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Background: There is an increasing demand for minimally invasive aortic valve replacement. This study aimed to investigate the safety and feasibility of minimally invasive aortic valve replacement through a right parasternal second intercostal transverse incision. Methods: This was a retrospective study, and we collected information from 111 patients who underwent isolated aortic valve replacement surgery performed by the same surgeon from January 2018 to December 2019. According to the operative approach, the patients were divided into a sternotomy aortic valve replacement (SAVR) group (n = 62) and a minimally invasive aortic valve replacement (Mini-AVR) group (n = 49). We compared the intraoperative and postoperative data between the two groups. Result: There was no difference in preoperative data between the Mini-AVR and SAVR. The postoperative ventilator-assisted time, CSICU time and postoperative hospital stay of the Mini-AVR were shorter than those of the SAVR [(15.45 ± 5.75) VS (18.51 ± 6.71) h; (1.77 ± 0.31) VS (2.04 ± 0.63) d; (8.69 ± 2.75) VS (10.77 ± 2.94) d], and the difference was statistically significant (P

Background The causes of gestational diabetes mellitus (GDM) are still unclear. Recent studies have found that the imbalance of the gut microbiome could lead to disorders of human metabolism and immune system, resulting in GDM. This study aims to reveal the different gut compositions between GDM and normoglycemic pregnant women and find the relationship between gut microbiota and GDM. Methods Fecal microbiota profiles from women with GDM (n = 21) and normoglycemic women (n = 32) were assessed by 16S rRNA gene sequencing. Fasting metabolic hormone concentrations were measured using multiplex ELISA. Results Metabolic hormone levels, microbiome profiles, and inferred functional characteristics differed between women with GDM and healthy women. Additionally, four phyla and seven genera levels have different correlations with plasma glucose and insulin levels. Corynebacteriales (order), Nocardiaceae (family), Desulfovibrionaceae (family), Rhodococcus (genus), and Bacteroidetes (phylum) may be the taxonomic biomarkers of GDM. Microbial gene functions related to amino sugar and nucleotide sugar metabolism were found to be enriched in patients with GDM. Conclusion Our study indicated that dysbiosis of the gut microbiome exists in patients with GDM in the second trimester of pregnancy, and gut microbiota might be a potential diagnostic biomarker for the diagnosis, prevention, and treatment of GDM.

OBJECTIVE: Diagnosis of tuberculosis (TB) in multi-slice spiral computed tomography (CT) images is a difficult task in many TB prevalent locations in which experienced radiologists are lacking. To address this difficulty, we develop an automated detection system based on artificial intelligence (AI) in this study to simplify the diagnostic process of active tuberculosis (ATB) and improve the diagnostic accuracy using CT images. DATA: A CT image dataset of 846 patients is retrospectively collected from a large teaching hospital. The gold standard for ATB patients is sputum smear, and the gold standard for normal and pneumonia patients is the CT report result. The dataset is divided into independent training and testing data subsets. The training data contains 337 ATB, 110 pneumonia, and 120 normal cases, while the testing data contains 139 ATB, 40 pneumonia, and 100 normal cases, respectively. METHODS: A U-Net deep learning algorithm was applied for automatic detection and segmentation of ATB lesions. Image processing methods are then applied to CT layers diagnosed as ATB lesions by U-Net, which can detect potentially misdiagnosed layers, and can turn 2D ATB lesions into 3D lesions based on consecutive U-Net annotations. Finally, independent test data is used to evaluate the performance of the developed AI tool. RESULTS: For an independent test, the AI tool yields an AUC value of 0.980. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value are 0.968, 0.964, 0.971, 0.971, and 0.964, respectively, which shows that the AI tool performs well for detection of ATB and differential diagnosis of non-ATB (i.e. pneumonia and normal cases). CONCLUSION: An AI tool for automatic detection of ATB in chest CT is successfully developed in this study. The AI tool can accurately detect ATB patients, and distinguish between ATB and non- ATB cases, which simplifies the diagnosis process and lays a solid foundation for the next step of AI in CT diagnosis of ATB in clinical application.

Backgrounds Emerging evidences has demonstrated that dysregulation of long non-coding RNAs (lncRNAs) is critically involved in esophageal squamous cell carcinoma (ESCC) progression. However, the function of lncRNA PSMA3-AS1 in ESCC is unclear. Therefore, we aimed to explore the functions and potential mechanisms of PSMA3-AS1 in ESCC cells progression. Results Here, we found that PSMA3-AS1 expression was significantly up-regulated in ESCC tissues. Forced PSMA3-AS1 expression was correlated with tumor size, distant metastasis, and poor prognosis in ESCC patients. Functionally, PSMA3-AS1-overexpression promoted ESCC cells proliferation, invasion, and migration in vitro. Mechanistically, PSMA3-AS1 up-regulated EZH2 expression by competitively binding to miR-101. Conclusion PSMA3-AS1 is significantly up-regulated in ESCC tissues, and the PSMA3-AS1/miR-101/EZH2 axis plays a critical role in ESCC progression. Taken together, our results may provide promising targets for ESCC therapy. Methods PSMA3-AS1 and miR-101 expression were explored using qRT-PCR in ESCC tissues and cell lines. Immunohistochemistry assays were carried out to analyze EZH2 (enhancer of zeste homolog) protein expression. RIP, dual-luciferase reporter, fluorescence in situ hybridization, and biotin pull-down assays were used to detect the interactions of PSMA3-AS1, miR-101 and EZH2. The biological functions of PSMA3-AS1 in PSMA3-AS1-altered cells were explored using CCK-8, colony formation, wound healing, and transwell assays in vitro.

Objectives: An increase in the trimethylation of lysine 4 of histone 3 (H3K4me3) has been reported to be involved in the development of several types of tumors. However, the level and role of H3K4me3 in human esophageal cancer (HEC) remain unknown. Here, we assessed the role and clinical significance of H3K4me3 in HEC. Methods: The level of H3K4me3 was determined in 15 pairs of HEC and paracancerous tissues by Western blotting. A tissue microarray including samples from 100 HEC patients was analyzed by immunohistochemistry to determine the relationship between the level of H3K4me3 and the clinicopathological features of HEC patients. Then, the levels of H3K4me3 in HEC cells were elevated via knockdown of inhibitor of growth family member 4(Ing4) expression. Finally, the prognostic significance of H3K4me3 levels in HEC patients was further analyzed. Results: We found that H3K4me3 levels were frequently elevated in HEC tissues compared with adjacent esophageal tissues, and elevated H3K4me3 was significantly associated with poor tumor differentiation (p =1.39×10-5) and advanced tumor stage (p=8.5×10-5). After Ing4 knockdown in HEC cells, we found that the cell proliferation, metastasis, invasion and colony formation abilities were enhanced compared to those in the control cells. Notably, we found that HEC patients with a high level of H3K4me3 exhibited an unfavorable 5-year survival rate compared to those with a low level of H3K4me3 (p=6.8×10-5). The univariate analysis showed that the tumor differentiation, TNM stage, and H3K4me3 level were predictors of the overall survival rate of HEC patients. In the multivariate analysis, tumor stage (p=0.015) and H3K4me3 level (p=0.034) were revealed to be independent parameters for predicting the prognosis of HEC patients. Conclusions: Thus, high levels of H3K4me3 may be used as a meaningful biomarker for HEC prognosis evaluation.

Background CD8+ T cells play a critical role in the innate antitumour immune response. Recently, CD8+ T cell dysfunction has been verified in various malignant cancers, including non-small cell lung cancer (NSCLC). However, the molecular biological mechanisms of CD8+ T cell dysfunction in human NSCLC are still unclear. Methods The expression of circular ubiquitin-specific protease-7 (circUSP7) in NSCLC tissues, exosomes, and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Exosomes were isolated from the culture medium of NSCLC cells and the plasma of NSCLC patients using an ultracentrifugation method and the ExoQuick Exosome Precipitation Solution kit. The exosomes were then characterized by transmission electronic microscopy (TEM), NanoSight and western blotting. The role of circUSP7 in CD8+ T cell dysfunction was assessed by enzyme-linked immunosorbent assay (ELISA). In vivo circular RNA (circRNA) precipitation (circRIP), RNA immunoprecipitation (RIP), and luciferase reporter assays were performed to explore the molecular mechanisms of circUSP7 in CD8+ T cells. In a retrospective study, the clinical characteristics and prognostic significance of circUSP7 in NSCLC tissues were determined. Results The expression levels of circUSP7 were higher in human NSCLC tissues than in matched adjacent nontumour tissues. Increased levels of circUSP7 indicate poor clinical prognosis and CD8+ T cell dysfunction in patients with NSCLC. The circUSP7 found in NSCLC patient plasma is predominantly secreted by NSCLC cells in an exosomal manner, and circUSP7 inhibits IFN-γ, TNF-α, Granzyme-B and Perforin secretion by CD8+ T cells. Furthermore, circUSP7 inhibits CD8+ T cell function by upregulating the expression of Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) via sponging miR-934. Finally, we show that circUSP7 may promote resistance to anti-PD1 immunotherapy in NSCLC patients. Conclusions Exosomal circUSP7 is predominantly secreted by NSCLC cells and contributes to immunosuppression by promoting CD8+ T cell dysfunction in NSCLC. CircUSP7 induces resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for NSCLC patients.

IntroductionExposure to antibiotics (ABX) during pregnancy can have a systematic effect on both fetal and maternal health. Although previous biomonitoring studies have indicated the effects on children of extensive exposure to ABX, studies on pregnant women remain scarce. To explore the effect on pregnant women of environmental exposure to ABX through accidental ingestion and identify potential health risks, the present study investigated 122 pregnant women in East China between 2019 and 2020.Research design and methodsThe presence of six categories of ABX (quinolones, sulfonamides, lincosamides, tetracyclines, amide alcohol ABX, and β-lactams) in plasma samples taken from the pregnant women was investigated using an ABX kit and a time-resolved fluorescence immunoassay.ResultsAll six ABX were detected in the plasma, with a detection rate of 17.2%. It was discovered that the composition of intestinal flora in pregnant women exposed to ABX was different from that of pregnant women who had not been exposed to ABX. The intestinal flora of pregnant women exposed to ABX also changed at both the phylum and genus levels, and several genera almost disappeared. Furthermore, the metabolic levels of glucose and insulin and the alpha diversity of pregnant women exposed to ABX were higher than those of pregnant women not exposed to ABX.ConclusionPregnant women are potentially at higher risk of adverse microbial effects. Glucose metabolism and insulin levels were generally higher in pregnant women exposed to ABX than in unexposed women. Also, the composition and color of the gut microbiome changed.

This study was to assess the effect of the predictive model for distinguishing clear cell RCC (ccRCC) from non-clear cell RCC (non-ccRCC) by establishing predictive radiomic models based on enhanced-computed tomography (CT) images of renal cell carcinoma (RCC). A total of 190 cases with RCC confirmed by pathology were retrospectively analyzed, with the patients being randomly divided into two groups, including the training set and testing set according to the ratio of 7:3. A total of 396 radiomic features were computationally obtained and analyzed with the Correlation between features, Univariate Logistics and Multivariate Logistics. Finally, 4 features were selected, and three machine models (Random Forest (RF), Support Vector Machine (SVM) and Logistic Regression (LR)) were established to discriminate RCC subtypes. The radiomics performance was compared with that of radiologist diagnosis. In the testing set, the RF model had an area under the curve (AUC) value of 0.909, a sensitivity of 0.956, and a specificity of 0.538. The SVM model had an AUC value of 0.841, a sensitivity of 1.0, and a specificity of 0.231, in the testing set. The LR model had an AUC value of 0.906, a sensitivity of 0.956, and a specificity of 0.692, in the testing set. The sensitivity and specificity of radiologist diagnosis to differentiate ccRCC from non-ccRCC were 0.850 and 0.581, respectively, with the AUC value of the radiologist diagnosis as 0.69. In conclusion, radiomics models based on CT imaging data show promise for augmenting radiological diagnosis in renal cancer, especially for differentiating ccRCC from non-ccRCC.

BACKGROUND Cancer/testis antigen (CTA) is a class of antigen molecules expressed only in the germinal epithelium of testis and some tumor tissues. As an important CTA molecule, the expression of F-box protein 39 (FBXO39) in breast cancer (BC) and its clinical significance remain unclear. The objective of this study is to explore the value of FBXO39 in the diagnosis, efficacy monitoring, and prognostic evaluation of BC. METHODS The expression of FBXO39 mRNA in the serum exosomes of patients with BC before and after the initial diagnosis and treatment was detected by qRT-PCR, and the corresponding ROC curve was plotted. The expression of FBXO39 protein in BC cancer tissues was detected by immunohistochemistry, along with the analysis of the correlation between FBXO39 expression and clinical pathological features as well as prognosis of BC cases. RESULTS The serum-derived exosomes were successfully isolated and identified. The positive rate of FBXO39 mRNA in serum exosomes of patients with BC was up to 86%; there was a correlation between the expression level of serum exosomal FBXO39 and clinical staging, HER2, and Ki-67 expression (all with p < 0.05). The sensitivity of serum exosomal FBXO39 in distinguishing BC patients from healthy controls was 88%, with the specificity as 86%, and AUC as 0.9432. The expression change of FBXO39 in serum-sourced exosomes of patients with BC was related to their treatment situation, indicating that the level of FBXO39 decreased significantly after treatment. The expression of FBXO39 in cancer tissue was related to the clinical stage (p = 0.023) and lymphatic metastasis (p = 0.015) of the BC patients. Survival analysis showed that the expression of FBXO39 was negatively correlated with the prognosis of BC patients, with the high expression of FBXO39 indicating poor prognosis. CONCLUSIONS Serum-derived exosomal FBXO39 could serve as an important indicator of BC diagnosis and efficacy evaluation; FBXO39 could be rated as an important indicator of BC prognosis evaluation.

In recent years, circular RNAs (circRNAs) have been increasingly reported to play a crucial role in the proliferation, migration, and invasion of non-small-cell lung cancer (NSCLC) cells. However, the circRNA MET (circMET) oncogenic mechanism that drives NSCLC development and progression remains largely unknown. In this study, the present results demonstrated that circMET expression was significantly higher in NSCLC tissues than in peritumoral tissues using quantitative real-time polymerase chain reaction. Notably, NSCLC patients with a large tumor diameter, poor differentiation and lymphatic metastasis had high RNA levels of circMET. Moreover, high circMET expression served as an independent risk factor for short overall survival (OS) and progression-free survival (PFS) in NSCLC patients. Next, we validated that circMET overexpression can enhance NSCLC cell proliferation, metastasis, and immune evasion in vitro. Mechanistically, our study uncovers that circMET acts as a miR-145-5p sponge to upregulate CXCL3 expression. Collectively, circMET regulates the miR-145-5p/CXCL3 axis and serves as a novel, promising diagnostic and prognostic biomarker in patients with NSCLC.

Background Immune system evasion, distance tumor metastases, and increased cell proliferation are the main reasons for the progression of non-small cell lung cancer (NSCLC) and the death of NSCLC patients. Dysregulation of circular RNAs plays a critical role in the progression of NSCLC; therefore, further understanding the biological mechanisms of abnormally expressed circRNAs is critical to discovering novel, promising therapeutic targets for NSCLC treatment. Methods The expression of circular RNA fibroblast growth factor receptor 1 (circFGFR1) in NSCLC tissues, paired nontumor tissues, and cell lines was detected by RT-qPCR. The role of circFGFR1 in NSCLC progression was assessed both in vitro by CCK-8, clonal formation, wound healing, and Matrigel Transwell assays and in vivo by a subcutaneous tumor mouse assay. In vivo circRNA precipitation, RNA immunoprecipitation, and luciferase reporter assays were performed to explore the interaction between circFGFR1 and miR-381-3p. Results Here, we report that circFGFR1 is upregulated in NSCLC tissues, and circFGFR1 expression is associated with deleterious clinicopathological characteristics and poor prognoses for NSCLC patients. Forced circFGFR1 expression promoted the migration, invasion, proliferation, and immune evasion of NSCLC cells. Mechanistically, circFGFR1 could directly interact with miR-381-3p and subsequently act as a miRNA sponge to upregulate the expression of the miR-381-3p target gene C-X-C motif chemokine receptor 4 (CXCR4), which promoted NSCLC progression and resistance to anti-programmed cell death 1 (PD-1)- based therapy. Conclusion Taken together, our results suggest the critical role of circFGFR1 in the proliferation, migration, invasion, and immune evasion abilities of NSCLC cells and provide a new perspective on circRNAs during NSCLC progression.

Sustainable polyurethanes prepared from castor oil and diisocyanates show very low strength and toughness, due to the highly cross-linked and flexible structure. Herein, we report a new strategy to simultaneously reinforce and toughen castor oil-based polyurethane via incorporating a stiff component (isosorbide, IS) to enhance network stiffness and reduce crosslink density. The crosslinking degree decreases while the strength, moduli, ductility and heat resistance significantly increase accordingly with increasing IS content. The tensile behaviors are tunable over a broad range (either as elastomers or as plastics) depending on the compositions. The polyurethanes show excellent thermal stability with onset decomposition temperature higher than 280°C. The investigation provides a new hint for future design and fabrication of high performance sustainable polymers from other vegetable oils.

Epoxidized plant oil (EPO) thermosets usually exhibit poor performance due to the short, brittle, and amorphous cross-link structures. To fabricate fully biobased high performance EPO thermoset, we synthesized dicarboxyl-terminated polyamide1010 (NYL) oligomers from castor oil derived monomers, i.e., sebacic acid and decamethylene diamine, and used the NYL to cure epoxidized soybean oil (ESO) to fabricate all plant oil derived epoxy thermoset through a catalyst-free curing method. Chemorheological study indicated that the curing rate decreases with increasing NYL chain length. The cross-link density of the epoxy thermoset decreases while the crystallization enhances with increasing NYL chain length, which results in drastic enhancement in tensile strength, Young’s modulus, and elongation at break of the resultant thermosets, enabling those parameters to enhance by up to 59, 145, and 18 times, respectively, compared to sebacic acid cured ESO thermoset. The melting temperature and thus the heat resistance o...

A novel miniature robotic needling device was developed to assist clinicians to improve the flexibility of needle insertion and accuracy of seed deposition in brachytherapy. The mechanical modeling of needle behavior that can estimate the trajectory of the needle tip during needle insertion was investigated, by incorporating the force and torque feedback from the needle. Based on the beveled-tip and rigid-beam model of the individual needle, the predictive control was applied to compensate on the lateral components of the generalized interactive force change, which is responsible for the disturbance of the surrounding tissue displacement and deformation. Thus, the needle deflection can be minimized during the insertion procedure. Experiments were performed and the results were evaluated with the clinical justification of tumor target coverage and organ at risk. The device model and control strategy were validated in the capability of the minimal needle deflection and the accurate needle tip displacement. This study has the clinical significance and provides a new approach towards smart needle system with broader applications in various clinical settings.

Background Circulatory arrest has been identified as an independent risk factor related to postoperative mortality in patients with Stanford type A aortic dissection. This study described a modified technique for distal aortic arch occlusion that markedly shortened the circulatory arrest time. The early results are encouraging. Methods From May 2016 to September 2018, 51 patients with Stanford type A aortic dissection underwent the modified procedure for aortic arch replacement. All operations were performed via transitory circulatory arrest by clamping the distal aorta between the left common carotid artery and the left subclavian artery. The in-hospital and follow-up data of the treated patients were investigated. Results Successful repair of the involved vasculature was achieved in all patients. One (1) patient died due to postoperative aspiration and infection, and three patients required continuous renal replacement therapy due to poor preoperative renal function. The remaining patients were successfully discharged. The median average circulatory arrest time was 5.0 (3.0–6.0) minutes. No cases of tracheotomy, delayed closure, secondary thoracotomy, or other complications occurred. During the follow-up period of 2.4–18.6 months, the implanted grafts and stented elephant trunks were all fully open and not kinked. Conclusions A modified distal aortic arch occlusion can considerably shorten the duration of circulatory arrest. Current experience suggests that this approach can serve as a feasible alternative for patients during aortic arch replacement because of its simplicity and satisfactory clinical effects.

In this paper, we present a novel design concept for a robot arm link with variable stiffness. Variable stiffness links are intended to grant a robot the safety benefits of compliance and the performance benefits of stiffness. Our compact design actively modulates stiffness via parallel, rotating beams actuated by simple servomotors. It achieves a lateral stiffness ratio greater than ten with a minimum stiffness under 0.2 N/mm. Our novel design offers many benefits over existing variable stiffness link solutions in its compactness, simplicity, and speed of actuation. One challenge of this research lies in the mechanics modeling of variable stiffness. Here we propose a comprehensive mechanics model that considers mechanical compliances due to deflections of parallel guided beams, column buckling, and bearing at the beam roots. By comparing with experimental testing data, we show that our analytical model accurately predicts the lateral stiffness of the robotic link. This model can be used as a design tool in future iterations, including for scaling the design.

The dysregulation of circular RNA (circRNA) expression is involved in the progression of several cancers, including non-small cell lung cancer (NSCLC). However, the role and underlying molecular mechanisms of circRNA FGFR3 (circFGFR3) in NSCLC progression remains unknown. Here, we used quantitative real-time polymerase chain reaction to validate that circFGFR3 expression was higher in NSCLC tissues than in the paratumor tissues. Furthermore, our study indicated that the forced circFGFR3 expression promoted NSCLC cell invasion and proliferation. Mechanistically, we found that circFGFR3 promoted NSCLC cell invasion and proliferation via competitively combining with miR-22-3p to facilitate the galectin-1 (Gal-1), p-AKT, and p-ERK1/2 expressions. Clinically, we revealed that the high circFGFR3 expression correlates with the poor clinical outcomes in patients with NSCLC. Together, these data provide mechanistic insights into the circFGFR3-mediated regulation of both the AKT and ERK1/2 signaling pathways by sponging miR-22-3p and increasing Gal-1 expression.

Background The novel compound XH601 is a synthesized derivative of formononetin. The present study was to investigate the hypolipidemia effect and potential mechanism of XH601. Methods Male Golden Syrian hamsters were induced by high-fat diet (HFD) for eight weeks and the hyperlipidemic model was established successfully. After XH601 treatment, serum and hepatic biochemistry parameters of hamsters were detected and the effect of XH601 on adipose tissue was also analyzed. Furthermore, 3 T3-L1 cell differentiation by Oil-Red-O staining was observed and the mRNA and protein expression of peroxisome proliferator-activated receptors (PPARs) were measured by qRT-PCR and Western-blot in mature adipocytes. Results The in vivo results suggest that XH601 significantly decreased the adipose weight and levels of serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C), apolipoprotein B (Apo-B), apolipoprotein E (Apo-E), while increased serum high-density lipoprotein (HDL-C). The in vitro results implied that XH601 up-regulated the mRNA and protein expression of both PPARα and PPARβ/δ in a dose-dependent manner. Conclusions The study suggests that XH601 exhibited strong ability to improve the dyslipidemia in hamsters fed with high-fat diet. The potential mechanism of XH601 was associated with the up-regulation of PPARα and PPARβ/δ mRNA and protein expression. Electronic supplementary material The online version of this article (doi:10.1186/s12944-017-0472-z) contains supplementary material, which is available to authorized users.

Apply the rapid prototyping in the 3D reconstruction of solid model of lumbar. By separating the original CT image data according to threshold value, filling and repairing the hole and generated the STL file of lumbar, using Geomagic and UG NX software to complete the model of intervertebral disc and assembly of lumbar. Finally, the model was manufactured through FDM Vantage i rapid prototyping machine.

This paper mainly presents a novel compliant universal joint with linear stiffness (CUJ-LS). This new type of architecture can maintain the linear stiffness while realizing two rotational DOFs. And the planar topology ensures that the rotation axis remains through the center of the moving platform, thus deducing the moment of inertia. According to the Freedom and Constrain Topology (FACT) theory, this paper firstly proposes a topological structure of the compliant universal joint. Then the stiffness model is established by the Beam Constraint Model (BCM) and the condition of achieving linear stiffness is derived: λ = 0.1273/0.8727. By introducing the intermediate platforms, the linear stiffness in two directions of rotation is realized. Finally, FEA method is implemented to verify and analyze the rotation performances of this compliant universal joint. Verified characteristics provide conditions for the applications of compliant universal joint in laser communication, antenna pointing, infrared tracking and aiming, laser processing, precision measurement and other fields which require high-speed, high-acceleration and high precision characteristics.

The estrogen receptors have played important roles in breast cancer development and progression. Selective estrogen receptor modulators, such as Tamoxifen, have showed great benefits in the treatment and prevention of breast cancer. But the disadvantages of induction of endometrial cancer and drug resistance have limited their use. Multiple ligand which act at multiple biomolecular targets may exert favorable advantages of improved efficacy with lower incidence of side effects. In this work, we described the synthesis and evaluation of a series of 6-aryl-indenoisoquinolone derivatives as dual ERα and VEGFR-2 inhibitors. These compounds presented good ERα binding affinity and ERα antagonistic activity, as well as potent VEGFR-2 inhibitory potency. They also possessed excellent anti-proliferative activities against MCF-7, MDA-MB-231, Ishikawa and HUVEC cell lines. Further investigation of selective compound 21c showed that it was able to inhibit the activation of VEGFR-2 and the signaling transduction of Raf-1/MAPK/ERK pathway in MCF-7 cells.

Troponin T (TnT) and troponin I (TnI) are two evolutionarily and functionally linked subunits of the troponin complex that regulates striated muscle contraction. We previously reported a single amino acid substitution in the highly conserved TnT-binding helix of cardiac TnI (cTnI) in wild turkey hearts in concurrence with an abnormally spliced myopathic cardiac TnT (cTnT) (Biesiadecki, B. J., Schneider, K. L., Yu, Z. B., Chong, S. M., and Jin, J. P. (2004) J. Biol. Chem. 279, 13825-13832). To investigate the functional effect of this cTnI mutation and its potential value in compensating for the cTnT abnormality, we developed transgenic mice expressing the mutant cTnI (K118C) in the heart with or without the deletion of the endogenous cTnI gene to mimic the homozygote and heterozygote of wild turkeys. Double and triple transgenic mice were created by crossing the cTnI-K118C lines with transgenic mice overexpressing the myopathic cTnT (exon 7 deletion). Functional studies of ex vivo working hearts found that cTnI-K118C alone had a dominantly negative effect on diastolic function and blunted the inotropic responses of cardiac muscle to beta-adrenergic stimuli without abolishing the protein kinase A-dependent phosphorylation of cTnI. When co-expressed with the cTnT mutation, cTnI-K118C corrected the significant depression of systolic function caused by cTnT exon 7 deletion, and the co-existence of exon 7-deleted cTnT minimized the diastolic abnormality of cTnI-K118C. Characterization of this naturally selected pair of mutually rescuing mutations demonstrated that TnI-TnT interaction is a critical link in the Ca(2+) signaling and beta-adrenergic regulation in cardiac muscle, suggesting a potential target for the treatment of troponin cardiomyopathies and heart failure.

Beam-based compliant mechanisms have been widely used in many precision applications due to their large-displacement characteristic. Meanwhile, a simple and accurate analytical tool is no doubt useful to assist design and optimize these mechanisms. The pseudo-rigid-body (PRB) model is such a good alternative. The PRB model in a traditional sense, however, is too approximate to calculate some precise characteristics such as center-shift of a flexural joint. In this paper, a new method is proposed to easily establish simple and accurate PRB models for a variety of beam-based compliant mechanisms. As is well known, for most of the beam-based compliant mechanisms, there is usually an instantaneous center of rotation (ICR) on each beam, and the beam can be considered as a fixed-guided beam with one end fixed while the other end moves along a certain curve that usually is an approximate arc around the ICR. In this case, the behavior of beams can be imitated by a rigid bar with two pin-joints. One of the pin-joints is directly added at the end of the rigid bar. The position of the other is determined by the characteristic radius factor, and a torsional spring is added at the position to represent the beam's stiffness. The modeling method is used to analyze two commonly used beam-based compliant mechanisms as examples, i.e. a parallel linear spring stage and a cross strip pivot. The performances of precision, stiffness and stroke for the two mechanisms are investigated, and the method is validated by comparing the results with other research work presented in the literatures. Both cases show the method is intuitive and accurate, and it will be useful in the early phases of the design for beam-based compliant mechanisms.

The highly organized contractile machinery in skeletal and cardiac muscles requires an assembly of myofilament proteins with stringent stoichiometry. To understand the maintenance of myofilament protein stoichiometry under dynamic protein synthesis and catabolism in muscle cells, we investigated the equilibrium of troponin I (TnI) in mouse cardiac muscle during developmental isoform switching and in under- and over-expression models. Compared with the course of developmental TnI isoform switching in normal hearts, the postnatal presence of slow skeletal muscle TnI lasted significantly longer in the hearts of cardiac TnI (cTnI) knockout (cTnI-KO) mice, in which the diminished synthesis was compensated by prolonging the life of myofilamental TnI. Transgenic postnatal expression of an N-terminal truncated cTnI (cTnI-ND) using alpha-myosin heavy chain promoter effectively rescued the lethality of cTnI-KO mice and shortened the postnatal presence of slow TnI in cardiac muscle. cTnI-KO mice rescued with different levels of cTnI-ND over-expression exhibited similar levels of myocardial TnI comparable to that in wild type hearts, demonstrating that excessive synthesis would not increase TnI stoichiometry in the myofilaments. Consistently, haploid under-expression of cTnI in heterozygote cTnI-KO mice was sufficient to sustain the normal level of myocardial cTnI, indicating that cTnI is synthesized in excess in wild type cardiomyocytes. Altogether, these observations suggest that under wide ranges of protein synthesis and turnover, myofilament incorporation determines the stoichiometry of troponin subunits in muscle cells.

The typical leaf-type isosceles-trapezoidal flexural (LITF) pivot consists of two flexural beams and two rigid-bodies. The single LITF pivot has the small range of motion and relatively large center shift. However, the vacancy in the pivot point makes LITF pivots much easier to be cascaded than other commonly used flexure joints. The performances of LITF pivots will be greatly improved by connecting them together in series. This paper presents an innovative design of LITF pivots. The single LITF pivot is regarded as a basic configurable module, and four of them can be used to construct new types of flexure joint, which are referred to here as quadri-LITF (Q-LITF) pivot. Ten types of Q-LITF pivots are synthesized in this paper. Compared with a single LIFT pivot, the stroke of a Q-LITF pivot is larger, and stiffness of the mechanism becomes smaller. The center-shift of the Q-LIFT pivot can be optimized by tuning geometric parameters of its single LITF modules. Based on the pseudorigid-body (PRB) model of the single LITF pivot, the method for analyzing the Q-LITF pivots is proposed. One type of the Q-LITF pivots is selected as an example to demonstrate the proposed method for the Q-LITF pivot analysis. The comparison between the results of PRB model analysis and the finite element analysis (FEA) shows the feasibility and efficiency of the analysis procedure.

Muscle contractility and cell motility play a vital role in various physiological and pathological processes, ranging from animal locomotion to cardiovascular function to myopathies and heart failure. Actin-activated myosin II motors power muscle contraction and non-muscle-cell motility. Actin-myosin-derived contractility has been most extensively studied in striated muscle (skeletal and cardiac muscles), but it is also the foundation for smooth muscle contraction and non-muscle-cell motility. Recent advances in biology and medicine have significantly enriched our understanding of the molecular mechanisms underlying muscle contractility and cell motility.

The leaf-type isosceles-trapezoidal flexural (LITF) pivot consists of two compliant beams and two rigid bodies. For a single LITF pivot, the range of motion is small while the center-shift is relatively large. The capability of performance can be improved greatly by the combination of two LITF pivots. Base on the pseudorigid-body (PRB) model of a LITF pivot, a method to construct the double-LITF pivots is presented by regarding a single LITF pivot as a the configurable flexure module. The trends of the center-shift are mainly considered by using this method with the combination of two LIFT pivots. Eight types of double-LITF pivots are synthesized. Compared with the single LIFT pivot, the stroke becomes larger, and stiffness becomes smaller. Four of them have the increased center-shift. The other four have the decreased center-shift. Two of the double-LITF pivots are selected as the examples to explain the proposed method. The comparison between PRB model and finite element analysis result shows the validity and effectiveness of the method. DOI: 10.1115/1.3046140

Transgenic mice were generated to express a restrictive cardiomyopathy (RCM) human cardiac troponin I (cTnI) R192H mutation in the heart (cTnI193Hismice). The objective of this study was to assess cardiac function during the development of diastolic dysfunction and to gain insight into the pathophysiological impact of the RCM cTnI mutation. Cardiac function and pathophysiological changes were monitored in cTnI193Hismice and wild-type littermates for a period of 12 mo. It progressed gradually from abnormal relaxation to diastolic dysfunction characterized with high-resolution echocardiography by a reversed E-to-A ratio, increased deceleration time, and prolonged isovolumetric relaxation time. At the age of 12 mo, cardiac output in cTnI193Hismice was significantly declined, and some transgenic mice showed congestive heart failure. The negative impact of cTnI193Hison ventricular contraction and relaxation was further demonstrated in isolated mouse working heart preparations. The main morphological change in cTnI193Hismyocytes was shortened cell length. Dobutamine stimulation increased heart rate in cTnI193Hismice but did not improve CO. The cTnI193Hismice had a phenotype similar to that in human RCM patients carrying the cTnI mutation characterized morphologically by enlarged atria and restricted ventricles and functionally by diastolic dysfunction and diastolic heart failure. The results demonstrate a critical role of the COOH-terminal domain of cTnI in the diastolic function of cardiac muscle.

The rate of relaxation from steady-state force in rabbit psoas fiber bundles was examined before and after phosphorylation of myosin regulatory light chain (RLC). Relaxation was initiated using diazo-2, a photolabile Ca2+ chelator that has low Ca2+ binding affinity (K(Ca) = 4.5 x 10(5) M(-1)) before photolysis and high affinity (K(Ca) = 1.3 x 10(7) M(-1)) after photolysis. Before phosphorylating RLC, the half-times for relaxation initiated from 0.27 +/- 0.02, 0.51 +/- 0.03, and 0.61 +/- 0.03 Po were 90 +/- 6, 140 +/- 6, and 182 +/- 9 ms, respectively. After phosphorylation of RLC, the half-times for relaxation from 0.36 +/- 0.03 Po, 0.59 +/- 0.03 Po, and 0.65 +/- 0.02 Po were 197 +/- 35 ms, 184 +/- 35 ms, and 179 +/- 22 ms. This slowing of relaxation rates from steady-state forces less than 0.50 Po was also observed when bundles of fibers were bathed with N-ethylmaleimide-modified myosin S-1, a strongly binding cross-bridge derivative of S1. These results suggest that phosphorylation of RLC slows relaxation, most likely by slowing the apparent rate of transition of cross-bridges from strongly bound (force-generating) to weakly bound (non-force-generating) states, and reduces or eliminates Ca2+ and cross-bridge activation-dependent changes in relaxation rates.