Multiple factors influence immunoglobulin G glycosylation, which in turn affect the glycoproteins' function on eliciting an anti-inflammatory or pro-inflammatory response. It is prudent to underscore ...these processes when considering the use of immunoglobulin G
-glycan moieties as an indication of disease presence, progress, or response to therapeutics. It has been demonstrated that the altered expression of genes that encode enzymes involved in the biosynthesis of immunoglobulin G
-glycans, receptors, or complement factors may significantly modify immunoglobulin G effector response, which is important for regulating the immune system. The immunoglobulin G
-glycome is highly heterogenous; however, it is considered an interphenotype of disease (a link between genetic predisposition and environmental exposure) and so has the potential to be used as a dynamic biomarker from the perspective of predictive, preventive, and personalised medicine. Undoubtedly, a deeper understanding of how the multiple factors interact with each other to alter immunoglobulin G glycosylation is crucial. Herein we review the current literature on immunoglobulin G glycoprotein structure, immunoglobulin G Fc glycosylation, associated receptors, and complement factors, the downstream effector functions, and the factors associated with the heterogeneity of immunoglobulin G glycosylation.
Although much work has linked the human microbiome to specific phenotypes and lifestyle variables, data from different projects have been challenging to integrate and the extent of microbial and ...molecular diversity in human stool remains unknown. Using standardized protocols from the Earth Microbiome Project and sample contributions from over 10,000 citizen-scientists, together with an open research network, we compare human microbiome specimens primarily from the United States, United Kingdom, and Australia to one another and to environmental samples. Our results show an unexpected range of beta-diversity in human stool microbiomes compared to environmental samples; demonstrate the utility of procedures for removing the effects of overgrowth during room-temperature shipping for revealing phenotype correlations; uncover new molecules and kinds of molecular communities in the human stool metabolome; and examine emergent associations among the microbiome, metabolome, and the diversity of plants that are consumed (rather than relying on reductive categorical variables such as veganism, which have little or no explanatory power). We also demonstrate the utility of the living data resource and cross-cohort comparison to confirm existing associations between the microbiome and psychiatric illness and to reveal the extent of microbiome change within one individual during surgery, providing a paradigm for open microbiome research and education.
We show that a citizen science, self-selected cohort shipping samples through the mail at room temperature recaptures many known microbiome results from clinically collected cohorts and reveals new ones. Of particular interest is integrating
= 1 study data with the population data, showing that the extent of microbiome change after events such as surgery can exceed differences between distinct environmental biomes, and the effect of diverse plants in the diet, which we confirm with untargeted metabolomics on hundreds of samples.
COVID-19 symptoms vary from asymptomatic cases to moderate and severe illness with patients needing hospitalization and intensive care treatment. Vitamin D is associated with severity of viral ...infections and has an immune-modulatory effect in immune response. Observational studies showed a negative association of low vitamin D levels and COVID-19 severity and mortality outcomes. In this study, we aimed to determine whether daily supplementation of vitamin D during intensive care unit (ICU) stay in COVID-19 patients with severe illness affects clinically relevant outcomes. Patients with COVID-19 disease in need of respiratory support admitted to the ICU were eligible for inclusion. Patients with low vitamin D levels were randomized into one of two groups: the intervention group received daily supplementation of vitamin D and the control group did not receive vitamin D supplementation. In total, 155 patients were randomized: 78 into the intervention group and 77 into the control group. There was no statistically significant difference in number of days spent on respiratory support, although the trial was underpowered for the main outcome. There was no difference in any of the secondary outcomes analyzed between two groups. Our study suggests no benefit in vitamin D supplementation to patients with severe COVID-19 disease admitted to the ICU and in need of respiratory support in any of the analyzed outcomes.
Immunoglobulin G (IgG) is a major effector molecule of the human immune response, and aberrations in IgG glycosylation are linked to various diseases. However, the molecular mechanisms underlying ...protein glycosylation are still poorly understood. We present a data-driven approach to infer reactions in the IgG glycosylation pathway using large-scale mass-spectrometry measurements. Gaussian graphical models are used to construct association networks from four cohorts. We find that glycan pairs with high partial correlations represent enzymatic reactions in the known glycosylation pathway, and then predict new biochemical reactions using a rule-based approach. Validation is performed using data from a GWAS and results from three in vitro experiments. We show that one predicted reaction is enzymatically feasible and that one rejected reaction does not occur in vitro. Moreover, in contrast to previous knowledge, enzymes involved in our predictions colocalize in the Golgi of two cell lines, further confirming the in silico predictions.
Nasal route of administration offers a unique opportunity of brain targeted drug delivery via olfactory and trigeminal pathway, providing effective CNS concentrations at lower doses and lower risk ...for adverse reactions compared to systemic drug administration. Therefore, it has been recently proposed as a route of choice for glucocorticoids to control neuroinflammation processes in patients with severe Covid-19. However, appropriate delivery systems tailored to enhance their efficacy yet need to emerge. In this work we present the development of sprayable brain targeting powder delivery platform of dexamethasone sodium phosphate (DSP). DSP-loaded microspheres, optimised employing Quality-by-Design approach, were blended with soluble inert carriers (mannitol or lactose monohydrate). Powder blends were characterized in terms of homogeneity, flow properties, sprayability, in vitro biocompatibility, permeability and mucoadhesion. Nasal deposition studies were performed using 3D printed nasal cavity model. Mannitol provided better powder blend flow properties compared to lactose. Microspheres blended with mannitol retained or enlarged their mucoadhesive properties and enhanced DSP permeability across epithelial model barrier. DSP dose fraction deposited in the olfactory region reached 17.0% revealing the potential of developed powder platform for targeted olfactory delivery. The observed impact of nasal cavity asymmetry highlighted the importance of individual approach when aiming olfactory region.
Chronic graft-versus-host disease (cGvHD) is a systemic alloimmune and autoimmune disorder and a major late complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). The disease ...is characterized by an altered homeostasis of the humoral immune response. Immunoglobulin G (IgG) glycoprotein is the main effector molecule of the humoral immune response. Changes in IgG glycosylation are associated with a number of autoimmune diseases. IgG glycosylation analysis was done by the means of liquid chromatography in the National Institutes of Health (NIH) cohort of 213 cGvHD patients. The results showed statistically significant differences with regards to cGvHD NIH joint/fascia and skin score, disease activity and intensity of systemic immunosuppression. ROC analysis confirmed that IgG glycosylation increases specificity and sensitivity of models using laboratory parameters and markers of inflammation associated with cGvHD (eosinophil count, complement components C3 and C4 and inflammation markers: albumin, CRP and thrombocyte count). This research shows that IgG glycosylation may play a significant role in cGvHD pathology. Further research could contribute to the understanding of the disease biology and lead to the clinical biomarker development to allow personalized approaches to chronic GvHD therapy.
Donepezil nasal delivery strategies are being continuously investigated for advancing therapy in Alzheimer's disease. The aim of this study was to develop a chitosan-based, donepezil-loaded ...thermogelling formulation tailored to meet all the requirements for efficient nose-to-brain delivery. A statistical design of the experiments was implemented for the optimisation of the formulation and/or administration parameters, with regard to formulation viscosity, gelling and spray properties, as well as its targeted nasal deposition within the 3D-printed nasal cavity model. The optimised formulation was further characterised in terms of stability, in vitro release, in vitro biocompatibility and permeability (using Calu-3 cells), ex vivo mucoadhesion (using porcine nasal mucosa), and in vivo irritability (using slug mucosal irritation assay). The applied research design resulted in the development of a sprayable donepezil delivery platform characterised by instant gelation at 34 °C and olfactory deposition reaching a remarkably high 71.8% of the applied dose. The optimised formulation showed prolonged drug release (
about 90 min), mucoadhesive behaviour, and reversible permeation enhancement, with a 20-fold increase in adhesion and a 1.5-fold increase in the apparent permeability coefficient in relation to the corresponding donepezil solution. The slug mucosal irritation assay demonstrated an acceptable irritability profile, indicating its potential for safe nasal delivery. It can be concluded that the developed thermogelling formulation showed great promise as an efficient donepezil brain-targeted delivery system. Furthermore, the formulation is worth investigating in vivo for final feasibility confirmation.
In recent years random sets were recognized as a valuable tool in modelling different processes from fields like biology, biomedicine or material sciences. Nevertheless, the full potential of ...applications has not still been reached and one of the main problems in advancement is the usual inability to correctly differentiate between underlying processes generating real world realisations. This paper presents a measure of dissimilarity of stationary and isotropic random sets through a heuristic based on convex compact approximations, support functions and envelope tests. The choice is justified through simulation studies of common random models like Boolean and Quermass-interaction processes.
PDF
