Na(+)-Ca(2+) Exchange Current and Submembrane [Ca(2+)] During the Cardiac Action Potential

Circulation Research. Feb, 2002  |  Pubmed ID: 11834711

Na(+)-Ca(2+) exchange (NCX) is crucial in the regulation of [Ca(2+)](i) and cardiac contractility, but key details of its dynamic function during the heartbeat are not known. In the present study, we assess how NCX current (I(NCX)) varies during a rabbit ventricular action potential (AP). First, we measured the steady-state voltage and [Ca(2+)](i) dependence of I(NCX) under conditions when [Ca(2+)](i) was heavily buffered. We then used this relationship to infer the submembrane [Ca(2+)](i) ([Ca(2+)](sm)) sensed by NCX during a normal AP and [Ca(2+)](i) transient (when the AP was interrupted to produce an I(NCX) tail current). The [Ca(2+)](i) dependence of I(NCX) at -90 mV allowed us to convert the peak inward I(NCX) tail currents to [Ca(2+)](sm). Peak [Ca(2+)](sm) measured via this technique was >3.2 micromol/L within < 32 ms of the AP upstroke (versus peak [Ca(2+)](i) of 1.1 micromol/L at 81 ms measured with the global Ca(2+) indicator indo-1). The voltage and [Ca(2+)](sm) dependence of I(NCX) allowed us to infer I(NCX) during the normal AP and Ca(2+) transient. The early rise in [Ca(2+)](sm) causes I(NCX) to be inward for the majority of the AP. Thus, little Ca(2+) influx via NCX is expected under physiological conditions, but this can differ among species and in pathophysiological conditions.

Intracellular Na(+) Concentration is Elevated in Heart Failure but Na/K Pump Function is Unchanged

Circulation. May, 2002  |  Pubmed ID: 12034663

Intracellular sodium concentration ([Na(+)](i)) modulates cardiac contractile and electrical activity through Na/Ca exchange (NCX). Upregulation of NCX in heart failure (HF) may magnify the functional impact of altered [Na(+)](i).

Simultaneous Measurement of [Na]i, [Ca]i, and I(NCX) in Intact Cardiac Myocytes

Annals of the New York Academy of Sciences. Nov, 2002  |  Pubmed ID: 12502556

Modulation of Contractility in Failing Human Myocytes by Reverse-mode Na/Ca Exchange

Annals of the New York Academy of Sciences. Nov, 2002  |  Pubmed ID: 12502596

A decrease in the peak systolic [Ca](i) and slow decay of the Ca(i) transient are common features of the end-stage failing human ventricular myocyte and may underlie the contractile abnormalities observed in congestive heart failure. The role of the Na/Ca exchanger has been a great area of interest given the changes observed at the molecular level. Results from these experiments have been inconsistent, however, and therefore cellular-based experiments may be required to characterize the role of the Na/Ca exchanger in failing human myocardium. We review recent data that suggest an increased ability of the Na/Ca exchanger to transport Ca into the cytoplasm in failing human myocytes. We hypothesize that this increased Ca influx can explain the slowed decay and impaired relaxation of failing human ventricular myocytes.

Calcium Influx Via I(NCX) is Favored in Failing Human Ventricular Myocytes

Annals of the New York Academy of Sciences. Nov, 2002  |  Pubmed ID: 12502599

Na/Ca Exchange Function in Intact Ventricular Myocytes

Annals of the New York Academy of Sciences. Nov, 2002  |  Pubmed ID: 12502604

Here, we address three issues in intact ventricular myocytes that specifically relate to the role of Na/Ca exchange (NCX) current under physiological conditions. First, we revisit the issue of NCX stoichiometry in light of some recent findings that the stoichiometry of the NCX may not be fixed at 3Na: 1Ca. We discuss some data that strongly favor the 3:1 stoichiometry, at least under physiological conditions. Second, we address the controversy over the role of allosteric Ca regulation in intact myocytes. We show that outward and inward I(NCX) can be activated dynamically by changing [Ca](i) over the physiological range and that outward I(NCX) can be activated quite rapidly with sarcoplasmic reticulum Ca release. These data are well described using an instantaneous equation for NCX current that includes an allosteric activation factor with K(mCaAct) = 125 nM. Finally, we consider the effect on NCX current of submembrane elevations in [Ca](i) (that are far greater than are measured in the bulk cytoplasm). Taken together with a NCX stoichiometry of 3, these findings have allowed us to make some predictions of the role of I(NCX) during an AP. Our simulations suggest that NCX current is outward for less than approximately 10 ms at the beginning of the action potential.

Cellular Basis of Abnormal Calcium Transients of Failing Human Ventricular Myocytes

Circulation Research. Apr, 2003  |  Pubmed ID: 12600875

Depressed contractility is a central feature of the failing human heart and has been attributed to altered [Ca2+]i. This study examined the respective roles of the L-type Ca2+ current (ICa), SR Ca2+ uptake, storage and release, Ca2+ transport via the Na+-Ca2+ exchanger (NCX), and Ca2+ buffering in the altered Ca2+ transients of failing human ventricular myocytes. Electrophysiological techniques were used to measure and control V(m) and measure I(m), respectively, and Fluo-3 was used to measure [Ca2+]i in myocytes from nonfailing (NF) and failing (F) human hearts. Ca2+ transients from F myocytes were significantly smaller and decayed more slowly than those from NF hearts. Ca2+ uptake rates by the SR and the amount of Ca2+ stored in the SR were significantly reduced in F myocytes. There were no significant changes in the rate of Ca2+ removal from F myocytes by the NCX, in the density of NCX current as a function of [Ca2+]i, ICa density, or cellular Ca2+ buffering. However, Ca2+ influx during the late portions of the action potential seems able to elevate [Ca2+]i in F but not in NF myocytes. A reduction in the rate of net Ca2+ uptake by the SR slows the decay of the Ca2+ transient and reduces SR Ca2+ stores. This leads to reduced SR Ca2+ release, which induces additional Ca2+ influx during the plateau phase of the action potential, further slowing the decay of the Ca2+ transient. These changes can explain the defective Ca2+ transients of the failing human ventricular myocyte.

Cardiac Submembrane [Na+] Transients Sensed by Na+-Ca2+ Exchange Current

Circulation Research. May, 2003  |  Pubmed ID: 12702644

Na+ influx via INa during cardiac action potentials can raise bulk [Na+]i by 10 to 15 micromol/L. However, larger rises in submembrane [Na+] ([Na+]sm) local to Na+-Ca2+ exchangers (NCX) could enhance Ca2+ influx via NCX (and Ca2+-induced Ca2+ release). We tested whether INa could increase [Na+]sm, using NCX current (INCX) as a biosensor in rabbit ventricular myocytes (with [Ca2+]i buffered, [Na+]i=10 mmol/L, and other currents blocked). We measured INCX as early as 5 ms after INa. Prior INa activation did not affect INCX at physiological membrane potentials (Em=-100 to +50 mV), but for Em >+50 mV (where INCX is especially sensitive to [Na+]i), INCX shifted outward. At 5 ms and +100 mV, INa shifted INCX outward by 0.23 A/F (corresponding to Delta[Na+]sm=0.24 mmol/L). The effect of INa dissipated with a time constant of approximately 15 ms. Thus, the impact of INa on NCX is almost undetectable at physiological Em and short lived. This suggests that INa effects on excitation-contraction coupling (via outward INCX) are minimal and limited to early during the action potential. However, local Delta[Na+]sm during INa may be 60 times higher than bulk Delta[Na+]i.

Dynamic Regulation of Sodium/calcium Exchange Function in Human Heart Failure

Circulation. Nov, 2003  |  Pubmed ID: 14557358

Sarcolemmal Na/Ca exchange (NCX) regulates cardiac Ca and contractility. NCX function during the cardiac cycle is determined by intracellular [Ca] and [Na] ([Ca]i, and [Na]i) and membrane potential (Em), which all change in human heart failure (HF). Therefore, changes in NCX function may contribute to abnormal Ca regulation in human HF.

A Mathematical Treatment of Integrated Ca Dynamics Within the Ventricular Myocyte

Biophysical Journal. Nov, 2004  |  Pubmed ID: 15347581

We have developed a detailed mathematical model for Ca2+ handling and ionic currents in the rabbit ventricular myocyte. The objective was to develop a model that: 1), accurately reflects Ca-dependent Ca release; 2), uses realistic parameters, particularly those that concern Ca transport from the cytosol; 3), comes to steady state; 4), simulates basic excitation-contraction coupling phenomena; and 5), runs on a normal desktop computer. The model includes the following novel features: 1), the addition of a subsarcolemmal compartment to the other two commonly formulated cytosolic compartments (junctional and bulk) because ion channels in the membrane sense ion concentrations that differ from bulk; 2), the use of realistic cytosolic Ca buffering parameters; 3), a reversible sarcoplasmic reticulum (SR) Ca pump; 4), a scheme for Na-Ca exchange transport that is [Na]i dependent and allosterically regulated by [Ca]i; and 5), a practical model of SR Ca release including both inactivation/adaptation and SR Ca load dependence. The data describe normal electrical activity and Ca handling characteristics of the cardiac myocyte and the SR Ca load dependence of these processes. The model includes a realistic balance of Ca removal mechanisms (e.g., SR Ca pump versus Na-Ca exchange), and the phenomena of rest decay and frequency-dependent inotropy. A particular emphasis is placed upon reproducing the nonlinear dependence of gain and fractional SR Ca release upon SR Ca load. We conclude that this model is more robust than many previously existing models and reproduces many experimental results using parameters based largely on experimental measurements in myocytes.

Distribution of Kv1-like Potassium Channels in the Electromotor and Electrosensory Systems of the Weakly Electric Fish Apteronotus Leptorhynchus

Journal of Neurobiology. Aug, 2006  |  Pubmed ID: 16779822

The electromotor and electrosensory systems of the weakly electric fish Apteronotus leptorhynchus are model systems for studying mechanisms of high-frequency motor pattern generation and sensory processing. Voltage-dependent ionic currents, including low-threshold potassium currents, influence excitability of neurons in these circuits and thereby regulate motor output and sensory filtering. Although Kv1-like potassium channels are likely to carry low-threshold potassium currents in electromotor and electrosensory neurons, the distribution of Kv1 alpha subunits in A. leptorhynchus is unknown. In this study, we used immunohistochemistry with six different antibodies raised against specific mammalian Kv1 alpha subunits (Kv1.1-Kv1.6) to characterize the distribution of Kv1-like channels in electromotor and electrosensory structures. Each Kv1 antibody labeled a distinct subset of neurons, fibers, and/or dendrites in electromotor and electrosensory nuclei. Kv1-like immunoreactivity in the electrosensory lateral line lobe (ELL) and pacemaker nucleus are particularly relevant in light of previous studies suggesting that potassium currents carried by Kv1 channels regulate neuronal excitability in these regions. Immunoreactivity of pyramidal cells in the ELL with several Kv1 antibodies is consistent with Kv1 channels carrying low-threshold outward currents that regulate spike waveform in these cells (Fernandez et al., J Neurosci 2005;25:363-371). Similarly, Kv1-like immunoreactivity in the pacemaker nucleus is consistent with a role of Kv1 channels in spontaneous high-frequency firing in pacemaker neurons. Robust Kv1-like immunoreactivity in several other structures, including the dorsal torus semicircularis, tuberous electroreceptors, and the electric organ, indicates that Kv1 channels are broadly expressed and are likely to contribute significantly to generating the electric organ discharge and processing electrosensory inputs.

A Stochastic Regression Approach to Analyzing Thermodynamic Uncertainty in Chemical Speciation Modeling

Environmental Science & Technology. Jun, 2006  |  Pubmed ID: 16830555

Chemical speciation modeling is a vital tool for assessing the bioavailability of inorganic species, yet significant uncertainties in thermodynamic parameters and model form limit its potential for decision-making. In this paper we present a novel method for the quantification of thermodynamic parameter uncertainty and ionic strength correction model uncertainty using Bayesian Markov Chain Monte Carlo (MCMC) estimation methods. These methods allow for the inclusion of correlation modeling, which has not been present in previous work. The MCMC simulations are used to model a natural river water to determine the uncertainty in the calculated environmental speciation of ethylenediamenetetraacetate, a chelating agent that has attracted considerable environmental interest. The results indicate that incorporating correlation among related thermodynamic parameters into the uncertainty model is necessary to correctly quantify the overall system uncertainty. This result indicates the superiority of MCMC estimation methods overtraditional Monte Carlo methods when available data are used to estimate parameter uncertainty in systems with closely related model parameters.

Modulation of the Pancreatic Islet Beta-cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate

The Journal of Biological Chemistry. Mar, 2007  |  Pubmed ID: 17197450

Glucose stimulates both insulin secretion and hydrolysis of arachidonic acid (AA) esterified in membrane phospholipids of pancreatic islet beta-cells, and these processes are amplified by muscarinic agonists. Here we demonstrate that nonesterified AA regulates the biophysical activity of the pancreatic islet beta-cell-delayed rectifier channel, Kv2.1. Recordings of Kv2.1 currents from INS-1 insulinoma cells incubated with AA (5 mum) and subjected to graded degrees of depolarization exhibit a significantly shorter time-to-peak current interval than do control cells. AA causes a rapid decay and reduced peak conductance of delayed rectifier currents from INS-1 cells and from primary beta-cells isolated from mouse, rat, and human pancreatic islets. Stimulating mouse islets with AA results in a significant increase in the frequency of glucose-induced [Ca(2+)] oscillations, which is an expected effect of Kv2.1 channel blockade. Stimulation with concentrations of glucose and carbachol that accelerate hydrolysis of endogenous AA from islet phosphoplipids also results in accelerated Kv2.1 inactivation and a shorter time-to-peak current interval. Group VIA phospholipase A(2) (iPLA(2)beta) hydrolyzes beta-cell membrane phospholipids to release nonesterified fatty acids, including AA, and inhibiting iPLA(2)beta prevents the muscarinic agonist-induced accelerated Kv2.1 inactivation. Furthermore, glucose and carbachol do not significantly affect Kv2.1 inactivation in beta-cells from iPLA(2)beta(-/-) mice. Stably transfected INS-1 cells that overexpress iPLA(2)beta hydrolyze phospholipids more rapidly than control INS-1 cells and also exhibit an increase in the inactivation rate of the delayed rectifier currents. These results suggest that Kv2.1 currents could be dynamically modulated in the pancreatic islet beta-cell by phospholipase-catalyzed hydrolysis of membrane phospholipids to yield non-esterified fatty acids, such as AA, that facilitate Ca(2+) entry and insulin secretion.

MMP25 (MT6-MMP) is Highly Expressed in Human Colon Cancer, Promotes Tumor Growth, and Exhibits Unique Biochemical Properties

The Journal of Biological Chemistry. Jul, 2007  |  Pubmed ID: 17513868

MMP25 (MT6-MMP) is one of the two glycosylphosphatidylinositol-anchored matrix metalloproteinases (MMPs) that have been suggested to play a role in pericellular proteolysis. However, its role in cancer is unknown, and its biochemical properties are not well established. Here we found a marked increase in MT6-MMP expression within in situ dysplasia and invasive cancer in 61 samples of human colon cancer. Expression of MT6-MMP in HCT-116 human colon cancer cells promoted tumori-genesis in nude mice. Histologically, the MT6-MMP-expressing tumors demonstrated an infiltrative leading edge in contrast to a rounded leading edge in vector control tumors. Biochemical and biosynthesis analyses revealed that MT6-MMP displayed on the cell surface exists as a major form of 120 kDa that likely represents enzyme homodimers linked by disulfide bonds. Upon reduction, a single 57-kDa active MT6-MMP was detected. Interestingly, neither membrane-anchored nor phosphatidylinositol-specific phospholipase C-released MT6-MMPs were found to be associated with tissue inhibitor of metalloproteinases (TIMPs) and did not activate pro-gelatinases (pro-MMP-2 and pro-MMP-9) even in the presence of exogenous TIMP-2 or TIMP-1. A catalytic domain of MT6-MMP was inhibited preferentially by TIMP-1 (K(i) = 0.2 nm) over TIMP-2 (K(i) = 2.0 nm), because of a slower association rate. These results show that MT6-MMP may play a role in colon cancer and exhibit unique biochemical and structural properties that may regulate proteolytic function at the cell surface.

Embodied Environmental Emissions in U.S. International Trade, 1997-2004

Environmental Science & Technology. Jul, 2007  |  Pubmed ID: 17711196

Significant recent attention has been given to quantifying the environmental impacts of international trade. However, the United States, despite being the world's largest emitter of greenhouse gases and having large recent growth in international trade, has seen little analysis. This work uses a multi-country input-output model of the U.S. and its seven largest trading partners (Canada, China, Mexico, Japan, Germany, the UK, and Korea) to analyze the environmental effects of changes to U.S. trade structure and volume from 1997 to 2004. It is shown that increased import volume and shifting trade patterns during this time period led to a large increase in the U.S.' embodied emissions in trade (EET) for CO2, SO2, and NO(x). Methodological uncertainties, especially related to uncertainties of international currency conversion, lead to large differences in estimation of the total EET, but we estimate that the overall embodied CO2 in U.S. imports has grown from between 0.5 and 0.8 Gt of CO2 in 1997 to between 0.8 and 1.8 Gt of CO2 in 2004, representing between 9-14% and 13-30% of U.S. (2-4% to 3-7% of global) CO2 emissions in 1997 and 2004, respectively.

China's Growing CO2 Emissions--a Race Between Increasing Consumption and Efficiency Gains

Environmental Science & Technology. Sep, 2007  |  Pubmed ID: 17937264

China's rapidly growing economy and energy consumption are creating serious environmental problems on both local and global scales. Understanding the key drivers behind China's growing energy consumption and the associated CO2 emissions is critical for the development of global climate policies and provides insight into how other emerging economies may develop a low emissions future. Using recently released Chinese economic input-output data and structural decomposition analysis we analyze how changes in China's technology, economic structure, urbanization, and lifestyles affect CO2 emissions. We find that infrastructure construction and urban household consumption, both in turn driven by urbanization and lifestyle changes, have outpaced efficiency improvements in the growth of CO2 emissions. Net trade had a small effect on total emissions due to equal, but significant, growth in emissions from the production of exports and emissions avoided by imports. Technology and efficiency improvements have only partially offset consumption growth, but there remains considerable untapped potential to reduce emissions by improving both production and consumption systems. As China continues to rapidly develop there is an opportunity to further implement and extend policies, such as the Circular Economy, that will help China avoid the high emissions path taken by today's developed countries.

Sensorineural Deafness and Seizures in Mice Lacking Vesicular Glutamate Transporter 3

Neuron. Jan, 2008  |  Pubmed ID: 18215623

The expression of unconventional vesicular glutamate transporter VGLUT3 by neurons known to release a different classical transmitter has suggested novel roles for signaling by glutamate, but this distribution has raised questions about whether the protein actually contributes to glutamate release. We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of glutamate release from hair cells at the first synapse in the auditory pathway. The early degeneration of some cochlear ganglion neurons in knockout mice also indicates an important developmental role for the glutamate released by hair cells before the onset of hearing. In addition, the mice exhibit primary, generalized epilepsy that is accompanied by remarkably little change in ongoing motor behavior. The glutamate release conferred by expression of VGLUT3 thus has an essential role in both function and development of the auditory pathway, as well as in the control of cortical excitability.

The Tight Junction Protein Complex Undergoes Rapid and Continuous Molecular Remodeling at Steady State

The Journal of Cell Biology. May, 2008  |  Pubmed ID: 18474622

The tight junction defines epithelial organization. Structurally, the tight junction is comprised of transmembrane and membrane-associated proteins that are thought to assemble into stable complexes to determine function. In this study, we measure tight junction protein dynamics in live confluent Madin-Darby canine kidney monolayers using fluorescence recovery after photobleaching and related methods. Mathematical modeling shows that the majority of claudin-1 (76 +/- 5%) is stably localized at the tight junction. In contrast, the majority of occludin (71 +/- 3%) diffuses rapidly within the tight junction with a diffusion constant of 0.011 microm(2)s(-1). Zonula occludens-1 molecules are also highly dynamic in this region, but, rather than diffusing within the plane of the membrane, 69 +/- 5% exchange between membrane and intracellular pools in an energy-dependent manner. These data demonstrate that the tight junction undergoes constant remodeling and suggest that this dynamic behavior may contribute to tight junction assembly and regulation.

Food-miles and the Relative Climate Impacts of Food Choices in the United States

Environmental Science & Technology. May, 2008  |  Pubmed ID: 18546681

Despite significant recent public concern and media attention to the environmental impacts of food, few studies in the United States have systematically compared the life-cycle greenhouse gas (GHG) emissions associated with food production against long-distance distribution, aka "food-miles." We find that although food is transported long distances in general (1640 km delivery and 6760 km life-cycle supply chain on average) the GHG emissions associated with food are dominated by the production phase, contributing 83% of the average U.S. household's 8.1 t CO2e/yr footprint for food consumption. Transportation as a whole represents only 11% of life-cycle GHG emissions, and final delivery from producer to retail contributes only 4%. Different food groups exhibit a large range in GHG-intensity; on average, red meat is around 150% more GHG-intensive than chicken or fish. Thus, we suggest that dietary shift can be a more effective means of lowering an average household's food-related climate footprint than "buying local." Shifting less than one day per week's worth of calories from red meat and dairy products to chicken, fish, eggs, or a vegetable-based diet achieves more GHG reduction than buying all locally sourced food.

Tumor Suppressor Foxo3a is Involved in the Regulation of Lipopolysaccharide-induced Interleukin-8 in Intestinal HT-29 Cells

Infection and Immunity. Oct, 2008  |  Pubmed ID: 18678662

Enteric bacteria and their products play an important role in intestinal inflammation; however, the complete mechanisms are not elucidated yet. Tumor suppressor Foxo3a regulates gene expression in the nucleus, and its translocation to the cytosol leads to inactivation. Proximally, Foxo3a is regulated by different pathways including the phosphoinositide 3-kinase (PI3K) pathway. The aim of this study was to determine the effect of bacterial infection on Foxo3a in intestinal epithelial cells and to examine the contribution of Foxo3a in intestinal inflammation. Bacterial lipopolysaccharide (LPS) and infection with mouse pathogen Citrobacter rodentium induce translocation of the nuclear Foxo3a into the cytosol, where it degrades in human HT-29 and mouse CMT-93 cells. In colonic epithelia of healthy mice, Foxo3a is localized in the epithelia at the bottom of the crypts in both the nucleus and the cytosol, while in C. rodentium-infected colon Foxo3a is expressed along the crypts and located mainly in the cytosol, suggesting its inactivation. LPS utilized the PI3K pathway to inhibit Foxo3a. Additionally, inhibition of PI3K attenuated LPS-induced proinflammatory interleukin-8 (IL-8). LPS-induced IL-8 is increased in HT-29 cells with silenced Foxo3a. Moreover, in HT-29 cells with silenced Foxo3a, the amount of IkappaBalpha, an NF-kappaB inhibitor, is decreased. In conclusion, LPS and bacterial infection inactivate Foxo3a in intestinal epithelia via the PI3K pathway and inactivated Foxo3a leads to the upregulation of IL-8 by suppressing inhibitory IkappaBalpha.

Claudin-1 and Claudin-2 Expression is Elevated in Inflammatory Bowel Disease and May Contribute to Early Neoplastic Transformation

Laboratory Investigation; a Journal of Technical Methods and Pathology. Oct, 2008  |  Pubmed ID: 18711353

Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal adenocarcinoma. The factors that result in IBD-associated carcinogenesis are not understood. We hypothesized that altered expression of intestinal epithelial tight junction proteins might contribute to neoplastic progression. Semiquantitative immunohistochemical staining of human biopsies was used to assess expression of the tight junction proteins claudin-1, claudin-2, claudin-4, and occludin in IBD, IBD-associated dysplasia, acute, self-limited colitis (ASLC), and sporadic adenomas. Claudin-1 and claudin-2 expression was elevated in active IBD, adenomas, and IBD-associated dysplasia, but not ASLC. In contrast, claudin-4 expression was elevated in both active IBD and ASLC. Occludin expression was similar to control in all cases. Importantly, in IBD, claudin-1 and claudin-2 expression correlated positively with inflammatory activity. To investigate mechanisms underlying altered claudin expression, beta-catenin activation was assessed as nuclear localization. Like claudin-1 and claudin-2, beta-catenin was markedly activated in IBD, sporadic dysplasia, and IBD-associated dysplasia, but was only slightly activated in ASLC. Taken together, these data suggest that beta-catenin transcriptional activity is elevated in chronic injury and that this may contribute to increased claudin-1 and claudin-2 expression. We speculate that increased claudin-1 and claudin-2 expression may be involved at early stages of transformation in IBD-associated neoplasia.

The Importance of Carbon Footprint Estimation Boundaries

Environmental Science & Technology. Aug, 2008  |  Pubmed ID: 18767634

Because of increasing concern about global climate change and carbon emissions as a causal factor, many companies and organizations are pursuing "carbon footprint" projects to estimate their own contributions to global climate change. Protocol definitions from carbon registries help organizations analyze their footprints. The scope of these protocols varies but generally suggests estimating only direct emissions and emissions from purchased energy, with less focus on supply chain emissions. In contrast approaches based on comprehensive environmental life-cycle assessment methods are available to track total emissions across the entire supply chain, and experience suggests that following narrowly defined estimation protocols will generally lead to large underestimates of carbon emissions for providing products and services. Direct emissions from an industry are, on average, only 14% of the total supply chain carbon emissions (often called Tier 1 emissions), and direct emissions plus industry energy inputs are, on average, only 26% of the total supply chain emissions (often called Tier 1 and 2 emissions). Without a full knowledge of their footprints, firms will be unable to pursue the most cost-effective carbon mitigation strategies. We suggest that firms use the screening-level analysis described here to set the bounds of their footprinting strategy to ensure that they do not ignore large sources of environmental effects across their supply chains. Such information can help firms pursue carbon and environmental emission mitigation projects not only within their own plants but also across their supply chain.

Retinoic Acid-induced Gene-1 (RIG-I) Associates with the Actin Cytoskeleton Via Caspase Activation and Recruitment Domain-dependent Interactions

The Journal of Biological Chemistry. Mar, 2009  |  Pubmed ID: 19122199

The actin cytoskeleton serves as a barrier that protects mammalian cells from environmental pathogens such as bacteria, fungi, and viruses. Several components of antimicrobial signaling pathways have been shown to associate directly with the actin cytoskeleton, indicating that the cytoskeleton may also serve as a platform for immune-associated molecules. Here we report that retinoic acid-induced gene-I (RIG-I), an important viral RNA recognition molecule, is associated with the actin cytoskeleton and localizes predominantly to actin-enriched membrane ruffles in non-polarized epithelial cells. Subcellular localization and fractionation experiments revealed that the association between RIG-I and the actin cytoskeleton was mediated by its N-terminal caspase activation and recruitment domains (CARDs), which were necessary and sufficient to induce cytoskeletal association. We also show that RIG-I plays a role in cellular migration, as ectopic expression of RIG-I enhanced cellular migration in a wound healing assay and depletion of endogenous RIG-I significantly reduced wound healing. We further show that in both cultured intestinal epithelial cells (IEC) and human colon and small intestine biopsies, RIG-I is enriched at apico-lateral cell junctions and colocalizes with markers of the tight junction. Depolymerization of the actin cytoskeleton in polarized IEC led to the rapid relocalization of RIG-I and to the induction of type I interferon signaling. These data provide evidence that RIG-I is associated with the actin cytoskeleton in non-polarized epithelial cells and with the junctional complex in polarized IECs and human intestine and colon biopsies and may point to a physiological role for RIG-I in the regulation of cellular migration.

Tumor Suppressor FOXO3 Participates in the Regulation of Intestinal Inflammation

Laboratory Investigation; a Journal of Technical Methods and Pathology. Sep, 2009  |  Pubmed ID: 19636295

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by chronic mucosal injury and the infiltration of inflammatory cells. Tumor suppressor FOXO3 regulates gene expression and its translocation to the cytosol leads to the abrogation of its transcriptional function. We have previously shown that bacterial infection regulates FOXO3 in intestinal epithelial cells and increases cytokine levels. As TNFalpha is a major contributor in intestinal inflammation, the aim of this study was to assess its effect on FOXO3 and FOXO3's contribution to intestinal inflammation in vitro and in vivo. TNFalpha induces the translocation of nuclear FOXO3 into the cytosol where it undergoes proteasomal degradation in human intestinal HT-29 cells. Proximally, the PI3K and IKK pathways mediate TNFalpha-induced FOXO3 phosphorylation. In FOXO3-silenced HT-29 cells, TNFalpha-induced IL-8 expression is increased approximately 83%. In vivo, Foxo3 is present in the nuclei and cytosol of colonic crypt epithelia. In DSS-induced colonic inflammation, Foxo3's nuclear localization is lost and it is only found in the cytosol. Consistent with a role for Foxo3 in colitis, Foxo3-deficient mice treated with DSS developed more severe colonic inflammation with an increased number of intraepithelial lymphocytes and PMNs infiltrated in the epithelia, than wild-type mice. In summary, TNFalpha inactivates FOXO3 in intestinal epithelia through the PI3K and IKK pathways and FOXO3 inactivation leads to the upregulation of IL-8 in vitro; in vivo Foxo3 is in the cytosol of inflamed colonic epithelia and Foxo3 deficiency leads to severe intestinal inflammation.

Categorization of Scope 3 Emissions for Streamlined Enterprise Carbon Footprinting

Environmental Science & Technology. Nov, 2009  |  Pubmed ID: 20028044

Many organizations look to carbon footprint protocols for guidance on measuring their greenhouse gas emissions, or carbon footprint. Existing protocols generally require estimation of direct emissions (Scope 1) and emissions from direct purchases of energy (Scope 2), but focus less on indirect emissions upstream and downstream of the supply chain (optional Scope 3). Because on average more than 75% of an industry sector's carbon footprint is attributed to Scope 3 sources, better knowledge of Scope 3 footprints can help organizations pursue emissions mitigation projects not just within their own plants but also across their supply chain. In this work, Scope 3 footprints of U.S. economic sectors are categorized using an Economic Input-Output Life Cycle Assessment (EIO-LCA) model to identify upstream emission sources that are likely to contribute significantly to different sectors' footprints. The portions of the upstream footprint captured by the sector's top-10 upstream suppliers are estimated at 3 different levels of specificity: general economy-wide, industry specific, and sector specific. The results show that enterprises can capture a large portion of their total upstream carbon footprint by collecting full emissions information from only a handful of direct suppliers, and Scope 3 footprint capture rates can be improved considerably by sector-specific categorization. Employee commuting and air transportation may be more important (7%-30%) for the services industries, but should not be a focus of detailed Scope 3 footprint estimates for the manufacturing industries (<1% of the total analyzed footprint). Protocol organizations should actively make more specific Scope 3 guidelines available for their constituents by developing sector-specific categorizations for as many sectors as they feasibly can and create broader industry-specific protocols for others.

Life Cycle Assessment and Grid Electricity: What Do We Know and What Can We Know?

Environmental Science & Technology. Mar, 2010  |  Pubmed ID: 20131782

The generation and distribution of electricity comprises nearly 40% of U.S. CO(2), emissions, as well as large shares of SO(2), NO(x), small particulates, and other toxins. Thus, correctly accounting for these electricity-related environmental releases is of great importance in life cycle assessment of products and processes. Unfortunately, there is no agreed-upon protocol for accounting for the environmental emissions associated with electricity, as well as significant uncertainty in the estimates. Here, we explore the limits of current knowledge about grid electricity in LCA and carbon footprinting for the U.S. electrical grid, and show that differences in standards, protocols, and reporting organizations can lead to important differences in estimates of CO(2) SO(2), and NO(x) emissions factors. We find a considerable divergence in published values for grid emissions factor in the U.S. We discuss the implications of this divergence and list recommendations for a standardized approach to accounting for air pollution emissions in life cycle assessment and policy analyses in a world with incomplete and uncertain information.

MLCK-dependent Exchange and Actin Binding Region-dependent Anchoring of ZO-1 Regulate Tight Junction Barrier Function

Proceedings of the National Academy of Sciences of the United States of America. May, 2010  |  Pubmed ID: 20404178

The perijunctional actomyosin ring contributes to myosin light chain kinase (MLCK)-dependent tight junction regulation. However, the specific protein interactions involved in this process are unknown. To test the hypothesis that molecular remodeling contributes to barrier regulation, tight junction protein dynamic behavior was assessed by fluorescence recovery after photobleaching (FRAP). MLCK inhibition increased barrier function and stabilized ZO-1 at the tight junction but did not affect claudin-1, occludin, or actin exchange in vitro. Pharmacologic MLCK inhibition also blocked in vivo ZO-1 exchange in wild-type, but not long MLCK(-/-), mice. Conversely, ZO-1 exchange was accelerated in transgenic mice expressing constitutively active MLCK. In vitro, ZO-1 lacking the actin binding region (ABR) was not stabilized by MLCK inhibition, either in the presence or absence of endogenous ZO-1. Moreover, the free ABR interfered with full-length ZO-1 exchange and reduced basal barrier function. The free ABR also prevented increases in barrier function following MLCK inhibition in a manner that required endogenous ZO-1 expression. In silico modeling of the FRAP data suggests that tight junction-associated ZO-1 exists in three pools, two of which exchange with cytosolic ZO-1. Transport of the ABR-anchored exchangeable pool is regulated by MLCK. These data demonstrate a critical role for the ZO-1 ABR in barrier function and suggest that MLCK-dependent ZO-1 exchange is essential to this mechanism of barrier regulation.

H2A.Z Nucleosomes Enriched over Active Genes Are Homotypic

Nature Structural & Molecular Biology. Dec, 2010  |  Pubmed ID: 21057526

Nucleosomes that contain the histone variant H2A.Z are enriched around transcriptional start sites, but the mechanistic basis for this enrichment is unknown. A single octameric nucleosome can contain two H2A.Z histones (homotypic) or one H2A.Z and one canonical H2A (heterotypic). To elucidate the function of H2A.Z, we generated high-resolution maps of homotypic and heterotypic Drosophila H2A.Z (H2Av) nucleosomes. Although homotypic and heterotypic H2A.Z nucleosomes mapped throughout most of the genome, homotypic nucleosomes were enriched and heterotypic nucleosomes were depleted downstream of active promoters and intron-exon junctions. The distribution of homotypic H2A.Z nucleosomes resembled that of classical active chromatin and showed evidence of disruption during transcriptional elongation. Both homotypic H2A.Z nucleosomes and classical active chromatin were depleted downstream of paused polymerases. Our results suggest that H2A.Z enrichment patterns result from intrinsic structural differences between heterotypic and homotypic H2A.Z nucleosomes that follow disruption during transcriptional elongation.

Epithelial Myosin Light Chain Kinase Activation Induces Mucosal Interleukin-13 Expression to Alter Tight Junction Ion Selectivity

The Journal of Biological Chemistry. Apr, 2010  |  Pubmed ID: 20177070

Intestinal barrier function is reduced in inflammatory bowel disease (IBD). Tumor necrosis factor (TNF) and interleukin (IL)-13, which are up-regulated in IBD, induce barrier defects that are associated with myosin light chain kinase (MLCK) activation and increased claudin-2 expression, respectively, in cultured intestinal epithelial monolayers. Here we report that these independent signaling pathways have distinct effects on tight junction barrier properties and interact in vivo. MLCK activation alters size selectivity to enhance paracellular flux of uncharged macromolecules without affecting charge selectivity and can be rapidly reversed by MLCK inhibition. In contrast, IL-13-dependent claudin-2 expression increases paracellular cation flux in vitro and in vivo without altering tight junction size selectivity but is unaffected by MLCK inhibition in vitro. In vivo, MLCK activation increases paracellular flux of uncharged macromolecules and also triggers IL-13 expression, claudin-2 synthesis, and increased paracellular cation flux. We conclude that reversible, MLCK-dependent permeability increases cause mucosal immune activation that, in turn, feeds back on the tight junction to establish long-lasting barrier defects. Interactions between these otherwise distinct tight junction regulatory pathways may contribute to IBD pathogenesis.

Caveolin-1-dependent Occludin Endocytosis is Required for TNF-induced Tight Junction Regulation in Vivo

The Journal of Cell Biology. Apr, 2010  |  Pubmed ID: 20351069

Epithelial paracellular barrier function, determined primarily by tight junction permeability, is frequently disrupted in disease. In the intestine, barrier loss can be mediated by tumor necrosis factor (alpha) (TNF) signaling and epithelial myosin light chain kinase (MLCK) activation. However, TNF induces only limited alteration of tight junction morphology, and the events that couple structural reorganization to barrier regulation have not been defined. We have used in vivo imaging and transgenic mice expressing fluorescent-tagged occludin and ZO-1 fusion proteins to link occludin endocytosis to TNF-induced tight junction regulation. This endocytosis requires caveolin-1 and is essential for structural and functional tight junction regulation. These data demonstrate that MLCK activation triggers caveolin-1-dependent endocytosis of occludin to effect structural and functional tight junction regulation.

Effects of China's Economic Growth

Science (New York, N.Y.). May, 2010  |  Pubmed ID: 20466901

Baculovirus-encoded Protein Expression for Epigenomic Profiling in Drosophila Cells

Fly. Jul, 2010  |  Pubmed ID: 20495356

The expression and genome-wide mapping of epitope-tagged DNA- and chromatin-binding proteins in cultured cells has become a powerful strategy for epigenome characterization, especially in Drosophila, where cell lines derived from numerous tissues are now available. However this strategy relies on establishing transfected cell lines, which is time-consuming and introduces variability. Here we show that baculovirus-encoded proteins can be efficiently produced following infection of Drosophila cell lines of different types. Using chromatin affinity purification, we show that epitope-tagged proteins produced in baculovirus-infected cells provide genome-wide profiles of the histone variant H2Av that are comparable to those produced by plasmid-transfected cells. The ability to express multiple epitope-tagged proteins for epigenome analysis from a single culture, and to do this in a variety of Drosophila cell lines, significantly extends the range of epigenome analysis.

Phosphoinositide 3-kinase Signaling Mediates Beta-catenin Activation in Intestinal Epithelial Stem and Progenitor Cells in Colitis

Gastroenterology. Sep, 2010  |  Pubmed ID: 20580720

Mechanisms responsible for crypt architectural distortion in chronic ulcerative colitis (CUC) are not well understood. Data indicate that serine/threonine protein kinase Akt (Akt) signaling cooperates with Wingless (Wnt) to activate beta-catenin in intestinal stem and progenitor cells through phosphorylation at Ser552 (P-beta-catenin(552)). We investigated whether phosphoinositide 3-kinase (PI3K) is required for Akt-mediated activation of beta-catenin during intestinal inflammation.

Primary and Embedded Steel Imports to the U.S.: Implications for the Design of Border Tax Adjustments

Environmental Science & Technology. Sep, 2010  |  Pubmed ID: 20687541

Carbon Border Tax Adjustments (BTAs) are a politically popular strategy for avoiding competitive disadvantage problems when a country implements a unilateral climate change policy. A BTA taxes carbon embodied in imported goods in order to protect domestic industry and motivate other countries to implement climate change policy. To estimate the effectiveness of a BTA, is it is necessary to know which products are covered, where they were originally produced and ultimately exported from, and how the covered amount compares to total production in foreign countries. Using a scrap-adjusted, mixed-unit input-output model in conjunction with a multiregional input-output model, this analysis evaluates the effectiveness of BTAs for the case study of U.S. steel imports. Most imported steel by mass is embedded in finished products (60%), and 30% of that steel is produced in a different country than the one from which the final good is exported. Given the magnitudes involved and complexities of global supply chains, a BTA that protects domestic industry will be a challenge to implement. We propose a logistically feasible BTA structure that minimizes the information burden while still accounting for these complexities. However, the amount of steel imported to the U.S. is negligible (5%) compared to foreign production in BTA-eligible countries and is unlikely to motivate affected countries to impose an emissions reduction policy.

Tight Junction Pore and Leak Pathways: a Dynamic Duo

Annual Review of Physiology. Mar, 2011  |  Pubmed ID: 20936941

Tissue barriers that restrict passage of liquids, ions, and larger solutes are essential for the development of multicellular organisms. In simple organisms this allows distinct cell types to interface with the external environment. In more complex species, the diversity of cell types capable of forming barriers increases dramatically. Although the plasma membranes of these barrier-forming cells prevent flux of most hydrophilic solutes, the paracellular, or shunt, pathway between cells must also be sealed. This function is accomplished in vertebrates by the zonula occludens, or tight junction. The tight junction barrier is not absolute but is selectively permeable and is able to discriminate between solutes on the basis of size and charge. Many tight junction components have been identified over the past 20 years, and recent progress has provided new insights into the proteins and interactions that regulate structure and function. This review presents these data in a historical context and proposes an integrated model in which dynamic regulation of tight junction protein interactions determines barrier function.

The Relationship Between Atypical Semantic Activation and Odd Speech in Schizotypy Across Emotionally Evocative Conditions

Schizophrenia Research. Mar, 2011  |  Pubmed ID: 20638247

Odd speech is prevalent in individuals with schizotypy compared to controls and this odd speech is particularly pronounced under stress-induced conditions. Despite a number of research studies that have examined odd speech, the mechanisms underlying this phenomenon remain unclear. There is reason to suspect that the increase in odd speech observed in schizotypy may reflect atypical semantic activation patterns, defined in terms of increased activation of weakly associated words within the semantic network.

Tumor Suppressor FOXO3 Mediates Signals from the EGF Receptor to Regulate Proliferation of Colonic Cells

American Journal of Physiology. Gastrointestinal and Liver Physiology. Feb, 2011  |  Pubmed ID: 21109589

Epithelial proliferation, critical for homeostasis, healing, and colon cancer progression, is in part controlled by epidermal growth factor receptor (EGFR). Proliferation of colonic epithelia can be induced by Citrobacter rodentium infection, and we have demonstrated that activity of tumor suppressor FOXO3 was attenuated after this infection. Thus the aim of this study was to determine the contribution of FOXO3 in EGFR-dependent proliferation of intestinal epithelia and colon cancer cell lines. In this study we show that, during infection with C. rodentium, EGFR was significantly phosphorylated in colonic mucosa and Foxo3 deficiency in this model lead to an increased number of bromodeoxyuridine-positive cells. In vitro, in human colon cancer cells, increased expression and activation of EGFR was associated with proliferation that leads to FOXO3 phosphorylation (inactivation). Following EGFR activation, FOXO3 was phosphorylated (via phosphatidylinositol 3-kinase/Akt) and translocated to the cytosol where it was degraded. Moreover, inhibition of proliferation by overexpressing FOXO3 was not reversed by the EGFR signaling, implicating FOXO3 as one of the regulators downstream of EGFR. FOXO3 binding to the promoter of the cell cycle inhibitor p27kip1 was decreased by EGFR signaling, suggesting its role in EGFR-dependent proliferation. In conclusion, we show that proliferation in colonic epithelia and colon cancer cells, stimulated by EGFR, is mediated via loss of FOXO3 activity and speculate that FOXO3 may serve as a target in the development of new pharmacological treatments of proliferative diseases.

Synthesis, Crystal Structures, and Photophysical Properties of Electron-accepting Diethynylindenofluorenediones

Organic Letters. Apr, 2011  |  Pubmed ID: 21428314

A series of 6,12-bis[(trialkylsilyl)ethynyl]indeno[1,2-b]fluorene-5,11-diones has been synthesized. X-ray crystallographic analysis of these compounds reveals that triisopropylsilyl (TIPS) substitution on the alkyne terminus affords the largest number of intermolecular π-π interactions in the solid state. Conversely, use of trialkylsilyl groups smaller or larger than TIPS furnishes a variety of crystal-packing motifs that contain fewer π-π interactions. Electrochemical and photophysical data suggest that these molecules are excellent electron-accepting materials.

Growth in Emission Transfers Via International Trade from 1990 to 2008

Proceedings of the National Academy of Sciences of the United States of America. May, 2011  |  Pubmed ID: 21518879

Despite the emergence of regional climate policies, growth in global CO(2) emissions has remained strong. From 1990 to 2008 CO(2) emissions in developed countries (defined as countries with emission-reduction commitments in the Kyoto Protocol, Annex B) have stabilized, but emissions in developing countries (non-Annex B) have doubled. Some studies suggest that the stabilization of emissions in developed countries was partially because of growing imports from developing countries. To quantify the growth in emission transfers via international trade, we developed a trade-linked global database for CO(2) emissions covering 113 countries and 57 economic sectors from 1990 to 2008. We find that the emissions from the production of traded goods and services have increased from 4.3 Gt CO(2) in 1990 (20% of global emissions) to 7.8 Gt CO(2) in 2008 (26%). Most developed countries have increased their consumption-based emissions faster than their territorial emissions, and non-energy-intensive manufacturing had a key role in the emission transfers. The net emission transfers via international trade from developing to developed countries increased from 0.4 Gt CO(2) in 1990 to 1.6 Gt CO(2) in 2008, which exceeds the Kyoto Protocol emission reductions. Our results indicate that international trade is a significant factor in explaining the change in emissions in many countries, from both a production and consumption perspective. We suggest that countries monitor emission transfers via international trade, in addition to territorial emissions, to ensure progress toward stabilization of global greenhouse gas emissions.

Occludin S408 Phosphorylation Regulates Tight Junction Protein Interactions and Barrier Function

The Journal of Cell Biology. May, 2011  |  Pubmed ID: 21536752

Although the C-terminal cytoplasmic tail of the tight junction protein occludin is heavily phosphorylated, the functional impact of most individual sites is undefined. Here, we show that inhibition of CK2-mediated occludin S408 phosphorylation elevates transepithelial resistance by reducing paracellular cation flux. This regulation requires occludin, claudin-1, claudin-2, and ZO-1. S408 dephosphorylation reduces occludin exchange, but increases exchange of ZO-1, claudin-1, and claudin-2, thereby causing the mobile fractions of these proteins to converge. Claudin-4 exchange is not affected. ZO-1 domains that mediate interactions with occludin and claudins are required for increases in claudin-2 exchange, suggesting assembly of a phosphorylation-sensitive protein complex. Consistent with this, binding of claudin-1 and claudin-2, but not claudin-4, to S408A occludin tail is increased relative to S408D. Finally, CK2 inhibition reversed IL-13-induced, claudin-2-dependent barrier loss. Thus, occludin S408 dephosphorylation regulates paracellular permeability by remodeling tight junction protein dynamic behavior and intermolecular interactions between occludin, ZO-1, and select claudins, and may have therapeutic potential in inflammation-associated barrier dysfunction.

Inventory Development and Input-output Model of U.S. Land Use: Relating Land in Production to Consumption

Environmental Science & Technology. Jun, 2011  |  Pubmed ID: 21561123

As populations and demands for land-intensive products, e.g., cattle and biofuels, increase the need to understand the relationship between land use and consumption grows. This paper develops a production-based inventory of land use (i.e., the land used to produce goods) in the U.S. With this inventory an input-output analysis is used to create a consumption-based inventory of land use. This allows for exploration of links between land used in production to the consumption of particular goods. For example, it is possible to estimate the amount of cropland embodied in processed foods or healthcare services. As would be expected, agricultural and forestry industries are the largest users of land in the production-based inventory. Similarly, we find that processed foods and forest products are the largest users of land in the consumption-based inventory. Somewhat less expectedly this work finds that the majority of manufacturing and service industries, not typically associated with land use, require substantial amounts of land to produce output due to the purchase of food and other agricultural and wood-based products in the supply chain. The quantitative land use results of this analysis could be integrated with qualitative metrics such as weighting schemes designed to reflect environmental impact or life cycle impact assessment methods.

Bone Regenerates Via Dedifferentiation of Osteoblasts in the Zebrafish Fin

Developmental Cell. May, 2011  |  Pubmed ID: 21571227

While mammals have a limited capacity to repair bone defects, zebrafish can completely regenerate amputated bony structures of their fins. Fin regeneration is dependent on formation of a blastema, a progenitor cell pool accumulating at the amputation plane. It is unclear which cells the blastema is derived from, whether it forms by dedifferentiation of mature cells, and whether blastema cells are multipotent. We show that mature osteoblasts dedifferentiate and form part of the blastema. Osteoblasts downregulate expression of intermediate and late bone differentiation markers and induce genes expressed by bone progenitors. Dedifferentiated osteoblasts proliferate in a FGF-dependent manner and migrate to form part of the blastema. Genetic fate mapping shows that osteoblasts only give rise to osteoblasts in the regenerate, indicating that dedifferentiation is not associated with the attainment of multipotency. Thus, bone can regenerate from mature osteoblasts via dedifferentiation, a finding with potential implications for human bone repair.

Comment on "Comparative Assessment of Life Cycle Assessment Methods Used for Personal Computers"

Environmental Science & Technology. Aug, 2011  |  Pubmed ID: 21732655

Electron-accepting 6,12-diethynylindeno[1,2-b]fluorenes: Synthesis, Crystal Structures, and Photophysical Properties

Angewandte Chemie (International Ed. in English). Nov, 2011  |  Pubmed ID: 21953794

Genistein Inhibits Proliferation of Colon Cancer Cells by Attenuating a Negative Effect of Epidermal Growth Factor on Tumor Suppressor FOXO3 Activity

BMC Cancer. 2011  |  Pubmed ID: 21639915

Soy consumption is associated with a lower incidence of colon cancer which is believed to be mediated by one of its of components, genistein. Genistein may inhibit cancer progression by inducing apoptosis or inhibiting proliferation, but mechanisms are not well understood. Epidermal growth factor (EGF)-induced proliferation of colon cancer cells plays an important role in colon cancer progression and is mediated by loss of tumor suppressor FOXO3 activity. The aim of this study was to assess if genistein exerts anti-proliferative properties by attenuating the negative effect of EGF on FOXO3 activity.

A "carbonizing Dragon": China's Fast Growing CO2 Emissions Revisited

Environmental Science & Technology. Nov, 2011  |  Pubmed ID: 21888374

China's annual CO(2) emissions grew by around 4 billion tonnes between 1992 and 2007. More than 70% of this increase occurred between 2002 and 2007. While growing export demand contributed more than 50% to the CO(2) emission growth between 2002 and 2005, capital investments have been responsible for 61% of emission growth in China between 2005 and 2007. We use structural decomposition analysis to identify the drivers for China's emission growth between 1992 and 2007, with special focus on the period 2002 to 2007 when growth was most rapid. In contrast to previous analysis, we find that efficiency improvements have largely offset additional CO(2) emissions from increased final consumption between 2002 and 2007. The strong increases in emissions growth between 2002 and 2007 are instead explained by structural change in China's economy, which has newly emerged as the third major emission driver. This structural change is mainly the result of capital investments, in particular, the growing prominence of construction services and their carbon intensive supply chain. By closing the model for capital investment, we can now show that the majority of emissions embodied in capital investment are utilized for domestic household and government consumption (35-49% and 19-36%, respectively) with smaller amounts for the production of exports (21-31%). Urbanization and the associated changes in lifestyle are shown to be more important than other socio-demographic drivers like the decreasing household size or growing population. We argue that mitigation efforts will depend on the future development of these key drivers, particularly capital investments which dictate future mitigation costs.

Polyethylene Glycol Diminishes Pathological Effects of Citrobacter Rodentium Infection by Blocking Bacterial Attachment to the Colonic Epithelia

Gut Microbes. Sep, 2011  |  Pubmed ID: 22067938

Infections from enteric bacteria such as enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic Escherichia coli (EHEC) are a public health threat worldwide. EPEC and EHEC are extracellular pathogens, and their interaction with host surface receptors is critical to the infection process. We previously demonstrated that polyethylene glycol (PEG) downregulates surface receptors in intestinal cells. Here we show that PEG decreases b 1-integrin, the surface receptor in intestinal cells that is critical for EPEC and EHEC attachment. We hypothesized that PEG would inhibit the attachment of these enteric pathogens to host cells and improve clinical signs of infection. We found that attachment of the mouse enteric pathogen Citrobacter rodentium, which belongs to the same group of pathogens as EPEC and EHEC, was attenuated by the concurrent presence of PEG. Pretreatment with PEG, without concurrent presence during infection, also reduced bacterial attachment. This finding was further supported in vivo such as that PEG administered by gavage daily during infection as well as prior to infection significantly decreased C. rodentium in the colon and improved the appearance of the infected colon in mice. In addition, PEG decreased the b 1-integrin in colonic mucosa and reduced the C. rodentium-induced activation of epidermal growth factor receptors. PEG also significantly reduced infection-induced colonic inflammation. Finally, PEG efficiently reduced C. rodentium shedding from the colon during infection. In conclusion, PEG can be an efficient and safe preventive agent against EPEC and EHEC infections.