A function of fascin1 in the colony formation of mouse embryonic stem cells.

Fascin1 is known to participate in the migration of cancer cells by binding to actin filaments. Recent studies evidenced that fascin1 also modulates processes such as the tumorigenesis and maintenance of pluripotency genes in cancer stem cells. However, the function of fascin1 in embryonic stem cells remains unclear. In this article, we report that fascin1 is highly expressed and widely distributed in mouse embryonic stem cells (mESCs), which are regulated by JAK-STAT3 and ß-catenin. We found that the overexpression of fascin1 impairs the formation of mESC colonies via the downregulation of intercellular adhesion molecules, and that mimicking the dephosphorylated mutation of fascin1 or inhibiting phosphorylation with Gö6983 significantly enhances colony formation. Hyperphosphorylated fascin1 can promote the maintenance of pluripotency in mESCs via nuclear localization and suppressing DNA methyltransferase expression. Our findings demonstrate a novel function of fascin1, as a vital regulator, in the colony formation and pluripotency of mESCs and provide insights into the molecular mechanisms underlying embryonic stem cell self-organization and development in vitro.

Silk fibroin peptide suppresses proliferation and induces apoptosis and cell cycle arrest in human lung cancer cells.

Silkworm cocoon was recorded to cure carbuncle in the Compendium of Materia Medica. Previous studies have demonstrated that the supplemental silk protein sericin exhibits anticancer activity. In the present study, we investigated the effects of silk fibroin peptide (SFP) extracted from silkworm cocoons against human lung cancer cells in vitro and in vivo and its possible anticancer mechanisms. SFP that we prepared had high content of glycine (~ 30%) and showed a molecular weight of ~ 10 kDa. Intragastric administration of SFP (30 g/kg/d) for 14 days did not affect the weights, vital signs, routine blood indices, and blood biochemical parameters in mice. MTT assay showed that SFP dose-dependently inhibited the growth of human lung cancer A549 and H460 cells in vitro with IC50 values of 9.921 and 9.083 mg/mL, respectively. SFP also dose-dependently suppressed the clonogenic activity of the two cell lines. In lung cancer H460 xenograft mice, intraperitoneal injection of SFP (200 or 500 mg/kg/d) for 40 days significantly suppressed the tumor growth, but did not induce significant changes in the body weight. We further examined the effects of SFP on cell cycle and apoptosis in H460 cells using flow cytometry, which revealed that SFP-induced cell cycle arrest at the S phase, and then promoted cell apoptosis. We demonstrated that SFP (20-50 mg/mL) dose-dependently downregulates Bcl-2 protein expression and upregulates Bax protein in H460 cells during cell apoptosis. The results suggest that SFP should be studied further as a novel therapeutic agent for the treatment of lung cancer.

Multi-functional topology optimization of Victoria cruziana veins.

The growth and development of biological tissues and organs strongly depend on the requirements of their multiple functions. Plant veins yield efficient nutrient transport and withstand various external loads. Victoria cruziana, a tropical species of the Nymphaeaceae family of water lilies, has evolved a network of three-dimensional and rugged veins, which yields a superior load-bearing capacity. However, it remains elusive how biological and mechanical factors affect their unique vein layout. In this paper, we propose a multi-functional and large-scale topology optimization method to investigate the morphomechanics of Victoria cruziana veins, which optimizes both the structural stiffness and nutrient transport efficiency. Our results suggest that increasing the branching order of radial veins improves the efficiency of nutrient delivery, and the gradient variation of circumferential vein sizes significantly contributes to the stiffness of the leaf. In the present method, we also consider the optimization of the wall thickness and the maximum layout distance of circumferential veins. Furthermore, biomimetic leaves are fabricated by using the three-dimensional printing technique to verify our theoretical findings. This work not only gains insights into the morphomechanics of Victoria cruziana veins, but also helps the design of, for example, rib-reinforced shells, slabs and dome skeletons.

Theoretical study of the competition between cell-cell and cell-matrix adhesions.

Adhesions between neighboring cells or between cells and their surrounding tissue/matrix play a crucial role in a wide range of biological processes. In order to investigate the competitive mechanisms between cell-cell and cell-matrix adhesions, we here develop a theoretical framework for multiple interacting cells lying on a planar matrix coated with distributed ligands. This model allows us to study, from the viewpoints of energy and statistics, the effects of such physical mechanisms as binding energy of bonds, nonspecific interactions, elastic deformation of cell membranes, and mixing entropy. Our calculations show that cell-matrix adhesion cannot occur when the ligand density on the matrix is lower than a threshold value, and cell-cell adhesion does not happen for a high ligand density. Glycocalyx repulsion plays a more important role in cell-matrix adhesion than in cell-cell adhesion. In addition, it is found that the cell-cell adhesion density decreases as the number of cells increases.

Heat Stress-Induced Multiple Multipolar Divisions of Human Cancer Cells.

Multipolar divisions of heated cells has long been thought to stem from centrosome aberrations of cells directly caused by heat stress. In this paper, through long-term live-cell imaging, we provide direct cellular evidences to demonstrate that heat stress can promote multiple multipolar divisions of MGC-803 and MCF-7 cells. Our results show that, besides facilitating centrosome aberration, polyploidy induced by heat stress is another mechanism that causes multipolar cell divisions, in which polyploid cancer cells engendered by mitotic slippage, cytokinesis failure, and cell fusion. Furthermore, we also find that the fates of theses polyploid cells depend on their origins, in the sense that the polyploid cells generated by mitotic slippage experience bipolar divisions with a higher rate than multipolar divisions, while those polyploid cells induced by both cytokinesis failure and cell fusion have a higher frequency of multipolar divisions compared with bipolar divisions. This work indicates that heat stress-induced multiple multipolar divisions of cancer cells usually produce aneuploid daughter cells, and might lead to genetically unstable cancer cells and facilitate tumor heterogeneity.

Elasticity-driven droplet movement on a microbeam with gradient stiffness: a biomimetic self-propelling mechanism.

Directional movement of liquid droplets is of significance not only for certain physiological processes in nature but also for design of some microfluidic devices. In this study, we report a novel way to drive directional movement of liquid droplets on a microbeam with a varying or gradient stiffness. We use the energy method to theoretically analyze the interaction between a droplet and the elastic microbeam. The system tends to have the minimum potential energy when the droplet moves to the softer end of the beam. Therefore, a gradient change of the bending stiffness may be utilized to help the directional motion of droplets. Similarly, one can also drive droplets to move in a designed direction by varying the cross sectional geometry of the beam. Finally, some possible applications of this self-propelling mechanism are suggested.

Synergistic adhesion mechanisms of spider capture silk.

It is well known that capture silk, the main sticky component of the orb web of a spider, plays an important role in the spider's ability to capture prey via adhesion. However, the detailed mechanism with which the spider achieves its unparalleled high-adhesion performance remains elusive. In this work, we combine experiments and theoretical analysis to investigate the adhesion mechanisms of spider silk. In addition to the widely recognized adhesion effect of the sticky glue, we reveal a synergistic enhancement mechanism due to the elasticity of silk fibres. A balance between silk stiffness, strength and glue stickiness is crucial to endow the silk with superior adhesion, as well as outstanding energy absorption capacity and structural robustness. The revealed mechanisms deepen our understanding of the working principles of spider silk and suggest guidelines for biomimetic designs of spider-inspired adhesion and capture devices.

Formal [7 + 2] Cycloaddition of Arynes with N-Vinyl-α,ß-Unsaturated Nitrones: Synthesis of Benzoxazonines and Their N-O Bond Cleavage.

Various benzoxazonines were synthesized through a formal [7 + 2] cycloaddition of arynes with N-vinyl-α,ß-unsaturated nitrones under mild conditions. Controllable N-O bond cleavage of benzoxazonines afforded polysubstituted pyrrole-tethered benzopyrans and acyclic ketone-substituted phenols in moderate to good yields. Further transformations provided a facile approach to access useful building blocks with specific stereoselectivity.

Swertia mussotii extracts induce mitochondria-dependent apoptosis in gastric cancer cells.

Swertia mussotii (Gentianaceae) is a traditional Chinese medicinal plant grown in the Qinghai-Tibet Plateau. Three fractions from S. mussotii extract, named SWF50, SWF 70 and SWF100, were screened for in vitro anti-proliferative activity on two gastric cancer cell lines, MGC-803 and BGC-823 cells using MTT assay. Our results demonstrated that SMF70 showed an anti-proliferative effect in MGC-803 cells and SMF100 showed an anti-proliferative effect in BGC-823 cells in vitro. Moreover, both two fractions induced apoptosis via depolymerization of cytoskeletal filaments, increased cytoplasmic levels of ROS and Ca2+ and disrupted mitochondrial transmembrane potential. In addition, flow cytometry analysis indicated that both two fractions could induce cell apoptosis and arrest the cell cycle at S phase. Our results indicate that SMF70 induces apoptosis of MGC-803 cells and SMF100 induces apoptosis of BGC-823 cells via a mitochondrial-dependent pathway. Meanwhile, we also investigated antitumor effect of SMF70 in vivo, and exhibited effective tumor growth inhibition. Our findings demonstrate that S. mussotii extracts could be a potential new alternative therapeutic agent gastric cancer.

Chemical constituents from Swertia mussotii Franch. (Gentianaceae).

The chemical investigation of ethanolic extract from Swertia mussotii Franch. has resulted in the isolation of 11 compounds which were identified as Orcinol-ß-D-glucoside (1), Shamimin (2), Mangiferin (3), Decussatin (4), Bellidifolin (5), Desmethylbellidifolin (6), Protocatechuic acid (7), 1,7-Dihydroxy-3,8-dimethoxyxanthone (8), 1,8-Dihydroxy-3,5-dimethoxyxanthone (9), 1-Hydroxy-3,5-dimethoxyxanthone (10), Telephioidin (11). The chemical structures of these compounds were identified by a combination of spectroscopic analysis and a comparison with those reported in literature. Among them, compounds 1, 2, 7 and 11 were isolated from the genus Swertia for the first time. Moreover, the chemotaxonomic significance of these compounds was summarised. The chemotaxonomic study suggests that there is a close chemotaxonomic relationship between S. mussotii and other species of Swertia, such as S. punicea, S. macrosperma, S. japonica, S. phragmitiphylla, S. chirayita, S. cordata and S. binchuanensis, with presence of compounds 3~6, 8~10. The xanthones and their glycosides may sever as important chemotaxonomic markers of Swertia genus.

Discontinued cardiovascular drugs in 2015.

INTRODUCTION: About 10,000 compounds will be tested for an individual drug to eventually reach the market. It might be helpful recapitulating previous failures and identifying the main factors of the disappointments. AREAS COVERED: In this review, the author(s) detailed the 7 cardiovascular compounds discontinued after reaching animal studies or Phase I-III clinical trials during 2015. Meanwhile, the reasons for these discontinuations were reported. Among these drugs, most discontinuations (6 drugs) were attributed to lack of efficacy. In general, failures due to lack of efficacy and safety demonstrate the need for the development of more predictive animal models. However, recent related studies showed that the absence of toxicity in animals provided little or virtually no evidential weight that adverse drug reactions would also be absent in humans. In this case, microdosing and collaborating more closely with biotech companies may be the better choices to improve the success ratio. EXPERT OPINION: Future researches may benefit from the seven developments and investigators conducting similar studies may learn from these failures.

Discontinued cardiovascular drugs in 2013 and 2014.

INTRODUCTION: Cardiovascular diseases (CVDs) are the number one cause of death globally. The dramatically high rate of cardiovascular morbidity and mortality has attracted wide concern and great attention within the pharmaceutical industry. However, ∼ 10,000 compounds are tested for every one drug that reaches the market. For this reason, it is helpful to recapitulate previous failures and learn from these experiences. AREAS COVERED: This paper focuses on the 10 cardiovascular drugs discontinued after reaching animal studies or Phase I - II clinical trials between 1 January 2013 and 31 December 2014. EXPERT OPINION: The trend of increasing numbers of cardiovascular drug development terminations seen in recent years has changed. Only 10 cardiovascular drugs were discontinued after reaching animal studies or Phase I - II clinical trials between 2013 and 2014. Only two candidates were discontinued in the Phase I clinical evaluation, and eight were discontinued during Phase II development. Most discontinuations were attributed to lack of efficacy and safety. One orphan drug (RTA-402) appeared in the list of discontinued cardiovascular drugs. The most eye-catching one of the 10 discontinued drugs is RG-7652, a monoclonal antibody against PCSK9, which is predicted as the next statin.

Structures, properties, and functions of the stings of honey bees and paper wasps: a comparative study.

Through natural selection, many animal organs with similar functions have evolved different macroscopic morphologies and microscopic structures. Here, we comparatively investigate the structures, properties and functions of honey bee stings and paper wasp stings. Their elegant structures were systematically observed. To examine their behaviors of penetrating into different materials, we performed penetration-extraction tests and slow motion analyses of their insertion process. In comparison, the barbed stings of honey bees are relatively difficult to be withdrawn from fibrous tissues (e.g. skin), while the removal of paper wasp stings is easier due to their different structures and insertion skills. The similarities and differences of the two kinds of stings are summarized on the basis of the experiments and observations.

Biomechanical tactics of chiral growth in emergent aquatic macrophytes.

Through natural selection, many plant organs have evolved optimal morphologies at different length scales. However, the biomechanical strategies for different plant species to optimize their organ structures remain unclear. Here, we investigate several species of aquatic macrophytes living in the same natural environment but adopting distinctly different twisting chiral morphologies. To reveal the principle of chiral growth in these plants, we performed systematic observations and measurements of morphologies, multiscale structures, and mechanical properties of their slender emergent stalks or leaves. Theoretical modeling of pre-twisted beams in bending and buckling indicates that the different growth tactics of the plants can be strongly correlated with their biomechanical functions. It is shown that the twisting chirality of aquatic macrophytes can significantly improve their survivability against failure under both internal and external loads. The theoretical predictions for different chiral configurations are in excellent agreement with experimental measurements.

On flaw tolerance of nacre: a theoretical study.

As a natural composite, nacre has an elegant staggered 'brick-and-mortar' microstructure consisting of mineral platelets glued by organic macromolecules, which endows the material with superior mechanical properties to achieve its biological functions. In this paper, a microstructure-based crack-bridging model is employed to investigate how the strength of nacre is affected by pre-existing structural defects. Our analysis demonstrates that owing to its special microstructure and the toughening effect of platelets, nacre has a superior flaw-tolerance feature. The maximal crack size that does not evidently reduce the tensile strength of nacre is up to tens of micrometres, about three orders higher than that of pure aragonite. Through dimensional analysis, a non-dimensional parameter is proposed to quantify the flaw-tolerance ability of nacreous materials in a wide range of structural parameters. This study provides us some inspirations for optimal design of advanced biomimetic composites.

Discontinued drugs in 2012: cardiovascular drugs.

The continued high rate of cardiovascular morbidity and mortality has attracted wide concern and great attention of pharmaceutical industry. In order to reduce the attrition of cardiovascular drug R&D, it might be helpful recapitulating previous failures and identifying the potential factors to success. This perspective mainly analyses the 30 cardiovascular drugs dropped from clinical development in 2012. Reasons causing the termination of the cardiovascular drugs in the past 5 years are also tabulated and analysed. The analysis shows that the attrition is highest in Phase II trials and financial and strategic factors and lack of clinical efficacy are the principal reasons for these disappointments. To solve the four problems (The 'better than the Beatles' problem, the 'cautious regulator' problem, the 'throw money at it' tendency and the 'basic researchbrute force' bias) is recommended as the main measure to increase the number and quality of approvable products.

Discontinued drugs in 2011: cardiovascular drugs.

This perspective is part of an annual series of papers discussing drugs dropped from development in the previous year. Specifically, this paper focuses on the 19 cardiovascular drugs discontinued in 2011 after reaching preclinical or Phase I - III clinical trials. Information for this perspective is mainly derived from a search of Pharmaprojects.

Discontinued drugs in 2010: cardiovascular drugs.

This perspective is a paper discussing drugs dropped from clinical development in the previous years. Specifically, this paper focuses on 16 cardiovascular drugs discontinued in 2010 after reaching Phase I - III clinical trials. Information for this perspective is mainly derived from a search of Pharmaprojects.

Coexpression of the mutated BRCA1 mRNA and p53 mRNA and its association in Chinese prostate cancer.

The mutations of BRCA1 and p53 genes have been simultaneously characterized in many tumors. However, their coexpression and associations have not been investigated quantitatively in prostate cancer. In the present study, the expressions of the mutated BRCA1 mRNA and p53 mRNA were examined in 48 Chinese prostate cancer cases and 10 corresponding adjacent benign tissues with in situ hybridization. The 5-year survival rates of the corresponding patients after operation were investigated. The results showed that the positive expressions of the mutated BCRA1 mRNA and p53 mRNA are involved in prostate cancer (P < 0.05). Moreover, there is a closed negative association between the expressions of the mutated BRCA1 gene and p53 gene in the mRNA level with the progression, angiogenesis, metastasis, and survival rate of prostate cancer. Their coexpression and negative association suggest that the two altered tumor suppressor genes might interact functionally in prostate cancer to provide a potential signal determining a prognosis of the tumor metastasis and survival rate. Further work will be done to elucidate the interaction mechanisms in prostate cancer.

[Comparison and analysis of human dentin matrix protein 1 promoter activity in three different cells].

OBJECTIVE: To observe and compare the luciferase activities of different length segments of human dentin matrix protein 1 promoter in human dental pulp stem cells (HDPSC), osteoblasts (OC) and Hela cells. METHODS: The differentlength desired DNA segments were obtained from 2 195 bp Dmp1 promoter cloned by PCR method. The amplified promoter segments with different length were cloned into luciferase report gene vector pGL3-Basic, the correct orientation of those inserts was verified by cutting with two different restrict enzymes. The luciferase activity was observed after different pGL3-PDmp1 vectors were transfected transiently into those three different-type cells. RESULTS: 6 Dmp1 promoter segments with different-length were obtained successfully, and luciferase report gene vectors with different promoter segments were successfully constructed after identified by restriction enzymes cutting. They had different luciferase activities when they were transfected transiently into HDPSC, and the region of -505(-)-193 bp and -935(-)-505 bp could be regarded as the specific promoters of Dmp1 promoter for HDPSC and OC respectively, which could include the basic regulatory elements. CONCLUSION: The correct clone of the upstream of human Dmp1 promoter segments with different length had been obtained, and they had strong luciferase activities in HDPSC and OC, but very low in Hela cell. These results will make an important basis for studying mineralized tissue-specific transcriptional regulation mechanisms of Dmp1.