Deciphering the in situ phonon evolution of potassium sodium niobate under varying temperature and electric fields.

The application of in situ Raman spectroscopy under multiple fields is widely recognized as an effective approach for investigating the physical mechanism of phase transitions in ferroelectrics, because it can directly provide the detailed information about the vibration evolution of various phonon modes within lattices, such as bond stretching and rotation. Based on this technique, our work aims to thoroughly probe the dynamics of phase transitions in traditional ferroelectric potassium sodium niobate [(K,Na)NbO3, KNN] under external fields, by analyzing the in situ dependence of wavenumber and intensity of phonon modes under the varying temperature and electric fields. The results indicate that different vibration modes respectively relating to the A-site ions and NbO6 octahedra in KNN exhibit distinct and abrupt distortion behavior during the orthorhombic-tetragonal and tetragonal-cubic transitions. Moreover, a certain degree of distortion can still be observed in the cubic phase above the Curie temperature. With an applied electric field, KNN presents quite different electrostriction in orthorhombic and tetragonal phases. Particularly, more than one kind of phonon mode undergoes non-linear variations under the varying electric fields, accompanied by the mutations at some fixed fields. These findings will be conducive to further understanding the phase transition mechanism in KNN from the perspective of phonon evolution. Simultaneously, it will also give crucial guidance for the design and development of KNN-based ferroelectrics as well as functional devices.

Effects of different types of zinc supplement on the growth, incidence of diarrhea, immune function, and rectal microbiota of newborn dairy calves.

Neonatal diarrhea in dairy calves causes huge economic and productivity losses in the dairy industry. Zinc is an effective anti-diarrheal agent, but high doses may pose a threat to the environment. Therefore, we aimed to evaluate the effects of low-dose zinc supplementation on the growth, incidence of diarrhea, immune function, and rectal microbiota of newborn Holstein dairy calves. Thirty newborn calves were allocated to either a control group (without extra zinc supplementation), or groups supplemented with either 104 mg of zinc oxide (ZnO, equivalent to 80 mg of zinc/d) or 457 mg of zinc methionine (Zn-Met, equivalent to 80 mg of zinc/d) and studied them for 14 d. The rectal contents were sampled on d 1, 3, 7, and 14, and blood samples were collected at the end of the study. Supplementation with ZnO reduced the incidence of diarrhea during the first 3 d of life, and increased serum IgG and IgM concentrations. The Zn-Met supplementation increased growth performance and reduced the incidence of diarrhea during the first 14 d after birth. The results of fecal microbiota analysis showed that Firmicutes and Proteobacteria were the predominant phyla, and Escherichia and Bacteroides were the dominant genera in the recta of the calves. As the calves grew older, rectal microbial diversity and composition significantly evolved. In addition, dietary supplementation with ZnO reduced the relative abundance of Proteobacteria in 1-d-old calves, and increased that of Bacteroidetes, Lactobacillus, and Faecalibacterium in 7-d-old calves, compared with the control group. Supplementation with Zn-Met increased the relative abundance of the phylum Actinobacteria and the genera Faecalibacterium and Collinsella on d 7, and that of the genus Ruminococcus after 2 wk, compared with the control group. Thus, the rectal microbial composition was not affected by zinc supplementation but significantly evolved during the calves' early life. Zinc supplementation reduced the incidence of diarrhea in young calves. In view of their differing effects, we recommend ZnO supplementation for dairy calves during their first 3 d of life and Zn-Met supplementation for the subsequent period. These findings suggest that zinc supplementation may be an alternative to antibacterial agents for the treatment of newborn calf diarrhea.

Short communication: Effects of different selenium supplements on rumen fermentation and apparent nutrient and selenium digestibility of mid-lactation dairy cows.

The aim of this study was to evaluate the dose-dependent effects of a hydroxy-analog of selenomethionine (HMSeBA) on rumen fermentation, apparent nutrient digestibility, and total selenium absorption in mid-lactation dairy cows, and to compare the effects with those of sodium selenite (SS). Fifty mid-lactation dairy cows with similar milk yields, days in milk, and parity were randomly assigned to 1 of 5 treatments according to a randomized complete block design. The cows were fed a basal diet containing 0.06 mg/kg dry matter (DM) of Se (control) or the same basal diet supplemented with SS, yielding 0.3 mg of Se/kg of DM (SS-0.3), or HMSeBA, yielding 0.1, 0.3, or 0.5 mg of Se/kg of DM (SO-0.1, SO-0.3, and SO-0.5, respectively), during the experimental period. The final content of Se in control, SS-0.3, SO-0.1, SO-0.3, and SO-0.5 was 0.06, 0.34, 0.15, 0.33, and 0.52 mg of Se/kg of DM. The experiment lasted for 10 wk, with a pretrial period of 2 wk. Supplementation with HMSeBA altered rumen fermentation by linearly increasing total volatile fatty acids and the molar proportions of propionate and butyrate but decreasing rumen pH, ammonia content, and the ratio of acetate to propionate. Compared with SS, HMSeBA enhanced the molar proportion of propionate in the rumen and the apparent digestibility of crude protein, neutral detergent fiber, acid detergent fiber, and selenium. We demonstrated that HMSeBA promoted rumen fermentation, apparent nutrient digestibility, and selenium absorption, implying that HMSeBA has a greater apparent absorption than SS.

[HIV and syphilis infection and related medical treatment status of low-fee female sex workers in three provinces of China, 2012-2015].

Objective: To understand the HIV and syphilis infection and related treatment status of low-fee female sex workers (FSWs) in 3 provinces of China. Methods: Four cross-sectional survey data of low-fee FSWs from six cities (counties) in Guangxi, Yunnan and Hunan Province between October 2012 and July 2015 were obtained from the national science and technology major special project intervention study for reducing sexually transmitted diseases (STDs) and acquired immunodeficiency syndrome (AIDS) in low-fee FSWs' database, which included social demographic characteristics, sexual service characteristics and related medical care seeking behaviors, etc. A total of 2 050 subjects were included in the database. Results: The age of the subjects was (35.16±9.76) years old, with a minimum age of 15 and a maximum age of 67. Those who use condoms every time in commercial sex accounted for 58.9% (n=1 206). Among the reasons of not using condom, the proportion of client reluctant to use was the highest (81.0% (n=682)). Only 38.1% (n=782) was tested for HIV in the last six months. HIV confirmed positive rate was 6.8% (n=139), previous positive accounts for 76.3% (n=106). Rate of antiviral therapy was 55.4% (n=77). By the end of 2015, the loss rate of antivirus treatment was 18.2% (n=14). Those who self-reported symptoms of sexually transmitted diseases in the last 6 months accounted for 9.4% (n=191). 50.3% (n=96) of reporters chose to go to formal hospitals, 23.0% (n=44) chose to go to private clinics and 20.4% (n=39) chose their own medication. The syphilis infection rate was 13.5% (n=277), among them, 91.3% (n=253) were asymptomatic. Conclusion: Among low-fee FSWs, the rates of HIV and syphilis infection are higher, the condom consistent use rate, HIV antibodies and syphilis test rate are lower. In this group, active seeking medical idea is poor, the rate of anti-virus treatment and the rate of seeking medical treatment in formal medical institutions is low.

[Safety and efficacy of DCV-based DAAs therapy for chronic HCV infection in China].

Objective: To evaluate the efficacy and safety of DCV-based DAAs therapy for chronic HCV infected Chinese patients. Methods: An open-label, non-randomized, prospective study was designed. Fifty-two patients with chronic HCV infection were enrolled. Among them, there was one patient after liver transplantation, 2 patients after kidney transplantation, 3 patients with hepatocellular carcinoma, and 4 patients with HBV infection. Thirteen cases with chronic hepatitis C (one compensated cirrhosis) who were negative for resistance-related variants [NS5A RAS (-)] of gene 1b and NS5A were treated with daclatasvir (DCV) + asunaprevir (ASV) for 24 weeks. Twenty-five cases of CHC (six compensated cirrhosis) with GT 1b, 2a, 3a, 3b, 6a were treated with DCV + SOF ± RBV for 24 weeks. 8 cases with decompensated cirrhosis of gene 1b and NS5A RAS(-) were given DCV + SOF + RBV regimen for 12 weeks. Six cases with decompensated cirrhosis, of gene 2a, 1b, 2a, 3a, 3b, were given DCV + SOF + RBV regimen for 24 weeks. HCV RNA, blood routine test, liver and kidney function, and upper abdominal ultrasound/MRI were measured at baseline, 4 weeks of treatment, end of treatment, and 12 weeks of follow-up. The incidence of adverse events and laboratory abnormalities during treatment were recorded. A t-test was used to compare the measurement data between two groups, and analysis of variance was used to compare the measurement data between multiple groups. Results: Sixteen patients (100%) achieved SVR12 after treatment, with 0% recurrence rate. Rapid virological response (RVR) of the four treatment regimens were 76.92%, 54.17%, 87.50%, and 83.33%, respectively, and 32 patients achieved 100% virological response after the completion of treatment. The incidence of adverse events of chronic hepatitis C with cirrhosis and decompensated cirrhosis was 62.5% and 64.29%, respectively. The most common adverse event was fatigue in CHC (25.00%), and elevated indirect bilirubin in decompensated cirrhosis (42.86%). No serious adverse drug events, deaths or adverse reactions occurred. Conclusion: DCV-based DAAs regimen is promising option for the treatment of HCV genotypes, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and HCV infection after liver/kidney transplantation in china. Above all, it has high SVR12 with good tolerability and safety profile.

[Human selenium-containing single-chain variable fragment with glutathione peroxidase activity protects NIH3T3 fibroblast against oxidative damage].

Ultraviolet B (UVB medium wave, 280-315 nm) induces cellular oxidative damage and apoptosis by producing reactive oxygen species (ROS). Glutathione peroxidase functions as an antioxidant by catalyzing the reduction of hydrogen peroxide, the more important member of reactive oxygen species. A human selenium-containing single-chain variable fragment (se-scFv-B3) with glutathione peroxidase activity of 1288 U/µmol was generated and investigated for its antioxidant effects in UVB-induced oxidative damage model. In particular, cell viability, lipid peroxidation extent, cell apoptosis, the change of mitochondrial membrane potential, caspase-3 activity and the levels of intracellular reactive oxygen species were assayed. Human se-scFv-B3 protects NIH3T3 cells against ultraviolet B-induced oxidative damage and subsequent apoptosis by prevention of lipid peroxidation, inhibition of the collapse of mitochondrial membrane potential as well as the suppression of the caspase-3 activity and the level of intracellular ROS. It seems that antioxidant effects of human se-scFv-B3 are mainly associated with its capability to scavenge reactive oxygen species, which is similar to that of the natural glutathione peroxidase.

[Clinical characteristics and prognostic factors of 40 cases of primary systemic anaplastic large cell lymphoma].

Objective: To analyze the clinical features and prognostic factors of primary systemic anaplastic large cell lymphoma (ALCL) . Methods: 40 ALCL cases treated in the First Affiliated Hospital of Zhejiang University from January 2013 to December 2018 were retrospectively analyzed. Results: ① With a median age of 41 (14-67) years, there were 29 males and 11 females, 36 patients (90.0%) had Ann Arbor stage Ⅲ-Ⅳ tumors, 23 patients (57.5%) were in high-intermediate or high international prognostic index (IPI) risk group. 25 patients (62.5%) had B symptoms, such as fever, emaciation and night sweat.38 patients (95.0%) had extranodal invasion, 25 patients (62.5%) had higher LDH level, and 25 patients (62.5%) had high expression of Ki-67 (80% or more) . With 22 ALK(+) patients (55.0%) and 18 ALK(-) patients (45.0%) , there was a significantly difference in the median age of the two groups [29 (14-67) years old vs 51.5 (19-67) years old, P=0.003]. ② All patients received chemotherapy, 18 cases were treated with CHOP (cyclophosphamide, doxorubicin, vindesine, prednisone) , 12 cases with ECHOP (cyclophosphamide, doxorubicin, vindesine, prednisone, etoposide) , 10 cases with other treatments and 26 patients (65.0%) obtained complete remission (CR) . ALK(-) (P=0.029, OR=13.458) and Ki-67 expression of 80% or more (P=0.04, OR=14.453) were independent factors of CR rate, the CR rate of ECHOP chemotherapy was higher than CHOP chemotherapy (P=0.026) . ③ LDH level, IPI score, ALK expression and chemotherapy regimen had significantly effect on progression free survival (PFS) and overall survival (OS) (P<0.05) . Conclusion: The study shows that primary systemic ALCL usually occurs in males, the average age of ALK(+) patients were younger than ALK(-) patients. Most patients are in stage Ⅲ-Ⅳ with extranodal invasion, more than half of the patients have B symptoms, elevated LDH, and high expression of Ki-67. The expression level of Ki-67, ALK expression, and chemotherapy regimen have prognostic value for CR rate, the LDH level, IPI score, ALK expression and chemotherapy regimen for PFS and OS. ECHOP is a better choice with improved prognosis.

[In vitro study of effects of transient receptor potential vanilloid 1 on autophagy in early hypoxic mouse cardiomyocytes and the mechanism].

Objective: To explore the effects of transient receptor potential vanilloid 1 (TRPV1) on autophagy in early hypoxic mouse cardiomyocytes and the mechanism in vitro. Methods: The hearts of 120 C57BL/6 mice aged 1-2 days, no matter male or female, were isolated, and then primary cardiomyocytes were cultured and used for the following experiments, the random number table was used for grouping. (1) The cells were divided into normoxia group and hypoxia 3, 6, and 9 h groups, with one well in each group. The cells in normoxia group were routinely cultured (the same below), the cells in hypoxia 3, 6, and 9 h groups were treated with fetal bovine serum-free and glucose-free Dulbecco' s modified Eagle medium under low oxygen condition in a volume fraction of 1% oxygen, 5% carbon dioxide, and 94% nitrogen for 3, 6, and 9 h, respectively. The protein expressions of microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, TRPV1 were determined with Western botting. (2) The cells were divided into normoxia group and hypoxia group, with two coverslips in each group. The cells in hypoxia group were treated with hypoxia for 6 h as above. The positive expression of TRPV1 was detected by immunofluorescence assay. (3) The cells were divided into 4 groups, with one well in each group. The cells in simple hypoxia group were treated with hypoxia for 6 h as above, and the cells in hypoxia+ 0.1 µmol/L capsaicin group, hypoxia+ 1.0 µmol/L capsaicin group, and hypoxia+ 10.0 µmol/L capsaicin group were respectively treated with 0.1, 1.0, 10.0 µmol/L capsaicin for 30 min before hypoxia for 6 h. The protein expressions of LC3, Beclin-1, and TRPV1 were detected by Western blotting. (4) The cells were divided into 5 groups, with 5 wells in each group. The cells in hypoxia group were treated with hypoxia for 6 h as above, the cells in hypoxia+ chloroquine group, hypoxia+ capsaicin group, and hypoxia+ capsaicin+ chloroquine group were treated with hypoxia for 6 h after being cultured with 50 µmol/L chloroquine, 10.0 µmol/L capsaicin, and 50 µmol/L chloroquine+ 10.0 µmol/L capsaicin for 30 min, respectively. Viability of cells was detected by cell counting kit 8 assay. (5) The cells were divided into simple hypoxia group and hypoxia+ 10.0 µmol/L capsaicin group, with one well in each group. The cells in hypoxia group were treated with hypoxia for 6 h as above, the cells in hypoxia+ 10.0 µmol/L capsaicin group were treated with 10.0 µmol/L capsaicin for 30 minutes and then with hypoxia for 6 h. The protein expressions of lysosomal associated membrane protein 1 (LAMP-1) and LAMP-2 were detected by Western blotting. Each experiment was repeated for 3 or 5 times. Data were processed with one-way analysis of variance, least significant difference t test, and Bonferroni correction. Results: (1) Compared with those of normoxia group, the protein expressions of LC3, Beclin-1, and TRPV1 were significantly increased in cardiomyocytes of hypoxia 3, 6, and 9 h groups (t(3 h)=4.891, 5.890, 4.928; t(6 h)=9.790, 6.750, 10.590; t(9 h)=6.948, 6.764, 5.049, P<0.05 or P<0.01), which of hypoxia 6 h group were the highest (1.08±0.05, 1.12±0.10, 0.953±0.071, respectively). (2) The density of TRPV1 in cell membrane and inside the cardiomyocytes in hypoxia group was significantly increased with lump-like distribution, and the expression of TRPV1 was higher than that in normoxia group. (3) Compared with those of simple hypoxia group, the protein expression of Beclin-1 in cardiomyocytes of hypoxia+ 0.1 µmol/L capsaicin group was increased (t=10.488, P<0.01), while the protein expressions of LC3 and TRPV1 were increased without statistically significant differences (t=4.372, 3.026, P>0.05); the protein expressions of LC3, TRPV1, and Beclin-1 in cardiomyocytes of hypoxia+ 1.0 µmol/L capsaicin group and hypoxia+ 10.0 µmol/L capsaicin group were significantly increased (t=15.505, 5.773, 13.430; 20.915, 8.054, 16.384; P<0.05 or P<0.01), which of hypoxia+ 10.0 µmol/L capsaicin group were the highest (2.33±0.09, 1.34±0.07, 1.246±0.053, respectively). (4) Compared with 0.585±0.045 in normoxia group, the cardiomyocyte viability in hypoxia group was significantly decreased (0.471±0.037, t=4.365, P<0.05). Compared with that in hypoxia group, the cardiomyocyte viability in hypoxia+ chloroquine group was further decreased (0.350±0.023, t=6.216, P<0.01), while 0.564±0.047 in hypoxia+ capsaicin group was significantly increased (t=3.489, P<0.05). Compared with that in hypoxia+ chloroquine group, the cardiomyocyte viability in hypoxia+ capsaicin+ chloroquine group did not significantly change (0.364±0.050, t=0.545, P>0.05). (5) Compared with 0.99±0.04 and 0.54±0.04 in simple hypoxia group, the protein expressions of LAMP-1 and LAMP-2 in hypoxia+ 10.0 µmol/L capsaicin group were significantly increased (1.49±0.06, 0.81±0.05, t=12.550, 7.442, P<0.01). Conclusions: TRPV1 can further promote the expression of autophagy-related proteins in hypoxic cardiomyocytes through autophagy-lysosomal pathway, enhance autophagy activity, and improve autophagic flow for alleviating early hypoxic cardiomyocyte injury.

Cardiotoxicity evaluation of nine alkaloids from Rhizoma Coptis.

PURPOSE: Alkaloids derived from Rhizoma Coptis (RC) has been widely applied to clinical treatments in China. However, the toxicity of RC and the alkaloids from RC remained controversial. The research is designed to clarify the cardiotoxic compounds found in RC. METHODS: In this study, the real-time cellular analysis cardio system and the high-content analysis were applied to monitor the function of cardiomyocytes (CMs) in the treatment of nine alkaloids in RC. Luciferase-coupled adenosine triphosphate (ATP) assay was used to detect cell viability. RESULTS: The results showed that berberine, palmatine, berbamine, and oxyberberine were cardiotoxic, which resulted in arrhythmia and cardiac arrest on CMs in a time- and dose-dependent manner. Meanwhile, berbamine and oxyberberine caused shrinkage and detachment on CMs at 10 µM. Cytotoxicity was induced by these two compounds with decline in cell index and ATP depletion. Cardiotoxicity or cytotoxicity was not observed in the other five alkaloids within 10 µM. CONCLUSION: For the first time, the cardiotoxicity of the nine alkaloids was evaluated to clarify the cardiotoxic components in RC. Furthermore, the experimental evidences were provided to support the safety of drug application.

Effect of age on myocardial adaptation to volume overload in the rat.

To test the hypothesis that the capacity for left ventricular (LV) adaptation to volume overload might diminish with age, we examined the hemodynamics and degree of myocardial hypertrophy in response to aortic insufficiency in young adult (9 mo) and old (18 or 22 mo) Fischer rats. Before, immediately after, and at 2 and 4 wk after creating aortic insufficiency, LV and aortic pressures were measured using a catheterization technique. 4 wk after surgery, we measured aortic flow, and estimated the LV passive pressure-volume relationship and the degree of LV hypertrophy after killing. Immediately after the surgical creation of aortic insufficiency, both young and old rats showed similar elevation of LV end-diastolic pressure (from 4.8 +/- 0.6 to 12.0 +/- 1.5 mmHg in the young rats, P less than 0.01; from 4.9 +/- 0.4 to 11.0 +/- 0.7 mmHg in the old rats, P less than 0.01). In the young rats LV, end-diastolic pressure decreased to 8.0 +/- 1.0 and to 8.5 +/- 0.9 mmHg at 2 and 4 wk (P less than 0.05). In contrast, LV end-diastolic pressure at 2 (16.9 +/- 3.1 mmHg) and 4 wk (16.1 +/- 2.7 mmHg) in the old rats was even higher, compared with the values measured immediately after aortic insufficiency. At 4 wk, LV end-diastolic meridional wall stress (calculated from the in vivo LV end-diastolic pressure, and the pressure-volume relationship and muscle mass obtained after killing) was higher in the old rats than in the young rats. In the young rats, the diastolic pressure-volume relationship at 4 wk shifted to the right (P less than 0.01), and LV dry weight, LV dry weight/tibial length, and protein content of the LV myocardium increased by 26% (P less than 0.01), 24% (P less than 0.01), and 33% (P less than 0.01), respectively. However, old rats with aortic insufficiency did not show a significant change in the pressure-volume relationship, dry weight, or protein content at 4 wk. These results suggest that advanced age diminishes the capacity for LV hypertrophy in response to a volume overload, and this reduced LV hypertrophic response in the old rats resulted in persistent elevation of LV end-diastolic pressure and wall stress.

Chronic exercise training protects aged cardiac muscle against hypoxia.

To test the hypothesis that chronic exercise may improve tolerance to hypoxia in aged hearts, we compared cardiac function of exercised rats to that of their age-matched, nonexercised controls. Right ventricular papillary muscles were removed from young adult (9 mo) and old (24-26 mo) male Fischer 344 rats that were chronically exercised on a rodent treadmill and from their age-matched, nonexercised controls. During isometric contraction, hypoxia depressed contraction and relaxation in all muscles, but to a lesser extent in the exercised groups. A significant exercise effect was observed in the following variables: the maximum developed tension, the maximum rate of tension development, the maximum rate of tension decline, and the time required for the hypoxia to reduce maximum tension by 20%. The maximum rate of tension decline was more sensitive to hypoxia than was the maximum rate of tension development in all groups. Exercise also had an effect on the temperature dependence of cardiac performance during hypoxia. Thus, chronic exercise results in the preservation of both contraction and relaxation during hypoxia for aged as well as young adult hearts.

Age-related differences in the expression of proto-oncogene and contractile protein genes in response to pressure overload in the rat myocardium.

Cardiac adaptation to hemodynamic stress involves both quantitative (hypertrophy) and qualitative (pattern of gene expression) changes. Our previous studies have shown that advancing age in the rat is associated with diminished capacity to develop left ventricular hypertrophy in response to either ascending aortic constriction (AoC). In this study, we examined whether the expression of protooncogenes and contractile protein genes in response to AoC differs between adult (9-mo-old) and old (18-mo-old) rats. RNA was isolated from the left ventricles of AoC animals of both age groups subjected to a similar hemodynamic stress. Immediately after AoC, the levels of the ventricular expression of c-fos and c-jun protooncogenes were markedly lower in the old rats than in the adult animals. 5 d after the operation, the ratio of beta- to alpha-myosin heavy chain mRNAs increased significantly after AoC in both age groups. In contrast, AoC was associated with a marked reduction in the levels of mRNAs encoding sarcoplasmic reticulum Ca(2+)-ATPase (by 69%) and cardiac calsequestrin (by 49%) in the old rats but not in the adults. The mRNAs encoding atrial natriuretic factor and skeletal alpha-actin increased in response to AoC only in the adult rats. There were no significant differences in expression of the cardiac alpha-actin mRNA among the experimental groups. These data suggest that (a) the expression of protooncogenes in response to acute pressure overload is significantly reduced in the aged rats and (b) the pattern of expression of the contractile protein gene in response to AoC in the old rats differs qualitatively as well as quantitatively from that in younger animals. These age-related differences may play a role in the higher frequency of heart failure in the aged during hemodynamic stress.

In vivo expression of mammalian BiP ATPase mutants causes disruption of the endoplasmic reticulum.

BiP possesses ATP binding/hydrolysis activities that are thought to be essential for its ability to chaperone protein folding and assembly in the endoplasmic reticulum (ER). We have produced a series of point mutations in a hamster BiP clone that inhibit ATPase activity and have generated a species-specific anti-BiP antibody to monitor the effects of mutant hamster BiP expression in COS monkey cells. The enzymatic inactivation of BiP did not interfere with its ability to bind to Ig heavy chains in vivo but did inhibit ATP-mediated release of heavy chains in vitro. Immunofluorescence staining and electron microscopy revealed vesiculation of the ER membranes in COS cells expressing BiP ATPase mutants. ER disruption was not observed when a "44K" fragment of BiP that did not include the protein binding domain was similarly mutated but was observed when the protein binding region of BiP was expressed without an ATP binding domain. This suggests that BiP binding to target proteins as an inactive chaperone is responsible for the ER disruption. This is the first report on the in vivo expression of mammalian BiP mutants and is demonstration that in vitro-identified ATPase mutants behave as dominant negative mutants when expressed in vivo.

p49/STRAP, a Serum Response Factor Binding Protein (SRFBP1), Is Involved in the Redistribution of Cytoskeletal F-Actin Proteins during Glucose Deprivation.

The functional decline that usually accompanies adult aging also encompasses cellular changes including cytoplasmic architecture. In addition to their role in cytoskeletal structure, actin microfilaments have important roles in various cellular processes, including cell-to-cell communication and intracellular signaling. Age-related diseases and late-stage cellular morphological appearances often correlate with altered f-actin structure, which has been observed most notably in cancer. What remains less clear are the molecular pathways that may be involved in normal and premature aging-induced f-actin changes. We report herein that p49/STRAP, a serum response factor binding protein (SRFBP1), is increased with normal aging and appears to be sensitive to low glucose-exposure. Our study results suggest that increased levels of p49/STRAP expression tend to correlate with f-actin redistribution genes, particularly cofilin, while siRNA-mediated knockdown of p49/STRAP resulted in a reduction of thymosin-ß4. Furthermore, with the redistribution of f-actin, we observed an increase in the intermediate filament vimentin, compatible with the notion that vimentin may be increased due to its greater role in cytoskeletal dynamics during advancing population doubling levels (PDLs) and in response to a low-glucose exposure. Taken together, these data suggest that p49/STRAP may play a role in glucose-deprivation associated cytoskeletal changes.

[A preliminary study on the outcome of lower-risk myelodysplastic syndrome by low-dose decitabine].

Objective: To assess the efficiency and safety of low-dose decitabine in patients with lower-risk myelodysplastic syndrome (MDS) to couple with the clinical significance of MDS-related gene mutations. Methods: This study was done in 4 institutions in Zhejiang Province. A total of 62 newly diagnosed patients with lower-risk MDS were assigned to two groups of decitabine (12 mg·m(-2)·d(-1) for 5 consecutive days) and best supportive care (BSC) . Their bone marrow samples were subject to examinations of MDS-related 15 gene mutations. The primary endpoints were the proportion of patients who achieved overall response (ORR) after at least two cycles and progression-free survival (PFS) , and their relevances to the gene mutations. Results: Of 62 enrolled patients, and 51 cases were included in the final analysis. 16 of 24 patients (66.7%) in decitabine group achieved ORR versus 8 of 27 (29.6%) in BSC group (χ(2)=6.996, P=0.008) ; PFS prolongation of decitabine versus BSC was statistically significant (not reached vs 13.7 months, P=0.037) . Among 51 patients, at least one gene mutation was identified in 20 patients (39.2%) , including 4 single SF3B1 mutation. PFS in cases with gene mutations (not including single SF3B1 mutation) was significantly shorter than of no gene mutation (9.2 months vs 18.5 months, P=0.008) , but not for ORR (37.5% vs 58.1%, P=0.181) . Among 16 patients with mutated genes, ORR in decitabine and BSC groups were 75% (6/8) and 0 (0/8) , respectively. The most adverse events in decitabine group were grade 3 to 4 neutropenia (45.8%) and grade 3 to 4 infections (33.3%) . Conclusion: This preliminary study showed that low-dose decitabine produced promising results with an acceptable safety in lower-risk MDS patients, especially for those with mutated genes. Further study targeting poor prognostic lower-risk MDS patients should be warranted.

Molecular and pharmacological analysis of cyclic nucleotide-gated channel function in the central nervous system.

Most functional studies of cyclic nucleotide-gated (CNG) channels have been confined to photoreceptors and olfactory epithelium, in which CNG channels are abundant and easy to study. The widespread distribution of CNG channels in tissues throughout the body has only recently been recognized and the functions of this channel family in many of these tissues remain largely unknown. The molecular biological and pharmacological properties of the CNG channel family are summarized in order to put in context studies aimed at probing CNG channel functions in these tissues using pharmacological and genetic methods. Compounds have now been identified that are useful in distinguishing CNG channel activated pathways from cAMP/cGMP dependent-protein kinases or other pathways. The ways in which these interact with CNG channels are understood and this knowledge is leading to the identification of more potent and more specific CNG channel subtype-specific agonists or antagonists. Recent molecular and genetic analyses have identified novel roles of CNG channels in neuronal development and plasticity in both invertebrates and vertebrates. Targeting CNG channels via specific drugs and genetic manipulation (such as knockout mice) will permit better understanding of the role of CNG channels in both basic and higher orders of brain function.

[Efficacy and safety analysis of different dose idarubicin plus cytarabine regimen as induction chemotherapy for young patients with de-novo acute myeloid leukemia].

OBJECTIVE: To compare the efficacy, safety and long-term prognosis between different dose idarubicin (IDA) combined with cytarabine (IA) as induction chemotherapy in newly diagnosed young patients of acute myeloid leukemia (AML). METHODS: A total of 149 newly diagnosed young AML patients (APL excluded) between January 2009 to July 2014 was enrolled. According to the dose of IDA, the patients were divided into three groups, high standard- dose IA group (10- 12 mg · m (- 2) · d(- 1)), low standard-dose IA group (8-9 mg·m(-2)·d(-1)) and low-dose IA group (<8 mg·m(-2)·d(-1)). The efficacy, adverse effects and long- term prognosis among the three groups were compared. RESULTS: Of them, 34 patients were in high standard-dose IA group, 53 in low standard-dose IA group and 62 in low-dose IA group. After one cycle of induction chemotherapy, the complete remission (CR) rate was 79.4%, 75.5% and 46.8%, the overall response (OR) rate was 97.1%, 94.3% and 64.5%, and the overall CR rate was 85.3%, 81.1% and 54.8%, respectively. Compared with low- dose IA group, high standard- dose IA group and low standard-dose IA group had significantly better result (P<0.05), but there was no significant difference between the latter two groups (P>0.05). Multivariate analysis also showed that standard-dose IA was favorable factor for induction chemotherapy (P<0.05). The adverse effects were similar in the three group, other than the lowest count of WBC (P=0.002). Low standard-dose IA can improve the OS compared to the low-dose IA (P=0.003), but EFS, RFS was similar in the three groups. CONCLUSIONS: For the newly diagnosed young(<55) AML patients, the standard-dose IA has better CR rate. The adverse effects were similar in the three groups. High-dose IA may improve the OS compared to the low-dose IA.