bluuebunny/crossref_metadata_2025 huggingface dataset:
A Putative Transmembrane Leucine Zipper of Agrobacterium VirB10 Is Essential for T-Pilus Biogenesis but Not Type IV Secretion
Authors: Garza Isaac , Christie Peter J.
Published: April 2013

The
Agrobacterium tumefaciens
VirB/VirD4 type IV secretion system is composed of a translocation channel and an extracellular T pilus. Bitopic VirB10, the VirB7 lipoprotein, and VirB9 interact to form a cell envelope-spanning structural scaffold termed the “core complex” that is required for the assembly of both structures. The related pKM101-encoded core complex is composed of 14 copies each of these VirB homologs, and the transmembrane (TM) α helices of VirB10-like TraF form a 55-Å-diameter ring at the inner membrane. Here, we report that the VirB10 TM helix possesses two types of putative dimerization motifs, a GxxxA (GA
4
) motif and two leucine (Leu1, Leu2) zippers. Mutations in the Leu1 motif disrupted T-pilus biogenesis, but these or other mutations in the GA
4
or Leu2 motif did not abolish substrate transfer. Replacement of the VirB10 TM domain with a nondimerizing poly-Leu/Ala TM domain sequence also blocked pilus production but not substrate transfer or formation of immunoprecipitable complexes with the core subunits VirB7 and VirB9 and the substrate receptor VirD4. The VirB10 TM helix formed weak homodimers in
Escherichia coli
, as determined with the TOXCAT assay, whereas replacement of the VirB10 TM helix with the strongly dimerizing TM helix from glycophorin A blocked T-pilus biogenesis in
A. tumefaciens
. Our findings support a model in which VirB10's TM helix contributes to the assembly or activity of the translocation channel as a weakly self-interacting membrane anchor but establishes a heteromeric TM-TM helix interaction via its Leu1 motif that is critical for T-pilus biogenesis.
Investigating the Functional Hierarchy of Bacillus megaterium PV361 Spore Germinant Receptors
Authors: Gupta Srishti , Üstok Fatma Işık , Johnson Christian L. , Bailey David M. D. , Lowe Christopher R. , Christie Graham
Published: April 2013

Spores of
Bacillus megaterium
QM B1551 germinate rapidly when exposed to a number of single-trigger germinant compounds, including glucose, proline, leucine, and certain inorganic salts. However, spores of strain PV361, a plasmidless QM B1551 derivative that lacks the GerU germinant receptor (GR) responsible for mediating germination in response to single-trigger compounds, can germinate efficiently when incubated in nutritionally rich media, presumably via activation of additional germinant receptors. In this work, we have identified five chromosomally encoded GRs and attempted to characterize, by mutational analysis, germinant recognition profiles associated with the respective receptors in strain PV361. Of strains engineered with single GR insertion-deletions, only GerK-null spores displayed significant defective germination phenotypes when incubated in 5% (wt/vol) beef extract or plated on rich solid medium. Cumulative decreases in viability were observed in GerK-null spores that also lacked GerA or GerA
2
, indicating that these GRs, which exerted little effect on spore germination when disrupted individually, have a degree of functionality. Unexpectedly, an efficient germination response to combinations of germinants was restored in GerA
+
spores, which lack all other functional GRs, providing evidence for negative cooperativity between some GRs within the spore. Tetrazolium-based germinative assays conducted with purified spores indicated that these newly characterized
B. megaterium
GRs are cognate for a wide and chemically diverse range of germinant molecules, but unlike GerU, can only be induced to trigger germination when stimulated by at least two different germinants.
Functional Properties and Structural Requirements of the Plasmid pMV158-Encoded MobM Relaxase Domain
Authors: Fernández-López Cris , Pluta Radoslaw , Pérez-Luque Rosa , Rodríguez-González Lorena , Espinosa Manuel , Coll Miquel , Lorenzo-Díaz Fabián , Boer D. Roeland
Published: April 2013

A crucial element in the horizontal transfer of mobilizable and conjugative plasmids is the relaxase, a single-stranded endonuclease that nicks the origin of transfer (
oriT
) of the plasmid DNA. The relaxase of the pMV158 mobilizable plasmid is MobM (494 residues). In solution, MobM forms a dimer through its C-terminal domain, which is proposed to anchor the protein to the cell membrane and to participate in type 4 secretion system (T4SS) protein-protein interactions. In order to gain a deeper insight into the structural MobM requirements for efficient DNA catalysis, we studied two endonuclease domain variants that include the first 199 or 243 amino acid residues (MobMN199 and MobMN243, respectively). Our results confirmed that the two proteins behaved as monomers in solution. Interestingly, MobMN243 relaxed supercoiled DNA and cleaved single-stranded oligonucleotides harboring
oriT
pMV158
, whereas MobMN199 was active only on supercoiled DNA. Protein stability studies using gel electrophoresis and mass spectrometry showed increased susceptibility to degradation at the domain boundary between the N- and C-terminal domains, suggesting that the domains change their relative orientation upon DNA binding. Overall, these results demonstrate that MobMN243 is capable of nicking the DNA substrate independently of its topology and that the amino acids 200 to 243 modulate substrate specificity but not the nicking activity
per se
. These findings suggest that these amino acids are involved in positioning the DNA for the nuclease reaction rather than in the nicking mechanism itself.
Stress-Induced Outer Membrane Vesicle Production by Pseudomonas aeruginosa
Authors: MacDonald Ian A. , Kuehn Meta J.
Published: April 2013

As an opportunistic Gram-negative pathogen,
Pseudomonas aeruginosa
must be able to adapt and survive changes and stressors in its environment during the course of infection. To aid survival in the hostile host environment,
P. aeruginosa
has evolved defense mechanisms, including the production of an exopolysaccharide capsule and the secretion of a myriad of degradative proteases and lipases. The production of outer membrane-derived vesicles (OMVs) serves as a secretion mechanism for virulence factors as well as a general bacterial response to envelope-acting stressors. This study investigated the effect of sublethal physiological stressors on OMV production by
P. aeruginosa
and whether the
Pseudomonas
quinolone signal (PQS) and the MucD periplasmic protease are critical mechanistic factors in this response. Exposure to some environmental stressors was determined to increase the level of OMV production as well as the activity of AlgU, the sigma factor that controls MucD expression. Overexpression of AlgU was shown to be sufficient to induce OMV production; however, stress-induced OMV production was not dependent on activation of AlgU, since stress caused increased vesiculation in strains lacking
algU
. We further determined that MucD levels were not an indicator of OMV production under acute stress, and PQS was not required for OMV production under stress or unstressed conditions. Finally, an investigation of the response of
P. aeruginosa
to oxidative stress revealed that peroxide-induced OMV production requires the presence of B-band but not A-band lipopolysaccharide. Together, these results demonstrate that distinct mechanisms exist for stress-induced OMV production in
P. aeruginosa
.
The UEFA injury study: 11-year data concerning 346 MCL injuries and time to return to play
Authors: Lundblad Matilda , Waldén Markus , Magnusson Henrik , Karlsson Jón , Ekstrand Jan
Published: April 2013

Background

Medial collateral ligament (MCL) injury is the most common knee ligament injury in professional football.

Aim

To investigate the rate and circumstances of MCL injuries and development over the past decade.

Methods

Prospective cohort study, in which 27 professional European teams were followed over 11 seasons (2001/2002 to 2011/2012). Team medical staffs recorded player exposure and time loss injuries. MCL injuries were classified into four severity categories. Injury rate was defined as the number of injuries per 1000 player-hours.

Results

346 MCL injuries occurred during 1 057 201 h (rate 0.33/1000 h). The match injury rate was nine times higher than the training injury rate (1.31 vs 0.14/1000 h, rate ratio 9.3, 95% CI 7.5 to 11.6, p<0.001). There was a significant average annual decrease of approximately 7% (p=0.023). The average lay-off was 23 days, and there was no difference in median lay-off between index injuries and reinjuries (18 vs 13, p=0.20). Almost 70% of all MCL injuries were contact-related, and there was no difference in median lay-off between contact and non-contact injuries (16 vs 16, p=0.74).

Conclusions

This largest series of MCL injuries in professional football suggests that the time loss from football for MCL injury is 23 days. Also, the MCL injury rate decreased significantly during the 11-year study period.
Twenty-two years of HIV-related consultations in Dutch general practice: a dynamic cohort study
Authors: Donker Gé , Dorsman Sara , Spreeuwenberg Peter , van den Broek Ingrid , van Bergen Jan
Published: April 2013

Objectives

To examine the role of general practitioners (GPs) in HIV counselling and testing over a 22-year period.

Design

A dynamic cohort study.

Setting

General practices (N=42) participating in the Dutch Sentinel General Practice Network at Nivel with a nationally representative patient population by age, gender, regional distribution and population density.

Outcome measures

HIV-related consultations from 1988 to 2009 were recorded using a questionnaire in which patient's characteristics, interventions and test results were recorded. Trends over time and effects of urbanisation (3 categories) were assessed by multilevel analysis to control for clustering of observations within general practices.

Results

Time trend analyses show an increasing trend in HIV-related consultations and in the total number of HIV tests per 10 000 registered patients from 1988 to 1996, followed by a declining period and an increase again in the period 2007–2009. Over the whole period, the number of HIV-related consultations was highest in the urban areas with a maximum of 18 per 10 000 patients in 1996. The proportion of people high at risk, men who have sex with men, decreased. The proportion of HIV-related consultations initiated by the GPs increased from 11% in 1988 to 23% in 2009.

Conclusion

In this 22-year period, HIV-related consultations and provider-initiated HIV testing in the Dutch general practice have increased. More attention for sexual health in general practice is required that focuses on high-risk groups and on more routine testing in high prevalence areas.
Does cognitive behaviour therapy have an enduring effect that is superior to keeping patients on continuation pharmacotherapy? A meta-analysis
Authors: Cuijpers Pim , Hollon Steven D , van Straten Annemieke , Bockting Claudi , Berking Matthias , Andersson Gerhard
Published: April 2013

Objectives

Although cognitive behaviour therapy (CBT) and pharmacotherapy are equally effective in the acute treatment of adult depression, it is not known how they compare across the longer term. In this meta-analysis, we compared the effects of acute phase CBT without any subsequent treatment with the effects of pharmacotherapy that either were continued or discontinued across 6–18 months of follow-up.

Design

We conducted systematic searches in bibliographical databases to identify relevant studies, and conducted a meta-analysis of studies meeting inclusion criteria.

Setting

Mental healthcare.

Participants

Patients with depressive disorders.

Interventions

CBT and pharmacotherapy for depression.

Outcome measures

Relapse rates at long-term follow-up.

Results

9 studies with 506 patients were included. The quality was relatively high. Short-term outcomes of CBT and pharmacotherapy were comparable, although drop out from treatment was significantly lower in CBT. Acute phase CBT was compared with pharmacotherapy discontinuation during follow-up in eight studies. Patients who received acute phase CBT were significantly less likely to relapse than patients who were withdrawn from pharmacotherapy (OR=2.61, 95% CI 1.58 to 4.31, p<0.001; numbers-needed-to-be-treated, NNT=5). The acute phase CBT was compared with continued pharmacotherapy at follow-up in five studies. There was no significant difference between acute phase CBT and continued pharmacotherapy, although there was a trend (p<0.1) indicating that patients who received acute phase CBT may be less likely to relapse following acute treatment termination than patients who were continued on pharmacotherapy (OR=1.62, 95% CI 0.97 to 2.72; NNT=10).

Conclusions

We found that CBT has an enduring effect following termination of the acute treatment. We found no significant difference in relapse after the acute phase CBT versus continuation of pharmacotherapy after remission. Given the small number of studies, this finding should be interpreted with caution pending replication.
Medicines information needs during pregnancy: a multinational comparison
Authors: Hämeen-Anttila Katri , Jyrkkä Johanna , Enlund Hannes , Nordeng Hedvig , Lupattelli Angela , Kokki Esa
Published: April 2013

Objectives

The aim was to assess the perceived needs of medicines information and information sources for pregnant women in various countries.

Design

Cross-sectional internet-based study.

Setting

Multinational.

Participants

Pregnant women and women with children less than 25 weeks.

Primary and secondary outcome measures

The need for information about medicines was assessed by a question: ‘Did you need information about medicines during the course of your pregnancy?’ A list of commonly used sources of information was given to explore those that are used.

Results

Altogether, 7092 eligible women responded to the survey (5090 pregnant women and 2002 women with a child less than 25 weeks). Of the respondents, 57% (n=4054, range between different countries 46–77%) indicated a need for information about medicines during their pregnancy. On average, respondents used three different information sources. The most commonly used information sources were healthcare professionals—physicians (73%), pharmacy personnel (46%) and midwifes or nurses (33%)—and the internet (60%). There were distinct differences in the information needs and information sources used in different countries.

Conclusions

A large proportion of pregnant women have perceived information needs about medicines during pregnancy, and they rely on healthcare professionals. The internet is also a widely used information source. Further studies are needed to evaluate the use of the internet as a medicines information source by pregnant women.
Long-term clinical results after cataract surgery with and without capsular tension ring in patients with retinitis pigmentosa: a retrospective study
Authors: Bayyoud Tarek , Bartz-Schmidt Karl Ulrich , Yoeruek Efdal
Published: April 2013

Objectives

To describe the long-term clinical outcomes after cataract surgery with and without capsular tension ring (CTR) in a group of patients with retinitis pigmentosa (RP).

Design

A retrospective study.

Setting

Tertiary referral centre.

Participants

52 eyes (46 patients) with RP.

Interventions

Cataract surgery was undertaken between October 2002 and May 2010.

Primary and secondary outcome measures

Visual acuity, secondary cataract, capsular contraction syndrome (CCS), intraocular pressure, cystoid macular edema (CME), intraocular lens dislocation and endophthalmitis.

Results

The mean age at surgery was about 53 years and the overall mean follow-up was 26 months (range 3–60 months). The mean preoperative logarithm of the minimal angle of resolution of the best corrected visual acuity (LogMAR BCVA) in the entire group was 1.45±0.85 (95% CI 1.21 to 1.69) and had increased to 1.32±0.95 (95% CI 1.06 to 1.58, p=0.02). The mean preoperative and the mean postoperative LogMAR BCVA in the non-CTR group (group 1) improved from 1.16±0.8 (95% CI 0.83 to 1.48) to 0.98±0.88 (95% CI 0.62 to 1.33, p=0.02) and in the CTR group (group 2) from 1.74±0.81 (95% CI 1.42 to 2.07) to 1.66±0.90 (95% CI 1.3 to 2.03, p=0.31), respectively. Secondary cataract was observed in a total of 23 eyes (44%), of which 13 (50%) were belonged to group 1 and 10 (38%) to group 2. CCS was seen in a total of two eyes (4%) all under group 1. CME was noted in two eyes (4%), of which one belonged to group 1 and a second one to group 2. Endophthalmitis was not observed in any group.

Conclusions

Both surgical approaches were beneficial to the RP patients. Eyes under group 2 showed less long-term postoperative complications. This includes secondary cataract and CCS. Eyes under group 1 performed significantly better in respect of visual acuity. Further research would include insights into the genetic subsets.
Safety and efficacy of liraglutide in patients with type 2 diabetes and end-stage renal disease: protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded, parallel intervention study
Authors: Idorn Thomas , Knop Filip K , Jørgensen Morten , Jensen Tonny , Resuli Marsela , Hansen Pernille M , Christensen Karl B , Holst Jens J , Hornum Mads , Feldt-Rasmussen Bo
Published: April 2013

Introduction

Diabetes is the leading cause of end-stage renal disease (ESRD). Owing to renal clearance, several antidiabetic agents cannot be used in patients with ESRD. The present protocol describes an investigator-initiated trial aiming to test safety and efficacy of treatment with the glucagon-like peptide-1 receptor agonist liraglutide in patients with type 2 diabetes and dialysis-dependent ESRD.

Methods and analysis

Twenty patients with type 2 diabetes and ESRD will be compared with 20 matched patients with type 2 diabetes and normal kidney function in a randomised, parallel, placebo-controlled (1 : 1), double-blinded setting. All participants will receive 12 weeks of daily treatment with liraglutide/placebo in an individually titrated dose of 0.6, 1.2 or 1.8 mg. Over nine visits, plasma liraglutide, glycaemic control, β-cell response, cardiovascular parameters, various biomarkers and adverse events will be assessed. The primary endpoint will be evaluated from dose-corrected plasma trough liraglutide concentration at the final trial visit to determine potential accumulation in the ESRD group.

Ethics and dissemination

The study has been approved by the Danish Medicines Agency, the Scientific-Ethical Committee of the Capital Region of Denmark and the Danish Data Protection Agency. An external monitoring committee (The Good Clinical Practice Unit at Copenhagen University Hospitals) will oversee the study. The results of the study will be presented at national and international scientific meetings, and publications will be submitted to peer-reviewed journals.

Trial registration

ClinicalTrials.gov Identifier:NCT01394341
Patients with hepatitis C infection and normal liver function: an evaluation of cognitive function
Authors: Abrantes Jefferson , Torres Daniel Simplício , de Mello Carlos Eduardo Brandão
Published: April 2013

Purpose of the study

Hepatitis C virus (HCV) is associated with neuropsychiatric complaints. Previous studies have associated cognitive alterations with HCV infection but have often included confounding factors in their samples. This study compares the cognitive performance between patients with HCV infection (HCV patients) and a control group while excluding other factors that may cause cognitive impairment.

Study design

This cross-sectional study was conducted from March 2010 through June 2011. HCV infected patients and healthy individuals between the ages of 18 and 80 years were considered eligible. The exclusion criteria included well established causes of cognitive impairment such as depression and cirrhosis. Study participants underwent neuropsychological testing involving measures of attention, memory, abstraction, visuoconstructive abilities, and executive function.

Results

Of 138 initial patients, 47 were excluded because of their medical records, three refused to participate, 23 did not attend the consultation, and 32 were excluded because of having Beck Depression Inventory (BDI) scores >11. In all, 33 patients underwent neuropsychological testing; however, three were excluded because of having hypothyroidism, and one was excluded because of having a cobalamin deficiency. For the control group, of the 33 healthy individuals that were selected, four were excluded because of having BDI scores >11. Thus, the final analysis included 29 HCV patients and 29 control participants. The groups did not differ in education, age, or gender. No statistically significant differences were found between the groups regarding cognitive performance.

Conclusions

In this study using strict selection criteria, there was no evidence of an association between HCV infection and cognitive impairment.
COMMENTS ON THE STRUCTURAL FEATURES OF THE PAIS–UHLENBECK OSCILLATOR
Authors: BAGCHI B. , CHOUDHURY A. GHOSE , GUHA PARTHA
Published: April 2013

We explore the Jacobi last multiplier (JLM) as a means for deriving the Lagrangian of a fourth-order differential equation. In particular, we consider the classical Pais–Uhlenbeck problem and write down the accompanying Hamiltonian. We then compare such an expression with our alternative derivation of the Hamiltonian that makes use of the Ostrogradski's method and show how a mapping from the one to the other is achievable by variable transformations.
RUTHENIUM DOPED ZnO SEMICONDUCTOR: SYNTHESIS, CHARACTERIZATION AND PHOTODEGRADATION OF AZO DYE
Authors: ARANGANAYAGAM K. R. , SENTHILKUMAAR S. , GANAPATHI SUBRAMANIAM N. , KANG T. WANG
Published: April 2013

Ruthenium doped zinc oxide was synthesized by a simple sol–gel method via ultrasonication. The samples were characterized by X-ray diffraction, high resolution scanning electron microscopy (HR-SEM), high resolution transmission electron microscope (HR-TEM), energy dispersive spectroscopy (EDS) and UV-visible spectroscopy techniques and tested for the feasibility as a heterogeneous photocatalyst. The photocatalytic activity of Ru doped ZnO was tested using an azo dye, congo red (CR) in an aqueous solution, as a model compound. For comparison, the photocatalytic activity of pure ZnO was also performed. The parameters studied include the effect of initial CR concentration, photocatalyst weight and charge transfer phenomenon. The observed reaction mechanism was rationalized based on the elementary chemical reaction occurring in the irradiated heterogeneous reaction mixture. Total mineralization of CR was observed for both pure and Ru doped ZnO system. However, the photocatalytic activity of Ru doped ZnO was found to be higher than that of a pure ZnO .
MODELING BRITTLE FRACTURE WITH THE NODAL-BASED DISCONTINUOUS DEFORMATION ANALYSIS
Authors: BAO HUIRONG , ZHAO ZHIYE
Published: April 2013

The finite element method (FEM) has been successfully applied to solve continuum-based engineering problems, and the discontinuous deformation analysis (DDA) has emerged as a more attractive model than the continuum-based methods for rock engineering problems due to its intrinsic feature of block discontinuity at the contact boundaries. This paper presents a hybrid approach for two-dimensional problems which takes the advantage of both the FEM and the DDA in solving problems involving continuum and discontinuum domains. The hybrid FEM/DDA method, named as the nodal-based DDA (NDDA), significantly improves not only the accuracy of stress distribution inside the DDA block but also the computational efficiency. A cracking scheme based on failure time is introduced to the NDDA so that it can handle the crack propagation inside blocks. Two validating examples show that the newly developed NDDA can model the brittle fracture well.
SHOOTING METHOD FOR SINGULARLY PERTURBED FOURTH-ORDER ORDINARY DIFFERENTIAL EQUATIONS OF REACTION-DIFFUSION TYPE
Authors: CHRISTY ROJA J. , TAMILSELVAN A.
Published: April 2013

A class of singularly perturbed boundary value problems (SPBVPs) for fourth-order ordinary differential equations (ODEs) is considered. The SPBVP is reduced into a weakly coupled system of two ODEs subject to suitable initial and boundary conditions. In order to solve them numerically, a method is suggested in which the given interval is divided into two inner regions (boundary layer regions) and one outer region. Two initial-value problems associated with inner regions and one boundary value problem corresponding to the outer region are derived from the given SPBVP. In each of the two inner regions, an initial value problem is solved by using fitted mesh finite difference (FMFD) scheme on Shishkin mesh and the boundary value problem corresponding to the outer region is solved by using classical finite difference (CFD) scheme on Shishkin mesh. A combination of the solution so obtained yields a numerical solution of the boundary value problem on the whole interval. First, in this method, we find the zeroth-order asymptotic expansion approximation of the solution of the weakly coupled system. Error estimates are derived. Examples are presented to illustrate the numerical method. This method is suitable for parallel computing.
TWO-SCALE 3D ANALYSIS OF REFLECTIVE CRACKS IN AIRFIELD PAVEMENTS
Authors: GARZON JORGE , KIM DAE-JIN , ARMANDO DUARTE C. , BUTTLAR WILLIAM G.
Published: April 2013

Prediction and simulation of load-related reflective cracking in airfield pavements require 3D models in order to accurately capture the effects of gear loads on crack initiation and propagation. Furthermore, the size relations between aircraft landing gear, pavement area and reflective cracks make this a multi-scale problem. This paper presents a generalized finite element method (GFEM) based on the solution of interdependent global and local problems. The macro-scale component of the solution is approximated by a finite element global model, while the fine-scale is addressed by a local model. This allows accurate modeling of cracks in airfield pavements that are orders of magnitude larger than the critical zones in which the initiation of reflective cracking occurs. Two 3D pavement models are created for this study. The first model is subjected to the gear loading of a Boeing 777 aircraft. This example demonstrates the accuracy of solving a multi-scale pavement problem with a GFEM enriched with local problem solutions. The second problem studies the effect of the size of the local domain on the accuracy of the GFEM solution. The numerical simulations show that 3D multi-scale problems such as reflective cracks in airfield pavements, can be efficiently solved by a GFEM based on interdependent global and local problems.
ANALYSIS OF GENERALIZED STRESS INTENSITY FACTORS OF V-SHAPED NOTCH PROBLEMS BY FEM
Authors: PING XUE-CHENG , CHEN MENG-CHENG , NODA NAO-AKI , XIAO YI-HUA
Published: April 2013

This paper deals with a-finite element method (FEM) based on a V-shaped notch corner tip stresses to solve generalized stress intensity factors (GSIFs) in 2D elastic bodies. The method does not need extremely refined meshes and special elements accounting for the analytical form of singularities around the V-shaped notch corner tip. The generalized stress intensity factors of the V-shaped notch problems are evaluated from the ratios of FEM stress values at the notch corner tip for a given problem and a reference one. Several numerical examples show that present method is effective and applicable to dealing with the V-shaped notch problems.
PASSIVE CONTROL OF HUMAN BODY COMPLEX SINGULAR SYSTEMS
Authors: LIU PEIYONG , ZHANG QINGLING , YANG LI , LIU CHAO
Published: April 2013

Due to the complexity of interaction among constituents inside the whole system, it is difficult to establish accurate mathematics models to describe and analyze the complex systems exactly. There are few attempts concerning on the moving process of endocrine disruptor in human bodies, which have been the polluted material worldwide related to the reproduction, existence and development of human being. Focusing on such two challenging issues, a multi-compartment model of endocrine disruptor Benzene moving in the human body complex system is established in this paper. Furthermore, passivity of this model is described systematically. A feedback controller for this descriptor biological complex system is used under the station of strict passivity, and an example of the controller is given for a particular instantiation of the model.
South Korea in 2012–2013
Authors: CHOO Jaewoo
Published: April 2013

South Koreans made history in the year of 2012 when it elected its first female president. Having won the general election in April, president-elect Park Geun-hye will enjoy strong support from the legislature in implementing her campaign promises. Park and her party have embarked on an “economic democratisation” policy to realise a fair-competition economy. She is also committed to improving relations with the North and adopting a balanced diplomacy with South Korea's neighbouring states.
Immediate effects of a single exercise bout on protein O-GlcNAcylation and chromatin regulation of cardiac hypertrophy
Authors: Medford Heidi M. , Porter Karen , Marsh Susan A.
Published: April 2013

Cardiac hypertrophy induced by pathological stimuli is regulated by a complex formed by the repressor element 1-silencing transcription factor (REST) and its corepressor mSin3A. We previously reported that hypertrophic signaling is blunted by O-linked attachment of β- N-acetylglucosamine ( O-GlcNAc) to proteins. Regular exercise induces a physiological hypertrophic phenotype in the heart that is associated with decreased O-GlcNAc levels, but a link between O-GlcNAc, the REST complex, and initiation of exercise-induced cardiac hypertrophy is not known. Therefore, mice underwent a single 15- or 30-min bout of moderate- to high-intensity treadmill running, and hearts were harvested immediately and compared with sedentary controls. Cytosolic O-GlcNAc was lower ( P < 0.05) following 15 min exercise with no differences in nuclear levels ( P > 0.05). There were no differences in cytosolic or nuclear O-GlcNAc levels in hearts after 30 min exercise ( P > 0.05). Cellular compartment levels of O-GlcNAc transferase (OGT, the enzyme that removes the O-GlcNAc moiety from proteins), REST, mSin3A, and histone deacetylases (HDACs) 1, 2, 3, 4, and 5 were not changed with exercise. Immunoprecipitation revealed O-GlcNAcylation of OGT and HDACs 1, 2, 4, and 5 that was not changed with acute exercise; however, exercised hearts did exhibit lower interactions between OGT and REST ( P < 0.05) but not between OGT and mSin3A. These data suggest that hypertrophic signaling in the heart may be initiated by as little as 15 min of exercise via intracellular changes in protein O-GlcNAcylation distribution and reduced interactions between OGT and the REST chromatin repressor.
Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish
Authors: Mishra Shikha , Guan Jian , Plovie Eva , Seldin David C. , Connors Lawreen H. , Merlini Giampaolo , Falk Rodney H. , MacRae Calum A. , Liao Ronglih
Published: April 2013

Systemic amyloid light-chain (AL) amyloidosis is associated with rapidly progressive and fatal cardiomyopathy resulting from the direct cardiotoxic effects of circulating AL light chain (AL-LC) proteins and the indirect effects of AL fibril tissue infiltration. Cardiac amyloidosis is resistant to standard heart failure therapies, and, to date, there are limited treatment options for these patients. The mechanisms underlying the development of cardiac amyloidosis and AL-LC cardiotoxicity are largely unknown, and their study has been limited by the lack of a suitable in vivo model system. Here, we establish an in vivo zebrafish model of human AL-LC-induced cardiotoxicity. AL-LC isolated from AL cardiomyopathy patients or control nonamyloidogenic LC protein isolated from multiple myeloma patients (Con-LC) was directly injected into the circulation of zebrafish at 48 h postfertilization. AL-LC injection resulted in impaired cardiac function, pericardial edema, and increased cell death relative to Con-LC, culminating in compromised survival with 100% mortality within 2 wk, independent of AL fibril deposition. Prior work has implicated noncanonical p38 MAPK activation in the pathogenesis of AL-LC-induced cardiotoxicity, and p38 MAPK inhibition via SB-203580 rescued AL-LC-induced cardiac dysfunction and cell death and attenuated mortality in zebrafish. This in vivo zebrafish model of AL-LC cardiotoxicity demonstrates that antagonism of p38 MAPK within the AL-LC cardiotoxic signaling response may serve to improve cardiac function and mortality in AL cardiomyopathy. Furthermore, this in vivo model system will allow for further study of the molecular underpinnings of AL cardiotoxicity and identification of novel therapeutic strategies.
Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α
Authors: Zhu Yi , Soto Jamie , Anderson Brandon , Riehle Christian , Zhang Yi Cheng , Wende Adam R. , Jones Deborah , McClain Donald A. , Abel E. Dale
Published: April 2013

Mechanistic target of rapamycin (mTOR) is essential for cardiac development, growth, and function, but the role of mTOR in the regulation of cardiac metabolism and mitochondrial respiration is not well established. This study sought to determine cardiac metabolism and mitochondrial bioenergetics in mice with inducible deletion of mTOR in the adult heart. Doxycycline-inducible and cardiac-specific mTOR-deficient mice were generated by crossing cardiac-specific doxycycline-inducible tetO-Cre mice with mice harboring mTOR floxed alleles. Deletion of mTOR reduced mTORC1 and mTORC2 signaling after in vivo insulin stimulation. Maximum and minimum dP/d t measured by cardiac catheterization in vivo under anesthesia and cardiac output, cardiac power, and aortic pressure in ex vivo working hearts were unchanged, suggesting preserved cardiac function 4 wk after doxycycline treatment. However, myocardial palmitate oxidation was impaired, whereas glucose oxidation was increased. Consistent with reduced palmitate oxidation, expression of fatty acid metabolism genes fatty acid-binding protein 3, medium-chain acyl-CoA dehydrogenase, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein)-α and -β was reduced, and carnitine palmitoyl transferase-1 and -2 enzymatic activity was decreased. Mitochondrial palmitoyl carnitine respiration was diminished. However, mRNA for peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and -1β, protein levels of PGC-1α, and electron transport chain subunits, mitochondrial DNA, and morphology were unchanged. Also, pyruvate-supported and FCCP-stimulated respirations were unchanged, suggesting that mTOR deletion induces a specific defect in fatty acid utilization. In conclusion, mTOR regulates mitochondrial fatty acid utilization but not glucose utilization in the heart via mechanisms that are independent of changes in PGC expression.
Aortic pulse wave velocity and reflecting distance estimation from peripheral waveforms in humans: detection of age- and exercise training-related differences
Authors: Pierce Gary L. , Casey Darren P. , Fiedorowicz Jess G. , Seals Douglas R. , Curry Timothy B. , Barnes Jill N. , Wilson DeMaris R. , Stauss Harald M.
Published: April 2013

We hypothesized that demographic/anthropometric parameters can be used to estimate effective reflecting distance (EfRD), required to derive aortic pulse wave velocity (APWV), a prognostic marker of cardiovascular risk, from peripheral waveforms and that such estimates can discriminate differences in APWV and EfRD with aging and habitual endurance exercise in healthy adults. Ascending aortic pressure waveforms were derived from peripheral waveforms (brachial artery pressure, n = 25; and finger volume pulse, n = 15) via a transfer function and then used to determine the time delay between forward- and backward-traveling waves (Δ tf-b). True EfRDs were computed as directly measured carotid-femoral pulse wave velocity (CFPWV) × ½Δ tf-b and then used in regression analysis to establish an equation for EfRD based on demographic/anthropometric data (EfRD = 0.173·age + 0.661·BMI + 34.548 cm, where BMI is body mass index). We found good agreement between true and estimated APWV (Pearson's R2 = 0.43; intraclass correlation = 0.64; both P < 0.05) and EfRD ( R2 = 0.24; intraclass correlation = 0.40; both P < 0.05). In young sedentary (22 ± 2 years, n = 6), older sedentary (62 ± 1 years, n = 24), and older endurance-trained (61 ± 2 years, n = 14) subjects, EfRD (from demographic/anthropometric parameters), APWV, and ½Δ tf-b (from brachial artery pressure waveforms) were 52.0 ± 0.5, 61.8 ± 0.4, and 60.6 ± 0.5 cm; 6.4 ± 0.3, 9.6 ± 0.2, and 8.1 ± 0.2 m/s; and 82 ± 3, 65 ± 1 and 76 ± 2 ms (all P < 0.05), respectively. Our results demonstrate that APWV derived from peripheral waveforms using age and BMI to estimate EfRD correlates with CFPWV in healthy adults. This method can reliably detect the distal shift of the reflecting site with age and the increase in APWV with sedentary aging that is attenuated with habitual endurance exercise.
Mitochondrial-localized NADPH oxidase 4 is a source of superoxide in angiotensin II-stimulated neurons
Authors: Case Adam J. , Li Shumin , Basu Urmi , Tian Jun , Zimmerman Matthew C.
Published: April 2013

Angiotensin II (ANG II) plays an important role in the central regulation of systemic cardiovascular function. ANG II-mediated intraneuronal signaling has been shown to be predicated by an increase in mitochondrial superoxide (O2˙−), yet the source of this reactive oxygen species (ROS) production remains unclear. NADPH oxidase 4 (Nox4), a member of the NADPH oxidase family, has been reported to be localized in mitochondria of various cell types and has been implicated in brain angiotensinergic signaling. However, the subcellular localization and function of Nox4 in neurons has not been fully elucidated. In this study, we hypothesized that Nox4 is expressed in neuron mitochondria and is involved in ANG II-dependent O2˙−-mediated intraneuronal signaling. To query this, Nox4 immunofluorescent staining and mitochondrial enrichment were performed in a mouse catecholaminergic neuronal cell model (CATH.a). Nox4 was shown to be present in neuron mitochondria as evidenced by colocalization with both the mitochondrial-localized protein manganese superoxide dismutase (MnSOD) and dye MitoTracker Red. Moreover, Nox4 expression was significantly increased in enriched mitochondrial fractions compared with whole cell lysates. Additionally, adenoviral-encoded small interfering RNA for Nox4 (AdsiNox4) caused a robust knockdown in Nox4 mRNA and protein levels, which led to the attenuation of ANG II-induced mitochondrial O2˙− production. Finally, in the subfornical organ (SFO) of the brain, Nox4 not only demonstrated mitochondrial localization but was induced by chronic, peripheral infusion of ANG II. Collectively, these data suggest that Nox4 is a source of O2˙− in neuron mitochondria that contributes to ANG II intraneuronal signaling.
Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1–7
Authors: Uhal Bruce D. , Nguyen Hang , Dang MyTrang , Gopallawa Indiwari , Jiang Jing , Dang Vinh , Ono Shinji , Morimoto Konosuke
Published: April 2013

Earlier work showed that apoptosis of alveolar epithelial cells (AECs) in response to endogenous or xenobiotic factors is regulated by autocrine generation of angiotensin (ANG) II and its counterregulatory peptide ANG1–7. Mutations in surfactant protein C (SP-C) induce endoplasmic reticulum (ER) stress and apoptosis in AECs and cause lung fibrosis. This study tested the hypothesis that ER stress-induced apoptosis of AECs might also be regulated by the autocrine ANGII/ANG1–7 system of AECs. ER stress was induced in A549 cells or primary cultures of human AECs with the proteasome inhibitor MG132 or the SP-C BRICHOS domain mutant G100S. ER stress activated the ANGII-generating enzyme cathepsin D and simultaneously decreased the ANGII-degrading enzyme ACE-2, which normally generates the antiapoptotic peptide ANG1–7. TAPI-2, an inhibitor of ADAM17/TACE, significantly reduced both the activation of cathepsin D and the loss of ACE-2. Apoptosis of AECs induced by ER stress was measured by assays of mitochondrial function, JNK activation, caspase activation, and nuclear fragmentation. Apoptosis induced by either MG132 or the SP-C BRICHOS mutant G100S was significantly inhibited by the ANG receptor blocker saralasin and was completely abrogated by ANG1–7. Inhibition by ANG1–7 was blocked by the specific mas antagonist A779. These data show that ER stress-induced apoptosis is mediated by the autocrine ANGII/ANG1–7 system in human AECs and demonstrate effective blockade of SP-C mutation-induced apoptosis by ANG1–7. They also suggest that therapeutic strategies aimed at administering ANG1–7 or stimulating ACE-2 may hold potential for the management of ER stress-induced fibrotic lung disorders.
The role of disturbed blood flow in the development of pulmonary arterial hypertension: lessons from preclinical animal models
Authors: Dickinson Michael G. , Bartelds Beatrijs , Borgdorff Marinus A. J. , Berger Rolf M. F.
Published: April 2013

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasoproliferative disorder characterized by the development of unique neointimal lesions, including concentric laminar intima fibrosis and plexiform lesions. Although the histomorphology of neointimal lesions is well described, the pathogenesis of PAH and neointimal development is largely unknown. After three decades of PAH pathobiology research the focus has shifted from vasoconstriction towards a mechanism of cancer-like angioproliferation. In this concept the role of disturbed blood flow is seen as an important trigger in the development of vascular remodeling. For instance, in PAH associated with congenital heart disease, increased pulmonary blood flow (i.e., systemic-to-pulmonary shunt) is an essential trigger for the occurrence of neointimal lesions and PAH development. Still, questions remain about the exact role of these blood flow characteristics in disease progression. PAH animal models are important for obtaining insight in new pathobiological processes and therapeutical targets. However, as for any preclinical model the pathophysiological mechanism and clinical course has to be comparable to the human disease that it mimics. This means that animal models mimicking human PAH ideally are characterized by: a hit recognized in human disease (e.g., altered pulmonary blood flow), specific vascular remodeling resembling human neointimal lesions, and disease progression that leads to right ventriclular dysfunction and death. A review that underlines the current knowledge of PAH due to disturbed flow is still lacking. In this review we will summarize the current knowledge obtained from PAH animal models associated with disturbed pulmonary blood flow and address questions for future treatment strategies for PAH.
FABP5 deficiency enhances susceptibility to H1N1 influenza A virus-induced lung inflammation
Authors: Gally Fabienne , Kosmider Beata , Weaver Michael R. , Pate Kathryn M. , Hartshorn Kevan L. , Oberley-Deegan Rebecca E.
Published: April 2013

The early inflammatory response to influenza A virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which inflammatory cells invade the respiratory tract remain unclear. Uncontrolled inflammation and oxidative stress cause lung damage in response to influenza A infection. We have previously shown that the fatty acid binding protein 5 (FABP5) has anti-inflammatory properties. We speculate that, as a transporter of fatty acids, FABP5 plays an important protective role against oxidative damage to lipids during infection as well. Using FABP5-/-and wild-type (WT) mice infected with influenza A virus, we showed that FABP5-/-mice had increased cell infiltration of macrophages and neutrophils compared with WT mice. FABP5-/-mice presented lower viral burden but lost as much weight as WT mice. The adaptive immune response was also increased in FABP5-/-mice as illustrated by the accumulation of T and B cells in the lung tissues and increased levels of H1N1-specific IgG antibodies. FABP5 deficiency greatly enhanced oxidative damage and lipid peroxidation following influenza A infection and presented with sustained tissue inflammation. Interestingly, FABP5 expression decreased following influenza A infection in WT lung tissues that corresponded to a decrease in the anti-inflammatory molecule PPAR-γ activity. In conclusion, our results demonstrate a previously unknown contribution of FABP5 to influenza A virus pathogenesis by controlling excessive oxidative damage and inflammation. This property could be exploited for therapeutic purposes.
Distinct responses of protein turnover regulatory pathways in hypoxia- and semistarvation-induced muscle atrophy
Authors: de Theije Chiel C. , Langen Ramon C. J. , Lamers Wouter H. , Schols Annemie M. W. J. , Köhler S. Eleonore
Published: April 2013

The balance of muscle protein synthesis and degradation determines skeletal muscle mass. We hypothesized that hypoxia-induced muscle atrophy and alterations in the regulation of muscle protein turnover include a hypoxia-specific component, in addition to the observed effects of reduction in food intake in response to hypoxia. Mice were subjected to normoxic, hypoxic (8% oxygen), or pair-fed conditions for 2, 4, and 21 days. Cell-autonomous effects of hypoxia on skeletal muscle were also assessed in differentiated C2C12 myotubes. Hypoxia induced an initial rapid loss of body and muscle weight, which remained decreased during chronic hypoxia and could only in part be explained by the hypoxia-induced reduction of food intake (semistarvation). Regulatory steps of protein synthesis (unfolded protein response and mammal target of rapamycin signaling) remained active in response to acute and sustained hypoxia but not to semistarvation. Activation of regulatory signals for protein degradation, including increased expression of Murf1, Atrogin-1, Bnip3, and Map1lc3b mRNAs, was observed in response to acute hypoxia and to a lesser extent following semistarvation. Conversely, the sustained elevation of Atrogin-1, Bnip3, and Map1lc3b mRNAs and the increased activity of their upstream transcriptional regulator Forkhead box O1 were specific to chronic hypoxia because they were not observed in response to reduced food intake. In conclusion, altered regulation of protein turnover during hypoxia-induced muscle atrophy resulted from an interaction of semistarvation and a hypoxia-specific component. The finding that food restriction but not hypoxia-induced semistarvation inhibited regulatory steps in protein synthesis suggests a hypoxia-specific impairment of the coordination between protein-synthesis signaling and protein-degradation signaling in skeletal muscle.