Effect of different environmental factors on epigenetic modification in allergy and asthma

In this study chromatin immunoprecipitation was established for using the method in cohort studies were only small amount of cells are available and the samples are routinely frozen and stored at low temperature. Additionally, the method was validated for that purpose. This method was validated using different well known validation protocols. Three different cohorts were analyzed using this method with three different perspectives. In the first cohort, the effect of folate status during pregnancy upon acetylation of Th1, TH2, Treg and TH17 cell loci in cord blood CD4+ T cells was investigated. For that purpose the two extremes very low vs. very high folate levels in maternal blood were picked and both DNA methylation and histone acetylation were investigated.. GATA3 and IL9 were significantly more acetylated at both histones H3 and H4 in the high folate group compared to the low folate group. This suggests that folate status during pregnancy can modify the epigenome toward a more Th2 phenotype supporting the development of allergic disease later in life. On the other hand, supplementation with fish oil during pregnancy showed adversary effects to what folate showed by causing the reduction in acetylation at the IL13 locus at both H3 and H4 histones. Parallel to that there was a reduction in the histone acetylation in H3 histone at the TBX21 locus. This proves to be consistent with the protein and mRNA data obtained from the same individual 11 years ago (Dunstan et al. 2003). Fish oil proves once again that it can attenuate inflammatory process through ω-3 fatty acids contained in it. Fatty acids in general cause a general DNA hypermethylation which can regulate different genes including inflammatory cytokines and genes (Burdge and Lillycrop 2014). Whether histone acetylation is affected through the same mechanisms illustrated earlier is still to be revealed. In the same fashion, a comparison between allergic asthmatics with healthy controls was explored. This picture looks more complex. It is not a single factor that causes these epigenetic modifications. Not all the allergy/asthma related genes were influenced in that scenario but there was susceptible gene, among them were IL13 and FOXP3 (FOXP3 data are courtesy of Diana Raedler PhD thesis). Both were significantly more acetylated at histone H3 in asthmatic children in comparison with healthy controls. Moreover, the acetylation at histone H4 for IL13 locus was as well increased in the asthmatic children compared to their fellow healthy controls. The effect of environmental factors on the development of allergic disease through the development and alteration of the human epigenome is now a major mechanism of disease development. How these effects and what are the most important marks are, is still an open question. There are still some open questions to be answered and they are of a great importance for future planning. 1- Folate is considered a methyl donor and affects DNA methylation. In this study we have seen another effect of folate comprising histone acetylation as a key factor driving the Th2 machinery. How folate as a methyl donor does affect histone acetylation remains to be clarified. 2- Fish oil with all the different ω-3 fatty acids is considered with different publications a protector against development of allergic disease. In this study we were able to show that fish oil supplementation is associated with histone acetylation and this was further correlated to allergic disease development later in life. The remaining question is how a fatty acid that is usually incorporated into cell membrane alters the epigenome of an individual causing the silencing or activation of certain genes. 3- It has been shown by many investigators that epigenetic modifications work not lonely but are interlinked with each other. Several studies showed interacted mechanisms between different epigenetic modifications. It is very important to have more detailed studies to shed more light on that prospective to understand more the complexity of the human genome. At the end, in this study one small step toward a better understanding of our complexity has been made and how does a small part of the human epigenome work has been revealed

A Study of the Number of Wavelengths Impact in the Optical Burst Switching Core Node

In Wavelength Division Multiplexing (WDM), several wavelengths run on an optical fiber link that connects two optical switches. The multiple wavelengths are exploited that minimized the contention problem in the Optical Burst Switching (OBS) core node. Mathematical model is used in order to investigate the impact of the wavelengths numbers OBS core node. Two performance metrics are proposed such as the steady-state throughput and the probability of burst loss using steady- state occupancy probabilities and Poisson traffic model arrivals. Numerical results show that at different values of network traffic and some design parameters such as wavelength conversion capability and the mean arrival rate could reveal the OBS performance

The role of histone protein modifications and mutations in histone modifiers in pediatric b-cell progenitor acute lymphoblastic leukemia

While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis

The impact of the covid-19 pandemic on theworking conditions, employment, career development and well-being of refugee researchers

The ongoing ‘refugee crisis’ of the past years has led to the migration of refugee researchers (RRs) to European countries. Due to the COVID-19 pandemic, RRs often had to work from home and/or to continue their social, cultural and economic integration process under new conditions. An online survey carried out to explore the impact of the pandemic on the refugee researchers showed that RRs found it difficult to adapt their everyday working life to the ‘home’ setting. The majority have had neither a suitable work environment at home nor the appropriate technology. Although they stated that they are rather pleased with the measures taken by the public authorities, they expressed concern about their vulnerability due to their precarious contracts and the bureaucratic asylum procedures, as the pandemic has had a negative impact on these major issues. The majority of RRs working in academia seem not to have been affected at all as far as their income is concerned, while the majority of those employed in other sectors became unemployed during the pandemic (58%). Recommendations are provided to the public authorities and policy makers to assist RRs to mitigate the consequences of the pandemic on their life

Bioavailability and allergoprotective capacity of milk-associated conjugated linoleic acid in a murine model of allergic airway inflammation

BACKGROUND Cross-sectional epidemiological studies have demonstrated that farm milk from traditional farm settings possesses allergoprotective properties. Up to now, it has not been clarified which milk ingredient is responsible for protection against allergic diseases. As farm milk is rich in conjugated linoleic acids (CLA), it is hypothesized that this n-3 polyunsaturated fatty acid family contributes to the allergoprotective capacity of farm milk. We aim to prove this hypothesis in a murine model of allergic airway inflammation. METHODS To prove the bioavailability and allergoprotective capacity of milk-associated CLA in a standardized protocol, milk batches that differed significantly in terms of their CLA content were spray dried and incorporated into a basic diet by substituting the regular sunflower fat fraction. Initially, the milk CLA uptake from the diet was monitored via measurement of the CLA content in plasma and erythrocyte membranes obtained from supplemented mice. To determine whether a milk CLA-enriched diet possesses allergoprotective properties, female Balb/c mice were fed the milk CLA-enriched diet ahead of sensitization and a challenge with ovalbumin (OVA) and the parameters of airway inflammation and eisosanoid pattern were measured. RESULTS In animals, supplementation with a diet rich in milk CLA resulted in elevated CLA levels in plasma and erythrocyte membranes, indicating bioavailability of milk fatty acids. Though membrane-associated phospholipid patterns were affected by supplementation with milk CLA, this application neither reduced the hallmarks of allergic airway inflammation in sensitized and OVA-challenged mice nor modified the eiconsanoid pattern in the bronchoalveolar lavage fluid of these animals. CONCLUSION Milk-associated CLA was not capable of preventing murine allergic airway inflammation in an animal model of OVA-induced allergic airway inflammation

The role of PKCzeta in cord blood T-cell maturation towards Th1 cytokine profile and its epigenetic regulation by fish oil

While immunodeficiency of immaturity of the neonate has been considered important as the basis for unusual susceptibility to infection, it has also been recognized that the ability to progress from an immature Th2 cytokine predominance to a Th1 profile has relevance in determining whether children will develop allergy, providing an opportunity for epigenetic regulation through environmental pressures. However, this notion remains relatively unexplored. Here, we present evidence that there are two major control points to explain the immunodeficiency in cord blood (CB) T-cells, a deficiency in interleukin (IL)-12 (IL-12) producing and IL-10 overproducing accessory cells, leading to a decreased interferon γ (IFNγ) synthesis and the other, an intrinsic defect in T-cell protein kinase C (PKC) ζ (PKCζ) expression. An important finding was that human CB T-cells rendered deficient in PKCζ, by shRNA knockdown, develop into low tumour necrosis factor α (TNFα) and IFNγ but increased IL-13 producing cells. Interestingly, we found that the increase in PKCζ levels in CB T-cells caused by prenatal supplementation with fish oil correlated with modifications of histone acetylation at the PKCζ gene (PRKCZ) promoter. The data demonstrate that PKCζ expression regulates the maturation of neonatal T-cells into specific functional phenotypes and that environmental influences may work via PKCζ to regulate these phenotypes and disease susceptibility.Hani Harb, James Irvine, Manori Amarasekera, Charles S. Hii, Dörthe A. Kesper, YueFang Ma, Nina D′Vaz, Harald Renz, Daniel P. Potaczek, Susan L. Prescott and Antonio Ferrant

Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma

Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Rα has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target– and tissue-specific manner to mediate heightened expression of a subset of IL-4– and IL-13–responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rα–dependent signaling

Trends in HIV/AIDS morbidity and mortality in Eastern 3 Mediterranean countries, 1990–2015: findings from the Global 4 Burden of Disease 2015 study

Objectives We used the results of the Global Burden of Disease 2015 study to estimate trends of HIV/AIDS burden in Eastern Mediterranean Region (EMR) countries between 1990 and 2015. Methods Tailored estimation methods were used to produce final estimates of mortality. Years of life lost (YLLs) were calculated by multiplying the mortality rate by population by age-specific life expectancy. Years lived with disability (YLDs) were computed as the prevalence of a sequela multiplied by its disability weight. Results In 2015, the rate of HIV/AIDS deaths in the EMR was 1.8 (1.4–2.5) per 100,000 population, a 43% increase from 1990 (0.3; 0.2–0.8). Consequently, the rate of YLLs due to HIV/AIDS increased from 15.3 (7.6–36.2) per 100,000 in 1990 to 81.9 (65.3–114.4) in 2015. The rate of YLDs increased from 1.3 (0.6–3.1) in 1990 to 4.4 (2.7–6.6) in 2015. Conclusions HIV/AIDS morbidity and mortality increased in the EMR since 1990. To reverse this trend and achieve epidemic control, EMR countries should strengthen HIV surveillance,and scale up HIV antiretroviral therapy and comprehensive prevention services

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, an