αv integrins: key regulators of tissue fibrosis

Chronic tissue injury with fibrosis results in the disruption of tissue architecture, organ dysfunction and eventual organ failure. Therefore, the development of effective anti-fibrotic therapies is urgently required. During fibrogenesis, complex interplay occurs between cellular and extracellular matrix components of the wound healing response. Integrins, a family of transmembrane cell adhesion molecules, play a key role in mediating intercellular and cell-matrix interactions. Thus, integrins provide a major node of communication between the extracellular matrix, inflammatory cells, fibroblasts and parenchymal cells and, as such, are intimately involved in the initiation, maintenance and resolution of tissue fibrosis. Modulation of members of the αv integrin family has exhibited profound effects on fibrosis in multiple organs and disease states. In this review, we discuss the current knowledge of the mechanisms of αv-integrin-mediated regulation of fibrogenesis and show that the therapeutic targeting of specific αv integrins represents a promising avenue to treat patients with a broad range of fibrotic diseases

Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly

Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and “major spliceosome-opathies” as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase

The HSA21 gene EURL/C21ORF91 controls neurogenesis within the cerebral cortex and is implicated in the pathogenesis of Down Syndrome

Copy number variations to chromosome 21 (HSA21) cause intellectual disability and Down Syndrome, but our understanding of the HSA21 genetic factors which contribute to fetal brain development remains incomplete. Here, we focussed on the neurodevelopmental functions for EURL (also known as C21ORF91, Refseq Gene ID:54149), a protein-coding gene at the centromeric boundary of the Down Syndrome Critical Region (DSCR) of HSA21. We report that EURL is expressed during human and mouse cerebral cortex development, and we report that alterations to EURL mRNA levels within the human brain underlie Down Syndrome. Our gene perturbation studies in mice demonstrate that disruptions to Eurl impair progenitor proliferation and neuronal differentiation. Also, we find that disruptions to Eurl impair the long-term positioning and dendritic spine densities of cortical projection neurons. We provide evidence that EURL interacts with the coiled-coil domain-containing protein CCDC85B so as to modulate ß-catenin levels in cells. Further, we utilised a fluorescent reporter (8xTOPFLASHd2EGFP) to demonstrate that disruptions to Eurl alter ß-catenin signalling in vitro as well as in vivo. Together, these studies highlight EURL as an important new player in neuronal development that is likely to impact on the neuropathogenesis of HSA21-related disorders including Down Syndrome

The (Un)Healthy Migrant Effect. The Role of Legal Status and Naturalization Timing

The current evidence on immigrant health in Europe is mixed, with some studies indicating a healthy migrant effect, and others pointing out that immigrants experience worse health outcomes compared to natives. Very few studies however have investigated the potential existence of a migrant health paradox in Switzerland, a country with one of the highest shares of both foreign- and native-born immigrants in Europe, as well as a restrictive and increasingly negative immigration context. Research is also yet to assess the role played by legal status, particularly the acquisition of Swiss citizenship and the life course stage at which it occurs, in moderating the health gradient between natives and immigrants. In this chapter, we use data from the Swiss Household Panel (1999–2014) and a sample of 10,010 respondents between 18 and 60 years old at the time of entry into the panel, to perform multilevel logistic models of self-rated health. Results do not show a migrant health paradox. Migrants display worse health than natives, even after adjusting for differences in socio-economic status. Furthermore, legal status has a significant influence on the health disparities between Swiss natives and immigrants. Whereas immigrants that hold Swiss nationality since birth or those who were naturalized early in life are not significantly different in health compared to natives, immigrants who are not naturalized or were naturalised later in life display worse health than natives