Rôle de la CTNNB1 et de ses nouveaux partenaires dans la régulation de l'immunité antivirale innée et de la voie WNT

L’immunité innée représente la première ligne de défense de l’organisme contre l’infection virale. La réponse antivirale est initiée par la reconnaissance du pathogène par des récepteurs spécifiques, qui reconnaissent les motifs moléculaires associés aux agents pathogènes, puis initient des voies de signalisation conduisant à l’activation des facteurs de transcription essentiels tels que IRF3 et NF-қB, ce qui entraîne la production des interférons de type I (IFNα et β). Notre laboratoire a réalisé le premier criblage aux ARN interférant à l’échelle génomique, qui a permis l’identification de centaines de nouveaux régulateurs de l’IFNβ en réponse à l’infection par le virus à ARN Sendai (VS). Le criblage ARNi a identifié WNT2B et WNT9B en tant que régulateurs négatifs de la réponse antivirale médiée par les RLRs. Nous avons démontré que WNT2B et WNT9B sont sécrétés suite à l’infection virale et qu'ils régulent négativement l'expression des gènes anti-viraux IFNB1, IFIT1 et TNF. Cette découverte nous a incités à explorer la contribution de la voie de signalisation WNT/CTNNB1 dans la régulation négative de la réponse innée aux virus à ARN. Nous avons démontré que l'infection virale induit l'accumulation d'une forme stabilisée de la CTNNB1 et que le silençage de la CTNNB1 augmente l'expression induite par le VS d’IFNB1, IFIT1 et TNF. Inversement, la stabilisation de la CTNNB1 par des inhibiteurs de GSK3 a entraîné une réduction drastique de la transcription d’IFNB1 et d’IFIT1, mais cette diminution est restaurée dans les cellules déplétées de la CTNNB1. Nous avons également démomtré que la CTNNB1 interagit de manière constitutive avec NF-қB (p65) alors que son interaction avec IRF3 est augmentée suite à l'infection par le VS. Pour mieux élucider le mécanisme d’action de la CTNNB1 dans la régulation de l’immunité antivirale, nous avons utilisé la spectrométrie de masse quantitative pour identifier l'interactome de la CTNNB1 en réponse à l’infection par le VS ou à l'inhibition de GSK3. Nous avons identifié DDB1(DNA Damage-Binding protein 1) comme un partenaire de la CTNNB1 dont l’interaction est réduite en réponse à l’infection par le VS ou à l’activation de la voie WNT/CTNNB1. Nous avons démontré que DDB1 régule négativement l'activité transcriptionnelle de la CTNNB1 en favorisant son ubiquitination et en réduisant sa demi-vie après une stimulation par WNT3A. De plus, nous avons caractérisé DDB1 comme un régulateur négatif de la transcription d’IFNB1. Sur le plan mécanistique, nos résultats préliminaires indiquent que l’ubiquitination de la CTNNB1, qui normalement conduit à sa dégradation par le protéasome, est inhibée suite à l’infection par le VS tandis que le silençage de DDB1 restaure cet effet. Ces résultats suggèrent que DDB1 contribue à une stabilisation de la CTNNB1 dans le contexte de l’infection virale, offrant ainsi un nouveau mécanisme post-transcriptionnel de la régulation négative de l’immunité antivirale innée par la CTNNB1. Nous avons également identifié le répresseur transcriptionnel NKRF (NF-қB repressing factor) en tant qu’interactant de la CTNNB1 qui régule négativement la transcription d’IFNB1 suite à l’infection virale. De plus, le silençage de NKRF et de la CTNNB1 individuellement ou en combinaison augmente la transcription endogène d’IFNB1, d’IFIT1 et de TNF à un niveau similaire suggérant que ces deux protéines fonctionnent par un même mécanisme. Ces données soutiennent fortement le recrutement de complexes protéiques contenant la CTNNB1 et NKRF afin de désactiver la transcription d’IFNB1, TNF et IFIT1 par des mécanismes de répression épigénétiques et/ou transcriptionnels, et de contrôler l’expression excessive des gènes de l’immunité innée suite à l’infection virale. En conclusion, nos résultats ont identifié une nouvelle régulation de l'immunité innée antivirale par la CTNNB1 et ses régulateurs, ouvrant la voie à de nouvelles avenues pour des cibles antivirales à large spectre et à la prévention des maladies liées à l’immunité lors d'une infection virale.The host innate response to viral infection relies on the presence of pattern recognition receptors (PRR) that specifically recognize pathogen associated molecular patterns (PAMPs) and then initiate signaling pathways and activate key transcription factors such as IRF3 and NF-қB, which lead to the synthesis of type I interferon (IFN-α/β). In a research program aimed at the discovery of regulators of innate immunity, we performed the first genome-wide silencing screen in response to Sendai virus (SeV) infection. The RNAi screen identified WNT2B and WNT9B as negative regulators of RLR-mediated antiviral response. We next showed that WNT2B and WNT9B are secreted upon viral infection and negatively regulate expression of representative inducible genes IFNB1, IFIT1 and TNF. We further investigated a canonical-like WNT pathway that culminates in CTNNB1 accumulation. Coherently, we found that viral infection induces the accumulation of a stabilized form of CTNNB1 and that CTNNB1 gene silencing increases SeV-induced IFNB1, IFIT1 and TNF expression. Conversely, CTNNB1 stabilization using GSK3 inhibitors resulted in a drastic reduction of virus-induced IFNB1 transcription and IFIT1 expression, but this decrease is restored in CTNNB1 knockdown cells. To uncover mechanistically how CTNNB1 regulated the antiviral immunity, we used quantitative mass-spectrometry to identify CTNNB1 interactome upon SeV infection or GSK3 inhibition. We identified DNA damage-binding protein 1 (DDB1) as an interactor of CTNNB1 that is reduced of CTNNB1 upon SeV or WNT3A stimulations. We showed that DDB1 negatively regulates CTNNB1 transcriptional activity by promoting its ubiquitination and reducing protein half-life following WNT3A stimulation. Strikingly, CTNNB1 ubiquitination is inhibited in SeV-infected cells and restored upon DDB1 depletion, consistent with a distinct role of DDB1 in preventing CTNNB1 degradation and inhibiting the antiviral innate response. We also identified the transcriptional repressor NKRF (NF-қB repressing factor) as a CTNNB1 interactor upon viral infection that negatively regulates IFNB1 production of SeV-infected cells without modulating the canonical pathway with WNT3A. We showed that NKRF KD, CTNNB1 KD and combination increase IFNB1, IFIT1 and TNF transcription to similar fold induction of mRNA levels. The data highly support the recruitment of CTNNB1-NKRF containing protein complexes to turn off IFNB1, TNF and IFIT1 transcription by epigenetic and/or transcriptional repression mechanisms, and control innate immune gene expression after virus recognition signals have resolved. Overall, our findings identify a novel regulation of antiviral innate immunity by CTNNB1 and its regulators, paving the way for novel avenues for broad-spectrum antiviral targets and preventing immune-mediated diseases upon viral infection

An analysis on the efficiency of the Malaysian Islamic banking industry: domestic vs. foreign

This paper examines productivity change of Islamic banks in Malaysiaduring the period 2006 to 2008. The data includes a panel of 12 Islamic banks and the productivity of each bank is analysed using the non-parametric Data Envelopment Analysis (DEA) method or the intermediation approach. In the DEA technique, efficiency is measured by the Malmquist index. We model Islamic banks in Malaysia as multi-product firms producing two outputs (total loan and income) by employing three inputs (total deposit, labour, fixed asset). Overall results suggest that scale efficiency dominates the pure technical efficiency effects in determining Malaysian Islamic banks’ overall or technical efficiency. Another important finding derived from the study is that Malaysian-owned Islamic banks’ performance is better compared to their foreign-owned counterparts. The findings of the study are important for Islamic banks in Malaysia to improve or maintain the ability to become more competitive and provide a viable and better alternative to the conventional banking system

RECENT ADVANCES AND FUTURE PROSPECTS OF NON-INVASIVE INSULIN DELIVERY SYSTEMS

Non-invasive insulin delivery systems have been of global interest. The goal of many studies was to optimize suitable delivery formulation capable of producing comparable insulin bioavailability and safety that match or supersedes conventional delivery by the invasive subcutaneous (SC) injections. Historically, Pfizer marketed the first insulin inhaler Exubera® in 2006 which was later retracted from the market before completing the two years. In recent years, Afrezza®, a new inhalator, and Oral-Lyn™, a buccal spray, have been introduced to the market. While Afrezza® lost the marketing and distribution support from Sanofi, Oral-Lyn™ have not secured US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) marketing approval yet. Different technologies to improve insulin’s permeation and absorption through different routes are in the pipelines. This review discusses several non-invasive strategies that have been appropriately tested and duly approved by the FDA. Other delivery systems are in different phases of development, ranging from in vitro studies to phase 3 clinical trials, providing indications towards the prospects of next-generation delivery systems. This review covers studies published in the past 10 y using Scopus, Clinicaltrials.gov, PubMed and Google scholar databases. The outcomes of this review indicate that the door is still open for more innovative, efficient and convenient non-invasive insulin delivery systems than currently available which may take several years before we can see a game changer in the market

Advanced intra-tumoural structural characterisation of hepatocellular carcinoma utilising FDG-PET/CT : a comparative study of radiomics and metabolic features in 3D and 2D

Purpose: The aim of our work is to evaluate the correlation of two-dimensional (2D) and three-dimensional (3D) radiomics and metabolic features of hepatocellular carcinoma (HCC) with tumour diameter, staging, and metabolic tumour volume (MTV). Material and methods: Thirty-three patients with HCC were studied using 18F-fluorodeoxyglucose positron-emission tomography with computed tomography (18F [FDG] PET/CT). The tumours were segmented from the PET images after CT correction. Metabolic parameters and 35 radiomics features were compared using 2D and 3D modes. The metabolic parameters and tumour morphology were compared using 2 different types of software. Tumour heterogeneity was studied in both metabolic parameters and radiomics features. Finally, the correlation between the metabolic and radiomics features in 3D mode, as well as tumour morphology and staging according to the American Joint Committee on Cancer (AJCC) staging were studied. Results: Most of the metabolic parameters and radiomics features are statically stable through the 2D and 3D modes. Most of the 3D mode features show a correlation with metabolic parameters; the total lesion glycolysis (TLG) shows the highest correlation, with a Spearman correlation coefficient (rs) of 0.9776. Also, the grey level run length matrix/ run length non-uniformity (GLRLM_RLNU) from radiomics features exhibits a correlation with a Spearman correlation coefficient of 0.9733. Maximum tumour diameter is correlated with TLG and GLRLM_RLNU, with rs equal to 0.7461 and 0.7143, respectively. Regarding AJCC staging, some features show a medium but prognostic correlation. In the case of 2D-mode features, all metabolic and radiomics features show no significant correlation with MTV, AJCC staging, and tumour maximum diameter. Conclusions: Most of the normal metabolic parameters and radiomics features are statistically stable through the 3D and 2D modes. 3D radiomics features are significantly correlated with tumour volume, maximum diameter, and staging. Conversely, 2D features have negligible correlation with the same parameters. Therefore, 3D mode features are preferable and can accurately evaluate tumour heterogeneity

Prediction on the wear rate of epoxy composites reinforced micro-filler of the natural material residue using Taguchi – neural network

The abrasive wear rate of epoxy composites reinforced with fillers sourced from recycled natural waste consisting of pollen of palm (PPW) and seashells (SSW) was studied. Due to the importance of polymer composites used in the tribological couplings of machinery structures, as well as their possible use in brake pads as alternative materials for harmful components in environmentally polluted asbestos, the current research seeks to develop the tribological properties of composite materials reinforced with natural fillers and environmentally friendly. The research investigated the effect of two factors, the weight percentage of natural filler wt. % (0.5 %,1 %, and 1.5 %) and testing loads (1000 g, 2000 g, 3000 g) upon the wear resistance of epoxy composites. The importance of developing epoxy compounds is evident, especially since their work does not require lubricating conditions in various industrial fields, and therefore the development of their bonding properties will increase their operational life and achieve economic benefit for the industrial sector and the environment at the same time. The epoxy composites were subjected to abrasive wear tests under dry friction conditions using a pin-on-disc system. Signal-to-noise (S/N) analysis is adopted to study the influence of the two factors, wt. % and test loads, upon the tribological wear resistance of epoxy composites. A predictive model depending on the regression equation was developed to predict the wear resistance of epoxy composites. The results showed an improvement in the wear resistance of the composite material compared to the epoxy sample without filling by about 47 %. The optimum condition for wear resistance of epoxy composites has been achieved with a weight ratio of (1.5 %) and an applied load of 1000 

Efeect of Kegel's Exercises on First Degree Pelvic Organ Prolapse Among Women

Background: Kegel's exercises are recommended to increase the strength and elasticity of the pelvic floor muscles and decrease the incidence of prolapse and stress urinary incontince. Aim: was to assess the effect of kegel's exercises on first degree pelvic organ prolapse among women. Design: quasi-experimental, non equivalent pre-post test research design was adopted. Setting: this research was carried out at gynecological clinic at El Galaa Obstetrics and Gynecology Teaching Hospital. Sample: Convenience sample, of 110 women were recruited for this study as one group to be measured before and after according to certain criteria. Tools: three tools were used for data collection: structured interview tool; assessment & follow up tool for clinical picture of prolapse and Prinometry to measure the strength of pelvic floor muscles. Result: revealed that, a statistically significantly differences were founded between before and after following of kegel's exercises in relation to sexual clinical picture P value was ≥ 0.05, urinary clinical picture was (χ2 = 145.4 and p value ≤ 0.001 and types of urinary problems. χ2 = 167.4 and p value≤ 0.001 ) . And bowel clinical picture was (χ2 =128.8 & P.value ≤ 0.001). Regarding to perinometry reading, the results revealed that, highly statistically significant differences was found between the three reading of prinometry (F=68.047, p≤0.001). In Conclusion: practicing kegel's exercises lead to decrease in the clinical picture of prolapse and improve strength of pelvic floor muscles. Recommendation: based on the study findings, its recommended kegel's exercises should be followed during each development phases of women's life span, so it should form an essential part of sex education and the nurse should work as educator and counselor to teach women benefits and technique of kegel's exercises. Keywords:  kegel's exercises, prolapse, prinometry

MYCOBACTERIUM AVIUM SUBSP. PARATUBERCULOSIS IN RAW CAPRINE MILK

ABSTRACT One hundred and fifty individual caprine milk samples were analyzed for Mycobacterium avium subsp. paratuberculosis (MAP). Out of 150 samples tested for MAP, 53 (35.33%) samples could be detected by Enzyme-Linked Immunosobent Assay (ELISA) technique. However, one (0.67%) sample was found positive in Polymerase Chain Reaction (PCR) method and failed to be isolated from all the examined samples

The effect of adding natural materials waste on the mechanical properties and water absorption of epoxy composite using grey relations analysis

Recently, there has been a tendency for scientific studies to deal with natural materials as fillers and reinforcement for polymer composites, which are used in many different applications due to their environmentally friendly properties when compared to synthetic materials. The current study aims to preserve the environment by dealing with natural materials and their influence on the mechanical properties and water absorption property of the polymer composites. In this study, epoxy composites were produced from local natural sourced non-hazardous raw natural materials using grey relational analysis (GRG). The materials used for fabrication include micro-filler of pollen palm 50 μm, seashell 75 μm and epoxy resin. Nine different composites were prepared using pollen palm and seashell as reinforcement material by varying the wt % of the micro-filler. Rule of the mixture was used for formulation and wt % of (0.5, 1 and 1.5) % reinforcement and 99.5, 99 and 98.5 % epoxy (binder) were used for composites. Grey relational analysis was conducted in order to scale the multi-response performance to a single response. The results indicate that optimum performance can be achieved with the addition of 1.5 wt % micro-filler of seashell, which achieved the first rank, while the second rank achieved by 0.5 wt % micro-filler of palm pollen and seashell when compared to other composites. The addition of micro-fillers has improved greatly the mechanical properties of epoxy composites. The loading of micro-fillers has influenced the water absorption property of composites based epoxy in ascending orde