Discovery of microvascular miRNAs using public gene expression data: miR-145 is expressed in pericytes and is a regulator of Fli1

International audienceBACKGROUND: A function for the microRNA (miRNA) pathway in vascular development and angiogenesis has been firmly established. miRNAs with selective expression in the vasculature are attractive as possible targets in miRNA-based therapies. However, little is known about the expression of miRNAs in microvessels in vivo. Here, we identified candidate microvascular-selective miRNAs by screening public miRNA expression datasets. METHODS: Bioinformatics predictions of microvascular-selective expression were validated with real-time quantitative reverse transcription PCR on purified microvascular fragments from mouse. Pericyte expression was shown with in situ hybridization on tissue sections. Target sites were identified with 3' UTR luciferase assays, and migration was tested in a microfluid chemotaxis chamber. RESULTS: miR-145, miR-126, miR-24, and miR-23a were selectively expressed in microvascular fragments isolated from a range of tissues. In situ hybridization and analysis of Pdgfb retention motif mutant mice demonstrated predominant expression of miR-145 in pericytes. We identified the Ets transcription factor Friend leukemia virus integration 1 (Fli1) as a miR-145 target, and showed that elevated levels of miR-145 reduced migration of microvascular cells in response to growth factor gradients in vitro. CONCLUSIONS: miR-126, miR-24 and miR-23a are selectively expressed in microvascular endothelial cells in vivo, whereas miR-145 is expressed in pericytes. miR-145 targets the hematopoietic transcription factor Fli1 and blocks migration in response to growth factor gradients. Our findings have implications for vascular disease and provide necessary information for future drug design against miRNAs with selective expression in the microvasculature

Defined Single-Gene and Multi-Gene Deletion Mutant Collections in Salmonella enterica sv Typhimurium

Artículo de publicación ISIWe constructed two collections of targeted single gene deletion (SGD) mutants and two collections of targeted multi-gene deletion (MGD) mutants in Salmonella enterica sv Typhimurium 14028s. The SGD mutant collections contain (1), 3517 mutants in which a single gene is replaced by a cassette containing a kanamycin resistance (KanR) gene oriented in the sense direction (SGD-K), and (2), 3376 mutants with a chloramphenicol resistance gene (CamR) oriented in the antisense direction (SGD-C). A combined total of 3773 individual genes were deleted across these SGD collections. The MGD collections contain mutants bearing deletions of contiguous regions of three or more genes and include (3), 198 mutants spanning 2543 genes replaced by a KanR cassette (MGD-K), and (4), 251 mutants spanning 2799 genes replaced by a CamR cassette (MGD-C). Overall, 3476 genes were deleted in at least one MGD collection. The collections with different antibiotic markers permit construction of all viable combinations of mutants in the same background. Together, the libraries allow hierarchical screening of MGDs for different phenotypic followed by screening of SGDs within the target MGD regions. The mutants of these collections are stored at BEI Resources (www.beiresources.org) and publicly available

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Adolescents Selling Sex and Sex as Self-Injury

There are today only a few population-based studies in the world investigating the prevalence of and associated risk-factors with adolescents selling sex and so far no earlier population-based study has been found investigating adolescents motives for selling sex. Further, to use sex in means of self-injury (SASI) is a behaviour that has been highlighted in Sweden the last years but it is a new field of research and a behaviour in need of conceptualization. The aim of this thesis was to investigate the prevalence of, associated risk factors with, motives for and manifestations of adolescents selling sex and the use of sex as self-injury (SASI). For the thesis, two nationally representative cross-sectional population surveys with third year students at Swedish high schools were collected in 2009 (n = 3498, mean age 18.3 +/- 0.6 years, response rate 60.4%) and in 2014 (n = 5839, mean age 18.0 +/- 0.6 years, response rate 59.7%). Further, the motives and manifestations of SASI were investigated in an anonymous self-selected, open-ended questionnaire published on websites of non-governmental organizations offering help and support to women and adolescents (n = 199, mean age 27.9 +/- 9.3 years). Quantitative and qualitative methods were used for data analyses. In the 2009 population-based survey, 1.5% (n = 51) of the adolescents reported having sold sex on at least one occasion, but in 2014 the prevalence was slightly lower at 0.9% (n = 51). SASI was reported by 3.2% of girls (n = 100) and 0.8% of boys (n = 20). Both selling sex and SASI were associated with various adverse factors such as experience of sexual abuse, emotional and physical abuse, poor mental health and self-injury. Adolescents selling sex had sought help and support for different problems and worries to a greater extent compared to peers. Contact with healthcare for various psychiatric problems such as suicide attempts, depression and eating disorders was common for adolescents using SASI. Further analysis showed that adolescents selling sex are a heterogeneous group in regard to underlying motives for selling sex, which included emotional and material reasons as well as pleasure. Depending on their underlying motives, adolescents selling sex were found to differ in regard to compensation received, age of the buyer, means of contact with the buyer, sexual orientation, experience of sexual abuse and the use of SASI. By using data from an open-ended questionnaire, SASI was described as deliberate or self-inflicted sexual situations that could include psychological and physical harm. SASI was used as a way to regulate negative feelings, such as anxiety, or to get positive or negative confirmation and the behaviour could be hard to stop. In conclusion, selling sex and SASI occurs among Swedish adolescents and the behaviours are associated with sexual, physical and emotional abuse and poor mental health, including trauma symptoms. In regard of the motives and manifestations of SASI, the behaviour could be compared to direct self-injurious behaviours. Data from this thesis suggest that more attention should be paid in healthcare to recognizing adolescents selling sex and SASI in order to prevent further traumatization and victimization

Perceived Help and Support for Sex as Self-Injury : A Qualitative Study of a Swedish Sample

Earlier research has found that sexual acts could be used as a means of self-injury, with comparable functions to nonsuicidal self-injury (NSSI) such as cutting or burning the skin. However, no previous study has investigated the experience of help and support in relation to sex as a means of self-injury (SASI), which this study aims to investigate. The study was based on an anonymous open-ended questionnaire published from December 2016 to April 2017 on the websites of NGOs working with help and support for women and youths in Sweden. In total, 197 participants (mostly women, mean age 27.9 years, range 15-64 years) with self-reported experiences of SASI were included in the study. Three main themes were found concerning experiences of help and support for SASI. The need for: (1) Framing the behavior of SASI, to find a word for SASI-to know it exists, to get questions and information about SASI and its function; (2) Flexible, respectful, and professional help and support from an early age, to be listened to and confirmed in ones experience of SASI; and (3) Help with underlying reasons to exit SASI such as finding ones own value and boundaries through conventional therapy, through life itself, or through therapy for underlying issues such as earlier traumatic events, PTSD, dissociation, or anxiety. In conclusion, similar interventions could be helpful for SASI as for NSSI, irrespective of the topographical differences between the behaviors, but the risk of victimization and traumatization must also be addressed in SASI.Funding Agencies|Linkoping University - Ostergotland Council (Region Ostergotland)</p

Motives and Manifestations of Sex as Self-Injury

To view destructive sexual behaviors as a form of self-injury is a new concept in the research field that needs further exploration and conceptualization. The aim of this study was to explore experiences of sex as self-injury to identify motives and manifestations of the behavior. An anonymous self-selected open-ended questionnaire was used for the study, and qualitative content analysis was used to identify patterns and themes in the text. A total of 199 informants participated in the study (M = 27.9, SD = 9.3 years), all of whom were recruited via a range of websites of Swedish nongovernmental organizations. Sex as self-injury was described as voluntary exposure to sexual situations including psychological and/or physical harm. Affect regulation and receiving positive or negative confirmation emerged as important motives for the behavior. Respondents described sex as self-injury as difficult to stop when it felt compulsive and addictive, with ever-higher risk-taking and self-harming described. Our findings indicate that sex as self-injury often includes deliberate sexual violence, and is similar to other self-injurious behaviors, including non-suicidal self-injury. Sex as self-injury needs to be addressed in healthcare, such as in psychiatry and gynecology departments, to prevent further traumatization

The Connection Between Sex as Self-Injury and Sexual Violence

Nonsuicidal self-injury (NSSI) is a suggested diagnosis recognized by DSM-5 as in need of further research. Recent studies conclude that sex as self-injury (SASI) and NSSI share similar functions, such as being used as emotional regulation. SASI has been associated with earlier sexual abuse, but the understanding of the association between sexual violence and SASI is still limited. The aim of this study was to further investigate the connection between sexual violence and the experience of SASI. How could SASI be related to sexual violence? The study used a qualitative design and was based on an anonymous questionnaire published on the websites of Swedish NGOs, providing help and support to women and youths, such as those in womens shelters. In total, 139 informants with a mean age of 27.9 years (range 15-64 years) were included in the study. Three main themes were found: (1) Normalization of sexual violence and a shift in boundaries could be seen as consequences of earlier experiences of sexual violence leading to SASI; (2) SASI could escalate into sexual violence through increased need of emotional regulation, increased risk-taking, and risk of victimization; (3) SASI could be used to regain control of re-experiences, the body, sexuality, and shame after sexual abuse. In conclusion, a complex connection was identified whereby SASI could escalate into sexual violence, and earlier experiences of sexual violence could lead to SASI in a vicious loop. Hence, SASI should be seen as a risk factor for further victimization and sexual abuse.Funding Agencies|We would like to acknowledge Malin Jenstav and Malin Meissner at Stockholms Tjejjour for their cooperation and support in the data collection. We would like to acknowledge all the NGOs that supported the data collection, and the participants w</p

School performance and the risk of suicidal thoughts in young adults: population-based study.

Although low school performance is related to attempted and completed suicide, its relationship with suicidal thoughts has been less clear. We conducted a population-based study including 10081 individuals aged 18-29 years in Stockholm, Sweden, and found a clear positive gradient in the risk of lifetime suicidal thoughts with decreasing levels of compulsory school leaving grades. This relationship was somewhat attenuated but remained significant in multivariate models accounting for family background, severe adult psychopathology and adult socioeconomic conditions. School failure is associated with an increased risk of experiencing suicidal thoughts and may also increase the tendency of acting upon them