Oligoasthenoteratozoospermia and Infertility in Mice Deficient for miR-34b/c and miR-449 Loci

Male fertility requires the continuous production of high quality motile spermatozoa in abundance. Alterations in all three metrics cause oligoasthenoteratozoospermia, the leading cause of human sub/infertility. Post-mitotic spermatogenesis inclusive of several meiotic stages and spermiogenesis (terminal spermatozoa differentiation) are transcriptionally inert, indicating the potential importance for the post-transcriptional microRNA (miRNA) gene-silencing pathway therein. We found the expression of miRNA generating enzyme Dicer within spermatogenesis peaks in meiosis with critical functions in spermatogenesis. In an expression screen we identified two miRNA loci of the miR-34 family (miR-34b/c and miR-449) that are specifically and highly expressed in post-mitotic male germ cells. A reduction in several miRNAs inclusive of miR-34b/c in spermatozoa has been causally associated with reduced fertility in humans. We found that deletion of both miR34b/c and miR-449 loci resulted in oligoasthenoteratozoospermia in mice. MiR-34bc/449-deficiency impairs both meiosis and the final stages of spermatozoa maturation. Analysis of miR-34bc-/-;449-/- pachytene spermatocytes revealed a small cohort of genes deregulated that were highly enriched for miR-34 family target genes. Our results identify the miR-34 family as the first functionally important miRNAs for spermatogenesis whose deregulation is causal to oligoasthenoteratozoospermia and infertility

Endogenous mouse Dicer is an exclusively cytoplasmic protein

Dicer is a large multi-domain protein responsible for the ultimate step of microRNA and short-interfering RNA biogenesis. In human and mouse cell lines, Dicer has been shown to be important in the nuclear clearance of dsRNA as well as the establishment of chromatin modifications. Here we set out to unambiguously define the cellular localization of Dicer in mice to understand if this is a conserved feature of mammalian Dicer in vivo. To this end, we utilized an endogenously epitope tagged Dicer knock-in mouse allele. From primary mouse cell lines and adult tissues, we determined with certainty by biochemical fractionation and confocal immunofluorescence microscopy that endogenous Dicer is exclusively cytoplasmic. We ruled out the possibility that a fraction of Dicer shuttles to and from the nucleus as well as that FGF or DNA damage signaling induce Dicer nuclear translocation. We also explored Dicer localization during the dynamic and developmental context of embryogenesis, where Dicer is ubiquitously expressed and strictly cytoplasmic in all three germ layers as well as extraembryonic tissues. Our data exclude a direct role for Dicer in the nuclear RNA processing in the mouse

[Basic symptoms and neurocognition: preliminary comparison of first-episode psychosis vs multi-episode long-term illness].

Schizophrenia is preceded by basic symptoms which may persist after long time and include subjective cognitive impairment. Furthermore, it is characterised by cognitive deficits that may deteriorate with the progression of illness. To examine the relationship between neurocognition and basic symptoms along the course of schizophrenia, we compared the cognitive performance and the basic symptoms of one population with first episode psychosis (FEP) and one with a chronic, multi-episode course (MEP).We tested 8 FEP (5 male) and 7 MEP (7 male) in- and outpatients, for basic symptoms with the Schizophrenia Proneness Instrument-Adult version (SPI-A) and for neurocognition with Raven's Color Progressive Matrices (CPM), Rey-Osterrieth's complex figure (Rey), Corsi's and Buschke-Fuld tests, the Wisconsin Card Sorting Test (WCST), the Stroop test, and the Trail Making Test (TMT).FEP patients did not differ from MEP patients as for SPI-A scores. MEP patients were significantly more impaired on several subtests of Buschke-Fuld, the Rey, and the WCST with respect to FEP. Impairment on the cognitive subscale of the SPI-A correlated with non-perseverative WCST errors, and on the self subscale of the SPI-A with impaired performance on the Buschke-Fuld. Further, in MEP, impairment on the body subscale of the SPI-A correlated inversely with number of categories completed of the WCST.Basic symptoms persist throughout the phases of schizophrenia and are relatively independent of cognitive performance. A chronic, multi-episode course is associated with increased cognitive impairment in schizophrenia

Suicide attempts in major affective disorders

Object: The aim of this study was to investigate variables associated with suicide attempts among patients suffering from major affective disorders. Methods: We retrospectively evaluated 106 patients diagnosed with major affective disorders. 53 patients with at least one suicide attempt were matched on a group basis for age, sex and diagnosis with 53 patients who had never attempted suicide. Results: In the bivariate comparisons, suicidal patients were more likely to have been treated with antipsychotic and anxiolytic drugs (OR: 4.50; 95%CI: 1.55/13.06), and less likely to be married (OR: .16; 95%CI: .07/36), have comorbid physical illnesses (OR: .29; 95%CI: .12/.67) and have been treated with antidepressants (OR: .14; 95%CI: .04/.47). Conclusions: Our results support previously reported findings in the literature that marital status, and treatment regimen may influence suicide risk. Limitations: The study findings may not generalize to other samples, settings, and treatment programs. © 2007 Giovanni Fioriti Editore s.r.l

Response to antidepressant treatment by suicidal major affective disorder patients

To test the prognostic value of suicidal status in depressed patients for responses to antidepressant treatment

Temperament in suicidal and non-suicidal psychiatric inpatients

Suicide is a serious public health problem. In the international literature there is evidence to support the notion that certain temperaments and personality traits are often associated with suicidal behavior. In this study, 150 psychiatric inpatients were investigated using the TEMPS-A, the MMPI-2 and the Beck Hopelessness Scale (BHS) and evaluated for suicide risk through the critical items of the Mini International Neuropsychiatric Interview (MINI). Statistical analysis, including linear regression analysis and multiple regression analysis, showed that suicide risk contributed to the prediction of hopelessness. Among the temperaments, only the Hyperthymic temperament, as a protective factor, and the Dys/Cyc/Anx temperament contributed significantly to the prediction of hopelessness. Irritable temperament and Social Introversion were protective factors for suicidal risk. Hopelessness and depression were associated with higher suicidal behavior and ideation, but, unexpectedly, depression as measured by the MMPI did not contribute significant to the multiple regression. The present study indicated that, although suicidal psychiatric patients have MMPI-2’s profiles in the pathologic range, they exhibit several differences from nonsuicidal patients. Patients at risk of suicide have specific temperaments as well as personality and defense mechanism profiles. They are more social introverted, depressed and psychasthenic, and use hysterical and schizoid mechanisms more often. Generalizability of the findings was limited by the small sample size, mix of BPD-I, BPD-II, MDD and psychotic disorder patients

mRNA 3' uridylation and poly(A) tail length sculpt the mammalian maternal transcriptome.

A fundamental principle in biology is that the program for early development is established during oogenesis in the form of the maternal transcriptome. How the maternal transcriptome acquires the appropriate content and dosage of transcripts is not fully understood. Here we show that 3' terminal uridylation of mRNA mediated by TUT4 and TUT7 sculpts the mouse maternal transcriptome by eliminating transcripts during oocyte growth. Uridylation mediated by TUT4 and TUT7 is essential for both oocyte maturation and fertility. In comparison to somatic cells, the oocyte transcriptome has a shorter poly(A) tail and a higher relative proportion of terminal oligo-uridylation. Deletion of TUT4 and TUT7 leads to the accumulation of a cohort of transcripts with a high frequency of very short poly(A) tails, and a loss of 3' oligo-uridylation. By contrast, deficiency of TUT4 and TUT7 does not alter gene expression in a variety of somatic cells. In summary, we show that poly(A) tail length and 3' terminal uridylation have essential and specific functions in shaping a functional maternal transcriptome