Investigation on Mechanism of Microstructure Evolution during Multi-Process Hot Forming of GH4169 Superalloy Forging.

Typically, in the manufacturing of GH4169 superalloy forgings, the multi-process hot forming that consists of pre-deformation, heat treatment and final deformation is required. This study focuses on the microstructural evolution throughout hot working processes. Considering that δ phase can promote nucleation and limit the growth of grains, a process route was designed, including pre-deformation, aging treatment (AT) to precipitate sufficient δ phases, high temperature holding (HTH) to uniformly heat the forging, and final deformation. The results show that the uneven strain distribution after pre-deformation has a significant impact on the subsequent refinement of the grain microstructure due to the complex coupling relationship between the evolution of the δ phase and recrystallization behavior. After the final deformation, the fine-grain microstructure with short rod-like δ phases as boundaries is easy to form in the region with a large strain of the pre-forging. However, necklace-like mixed grain microstructure is formed in the region with a small strain of the pre-forging. In addition, when the microstructure before final deformation consists of mixed grains, dynamic recrystallization (DRX) nucleation behavior preferentially depends on kernel average misorientation (KAM) values. A large KAM can promote the formation of DRX nuclei. When the KAM values are close, a smaller average grain size of mixed-grain microstructure is more conductive to promote the DRX nucleation. Finally, the interaction mechanisms between δ phase and DRX nucleation are revealed.

Investigation of the enhancement for Echinocandin B fermentation with methyl oleate from transcription level.

Echinocandin B (ECB) is the key precursor compound of the antifungal drug Anidulafungin. The effects of the five precursor amino acids on ECB biosynthesis were firstly investigated. It showed that although L-threonine was a main compound of the hexapeptide scaffold of ECB, exogenous addition of L-threonine had no significant effect on the increase of ECB fermentation titer. Meanwhile, the ECB fermentation titer with methyl oleate showed two times higher than that of the other carbon sources. Transcription level analysis of the key genes for ECB biosynthesis indicated that the gene an655543 related to L-threonine biosynthesis showed higher value during the fermentation process, therefore, the exogenous addition of L-threonine had no obvious affection. Furthermore, it indicated that the transcription level of gene ecdA might be the main restriction factor for the ECB biosynthesis. The study provided the research foundation for the modification of the ECB producing strains in the following work.

Replacing permuted block design with big stick design in stratified randomization.

The PBD (Permuted Block Design) is the most widely used randomization method in clinical trials due to its comparatively simplicity. However, greater selection bias may appear, especially in open-labeled trials, because the PBD requires absolute balance at the end of each block . The BSD(Big Stick Design) method is one of the MTI(Maximum Tolerated Imbalance) procedures, which can make the allocation process more unpredictable while maintaining the advantages the PBD. So it is theoretically superior to the PBD method. However, some practical problems in stratified randomization hinder the application of the BSD method: such as the risk of serious imbalance for entire trials with the increasing of strata, the uncertainty of the reproducibility of randomization schedule, and the danger of greater selection bias in extreme cases. We propose solutions to the above three implementation problems, and explores the feasibility and effects of the solutions through simulations.

The role of the maximal first derivative of the radial pulse wave (Rad dP/dtmax) in monitoring cardiac function.

BACKGROUND: This study aimed to assess the clinical significance of the maximal first derivative of the radial pulse wave (Rad dP/dtmax) in monitoring cardiac function with different perioperative patients by researching the relationship between Rad dP/dtmax and cardiac output (CO). METHODS: Patients with non-pump coronary artery bypass grafting (CABG) and open liver tumor resection (OLTR) were enrolled in this study (n=10). CO was measured using the thermodilution Swan-Ganz catheter method and Rad dP/dtmax was acquired by the analysis of patients' left radial artery pressure waveform through the PowerLab data acquisition device. CO, Rad dP/dtmax, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure, central venous pressure, mean pulmonary arterial pressure, pulmonary artery wedge pressure (PAW), and body surface area was recorded. Data were analyzed using a mixed linear model of time-dependent covariates to duplicate the data. RESULTS: The bivariate correlation coefficients of Rad dP/dtmax and CO were 0.526 and 0.413. The result of the multivariate mixed linear model analysis showed that compared with other indicators, Rad dP/dtmax had the greatest standardized coefficient with CO in CABG patients. While in OLTR patients, HR, SBP, PAW, and DBP had larger standardized coefficients. CONCLUSIONS: Rad dP/dtmax could be a useful indicator to reflect and predict the acute changes in cardiac function in perioperative patients, especially for patients with cardiac dysfunction or contractility abnormality.

Locus coeruleus-CA1 projections are involved in chronic depressive stress-induced hippocampal vulnerability to transient global ischaemia.

Depression and transient ischaemic attack represent the common psychological and neurological diseases, respectively, and are tightly associated. However, studies of depression-affected ischaemic attack have been limited to epidemiological evidences, and the neural circuits underlying depression-modulated ischaemic injury remain unknown. Here, we find that chronic social defeat stress (CSDS) and chronic footshock stress (CFS) exacerbate CA1 neuron loss and spatial learning/memory impairment after a short transient global ischaemia (TGI) attack in mice. Whole-brain mapping of direct outputs of locus coeruleus (LC)-tyrosine hydroxylase (TH, Th:) positive neurons reveals that LC-CA1 projections are decreased in CSDS or CFS mice. Furthermore, using designer receptors exclusively activated by designer drugs (DREADDs)-based chemogenetic tools, we determine that Th:LC-CA1 circuit is necessary and sufficient for depression-induced aggravated outcomes of TGI. Collectively, we suggest that Th:LC-CA1 pathway plays a crucial role in depression-induced TGI vulnerability and offers a potential intervention for preventing depression-related transient ischaemic attack.

Sweet Sorghum Originated through Selection of Dry, a Plant-Specific NAC Transcription Factor Gene.

Sorghum (Sorghum bicolor) is the fifth most popular crop worldwide and a C4 model plant. Domesticated sorghum comes in many forms, including sweet cultivars with juicy stems and grain sorghum with dry, pithy stems at maturity. The Dry locus, which controls the pithy/juicy stem trait, was discovered over a century ago. Here, we found that Dry gene encodes a plant-specific NAC transcription factor. Dry was either deleted or acquired loss-of-function mutations in sweet sorghum, resulting in cell collapse and altered secondary cell wall composition in the stem. Twenty-three Dry ancestral haplotypes, all with dry, pithy stems, were found among wild sorghum and wild sorghum relatives. Two of the haplotypes were detected in domesticated landraces, with four additional dry haplotypes with juicy stems detected in improved lines. These results imply that selection for Dry gene mutations was a major step leading to the origin of sweet sorghum. The Dry gene is conserved in major cereals; fine-tuning its regulatory network could provide a molecular tool to control crop stem texture.

Cdk5 suppression blocks SIRT1 degradation via the ubiquitin-proteasome pathway in Parkinson's disease models.

The NAD+-dependent protein deacetylase sirtuin 1 (SIRT1), a member of the sirtuin family, may have a neuroprotective effect in multiple neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Many studies have suggested that overexpression-induced or resveratrol-treated activation of SIRT1 could significantly ameliorate several neurodegenerative diseases in mouse models. However, the type of SIRT1, protein expression levels and underlying mechanisms remain unclear, especially in PD. In this study, the results demonstrated that SIRT1 knockout markedly worsened the movement function in MPTP-lesioned animal model of PD. SIRT1 expression was found to be markedly decreased not only in environmental factor PD models, neurotoxin MPP+-treated primary culture neurons and MPTP-induced mice but also in genetic factor PD models, overexpressed α-synuclein-A30PA53T SH-SY5Y stable cell line and hm2α-SYN-39 transgenic mouse strain. Importantly, the degradation of SIRT1 during MPP+ treatment was mediated by the ubiquitin-proteasome pathway. Furthermore, the results indicated that cyclin-dependent kinase 5 (Cdk5) was also involved in the decrease of SIRT1 expression, which could be efficiently blocked by the inhibition of Cdk5. In conclusion, our findings revealed that the Cdk5-dependent ubiquitin-proteasome pathway mediated degradation of SIRT1 plays a vital role in the progression of PD.

CDK5-mediated phosphorylation of Sirt2 contributes to depressive-like behavior induced by social defeat stress.

Major depressive disorder (MDD) is a common, severe and recurrent psychiatric disorder worldwide; however, the underlying neuropathological mechanisms remain elusive. Histone deacetylases (HDACs) appear to play an essential role in depression. As the class III HDACs, Sirt1 and Sirt2 have attracted the most interest in the nervous system. Indeed, chronic stress decreased Sirt1 activity and down-regulated Sirt1 gene expression in MDD. Nevertheless, there is a paucity of literature on the role of Sirt2. To study the role of Sirt2 we established a MDD mouse model in wild type and Sirt2 knockout C57BL/6 mice using social defeat stress (SDS). We found that a lack of Sirt2 blocked the development of SDS-induced depressive-like behavior. Moreover, SDS led to Sirt2 phosphorylation in the amygdala without changing total Sirt2 levels, and blocking the phosphorylation of Sirt2 by CDK5 at serine residues 368 and 372 prevented SDS-induced depressive-like behavior and Sirt2 nuclear import. We also discovered that SDS-induced Sirt2 phosphorylation was involved in VTA-amygdala modulation using TetTag-pharmacogenetic method. These results suggest that CDK5 mediates phosphorylation of Sirt2 in the amygdala and contributes to the depressive-like behavior induced by SDS. This study highlights that inhibiting CDK5-dependent phosphorylation of Sirt2 at serine residues 368 and 372 by myristoylated membrane-permeabilising peptide (Sirt2-p), rather than using non-specific sirtuin inhibitors, may be a novel strategy for treating depression.

CDK5-mediated phosphorylation of XBP1s contributes to its nuclear translocation and activation in MPP+-induced Parkinson's disease model.

Parkinson's disease (PD) is an irreversible and progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta. Growing evidence indicates that endoplasmic reticulum stress is a hallmark of PD; however, its exact contribution to the disease process remains poorly understood. Here, we used molecular biology methods and RNA-Seq analysis to explored an unexpected role of spliced X-Box binding protein 1 (XBP1s) in the nervous system. In this study, we determined that the IRE1α/XBP1 pathway is activated in MPP+-treated neurons. Furthermore, XBP1s was identified as a substrate of CDK5 and that the phosphorylation of XBP1s at the Ser61 residue enhances its nuclear migration, whereas mutation of the residue to alanine substantially reduces its nuclear translocation and activity. Importantly, phosphorylated XBP1s acts as a nuclear transcription factor for multiple target genes, including metabolic-related genes, FosB, and non-coding RNAs. Our findings confirm that the IRE1α/XBP1 pathway is activated in PD, and reveal a novel role of XBP1s in the pathogenesis of PD. This pathway may be a new therapeutic strategy for PD.

Impact of different analgesic depths and abdominal trauma of different severities on stress and recovery of rats undergoing total intravenous anesthesia.

A number of animal models have been developed to examine the pathophysiological consequences of surgical procedures, but anesthetic methods, monitoring, and management measures in these models are very different from those used in humans. This study was designed to create a rat model of abdominal surgery using anesthetic methods and perioperative treatment similar to those used in the clinic and to investigate the effects of different injury severities and depths of anesthesia and analgesia on surgical stress and postoperative recovery. Abdominal skin/muscle incision was compared with exploratory laparotomy in rats under propofol intravenous anesthesia, accompanied by perioperative measures such as oxygen inhalation, fluid infusion, warmth, blood gas analysis, and infection prevention. Stress indices (mean arterial pressure, heart rate, blood glucose, and plasma corticosterone) were monitored during anesthesia and surgery, and recovery indicators (body weight, food consumption, and pain) were measured after surgery. In addition, animals undergoing laparotomy were subjected to low and high dosages of propofol and sufentanil, in order to examine the relationship between anesthetic and analgesic depth and stress on recovery. Exploratory laparotomy induced a greater stress response and caused slower postoperative recovery as measured than somatic injury. High-dose sufentanil downregulated plasma corticosterone and improved postoperative recovery more effectively than high-dose propofol (P<0.05). Taken together, a rat model of abdominal surgery using anesthetic methods and perioperative treatment similar to those used in the clinic was successfully developed. It showed a positive correlation between severity of surgical trauma and stress response and postoperative recovery and a significant role of adequate analgesia in reducing surgical stress and improving postoperative recovery.

[The significance, development and prospects of healthcare data integration in new drug clinical trials].

With the deployment of electronic medical records systems, more and more routine clinical data are recorded electronically, which become a potential data source for new drug clinical trials. In this paper, we summarized the opportunities, challenges, obstacles and the latest development in this field.

[Efficacy of modified Roux-en-Y gastric bypass in the treatment of non-obese type 2 diabetes mellitus:one year follow-up].

OBJECTIVE: To evaluate the one year effect of modified Roux-en-Y gastric bypass (RYGP) in the treatment of non-obese type 2 diabetes and to investigate the reasonable indications for surgery. METHODS: Totally 72 patients diagnosed as type 2 diabetes underwent RYGP from May 2009 to June 2010. There were 45 male and 27 female patients, with an average age of (47 ± 10) years. Preoperative body mass index (BMI) of the patients was 18.69 to 31.22 kg/m(2), average (26 ± 4) kg/m(2). The follow-up data included fasting plasma glucose (FPG), 2 h plasma glucose after oral glucose challenge (2hPG), weight, BMI and medication usage in 1, 3, 6 and 12 months postoperative; hemoglobin A1c (HbA1c), fasting C-peptide (C-P), fasting serum insulin (Fins) and homeostasis model assessment of insulin resistance index (HOMA-IR) in 6 and 12 months postoperative, respectively. RESULTS: Compared with the preoperative, FPG, 2hPG, weight and BMI in 1, 3, 6 and 12 months after surgery were improved (t = 7.014 to 10.254, P = 0.000), while HbA1c, C-P and HOMA-IR in 6 and 12 months after surgery were improved (t = 1.782 to 7.789, P = 0.000 to 0.103) and there was no significant difference in Fins (P > 0.05). The rates of complete remission in 1, 3, 6 and 12 months after surgery were gradually improved to 22.2%, 27.8%, 36.1% and 60.6%, respectively, and the rate of remission in 1 year was 94.3%. The complete remission of 1 year after surgery was associated with normal C-P, insulin antibody and oral antidiabetic drugs (χ(2) = 11.730, P = 0.003; χ(2) = 7.131, P = 0.028;χ(2) = 6.149, P = 0.046). CONCLUSIONS: Modified RYGP is safely and effectively in the treatment of no-obese type 2 diabetes patients. The function of islet cells is significantly improved after operation. Especially for the patients of whom C-P is normal, insulin antibody is negative before surgery, the rate of complete remission after 1 year is better.

Inhibitory effect of toll-like receptor 7 agonist on K562 cells / 中国实验血液学杂志

The aim of this study was to investigate the inhibitory effect of Toll-like receptor 7 (TLR7) agonist gardiquimod on K562 cells. Human γδT cells from peripheral blood cells were amplified by isopentenyl pyrophosphate. The proliferation capacity of γδT cells and K562 cells were measured with MTT assay after treatment with different concentrations of gardiquimod. Cytotoxicity of γδT cells on K562 cells was detected by CCK-8 kit, and the intracellular expression of TLR7, cell cycle and apoptosis of K562 cells before and after treatment with gardiquimod were measured by flow cytometry. The results demonstrated that gardiquimod could significantly stimulate the proliferation of γδT cells, and inhibit proliferation of K562 cells under the concentration of 11.0 µg/ml for 48 h. The expression of TLR7 increased after treatment with gardiquimod. No apoptosis was observed, but there were significant changes in cell cycle, moreover the K562 cells treated with gardiquimod were more killed by γδT cells. It is concluded that the gardiquimod can inhibit the proliferation of K562 cells and enhance their sensitivity to killing activity of human γδT cells.

[Effect of intravenous lornoxicam at different doses on the immune function in patients undergoing total abdominal hysterectomy].

OBJECTIVE: To investigate the effect of intravenous lornoxicam (LOR) at different doses given preoperatively on the immune function of patients undergoing total abdominal hysterectomy (TAH). METHODS: Forty-five patients undergoing TAH were randomly divided into 3 groups, namely NS group, L8 group and L16 group with intravenous injection of 4 ml saline, 8 mg LOR, and 16 mg LOR before the induction of anesthesia respectively. Venous blood samples were taken before anesthesia (T0), at 30 min during the operation (T1), at the end of the operation (T2), and at 24 h and 48 h after the operation (T3 and T4, respectively) to determine the serum levels of regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemotactic protein-1 (MCP-1), and stromal cell-derived factor 1 alpha (SDF-1alpha) by enzyme-linked immunosorbent assay (ELISA). RESULTS: The serum RANTES levels in NS group and L8 group at T1-T3 were significantly lower than those at T0 (P<0.05), but the levels in L8 group at each time point were all higher than those in NS group NS (P<0.05). The serum RANTES levels in L16 group L16 only decreased at T1-T2 as compared to those at T0, and were significantly higher than those in NS group and L8 group (P<0.05). The expressions of MCP-1 and SDF-1alpha in the 3 groups all increased at T1 and reached the peak levels after the operation. In L8 group and L16 group, MCP-1 expression at T2-T3 and SDF-1alpha at T1-T2 were both significantly lower than those in NS group (P<0.05). SDF-1alpha expression at T1-T2 was significantly lower in L16 group than in L8 group (P<0.05). The decrements of MCP-1 and SDF-1alpha were more obvious in L16 group than L8 group. CONCLUSIONS: Preoperative intravenous LOR injection may increase serum RANTES level and decrease MCP-1 and SDF-1alpha expressions to effectively relieve the perioperative immune disorders caused by TAH, and the effect is more potent at the dose of 16 mg.

Implementation and experience of a web-based allocation system with Pocock and Simon's minimization methods.

Minimization is a type of dynamic randomization method that is recommended for use in clinical trials. However, partly due to its organizational complexity in implementation, the utilization of minimization is seldom reported. We developed a centralized random allocation system named "MagMin" using Pocock and Simon's minimization methods, which has been in use since 2006. To date, 5 clinical trials have been randomized using this system, and the other 17 clinical trials are still running on this system. An example is introduced in this paper to describe the implementation of this system. Problems and countermeasures are also discussed.

[Effect of controlled hypotension with different drugs combined with acute hypervolemic hemodilution on bleeding volume and gastrointestinal perfusion in nasal endoscopic surgery].

OBJECTIVE: To investigate the effect of controlled hypotension using different drugs on gastrointestinal perfusion and bleeding volume in nasal endoscopic surgery. METHODS: Thirty ASA class I or II patients scheduled for nasal endoscopic surgery were randomized into three groups, including a routine general anesthesia group (group A) and two controlled hypotension groups (groups B and C). After anesthesia induction, anesthesia was maintained with 1%-2% isoflurane and vecuronium. ECG, mean arterial blood pressure (MAP), heart rate (HR), SpO(2) and PETCO(2) were continuously monitored. TRIP tonometry catheter 14 F was inserted into the stomach and connected to Tonocap (Datex-Ohmeda, Finland ). In groups B and C, hypotension was induced with isoflurane (1%-2%) and sodium nitroprusside (0.3-3 microg.kg(-1).min(-1)), and with isoflurane (1%-2%) and glonoine (0.5-5 microg.kg(-1).min(-1)), respectively, and the MAP was reduced to 50-55 mmHg in 10-15 min. In groups B and C, blood samples were taken for blood gas analysis after anesthesia (T(0)), after acute hypervolemic hemodilution (T(1)), at 30 and 60 min after controlled hypotension (T(2) and T(3)), and 30 min after recovery from hypotension (T(4)). In group A, blood samples were taken at different time points in the perioperative period. RESULTS: The patients in groups B and C had smaller bleeding volume than those in group A. HR was decreased after moderate acute hypervolemic hemodilution, and increased after controlled hypotension (T(2) and T(3)) in comparison with that at T(1) to a level similar to that at T(0). No significant changes were found in pHi at T(2) and T(3) in comparison with that at T(1) in the three groups. CONCLUSION: When appropriate measures are taken, induced hypotension at 50-55 mmHg does not necessarily produce disturbance in gastrointestinal perfusion. Induced hypotension with glonoin can decrease the bleeding volume better than sodium nitroprusside in nasal endoscopic surgery.

[Effect of different tidal volume ventilations on atelectasis in patients during general anesthesia by CT scan].

OBJECTIVE: To investigate the effect of different tidal volume ventilations on the amount of atelectasis during general anesthesia. METHODS: Twenty adults, ASA physical status I and status II patients, who were scheduled for elective excision of intracranial lesion were randomly divided into 2 groups: Group TV (traditional tidal volume ventilation, 10 mL/kg) and Group LV (low tidal volume ventilation, 6 mL/kg). Atelectasis, as determined by CT and artery blood gas (ABG) analysis, was measured before the anesthesia, after the tracheal intubation, and at the end of the operation, respectively. Respiratory mechanical parameters were measured at 30, 120, and 240 min after the intubation. RESULTS: After the tracheal intubation, CT scan showed obvious atelectasis in both groups. The atelectasis area was(4.35+/-2.15)cm2 (3.12%+/-1.94%) in the TV group and (4.80+/-2.45)cm2 (3.89%+/-2.11%) in the LV group, with a nonsignificant difference between the 2 groups. At the end of the operation, there was no significant increase in the amount of atelectasis between and within the 2 groups. Artery blood gas analysis showed no difference after the tracheal intubation and at the end of the operation in either group. Ppeak, Pplat, Pmean and lung compliance(Cst)were significantly higher in the TV group than those in the LV group. CONCLUSION: Low tidal volume(6 mL/kg) ventilation is more feasible during general anesthesia in patients with healthy lungs, and it does not increase the atelectasis and impairment of gas exchange.