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Schizophrenia is a complex illness with unknown aetiology and pathogenesis. Currently, a considerable number of patients with schizophrenia do not receive standardised and systematic treatment in China. In the past years, many controlled trials have been conducted in chronic schizophrenia. In contrast, research on first-episode schizophrenia is lacking. This paper describes the background and design of the Chinese First-Episode Schizophrenia Trial project — a multicentre, randomised, open-label clinical trial. A total of 600 first-episode schizophrenia patients were randomly divided into 3 groups and treated with risperidone, aripiprazole, and olanzapine for 1 year. During the study period, only 1 medication change of the 3 antipsychotic medications was allowed. [ABSTRACT FROM AUTHOR]

Objective: To summarize the clinical features, treatment and prognosis of asparaginase (ASP) related cerebral venous sinus thrombosis (CVST). Methods: Clinical profiles including age, sex, first symptoms, coagulation function, imaging findings, ASP type, treatment and prognosis of eight acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) children with ASP related CVST at the Department of Pediatrics, First Affiliated Hospital of Zhengzhou University from November 2016 to October 2021 were analyzed retrospectively. Results: Eight CVST children were all male, including 6 ALL and 2 LBL, with the onset age ranged from 5 to 15 years, 6 cases occurred in the stage of first induction remission, and the initial symptom were mainly epileptic seizures (7 cases). Magnetic resonance imaging combined magnetic resonance venography (MRV) showed the most common site of venous sinus enlargement was superior sagittal sinus (8 cases). Secondary cerebral hemorrhage was found in 5 cases. D-dimer elevated on the day of onset in all cases. Three patients were treated with intravascular mechanical thrombectomy and thrombolysis combined with anticoagulant therapy, 3 patients were treated with continuous anticoagulant therapy only, 2 patients were not treated with anticoagulant therapy. MRV follow-up for 3 months showed that the thrombi in patients were almost completely absorbed except in 2 patients who were not treated with anticoagulant therapy. Thrombolysis combined with anticoagulant therapy was the fastest way for thrombosis absorption. Among 8 patients, 1 died of early recurrence of ALL, and 7 patients accepted further asparaginase and no CVST recurrence or progression was found. There were no sequelae of nervous system except 1 patient with left upper limb muscle strength impairment. Conclusions: ASP related CVST is more common in older male children and the prognosis is good. ASP related CVST occurred mostly in the stage of first induction remission, and most initial manifestation is epileptic seizure. The superior sagittal region is a common site of thrombus, magnetic resonance imaging combined with MRV is helpful for accurately diagnosis. Timely anticoagulant treatment can improve the prognosis, and mechanical thrombectomy and thrombolysis can quickly recanalize the vessel.

Eucaryotic ribonucleotide reductases (RR) catalyze the reduction of ribonucleoside diphosphates to 2'-deoxyribonucleoside diphosphates. Each has an R1(2)R2(2) quaternary structure with each subunit playing a critical role in catalysis. Separation of the subunits results in loss of activity. Previous studies have demonstrated that peptides corresponding to the C-terminus of R2 disrupt subunit association by competion with R2 and have potential usefulness as therapeutics. Extensive structure-function studies have been carried out on peptide inhibition of herpes simplex RR in an effort to develop antiviral agents based on the observation that the herpes simplex R2 C-terminus, YAGAVVNDL, is quite different from the corresponding mammalian sequence. In this work we report a detailed structure-function analysis of peptide inhibition of mammalian and, to a more limited extent, Saccharomyces cerevisiae RRs. Our results for mammalian RR support the following conclusions with regard to the effect of substitution on inhibitory potency: (a) the N-acetylated R2 C-terminal heptapeptide N-AcPhe384Thr385Leu386Asp387Ala388Asp389Phe390 (N-AcF7TLDADF1) is the minimal core peptide length required; deletion of the N-terminus or of middle positions (resulting in penta- and hexapeptides) results in large losses in inhibitory potency; (b) a free carboxylate is required on the C-terminal Phe; (c) Phe is strongly preferred to Leu in positions 1 and 7 and a bulky aliphatic group is preferred in position 5; (d) neither negative charge in positions 2 or 4 nor a polar side chain in position 6 are required for peptide binding, contrary to what evolutionary patterns in the R2 C-terminus of RR would suggest. S. cerevisiae RR displays a similar length dependence on the corresponding N-acetylated R2 C-terminal heptapeptide, N-AcFTFNEDF. This peptide has a 4-fold higher inhibitory potency toward S. cerevisiae RR than toward mammalian RR. Such selectivity raises the possibility that peptide analogs related to R2 C-termini can be developed as therapeutic agents even against organisms having R2 C-terminal sequences similar to that of mammalian RR.

The heptapeptide, FTLDADF, identical in sequence to the last seven amino acid residues of the carboxyl terminus of the R2 subunit of mouse ribonucleotide reductase (RR), and its N alpha-acetyl derivative both inhibit calf thymus RR. The N alpha-acetyl derivative is considerably more potent, displaying a K1 of 20 microM. The same K1 was found for N-AcFTLDADF inhibition of a reconstituted ribonucleotide reductase from calf thymus R1 and mouse R2, indicating that the C-termini of calf R2 and mouse R2 might be identical. Our results, taken together with previous results of others on inhibition of viral RR, suggest that inhibition of RRs by peptides mimicking the C-terminus of R2 may be a general phenomenon. In addition, we have shown that an affinity column, FTLDADF-Sepharose 4B, can be used to prepare approximately 95% pure calf thymus R1, devoid of contamination with R2, in a very simple procedure that should be generally applicable to R1 purification from many sources.

Dibromothymoquinone (DBMIB) inhibits antimycin A-sensitive ubiquinol-cytochrome c reductase activity; the maximal inhibition is 90%. DBMIB alters the EPR spectra of reduced iron-sulfur protein in intact ubiquinol-cytochrome c reductase. The maximal spectral change occurs with 60 mol inhibitor per mol cytochrome c1 in the reductase. DBMIB causes little alteration in the EPR characteristics of iron-sulfur protein when ubiquinol-cytochrome c reductase is delipidated. When delipidated ubiquinol-cytochrome c reductase is replenished with phospholipid, the effect of DBMIB reappears. However, when DBMIB is added to delipidated protein prior to replenishment with phospholipid, very little spectral alteration is observed. DBMIB does not alter the EPR spectra of purified iron-sulfur protein, with or without phospholipid in the preparation. Reduced DBMIB does not alter the EPR characteristics of iron-sulfur protein in intact or delipidated ubiquinol-cytochrome c reductase. Cysteine and other thiol compounds can reverse the spectral alternation caused by DBMIB. This reversal probably results from the reduction of DBMIB.

An azido-ubiquinone derivative, 3-azido-2-methyl-5-methoxy-6-(3,7-dimethyloctyl)-1,4-benzoquinone, was used to study the ubiquinone-protein interaction and to identify the ubiquinone-binding proteins in yeast mitochondrial ubiquinone-cytochrome c reductase. The phospholipids and Q6 in purified reductase were removed by repeated ammonium sulfate precipitation in the presence of 0.5% sodium cholate. The resulting phospholipid- and ubiquinone-depleted reductase shows no enzymatic activity; activity can be completely restored by the addition of phospholipids and Q6 or Q2. The ubiquinone- and phospholipid-replenished ubiquinonol-cytochrome c reductase is also fully active upon reconstituting with bovine succinate-ubiquinone reductase to form succinate-cytochrome c reductase. When an azido-ubiquinone derivative was added to the ubiquinone and phospholipid-depleted reductase in the dark, followed by the addition of phospholipids, partial reconstitutive activity was restored, while full ubiquinol-cytochrome c reductase activity was observed when Q2H2 was used as substrate in the assay mixture. Apparently, the large amount of Q2H2 present in the assay mixture displaces the azido-ubiquinone in the system. Photolysis of the azido-Q-treated reductase with long-wavelength ultraviolet light abolishes about 70% of both the restored reconstitutive activity and Q2H2-cytochrome c reductase activity. The activity loss is directly proportional to the covalent binding of [3H]azido-ubiquinone to the reductase protein. When the photolyzed, [3H]azido-ubiquinone-treated sample was subjected to SDS-polyacrylamide gel electrophoresis followed by analysis of the distribution of radioactivity among the subunits, the cytochrome b protein and a protein with an apparent molecular weight of 14 000 were heavily labeled. The amount of radioactive labeling in both these proteins was affected by the presence of phospholipids.