Endothelium-derived nitric oxide: the endogenous nitrovasodilator in the human cardiovascular system

The L-arginine pathway within endothelial cells in the blood vessel wall is the source of production of the endogenous nitrovasodilator, nitric oxide (NO). NO is released under basal conditions and in response to various stimuli such as shear stress and in response to platelet-derived products, coagulation factors and hormones. NO is the mediator of endothelium-dependent relaxation in the circulation and exerts its effects by activating soluble guanylyl cyclase in vascular smooth muscle, which in turn leads to the formation of cyclic guanosine monophosphate (cGMP) and to relaxation. In addition to its effects on vascular smooth muscle, NO is also released abluminally to interact with circulating platelets. Increases in cGMP in platelets are associated with a decreased adhesion and aggregation of cells. Thus, endothelium-derived NO, through its vasodilator and anti-aggregatory properties, prevents vasospasm and thrombus formation in the circulation and thereby helps to maintain blood flow to vital organs such as the heart. Therapeutic nitrates also exert their effects by releasing NO from their molecules and activating soluble guanylyl cyclase. Their effects are particularly pronounced in arteries without endothelium and are reduced in the presence of the basal formation of endothelium-derived NO in intact arteries. The lower basal formation of endothelium-derived NO in veins, as compared to arteries, contributes to the greater sensitivity of venous circulation to nitrates. Thus, the endothelial L-arginine pathway plays an important protective role in the local regulation of blood flow and through its vasodilator and antiplatelet propertie

Modulation of the Nuclear Transcription Factor of Activated T Cells by Duck Hepatitis B Virus

During infection with hepadnaviruses besides the infectious agent a high number of subviral particles without nucleocapsids are produced, which are able to change the infection dramatically. In addition, it was observed that the activation of the nuclear factor of activated T cells, regulated usually in cells of the immune system, was strongly influenced after infection. When primary duck liver cells were infected with purified virions of duck hepatitis B virus the activation of this factor was reduced in a similar way as it was achieved by inhibition of calcineurin, a cellular phosphatase necessary to control the factor, whereas the addition of subviral particles inhibited this reduction. It was found that the large surface protein of the virus was responsible for the reduced activity. Although this protein was embedded in similar amounts into the envelopes of both particles, only virions were able to inhibit the activity of the nuclear factor. An explanation of the different performances of the particles in primary duck liver cells apparently depends on the individual mode of insertion of the large surface proteins into the viral membrane. Furthermore, the nuclear factor of activated T cells could only be detected in liver sinusoidal endothelial cells, which was shown being attracted by virions but not by subviral particles

Strategies for Enhancing the Mature Student Experience in Higher Education

A principle of the Irish Education system is its endorsement of equity of access to higher education for all Irish citizens. This principle has been enacted through successive government policies including the National Plan for Equity of Access to Higher Education 2015-2019 (HEA, 2015). The aim of this policy is to “ensure that the student body entering, participating in and completing higher education at all levels reflects the diversity and social mix of Ireland’s population” (p.8). Data from this plan shows that participation in higher education by the adult population has increased and that there is a potential for increasing the overall educational attainment levels of the adult population as a whole. Mature students are those aged 23 years or over. Among the many reasons why mature students enter full time higher education are; career orientations, replacing of redundant skill sets, being a role model for children, the enjoyment of learning. Our objective is to examine the literature relating to curriculum design, in particular, teaching (including technology), learning and assessment strategies and how programme and module designers (new and longstanding lecturers) might support the needs of mature students within a programme/module. The report also provides information on policy and statistics of the current mature education landscape in Ireland

Adaptive Evolution as a Predictor of Species-Specific Innate Immune Response

It has been proposed that positive selection may be associated with protein functional change. For example, human and macaque have different outcomes to HIV infection and it has been shown that residues under positive selection in the macaque TRIM5α receptor locate to the region known to influence species-specific response to HIV. In general, however, the relationship between sequence and function has proven difficult to fully elucidate, and it is the role of large-scale studies to help bridge this gap in our understanding by revealing major patterns in the data that correlate genotype with function or phenotype. In this study, we investigate the level of species-specific positive selection in innate immune genes from human and mouse. In total, we analyzed 456 innate immune genes using codon-based models of evolution, comparing human, mouse, and 19 other vertebrate species to identify putative species-specific positive selection. Then we used population genomic data from the recently completed Neanderthal genome project, the 1000 human genomes project, and the 17 laboratory mouse genomes project to determine whether the residues that were putatively positively selected are fixed or variable in these populations. We find evidence of species-specific positive selection on both the human and the mouse branches and we show that the classes of genes under positive selection cluster by function and by interaction. Data from this study provide us with targets to test the relationship between positive selection and protein function and ultimately to test the relationship between positive selection and discordant phenotypes

The emerging roles of intestinal macrophages in sickness and in health

The immune system in the intestine represents a unique environment that can quickly respond to harmful pathogens, but it remains tolerant to antigens from food and commensal bacteria. This balance between protective immunity and tolerance is largely dependent on the mononuclear phagocytes in the intestine, such as macrophages. Intestinal macrophages, unlike other macrophage populations in the body, are hypo-responsive to stimuli although they originate from fully responsive blood monocytes. The intestinal environment seems to instruct monocytes to mute their function upon arrival to the gut in order to adapt to the antigen-rich environment. While their main role in the healthy gut is to maintain homeostasis, in disease macrophage phenotype and function is changed and these cells become the drivers of inflammation and disease progression

Metabolome analysis of Arabidopsis thaliana roots identifies a key metabolic pathway for iron acquisition

Fe deficiency compromises both human health and plant productivity. Thus, it is important to understand plant Fe acquisition strategies for the development of crop plants which are more Fe-efficient under Fe-limited conditions, such as alkaline soils, and have higher Fe density in their edible tissues. Root secretion of phenolic compounds has long been hypothesized to be a component of the reduction strategy of Fe acquisition in non-graminaceous plants. We therefore subjected roots of Arabidopsis thaliana plants grown under Fe-replete and Fe-deplete conditions to comprehensive metabolome analysis by gas chromatography-mass spectrometry and ultra-pressure liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry. Scopoletin and other coumarins were found among the metabolites showing the strongest response to two different Fe-limited conditions, the cultivation in Fe-free medium and in medium with an alkaline pH. A coumarin biosynthesis mutant defective in ortho-hydroxylation of cinnamic acids was unable to grow on alkaline soil in the absence of Fe fertilization. Co-cultivation with wild-type plants partially rescued the Fe deficiency phenotype indicating a contribution of extracellular coumarins to Fe solubilization. Indeed, coumarins were detected in root exudates of wild-type plants. Direct infusion mass spectrometry as well as UV/vis spectroscopy indicated that coumarins are acting both as reductants of Fe(III) and as ligands of Fe(II)

FAUSTA: Scaling Dynamic Analysis with Traffic Generation at WhatsApp

We introduce Fausta, an algorithmic traffic gener-ation platform that enables analysis and testing at scale. Fausta has been deployed at Meta to analyze and test the WhatsApp plat-form infrastructure since September 2020, enabling WhatsApp developers to deploy reliable code changes to a code base of millions of lines of code, supporting over 2 billion users who rely on WhatsApp for their daily communications. Fausta covers expected and unexpected program behaviors in a privacy-safe controlled environment to support multiple use cases such as reliability testing, privacy analysis and performance regression detection. It currently supports three different algorithmic input generation strategies, each of which construct realistic backend server traffic that closely simulates production data, without replaying any real user data. Fausta has been deployed and closely integrated into the WhatsApp continuous integration process, catching bugs in development before they hit production. We report on the development and deployment of Fausta's reliability use case between September 2020 and August 2021. During this period it has found 1,876 unique reliability issues, with a fix rate of 74%, indicating a high degree of true positive fault revelation. We also report on the distribution of fault types revealed by Fausta, and the correlation between coverage and faults found. Overall, we do find evidence that higher coverage is correlated with fault revelation

Prevalence of Pulmonary Tuberculosis among Prison Inmates in Ethiopia, a Cross-Sectional Study

Setting Tuberculosis (TB) is one of the major health problems in prisons. Objective This study was done to assess the prevalence and determinants of active tuberculosis in Ethiopian prisons. Design A cross-sectional study was conducted from January 2013 to December 2013 in 13 zonal prisons. All incarcerated inmates underwent TB symptom screening according to WHO criteria. From identified TB-suspects two sputum samples were analyzed using smear microscopy and solid culture. A standardized questionnaire assessing TB risk factors was completed for each TB suspect. Results 765 (4.9%) TB suspects were identified among 15, 495 inmates. 51 suspects were already on anti-TB treatment (6.67%) and 20 (2.8%) new culture-confirmed TB cases were identified in the study, resulting in an overall TB prevalence of 458.1/100, 000 (95% CI: 350-560/100, 000). Risk factors for active TB were alcohol consumption, contact with a TB case before incarceration and no window in prison cell. HIV prevalence was not different between TB suspects and active TB cases. Further, the TB burden in prisons increased with advancing distance from the capital Addis Ababa. Conclusions The overall TB prevalence in Ethiopian prisons was high and extremely variable among different prisons. TB risk factors related to conditions of prison facilities and the impact of implemented TB control measures need to be further studied in order to improve TB control among inmates