The IRE1/Xbp1 axis restores ER and tissue homeostasis perturbed by excess Notch in Drosophila.

Notch signaling controls numerous key cellular processes including cell fate determination and cell proliferation. Its malfunction has been linked to many developmental abnormalities and human disorders. Overactivation of Notch signaling is shown to be oncogenic. Retention of excess Notch protein in the endoplasmic reticulum (ER) can lead to altered Notch signaling and cell fate, but the mechanism is not well understood. In this study, we show that V5-tagged or untagged exogenous Notch is retained in the ER when overexpressed in fly tissues. Furthermore, we show that Notch retention in the ER leads to robust ER enlargement and elicits a rough eye phenotype. Gain-of-function of unfolded protein response (UPR) factors IRE1 or spliced Xbp1 (Xbp1-s) alleviates Notch accumulation in the ER, restores ER morphology and ameliorates the rough eye phenotype. Our results uncover a pivotal role of the IRE1/Xbp1 axis in regulating the detrimental effect of ER-localized excess Notch protein during development and tissue homeostasis.

RACK1 and IRE1 participate in the translational quality control of amyloid precursor protein in Drosophila models of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by dysregulation of the expression and processing of the amyloid precursor protein (APP). Protein quality control systems are dedicated to remove faulty and deleterious proteins to maintain cellular protein homeostasis (proteostasis). Identidying mechanisms underlying APP protein regulation is crucial for understanding AD pathogenesis. However, the factors and associated molecular mechanisms regulating APP protein quality control remain poorly defined. In this study, we show that mutant APP with its mitochondrial-targeting sequence ablated exhibited predominant endoplasmic reticulum (ER) distribution and led to aberrant ER morphology, deficits in locomotor activity, and shortened lifespan. We searched for regulators that could counteract the toxicity caused by the ectopic expression of this mutant APP. Genetic removal of the ribosome-associated quality control (RQC) factor RACK1 resulted in reduced levels of ectopically expressed mutant APP. By contrast, gain of RACK1 function increased mutant APP level. Additionally, overexpression of the ER stress regulator (IRE1) resulted in reduced levels of ectopically expressed mutant APP. Mechanistically, the RQC related ATPase VCP/p97 and the E3 ubiquitin ligase Hrd1 were required for the reduction of mutant APP level by IRE1. These factors also regulated the expression and toxicity of ectopically expressed wild type APP, supporting their relevance to APP biology. Our results reveal functions of RACK1 and IRE1 in regulating the quality control of APP homeostasis and mitigating its pathogenic effects, with implications for the understanding and treatment of AD.

Hadh deficiency induced oligoasthenoteratozoospermia through the TNF-α/Bcl-2 pathway in male mice.

The process of spermatogenesis is a complex and delicate process that is still not fully understood. In this study, we examined the role of fatty acid oxidase 3-hydroxy acyl CoA dehydrogenase (HADH) in maintaining normal spermatogenesis in mice. In male mice, ablation of the Hadh gene using CRISPR/Cas9 technology arrested spermatocyte meiosis, increased multinucleated giant germ cells and vacuoles in seminiferous tubules, and accompanied with acrosomal dysplasia. Hadh-/- male mice showed the typical features of oligoasthenoteratozoospermia (OAT), including decreased sperm concentration and motility and increased sperm abnormalities. Next, we explored the molecular events in the testes of the mutant mice. We found fatty acids accumulated in the testis of Hadh-/- mice. And also, inflammatory factors TNF-α, IL-1ß, and IL-6 were significantly increased, apoptosis-related protein Bcl-2 was decreased, and Bax and cleaved-Caspase3 were increased in Hadh-/- male mice testis. After using etanercept, a specific inhibitor of TNF-α, testis injury caused by Hadh knockout was significantly alleviated, the sperm quality and motility were improved, and germ cell apoptosis was reduced. So our study demonstrated that Hadh deletion caused an increase in fatty acids. The accumulated fatty acids further induced testicular inflammation and germ cell apoptosis through the TNF-α/Bcl-2 signaling pathway, finally resulting in OAT in the Hadh-/- mice. Inhibiting TNF-α may be used as a new treatment approach for testicular inflammation and OAT.

Co-expression of recombinant human collagen α1(III) chain with viral prolyl 4-hydroxylase in Pichia pastoris GS115.

The Collagen α1(Ш) chain (COL3A1) is an important structural protein on the surface of human skin. The activity of prolyl 4-hydroxylase (P4H) is crucial to maintaining the stable triple-helix structure and function of human COL3A1. To obtain hydroxylated human COL3A1, virus-derived P4H A085R was co-expressed with human COL3A1 in Pichia pastoris GS115. Colony PCR analysis and sequencing after transfection confirmed that the target gene was successfully inserted. Quantitative reverse transcription PCR (RT-qPCR) indicated that human COL3A1 and P4H A085R were expressed at mRNA levels in the clones. SDS-PAGE and Western blot analysis of supernatant from the recombinant methylotrophic yeast culture showed that recombinant human COL3A1 (rhCOL3A1) was secreted into the culture medium with an apparent molecular mass of approximately 130 kDa. It was observed that the amount of secreted rhCOL3A1 was highest at 120 h after induction. Furthermore, mass spectrometry analysis demonstrated that rhCOL3A1 was successfully expressed in P. pastoris. The His-tagged rhCOL3A1 protein was purified by Ni-affinity column chromatography.

Deficiency for Lcn8 causes epididymal sperm maturation defects in mice.

Lipocalin family members, LCN8 and LCN9, are specifically expressed in the initial segment of mouse caput epididymis. However, the biological functions of the molecules in vivo are yet to be clarified. In this study, CRISPR/Cas9 technology was used to generate Lcn8 and Lcn9 knockout mice, respectively. Lcn8-/- and Lcn9-/- male mice showed normal spermatogenesis and fertility. In the cauda epididymis of Lcn8-/- male mice, morphologically abnormal sperm was increased significantly, the proportion of progressive motility sperm was decreased, the proportion of immobilized sperm was elevated, and the sperm spontaneous acrosome reaction (AR) frequency was increased. Conversely, the knockout of Lcn9 did not have any effect on the ratio of morphologically abnormal sperm, sperm motility, and sperm spontaneous AR frequencies. These results demonstrated the role of LCN8 in maintaining the sperm quality in the epididymis, and suggested that the deficiency of LCN8 leads to epididymal sperm maturation defects.

Discovery of a novel and selective cathepsin L inhibitor with anti-metastatic ability in vitro and in vivo against breast cancer cells.

Asperphenamate is a natural product that has attracted considerable interest from researchers worldwide. In the last decade, aiming to increase the biological activity and improve druggability, modifications of the A-ring moiety in asperphenamate have been performed. Our laboratory has also recently reported functional derivatizations of the A ring and studied its effect on the inhibition of cysteine cathepsin L. However, the functional significance of the B-ring fragment toward cathepsin L has not been evaluated thus far. In this paper, forty-four derivatives of the B-ring substituted with different N-phenylsulfonyl groups were designed and synthesized. Among them, the paratrifluromethyl analog B-2a and the 2, 4-difluoro-5-chloro derivative B-11b showed more potent inhibitory activity against cathepsin L than the control compound, ABR, which displayed the strongest inhibitory effect on cathepsin L and S among all reported asperphenamate derivatives. In particular, compound B-2a showed more pronounced selectivity against cathepsin L than the other derivatives. Molecular docking revealed that the N-phenylsulfonylamide moiety was vital for the interactions between B-2a and cathepsin L. Moreover, B-2a displayed no toxicity against normal cells. Therefore, compound B-2a was selected for further studies. Wound-healing assays, Transwell chamber assays and breast cancer lung metastasis mouse models demonstrated that B-2a exhibited antimetastatic ability in vitro and in vivo.

Cdc14a has a role in spermatogenesis, sperm maturation and male fertility.

Cdc14a is an evolutionarily conserved dual-specific protein phosphatase, and it plays different roles in different organisms. Cdc14a mutations in human have been reported to cause male infertility, while the specific role of Cdc14a in regulation of the male reproductive system remains elusive. In the present study, we established a knockout mouse model to study the function of Cdc14a in male reproductive system. Cdc14a-/- male mice were subfertile and they could only produce very few offspring. The number of sperm was decreased, the sperm motility was impaired, and the proportion of sperm with abnormal morphology was elevated in Cdc14a-/- mice. When we mated Cdc14a-/- male mice with wild-type (WT) female mice, fertilized eggs could be found in female fallopian tubes, however, the majority of these embryos died during development. Some empty spaces were observed in seminiferous tubule of Cdc14a-/- testes. Compared with WT male mice, the proportions of pachytene spermatocytes were increased and germ cells stained with γH2ax were decreased in Cdc14a-/- male mice, indicating that knockout of Cdc14a inhibited meiotic initiation. Subsequently, we analyzed the expression levels of some substrate proteins of Cdc14a, including Cdc25a, Wee1, and PR-Set7, and compared those with WT testes, in which the expression levels of these proteins were significantly increased in Cdc14a-/- testes. Our results revealed that Cdc14a-/- male mice are highly subfertile, and Cdc14a is essential for normal spermatogenesis and sperm function.

The relationship between post traumatic stress disorder and post traumatic growth: gender differences in PTG and PTSD subgroups.

PURPOSE: This study investigated the post traumatic stress disorder (PTSD) and post traumatic growth (PTG) in 2,300 earthquake survivors 1 year after the 2008 Wenchuan earthquake. This study aimed to investigate the relationship between PTSD and PTG and also tested for the gender differences in PTSD and PTG subgroups. METHODS: A stratification random sampling strategy and questionnaires were used to collect the data. The PTSD was assessed using the PTSD Check list-Civilian and the PTG was assessed using the Post traumatic growth inventory. 2,300 individuals were involved in the initial survey with 2,080 completing the final questionnaire, a response rate of 90.4%. One-way ANOVA analyses were performed to investigate the gender differences in the PTSD and PTG subgroups. RESULTS: One year following the earthquake, 40.1 and 51.1% of survivors reported PTSD and PTG, respectively. A bivariate correlation analysis indicated that there was a positive association between PTG and PTSD. The PTG and PTSD variance analysis conducted on female and male subgroups suggested that women were more affected than men. CONCLUSIONS: Given the relatively high PTG prevalence, it was concluded that researchers need to pay more attention to the positive outcomes of an earthquake rather than just focusing on the negative effects. The surveys and analyses indicated that psychological intervention and care for the earthquake disaster survivors should focus more on females and older people, who tend to be more adversely affected.

Posttraumatic stress disorder and posttraumatic growth among adult survivors of Wenchuan earthquake after 1 year: prevalence and correlates.

This study investigates the prevalence and predictors for posttraumatic stress disorder (PTSD) and posttraumatic growth (PTG) in adult survivors 1year after the 2008 Wenchuan earthquake. Questionnaires were used to collect the data. PTSD was assessed using the PTSD Check List-Civilian (PCL-C), and PTG was assessed using the Post Traumatic Growth Inventory (PTGI). A total of 2,300 individuals were involved in the survey with 2,080 completing the questionnaire, a response rate of 90.4%. The PTSD prevalence estimate in this study was found to be 40.1%, and the prevalence for PTG among the participants was measured at 51.1%. A bivariate correlation analysis indicated that there was a positive association between PTG and PTSD. In the conclusions, possible explanations for the findings and implications for future research are discussed.

Wavenumber Calibration Protocol for Raman Spectrometers Using Physical Modelling and a Fast Search Algorithm.

A wavenumber calibration protocol is proposed that replaces polynomial fitting to relate the detector axis and the wavenumber shift. The physical model of the Raman spectrometer is used to derive a mathematical expression relating the detector plane to the wavenumber shift, in terms of the system parameters including the spectrograph focal length, the grating angle, and the laser wavelength; the model is general to both reflection and transmission gratings. A fast search algorithm detects the set of parameters that best explains the position of spectral lines recorded on the detector for a known reference standard. Using three different reference standards, four different systems, and hundreds of spectra recorded with a rotating grating, we demonstrate the superior accuracy of the technique, especially in bands outside of the outermost reference peaks when compared with polynomial fitting. We also provide a thorough review of wavenumber calibration for Raman spectroscopy and we introduce several new evaluation metrics to this field borrowed from chemometrics, including leave-one-out and leave-half-out cross-validation.

TRP channel-related LncRNAs, AC092535.4 and LINC01637, as novel prognostic biomarkers for uveal melanoma.

Introduction: Transient receptor potential (TRP) channels function as cellular sensors with a broad impact, and their dysregulation is linked to numerous cancers. The influence of TRP channel-related long noncoding RNAs (TCRLs) on uveal melanoma (UM) remains poorly understood. Methods: We employed bioinformatics to examine the RNA-seq data and relevant clinical information of UM in the TCGA databases. By implementing coexpression analysis, we identified differentially expressed TCRLs. Using univariate Cox regression analysis, selection operator (LASSO) algorithm and stepwise regression, five key prognostic biomarkers were chosen. The high- and low-risk groups were divided based on the risk scores. Afterwards, the prediction performance of the signature was evaluated by receiver operating characteristic (ROC) curve and Kaplan-Meier (K-M) survival analysis. The functional enrichment analysis of TCRLs was also investigated. Following that, we examined immune cell infiltration, immune checkpoint expression, and tumor immune microenvironment between patients in high and low risk groups. TCRLs were validated using Random forests and multifactor Cox analysis. Candidate biomarkers were identified and screened. Finally, the effects of the candidate biomarkers on the proliferation, migration and invasion of UM cells were detected by CCK-8 assay, migration assay and perforation invasion assay. Results: The risk score generated by five TCRLs demonstrated robust predictive power. The high-risk group exhibited a poorer prognosis, increased immune cell infiltration, and an active tumor immune microenvironment compared to the low-risk group. Furthermore, two TCRLs of risk score, AC092535.4 and LINC01637, were screened to multiplex modelling. The in vitro experiments demonstrated that UM cells were suppressed following AC092535.4 or LINC01637 knockdown. Discussion: Two TCRLs, AC092535.4 and LINC01637, serve as novel prognostic biomarkers for uveal melanoma and may present potential therapeutic targets.

Superoxide dismutase induces G1-phase cell cycle arrest by down-regulated expression of Cdk-2 and cyclin-E in murine sarcoma S180 tumor cells.

As an efficient reactive oxygen species-scavenging enzyme, superoxide dismutase (SOD) has been shown to inhibit tumor growth and interfere with motility and invasiveness of cancer cells. In this study, the molecular mechanisms of cell cycle arrest when S180 tumor cells were exposed to high levels of SOD were investigated. Here, both murine sarcoma S180 tumor cells and NIH-3T3 mouse fibroblasts were respectively treated with varying concentrations of Cu/Zn-SOD for 24, 48 and 72 h to determine optimal dose of SOD, which was a concentration of 800 U/ml SOD for 48 h. It is found that SOD induced S180 cell cycle arrest at G1-phase with decreasing level of superoxide production, whereas SOD had less effect on proliferation of NIH-3T3 cells. Moreover, the expression rate of Proliferating Cell Nuclear Antigen (PCNA) in S180 tumor cells was suppressed after SOD treatment, which indicated the inhibition of DNA synthesis in S180 cells. Besides, there were significant down-regulations of cyclin-E and Cdk-2 in S180 cells after SOD treatment, which contributed to the blockage of G1/S transition in S180 cell cycle. Together, our data confirmed that SOD could notably inhibit proliferation of S180 tumor cell and induce cell cycle arrest at G1-phase by down-regulating expressions of cyclin-E and Cdk-2.

RhoGDIα regulates spermatogenesis through Rac1/cofilin/F-actin signaling.

Spermatogenesis is an extremely complex process, and any obstruction can cause male infertility. RhoGDIα has been identified as a risk of male sterility. In this study, we generate RhoGDIα knockout mice, and find that the males have severely low fertility. The testes from RhoGDIα-/- mice are smaller than that in WT mice. The numbers of spermatogonia and spermatocytes are decreased in RhoGDIα-/- testis. Spermatogenesis is compromised, and spermatocyte meiosis is arrested at zygotene stage in RhoGDIα-/- mice. Acrosome dysplasia is also observed in sperms of the mutant mice. At the molecular level, RhoGDIα deficiency activate the LIMK/cofilin signaling pathway, inhibiting F-actin depolymerization, impairing testis and inducing low fertility in mouse. In addition, the treatment of RhoGDIα-/- mice with Rac1 inhibitor NSC23766 alleviate testis injury and improve sperm quality by inhibiting the LIMK/cofilin/F-actin pathway during spermatogenesis. Together, these findings reveal a previously unrecognized RhoGDIα/Rac1/F-actin-dependent mechanism involved in spermatogenesis and male fertility.

Longitudinal real world correlation study of blood pressure and novel features of cerebral magnetic resonance angiography by artificial intelligence analysis on elderly cognitive impairment.

Objective: This study aims to investigate novel clinical risk factors for cognitive impairment (CI) in elderly. Methods: A total of 3221 patients (259 patients with CI and 2,962 subjects without CI) were recruited into this nested case-control study who underwent cerebral magnetic resonance angiography (MRA) from 2007 to 2021. All of the clinical data with MRA imaging were recorded followed by standardization processing blindly. The maximum stenosis score of the posterior circulatory artery, including the basilar artery, and bilateral posterior cerebral artery (PCA), was calculated by the cerebral MRA automatic quantitative analysis method. Logistic regression (LR) analysis was used to evaluate the relationship between risk factors and CI. Four machine learning approaches, including LR, decision tree (DT), random forest (RF), and support vector machine (SVM), employing 5-fold cross-validation were used to establish CI predictive models. Results: After matching with age and gender, 208 CI patients and 208 control subjects were finalized the follow-up (3.46 ± 3.19 years) with mean age at 84.47 ± 6.50 years old. Pulse pressure (PP) in first tertile (<58 mmHg) (OR 0.588, 95% confidence interval (CI): 0.362-0.955) was associated with a decreased risk for CI, and ≥50% stenosis of the left PCA (OR 2.854, 95% CI: 1.387-5.872) was associated with an increased risk for CI after adjusting for body mass index, myocardial infarction, and stroke history. Based on the means of various blood pressure (BP) parameters, the performance of the LR, DT, RF and SVM models accurately predicted CI (AUC 0.740, 0.786, 0.762, and 0.753, respectively) after adding the stenosis score of posterior circulatory artery. Conclusion: Elderly with low pulse differential pressure may have lower risk for cognitive impairment. The hybrid model combined with the stenosis score of posterior circulatory artery, clinical indicators, and the means of various BP parameters can effectively predict the risk of CI in elderly individuals.

Translational large animal model of coronary microvascular embolism: characterization by serial cardiac magnetic resonance and histopathology.

This study aimed to construct a large animal model of coronary microvascular embolism, and investigate whether it could mimic the clinical imaging phenotypes of myocardial hypoperfusion in patients with ST-segment elevation myocardial infarction (STEMI). Nine minipigs underwent percutaneous coronary embolization with microspheres, followed by cardiac magnetic resonance (CMR) on week 1, 2 and 4 post operation. Microvascular obstruction (MVO) was defined as the isolated hypointense core within the enhanced area on late gadolinium enhancement images, which evolved during a 4-week follow-up. Fibrotic fraction of the segments was measured by Masson trichrome staining using a panoramic analysis software. Iron deposit and macrophage infiltration were quantified based on Perl's blue and anti-CD163 staining, respectively. Seven out of 9 (77.8%) minipigs survived and completed all of the imaging follow-ups. Four out of 7 (57.1%) minipigs were identified as transmural infarct with MVO. The systolic wall thickening (SWT) of MVO zone was similar to that of infarct zone (P = 0.762). Histopathology revealed transmural deposition of collagen, with microvessels obstructed by microspheres. The fibrotic fraction of infarct with MVO segments was similar to that of infarct without MVO segments (P = 0.954). The fraction of iron deposit in infarct with MVO segments was higher than that of infarct without MVO segments (P < 0.05), but the fraction of macrophage infiltration between these two segments did not show statistical difference (P = 0.723). Large animal model of coronary microvascular embolism could mimic most clinical imaging phenotypes of myocardial hypoperfusion in patients with STEMI, demonstrated by serial CMR and histopathology.

Improved Wavelength Calibration by Modeling the Spectrometer.

Wavelength calibration is a necessary first step for a range of applications in spectroscopy. The relationship between wavelength and pixel position on the array detector is approximately governed by a low-order polynomial and traditional wavelength calibration involves first-, second-, and third-order polynomial fitting to the pixel positions of spectral lines from a well known reference lamp such as neon. However, these methods lose accuracy for bands outside of the outermost spectral line in the reference spectrum. We propose a fast and robust wavelength calibration routine based on modeling the optical system that is the spectrometer. For spectral bands within the range of spectral lines of the lamp, we report similar accuracy to second- and third-order fitting. For bands that lie outside of the range of spectral lines, we report an accuracy 12-121 times greater than that of third-order fitting and 2.5-6 times more accurate than second-order fitting. The algorithm is developed for both reflection and transmission spectrometers and tested for both cases. Compared with similar algorithms in the literature that use the physical model of the spectrometer, we search over more physical parameters in shorter time, and obtain superior accuracy. A secondary contribution in this paper is the introduction of new evaluation methods for wavelength accuracy that are superior to traditional evaluation.

ASPER-29 suppresses the metastasis of pancreatic cancer cells by dual inhibition of cathepsin-L and cathepsin-S.

Pancreatic cancer will be the second leading cause of cancer-related mortality worldwide due to its high rate of metastasis. Cathepsins (CATs) are effectors of invasive growth in various cancers. Currently, targeting CATs represents an attractive strategy for the treatment of highly metastatic cancers with high CATs activity, such as pancreatic cancer. To develop a stronger antimetastatic agent, ASPER-29, a novel inhibitor of CATs designed by using the asperphenamate derivative BBP as a lead compound, was synthesized, and its therapeutic potential in pancreatic cancer metastasis was investigated in this study. Molecular docking and enzyme inhibition assays proved that ASPER-29 can inhibit the activity of CAT-L and CAT-S by binding with these enzymes in classical action modes. Furthermore, ASPER-29 significantly inhibited the activity of CAT-L and CAT-S but had no effect on their expression in PANC-1 and BxPC-3 cells. The in vitro antimetastatic activities of ASPER-29 were examined by wound healing and Transwell chamber assays. We found that ASPER-29 inhibited the migration and invasion of PANC-1 and BxPC-3 cells in a concentration-dependent manner. Moreover, the in vivo antimetastatic effects of ASPER-29 were confirmed in a mouse xenotransplantation model. H&E staining and immunohistochemistry assays of Ki67 and CEACAM6 proved that ASPER-29 treatment significantly blocked the metastasis of pancreatic cancer cells to lung and liver tissues. Additionally, the activity of both CAT-L and CAT-S was markedly inhibited in the lung and liver tissues of ASPER-29-administered mice compared with the mice in the model group, suggesting that the metastasis-blocking effect of ASPER-29 should be mediated via inhibition of the activity of CAT-L and CAT-S in pancreatic cancer cells. Together, our results demonstrated that ASPER-29, as a novel inhibitor of CAT-L and CAT-S, possessed the evident ability to block the metastasis of pancreatic cancer cells.

Health Effects of Peptides Extracted from Deer Antler.

Deer antler is widely used as a nutraceutical in Asian countries. In the past decades, deer antler peptides (DAPs) have received considerable attention because of their various biological properties such as antioxidant, anti-inflammatory, anti-bone damage, anti-neurological disease, anti-tumor and immunomodulatory properties. This review describes the production methods of DAPs and the recent progress of research on DAPs, focusing on the physiological functions and their regulatory mechanisms.

A Comparative Study of Systolic and Diastolic Mechanical Synchrony in Canine, Primate, and Healthy and Failing Human Hearts.

Aim: Mechanical dyssynchrony (MD) is associated with heart failure (HF) and may be prognostically important in cardiac resynchronization therapy (CRT). Yet, little is known about its patterns in healthy or diseased hearts. We here investigate and compare systolic and diastolic MD in both right (RV) and left ventricles (LV) of canine, primate and healthy and failing human hearts. Methods and Results: RV and LV mechanical function were examined by pulse-wave Doppler in 15 beagle dogs, 59 rhesus monkeys, 100 healthy human subjects and 39 heart failure (HF) patients. This measured RV and LV pre-ejection periods (RVPEP and LVPEP) and diastolic opening times (Q-TVE and Q-MVE). The occurrence of right (RVMDs) and left ventricular systolic mechanical delay (LVMDs) was assessed by comparing RVPEP and LVPEP values. That of right (RVMDd) and left ventricular diastolic mechanical delay (LVMDd) was assessed from the corresponding diastolic opening times (Q-TVE and Q-MVE). These situations were quantified by values of interventricular systolic (IVMDs) and diastolic mechanical delays (IVMDd), represented as positive if the relevant RV mechanical events preceded those in the LV. Healthy hearts in all species examined showed greater LV than RV delay times and therefore positive IVMDs and IVMDd. In contrast a greater proportion of the HF patients showed both markedly increased IVMDs and negative IVMDd, with diastolic mechanical asynchrony negatively correlated with LVEF. Conclusion: The present IVMDs and IVMDd findings have potential clinical implications particularly for personalized setting of parameter values in CRT in individual patients to achieve effective treatment of HF.

Up regulation of annexin A2 on murine H22 hepatocarcinoma cells induced by cartilage polysaccharide.

In this study, we investigated the antitumor effect of a tumor vaccine prepared from H22 hepatocarcinoma cells induced by cartilage polysaccharide. We found out there were specific antigens which combined with antigen-specific antibodies from immune murine serum. Results of western blot analysis showed that about 36 kDa make specific antibodies appeared specific antibodies in antiserum of immune mice, whereas the best immune effects became visible at the induction time of 48 h. Analyses of 2-dimensional electrophoresis identified the specific antigen was annexin A2, which was a glycosylated protein that contained a glycosylation site, closely related to oncogenesis, cancer development, invasion and metastasis. Proteomics indicated that both quantity and conformation of annexin A2 were changed after induced by cartilage polysaccharide. Lastly, we found there was a major increase of annexin A2 mRNA on H22 cells induced by cartilage polysaccharide. In summary, our data suggested that annexin A2, a specific antigen played a key role in antitumor immune response and activating the immune system. It would be a potential type of tumor vaccine which provided new ideas for tumor immunoprophylaxis.