Potential Celiac Patients: A Model of Celiac Disease Pathogenesis

BACKGROUND AND AIM: Potential celiacs have the 'celiac type' HLA, positive anti-transglutaminase antibodies but no damage at small intestinal mucosa. Only a minority of them develops mucosal lesion. More than 40 genes were associated to Celiac Disease (CD) but we still do not know how those pathways transform a genetically predisposed individual into an affected person. The aim of the study is to explore the genetic features of Potential CD individuals. METHODS: 127 'potential' CD patients entered the study because of positive anti-tissue transglutaminase and no mucosal lesions; about 30% of those followed for four years become frankly celiac. They were genotyped for 13 polymorphisms of 'candidate genes' and compared to controls and celiacs. Moreover, 60 biopsy specimens were used for expression studies. RESULTS: Potential CD bear a lighter HLA-related risk, compared to celiac (??(2)???=???48.42; p value???=???1×10(-8)). They share most of the polymorphisms of the celiacs, but the frequency of c-REL* G allele was suggestive for a difference compared to celiac (??(2)???=???5.42; p value???=???0.02). One marker of the KIAA1109/IL-2/IL-21 candidate region differentiated potentials from celiac (rs4374642: ??2???=???7.17, p value???=???0.01). The expression of IL-21 was completely suppressed in potentials compared to celiacs (p value???=???0.02) and to controls (p value???=???0.02), in contrast IL-2, KIAA1109 and c-REL expression were over-expressed. CONCLUSIONS: Potential CD show genetic features slightly different from celiacs. Genetic and expression markers help to differentiate this condition. Potential CD is a precious biological model of the pathways leading to the small intestinal mucosal damage in genetically predisposed individuals

Techno-economics of algae production in the Arabian Peninsula

The Arabian Peninsula's advantageous climate, availability of non-arable land, access to seawater and CO2-rich flue gas, make it an attractive location for microalgae biomass production. Despite these promising aspects, the region has seen very few studies into the commercial feasibility of algae-based value chains. This work aims to address this gap through a techno-economic feasibility study of algae biomass production costs, comparing different photobioreactor types, locations, and production scales. Flat panel and raceway pond cultivation systems were found to be the most economically attractive cultivation systems, with biomass production costs as low as 2.9 €·kg−1. Potential cost reductions of up to 42.5% and 25% could be accomplished with improvements in photosynthetic efficiencies and increased culture temperatures, respectively. As of such, efforts to source local thermo- and photo- tolerant strains could be the key to unlock the potential of the region for algae commercialization, linking into food, feed and nutraceutical industries.The authors would like to thank Tommaso de Santis, Probir Das, Mahmoud Taher, and the QDVC team for their support. This work was sponsored by QDVC and Qatar University [Project: QUEX-CAS-QDVC-14/15-7]. Open Access funding was provided by the Qatar National Library

Investigating algal CO2 capture through screening of Qatari desert microalgae & cyanobacteria strains

CO2 fixation by phototrophic microalgae has been addressed as a possible global carbon emissions reducer, whilst simultaneously producing useful products. Especially in Qatar, the prospect of using microalgae for CO2 abatement is promising: high solar irradiance, large areas of non-arable land, and large amounts of CO2 emissions make it seemingly the ideal place for algae cultivation. In order to promote high biomass productivities, and subsequent CO2 uptake rates, effective CO2 supply to the cultivation system is of high importance. However, the low solubility of CO2 in water, as well as the limiting tolerance of microalgae to increased CO2 concentrations, results in low efficiency of CO2 capture by microalgal production systems. In order to overcome these hurdles, this research focused on selecting local desert microalgae strains with high tolerance to increased CO2 levels, and developing growth media in order to increase the solubility of CO2. Forty-five locally isolated marine microalgae strains were screened for growth under increased CO2 concentrations, ranging from 0.04% to 30% (v/v). A number of different trends in CO2 tolerance could be identified from the results; a number of strains showed a clear inhibition of growth with CO2 concentrations of 5% and higher, whilst others showed increasing growth rates for increasing CO2 concentrations up to 30%. The trend in growth rate suggests that even higher CO2 concentration could be applied without growth-limiting effects, and could even stimulate higher growth-rates. In order to further increase the productivity of high CO2-tolerant strains, as well as to investigate the effects of pH on the CO2 tolerance of low-tolerant strains, various strains were cultivated in alkaline media and high CO2 concentrations. Besides leading to an increased solubility of CO2 in the culture media, increasing the pH is thought to balance the acidification effect of CO2 - possibly leading to higher CO2 tolerances. Overall, applying these strains and media adaptations for large-scale applications is expected to increase the CO2 transfer efficiency to the culture, resulting in decreased operational costs and higher overall productivities.qscienc

High diversity of responses among Medicago truncatula lines to Phoma medicaginis infection.

Medicago truncatula is an omni-Mediterranean species grown as an annual forage legume. In addition to its small genome size and simple genetics, M. truncatula harbors several attributes, which make it an attractive model forage plant. In this study, we investigated the variation of responses in ten parental lines of M. truncatula to Phoma medicaginis infection. Plants were cultivated in the growth chamber under controlled conditions and were inoculated after two months with P. medicaginis. At harvest, 13 quantitative traits of growth and pathogenicity were measured. Results from ANOVA showed that the variation of analyzed parameters was explained by the effect of line. All measured parameters, except the root fresh weight, showed significant difference among the 10 studied lines. Most tolerant lines are those with the lowest ratios of the number of infected and dead leaves. Studied lines were clustered into three groups according to their responses to P. medicaginis infection. The most resistant TN6.18 line and most sensitive F83005.5 to P. medicaginis are useful for the exploration of physiological mechanisms and genetic determinants for M. truncatula tolerance to this constraint

Reprogramming of CTLs into natural killer–like cells in celiac disease

Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon γ–producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases

Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15

IL-15 and NKG2D promote autoimmunity and celiac disease by arming cytotoxic T lymphocytes (CTLs) to cause tissue destruction. However, the downstream signaling events underlying these functional properties remain unclear. Here, we identify cytosolic phospholipase A2 (cPLA2) as a central molecule in NKG2D-mediated cytolysis in CTLs. Furthermore, we report that NKG2D induces, upon recognition of MIC+ target cells, the release of arachidonic acid (AA) by CTLs to promote tissue inflammation in association with target killing. Interestingly, IL-15, which licenses NKG2D-mediated lymphokine killer activity in CTLs, cooperates with NKG2D to induce cPLA2 activation and AA release. Finally, cPLA2 activation in intraepithelial CTLs of celiac patients provides an in vivo pathophysiological dimension to cPLA2 activation in CTLs. These results reveal an unrecognized link between NKG2D and tissue inflammation, which may underlie the emerging role of NKG2D in various immunopathological conditions and define new therapeutic targets

Вероятностно-временные характеристики и оптимизация ожидаемых доходов моделей информационных систем и сетей

В работе приведен обзор методов и методик исследования сетей массового обслуживания (МО) некоторых новых типов - различных марковских сетей с доходами (НМ-сетей) с дисциплинами обслуживания заявок FIFO в системах, сетей с ограниченным временем ожидания разнотипных заявок в них, обходами систем обслуживания заявками и сетей с положительными и отрицательными заявками (G-сетей), применяемых при нахождении вероятностно-временных характеристик и доходов в информационных системах и сетях (ИСС) и других объектах в переходном режиме

Real-life data on treatment and outcomes in advanced ovarian cancer : An observational, multinational cohort study (RESPONSE trial)

Background This study aimed to describe the treatment strategies and outcomes for women with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer (OC). Methods This observational study collected real-world medical record data from eight Western countries on the diagnostic workup, clinical outcomes, and treatment of adult women with newly diagnosed advanced (Stage III-IV) high-grade serous or endometrioid OC. Patients were selected backward in time from April 1, 2018 (the index date), with a target of 120 patients set per country, followed for >= 20 months. Results Of the 1119 women included, 66.9% had Stage III disease, 11.7% had a deleterious BRCA mutation, and 26.6% received bevacizumab; 40.8% and 39.3% underwent primary debulking surgery (PDS) and interval debulking surgery (IDS), respectively. Of the patients who underwent PDS, 55.5% had no visible residual disease (VRD); 63.9% of the IDS patients had no VRD. According to physician-assessed responses (at the first assessment after diagnosis and treatment), 53.2% of the total population had a complete response and 25.7% had a partial response to first-line chemotherapy after surgery. After >= 20 months of follow-up, 32.9% of the patients were disease-free, 46.4% had progressive disease, and 20.6% had died. Bevacizumab use had a significant positive effect on overall survival (hazard ratio [HR], 0.62; 95% CI, 0.42-0.91; p = .01). A deleterious BRCA status had a significant positive effect on progression-free survival (HR, 0.60; 95% CI, 0.41-0.84; p < .01). Conclusions Women with advanced high-grade serous or endometrioid OC have a poor prognosis. Bevacizumab use and a deleterious BRCA status were found to improve survival in this real-world population. Lay summary Patients with advanced (Stage III or IV) ovarian cancer (OC) have a poor prognosis. The standard treatment options of surgery and chemotherapy extend life beyond diagnosis for 5 years or more in only approximately 45% of patients. This study was aimed at describing the standard of care in eight Western countries and estimating how many patients who are diagnosed with high-grade serous or endometrioid OC could potentially be eligible for first-line poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) maintenance therapy. The results highlight the poor prognosis for these patients and suggest that a significant proportion (79%) would potentially be eligible for first-line PARPi maintenance treatment.Peer reviewe

Gliadin Peptide P31-43 Localises to Endocytic Vesicles and Interferes with Their Maturation

BACKGROUND: Celiac Disease (CD) is both a frequent disease (1:100) and an interesting model of a disease induced by food. It consists in an immunogenic reaction to wheat gluten and glutenins that has been found to arise in a specific genetic background; however, this reaction is still only partially understood. Activation of innate immunity by gliadin peptides is an important component of the early events of the disease. In particular the so-called "toxic" A-gliadin peptide P31-43 induces several pleiotropic effects including Epidermal Growth Factor Receptor (EGFR)-dependent actin remodelling and proliferation in cultured cell lines and in enterocytes from CD patients. These effects are mediated by delayed EGFR degradation and prolonged EGFR activation in endocytic vesicles. In the present study we investigated the effects of gliadin peptides on the trafficking and maturation of endocytic vesicles. METHODS/PRINCIPAL FINDINGS: Both P31-43 and the control P57-68 peptide labelled with fluorochromes were found to enter CaCo-2 cells and interact with the endocytic compartment in pulse and chase, time-lapse, experiments. P31-43 was localised to vesicles carrying early endocytic markers at time points when P57-68-carrying vesicles mature into late endosomes. In time-lapse experiments the trafficking of P31-43-labelled vesicles was delayed, regardless of the cargo they were carrying. Furthermore in celiac enterocytes, from cultured duodenal biopsies, P31-43 trafficking is delayed in early endocytic vesicles. A sequence similarity search revealed that P31-43 is strikingly similar to Hrs, a key molecule regulating endocytic maturation. A-gliadin peptide P31-43 interfered with Hrs correct localisation to early endosomes as revealed by western blot and immunofluorescence microscopy. CONCLUSIONS: P31-43 and P57-68 enter cells by endocytosis. Only P31-43 localises at the endocytic membranes and delays vesicle trafficking by interfering with Hrs-mediated maturation to late endosomes in cells and intestinal biopsies. Consequently, in P31-43-treated cells, Receptor Tyrosine Kinase (RTK) activation is extended. This finding may explain the role played by gliadin peptides in inducing proliferation and other effects in enterocytes from CD biopsies