Genome-wide HP1 binding in Drosophila: developmental plasticity and genomic targeting signals

Heterochromatin protein 1 (HP1) is a major component of heterochromatin. It was reported to bind to a large number of genes and to many, but not all, transposable elements (TEs). The genomic signals responsible for targeting of HP1 have remained elusive. Here, we use whole-genome and computational approaches to identify genomic features that are predictive of HP1 binding in Drosophila melanogaster. We show that genes in repeat-dense regions are more likely to be bound by HP1, particularly in pericentric chromosomal regions. We also demonstrate that TEs are only bound by HP1 if they are flanked by other repeats, suggesting a cooperative mechanism of binding. Genome-wide DamID mapping of HP1 in larvae and adult flies reveals that repeat-flanked genes typically bind HP1 throughout development, whereas repeat-free genes display developmentally dynamic HP1 association. Furthermore, computational analysis shows that HP1 preferentially binds to transcribed regions of long genes. Finally, we detect low but significant amounts of HP1 along the entire X chromosome in male, but not female, flies, suggesting a link between HP1 and the dosage compensation complex. These results provide insights into the mechanisms of HP1 targeting in the natural genomic context.     

Which clinical factors predict response to prophylactic lithium? A systematic review for bipolar disorders

OBJECTIVES: The aim of this study was to systematically integrate the available evidence on response prediction to prophylactic lithium based on clinical factors. METHODS: Each clinical variable that was related to lithium response in at least one prior study was examined with respect to response prediction. If several studies were located for the same variable, results were integrated using the meta-analytic approach as suggested by DerSimonian and Laird which was developed for substantial heterogeneity in primary studies. RESULTS: Of 42 potential clinical predictors investigated, five variables were identified as possible response predictors of prophylactic lithium: [1] An episodic pattern of mania-depression-interval, and [2] a high age of illness onset were identified as potentially protective against a recurrence under lithium. [3] A high number of previous hospitalizations, [4] an episodic pattern of depression-mania-interval, and [5] continuous cycling were identified as potential risk factors. Six further variables were found to be significantly related to lithium response, though calculation of fail-safe numbers indicates that current evidence is not sufficient to hold these variables as reliable predictors of lithium response. All effect-sizes relating clinical predictors to response were small to moderate. CONCLUSIONS: Although a few variables are quite robustly supported as response-predictors in this review, a more in-depth analysis of each potential predictor is needed. As none of the potential predictors had a very strong impact on response, prediction of lithium response should be based on a multitude of variables.     

Are illness concepts a powerful predictor of adherence to prophylactic treatment in bipolar disorder?

BACKGROUND: Predicting and preventing premature discontinuation of medication would substantially improve prophylactic treatment of bipolar disorder. Patients' concepts regarding illness proved to have an impact on noncompliance in a retrospective study of patients with affective or schizoaffective illness treated with lithium. The present study is the first to prospectively investigate the influence of illness concepts on adherence of bipolar patients to different medications. METHOD: 171 bipolar patients (DSM-IV) were randomly assigned to receive either lithium (N = 86) or carbamazepine (N = 85) and observed for a maintenance period of 2.5 years (Multi-center Study of Affective and Schizoaffective Psychoses). The total score and 7 dimensions of illness concepts and treatment expectations of the Illness Concept Scale (ICS) were calculated for 141 patients with completed questionnaires and used to predict time to dropout (Cox regression). Analyses were corroborated by further multivariate analyses with sex, age, and premorbid personality as covariates. RESULTS: With lithium treatment, but not carbamazepine treatment, the total ICS score at study entry was associated with a longer time to study dropout (p =.001 and p =.224, respectively). The relevant ICS subscales affecting time to dropout in patients treated with lithium were trust in medication, trust in the treating physician, and absence of negative treatment expectations. Multivariate analyses suggested that the impact of these variables on adherence to lithium was largely independent of sociodemographic, clinical, and psychological variables. Our data indicate that the stronger impact of illness concepts with lithium as compared with carbamazepine treatment might be related to the drugs' different side effect profiles. CONCLUSION: As trust in drug treatment and trust in the treating physician had a clear impact on adherence to prophylactic lithium, patients' illness concepts and treatment expectations might be promising targets for psychoeducation and psychotherapy in the treatment of bipolar disorder.     

Disinhibition of libido: an adverse effect of SSRI?

BACKGROUND: The article focuses on adverse drug reactions (ADR) to selective serotonin reuptake inhibitors (SSRI) concerning libido and sexual behaviour: cases of disinhibition of libido observed at the Psychiatric Hospital of Kilchberg near Zurich are described. METHOD: Within the scope of a drug safety program, the physicians of the hospital are regularly asked about severe and unexpected events under drug treatment. RESULTS: During remission of depression, five outpatients noticed an increase of libido experienced as strange to them, i.e. preoccupation with sexual thoughts, first appearance of promiscuity, of unsafe sexual intercourse, and of excessive pursuit of pornography, respectively, during administration, change in dose or discontinuation of SSRI. DISCUSSION: The case studies suggest that SSRI treatment might be associated with increase and disinhibition of libido. The phenomena are discussed as a "selective switch" into partly manic symptomatology or an induction of mixed states with prevailing sexual symptoms.     

MLL-ENL causes a reversible and myc-dependent block of myelomonocytic cell differentiation

The translocation t(11;19) is a recurrent feature of a subgroup of acute leukemias occurring in infants. This event fuses the genes MLL and ENL and creates the leukemogenic oncoprotein MLL-ENL. We studied the effect of retroviral MLL-ENL expression in primary mouse hematopoietic cells and show here that MLL-ENL requires the oncoprotein Myc to establish a reversible differentiation arrest of a myelomonocytic precursor population. MLL-ENL-transduced cells proliferated as immature myeloid cells in the presence of interleukin 3. The addition of granulocyte colony-stimulating factor reversed the maturation block set by MLL-ENL and induced the development of mature granulocytes and macrophages accompanied by growth arrest. Gene expression analysis indicated a down-regulation of the proto-oncogene c-myc and of several c-myc target genes during granulocyte colony-stimulating factor-mediated differentiation. The role of c-myc in the MLL-ENL transformation pathway was tested by modulating the effective Myc protein concentrations in MLL-ENL transduced cells. Cotransduction of dominant-negative Myc neutralized the MLL-ENL effect and precluded transformation. In contrast, constitutive expression of Myc cooperated with MLL-ENL and caused the transformation of a cell population with an irreversible maturation arrest.