bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure and Pathology of Tau Protein in Alzheimer Disease
Authors: Kolarova Michala , García-Sierra Francisco , Bartos Ales , Ricny Jan , Ripova Daniela
Published: June 2012

Alzheimer's disease (AD) is the most common type of dementia. In connection with the global trend of prolonging human life and the increasing number of elderly in the population, the AD becomes one of the most serious health and socioeconomic problems of the present. Tau protein promotes assembly and stabilizes microtubules, which contributes to the proper function of neuron. Alterations in the amount or the structure of tau protein can affect its role as a stabilizer of microtubules as well as some of the processes in which it is implicated. The molecular mechanisms governing tau aggregation are mainly represented by several posttranslational modifications that alter its structure and conformational state. Hence, abnormal phosphorylation and truncation of tau protein have gained attention as key mechanisms that become tau protein in a pathological entity. Evidences about the clinicopathological significance of phosphorylated and truncated tau have been documented during the progression of AD as well as their capacity to exert cytotoxicity when expressed in cell and animal models. This paper describes the normal structure and function of tau protein and its major alterations during its pathological aggregation in AD.
Mitochondrial- and Endoplasmic Reticulum-Associated Oxidative Stress in Alzheimer's Disease: From Pathogenesis to Biomarkers
Authors: Ferreiro E. , Baldeiras I. , Ferreira I. L. , Costa R. O. , Rego A. C. , Pereira C. F. , Oliveira C. R.
Published: June 2012

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting several million of people worldwide. Pathological changes in the AD brain include the presence of amyloid plaques, neurofibrillary tangles, loss of neurons and synapses, and oxidative damage. These changes strongly associate with mitochondrial dysfunction and stress of the endoplasmic reticulum (ER). Mitochondrial dysfunction is intimately linked to the production of reactive oxygen species (ROS) and mitochondrial-driven apoptosis, which appear to be aggravated in the brain of AD patients. Concomitantly, mitochondria are closely associated with ER, and the deleterious crosstalk between both organelles has been shown to be involved in neuronal degeneration in AD. Stimuli that enhance expression of normal and/or folding-defective proteins activate an adaptive unfolded protein response (UPR) that, if unresolved, can cause apoptotic cell death. ER stress also induces the generation of ROS that, together with mitochondrial ROS and decreased activity of several antioxidant defenses, promotes chronic oxidative stress. In this paper we discuss the critical role of mitochondrial and ER dysfunction in oxidative injury in AD cellular and animal models, as well as in biological fluids from AD patients. Progress in developing peripheral and cerebrospinal fluid biomarkers related to oxidative stress will also be summarized.
A Matrix Method for Determining Eigenvalues and Stability of Singular Neutral Delay‐Differential Systems
Authors: Ma Jian , Zheng Baodong , Zhang Chunrui
Published: June 2012

The eigenvalues and the stability of a singular neutral differential
system with single delay are considered. Firstly, by applying the matrix pencil
and the linear operator methods, new algebraic criteria for the imaginary axis
eigenvalue are derived. Second, practical checkable criteria for the asymptotic
stability are introduced.
Towards Therapeutic Applications of Arthropod VenomK+-Channel Blockers in CNS Neurologic Diseases Involving Memory Acquisition and Storage
Authors: Gati Christiano D. C. , Mortari Márcia R. , Schwartz Elisabeth F.
Published: June 2012

Potassium channels are the most heterogeneous and widely distributed group of ion channels and play important functions in all cells, in both normal and pathological mechanisms, including learning and memory processes. Being fundamental for many diverse physiological processes, K+-channels are recognized as potential therapeutic targets in the treatment of several Central Nervous System (CNS) diseases, such as multiple sclerosis, Parkinson's and Alzheimer's diseases, schizophrenia, HIV-1-associated dementia, and epilepsy. Blockers of these channels are therefore potential candidates for the symptomatic treatment of these neuropathies, through their neurological effects. Venomous animals have evolved a wide set of toxins for prey capture and defense. These compounds, mainly peptides, act on various pharmacological targets, making them an innumerable source of ligands for answering experimental paradigms, as well as for therapeutic application. This paper provides an overview of CNS K+-channels involved in memory acquisition and storage and aims at evaluating the use of highly selective K+-channel blockers derived from arthropod venoms as potential therapeutic agents for CNS diseases involving learning and memory mechanisms.
Predictors of Treatment with Duloxetine or Venlafaxine XR among Adult Patients Treated for Depression in Primary Care Practices in the United Kingdom
Authors: Shi Nianwen , Durden Emily , Torres Amelito , Cao Zhun , Happich Michael
Published: June 2012

Background.Knowledge about real-world use of duloxetine and venlafaxine XR to treat depression in the UK is limited.Aims.To identify predictors of duloxetine or venlafaxine XR initiation.Method.Adult depressed patients who initiated duloxetine or venlafaxine XR between January 1, 2006 and September 30, 2007 were identified in the UK’s General Practice Research Database. Demographic and clinical predictors of treatment initiation with duloxetine and venlafaxine XR were identified using logistic regression.Results.Patients initiating duloxetine (n=909) were 4 years older than venlafaxine XR recipients (n=1286). Older age, preexisting unexplained pain, respiratory disease, and pre-period use of anticonvulsants, opioids, and antihyperlipidemics were associated with increased odds of initiating duloxetine compared to venlafaxine XR. Pre-period anxiety disorder was associated with decreased odds of receiving duloxetine.Conclusion.Initial treatment choice with duloxetine versus venlafaxine XR was primarily driven by patient-specific mental and medical health characteristics. General practitioners in the UK favor duloxetine over venlafaxine XR when pain conditions coexist with depression.
Low‐Order Nonconforming Mixed Finite Element Methods for Stationary Incompressible Magnetohydrodynamics Equations
Authors: Shi Dongyang , Yu Zhiyun
Published: June 2012

The nonconforming mixed finite element methods (NMFEMs) are introduced and analyzed for the numerical discretization of a nonlinear, fully coupled stationary incompressible magnetohydrodynamics (MHD) problem in 3D. A family of the low‐order elements on tetrahedra or hexahedra are chosen to approximate the pressure, the velocity field, and the magnetic field. The existence and uniqueness of the approximate solutions are shown, and the optimal error estimates for the corresponding unknown variables in L2‐norm are established, as well as those in a broken
H1‐norm for the velocity and the magnetic fields. Furthermore, a new approach is adopted to prove the discrete Poincaré‐Friedrichs inequality, which is easier than that of the previous literature.
Amino Acids That Centrally Influence Blood Pressure and Regional Blood Flow in Conscious Rats
Authors: Takemoto Yumi
Published: June 2012

Functional roles of amino acids have increasingly become the focus of research. This paper summarizes amino acids that influence cardiovascular system via the brain of conscious rats. This paper firstly describes why amino acids are selected and outlines how the brain regulates blood pressure and regional blood flow. This section includes a concise history of amino acid neurotransmitters in cardiovascular research and summarizes brain areas where chemical stimulations produce blood pressure changes mainly in anesthetized animals. This is followed by comments about findings regarding several newly examined amino acids with intracisternal stimulation in conscious rats that produce changes in blood pressure. The same pressor or depressor response to central amino acid stimulations can be produced by distinct mechanisms at central and peripheral levels, which will be briefly explained. Thereafter, cardiovascular actions of some of amino acids at the mechanism level will be discussed based upon findings of pharmacological and regional blood flow measurements. Several examined amino acids in addition to the established neurotransmitter amino acids appear to differentially activate brain structures to produce changes in blood pressure and regional blood flows. They may have physiological roles in the healthy brain, but pathological roles in the brain with cerebral vascular diseases such as stroke where the blood-brain barrier is broken.
Fixed Point Theorems for Asymptotically Contractive Multimappings
Authors: Djedidi M. , Nachi K.
Published: June 2012

We present fixed point theorems for a nonexpansive set-valued mapping from a closed convex subset of a reflexive Banach space into itself under some asymptotic contraction assumptions. Some existence results of coincidence points and eigenvalues for multimappings are given.
Development of Protective Clothing against Nanoparticle Based on Electrospun Nanofibers
Authors: Faccini M. , Vaquero C. , Amantia D.
Published: June 2012

In this paper, the development of efficient protective clothing against nanoparticulate aerosols is presented. Nanofibrous mats of polyamide 6 (PA6) were deposited onto a nonwoven viscose substrate by electrospinning technique. The influence of electrospinning parameters, including solution concentration, viscosity, and conductivity, was studied for the production of nonwovens with controlled fiber diameter showing a size distribution ranging from 66 to 195 nm. By varying several process parameters, textiles with different thickness of the nanofiber layer and thus air permeability were obtained. A hot‐press lamination process using a thermoplastic resin as glue was applied to improve the adhesion of the nanofiber layer onto the textile support. After 1500 cycles of repeated compression and torsion, the nanofiber layer was still firmly attached to the support, while mechanical damage is visible in some areas. The penetration of NaCl particles with diameter ranging from 15 to 300 nm through the electrospun textiles was found to be strongly dependent on nanofiber layer thickness. A really thin nanofiber coating provides up to 80% retention of 20 nm size particles and over 50% retention of 200 nm size nanoparticles. Increasing the thickness of the nanofiber mat, the filtration efficiency was increased to over 99% along the whole nanoparticle range. The results obtained highlight the potential of nanofibers in the development of efficient personal protective equipments against nanoparticles.
Common Fixed‐Point Theorems in Complete Generalized Metric Spaces
Authors: Chen Chi-Ming
Published: June 2012

We introduce the notions of the 𝒲 function and 𝒮 function, and then we prove two common fixed point theorems in complete generalized metric spaces under contractive conditions with these two functions. Our results generalize or improve many recent common fixed point results in the literature.
Measuring Non-Gaussianity by Phi-Transformed and Fuzzy Histograms
Authors: Plant Claudia , Thai Son Mai , Shao Junming , Theis Fabian J. , Meyer-Baese Anke , Böhm Christian
Published: June 2012

Independent component analysis (ICA) is an essential building block for data analysis in many applications. Selecting the truly meaningful components from the result of an ICA algorithm, or comparing the results of different algorithms, however, is nontrivial problems. We introduce a very general technique for evaluating ICA results rooted in information-theoretic model selection. The basic idea is to exploit the natural link between non-Gaussianity and data compression: the better the data transformation represented by one or several ICs improves the effectiveness of data compression, the higher is the relevance of the ICs. We propose two different methods which allow an efficient data compression of non-Gaussian signals: Phi-transformed histograms and fuzzy histograms. In an extensive experimental evaluation, we demonstrate that our novel information-theoretic measures robustly select non-Gaussian components from data in a fully automatic way, that is, without requiring any restrictive assumptions or thresholds.
FEM Analyses for T‐H‐M‐M Coupling Processes in Dual‐Porosity Rock Mass under Stress Corrosion and Pressure Solution
Authors: Zhang Yu-Jun , Yang Chao-Shuai , Xu Gang
Published: June 2012

The models of stress corrosion and pressure solution established by Yasuhara et al. were introduced into the 2D FEM code of thermo‐hydro‐mechanical‐migratory coupling analysis for dual‐porosity medium developed by the authors. Aiming at a hypothetical model for geological disposal of nuclear waste in an unsaturated rock mass from which there is a nuclide leak, two computation conditions were designed. Then the corresponding two‐dimensional numerical simulation for the coupled thermo‐hydro‐mechanical‐migratory processes were carried out, and the states of temperatures, rates and magnitudes of aperture closure, pore and fracture pressures, flow velocities, nuclide concentrations and stresses in the rock mass were investigated. The results show: the aperture closure rates caused by stress corrosion are almost six orders higher than those caused by pressure solution, and the two kinds of closure rates climb up and then decline, furthermore tend towards stability; when the effects of stress corrosion and pressure solution are considered, the negative fracture pressures in near field rise very highly; the fracture aperture and porosity are decreases in the case 1, so the relative permeability coefficients reduce, therefore the nuclide concentrations in pore and fracture in this case are higher than those in case 2.
Uncoupling of PI3K from ErbB3 Impairs Mammary Gland Development but Does Not Impact on ErbB2-Induced Mammary Tumorigenesis
Authors: Lahlou Hicham , Müller Thomas , Sanguin-Gendreau Virginie , Birchmeier Carmen , Muller William J.
Published: June 2012

The formation of ErbB2/ErbB3 heterodimers plays a critical role in ErbB2-mediated signaling in both normal mammary development and mammary tumor progression. Through 7 phosphoinositide 3-kinase (PI3K) phosphotyrosine-binding sites, ErbB3 is able to recruit PI3K and initiate the PI3K/AKT signaling pathway. To directly explore the importance of the ErbB3/PI3K pathway in mammary development and tumorigenesis, we generated a mouse model that carries a mutant ErbB3 allele lacking the seven known PI3K-binding sites (ErbB3Δ85). Mice homozygous for the ErbB3Δ85 allele exhibited an initial early growth defect and a dramatic impairment of mammary epithelial outgrowth. Although homozygous adult mice eventually recovered from the growth defect, their mammary glands continued to manifest the mammary outgrowth and lactation defects throughout their adult life. Interestingly, despite the presence of a profound mammary gland defect, all of the female ErbB3Δ85 mice developed metastatic ErbB2-induced mammary tumors secondary to mammary epithelial expression of an activated ErbB2 oncogene capable of compensatory PI3K signaling from both EGF receptor and ErbB2. Our findings therefore indicate that, although ErbB3-associated PI3K activity is critical for mammary development, it is dispensable for ErbB2-induced mammary tumor progression. Cancer Res; 72(12); 3080–90. ©2012 AACR.
A Replication Study and Genome-Wide Scan of Single-Nucleotide Polymorphisms Associated with Pancreatic Cancer Risk and Overall Survival
Authors: Willis Jason A. , Olson Sara H. , Orlow Irene , Mukherjee Semanti , McWilliams Robert R. , Kurtz Robert C. , Klein Robert J.
Published: June 2012

Purpose: To explore the effects of single-nucleotide polymorphisms (SNP) on pancreatic cancer risk and overall survival (OS).

Experimental Design: The germ line DNA of 531 pancreatic cancer cases and 305 healthy controls from a hospital-based study was genotyped at SNPs previously reported to be associated with pancreatic cancer risk or clinical outcome. We analyzed putative risk SNPs for replication of their reported effects on risk and tested for novel effects on OS. Similarly, we analyzed putative survival-associated SNPs for replication of their reported effects on OS and tested for novel effects on risk. Finally, we conducted a genome-wide association study (GWAS) of OS using a subset of 252 cases, with two subsequent validation sets of 261 and 572 patients, respectively.

Results: Among seven risk SNPs analyzed, two (rs505922 and rs9543325) were associated with risk (P < 0.05). Among 24 survival-associated SNPs analyzed, one (rs9350) was associated with OS (P < 0.05). No putative risk SNPs or putative survival-associated SNPs were found to be associated with OS or risk, respectively. Furthermore, our GWAS identified a novel SNP [rs1482426, combined stage I and II, P = 1.7 × 10−6, per-allele HR, 1.74; 95% confidence interval (CI), 1.38–2.18] to be putatively associated with OS.

Conclusions: The effects of SNPs on pancreatic cancer risk and OS were replicated in our study, although further work is necessary to understand the functional mechanisms underlying these effects. More importantly, the putative association with OS identified by GWAS suggests that GWAS may be useful in identifying SNPs associated with clinical outcome in pancreatic cancer. Clin Cancer Res; 18(14); 3942–51. ©2012 AACR.
Vandetanib for the Treatment of Symptomatic or Progressive Medullary Thyroid Cancer in Patients with Unresectable Locally Advanced or Metastatic Disease: U.S. Food and Drug Administration Drug Approval Summary
Authors: Thornton Katherine , Kim Geoffrey , Maher V. Ellen , Chattopadhyay Somesh , Tang Shenghui , Moon Young Jin , Song Pengfei , Marathe Anshu , Balakrishnan Suchitra , Zhu Hao , Garnett Christine , Liu Qi , Booth Brian , Gehrke Brenda , Dorsam Robert , Verbois Leigh , Ghosh Debasis , Wilson Wendy , Duan John , Sarker Haripada , Miksinski Sarah Pope , Skarupa Lisa , Ibrahim Amna , Justice Robert , Murgo Anthony , Pazdur Richard
Published: June 2012

On April 6, 2011, the U.S. Food and Drug Administration approved vandetanib (Caprelsa tablets; AstraZeneca Pharmaceuticals LP) for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease. Vandetanib is the first drug approved for this indication, and this article focuses on the basis of approval. Approval was based on the results of a double-blind trial conducted in patients with medullary thyroid carcinoma. Patients were randomized 2:1 to vandetanib, 300 mg/d orally (n = 231), or to placebo (n = 100). The primary objective was demonstration of improvement in progression-free survival (PFS) with vandetanib compared with placebo. Other endpoints included evaluation of overall survival and objective response rate. The PFS analysis showed a marked improvement for patients randomized to vandetanib (hazard ratio = 0.35; 95% confidence interval, 0.24–0.53; P < 0.0001). The objective response rate for the vandetanib arm was 44% compared with 1% for the placebo arm. The most common grade 3 and 4 toxicities (>5%) were diarrhea and/or colitis, hypertension and hypertensive crisis, fatigue, hypocalcemia, rash, and corrected QT interval (QTc) prolongation. This approval was based on a statistically significant and clinically meaningful improvement in PFS. Given the toxicity profile, which includes prolongation of the QT interval and sudden death, only prescribers and pharmacies certified through the vandetanib Risk Evaluation Mitigation Strategy Program are able to prescribe and dispense vandetanib. Treatment-related risks should be taken into account when considering the use of vandetanib in patients with indolent, asymptomatic, or slowly progressing disease. Clin Cancer Res; 18(14); 3722–30. ©2012 AACR.
Calmodulin-Dependent Protein Kinase II: Linking Heart Failure and Arrhythmias
Authors: Swaminathan Paari Dominic , Purohit Anil , Hund Thomas J. , Anderson Mark E
Published: June 2012

Understanding relationships between heart failure and arrhythmias, important causes of suffering and sudden death, remains an unmet goal for biomedical researchers and physicians. Evidence assembled over the past decade supports a view that activation of the multifunctional Ca
2+
and calmodulin-dependent protein kinase II (CaMKII) favors myocardial dysfunction and cell membrane electrical instability. CaMKII activation follows increases in intracellular Ca
2+
or oxidation, upstream signals with the capacity to transition CaMKII into a Ca
2+
and calmodulin-independent constitutively active enzyme. Constitutively active CaMKII appears poised to participate in disease pathways by catalyzing the phosphorylation of classes of protein targets important for excitation–contraction coupling and cell survival, including ion channels and Ca
2+
homeostatic proteins, and transcription factors that drive hypertrophic and inflammatory gene expression. This rich diversity of downstream targets helps to explain the potential for CaMKII to simultaneously affect mechanical and electrical properties of heart muscle cells. Proof-of-concept studies from a growing number of investigators show that CaMKII inhibition is beneficial for improving myocardial performance and for reducing arrhythmias. We review the molecular physiology of CaMKII and discuss CaMKII actions at key cellular targets and results of animal models of myocardial hypertrophy, dysfunction, and arrhythmias that suggest CaMKII inhibition may benefit myocardial function while reducing arrhythmias.
Expansion of a Regional ST-Segment–Elevation Myocardial Infarction System to an Entire State
Authors: Jollis James G. , Al-Khalidi Hussein R. , Monk Lisa , Roettig Mayme L. , Garvey J. Lee , Aluko Akinyele O. , Wilson B. Hadley , Applegate Robert J. , Mears Greg , Corbett Claire C. , Granger Christopher B.
Published: June 2012

Background—

Despite national guidelines calling for timely coronary artery reperfusion, treatment is often delayed, particularly for patients requiring interhospital transfer.

Methods and Results—

One hundred nineteen North Carolina hospitals developed coordinated plans to rapidly treat patients with ST-segment–elevation myocardial infarction according to presentation: walk-in, ambulance, or hospital transfer. A total of 6841 patients with ST-segment–elevation myocardial infarction (3907 directly presenting to 21 percutaneous coronary intervention hospitals, 2933 transferred from 98 non–percutaneous coronary intervention hospitals) were treated between July 2008 and December 2009 (age, 59 years; 30% women; 19% uninsured; chest pain duration, 91 minutes; shock, 9.2%). The rate of patients not receiving reperfusion fell from 5.4% to 4.0% (
P
=0.04). Treatment times for hospital transfer patients substantially improved. First-hospital-door-to-device time for hospitals that adopted a “transfer for percutaneous coronary intervention” reperfusion strategy fell from 117 to 103 minutes (
P
=0.0008), whereas times at hospitals with a mixed strategy of transfer or fibrinolysis fell from 195 to 138 minutes (
P
=0.002). Median door-to-device times for patients presenting directly to PCI hospitals fell from 64 to 59 minutes (
P
<0.001). Emergency medical services–transported patients were most likely to reach door-to-device goals, with 91% treated within 90 minutes and 52% being treated with 60 minutes. Patients treated within guideline goals had a mortality of 2.2% compared with 5.7% for those exceeding guideline recommendations (
P
<0.001).

Conclusion—

Through extension of regional coordination to an entire state, rapid diagnosis and treatment of ST-segment–elevation myocardial infarction has become an established standard of care independently of healthcare setting or geographic location.
Diets Containing Pistachios Reduce Systolic Blood Pressure and Peripheral Vascular Responses to Stress in Adults With Dyslipidemia
Authors: West Sheila G. , Gebauer Sarah K. , Kay Colin D. , Bagshaw Deborah M. , Savastano David M. , Diefenbach Christopher , Kris-Etherton Penny M.
Published: June 2012

Nut consumption reduces cardiovascular risk, and reductions in blood pressure and peripheral vascular resistance may be important mediators of this relationship. We evaluated effects of pistachios on flow-mediated dilation and blood pressure response to acute stress. Twenty-eight adults with dyslipidemia completed a randomized, crossover, controlled-feeding study. All of the meals were provided and calories were controlled. After 2 weeks on a typical Western diet (35% total fat and 11% saturated fat), test diets were presented in counterbalanced order for 4 weeks each, a low-fat control diet (25% total fat and 8% saturated fat), a diet containing 10% of energy from pistachios (on average, 1 serving per day; 30% total fat and 8% saturated fat), and a diet containing 20% of energy from pistachios (on average, 2 servings per day, 34% total fat and 8% saturated fat). None of the resting hemodynamic measures significantly differed from pretreatment values. When resting and stress levels were included in the repeated-measures analysis, average reductions in systolic blood pressure were greater after the diet containing 1 serving per day versus 2 servings per day of pistachios (mean change in systolic blood pressure, −4.8 vs −2.4 mm Hg, respectively;
P
<0.05). After the higher dose, there were significant reductions in peripheral resistance (−62.1 dyne·s×cm
−5
) and heart rate (−3 bpm) versus the control diet (
P
<0.0001). These changes were partially offset by increases in cardiac output. There was no effect of diet on fasting flow-mediated dilation. Reductions in peripheral vascular constriction and the resulting decrease in hemodynamic load may be important contributors to lower risk in nut consumers.
Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT
R141W
Dilated Cardiomyopathy Transgenic Mice
Authors: Lu Dan , Ma Yuanwu , Zhang Wei , Bao Dan , Dong Wei , Lian Hong , Huang Lan , Zhang Lianfeng
Published: June 2012

Cytochrome P450 2E1 (CYP2E1) is a cytochrome P450 enzyme that catalyzes the metabolism of toxic substrates. CYP2E1 is upregulated in heart disease, including the dilated cardiomyopathy (DCM) mouse model. Here, knockdown of CYP2E1 significantly ameliorated the dilated left ventricle, thin wall, and dysfunctional contraction in the cTnT
R141W
and adriamycin-induced DCM mouse models. Interstitial fibrosis, poorly organized myofibrils, and swollen mitochondria with loss of cristae were improved in the myocardium of α-myosin heavy chain (MHC)-cTnT
R141W
×CYP2E1-silence double-transgenic mice when compared with the cTnT
R141W
transgenic mice. Oxidative stress, the activation of caspase 3 and caspase 9, the release of cytochrome
c
, and the apoptosis in the myocardium were significantly decreased in double-transgenic mice compared with the cTnT
R141W
transgenic mice. In summary, the expression of CYP2E1 is upregulated in heart disease and might be induced by hypoxemia in cardiomyopathy. The overexpression of CYP2E1 can enhance the metabolism of endogenous ketones to meet the energy demand of the heart in certain disease states, but the overexpression of CYP2E1 can also increase oxidative stress and apoptosis in the DCM heart. Knockdown or downregulation of CYP2E1 might be a therapeutic strategy to control the development of DCM after mutations of cTnT
R141W
or other factors, because DCM is the third most common cause of heart failure and the most frequent cause of heart transplantation.
A Novel Role for Epidermal Growth Factor Receptor Tyrosine Kinase and Its Downstream Endoplasmic Reticulum Stress in Cardiac Damage and Microvascular Dysfunction in Type 1 Diabetes Mellitus
Authors: Galán Maria , Kassan Modar , Choi Soo-Kyoung , Partyka Megan , Trebak Mohamed , Henrion Daniel , Matrougui Khalid
Published: June 2012

Epidermal growth factor receptor tyrosine kinase (EGFRtk) and endoplasmic reticulum (ER) stress are important factors in cardiovascular complications. Understanding whether enhanced EGFRtk activity and ER stress induction are involved in cardiac damage, and microvascular dysfunction in type 1 diabetes mellitus is an important question that has remained unanswered. Cardiac fibrosis and microvascular function were determined in C57BL/6J mice injected with streptozotocin only or in combination with EGFRtk inhibitor (AG1478), ER stress inhibitor (Tudca), or insulin for 2 weeks. In diabetic mice, we observed an increase in EGFRtk phosphorylation and ER stress marker expression (CHOP, ATF4, ATF6, and phosphorylated-eIF2α) in heart and mesenteric resistance arteries, which were reduced with AG1478, Tudca, and insulin. Cardiac fibrosis, enhanced collagen type I, and plasminogen activator inhibitor 1 were decreased with AG1478, Tudca, and insulin treatments. The impaired endothelium-dependent relaxation and -independent relaxation responses were also restored after treatments. The inhibition of NO synthesis reduced endothelium-dependent relaxation in control and treated streptozotocin mice, whereas the inhibition of NADPH oxidase improved endothelium-dependent relaxation only in streptozotocin mice. Moreover, in mesenteric resistance arteries, the mRNA levels of Nox2 and Nox4 and the NADPH oxidase activity were augmented in streptozotocin mice and reduced with treatments. This study unveiled novel roles for enhanced EGFRtk phosphorylation and its downstream ER stress in cardiac fibrosis and microvascular endothelial dysfunction in type 1 diabetes mellitus.
Excess Mutual Catalysis Is Required for Effective Evolvability
Authors: Markovitch Omer , Lancet Doron
Published: June 2012

It is widely accepted that autocatalysis constitutes a crucial facet of effective replication and evolution (e.g., in Eigen's hypercycle model). Other models for early evolution (e.g., by Dyson, Gánti, Varela, and Kauffman) invoke catalytic networks, where cross-catalysis is more apparent. A key question is how the balance between auto- (self-) and cross- (mutual) catalysis shapes the behavior of model evolving systems. This is investigated using the graded autocatalysis replication domain (GARD) model, previously shown to capture essential features of reproduction, mutation, and evolution in compositional molecular assemblies. We have performed numerical simulations of an ensemble of GARD networks, each with a different set of lognormally distributed catalytic values. We asked what is the influence of the catalytic content of such networks on beneficial evolution. Importantly, a clear trend was observed, wherein only networks with high mutual catalysis propensity (pmc) allowed for an augmented diversity of composomes, quasi-stationary compositions that exhibit high replication fidelity. We have reexamined a recent analysis that showed meager selection in a single GARD instance and for a few nonstationary target compositions. In contrast, when we focused here on compotypes (clusters of composomes) as targets for selection in populations of compositional assemblies, appreciable selection response was observed for a large portion of the networks simulated. Further, stronger selection response was seen for high pmcvalues. Our simulations thus demonstrate that GARD can help analyze important facets of evolving systems, and indicate that excess mutual catalysis over self-catalysis is likely to be important for the emergence of molecular systems capable of evolutionlike behavior.
Evolution of Resistance to Quorum Quenching in Digital Organisms
Authors: Beckmann Benjamin E. , Knoester David B. , Connelly Brian D. , Waters Christopher M. , McKinley Philip K.
Published: June 2012

Quorum sensing (QS) is a collective behavior whereby actions of individuals depend on the density of the surrounding population. Bacteria use QS to trigger secretion of digestive enzymes, formation and destruction of biofilms, and, in the case of pathogenic organisms, expression of virulence factors that cause disease. Investigations of mechanisms that prevent or disrupt QS, referred to as quorum quenching, are of interest because they provide a new alternative to antibiotics for treating bacterial infections. Traditional antibiotics either kill bacteria or inhibit their growth, producing selective pressures that promote resistant strains. In contrast, quorum quenching and other so-called anti-infective strategies focus on altering behavior. In this article we evolve QS in populations of digital organisms, a type of self-replicating computer program, and investigate the effects of quorum quenching on these populations. Specifically, we injected the populations with mutant organisms that were impaired in selected ways to disrupt the QS process. The experimental results indicate that the rate at which these mutants are introduced into a population influences both the evolvability of QS and the persistence of an existing QS behavior. Surprisingly, we also observed resistance to quorum quenching. Effectively, populations evolved resistance by reaching quorum at lower cell densities than did the parent strain. Moreover, the level of resistance was highest when the rate of mutant introduction increased over time. These results show that digital organisms can serve as a model to study the evolution and disruption of QS, potentially informing wet-lab studies aimed at identifying targets for anti-infective development.
Naming Game on Adaptive Weighted Networks
Authors: Lipowska Dorota , Lipowski Adam
Published: June 2012

We examine a naming game on an adaptive weighted network. A weight of connection for a given pair of agents depends on their communication success rate and determines the probability with which the agents communicate. In some cases, depending on the parameters of the model, the preference toward successfully communicating agents is essentially negligible and the model behaves similarly to the naming game on a complete graph. In particular, it quickly reaches a single-language state, albeit some details of the dynamics are different from the complete-graph version. In some other cases, the preference toward successfully communicating agents becomes much more important and the model gets trapped in a multi-language regime. In this case gradual coarsening and extinction of languages lead to the emergence of a dominant language, albeit with some other languages still present. A comparison of distribution of languages in our model and in the human population is discussed.
Energy Efficiency and Economic Development in China
Authors: Yao Shujie , Luo Dan , Rooker Tyler
Published: June 2012

China is now the world's second largest economy, and it is expected to overtake the United States to become the largest by 2020. What are the implications for the global environment and climate change if China surpasses the United States? There are major concerns with China's rapid rise because its economic and industrial structure is increasingly dependent on the consumption of energy, raw materials, and electricity. In 2010, China's GDP was approximately 40 percent of the United States' GDP, yet it was the world's largest polluter and the biggest consumer of energy and electricity. This implies that the energy efficiency of the Chinese economy measured by energy consumption per unit of GDP is about one-third of that of the United States and one-fourth that of the EU and Japan. If the Chinese economy continues to grow as fast as it has in the past, without changing its structure and improving energy efficiency, China's growth will cause severe damage to the global environment. This paper analyzes the evolution of energy efficiency in the Chinese economy and stresses the importance of transforming China's economic structure.
A Short-Term Ensemble Wind Speed Forecasting System for Wind Power Applications
Authors: Traiteur Justin J. , Callicutt David J. , Smith Maxwell , Roy Somnath Baidya
Published: June 2012

This study develops an adaptive, blended forecasting system to provide accurate wind speed forecasts 1 h ahead of time for wind power applications. The system consists of an ensemble of 21 forecasts with different configurations of the Weather Research and Forecasting Single Column Model and persistence, autoregressive, and autoregressive moving-average models. The ensemble is calibrated against observations for a 6-month period (January–June 2006) at a potential wind-farm site in Illinois using the Bayesian model averaging technique. The forecasting system is evaluated against observations for the July 2006–December 2007 period at the same site. The calibrated ensemble forecasts significantly outperform the forecasts from the uncalibrated ensemble as well the time series models under all environmental stability conditions. This forecasting system is computationally more efficient than traditional numerical weather prediction models and can generate a calibrated forecast, including model runs and calibration, in approximately 1 min. Currently, hour-ahead wind speed forecasts are almost exclusively produced using statistical models. However, numerical models have several distinct advantages over statistical models including the potential to provide turbulence forecasts. Hence, there is an urgent need to explore the role of numerical models in short-term wind speed forecasting. This work is a step in that direction and is likely to trigger a debate within the wind speed forecasting community.
Observational Evidence for Relationships between the Degree of Aggregation of Deep Convection, Water Vapor, Surface Fluxes, and Radiation
Authors: Tobin Isabelle , Bony Sandrine , Roca Remy
Published: June 2012

Tropical deep convection exhibits complex organization over a wide range of scales. This study investigates the relationships between the spatial organization of deep convection and the large-scale atmospheric state. By using several satellite datasets and reanalyses, and by defining a simple diagnostic of convective aggregation, relationships between the degree of convective aggregation and the amount of water vapor, turbulent surface fluxes, and radiation are highlighted above tropical oceans. When deep convection is more aggregated, the middle and upper troposphere are drier in the convection-free environment, turbulent surface fluxes are enhanced, and the low-level and midlevel cloudiness is reduced in the environment. Humidity and cloudiness changes lead to a large increase in outgoing longwave radiation. Cloud changes also result in reduced reflected shortwave radiation. Owing to these opposing effects, the sensitivity of the radiative budget at the top of the atmosphere to convective aggregation turns out to be weak, but the distribution of radiative heating throughout the troposphere is affected. These results suggest that feedbacks between convective aggregation and the large-scale atmospheric state might influence large-scale dynamics and the transports of water and energy and, thus, play a role in the climate variability and change. These observational findings are qualitatively consistent with previous cloud-resolving model results, except for the effects on cloudiness and reflected shortwave radiation. The proposed methodology may be useful for assessing the representation of convective aggregation and its interaction with the large-scale atmospheric state in various numerical models.
Simulation of the East Asian Summer Monsoon during the Last Millennium with the MPI Earth System Model
Authors: Man Wenmin , Zhou Tianjun , Jungclaus Johann H.
Published: June 2012

The decadal–centennial variations of East Asian summer monsoon (EASM) and the associated rainfall change during the past millennium are simulated using the earth system model developed at the Max Planck Institute for Meteorology. The model was driven by up-to-date reconstructions of external forcing including the recent low-amplitude estimates of solar variations. Analysis of the simulations indicates that the EASM is generally strong during the Medieval Warm Period (MWP; A.D. 1000–1100) and weak during the Little Ice Age (LIA; A.D. 1600–1700). The monsoon rainband exhibits a meridional tripolar pattern during both epochs. Excessive (deficient) precipitation is found over northern China (35°–42°N, 100°–120°E) but deficient (excessive) precipitation is seen along the Yangtze River valley (27°–34°N, 100°–120°E) during the MWP (LIA). Both similarities and disparities of the rainfall pattern between the model results herein and the proxy data have been compared, and reconstructions from Chinese historical documents and some geological evidence support the results. The changes of the EASM circulation including the subtropical westerly jet stream in the upper troposphere and the western Pacific subtropical high (WPSH) in the middle and lower troposphere are consistent with the meridional shift of the monsoon rain belt during both epochs. The meridional monsoon circulation changes are accompanied with anomalous southerly (northerly) winds between 20° and 50°N during the MWP (LIA). The land–sea thermal contrast change caused by the effective radiative forcing leads to the MWP and LIA monsoon changes. The “warmer land–colder ocean” anomaly pattern during the MWP favors a stronger monsoon, while the “colder land–warmer ocean” anomaly pattern during the LIA favors a weaker monsoon.
Carbon Cycle Uncertainty Increases Climate Change Risks and Mitigation Challenges
Authors: Higgins Paul A. T. , Harte John
Published: June 2012

Projections of greenhouse gas concentrations over the twenty-first century generally rely on two optimistic, but questionable, assumptions about the carbon cycle: 1) that elevated atmospheric CO2concentrations will enhance terrestrial carbon storage and 2) that plant migration will be fast relative to climate changes. This paper demonstrates that carbon cycle uncertainty is considerably larger than currently recognized and that plausible carbon cycle responses could strongly amplify climate warming. This has important implications for societal decisions that relate to climate change risk management because it implies that a given level of human emissions could result in much larger climate changes than we now realize or that stabilizing atmospheric greenhouse gas concentrations at a “safe” level could require lower human emissions than currently understood. These results also suggest that terrestrial carbon cycle responses could be sufficiently strong to account for the changes in atmospheric carbon dioxide that occurred during transitions between ice age and interglacial periods.
On the Correspondence between Short- and Long-Time-Scale Systematic Errors in CAM4/CAM5 for the Year of Tropical Convection
Authors: Xie Shaocheng , Ma Hsi-Yen , Boyle James S. , Klein Stephen A. , Zhang Yuying
Published: June 2012

The correspondence between short- and long-time-scale systematic errors in the Community Atmospheric Model, version 4 (CAM4) and version 5 (CAM5), is systematically examined. The analysis is based on the annual-mean data constructed from long-term “free running” simulations and short-range hindcasts. The hindcasts are initialized every day with the ECMWF analysis for the Year(s) of Tropical Convection. It has been found that most systematic errors, particularly those associated with moist processes, are apparent in day 2 hindcasts. These errors steadily grow with the hindcast lead time and typically saturate after five days with amplitudes comparable to the climate errors. Examples include the excessive precipitation in much of the tropics and the overestimate of net shortwave absorbed radiation in the stratocumulus cloud decks over the eastern subtropical oceans and the Southern Ocean at about 60°S. This suggests that these errors are likely the result of model parameterization errors as the large-scale flow remains close to observed in the first few days of the hindcasts. In contrast, other climate errors are present in the hindcasts, but with amplitudes that are significantly smaller than and do not approach their climate errors during the 6-day hindcasts. These include the cold biases in the lower stratosphere, the unrealistic double–intertropical convergence zone pattern in the simulated precipitation, and an annular mode bias in extratropical sea level pressure. This indicates that these biases could be related to slower processes such as radiative and chemical processes, which are important in the lower stratosphere, or the result of poor interactions of the parameterized physics with the large-scale flow.
Baroclinic Frontal Instabilities and Turbulent Mixing in the Surface Boundary Layer. Part I: Unforced Simulations
Authors: Skyllingstad Eric D. , Samelson R. M.
Published: June 2012

Interaction between mixed layer baroclinic eddies and small-scale turbulence is studied using a nonhydrostatic large-eddy simulation (LES) model. Free, unforced flow evolution is considered, for a standard initialization consisting of an 80-m-deep mixed layer with a superposed warm filament and two frontal interfaces in geostrophic balance, on a model domain roughly 5 km × 10 km × 120 m, with an isotropic 3-m computational grid. Results from these unforced experiments suggest that shear generated in narrow frontal zones can support weak three-dimensional turbulence that is directly linked to the larger-scale baroclinic waves. Two separate but closely related issues are addressed: 1) the possible development of enhanced turbulent mixing associated with the baroclinic wave activity and 2) the existence of a downscale transfer of energy from the baroclinic wave scale to the turbulent dissipation scale. The simulations show enhanced turbulence associated with the baroclinic waves and enhanced turbulent heat flux across the isotherms of the imposed frontal boundary, relative to background levels. This turbulence develops on isolated small-scale frontal features that form as the result of frontogenetic processes operating on the baroclinic wave scale and not as the result of a continuous, inertial forward cascade through the intermediate scales. Analysis of the spectrally decomposed kinetic energy budget indicates that large-scale baroclinic eddy energy is directly transferred to small-scale turbulence, with weaker forcing at intermediate scales. For fronts with significant baroclinic wave activity, cross-frontal eddy fluxes computed from correlations of fluctuations from means along the large-scale frontal axis generally agreed with simple theoretical estimates.