HyperNotifier

In every company there is a great amount of information that should be delivered to the employees. Some of them are administrators and they want to know if something was changed in the environment they administrate. If there are many different environments, the employees are getting many different notifications from different sources and in different layouts. This thesis illustrates a solution that is used to handle different environments to get a plain and compact, unified report about changes that were made. The solution includes collecting of data, storing it and notifying about it. It is a Windows service and a web application using database and interchangeable DLL libraries involved in handling of the specific sources of changes. The solution provides a simple mechanism for the creation and maintenance of reports containing selected changes from selected sources supplied at specified time and frequency. The Hypernotifier solution is created using C# programming language, and it runs in the Microsoft® .NET Framework. It also takes advantage of the existing software infrastructure. The solution was made for the employees of VSoft, who would like to be notified about changes in some areas of their interests, for example a folder in file system or a list at the SharePoint web page

Scheduling Lockdowns Under Conditions of Pandemic Uncertainty

The objective of our work was to develop a tool to support the process of making strategic decisions about the COVID-19 pandemic by optimizing suppression intervention schedules. We focus mainly on hard lockdowns that have the effect of containing the spread of the virus and, consequently, minimizing the number of infections and keeping the incidence of COVID-19 at low levels. Properly implemented restrictions can reduce the likelihood of infection and thus push the pandemic back. On the contrary, lifting restrictions results in a sharp increase in likelihood of infection and the development of a pandemic. The model proposed in this paper indicates the optimal moments to implement full lockdown, accounting for both the costs of lockdown and the costs of not applying lockdown

Neural Plasticity in Multiple Sclerosis: The Functional and Molecular Background

Multiple sclerosis is an autoimmune neurodegenerative disorder resulting in motor dysfunction and cognitive decline. The inflammatory and neurodegenerative changes seen in the brains of MS patients lead to progressive disability and increasing brain atrophy. The most common type of MS is characterized by episodes of clinical exacerbations and remissions. This suggests the presence of compensating mechanisms for accumulating damage. Apart from the widely known repair mechanisms like remyelination, another important phenomenon is neuronal plasticity. Initially, neuroplasticity was connected with the developmental stages of life; however, there is now growing evidence confirming that structural and functional reorganization occurs throughout our lifetime. Several functional studies, utilizing such techniques as fMRI, TBS, or MRS, have provided valuable data about the presence of neuronal plasticity in MS patients. CNS ability to compensate for neuronal damage is most evident in RR-MS; however it has been shown that brain plasticity is also preserved in patients with substantial brain damage. Regardless of the numerous studies, the molecular background of neuronal plasticity in MS is still not well understood. Several factors, like IL-1β, BDNF, PDGF, or CB1Rs, have been implicated in functional recovery from the acute phase of MS and are thus considered as potential therapeutic targets

Dietary Polyphenols Decrease Chemokine Release by Human Primary Astrocytes Responding to Pro-Inflammatory Cytokines

Astrocytes are considered to be the dominant cell fraction of the central nervous system. They play a supportive and protective role towards neurons, and regulate inflammatory processes; they thus make suitable targets for drugs and supplements, such as polyphenolic compounds. However, due to their wide range, knowledge of their anti-inflammatory potential remains relatively incomplete. The aim of this study was therefore to determine whether myricetin and chrysin are able to decrease chemokine release in reactive astrocytes. To assess the antioxidant and anti-inflammatory potential of polyphenols, human primary astrocytes were cultured in the presence of a reactive and neurotoxic astrocyte-inducing cytokine mixture (TNF-α, IL-1a, C1q), either alone or in the presence of myricetin or chrysin. The examined polyphenols were able to modify the secretion of chemokines by human cortical astrocytes, especially CCL5 (chrysin), CCL1 (myricetin) and CCL2 (both), while cell viability was not affected. Surprisingly, the compounds did not demonstrate any antioxidant properties in the astrocyte cultures

Interactions between Neutrophils, Th17 Cells, and Chemokines during the Initiation of Experimental Model of Multiple Sclerosis

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) in which activated T cell and neutrophil interactions lead to neuroinflammation. In this study the expression of CCR6, CXCR2, and CXCR6 in Th17 cells and neutrophils migrating to the brain during EAE was measured, alongside an evaluation of the production of IL-17, IL-23, CCL-20, and CXCL16 in the brain. Next, inflammatory cell subpopulations accumulating in the brain after intracerebral injections of IL-17 or CXCL1, as well as during modulation of EAE with anti-IL-23R or anti-CXCR2 antibodies, were analyzed. Th17 cells upregulate CXCR2 during the preclinical phase of EAE and a significant migration of these cells to the brain was observed. Neutrophils upregulated CCR6, CXCR2, and CXCR6 during EAE, accumulating in the brain both prior to and during acute EAE attacks. Production of IL-17, IL-23, CCL20, and CXCL16 in the CNS was increased during both preclinical and acute EAE. Intracerebral delivery of CXCL1 stimulated the early accumulation of neutrophils in normal and preclinical EAE brains but reduced the migration of Th17 cells to the brain during the preclinical stage of EAE. Modulation of EAE by anti-IL-23R antibodies ameliorated EAE by decreasing the intracerebral accumulation of Th17 cells

Transcription factor 7-like 2 (TCF7L2) gene polymorphism and clinical phenotype in end-stage renal disease patients

Variants of the transcription factor 7-like 2 gene (TCF7L2) have been associated with type 2 diabetes and cardiovascular disease in different populations. Here we investigated the potential association of the rs7903146 polymorphism in the TCF7L2 gene with clinical profile of end-stage renal disease (ESRD) patients. We examined a cohort of 1065 ESRD patients with diabetic and non-diabetic renal disease. The control group consisted of 924 healthy individuals. All subjects were genotyped for the rs7903146 single nucleotide polymorphism by polymerase chain reaction. The genotype distribution and allele frequencies were significantly different between ESRD patients and controls (p < 0.01). The OR for the TT genotype was 2.81 (95 % CI 2.08–3.79). Genotype and allele frequencies were compared between subgroups of patients with different clinical phenotypes. The frequency of the T allele was significantly higher in patients with diabetic nephropathy versus non-diabetic renal disease (p = 0.007, OR 1.70, 95 % CI 1.36–2.11). The statistically significant differences were demonstrated between patients with and without cardiovascular disease, with the OR for T allele 1.57 (95 % CI 1.31–1.90). The odds ratio for TT genotype was 2.38 (95 % CI 1.62–3.51). In our study the T allele of the rs7903146 SNP in the TCF7L2 gene confers the risk of developing diabetic nephropathy. We described for the first time a strong relationship between the TCF7L2 gene variant rs7903146 and cardiovascular disease in end-stage renal disease patients

Developing a diagnostic test to identify the selected mutation within the CFTR gene that determines the onset of cystic fibrosis

Cystic fibrosis is one of the most common genetic diseases among Caucasians due to its prevalence. Modern methods of molecular diagnostics and treatment of the disease allow to prolong the life of patients. In order to apply the appropriate treatment, the genetic basis of this disease should, however, first be known. The most common and the most severe mutation present in the CFTR gene (60-70% of cases) takes the form of an allele. This is responsible for the deletion of phenylalanine in position 508 (Δ508) of the CFTR protein. Determination of mutations in the CFTR gene using molecular techniques makes it possible to identify the causes of the disease in people who do not show the characteristic symptoms of cystic fibrosis

Astrocyte-Derived Exosomes Differentially Shape T Cells’ Immune Response in MS Patients

Astrocytes, the most abundant group of glia cells in the brain, provide support for neurons and indicate multiple various functions in the central nervous system (CNS). Growing data additionally describe their role in the regulation of immune system activity. They exert their function not only by direct contact with other cell types, but also through an indirect method, e.g., by secreting various molecules. One such structure is extracellular vesicles, which are important mediators of crosstalk between cells. In our study, we observed that the impact of exosomes derived from astrocytes with various functional phenotype differently affect the immune response of CD4+ T cells, both from healthy individuals and from patients with multiple sclerosis (MS). Astrocytes, by modulating exosome cargo, impacts the release of IFN-γ, IL-17A and CCL2 in our experimental conditions. Considering the proteins concentration in cell culture supernatants and the cellular percentage of Th phenotypes, it could be stated that human astrocytes, by the release of exosomes, are able to modify the activity of human T cells

Development of a novel, high-affinity ssDNA trypsin inhibitor

Inhibitors of serine proteases are not only extremely useful in the basic research but are also applied extensively in clinical settings. Using Systematic Evolution of Ligands by Exponential Enrichment (SELEX) approach we developed a family of novel, single-stranded DNA aptamers capable of specific trypsin inhibition. Our most potent candidate (T24) and its short version (T59) were thoroughly characterised in terms of efficacy. T24 and T59 efficiently inhibited bovine trypsin with Ki of 176 nM and 475 nM, respectively. Interestingly, in contrast to the majority of known trypsin inhibitors, the selected aptamers have superior specificity and did not interact with porcine trypsin or any human proteases tested. These included plasmin and thrombin characterised by trypsin-like substrate specificity. Our results demonstrate that SELEX may be successfully employed in the development of potent and specific DNA based protease inhibitors