Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis

Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment

Perpetrators, victims, bystanders and up standers: cyber bullying in a special school context.

This study offers a multi-dimensional analysis of ‘real world’ cyberbullying between members of a special school community. The purpose of this article is to analyse the social and educational contexts within which interactions of this nature are embedded.The interview both illuminated a number of themes pertinent to the current literature and extended those related to the call for further analysis of the contextual determinants of cyberbullying.The influence of the conditions experienced by the children involved (Attention Deficit Hyperactivity Disorder (ADHD) and Autistic Spectrum Condition (ASC)) is discussed and demonstrated. This use of natural observation provides a current and ‘real world’ illustration of teacher perceptions of the complex behaviours and interactions occurring in cyberspace, which hold potential for grave consequences. A hopeful tone is maintained as the potential for selfless upstander behaviour and resolution via the involvement of supportive and knowledgeable pastoral staff is realised in the article’s conclusion.<br/

Adolescents' involvement in cyber bullying and perceptions of school: the importance of perceived peer acceptance for female adolescents

Young people are spending increasing amounts of time using digital technology and, as such, are at great risk of being involved in cyber bullying as a victim, bully, or bully/victim. Despite cyber bullying typically occurring outside the school environment, the impact of being involved in cyber bullying is likely to spill over to school. Fully 285 11- to 15-year-olds (125 male and 160 female, M age = 12.19 years, SD = 1.03) completed measures of cyber bullying involvement, self-esteem, trust, perceived peer acceptance, and perceptions of the value of learning and the importance of school. For young women, involvement in cyber bullying as a victim, bully, or bully/victim negatively predicted perceptions of learning and school, and perceived peer acceptance mediated this relationship. The results indicated that involvement in cyber bullying negatively predicted perceived peer acceptance which, in turn, positively predicted perceptions of learning and school. For young men, fulfilling the bully/victim role negatively predicted perceptions of learning and school. Consequently, for young women in particular, involvement in cyber bullying spills over to impact perceptions of learning. The findings of the current study highlight how stressors external to the school environment can adversely impact young women's perceptions of school and also have implications for the development of interventions designed to ameliorate the effects of cyber bullying

Infection of human fibroblasts and osteoblast-like cells with HIV-1.

Primary human skin- and lung-derived fibroblast cell cultures and continuous human osteoblast-like and fibroblast-like cell lines were infected with different strains of HIV-1. Infection was measured at the single-cell level using the immunoperoxidase staining method to detect viral proteins. No cytopathic effects were observed in HIV-1-infected cell cultures. One continuous cell line (LC5), derived from embryonic lung, was readily infectable with HIV-1 and showed continuous production of infectious virus. Infection of LC5 cells could be blocked with anti-CD4 monoclonal antibodies. These findings indicate that fibroblasts of skin and lung, and osteogenic cells may be considered as potential target cells for HIV-1, thereby possibly contributing to the establishment of local HIV reservoirs

Hinweise fuer ein einheitliches, automationsgeeignetes Verfahren bei Ausschreibung, Vergabe und Abrechnung von Bauleistungen Teil 3: Eingabe zur Erstellung des Leistungsverzeichnisses

TIB: RN 5973 (1798) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman