The serotonin-3 (5-HT-3A) receptor has been localized in limbic and brainstem structures that regulate anxiety-related behavior and hypothalamic–pituitary–adrenal (HPA) activity, but its role in ...regulating anxiety-related behaviors is equivocal, and evidence for its role in regulating HPA activity is limited. Therefore, we used 5-HT-3A receptor knockout (KO) mice to further study these issues. Behavior in the elevated plus maze, open field, light–dark box and after Pavlovian fear conditioning was examined in addition to HPA activity under basal and acute stress conditions. Compared to age-matched adult male wild-type (WT) controls, adult male KO mice exhibited increased distance traveled in the open arms of the elevated plus maze, consistent with decreased measures of anxiety. There were no differences between the two genotypes in exploratory behavior in the open field or light–dark test. KO mice displayed enhanced fear conditioning indexed by fear-induced freezing behavior. KO mice displayed lower adrenocorticotropin (ACTH) responses to restraint or lipopolysaccharide (LPS). In addition, lower vasopressin mRNA in the paraventricular nucleus of the hypothalamus (PVN) and higher corticotropin-releasing hormone (CRH) mRNA in the central amygdala were observed in KO compared to WT mice. Therefore, deletion of the 5-HT-3A receptor revealed an important role for this receptor in regulating HPA responses to acute stress and a potential interaction between the 5-HT-3A receptor and CRH in the amygdala. Together, these data suggest that the 5-HT-3A receptor does not have a unitary role in the regulation of anxiety- and fear-related behaviors but has a potentially substantial role in the regulation of HPA activity.
Although ErbB2 is known to enhance breast cancer metastasis, the signaling events responsible for this remain elusive. Alpha-isozyme of protein kinase C (PKCalpha), which is involved in cancer ...development and progression, has been suggested to be activated by ErbB2 without direct evidence. In addition, the roles of PKCalpha in ErbB2-mediated cancer cell malignancy have not been clearly identified. In this study, we investigated whether ErbB2 can activate PKCalpha and determined what role PKCalpha plays in ErbB2-mediated breast cancer cell invasion. We expressed wild-type and mutant ErbB2 with altered signaling capacities in MDA-MB-435 breast cancer cells and revealed that overexpression or activation of ErbB2 in MDA-MB-435 cells upregulated and activated PKCalpha and that downregulation of ErbB2 by small-interfering RNA decreased the expression and activity of PKCalpha in BT474 breast cancer cells. These in vitro results were supported by data from breast cancer patient samples. In 150 breast cancer tumor samples, ErbB2-overexpressing tumors showed significantly higher positive rates of PKCalpha membrane immunohistochemistry staining than that of ErbB2-low-expressing tumors. Mechanistically, we found that PKCalpha is co-immunoprecipitated with Src and PKCalpha expression and activity can be decreased by Src inhibitor PP2 and by the expression of a dominant-negative mutant of Src. Moreover, ErbB2-mediated upregulation of urokinase-type plasminogen activator receptor (uPAR) is reduced by either the PKCalpha inhibitor Go6976 or the Src inhibitor PP2, and the combination of Go6976 with PP2 is superior to either agent alone in suppressing uPAR expression and cell invasion. These results demonstrate that PKCalpha is critical for ErbB2-mediated cancer cell invasion and provide valuable insights for current and future PKCalpha and Src inhibitor clinical trials.
Many computational methods have been widely used to identify transcription regulatory interactions based on gene expression profiles. The selection of dependency measure is very important for ...successful regulatory network inference. In this paper, we develop a new method-DBoMM (Difference in BIC of Mixture Models)-for estimating dependency of gene by fitting the gene expression profiles into mixture Gaussian models. We show that DBoMM out-performs 4 other existing methods, including Kendall's tau correlation (TAU), Pearson Correlation (COR), Euclidean distance (EUC) and Mutual information (MI) using Escherichia coli, Saccharomyces cerevisiae, Drosophila melanogaster, Arabidopsis thaliana data and synthetic data. DBoMM can also identify condition-dependent regulatory interactions and is robust to noisy data. Of the 741 Escherichia coli regulatory interactions inferred by DBoMM at a 60% true positive rate, 65 are previously known interactions and 676 are novel predictions. To validate the new prediction, the promoter sequences of target genes regulated by the same transcription factors were analyzed and significant motifs were identified.
Severe acute pancreatitis (SAP) can often be complicated by acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), leading to increased mortality. Early blood purification clears ...inflammatory cytokines and promotes immune function recovery. Here we evaluated the usefulness of this therapy in SAP complicated by ALI.
32 patients received routine treatment (control group), whereas other 32 patients received routine treatment and early blood purification therapy (study group). We evaluated respiratory indexes (PaO2, PaO2/FiO2, alveolar-arterial oxygen difference, intrapulmonary arteriovenous shunt percentage, and respiratory rate), blood biochemical (creatinine, blood urea nitrogen, alanine aminotransferase, and lactate levels) and inflammatory (CRP, IL-10, TNF-α, and IL-10/TNF-α ratio) markers, and prognostic outcomes (multiple organ dysfunction syndrome MODS and APACHE II scores) before and 72 hours after the treatment. We also documented mechanical ventilation use, occurrence of MODS and ARDS, and mortality rates.
There were no deaths. Mechanical ventilation was used in a similar percentage of patients in either group. Treatment in study group led to a faster and better recovery of respiratory indexes, and less pronounced changes in the levels of blood urea nitrogen and alanine aminotransferase. Inflammatory markers also normalized better in the study group. Furthermore, MODS and APACHE II scores decreased to a greater extent in the study group, paralleled by a lower occurrence of MPDS and ARDS.
Early blood purification therapy improves respiratory function and inflammatory markers in patients with SAP complicated by ALI, and decreases the occurrence of MODS and ARDS.
In this paper, three different rock-soil mixtures were reconstituted in laboratory, which were designed to mimic the proportions of coarse and fine particles in the high fill used at the airport ...construction sites. The shear strength of the reconstituted mixtures was determined by both large-scale direct shear tests (DSTs) with different plate opening sizes and triaxial compression tests. By comparing the test results, the most appropriate plate opening size for DSTs on coarse gap-graded rock-soil mixtures is discussed. The test results indicate that the opening size has a significant effect on the measured shear strength of gap-graded rock-soil mixtures. For DSTs under the same normal stress, the peak strength decreases with increasing plate opening size. For the gap-graded mixture with a small proportion of coarse particles, a plate opening size of one-third to one-quarter of the maximum particle size (dmax) is suitable. With a higher coarse particle content, the opening size should be increased appropriately. If the percentage of gravels (5.0 mm < d < 20.0 mm) is more than 47%, a plate opening size of slightly greater or less than one-half dmax is more appropriate.
In this work, we theoretically study the linear and non-linear optical absorption properties of graphene, armchair, zigzag, and hybrid edge bilayer graphene (BLG) and visualize the exciton ...localization and charge transfer behavior of its transition process. Then, the relationship between the Moiré pattern and the chiral properties of BLG is revealed by the visualization method. We found that the energy level of the Moiré pattern is between the orbital energy levels of the zigzag and the armchair edges, and the addition of Moiré can significantly enhance the interlayer charge transfer of normal BLG and twisted BLG. Moiré itself has a local effect on charge transfer excitons and local excitons on BLG. Moreover, the Moiré can effectively regulate the distribution of the magnetic transition dipole moment to control the chirality of twisted bilayer graphene (TwBLG). These laws will help the application of TwBLG in optical and optoelectronic devices. These regulars will guide the design and manufacture of TwBLG-based optoelectronic, photobiological, and photochemical reaction devices.
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•We report the linear and non-linear optical absorption properties of graphene, armchair, zigzag, and hybrid edge bilayer and visualize the local and charge transfer behavior of its transition process.•The chiral properties of bilayer graphene (BLG) were visualized.•The Moiré energy level is between the orbital energy levels of the zigzag edge and the armchair edge, and the addition of Moiré can significantly enhance the interlayer charge transfer of normal BLG and reverse BLG.•Moiré itself has a local effect on charge transfer excitons and local excitons on BLG.•Moreover, the moiré can effectively regulate the distribution of the magnetic transition dipole moment to control the chirality of twisted bilayer graphene (TwBLG).•These laws will help the application of TwBLG in optical and optoelectronic devices.•Our results can guide the design and manufacture of TwBLG-based optoelectronic, photobiological, and photochemical reaction devices.
A 9‐week feeding trial was conducted to investigate the dietary methionine requirement of juvenile Megalobrama amblycephala at a constant dietary cystine level. Six semipurified diets were formulated ...to contain graded dietary methionine levels from 3.9 to 15.4 g kg⁻¹ in about 2.5 g kg⁻¹ increments in the presence of 2.2 g kg⁻¹ cystine. Results showed that specific growth rate (SGR) and protein efficiency ratio (PER) significantly increased with increasing dietary methionine levels from 3.9 to 12.4 g kg⁻¹ and thereafter kept stable. Maximum protein productive value (PPV), nitrogen retention efficiency (NRE) and liver weight were observed in 8.5 g methionine kg⁻¹ diet. Protein contents in whole fish body were positively correlated with dietary methionine level, while lipid contents were negatively correlated with it. Morphological index and hepatic glutamate‐pyruvate transaminase (GPT) activities were independent of dietary methionine levels. However, dietary methionine supplementation significantly improved haematological parameters, plasma methionine and total essential amino acid contents and hepatic glutamate‐oxaloacetate transaminase (GOT) activities. Analysis of dose response using broken‐line regression on the basis of SGR and PPV versus dietary methionine level estimated the optimum dietary methionine requirements of juvenile M. amblycephala to be between 8.5 and 8.4 g kg⁻¹ of diet (25.0 and 24.7 g kg⁻¹ of protein) in the presence of 2.2 g kg⁻¹ cystine, respectively. Hence, the corresponding total sulphur amino acids requirements of this species were calculated to be 10.7 and 10.6 g kg⁻¹ of diet (31.5 and 31.2 g kg⁻¹ of dietary protein).
Many parallel-group studies of migraine prophylaxis using valproate medications were reported in recent decades. This meta-analysis assessed the efficacy and safety of valproate medications for ...migraine prophylaxis in adults.
Searches were conducted in five databases: PubMed, Wiley, ScienceDirect, Web of Science, and the Cochrane Library. The data were acquired through December 31, 2018. Two independent authors searched for controlled clinical trials involving the use of valproate medications in migraine prophylaxis. Studies that met the inclusion criteria were assessed, and their methodological quality was examined.
Seven placebo-controlled studies (782 participants) and seven controlled trials against active comparators (554 participants) were included in the final analysis. The active treatment of valproate medications was significantly superior to placebo (OR, 4.02; 95% CI 2.17-7.44; I2 = 66%). Compared with the other active comparators, there were no significant differences between treatments in the proportion of responders.
Valproate medications were more effective than placebo in migraine prevention, with statistically significant differences. Both valproate and the other active comparators were well-tolerated, and no significant difference was noted in efficacy and safety for the prophylaxis of migraine.
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•Self-developed vibration cast-rolling technology to solve rapid prototyping and hydrogen embrittlement.•Cross-scale research of the mechanism was carried out by finite element and ab ...initio calculation.•Grain refinement leads to the decrease of diffusible hydrogen content in strips of vibration cast-rolling.•Dispersed second-phase carbides act as effective hydrogen traps in strips of vibration cast-rolling.
Hydrogen embrittlement is a serious concern for advanced steels. In this research, twin-roll strip vibration cast-rolling was developed independently as a novel method for steel strip industrial production that inhibits hydrogen embrittlement. It reduces the hydrogen embrittlement sensitivity by optimizing the microstructure of strip steel products during the manufacturing process. Control experiments and cross-scale simulations were performed to reveal the phenomena and mechanisms that inhibit hydrogen embrittlement. The results show that the twin-roll strip vibration cast-rolling process can effectively reduce the hydrogen embrittlement sensitivity of steel strips.
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