Asparagine Synthetase Marks a Distinct Dependency Threshold for Cardiomyocyte Dedifferentiation.

BACKGROUND: Adult mammalian cardiomyocytes have limited proliferative capacity, but in specifically induced contexts they traverse through cell-cycle reentry, offering the potential for heart regeneration. Endogenous cardiomyocyte proliferation is preceded by cardiomyocyte dedifferentiation (CMDD), wherein adult cardiomyocytes revert to a less matured state that is distinct from the classical myocardial fetal stress gene response associated with heart failure. However, very little is known about CMDD as a defined cardiomyocyte cell state in transition. METHODS: Here, we leveraged 2 models of in vitro cultured adult mouse cardiomyocytes and in vivo adeno-associated virus serotype 9 cardiomyocyte-targeted delivery of reprogramming factors (Oct4, Sox2, Klf4, and Myc) in adult mice to study CMDD. We profiled their transcriptomes using RNA sequencing, in combination with multiple published data sets, with the aim of identifying a common denominator for tracking CMDD. RESULTS: RNA sequencing and integrated analysis identified Asparagine Synthetase (Asns) as a unique molecular marker gene well correlated with CMDD, required for increased asparagine and also for distinct fluxes in other amino acids. Although Asns overexpression in Oct4, Sox2, Klf4, and Myc cardiomyocytes augmented hallmarks of CMDD, Asns deficiency led to defective regeneration in the neonatal mouse myocardial infarction model, increased cell death of cultured adult cardiomyocytes, and reduced cell cycle in Oct4, Sox2, Klf4, and Myc cardiomyocytes, at least in part through disrupting the mammalian target of rapamycin complex 1 pathway. CONCLUSIONS: We discovered a novel gene Asns as both a molecular marker and an essential mediator, marking a distinct threshold that appears in common for at least 4 models of CMDD, and revealing an Asns/mammalian target of rapamycin complex 1 axis dependency for dedifferentiating cardiomyocytes. Further study will be needed to extrapolate and assess its relevance to other cell state transitions as well as in heart regeneration.

Analysis of influencing factors of HPV vaccination willingness of female sex workers in urban entertainment venues based on the IMB model in Guangxi, China.

OBJECTIVE: Understanding HPV vaccination willingness and its influencing factors among female sex workers (FSWs) in entertainment venues in an urban area of Guangxi, China. METHODS: From 15 August to 15 October 2022, FSWs in entertainment venues with commercial sex trade in an urban area of Guangxi were selected as the study subjects for the questionnaire survey using the method of intentional sampling. The questionnaire based on the information-motivation-behavior (IMB) skills model was used to collect the basic characteristics, HPV and HPV vaccine-related information and cognition, motivation to vaccinate, behavioral skills and willingness to vaccinate from the research targets. A multifactor logistic regression model was used to analyze the factors influencing the research targets' willingness to receive HPV vaccination. RESULTS: Of the 921 research targets, 712 (77.31%) were willing to receive HPV vaccination. The higher the level of knowledge regarding HPV and HPV vaccine-related information, the higher the motivation for HPV vaccination. In addition, the higher the behavioral skills score, the higher the willingness of FSWs in entertainment venues to receive HPV vaccination (P<0.001). FSWs in entertainment venues with lower venue grades [OR(95% CI)=0.693 (0.539, 0.891), P=0.004] were more reluctant to receive HPV vaccination. Those who favored the effectiveness of the vaccine in preventing the disease [OR(95% CI)=2.144 (1.449, 3.174), P<0.001] and those who had heard of HPV vaccine [OR(95% CI)=2.105 (1.451, 3.054), P<0.001], were able to perceive the benefits of HPV vaccination [OR(95% CI)=1.134 (1.045, 1.230), P=0.002]. These individuals acquired greater behavioral skills i.e., self-decision making for HPV vaccination [OR(95% CI)=1.130 (1.008, 1.267), P=0.036] and self-efficacy [OR(95% CI)=1.135 (1.081, 1.191), P<0.001] and they were more willing to receive HPV vaccine. CONCLUSIONS: There was a relatively high HPV vaccination willingness among FSWs in entertainment venues in an urban area of Guangxi, China. Attention should be focused on introducing the benefits of primary prevention measures such as the HPV vaccine for individuals and behavioral skills for HPV vaccination in order to increase their willingness to be vaccinated thus increasing their HPV vaccination rate.

Systematic in vivo candidate evaluation uncovers therapeutic targets for LMNA dilated cardiomyopathy and risk of Lamin A toxicity.

BACKGROUND: Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most common form of autosomal dominant DCM. LMNA DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate LMNA DCM. However, it is unknown whether these candidates could serve as potential therapeutic targets especially in long term efficacy. METHODS: We evaluated 14 potential candidates including Lmna gene products (Lamin A and Lamin C), key signaling pathways (Tgfß/Smad, mTor and Fgf/Mapk), calcium handling, proliferation regulators and modifiers of LINC complex function in a cardiac specific Lmna DCM model. Positive candidates for improved cardiac function were further assessed by survival analysis. Suppressive roles and mechanisms of these candidates in ameliorating Lmna DCM were dissected by comparing marker gene expression, Tgfß signaling pathway activation, fibrosis, inflammation, proliferation and DNA damage. Furthermore, transcriptome profiling compared the differences between Lamin A and Lamin C treatment. RESULTS: Cardiac function was restored by several positive candidates (Smad3, Yy1, Bmp7, Ctgf, aYAP1, Sun1, Lamin A, and Lamin C), which significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. Importantly, Lamin A treatment improved but could not reproduce long term survival, and Lamin A administration to healthy hearts itself induced DCM. Mechanistically, we identified this lapse as caused by a dose-dependent toxicity of Lamin A, which was independent from its maturation. CONCLUSIONS: In vivo candidate evaluation revealed that supplementation of Lamin C or knockdown of Sun1 significantly suppressed Lmna DCM and achieve prolonged survival. Conversely, Lamin A supplementation did not rescue long term survival and may impart detrimental cardiotoxicity risk. This study highlights a potential of advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.

Integration of external signaling pathways with the core transcriptional network in embryonic stem cells.

Transcription factors (TFs) and their specific interactions with targets are crucial for specifying gene-expression programs. To gain insights into the transcriptional regulatory networks in embryonic stem (ES) cells, we use chromatin immunoprecipitation coupled with ultra-high-throughput DNA sequencing (ChIP-seq) to map the locations of 13 sequence-specific TFs (Nanog, Oct4, STAT3, Smad1, Sox2, Zfx, c-Myc, n-Myc, Klf4, Esrrb, Tcfcp2l1, E2f1, and CTCF) and 2 transcription regulators (p300 and Suz12). These factors are known to play different roles in ES-cell biology as components of the LIF and BMP signaling pathways, self-renewal regulators, and key reprogramming factors. Our study provides insights into the integration of the signaling pathways into the ES-cell-specific transcription circuitries. Intriguingly, we find specific genomic regions extensively targeted by different TFs. Collectively, the comprehensive mapping of TF-binding sites identifies important features of the transcriptional regulatory networks that define ES-cell identity.

O-Fluorobenzoic Acid-Mediated Construction of Porous Graphitic Carbon Nitride with Nitrogen Defects for Multicolor Electrochemiluminescence Imaging Sensing.

Graphitic carbon nitride (g-CN) is an attractive electrochemiluminescence (ECL) luminophore. However, g-CN with wavelength-tunable ECL emission is still limited, which limits its application in multicolor ECL sensing and imaging analysis. In this study, porous g-CN (PCN) with nitrogen defects was synthesized through the condensation of melamine by using o-fluorobenzoic acid (o-FBA) as an effective regulation reagent. A series of PCNs, including PCN-5%, PCN-10%, and PCN-30%, were obtained by changing the mass ratio of o-FBA and melamine. The porous structure and tunable chemical composition change of the PCNs were carefully characterized. The nitrogen defects and porous structure of the synthesized PCNs can enlarge the specific surface area, facilitate electron transfer, and generate various surface states with gradually changed energy bands, leading to wavelength-tunable multicolor ECL emissions. Accordingly, g-CN, PCN-5%, PCN-10%, and PCN-30% can generate navy blue, turquoise blue, turquoise green, and olive green ECL emissions, respectively, with the peak ECL wavelength varied from 465 to 550 nm. Then, a multicolor ECL sensing array was proposed for the discrimination of polyphenols based on the prepared g-CN and PCNs by using a smartphone as a portable detector for the first time. Five polyphenol substances including vitamin P, resveratrol, phloretin, phlorizin, and caffeic acid were discriminated by using principal component analysis and hierarchical cluster analysis. The present work provides a simple strategy to adjust the ECL wavelength of g-CN and presents a simple way to fabricate multicolor ECL sensing array, which has great application potential for multiplexed analysis and multicolor ECL imaging sensing.

Multifunctionalized Hydrogel Beads for Label-Free Chemiluminescence Imaging Immunoassay of Acute Myocardial Infarction Biomarkers.

Hydrogel beads exhibit good biocompatibility, high stability, and monodispersity. However, hydrogel beads possessing intensive and multicolor chemiluminescence (CL) have not been reported. In this work, two kinds of multifunctionalized hydrogel beads, one consisting of chitosan (CS), Co2+, luminol, and gold nanoparticles (AuNPs) (CS-Co2+-Lu-Au), and another consisting of CS, Co2+, luminol, fluorescein, and AuNPs (CS-Co2+-Lu-FL-Au), were prepared via a facile synthesis method. The synthesized CS-Co2+-Lu-Au and CS-Co2+-Lu-FL-Au hydrogel beads exhibit high stability, simple operability, and can generate strong and uniform blue- and green-colored CL emission, respectively, when reacting with H2O2. Specific antibodies (Ab) can be assembled onto the surface of CS-Co2+-Lu-Au and CS-Co2+-Lu-FL-Au hydrogel beads directly via CS and surface-coated AuNPs as binding sites to obtain multifunctionalized hydrogel beads with both good CL activity and immunoactivity. Then, simple, fast, and versatile label-free CL imaging immunoassays were fabricated for the determination of two important acute myocardial infarction (AMI) biomarkers, including cardiac troponins I (cTnI) and heart-type fatty acid-binding protein (h-FABP), using a smartphone as a portable detector. The proposed CL imaging immunoassays using CS-Co2+-Lu-Au-Ab and CS-Co2+-Lu-FL-Au-Ab as sensing platforms can be carried out without complex instruments or time-consuming centrifugation or magnetic separation, greatly simplifying the assay procedures. The linear ranges for cTnI and h-FABP detection were 1.0 × 10-11 to 1.0 × 10-5 g/mL with detection limits as low as 1.57 and 1.61 pg/mL, respectively. Furthermore, the fabricated CL imaging immunoassays were successfully applied to determine cTnI and h-FABP in healthy human and patient serum samples, demonstrating their practicability in AMI diagnosis. The easy synthesis and versatility of the as-prepared CL hydrogel beads for the direct immobilization of Ab provide universal platforms for a wide range of CL immunoassays.

Health-related quality of life and influencing factors in drug addicts based on the scale QLICD-DA: a cross-sectional study.

BACKGROUND: Drug abuse has many negative effects not only on individuals but also on society. Nowadays, researchers pay a lot of attention to quality of life of drug addicts. However, there are few scales available to measure quality of life of drug addicts. The scale QLICD-DA (quality of life instrument for chronic diseases-drug addition) developed by modular approach could be used to measure quality of life of drug addicts with good validity, reliability and sensitivity. OBJECTIVE: This study is aimed to understand the quality of life status and influencing factors in drug addicts by suitable sensitively scale, with the hypothesis of the quality of life in drug addicts being different from that of other peoples and possibly being influenced by many factors. METHODS: By cluster random sampling method, 192 drug addicts at Kunming compulsory drug rehabilitation center were recruited to take part in the investigation. All participants completed the general information questionnaire and the scale QLICD-DA. We used a t-test to compare the scores of the quality of life of the participants with the norm (QOL scores from 1953 patients of 10 chronic diseases). A stepwise regression method was applied to explore the influencing factors of the quality of life in drug addicts. RESULTS: 192 participants ranged in age from 19 to 59 with an average age of 34.86. Most of them were male (70.3%), high school education level (67.7%) and of Han nationality (82.8%). The quality of life of drug addicts was lower than the norm in the physical domain, psychological domain, social domain, and general module, and the differences were statistically significant (p < 0.001). Sex and mode of drug abuse were the influencing factors in total score (p = 0.006) and specific module (p = 0.019). Past family atmosphere and the mode of drug abuse were the influencing factors in the general module (p = 0.027, p = 0.037). CONCLUSION: The quality of life of drug addicts was worse than that of patients with other chronic diseases, and the influencing factors of the quality of life of drug abusers were sex, mode of drug abuse, and past family atmosphere.

Yin Yang 1 Suppresses Dilated Cardiomyopathy and Cardiac Fibrosis Through Regulation of Bmp7 and Ctgf.

RATIONALE: Pathogenic variations in the lamin gene (LMNA) cause familial dilated cardiomyopathy (DCM). LMNA insufficiency caused by LMNA pathogenic variants is believed to be the basic mechanism underpinning LMNA-related DCM. OBJECTIVE: To assess whether silencing of cardiac Lmna causes DCM and investigate the role of Yin Yang 1 (Yy1) in suppressing Lmna DCM. METHODS AND RESULTS: We developed a Lmna DCM mouse model induced by cardiac-specific Lmna short hairpin RNA. Silencing of cardiac Lmna induced DCM with associated cardiac fibrosis and inflammation. We demonstrated that upregulation of Yy1 suppressed Lmna DCM and cardiac fibrosis by inducing Bmp7 expression and preventing upregulation of Ctgf. Knockdown of upregulated Bmp7 attenuated the suppressive effect of Yy1 on DCM and cardiac fibrosis. However, upregulation of Bmp7 alone was not sufficient to suppress DCM and cardiac fibrosis. Importantly, upregulation of Bmp7 together with Ctgf silencing significantly suppressed DCM and cardiac fibrosis. Mechanistically, upregulation of Yy1 regulated Bmp7 and Ctgf reporter activities and modulated Bmp7 and Ctgf gene expression in cardiomyocytes. Downregulation of Ctgf inhibited TGF-ß (transforming growth factor-ß)/Smad signaling in DCM hearts. Regulation of both Bmp7 and Ctgf further suppressed TGFß/Smad signaling. In addition, co-modulation of Bmp7 and Ctgf reduced CD3+ T cell numbers in DCM hearts. CONCLUSIONS: Our findings demonstrate that upregulation of Yy1 or co-modulation of Bmp7 and Ctgf offer novel therapeutic strategies for the treatment of DCM caused by LMNA insufficiency.

Cobalt-imidazole metal-organic framework loaded with luminol for paper-based chemiluminescence detection of catechol with use of a smartphone.

Chemiluminescence (CL) reagent luminol was loaded into the porous structure of cobalt-imidazole metal-organic framework (MOF) ZIF-67 to obtain luminol-functionalized ZIF-67 (luminol@ZIF-67) with CL property. The morphology, composition, CL property, and CL mechanism of luminol@ZIF-67 were carefully investigated. The obtained luminol@ZIF-67 exhibited strong, stable, and visible CL emission that reacted with H2O2, attributed to the strong catalytic effect of ZIF-67 combined with the shortened diffusion distance between luminol and the catalytic center. The CL intensity of luminol@ZIF-67 was more than 550 times higher than that of luminol. Catechol can effectively quench the CL emission of luminol@ZIF-67 that reacted with H2O2. Then, a simple paper-based CL imaging detection method was developed for the detection of catechol by using a smartphone as a portable detector. The linear calibration curve of the developed CL assay for catechol ranged from 5 to 100 mg/L with detection limit of 1.1 mg/L (S/N = 3δ). The strong CL emission of luminol@ZIF-67 combined with the effective quench ability of catechol guaranteed high sensitivity of the detection method. The practical application ability of the developed CL assay was tested by the determination of catechol in tea and tap water samples, resulting in acceptable results. This work provides an effective paper-based CL detection method for catechol and enriches the species of the chemiluminescent MOF material.

Engineered Circular RNA Sponges Act as miRNA Inhibitors to Attenuate Pressure Overload-Induced Cardiac Hypertrophy.

Circular RNAs (circRNAs) sequester microRNAs (miRNAs) and repress their endogenous activity. We hypothesized that artificial circRNA sponges (circmiRs) can be constructed to target miRNAs therapeutically, with a low dosage requirement and extended half-lives compared to current alternatives. This could present a new treatment approach for critical global pathologies, including cardiovascular disease. Here, we constructed a circmiR sponge to target known cardiac pro-hypertrophic miR-132 and -212. Expressed circmiRs competitively inhibited miR-132 and -212 activity in luciferase rescue assays and showed greater stability than linear sponges. A design containing 12 bulged binding sites with 12 nucleotides spacing was determined to be optimal. Adeno-associated viruses (AAVs) were used to deliver circmiRs to cardiomyocytes in vivo in a transverse aortic constriction (TAC) mouse model of cardiac disease. Hypertrophic disease characteristics were attenuated, and cardiac function was preserved in treated mice, demonstrating the potential of circmiRs as novel therapeutic tools. Subsequently, group I permutated intron-exon sequences were used to directly synthesize exogenous circmiRs, which showed greater in vitro efficacy than the current gold standard antagomiRs in inhibiting miRNA function. Engineered circRNAs thus offer exciting potential as future therapeutics.

Robust CTCF-Based Chromatin Architecture Underpins Epigenetic Changes in the Heart Failure Stress-Gene Response.

BACKGROUND: The human genome folds in 3 dimensions to form thousands of chromatin loops inside the nucleus, encasing genes and cis-regulatory elements for accurate gene expression control. Physical tethers of loops are anchored by the DNA-binding protein CTCF and the cohesin ring complex. Because heart failure is characterized by hallmark gene expression changes, it was recently reported that substantial CTCF-related chromatin reorganization underpins the myocardial stress-gene response, paralleled by chromatin domain boundary changes observed in CTCF knockout. METHODS: We undertook an independent and orthogonal analysis of chromatin organization with mouse pressure-overload model of myocardial stress (transverse aortic constriction) and cardiomyocyte-specific knockout of Ctcf. We also downloaded published data sets of similar cardiac mouse models and subjected them to independent reanalysis. RESULTS: We found that the cardiomyocyte chromatin architecture remains broadly stable in transverse aortic constriction hearts, whereas Ctcf knockout resulted in ≈99% abolition of global chromatin loops. Disease gene expression changes correlated instead with differential histone H3K27-acetylation enrichment at their respective proximal and distal interacting genomic enhancers confined within these static chromatin structures. Moreover, coregulated genes were mapped out as interconnected gene sets on the basis of their multigene 3D interactions. CONCLUSIONS: This work reveals a more stable genome-wide chromatin framework than previously described. Myocardial stress-gene transcription responds instead through H3K27-acetylation enhancer enrichment dynamics and gene networks of coregulation. Robust and intact CTCF looping is required for the induction of a rapid and accurate stress response.

Correlation between lumbar multifidus fat infiltration and lumbar postoperative infection: a retrospective case-control study.

BACKGROUND: The aim of this study was to investigate the correlation between lumbar multifidus fat infiltration and lumbar postoperative surgical site infection (SSI). Several clinical studies have found that spine postoperative SSI is associated with age, diabetes, obesity, and multilevel surgery. However, few studies have focused on the correlation between lumbar multifidus fat infiltration and SSI. METHOD: A retrospective review was performed on patients who underwent posterior lumbar interbody fusion (PLIF) between 2011 and 2016 at our hospital. The patients were divided into SSI and non-SSI groups. Data of risk factors [age, diabetes, obesity, body mass index (BMI), number of levels, and surgery duration] and indicators of body mass distribution (subcutaneous fat thickness and multifidus fat infiltration) were collected. The degree of multifidus fat infiltration was analyzed on magnetic resonance images using Image J. RESULTS: Univariate analysis indicated that lumbar spine postoperative SSI was associated with urinary tract infection, subcutaneous fat thickness, lumbar multifidus muscle (LMM) fat infiltration, multilevel surgery (≥2 levels), surgery duration, drainage duration, and number of drainage tubes. In addition, multiple logistic regression analysis revealed that spine SSI development was associated with sex (male), age (> 60 years), subcutaneous fat thickness, LMM fat infiltration, and drainage duration. Receiver operating characteristic curve analysis indicated that the risk of SSI development was higher when the percentage of LMM fat infiltration exceeded 29.29%. Furthermore, Pearson's correlation analysis demonstrated that LMM fat infiltration was correlated with age but not with BMI. CONCLUSION: Indicators of body mass distribution may better predict SSI risk than BMI following PLIF. Lumbar Multifidus fat infiltration is a novel spine-specific risk factor for SSI development.

De novo mutations in histone-modifying genes in congenital heart disease.

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.

[Breeding and variety characteristics of a new variety of Fritillaria thunbergii "Zhebei 3"].

A new variety "Zhebei 3(Zhejiao Pharmaceutical 2018002)" was selected and bred from multi seeded Fritillaria thunbergii mutants by systematic breeding method. From 2012 to 2016, the traits assessment, disease resistance appraisal, plot ratios and regional trials of the variety were continuously carried out. The results showed that "Zhebei 3" emerged early and had late seedlings. The average growth period was about 100 days, which was 6 days and 12 days higher than the "Zhebei 1" and "Zhebei 2". The average yield was 5 095.5 kg·hm~(-2), which was 14.42% and 17.71% higher than of the control respectively. The average proliferation rate of bulbs was 261.2%, which was 37.46% and 31.58% higher than that of the control, respectively. The propagation coefficient of bulbs was about 1∶2.6, and the total amount of peimine and peiminine was 0.172 2%, which was 4.49% and 29.47% higher than the control, respectively. The identification of disease resistance showed that it was resistance to bulb stem(soft) rot, better than the control. "Zhebei 3" has stable characters, high yield, good quality, strong disease resistance, and moderate propagation coefficient which is suitable for planting in Zhejiang province.

Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis.

Homozygous cardiac myosin binding protein C-deficient (Mybpc(t/t)) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold. We have investigated the mechanism of cardiac enlargement in these hearts. Throughout embryogenesis myocytes undergo cell division while maintaining the capacity to pump blood by rapidly disassembling and reforming myofibrillar components of the sarcomere throughout cell cycle progression. Shortly after birth, myocyte cell division ceases. Cardiac MYBPC is a thick filament protein that regulates sarcomere organization and rigidity. We demonstrate that many Mybpc(t/t) myocytes undergo an additional round of cell division within 10 d postbirth compared with their wild-type counterparts, leading to increased numbers of mononuclear myocytes. Short-hairpin RNA knockdown of Mybpc3 mRNA in wild-type mice similarly extended the postnatal window of myocyte proliferation. However, adult Mybpc(t/t) myocytes are unable to fully regenerate the myocardium after injury. MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression. We suggest that human patients with homozygous MYBPC3-null mutations develop dilated cardiomyopathy, coupled with myocyte hyperplasia (increased cell number), as observed in Mybpc(t/t) mice. Human patients, with heterozygous truncating MYBPC3 mutations, like mice with similar mutations, have hypertrophic cardiomyopathy. However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3(+/-) individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3(-/-) mice is primarily myocyte hyperplasia.

[Ecology suitability study of Trollius chinensis].

Based on the distribution information of 110 samples and 55 environmental factors, Maxent model was used to predict the ecology suitability regions of Trollius chinensis. The study aims at providing theory basis for the cultivation of T. chinensis. The results showed that the Maxent model prediction result was good (AUC>0.9) and the main factors effecting the ecology suitability regions of T. chinensis were precipitation in July, standard deviation of seasonal variation of temperature, annual mean temperature, precipitation in August and altitude. The ecology suitable regions of T. chinensis mainly concentrated in Shanxi, Hebei, east of Inner Mongolia, west of Jilin and Liaoning, north of Shaanxi, south of Ningxia, east and south of Gansu, and east of Qinghai. The results indicated that except for traditional distribution regions, north of Shaanxi, south of Ningxia, east and south of Gansu, and east of Qinghai could selected as the regions for cultivation of T. chinensis. It provides theory basis for selecting suitable regions to cultivate T. chinensis.

Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model.

RATIONALE: Yes-associated protein (YAP), the terminal effector of the Hippo signaling pathway, is crucial for regulating embryonic cardiomyocyte proliferation. OBJECTIVE: We hypothesized that YAP activation after myocardial infarction (MI) would preserve cardiac function and improve survival. METHODS AND RESULTS: We used a cardiac-specific, inducible expression system to activate YAP in adult mouse heart. Activation of YAP in adult heart promoted cardiomyocyte proliferation and did not deleteriously affect heart function. Furthermore, YAP activation after MI preserved heart function and reduced infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery vector, we expressed human YAP (hYAP) in the adult murine myocardium immediately after MI. We found that AAV9:hYAP significantly improved cardiac function and mouse survival. AAV9:hYAP did not exert its salutary effects by reducing cardiomyocyte apoptosis. Rather, AAV9:hYAP stimulated adult cardiomyocyte proliferation. Gene expression profiling indicated that AAV9:hYAP stimulated expression of cell cycle genes and promoted a less mature cardiac gene expression signature. CONCLUSIONS: Cardiac-specific YAP activation after MI mitigated myocardial injury, improved cardiac function, and enhanced survival. These findings suggest that therapeutic activation of YAP or its downstream targets, potentially through AAV-mediated gene therapy, may be a strategy to improve outcome after MI.

A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity.

The derivation of human ES cells (hESCs) from human blastocysts represents one of the milestones in stem cell biology. The full potential of hESCs in research and clinical applications requires a detailed understanding of the genetic network that governs the unique properties of hESCs. Here, we report a genome-wide RNA interference screen to identify genes which regulate self-renewal and pluripotency properties in hESCs. Interestingly, functionally distinct complexes involved in transcriptional regulation and chromatin remodelling are among the factors identified in the screen. To understand the roles of these potential regulators of hESCs, we studied transcription factor PRDM14 to gain new insights into its functional roles in the regulation of pluripotency. We showed that PRDM14 regulates directly the expression of key pluripotency gene POU5F1 through its proximal enhancer. Genome-wide location profiling experiments revealed that PRDM14 colocalized extensively with other key transcription factors such as OCT4, NANOG and SOX2, indicating that PRDM14 is integrated into the core transcriptional regulatory network. More importantly, in a gain-of-function assay, we showed that PRDM14 is able to enhance the efficiency of reprogramming of human fibroblasts in conjunction with OCT4, SOX2 and KLF4. Altogether, our study uncovers a wealth of novel hESC regulators wherein PRDM14 exemplifies a key transcription factor required for the maintenance of hESC identity and the reacquisition of pluripotency in human somatic cells.

Comparison of VerifyNow P2Y12 and thrombelastography for assessing clopidogrel response in stroke patients in China.

Poor response to clopidogrel is often associated with recurrent ischemic events, and reliable platelet function tests are needed to identify clopidogrel low response (CLR). The aim of the study was to compare the consistency of VerifyNow P2Y12 and thrombelastography (TEG) in acute ischemic stroke patients treated with clopidogrel. Patients hospitalized in Changhai Hospital from August 2012 to September 2013 and assigned to treatment with a daily 75-mg dose of clopidogrel. The blood samples were taken on the 5-7th day to assess the capability of VerifyNow P2Y12 and TEG for evaluation of clopidogrel response, and all instrument parameters were used to perform correlation analysis. Patients with CLR were detected by using the methods and criteria published earlier (PRU ≥ 230 assayed by VerifyNow P2Y12 or TEG-Inhib% ≤30 % measured by TEG). Totally 58 patients were enrolled for the study and there were wide varieties in parameters of VerifyNow P2Y12 and TEG. Results showed a total of 17 and 9 patients, respectively, identified as CLR assessed by VerifyNow P2Y12 and TEG, but only three patients were detected to be clopidogrel low responders with both tests. The kappa consistency analysis showed poor consistency between VerifyNow P2Y12 and TEG results in terms of CLR (Kappa = -0.0349, p = 0.7730). Linear regression also demonstrated poor correlation between VerifyNow-PRU/VerifyNow-Inhib% and TEG-Inhib% (p = 0.07901 and p = 0.3788, respectively). Our study demonstrated that there was poor correlation between VerifyNow P2Y12 and TEG results, and VerifyNow P2Y12 showed a larger proportion of CLR than TEG.

Is duration of preoperative anti-tuberculosis treatment a risk factor for postoperative relapse or non-healing of spinal tuberculosis?

PURPOSE: This study evaluated the relationship between spinal TB postoperative recurrence or non-healing and duration of preoperative anti-TB treatment (ATT). METHODS: From January 2004 to January 2013, patients who underwent surgery for spinal TB and met this study's inclusion criteria were retrospectively reviewed. Observed parameters were age, sex, initial ESR, preoperative ESR, degree of ESR change, initial CRP, preoperative CRP, degree of CRP change, duration of preoperative ATT, surgical approach, presence of internal fixation, location of spinal lesion, number of involved segments, duration of operation, and intraoperative blood loss. The data were analyzed by univariate and multivariate analyses for spinal TB recurrence or non-healing to determine related risk factors. RESULTS: A total of 223 patients met the inclusion criteria. There were 84 female and 139 male patients with a mean age of 42.2 years (range 2-85 years). The follow-up period was 18-72 months (average 28.7 months). Among 223 patients observed, 23 patients had postoperative relapse or non-healing (10.3 %) during the follow-up period. Statistical analysis indicated that the location of a spinal lesion was significantly associated with postoperative relapse or non-healing. Risk of postoperative relapse or non-healing in thoracolumbar TB was 2.524-fold (95 % CI 1.026-6.580) that of lumbosacral TB. CONCLUSIONS: Duration of preoperative ATT may not be a risk factor for postoperative recurrence or non-healing of spinal TB. Junctional zones such as the lumbosacral and thoracolumbar junction have a higher recurrence rate than non junctional.