| 1 | Biochemistry 2004 Oct 43: 12539-48 |
|---|---|
| PMID | 15449943 |
| Title | Structures of the Escherichia coli PutA proline dehydrogenase domain in complex with competitive inhibitors. |
| Abstract | Proline dehydrogenase (PRODH) catalyzes the first step of proline catabolism, the flavin-dependent oxidation of proline to Delta(1)-pyrroline-5-carboxylate. Here we present a structure-based study of the PRODH active site of the multifunctional Escherichia coli proline utilization A (PutA) protein using X-ray crystallography, enzyme kinetic measurements, and site-directed mutagenesis. Structures of the PutA PRODH domain complexed with competitive inhibitors acetate (K(i) = 30 mM), L-lactate (K(i) = 1 mM), and L-tetrahydro-2-furoic acid (L-THFA, K(i) = 0.2 mM) have been determined to high-resolution limits of 2.1-2.0 A. The discovery of acetate as a competitive inhibitor suggests that the carboxyl is the minimum functional group recognized by the active site, and the structures show how the enzyme exploits hydrogen-bonding and nonpolar interactions to optimize affinity for the substrate. The PRODH/L-THFA complex is the first structure of PRODH with a five-membered ring proline analogue bound in the active site and thus provides new insights into substrate recognition and the catalytic mechanism. The ring of L-THFA is nearly parallel to the middle ring of the FAD isoalloxazine, with the inhibitor C5 atom 3.3 A from the FAD N5. This geometry suggests direct hydride transfer as a plausible mechanism. Mutation of conserved active site residue Leu432 to Pro caused a 5-fold decrease in k(cat) and a severe loss in thermostability. These changes are consistent with the location of Leu432 in the hydrophobic core near residues that directly contact FAD. Our results suggest that the molecular basis for increased plasma proline levels in schizophrenic subjects carrying the missense mutation L441P is due to decreased stability of human PRODH2. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Spinal Cord 2007 Jun 45: 437-43 |
| PMID | 17339888 |
| Title | Spinal cord and related injuries after attempted suicide: psychiatric diagnosis and long-term follow-up. |
| Abstract | Retrospective analysis of acute spinal cord injuries (ASCI). Determine incidence of ASCI due to suicide attempt from 1970 to 2000. Describe demographics, injuries, mental illness, functional outcomes and nature of subsequent deaths. State spinal cord injury services, New South Wales, Australia. Retrospective record review and follow-up interview. Of 2752 ASCI admissions, 56 were because of attempted suicide (55 falls, one gun-shot wound). Thirty-six males and 20 females. Median age 30 years (15-74). Most common levels of vertebral injury were C5 and L1. Twenty-three had complete spinal cord injury. Thirty-two had an Injury Severity Score of >15. Forty had more than one major injury. There was a significant rise in the incidence of ASCI following self-harm over time (Poisson regression, P=0.004). There was a significant change in scene of injury away from hospitals over time (chi (2) test, df=1, P=0.0001). Psychiatric diagnoses were personality disorder 27; schizophrenia 16; depression 14; chronic alcohol abuse 10; mood disorder 10; chronic substance abuse 10; other four. Follow-up was available in 47 cases (84%) at an average of 8 years. Four subsequent deaths were by suicide. Domiciliary arrangements were: home 28; hospital five; nursing home three; group home/hostel four. Community placement outcomes for survivors were good. Subsequent death by suicide was high. There was a significant rise in cases and a change in injury scene away from hospitals over time. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Int. Rev. Neurobiol. 2009 -1 89: 67-84 |
| PMID | 19900616 |
| Title | The role of DNA methylation in the central nervous system and neuropsychiatric disorders. |
| Abstract | DNA methylation is an epigenetic mechanism in which the methyl group is covalently coupled to the C5 position of the cytosine residue of CpG dinucleotides. DNA methylation generally leads to gene silencing and is catalyzed by a group of enzymes known as DNA methyltransferases (Dnmt). During development, the epigenome undergoes waves of demethylation and methylation changes. As a result, there are cell type/tissue-specific DNA methylation patterns. Since DNA methylation changes only happen during DNA replication to maintain methylation patterns on hemimethylated DNA or establish new methylation, Dnmt expression generally decreases greatly after cell division. However, significant levels of Dnmts were noticed specifically in postmitotic neurons, suggesting a functional importance of Dnmt in the nervous system. Accumulating evidence showed that DNA methylation correlates with certain neuropsychiatric disorders such as schizophrenia, Rett syndrome, and ICF syndrome. Studies of methyl-CpG-binding proteins, Dnmt inhibitors, and Dnmt knockout mice also explored the key role of DNA methylation in neural development, plasticity, learning, and memory. Though an enzyme exhibiting DNA demethylation capability in vertebrates still remains to be identified, DNA methylation status in the CNS appeared to be reversible at certain genomic loci. This supports a maintenance role of Dnmt to prevent active demethylation in postmitotic neurons. Taken together, DNA methylation provides an epigenetic mechanism of gene regulation in neural development, function, and disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Niger J Physiol Sci 2012 Jun 27: 19-21 |
| PMID | 23235303 |
| Title | Complement factors in newly diagnosed Nigerian schizoprenic patients and those on antipsychotic therapy. |
| Abstract | The role of Complement factors in the pathogenesis of psychiatric disorders is enormous, but the data on levels and functions of complement factors in patients with schizophrenia are scanty and conflicting. To address this issue, levels of Complement regulators (C1 inhibitor and C3 activator) and complement factors (C1q, C3c, C4 and C5) were determined in the serum of newly diagnosed drug free schizophrenic patients, schizophrenic patients on medication and healthy subjects using immune-plates. C1q was significantly reduced in newly diagnosed schizophrenic patients or schizophrenic patients on medication compared with the controls. C3c was significantly reduced in newly diagnosed schizophrenic patients compared with controls or schizophrenic patients on medication. The levels of C3 activators, C1 inhibitors and C4 were similar in the two groups of schizophrenic patients compared with the controls. It may be concluded from this study that C1q is deficient in schizophrenic patients; and that C3c may differentiate newly diagnosed schizophrenia from schizophrenic patients on medication. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Niger J Physiol Sci 2012 Jun 27: 19-21 |
| PMID | 23235303 |
| Title | Complement factors in newly diagnosed Nigerian schizoprenic patients and those on antipsychotic therapy. |
| Abstract | The role of Complement factors in the pathogenesis of psychiatric disorders is enormous, but the data on levels and functions of complement factors in patients with schizophrenia are scanty and conflicting. To address this issue, levels of Complement regulators (C1 inhibitor and C3 activator) and complement factors (C1q, C3c, C4 and C5) were determined in the serum of newly diagnosed drug free schizophrenic patients, schizophrenic patients on medication and healthy subjects using immune-plates. C1q was significantly reduced in newly diagnosed schizophrenic patients or schizophrenic patients on medication compared with the controls. C3c was significantly reduced in newly diagnosed schizophrenic patients compared with controls or schizophrenic patients on medication. The levels of C3 activators, C1 inhibitors and C4 were similar in the two groups of schizophrenic patients compared with the controls. It may be concluded from this study that C1q is deficient in schizophrenic patients; and that C3c may differentiate newly diagnosed schizophrenia from schizophrenic patients on medication. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Int J Psychophysiol 2013 Jul 89: 63-71 |
| PMID | 23707337 |
| Title | Interhemispheric EEG coherence is reduced in auditory cortical regions in schizophrenia patients with auditory hallucinations. |
| Abstract | Central auditory processing has been reported to be impaired in schizophrenia patients who experience auditory hallucinations, and interhemispheric transfer in auditory circuits may be compromised. In this study, we used EEG spectral coherence to examine interhemispheric connectivity between cortical areas known to be important in the processing of auditory information. Coherence was compared across three subject groups: schizophrenia patients with a recent history of auditory hallucinations (AH), schizophrenia patients who did not experience auditory hallucinations (nonAH), and healthy controls (HC). Subjects listened to pure tone and word stimuli while EEG was recorded continuously. Upper alpha and upper beta band coherence was calculated from six pairs of electrodes located over homologous auditory areas in the left and right cerebral hemispheres. Significant between-group differences were found on four electrode pairs (C3-C4, C5-C6, Ft7-Ft8 and Cp5-Cp6) in the upper alpha band. Relative to both the HC and nonAH groups, coherence was lower in the AH patients, consistent with the hypothesis that interhemispheric connectivity is reduced in these patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Psychiatry Res 2014 Dec 220: 669-78 |
| PMID | 25150922 |
| Title | Differential predictive validity of the Historical, Clinical and Risk Management Scales (HCR-20) for inpatient aggression. |
| Abstract | The Historical, Clinical and Risk Management Scales (HCR-20) may be a better predictor of inpatient aggression for selected demographic and clinical groups but homogeneity of study samples has prevented definitive conclusions. The aim of this study, therefore, was to test the predictive validity of the HCR-20 as a function of gender, diagnosis, age, and ethnicity while controlling for potential covariates. A pseudo-prospective cohort study (n=505) was conducted in a UK secure/forensic mental health setting using routinely collected data. The HCR-20 predicted aggression better for women than men, and for people with schizophrenia and/or personality disorder than for other diagnostic groups. In women, the presence of the risk management items (R5) was important while men?s aggression was best predicted solely by current clinical features from the C5 scale. R5 items were better than C5 items for predicting aggression in people with organic and developmental diagnoses. Our data provide additional information on which HCR-20 raters can formulate overall summary judgements about risk for inpatient aggression based on important demographic and clinical characteristics. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Proteomics Clin Appl 2015 Oct 9: 907-16 |
| PMID | 25821032 |
| Title | Effects of olanzapine on serum protein phosphorylation patterns in patients with schizophrenia. |
| Abstract | Previous studies have shown that blood serum phosphoproteins are altered in schizophrenia patients in comparison to controls. However, it is not known whether phosphoproteins are also changed in response to treatment with antipsychotics. Blood samples were taken from patients (n = 23) at baseline and after 6 weeks of olanzapine treatment. Immobilized metal ion affinity chromatography (IMAC) was used for enrichment of serum phosphoproteins and these were analyzed by label-free LC-MS in expression mode (LC-MS(E) ). We identified 11 proteins that were changed significantly in overall abundance and 45 proteins that showed changes in phosphorylation after the antipsychotic treatment. The altered phosphoproteins were mainly involved in the acute phase response, lipid and glucose homeostasis (LXR), retinoic acid signaling (RXR), and complement pathways. Some of the proteins showed a marked increase in phosphorylation, including apolipoprotein A-I (3.4-fold), alpha-1-anti-chymotrypsin (3.1-fold), and apolipoprotein B-100 (2.2-fold). In addition, several proteins showed either decreased phosphorylation (e.g. complement C4A, collagen alpha-1 chain, complement factor H) or a mixture of increased and decreased phoshphorylation (e.g. afamin, complement C5, complement factor B). Finally, 24 of the altered phosphoproteins showed opposite directional changes in a comparison of baseline schizophrenia patients before and after treatment with olanzapine. These included alpha-1B-glycoprotein, apolipoprotein A-IV, vitamin D-binding protein, and prothrombin. These data demonstrate the potential for future studies of serum phosphoproteins as a readout of physiological function and might have utility in studies aimed at identification of biomarkers for drug response prediction or monitoring. |
| SCZ Keywords | schizophrenia, schizophrenic |