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Witnessing violent or traumatic events is common during childhood and adolescence and could cause detrimental effects such as increased risks of psychiatric disorders. This stressor could be modeled in adolescent laboratory animals using the chronic witnessing social defeat (CWSD) paradigm, but the behavioral consequences of CWSD in adolescent animals remain to be validated for cognitive, anxiety-like, and depression-like behaviors and, more importantly, the underlying neural mechanisms remain to be uncovered. In this study, we first established the CWSD model in adolescent male mice and found that CWSD impaired cognitive function and increased anxiety levels and that these behavioral deficits persisted into adulthood. Based on the dorsal-ventral functional division in hippocampus, we employed immediate early gene c-fos immunostaining after behavioral tasks and found that CWSD-induced cognition deficits were associated with dorsal CA3 overactivation and anxiety-like behaviors were associated with ventral CA3 activity reduction. Indeed, chemogenetic activation and inhibition of dorsal CA3 neurons mimicked and reversed CWSD-induced recognition memory deficits (not anxiety-like behaviors), respectively, whereas both inhibition and activation of ventral CA3 neurons increased anxiety-like behaviors in adolescent mice. Finally, chronic administration of vortioxetine (a novel multimodal antidepressant) successfully restored the overactivation of dorsal CA3 neurons and the cognitive deficits in CWSD mice. Together, our findings suggest that dorsal CA3 overactivation mediates CWSD-induced recognition memory deficits in adolescent male mice, shedding light on the pathophysiology of adolescent CWSD-induced adverse effects and providing preclinical evidence for early treatment of stress-induced cognitive deficits.

Low cycle fatigue behavior of a quenched and tempered high-strength steel (Q960E) was studied in the strain amplitude ranging from ± 0.5% to ± 1.2% at room temperature. As a result of fatigue loading, the dislocation structural evolution and fracture mechanism were examined and studied by transmission electron microscopy and scanning electron microscopy (SEM). The results showed that this Q960E steel showed cyclic softening at different strain amplitudes, and the softening tendency was more apparent at strain amplitude of ± (0.6–1.2)% than that at ± 0.5%. The reduction in dislocation density with increasing strain amplitude is responsible for the softening tendency of cyclic stress with the strain amplitude. The material illustrates near-Masing behavior at strain amplitude ranging from ± 0.6% to ± 1.2%. The near-Masing behavior of Q960E high-strength steel can be the result of stability of martensite lath at different strain amplitudes. Partial transformation from martensite laths to dislocation cells is responsible for the derivation from ideal Masing behavior. In the SEM examination of fracture surfaces, transgranular cracks initiate on the sample surface. Striations can be found during the crack propagation stage.

Calbindin modulates intracellular Ca2+dynamics and synaptic plasticity. Reduction of hippocampal calbindin levels has been implicated in early-life stress-related cognitive disorders, but it remains unclear how calbindin in distinct populations of hippocampal neurons contributes to stress-induced memory loss. Here we report that early-life stress suppressed calbindin levels in CA1 and dentate gyrus (DG) neurons, and calbindin knockdown in adult CA1 or DG excitatory neurons mimicked early-life stress-induced memory loss. In contrast, calbindin knockdown in CA1 interneurons preserved long-term memory even after an acute stress challenge. These results indicate that the dysregulation of calbindin in hippocampal excitatory, but not inhibitory, neurons conveys susceptibility to stress-induced memory deficits. Moreover, calbindin levels were downregulated by early-life stress through the corticotropin-releasing hormone receptor 1-nectin3 pathway, which in turn reduced inositol monophosphatase levels. Our findings highlight calbindin as a molecular target of early-life stress and an essential substrate for memory.

The nuclear receptors (NR)—farnesoid X receptor (FXR, NR1H4) and pregnane X receptor (PXR, NR1I2)—have important effects on the expression of genes related to the pharmacokinetics (PKs) of rosuvastatin. This study was designed to investigate whether the genetic variants in drug disposition genes (SLCO1B1and ABCG2) combined with their upstream regulators (NR1H4and NR1I2) would affect the PKs of rosuvastatin in a Chinese population. Sixty-one healthy male volunteers were enrolled and the plasma concentrations of rosuvastatin were measured using the liquid chromatographic—tandem mass spectrometry/MS method. All subjects were analyzed and grouped according to the genotypes of NR1H4, NR1I2, SLCO1B1, and ABCG2. The exposure of rosuvastatin was higher in subjects carrying the SLCO1B1521C or ABCG2421A allele compared with noncarriers. No association was observed of single-nucleotide polymorphisms in NR1H4or NR1I2genes with the PKs of rosuvastatin. After adjusting for the 421C>A and 521T>C variants, the Cmaxin subjects with NR1I263396TT wild type were about 2-fold of those of NR1I2mutant type (63396CC and CT) (10.7 vs. 20.4 ng/mL, P= 0.023), whereas no significant differences were observed for other parameters. Polymorphisms investigated in the genes of NR1H4and NR1I2seemed to play no significant role in the disposition of rosuvastatin.

The deficiency of effective length approach and the necessity of second order analysis design on nonferrous engineering steel industrial plant are emphasized. Second order analysis approach by nonlinear finite-element with ANSYS is used to design an industrial plant. The example indicates that second-order effect should not be neglect and the result of first order analysis is not safe enough for industrial plant.

The aim of this study was to retrospectively evaluate the effect of polymorphisms in the CYP3A4, CYP3A5and ABCB1genes on the dose-adjusted concentration and dose requirement of cyclosporine A (CsA) in Chinese recipients during the early period after bone marrow or hematopoietic stem cell transplantation. Ninety-one bone marrow transplant recipients were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay or by direct sequencing for the C1236T, G2677T/A and C3435T polymorphisms in CYP3A4*18B, CYP3A5*3, and ABCB1, respectively. The concentration at zero before administration (C0) and concentration at 2 h after administration (C2) of whole blood CsA were measured by fluorescence polarization immunoassay. Dose-adjusted C0and C2were determined and compared among groups with different genotypes. Compared with CYP3A5*3/*3 individuals, CYP3A5*1/*1 subjects have a significantly lower dose-adjusted C0and C2at days 1–10 and a higher dose requirement for CsA at days 16–30 (p < 0.05). In addition, homozygotes for the ABCB13435T mutant have a significantly higher dose-adjusted C0and C2and a lower dose requirement compared with wildtype (p < 0.05). Similar results were also derived for carriers of the T-G-C haplotype in CYP3A5producers compared with non-carriers (p < 0.05 andp < 0.01, respectively). In summary, the ABCB13435T SNP, T-G-C haplotype in CYP3A5producers, and CYP3A5*3 SNP are all associated with differences in CsA pharmacokinetics and dose requirements during the first month after bone marrow or hematopoietic stem cell transplantation. Genetic testing can therefore help to determine initial dosage and individualize immunosuppressive therapy.

The aim of this study was to evaluate the effects of ABCB1gene polymorphisms on azithromycin pharmacokinetics in Chinese Han ethnic subjects. In total, 20 healthy volunteers with various ABCB1genotypes (6 with 2677GG/3435CC, 8 with 2677GT/3435CT, 6 with 2677TT/3435TT) were enrolled. Each was given a single oral dose of 500 mg azithromycin. Plasma concentration was measured for up to 96 h by LC/MS/MS. As shown, Cmaxwas significantly lower among individuals with 2677TT/3435TT genotype (468.0 ± 173.4 ng • h/ml) than those with 2677GG/3435CC (911.2 ± 396.4 ng • h/ml, p = 0.013). However, the tmaxvalue was higher among subjects with 2677TT/3435TT (2.0 ± 0.5 h) than those with 2677GT/3435CT (1.6 ± 0.3 h) or 2677GG/3435CC (1.4 ± 0.4 h) genotypes (p = 0.068 and p = 0.026, respectively). Furthermore, the AUCast tended to be higher among subjects with 2677GG/3435CC than those with 2677GT/3435CT or 2677TT/3435TT genotypes (5000.2 ±1610.0 vs. 4558.0 ± 805.0 vs. 4131.0 ± 995.1 ng/ml). Our results showed for the first time that azithromycin pharmacokinetics may be influenced by particular polymorphisms of theABCB1gene. Individualized dosage regimen design incorporating such information may improve the efficacy of the drug while reducing adverse reactions.