The Grace Programming Language Draft Specification Version 0.3.1261

This is a specification of the Grace Programming Language. This specification is notably incomplete, and everything is subject to change

The Importance of Being Eelco

Programming language designers and implementers are taught that: semantics are more worthwhile than syntax, that programs exist to embody proofs, rather than to get work done, and to value Dijkstra more than Van Wijngaarden. Eelco Visser believed that, while there is value in the items on the left, there is at least as much value in the items on the right. This short paper explores how Eelco Visser embodied these values, and how he encouraged our work on the Grace programming language, supported that work withio Spoofax, and provided a venue for discussion within the WG2.16 Programming Language Design working group

Modules and Dialects as Objects in Grace

Grace is a gradually typed, object-oriented language for use in education; consonant with that use, we have tried to keep Grace as simple and straightforward as possible. Grace needs a module system for several reasons: to teach students about modular program design, to organise large programs, especially its self-hosted implementation, to provide access to resources defined in other languages, and to support different “dialects”—language subsets, or domain specific languages, for particular parts of the curriculum. Grace already has several organising constructs; this paper describes how Grace uses two of them, objects and lexical scope, to provide modules and dialects

Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT

Interactions between natural killer (NK) cells and dendritic cells (DC) aid DC maturation and promote T cell responses. Here, we have analysed the response of human NK cells to tumor cells and we identify a pathway by which NK-DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNFSF14 (also known as LIGHT), a cytokine implicated in the enhancement of anti-tumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely via the engagement of CD16, by the synergistic activity of multiple target cell-sensing NK cell activation receptors and by the cytokines IL-2 and IL-15. For anti-tumor responses, TNFSF14 was preferentially produced by the licensed NK cell population, defined by the expression of inhibitory receptors specific for self-MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of pro-inflammatory conditions to override the licensing mechanism. Importantly, both tumor and cytokine activated NK cells induced DC maturation in a TNFSF14-dependent manner. The coupling of TNFSF14 production to tumor-sensing NK cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues

IgG antibody production and persistence to 6 months following SARS-CoV-2 vaccination: a Northern Ireland observational study

BACKGROUND: This study evaluates spike protein IgG antibody response following Oxford-AstraZeneca COVID-19 vaccination using the AbC-19™ lateral flow device. METHODS: Plasma samples were collected from n=111 individuals from Northern Ireland. The majority were >50 years old and/or clinically vulnerable. Samples were taken at five timepoints from pre-vaccination until 6-months post-first dose. RESULTS: 20.3% of participants had detectable IgG responses pre-vaccination, indicating prior COVID-19. Antibodies were detected in 86.9% of participants three weeks after the first vaccine dose, falling to 74.7% immediately prior to the second dose, and rising to 99% three weeks post-second vaccine. At 6-months post-first dose, this decreased to 90.5%. At all timepoints, previously infected participants had significantly higher antibody levels than those not previously infected. CONCLUSION: This study demonstrates that strong anti-spike protein antibody responses are evoked in almost all individuals that receive two doses of Oxford-AstraZeneca vaccine, and largely persist beyond six months after first vaccination

Interleukin 7 from Maternal Milk Crosses the Intestinal Barrier and Modulates T- Cell Development in Offspring

Background Breastfeeding protects against illnesses and death in hazardous environments, an effect partly mediated by improved immune function. One hypothesis suggests that factors within milk supplement the inadequate immune response of the offspring, but this has not been able to account for a series of observations showing that factors within maternally derived milk may supplement the development of the immune system through a direct effect on the primary lymphoid organs. In a previous human study we reported evidence suggesting a link between IL-7 in breast milk and the thymic output of infants. Here we report evidence in mice of direct action of maternally-derived IL-7 on T cell development in the offspring. Methods and Findings  We have used recombinant IL-7 labelled with a fluorescent dye to trace the movement in live mice of IL-7 from the stomach across the gut and into the lymphoid tissues. To validate the functional ability of maternally derived IL- 7 we cross fostered IL-7 knock-out mice onto normal wild type mothers. Subsets of thymocytes and populations of peripheral T cells were significantly higher than those found in knock-out mice receiving milk from IL-7 knock-out mothers. Conclusions/Significance Our study provides direct evidence that interleukin 7, a factor which is critical in the development of T lymphocytes, when maternally derived can transfer across the intestine of the offspring, increase T cell production in the thymus and support the survival of T cells in the peripheral secondary lymphoid tissue

Impact of type 2 diabetes and the metabolic syndrome on myocardial structure and microvasculature of men with coronary artery disease

<p>Abstract</p> <p>Background</p> <p>Type 2 diabetes and the metabolic syndrome are associated with impaired diastolic function and increased heart failure risk. Animal models and autopsy studies of diabetic patients implicate myocardial fibrosis, cardiomyocyte hypertrophy, altered myocardial microvascular structure and advanced glycation end-products (AGEs) in the pathogenesis of diabetic cardiomyopathy. We investigated whether type 2 diabetes and the metabolic syndrome are associated with altered myocardial structure, microvasculature, and expression of AGEs and receptor for AGEs (RAGE) in men with coronary artery disease.</p> <p>Methods</p> <p>We performed histological analysis of left ventricular biopsies from 13 control, 10 diabetic and 23 metabolic syndrome men undergoing coronary artery bypass graft surgery who did not have heart failure or atrial fibrillation, had not received loop diuretic therapy, and did not have evidence of previous myocardial infarction.</p> <p>Results</p> <p>All three patient groups had similar extent of coronary artery disease and clinical characteristics, apart from differences in metabolic parameters. Diabetic and metabolic syndrome patients had higher pulmonary capillary wedge pressure than controls, and diabetic patients had reduced mitral diastolic peak velocity of the septal mitral annulus (E'), consistent with impaired diastolic function. Neither diabetic nor metabolic syndrome patients had increased myocardial interstitial fibrosis (picrosirius red), or increased immunostaining for collagen I and III, the AGE Nε-(carboxymethyl)lysine, or RAGE. Cardiomyocyte width, capillary length density, diffusion radius, and arteriolar dimensions did not differ between the three patient groups, whereas diabetic and metabolic syndrome patients had reduced perivascular fibrosis.</p> <p>Conclusions</p> <p>Impaired diastolic function of type 2 diabetic and metabolic syndrome patients was not dependent on increased myocardial fibrosis, cardiomyocyte hypertrophy, alteration of the myocardial microvascular structure, or increased myocardial expression of Nε-(carboxymethyl)lysine or RAGE. These findings suggest that the increased myocardial fibrosis and AGE expression, cardiomyocyte hypertrophy, and altered microvasculature structure described in diabetic heart disease were a consequence, rather than an initiating cause, of cardiac dysfunction.</p

Conformational effects on the Circular Dichroism of Human Carbonic Anhydrase II: a multilevel computational study

Circular Dichroism (CD) spectroscopy is a powerful method for investigating conformational changes in proteins and therefore has numerous applications in structural and molecular biology. Here a computational investigation of the CD spectrum of the Human Carbonic Anhydrase II (HCAII), with main focus on the near-UV CD spectra of the wild-type enzyme and it seven tryptophan mutant forms, is presented and compared to experimental studies. Multilevel computational methods (Molecular Dynamics, Semiempirical Quantum Mechanics, Time-Dependent Density Functional Theory) were applied in order to gain insight into the mechanisms of interaction between the aromatic chromophores within the protein environment and understand how the conformational flexibility of the protein influences these mechanisms. The analysis suggests that combining CD semi empirical calculations, crystal structures and molecular dynamics (MD) could help in achieving a better agreement between the computed and experimental protein spectra and provide some unique insight into the dynamic nature of the mechanisms of chromophore interactions