A microstructurally driven model for pulmonary artery tissue

A new constitutive model for elastic, proximal pulmonary artery tissue is presented here, called the total crimped fiber model. This model is based on the material and microstructural properties of the two main, passive, load-bearing components of the artery wall, elastin, and collagen. Elastin matrix proteins are modeled with an orthotropic neo-Hookean material. High stretch behavior is governed by an orthotropic crimped fiber material modeled as a planar sinusoidal linear elastic beam, which represents collagen fiber deformations. Collagen-dependent artery orthotropy is defined by a structure tensor representing the effective orientation distribution of collagen fiber bundles. Therefore, every parameter of the total crimped fiber model is correlated with either a physiologic structure or geometry or is a mechanically measured material property of the composite tissue. Further, by incorporating elastin orthotropy, this model better represents the mechanics of arterial tissue deformation. These advancements result in a microstructural total crimped fiber model of pulmonary artery tissue mechanics, which demonstrates good quality of fit and flexibility for modeling varied mechanical behaviors encountered in disease states.     

Changes in the endopolyploidy pattern of different tissues in diploid and tetraploid Phalaenopsis aphrodite subsp. formosana (Orchidaceae)

Endopolyploidy is frequently observed during development in plant species. Patterns of endopolyploidy are diverse in the various organs of different plant species. However, little is known about the role of endopolyploidization and its significance in orchids. This study was undertaken to determine the extent of endopolyploidy in different tissues of the diploid and tetraploid genotypes of Phalaenopsis aphrodite subsp. formosana and to examine the factors that contribute to increased ploidy levels. Endopolyploidy occurs in various tissues of diploid and tetraploid orchids, at different developmental stages and under different culture conditions, as determined by flow cytometry. In this study, different patterns of endopolyploidy were observed in parts of the protocorms, leaves, roots and flowers. Endopolyploidy was found in all tissues studied except the pollinia and the tetraploid ovaries. A higher degree of endopolyploidy was observed in mature tissues compared to young tissues, greenhouse-grown plants compared to in vitro plants and diploid plants compared to tetraploid plants. We discuss the relationships between endopolyploidization and several factors related to plant growth, as well as some practical considerations of these findings.     

Endogenous HMGB1 contributes to ischemia-reperfusion-induced myocardial apoptosis by potentiating the effect of TNF-α/JNK

High-mobility group box 1 (HMGB1) is a nuclear protein that has been implicated in the myocardial inflammation and injury induced by ischemia-reperfusion (I/R). The purpose of the present study was to assess the role of HMGB1 in myocardial apoptosis induced by I/R. In vivo, myocardial I/R induced an increase in myocardial HMGB1 expression and apoptosis. Inhibition of HMGB1 (A-box) ameliorated the I/R-induced myocardial apoptosis. In vitro, isolated cardiac myocytes were challenged with anoxia-reoxygenation (A/R; in vitro correlate to I/R). A/R-challenged myocytes also generated HMGB1 and underwent apoptosis. Inhibition of HMGB1 attenuated the A/R-induced myocyte apoptosis. Exogenous HMGB1 had no effect on myocyte apoptosis. However, inhibition of HMGB1 attenuated myocyte TNF-α production after the A/R was challenged; surprisingly, HMGB1 itself did not induce myocyte TNF-α production. Exogenous TNF-α induced a moderate proapoptotic effect on the myocytes, an effect substantially potentiated by coadministration of HMGB1. It is generally accepted that apoptosis induced by TNF-α is regulated by the balance of activation of c-Jun NH(2)-terminal kinase (JNK) and NF-κB. Indeed, in the present study, TNF-α increased the phosphorylation status of JNK and p65, a subunit of NF-κB; HMGB1 greatly potentiated TNF-α-induced JNK phosphorylation. Furthermore, inhibition of JNK (SP-600125) prevented the myocyte apoptosis induced by a TNF-α/HMGB1 cocktail. Finally, A/R increased HMGB1 production in both wild-type and toll-like receptor 4-deficient myocytes; however, deficiency in toll-like receptor 4 diminished A/R-induced myocyte apoptosis, TNF-α, and JNK activation. Our results indicate that myocyte-derived HMGB1 and TNF-α work in concert to promote I/R-induced myocardial apoptosis through JNK activation.     

Synthesis and antiproliferative evaluation of 6-aryl-11-iminoindeno[1,2-c]quinoline derivatives

A number of 6-aryl-11-iminoindeno[1,2-c]quinoline derivatives were synthesized and evaluated for their antiproliferative activities. Among them, (E)-6-{4-[3-(dimethylamino)propoxy]phenyl}-2-fluoro-9-hydroxy-11H-indeno[1,2-c]quinolin-11-one O-3-(dimethylamino)propyl oxime (23a) was the most active, exhibited GI₅₀ values of 0.64, 0.39, 0.55, 0.67, and 0.65 μM against the growth of Hep G2, Hep 3B, A549, H1299, and MDA-MB-231, respectively. Compound 23a inhibited the growth of hepatoma cell lines in a dose- and time-dependent manner. The proportion of cells was decreased in the G1 and accumulated in G2/M phase after 12 h treatment of 23a, while the hypodiploid (sub-G0/G1 phase) cells increased. Further investigations have shown that 23a induced cell cycle arrest at G2/M phase and induce apoptosis via activation of p53, Bax, and caspase-8 which consequently cause cell death.     

Loss of MAP3K1 enhances proliferation and apoptosis during retinal development

Precise coordination of progenitor cell proliferation and differentiation is essential for proper organ morphogenesis and function during mammalian development. The mitogen-activated protein kinase kinase kinase 1 (MAP3K1) has a well-established role in anterior eyelid development, as Map3k1-knockout mice have defective embryonic eyelid closure and an `eye-open at birth' (EOB) phenotype. Here, we show that MAP3K1 is highly expressed in the posterior of the developing eye and is required for retina development. The MAP3K1-deficient mice exhibit increased proliferation and apoptosis, and Müller glial cell overproduction in the developing retinas. Consequently, the retinas of these mice show localized rosette-like arrangements in the outer nuclear layer, and develop abnormal vascularization, broken down retinal pigment epithelium, photoreceptor loss and early onset of retinal degeneration. Although the retinal defect is associated with increased cyclin D1 and CDK4/6 expression, and RB phosphorylation and E2F-target gene upregulation, it is independent of the EOB phenotype and of JNK. The retinal developmental defect still occurs in knockout mice that have undergone tarsorrhaphy, but is absent in compound mutant Map3k1(+/ΔKD)Jnk1(-/-) and Map3k1(+/ΔKD)Jnk(+/-)Jnk2(+/-) mice that have EOB and reduced JNK signaling. Our results unveil a novel role for MAP3K1 in which it crosstalks with the cell cycle regulatory pathways in the prevention of retina malformation and degeneration.     

Multiplexed detection and differentiation of the DNA strains for influenza A (H1N1 2009) using a silicon-based microfluidic system

Pandemic influenza by the swine-origin influenza virus (H1N1 2009) has attracted considerable concern worldwide. A convenient and accurate diagnostic approach that can be deployed at the point of care, such as in a doctor's office or at an airport, is critical for disease control. Here we report the development of a silicon-based microfluidic system for subtype differentiation of the novel H1N1 2009 strain vs. the seasonal influenza A (FluA) strain. The proposed system included two functional modules: a multiplexed PCR module for amplification of nucleic acid targets and a multiplexed silicon nanowire (SiNW) module for sequence determination. The PCR module consisted of a microfluidic PCR chamber and an electrical controller to perform a multiplexed protocol that simultaneously enriched specific segments of both H1N1 and FluA strains (if present), with 10(4)-10(5) amplification efficiency. The PCR amplicon was subsequently denatured and transferred to the SiNW sensing module for a label-free, multiplexed detection. A control SiNW was implemented, for the first time, in order to eliminate background interference. The detection module demonstrated a 10× change in the magnitude of differential current when the target DNA was injected. Overall, the system achieved a sensitivity of 20-30 fg/μl for H1N1 and seasonal FluA nucleic acids in a 10 μl sample. The low sample consumption, high sensitivity and high specificity render it a potential point-of-care (POC) platform to help doctors reach a yes/no decision for infectious diseases.     

Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species

Lon protease is a multifunction protein and operates in protein quality control and stress response pathways in mitochondria. Human Lon is upregulated under oxidative and hypoxic stresses that represent the stress phenotypes of cancer. However, little literature undertakes comprehensive and detailed investigations on the tumorigenic role of Lon. Overexpression of Lon promotes cell proliferation, apoptotic resistance to stresses, and transformation. Furthermore, Lon overexpression induces the production of mitochondrial reactive oxygen species (ROS) that result from Lon-mediated upregulation of NDUFS8, a mitochondrial Fe-S protein in complex I of electron transport chain. Increased level of mitochondrial ROS promotes cell proliferation, cell survival, cell migration, and epithelial–mesenchymal transition through mitogen-activated protein kinase (MAPK) and Ras-ERK activation. Overall, the present report for the first time demonstrates the role of Lon overexpression in tumorigenesis. Lon overexpression gives an apoptotic resistance to stresses and induces mitochondrial ROS production through Complex I as signaling molecules to activate Ras and MAPK signaling, giving the survival advantages and adaptation to cancer cells. Finally, in silico and immunohistochemistry analysis showed that Lon is overexpressed specifically in various types of cancer tissue including oral cancer.