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Systemic autoinflammatory diseases (SAIDs) are a group of inflammatory disorders caused by dysregulation in the innate immune system that leads to enhanced immune responses. The clinical diagnosis of SAIDs can be difficult since individually these are rare diseases with considerable phenotypic overlap. Most SAIDs have a strong genetic background, but environmental and epigenetic influences can modulate the clinical phenotype. Molecular diagnosis has become essential for confirmation of clinical diagnosis. To date there are over 30 genes and a variety of modes of inheritance that have been associated with monogenic SAIDs. Mutations in the same gene can lead to very distinct phenotypes and can have different inheritance patterns. In addition, somatic mutations have been reported in several of these conditions. New genetic testing methods and databases are being developed to facilitate the molecular diagnosis of SAIDs, which is of major importance for treatment, prognosis and genetic counselling. The aim of this review is to summarize the latest advances in genetic testing for SAIDs and discuss potential obstacles that might arise during the molecular diagnosis of SAIDs.
The pyrin inflammasome has evolved as an innate immune sensor to detect bacterial toxin-induced Rho guanosine triphosphatase (Rho GTPase)-inactivation, a process that is similar to the "guard" mechanism in plants. Rho GTPases act as molecular switches to regulate a variety of signal transduction pathways including cytoskeletal organization. Pathogens can modulate Rho GTPase activity to suppress host immune responses such as phagocytosis. Pyrin is encoded by MEFV, the gene that is mutated in patients with familial Mediterranean fever (FMF). FMF is the prototypic autoinflammatory disease characterized by recurring short episodes of systemic inflammation and is a common disorder in many populations in the Mediterranean basin. Pyrin specifically senses modifications in the activity of the small GTPase RhoA, which binds to many effector proteins including the serine/threonine-protein kinases PKN1 and PKN2 and actin-binding proteins. RhoA activation leads to PKN-mediated phosphorylation-dependent pyrin inhibition. Conversely, pathogen virulence factors downregulate RhoA activity in a variety of ways, and these changes are detected by the pyrin inflammasome irrespective of the type of modifications. MEFV pathogenic variants favor the active state of pyrin and elicit proinflammatory cytokine release and pyroptosis. They can be inherited either as a dominant or recessive trait depending on the variant's location and effect on the protein function. Mutations in the C-terminal B30.2 domain are usually considered recessive, although heterozygotes may manifest a biochemical or even a clinical phenotype. These variants are hypomorphic in regard to their effect on intramolecular interactions, but ultimately accentuate pyrin activity. Heterozygous mutations in other domains of pyrin affect residues critical for inhibition or protein oligomerization, and lead to constitutively active inflammasome. In healthy carriers of FMF mutations who have the subclinical inflammatory phenotype, the increased activity of pyrin might have been protective against endemic infections over human history. This finding is supported by the observation of high carrier frequencies of FMF-mutations in multiple populations. The pyrin inflammasome also plays a role in mediating inflammation in other autoinflammatory diseases linked to dysregulation in the actin polymerization pathway. Therefore, the assembly of the pyrin inflammasome is initiated in response to fluctuations in cytoplasmic homeostasis and perturbations in cytoskeletal dynamics.
The generation and maintenance of intricate spatiotemporal patterns of gene expression in multicellular organisms requires the establishment of complex mechanisms of transcriptional regulation. Estimations that up to one million enhancers exist in the human genome accentuates the utmost importance of this type of cis-regulatory element for gene regulation. However, surprisingly little is known about the mechanisms used to temporarily or permanently activate or inactivate enhancers during cellular differentiation. The current work addresses the question how enhancer regulation can be achieved.
Using the chemokine (C-C motif) ligand gene Ccl22 as a model, the first example is based on the question how the activation of an enhancer can be prevented in a physiological context. Ccl22 is expressed by myeloid cells, such as dendritic cells, upon exposure to inflammatory stimuli. The expression in other cell types, such as fibroblasts, is prevented by the strong accumulation of H3K9me3 at the enhancer's proximal region. This accumulation is attenuated in myeloid cells through activity of the stimulus-induced demethylase Jmjd2d. To tease out which genomic fragment or fragments in the Ccl22 locus could be responsible for the maintenance of enhancer inactivity, potentially through the recruitment of H3K9 methyltransferases, the enhancer repressing capacity of 1 kb fragments of the gene locus was analysed in retroviral reporter assays. It was found that a fragment adjacent to the Ccl22 enhancer that overlaps with a member of a subfamily of long interspersed nuclear elements (LINEs) showed strong repressive potential on a model enhancer. Subsequent retroviral reporter assays with LINEs from loci of other stimulus-dependent genes identified additional LINE fragments that exhibit strong enhancer repressive capacity. These findings suggest a mechanism for enhancer silencing involving LINEs.
The second example concentrates on the inactivation of an enhancer during colorectal cancer (CRC) progression. The adenoma to carcinoma transition during CRC progression often is accompanied by a downregulation of the tumour suppressor gene EPHB2. The EMT inducing factor SNAIL1 strongly downregulated EPHB2 expression in a CRC cell model. To gain insights into the transcriptional regulation of EPHB2, potential cis-regulatory elements in the EPHB2 upstream region were analysed using reporter assays. A cell-type-specific enhancer was identified and subsequent chromatin analyses revealed a correlation between enhancer chromatin conformation and EPHB2 expression in different CRC cell lines. Additionally, the overexpression of the murine Snail1 induced chromatin changes at the EPHB2 enhancer towards a poised, transcriptionally silent chromatin conformation. Mutational analyses of the minimal enhancer region pinpointed three transcription factor binding motifs to be essential for full enhancer activity. Different binding patterns between CRC cell lines at the TCF/LEF motif were subsequently identified. Furthermore, a switch from TCF7L2 to LEF1 occupancy was found upon overexpression of Snail1 in vitro and in vivo. The generation of LS174T CRC cells overexpressing LEF1 confirmed the involvement of LEF1 in the downregulation of EPHB2 and the competitive displacement of TCF7L2. This part of the work demonstrated that the SNAIL1 induced downregulation of EPHB2 is dependent on the decommissioning of a transcriptional enhancer and led to a hypothetical model involving LEF1 and ZEB1.
In summary, this work highlighted two distinct mechanisms for enhancer regulation. One mechanism is based on enhancer repressive LINE fragments that might prevent stimulus-dependent enhancer activation. In the second, enhancer silencing was shown to be based on a competitive transcription factor binding mechanism.
The access to electricity and water in rural areas in Côte d’Ivoire as well as in large parts of Africa is limited. According to Ivorian government sources, the national coverage rate of drinkable water and electricity was about 80% in 2020, whereas there are differences between rural and urban regions. The coverages are lower in rural areas that are situated far from the governmental infrastructures. The poor supply of electricity also hinders education, since petroleum lamps are often the only source of light for learning after sunset. Besides, increasing demand for electricity is predicted in Côte d’Ivoire due to economic growth. The economic power is also affected by the poor supply of electricity, so only a limited production of goods is possible. A further big concern in Côte d’Ivoire is the employability of graduate students, as the educational system has a strong theoretic character, not yet taking enough into account practice orientation. Scientific public universities in Côte d'Ivoire often offer only subjects such as mathematics, physics, or chemistry but hardly any engineering.
The paper investigates the nature of Kenya's entrepreneurship education ecosystem (EEE) through a comparative analysis of three entrepreneurship education programs and an examination of how the institutions foster a favourable entrepreneurial environment. This study looks at the entrepreneurship education ecosystem through the lens of universities, NGO's and private institutes in Kenya.
A systemic analysis of EEE is provided by utilizing the Actiotope Model as a conceptual framework. The exploratory research adopts a pragmatic mixed-method methodological approach best suited to understand the research problem.
The results reveal that entrepreneurship education at higher education institutions was primarily theoretical and relied on traditional forms of entrepreneurship education. Recurring rigid patterns show minimal personalization of content and learning styles within the University, with more personalization reported in the Mully Model of education and the more specialized entrepreneurship program of the Identity Projects.
The adaptation of the Actiotope Model provided a new and unique approach to analyzing entrepreneurship ecosystems. The person-centred approach of the model provides valuable insights to learners and to entrepreneurship education institutions and researchers.
Enhanced collaboration between the different entrepreneurial education stakeholders could be a more effective short to medium-term solution to addressing the gaps in entrepreneurial education at tertiary institutions.
In the long term, the study recommends adopting practical-based and goal-oriented entrepreneurship teaching models.
Social businesses have a great positive impact on communities and are a sustainable way to do business today and in the future. This impact can be amplified through the means of digitalization. In the past, traditional for-profit business models have been used to understand the structures of business operations. However, the underlying business model of digital social businesses has not yet been explored. This study presents a building block analysis of business models and a subsequent typology. Digital and social business models are identified via a literature review. The building block analysis encompasses an assessment of the individual business activities contained in the business models. The typology is developed from existing literature utilizing a matrix for the evaluation of digital social businesses. Additionally, five semi-structured expert interviews are conducted to inform, extend, or content the findings of this study. To this end, an inductive coding procedure is applied to the transcribed interviews for the detection of themes within the text. This study contributes to social business model research by providing a first insight into the unique building blocks of digital social business models. It also creates a typology tool based on two parameters, which enables the comparison of digital social businesses.