribution is usually a long-term strategy for regional development within a county, and any reduction effects on CO2 emissions are likely to need time to appear. Industrial (and other economic activity) redistribution within a county can be not only an economic policy, but also an important policy instrument to mitigate CO2 emissions. This is the case in China. In the process of regional industrial redistribution, policymakers should aim to reduce the emission increase effect of transfer of carbon-intensive industries to host regions and to raise the emission reduction effect induced by an agglomeration of clean industries in home regions. Industrial redistribution is usually a long-term strategy for regional development within a county, and any reduction effects on CO2 emissions are likely to need time to appear.</p

Antibacterial activity and antibacterial mechanism of flavaspidic acid BB against Staphylococcus haemelyticus

Abstract Background Staphylococcus haemolyticus (S. haemolyticus) is the main etiological factor in skin and soft tissue infections (SSTI). S. haemolyticus infections are an important concern worldwide, especially with the associated biofilms and drug resistance. Herein, we investigated the inhibitory effect of Flavaspidic acid BB obtained from plant extractions on clinical S. haemolyticus strains and their biofilms. Moreover, we predicted its ability to bind to the protein-binding site by molecular simulation. Since the combination of Hsp70 and RNase P synthase after molecular simulation with flavaspidic acid BB is relatively stable, enzyme-linked immunosorbent assay (ELISA) was used to investigate Hsp70 and RNase P synthase to verify the potential antimicrobial targets of flavaspidic acid BB. Results The minimum inhibitory concentrations (MIC) of flavaspidic acid BB on 16 clinical strains of S. haemolyticus was 5 ~ 480 µg/mL, and BB had a slightly higher inhibitory effect on the biofilm than MUP. The inhibitory effect of flavaspidic acid BB on biofilm formation was better with an increase in the concentration of BB. Molecular simulation verified its ability to bind to the protein-binding site. The combination of ELISA kits showed that flavaspidic acid BB promoted the activity of Hsp70 and inhibited the activity of RNase P, revealing that flavaspidic acid BB could effectively inhibit the utilization and re-synthesis of protein and tRNA synthesis, thus inhibiting bacterial growth and biofilm formation to a certain extent. Conclusions This study could potentially provide a new prospect for the development of flavaspidic acid BB as an antibacterial agent for resistant strains