Reactive Glia in the Injured Brain Acquire Stem Cell Properties in Response to Sonic Hedgehog

SummaryAs a result of brain injury, astrocytes become activated and start to proliferate in the vicinity of the injury site. Recently, we had demonstrated that these reactive astrocytes, or glia, can form self-renewing and multipotent neurospheres in vitro. In the present study, we demonstrate that it is only invasive injury, such as stab wounding or cerebral ischemia, and not noninvasive injury conditions, such as chronic amyloidosis or induced neuronal death, that can elicit this increase in plasticity. Furthermore, we find that Sonic hedgehog (SHH) is the signal that acts directly on the astrocytes and is necessary and sufficient to elicit the stem cell response both in vitro and in vivo. These findings provide a molecular basis for how cells with neural stem cell lineage emerge at sites of brain injury and imply that the high levels of SHH known to enter the brain from extraneural sources after invasive injury can trigger this response

Zur nichtkonsensuellen Weiterleitung persönlicher erotischer Fotos an Schulen

Background!#!The Internet and digital media entail both risks and opportunities for children and young people. One risk is posed by cases in which personal erotic photos of schoolchildren are forwarded against their will. For the children and adolescents concerned, the psychosocial consequences can be serious.!##!Objective!#!The aim of this study is to investigate the prevalence and consequences of non-consensual forwarding of personal erotic photos among children and adolescents at schools in the German state of Schleswig-Holstein.!##!Methods!#!From 25 April to 7 June 2019, principals of secondary schools were surveyed via an online brief questionnaire about both the incidence of non-consensual forwarding of erotic photos at their respective schools, as well as actions taken, consequences for the students depicted, and consequences for those who sent the photos. Information from 74 school administrators was included in the data analysis.!##!Results!#!In more than two-thirds of the schools, school principals were aware of at least one case of non-consensual forwarding of personal erotic photos. Measures taken were mostly informing the parents of all involved and a 'guided exchange' between the involved students. The consequences for the affected students were reported to be social withdrawal, psychological suffering, school performance problems, and experiences with cyberbullying. In eight cases, affected students left the school.!##!Discussion!#!Non-consensual forwarding of personal erotic photos in schools is a problem of considerable magnitude. Up-to-date specific prevention measures are urgently needed

Dynamic evolution of the sofosbuvir-associated variant A1343V in HEV-infected patients under concomitant sofosbuvir-ribavirin treatment

Background & Aims: In the absence of a hepatitis E virus (HEV)-specific antiviral treatment, sofosbuvir has recently been shown to have antiviral activity against HEV in vivo. However, a variant, A1343V, that is strongly associated with viral relapse impedes treatment success. In this study, we investigated the occurrence of variants during sofosbuvir and ribavirin treatment in vivo and assessed the sensitivity of resistance-associated variants to concurrent treatment in cell culture. Methods: Two patients with chronic HEV infection that did not clear infection under ribavirin treatment were subsequently treated with a combination of sofosbuvir and ribavirin. We determined response to treatment by measuring liver enzymes and viral load in blood and stool. Moreover, we analyzed viral evolution using polymerase-targeted high-throughput sequencing and assessed replication fitness of resistance-associated variants using a HEV replicon system. Results: Combination treatment was successful in decreasing viral load towards the limit of quantification. However, during treatment sustained virological response was not achieved. Variants associated with sofosbuvir or ribavirin treatment emerged during treatment, including A1343V and G1634R. Moreover, A1343V, as a single or double mutation with G1634R, was associated with sofosbuvir resistance during concomitant treatment in vitro. Conclusions: These results highlight the importance of variant profiling during antiviral treatment of patients with chronic infection. Understanding how intra-host viral evolution impedes treatment success will help guide the design of next-generation antivirals. Impact and implications: The lack of hepatitis E virus (HEV)-specific antivirals to treat chronic infection remains a serious health burden. Although ribavirin, interferon and sofosbuvir have been reported as anti-HEV drugs, not all patients are eligible for treatment or clear infection, since resistant-associated variants can rapidly emerge. In this study, we analyzed the efficacy of sofosbuvir and ribavirin combination treatment in terms of HEV suppression, the emergence of resistance-associated variants and their ability to escape treatment inhibition in vitro. Our results provide novel insights into evolutionary dynamics of HEV during treatment and thus will help guide the design of next-generation antivirals

Cleavage of urokinase receptor regulates its interaction with integrins in thyroid cells

The urokinase-type plasminogen activator uPA-R can regulate integrin functions by associating with several types of beta-subunit. We have recently shown that normal thyroid TAD-2 cells express both a native and a cleaved form of uPA-R which lacks the binding domain for uPA. We found this cleaved form to be present in reduced amounts in papillary and follicular thyroid carcinoma cells and completely absent in cells derived from an anaplastic thyroid carcinoma (ARO). We now report that in normal thyroid cells the intact form of uPA-R strongly associates with beta-1 integrins, whereas its cleaved form does not. uPA-R expressed by ARO cells shows a stronger resistance to the cleavage mediated by uPA, plasmin and chymotrypsin than does uPA-R expressed by normal thyroid cells. This resistance to cleavage correlates with the higher level of glycosylation of uPA-R of ARO cells as compared to that of cleavable uPA-R of normal thyroid cells. These results suggest that uPA-R cleavage, which occurs in several cell types, represents a mechanism regulating the interactions of uPA-R with integrins and, possibly, the subsequent integrin-mediated cell adhesion. Moreover we hypothesize that glycosylation regulates uPA-R cleavage and, indirectly, its interaction with integrins