Structural basis for recognition of cognate tRNA by tyrosyl-tRNA synthetase from three kingdoms

The specific aminoacylation of tRNA by tyrosyl-tRNA synthetases (TyrRSs) relies on the identity determinants in the cognate tRNATyrs. We have determined the crystal structure of Saccharomyces cerevisiae TyrRS (SceTyrRS) complexed with a Tyr-AMP analog and the native tRNATyr(GΨA). Structural information for TyrRS–tRNATyr complexes is now full-line for three kingdoms. Because the archaeal/eukaryotic TyrRSs–tRNATyrs pairs do not cross-react with their bacterial counterparts, the recognition modes of the identity determinants by the archaeal/eukaryotic TyrRSs were expected to be similar to each other but different from that by the bacterial TyrRSs. Interestingly, however, the tRNATyr recognition modes of SceTyrRS have both similarities and differences compared with those in the archaeal TyrRS: the recognition of the C1-G72 base pair by SceTyrRS is similar to that by the archaeal TyrRS, whereas the recognition of the A73 by SceTyrRS is different from that by the archaeal TyrRS but similar to that by the bacterial TyrRS. Thus, the lack of cross-reactivity between archaeal/eukaryotic and bacterial TyrRS-tRNATyr pairs most probably lies in the different sequence of the last base pair of the acceptor stem (C1-G72 vs G1-C72) of tRNATyr. On the other hand, the recognition mode of Tyr-AMP is conserved among the TyrRSs from the three kingdoms

PET quantification of the norepinephrine transporter in human brain with (S,S)-18F-FMeNER-D2.

Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, (S,S)-(11)C-MRB and (S,S)-(18)F-FMeNER-D2, have been used for imaging NETs in the thalamus and midbrain (including locus coeruleus) using positron emission topography (PET) in humans. However, NET density in the equally important cerebral cortex has not been well quantified because of unfavorable kinetics with (S,S)-(11)C-MRB and defluorination with (S,S)-(18)F-FMeNER-D2, which can complicate NET quantification in the cerebral cortex adjacent to the skull containing defluorinated (18)F radioactivity. In this study, we have established analysis methods of quantification of NET density in the brain including cerebral cortex using (S,S)-(18)F-FMeNER-D2 PET

Affinity states of striatal dopamine D2 receptors in antipsychotic-free patients with schizophrenia

Background: Dopamine D2 receptors (D2Rs) are reported to have high-affinity (D2High) and low-affinity (D2Low) states. Although an increased proportion of D2High has been demonstrated in animal models of schizophrenia, few clinical studies have investigated this alteration of D2High in schizophrenia in vivo.Methods: Eleven patients with schizophrenia, including ten antipsychotic-naive and one antipsychotic-free individuals, and seventeen healthy controls were investigated. Psychopathology was assessed by Positive and Negative Syndrome Scale (PANSS), and a 5-factor model was used. Two radioligands, [11C]raclopride and [11C]MNPA, were employed to quantify total D2R and D2High, respectively, in the striatum by measuring their binding potential (BPND). BPND values of [11C]raclopride and [11C]MNPA, and in the BPND ratio of [11C]MNPA to [11C]raclopride in the striatal subregions were statistically compared between the two diagnostic groups using multivariate analysis of covariance (MANCOVA) controlling for age, gender, and smoking. Correlations between BPND and PANSS scores were also examined.Results: MANCOVA demonstrated a significant effect of diagnosis (schizophrenia and control) on the BPND ratio (p=0.018), although the effects of diagnosis on both BPND of [11C]raclopride and of [11C]MNPA were not significant. Post-hoc test showed that the BPND ratio was significantly higher in the putamen of patients (p=0.017). PANSS “depressed” factor in patients was positively correlated with BPND of both ligands in the caudate.Conclusions: The present study indicates the possibilities of: 1) a higher proportion of D2High in the putamen despite unaltered amounts of total D2Rs; and 2) associations between depressive symptoms and amounts of caudate D2Rs in patients with schizophrenia

Norepinephrine Transporter in Major Depressive Disorder: A PET Study.

The norepinephrine transporter has been suggested to play a crucial role in major depressive disorder. However, norepinephrine transporter availability in major depressive disorder and its role with clinical symptoms are not known. The authors tested norepinephrine transporter availability in patients with major depressive disorder with the aim to identify any associations between test results and clinical symptoms