OncomiR Addiction Is Generated by a miR-155 Feedback Loop in Theileria-Transformed Leukocytes.

OncomiR Addiction Is Generated by a miR-155 Feedback Loop in Theileria-Transformed Leukocytes.

PLoS Pathog. 2013 Apr; 9(4): e1003222
Marsolier J, Pineau S, Medjkane S, Perichon M, Yin Q, Flemington E, Weitzman MD, Weitzman JB

The intracellular parasite Theileria is the only eukaryote known to transform its mammalian host cells. We investigated the host mechanisms involved in parasite-induced transformation phenotypes. Tumour progression is a multistep process, yet ‘oncogene addiction’ implies that cancer cell growth and survival can be impaired by inactivating a single gene, offering a rationale for targeted molecular therapies. Furthermore, feedback loops often act as key regulatory hubs in tumorigenesis. We searched for microRNAs involved in addiction to regulatory loops in leukocytes infected with Theileria parasites. We show that Theileria transformation involves induction of the host bovine oncomiR miR-155, via the c-Jun transcription factor and AP-1 activity. We identified a novel miR-155 target, DET1, an evolutionarily-conserved factor involved in c-Jun ubiquitination. We show that miR-155 expression led to repression of DET1 protein, causing stabilization of c-Jun and driving the promoter activity of the BIC transcript containing miR-155. This positive feedback loop is critical to maintain the growth and survival of Theileria-infected leukocytes; transformation is reversed by inhibiting AP-1 activity or miR-155 expression. This is the first demonstration that Theileria parasites induce the expression of host non-coding RNAs and highlights the importance of a novel feedback loop in maintaining the proliferative phenotypes induced upon parasite infection. Hence, parasite infection drives epigenetic rewiring of the regulatory circuitry of host leukocytes, placing miR-155 at the crossroads between infection, regulatory circuits and transformation. HubMed – addiction


Blended E-health module on return to work embedded in collaborative occupational health care for common mental disorders: design of a cluster randomized controlled trial.

Neuropsychiatr Dis Treat. 2013; 9: 529-37
Volker D, Vlasveld MC, Anema JR, Beekman AT, Roijen LH, Brouwers EP, van Lomwel AG, van der Feltz-Cornelis CM

Common mental disorders (CMD) have a major impact on both society and individual workers, so return to work (RTW) is an important issue. In The Netherlands, the occupational physician plays a central role in the guidance of sick-listed workers with respect to RTW. Evidence-based guidelines are available, but seem not to be effective in improving RTW in people with CMD. An intervention supporting the occupational physician in guidance of sick-listed workers combined with specific guidance regarding RTW is needed. A blended E-health module embedded in collaborative occupational health care is now available, and comprises a decision aid supporting the occupational physician and an E-health module, Return@Work, to support sick-listed workers in the RTW process. The cost-effectiveness of this intervention will be evaluated in this study and compared with that of care as usual.This study is a two-armed cluster randomized controlled trial, with randomization done at the level of occupational physicians. Two hundred workers with CMD on sickness absence for 4-26 weeks will be included in the study. Workers whose occupational physician is allocated to the intervention group will receive the collaborative occupational health care intervention. Occupational physicians allocated to the care as usual group will give conventional sickness guidance. Follow-up assessments will be done at 3, 6, 9, and 12 months after baseline. The primary outcome is duration until RTW. The secondary outcome is severity of symptoms of CMD. An economic evaluation will be performed as part of this trial.It is hypothesized that collaborative occupational health care intervention will be more (cost)-effective than care as usual. This intervention is innovative in its combination of a decision aid by email sent to the occupational physician and an E-health module aimed at RTW for the sick-listed worker. HubMed – addiction


Cocaine-evoked synaptic plasticity of excitatory transmission in the ventral tegmental area.

Cold Spring Harb Perspect Med. 2013; 3(5):
Lüscher C

Cocaine leads to a strong euphoria, which is at the origin of its recreational use. Past the acute effects, the drug leaves traces in the brain that persist long after it has been cleared from the body. These traces eventually shape behavior such that drug use may become compulsive and addiction develops. Here we discuss cocaine-evoked synaptic plasticity of glutamatergic transmission onto dopamine (DA) neurons of the ventral tegmental area (VTA) as one of the earliest traces after a first injection of cocaine. We review the literature that has examined the induction requirements as well as the expression mechanism of this form of plasticity and ask the question about its functional significance. HubMed – addiction


Maternal Immune Activation during Gestation Interacts with Disc1 Point Mutation to Exacerbate Schizophrenia-Related Behaviors in Mice.

J Neurosci. 2013 May 1; 33(18): 7654-66
Lipina TV, Zai C, Hlousek D, Roder JC, Wong AH

Schizophrenia is thought to result from interactions between susceptible genotypes and environmental risk factors. DISC1 is an important gene for schizophrenia and mood disorders based on both human and animal studies. In the present study we sought to investigate interactions between two distinct point mutations in the mouse Disc1 gene (L100P and Q31L) and maternal immune activation (MIA) during pregnancy with polyinosinic:polycytidylic acid (polyI:C). PolyI:C given at 5 mg/kg impaired cognitive and social behavior in both wild-type (WT) and Disc1-Q31L(+/-) offspring, and reduced prepulse inhibition at 16 but not 8 weeks of age. Disc1-L100P(+/-) mutants were more sensitive to MIA than WT or Disc1-Q31L(+/-) mice. Interleukin-6 (IL-6) is a critical cytokine for mediating the behavioral and transcriptional effects of polyI:C. We found a more pronounced increase of IL-6 in response to polyI:C in fetal brain in Disc1-L100P(+/-) mice compared with WT or Disc1-Q31L(+/-) mice. Coadministration of an anti-IL-6 antibody with polyI:C reversed schizophrenia-related behavioral phenotypes in Disc1-L100P(+/-) mice. In summary, we found specific interactions between discrete genetic (Disc1-L100P(+/-)) and environmental factors (MIA) that exacerbate schizophrenia-related phenotypes. IL-6 may be important in the pathophysiology of this interaction. HubMed – addiction