[Evaluation of drug-drug interactions between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets].

Objective: To evaluate the drug-drug interactions and the tolerability of combined medication between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets in healthy volunteers. Methods: A randomized, open, and continuous administration design was used in trial 1 (yimitasvir phosphate capsules with sofosbuvir tablets). 28 subjects were randomly divided into two groups. A non-randomized, open design was used in trial 2 (yimitasvir phosphate capsules with omeprazole magnesium enteric-coated tablets), and included 42 subjects divided into three groups. The open design method was used in trial 3 (yimitasvir phosphate capsules with rosuvastatin calcium tablets), and included 14 subjects. The plasma concentrations of yimitasvir phosphate, sofosbuvir and their main metabolites GS-331007, omeprazole and rosuvastatin were validated by a liquid chromatography/tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated by Phoenix winNonlin software. Results: (1) in trial 1, after single and co-administration, the 90% CI of sofosbuvir C(max) and AUC(0-tau) geometric mean ratio (GMR) were 152.0% (118.0% ~ 197.0%) and 230.0% (184.0% ~ 287.0%), with an increase of 52.0% and 130.0% compared to single dose of sofosbuvir, respectively. The 90% CI of GS-331007 C(max) GMR was 74.0% (67.5% ~ 81.2%) and reduced by 26% compared to single dose of sofosbuvir. (2) in trial 2, the 90% CI of C(max) GMR after yimitasvir single or co-administration at the same time, with a 4-hours interval, or with a 12- hours interval were 68.9% (44.5% ~ 106.7%) , 64.0% (43.8% ~ 93.6%) and 56.4%(38.9% ~ 81.9%), and the 90% CI of AUC(0-t) GMR were 68.6% (46.5% ~ 101.2%), 68.3% (47.6% ~ 98.0%) and 60.5% (41.8% ~ 87.5%), respectively. Compared with single dose of yimitasvir, the C(max) and AUC(0-t) were decreased by 31.1% and 31.4%, 36.0% and 31.7%, 43.6% and 39.5%, respectively. (3) In trial 3, after single and co-administration, the 90% CI of rosuvastatin C(max) and AUC(0-72) GMR were 172.4% (153.6% ~ 193.5%) and 158.0% (144.3% ~ 172.9%), respectively, with an increase of 74.9% and 60.5% compared to single dose of rosuvastatin. There were no serious adverse events and adverse events leading to withdrawal from the trial. Conclusion: Yimitasvir phosphate capsules have drug-drug interactions with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets.

Rare structural variation of synapse and neurotransmission genes in autism.

Autism spectrum disorders (ASDs) comprise a constellation of highly heritable neuropsychiatric disorders. Genome-wide studies of autistic individuals have implicated numerous minor risk alleles but few common variants, suggesting a complex genetic model with many contributing loci. To assess commonality of biological function among rare risk alleles, we compared functional knowledge of genes overlapping inherited structural variants in idiopathic ASD subjects relative to healthy controls. In this study we show that biological processes associated with synapse function and neurotransmission are significantly enriched, with replication, in ASD subjects versus controls. Analysis of phenotypes observed for mouse models of copy-variant genes established significant and replicated enrichment of observable phenotypes consistent with ASD behaviors. Most functional terms retained significance after excluding previously reported ASD loci. These results implicate several new variants that involve synaptic function and glutamatergic signaling processes as important contributors of ASD pathophysiology and suggest a sizable pool of additional potential ASD risk loci.

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes.

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD.

[A study on the effect of rare earth metal ions on fluorescence spectra of the tryptophan using fluorescence spectroscopy].

Rare earth metal ions and tryptophan form ion-association complex in basic medium. The complex causes fluorescence quenching of tryptophan. Fluorescence emission of tryptophan and quenching caused by rare earth metal ions both reach a climax in H3BO4-HAc-H3PO4-NaOH at pH 10 to 11, and all rare earth metal ions have the approximate effects on fluorescence quenching of tryptophan. The molecular mode of complex of rare earth metal ions and tryptophan has been founded and mechanism of fluorescence quenching has been studied in this paper.

Alleviation of pre-exposure to low-dose 16O8+ ion on mouse testicular histological damage induced by subsequent high-dose irradiation.

The testes of the B6C3F1 hybrid strain mice were irradiated with 0.05 Gy of 16O8+ ion as the pre-exposure dose (D1), and were then irradiated with 2 Gy of 16O8+ ion as challenging radiation dose (D2) at 4 h after per-exposure. Testicular morphology was observed by light microscope at 35th day after radiation. The results showed that irradiation of mouse testes with 2 Gy of 16O8+ ion significantly impaired, mainly reduction of tubule diameter and decrease or loss of germ cells in various developing stages, especially spermatogenic elements. Pre-exposure to a low-dose (0.05 Gy) of 16O8+ ion significantly alleviated above mentioned damage on testicular morphology induced by subsequent a high-dose (2 Gy) radiation.

Effects of 16O+6 ion irradiation on human sperm spontaneous chemiluminescence, motility, acrosome reaction and viability in vitro.

Effects of 16O+6 ion irradiation with different doses on human sperm spontaneous chemiluminescence (SCL), motility, acrosome reaction (AR) and viability were examined. Spermatozoa were irradiated with 0, 0.25, 0.5, 1, 2, 4, 8, 16, 32, or 64 Gy 16O+6 ion beam at the energy of 3.17 MeV/u. After irradiation, samples were analyzed by SCL measurement at 1, 2 and 3 h of incubation; motility was determined by the transmembrane migration method within 2 h of incubation; the percentage of AR and viability was evaluated by the triple-stain technique at 3.5 h of incubation. The results showed: sperm SCL was significantly increased with irradiation doses and the lowest effective dose was 0.5 Gy; compared with controls, the transmembrane migration ratio of spermatozoa progressively elevated with irradiation doses at 0.5, 1, and 2 Gy; the percentage of sperm AR markedly increased in 0.5-4 Gy irradiation and the optimal dose was 2 Gy, and then significant decreased with further increase of irradiation doses; the viability had no significant change within 0.25-8 Gy, but was progressively decreased at 16, 32 and 64 Gy. These data suggested that heavy ion at low doses increased motility and AR, whereas had deleterious effects at higher doses, which are associated with free radical reactions induced by heavy ion irradiation.

Effects of pre-exposure of mouse testis with low-dose (16)O8+ ions or 60Co gamma-rays on sperm shape abnormalities, lipid peroxidation and superoxide dismutase (SOD) activity induced by subsequent high-dose irradiation.

PURPOSE: To investigate the effects of pre-exposure of mouse testis with low-doses of (16)O8+ ions or 60Co gamma-rays on sperm shape abnormalities, lipid peroxidation and superoxide dismutase (SOD) activity induced by subsequent high-dose irradiation. MATERIALS AND METHODS: Testes of the B6C3F1 hybrid strain mice were pre-irradiated with 0.05 Gy of (16)O8+ ions or 60Co gamma-rays and then after 4 h given a test irradiation with 2 Gy of the same radiation type. SOD activity and thiobarbituric acid reactive substances (TBARS) in the testes were determined by spectrophotometric and TBA methods respectively at 4 h after irradiation. Testis weight, sperm count and sperm morphology were analysed at day 35 after irradiation. RESULTS: Compared with controls, there was a significant increase in SOD activity and a significant decrease in TBARS level of pretreated testes. Testis weight loss, sperm count reduction and sperm abnormalities were significantly lower in the pretreated testes. The bioeffects of a 2 Gy dose of (16)O8+ ions relative to 60Co gamma-rays were 1.84 +/- 0.28 for testis weight, 1.22 +/- 0.25 for sperm count and 1.29 +/- 0.10 for sperm abnormalities. CONCLUSIONS: These data suggest that pre-exposure of testes with a low dose of heavy ions or gamma-rays renders the organ more resistant to subsequent high-dose irradiation. The increase of SOD activity and the decrease of lipid peroxidation levels induced by low-dose ionizing irradiation may be involved in this resistance. The effects with heavy ion irradiation were greater than with gamma-rays.

An in vitro study on roughening of the metal surface with lost crystal salts to increase the metal-resin bond strength.

Good mechanical retention between metal and resin or luting agent can be obtained by roughening the metal surface with lost crystal salts. The relationship of metal-resin bond strength to the shape and size of the crystals was studied. The results indicated that cuboid crystal salts provided the best roughening among the tested crystal shapes (cube, irregular, spherical, and cuboid). There was no relationship between the tensile bond strength and the size of the crystals. Furthermore, the bending strength of metal coated with resin was improved by the roughening of the metal surface.

[A PM visible light-cured dental bonding agent].

In order to get a better adhesion, less tooth abrasion and a good marginal sealing, bonding agent was used in the composites restorations. PM visible light cured bonding agent containing coupling agent 4-META was made. Polyfunctional monomer was used as the resin matrix. CQ and PA were used as the initiator. The tensile bonding strength of this bondx286p4ent to enamel was 84.5 kg/cm2. The shear bonding strength of this bonding agent to enamel when used with visible light cured composites together was 317.3 kg/cm2, which was higher then the report in the recent literatures. PM visible light cured bonding agent got a satisfied clinical result.