bluuebunny/crossref_metadata_2025 huggingface dataset:
Skeletal muscle proteomics: carbohydrate metabolism oscillates with seasonal and torpor-arousal physiology of hibernation
Authors: Hindle Allyson G. , Karimpour-Fard Anis , Epperson L. Elaine , Hunter Lawrence E. , Martin Sandra L.
Published: August 2011

The physiology of small mammalian hibernators shifts profoundly over a year, from summer homeothermy to winter heterothermy. Torpor-arousal cycles define high-amplitude tissue activity fluctuations in winter, particularly for skeletal muscle, which contributes to the energetically demanding rewarming process via shivering. To better understand the biochemistry underlying summer-winter and torpor-arousal transitions, we applied two-dimensional gel electrophoresis coupled with liquid chromatography/mass spectrometry/mas spectrometry to the soluble proteins from hindlimb muscle of 13-lined ground squirrels ( Ictidomys tridecemlineatus) in two summer and six winter states. Two hundred sixteen protein spots differed by sampled state. Significantly, intrawinter protein adjustment was a minor component of the dataset despite large discrepancies in muscle activity level among winter states; rather, the bulk of differences (127/138 unequivocally identified proteins spots) occurred between summer and winter. We did not detect any proteomic signatures of skeletal muscle atrophy in this hibernator nor any differential seasonal regulation of protein metabolism. Instead, adjustments to metabolic substrate preferences dominated the detected proteomic differences. Pathways of carbohydrate metabolism (glycolysis and gluconeogenesis) were summer enriched, whereas the winter proteome was enriched for fatty acid β-oxidation. Nevertheless, our data suggest that some reliance on carbohydrate reserves is maintained during winter. Phosphoglucomutase (PGM1), which reversibly prepares glucose subunits for either glycolysis or glycogenesis, showed apparent winter state-specific phosphorylation. PGM1 was phosphorylated during rewarming and dephosphorylated by interbout arousal, implying that glucose supplements lipid fuels during rewarming. This, along with winter elevation of TCA cycle enzymes, suggests that hindlimb muscles are primed for rapid energy production and that carbohydrates are an important fuel for shivering thermogenesis.
Induction of heme oxygenase-1 attenuates sFlt-1-induced hypertension in pregnant rats
Authors: George Eric M. , Arany Marietta , Cockrell Kathy , Storm Megan V. , Stec David E. , Granger Joey P.
Published: August 2011

Preeclampsia (PE) is one of the leading causes of fetal and maternal morbidity, affecting 5–10% of all pregnancies, and lacks an effective treatment. The exact etiology of the disorder is unclear, but placental ischemia has been shown to be a central causative agent. In response to placental ischemia, the antiangiogenic protein fms-like tyrosine kinase-1 (sFlt-1), a VEGF antagonist, and reactive oxygen species are secreted, leading to the maternal syndrome. One promising therapeutic approach to treat PE is through manipulation of the heme oxygenase-1 (HO-1) protein. It has been previously reported that HO-1 and carbon monoxide downregulate sFlt-1 production in vitro, and we have recently shown that HO-1 induction significantly attenuates placental ischemia-induced hypertension, partially through normalization of the sFlt-1-to-VEGF ratio in the placenta. The purpose of this study was to determine whether HO-1 induction would have beneficial effects independently of sFlt-1 suppression. To that end, pregnant rats were continuously infused with recombinant sFlt-1 from gestational days 14–19, and circulating sFlt-1 increased approximately twofold, similar to rats with experimentally induced placental ischemia. In response, mean arterial pressure increased 17 mmHg, which was completely normalized by HO-1 induction. Unbound circulating VEGF was decreased ∼17% in response to sFlt-1 infusion but was increased ∼50% in response to HO-1 induction. Finally, endothelial function was improved as measured by reductions in vascular expression of preproendothelin mRNA. In conclusion, manipulation of HO-1 presents an intriguing therapeutic approach to the treatment of PE.
Sympathetic nerve activity and whole body heat stress in humans
Authors: Low David A. , Keller David M. , Wingo Jonathan E. , Brothers R. Matthew , Crandall Craig G.
Published: August 2011

We and others have shown that moderate passive whole body heating (i.e., increased internal temperature ∼0.7°C) increases muscle (MSNA) and skin sympathetic nerve activity (SSNA). It is unknown, however, if MSNA and/or SSNA continue to increase with more severe passive whole body heating or whether these responses plateau following moderate heating. The aim of this investigation was to test the hypothesis that MSNA and SSNA continue to increase from a moderate to a more severe heat stress. Thirteen subjects, dressed in a water-perfused suit, underwent at least one passive heat stress that increased internal temperature ∼1.3°C, while either MSNA ( n = 8) or SSNA ( n = 8) was continuously recorded. Heat stress significantly increased mean skin temperature (Δ∼5°C, P < 0.001), internal temperature (Δ∼1.3°C, P < 0.001), mean body temperature (Δ∼2.0°C, P < 0.001), heart rate (Δ∼40 beats/min, P < 0.001), and cutaneous vascular conductance [Δ∼1.1 arbitrary units (AU)/mmHg, P < 0.001]. Mean arterial blood pressure was well maintained ( P = 0.52). Relative to baseline, MSNA increased midway through heat stress (Δ core temperature 0.63 ± 0.01°C) when expressed as burst frequency (26 ± 14 to 45 ± 16 bursts/min, P = 0.001), burst incidence (39 ± 13 to 48 ± 14 bursts/100 cardiac cyles, P = 0.03), or total activity (317 ± 170 to 489 ± 150 units/min, P = 0.02) and continued to increase until the end of heat stress (burst frequency: 61 ± 15 bursts/min, P = 0.01; burst incidence: 56 ± 11 bursts/100 cardiac cyles, P = 0.04; total activity: 648 ± 158 units/min, P = 0.01) relative to the mid-heating stage. Similarly, SSNA (total activity) increased midway through the heat stress (normothermia; 1,486 ± 472 to mid heat stress 6,467 ± 5,256 units/min, P = 0.03) and continued to increase until the end of heat stress (11,217 ± 6,684 units/min, P = 0.002 vs. mid-heat stress). These results indicate that both MSNA and SSNA continue to increase as internal temperature is elevated above previously reported values.
HLA-B∗57 and Gender Influence the Occurrence of Tuberculosis in HIV Infected People of South India
Authors: Jagannathan Latha , Chaturvedi Mrinalini , Satish Bhuthaiah , Satish Kadappa Shivappa , Desai Anita , Subbakrishna D. K. , Satishchandra Parthasarathy , Pitchappan Ramasamy , Balakrishnan Kamala , Kondaiah Paturu , Ravi Vasanthapuram
Published: August 2011

Background. Substantial evidence exists for HLA and other host genetic factors being determinants of susceptibility or resistance to infectious diseases. However, very little information is available on the role of host genetic factors in HIV-TB coinfection. Hence, a longitudinal study was undertaken to investigate HLA associations in a cohort of HIV seropositive individuals with and without TB in Bangalore, South India.Methods. A cohort of 238 HIV seropositive subjects were typed for HLA-A, B, and DR by PCR-SSP and followed up for 5 years or till manifestation of Tuberculosis. HLA data of 682 HIV Negative healthy renal donors was used as control.Results. The ratio of males and females in HIV cohort was comparable (50.4% and 49.6%). But the incidence of TB was markedly lower in females (12.6%,) than males (25.6%). Further, HLA-B*57 frequency in HIV cohort was significantly higher among females without TB (21.6%, 19/88) than males (1.7%, 1/59);P=0.0046;OR=38. CD4 counts also were higher among females in this cohort.Conclusion. This study suggests that HIV positive women with HLA-B*57 have less occurrence of TB as compared to males.
Theoretical Investigation on the Electronic and Optical Properties of Poly(fluorenevinylene) Derivatives as Light-Emitting Materials
Authors: Yakhanthip Thanisorn , Kungwan Nawee , Jitonnom Jitrayut , Anuragudom Piched , Jungsuttiwong Siriporn , Hannongbua Supa
Published: August 2011

Density functional theory (DFT) and time-dependent DFT (TDDFT) were employed to study ground-state properties, HOMO-LUMO gaps(ΔH-L), excitation energies(Eg), ionization potentials (IPs), and electron affinities (EA) for PFV-alt-PDONV and PFV-alt-PDIH-PPV having different alternating groups. Excited-state properties were investigated using configuration interaction singles (CISs) while fluorescence energies were calculated using TDDFT. The results show that PFV-alt-PDONV exhibits blue-shifted energies for both HOMO-LUMO gaps(ΔH-L)and excitation energies(Eg)compared with PFV-alt-PDIH-PPV. The predicted IP and EA clearly indicate that PFV-alt-PDIH-PPV has both easier hole creation and electron injection than that of PFV-alt-PDONV. The maximal absorption wavelengths of all polymers are strongly assigned toπ→π∗transition. The predicted radiative lifetimes of PFV-alt-PDONV and PFV-alt-PDIH-PPV for B3LYP/6-31G(d) are 0.36 and 0.61 ns, respectively, indicating that PFV-alt-PDIH-PPV should have a better performance for long-time emission than that of PFV-alt-PDONV.
Bayesian Prediction of the Overhaul Effect on a Repairable System with Bounded Failure Intensity
Authors: Srivastava Preeti Wanti , Jain Nidhi
Published: August 2011

This paper deals with the Bayes prediction of the future failures of a deteriorating repairable mechanical system subject to minimal repairs and periodic overhauls. To model the effect of overhauls on the reliability of the system a proportional age reduction model is assumed and the 2‐parameter Engelhardt‐Bain process (2‐EBP) is used to model the failure process between two successive overhauls. 2‐EBP has an advantage over Power Law Process (PLP) models. It is found that the failure intensity of deteriorating repairable systems attains a finite bound when repeated minimal repair actions are combined with some overhauls. If such a data is analyzed through models with unbounded increasing failure intensity, such as the PLP, then pessimistic estimates of the system reliability will arise and incorrect preventive maintenance policy may be defined. On the basis of the observed data and of a number of suitable prior densities reflecting varied degrees of belief on the failure/repair process and effectiveness of overhauls, the prediction of the future failure times and the number of failures in a future time interval is found. Finally, a numerical application is used to illustrate the advantages from overhauls and sensitivity analysis of the improvement parameter carried out.
Mannan-Modified PLGA Nanoparticles for Targeted Gene Delivery
Authors: Kong Fansheng , Ge Linfu , Liu Ximin , Huang Ning , Zhou Fang
Published: August 2011

The studies of targeted gene delivery nanocarriers have gained increasing attention during the past decades. In this study, mannan modified DNA loaded bioadhesive PLGA nanoparticles (MAN-DNA-NPs) were investigated for targeted gene delivery to the Kupffer cells (KCs). Bioadhesive PLGA nanoparticles were prepared and subsequently bound withpEGFP. Following the coupling of the mannan-based PE-grafted ligands (MAN-PE) with the DNA-NPs, the MAN-DNA-NPs were delivered intravenously to rats. The transfection efficiency was determined from the isolated KCs and flow cytometry was applied for the quantitation of gene expression after 48 h post transfection. The size of the MAN-DNA-NPs was found to be around 190 nm and the Zeta potential was determined to be −15.46mV. ThepEGFPbinding capacity of MAN-DNA-NPs was ()% and thein vitrorelease profiles of the MAN-DNA-NPs follow the Higuchi model. When compared with non-modified DNA-NPs and Lipofectamine 2000-DNA, MAN-DNA-NPs produced the highest gene expressions, especiallyin vivo. Thein vivodata from flow cytometry analysis showed that MAN-DNA-NPs displayed a remarkably higher transfection efficiency (39%) than non-modified DNA-NPs (25%) and Lipofectamine 2000-DNA (23%) in KCs. The results illustrate that MAN-DNA-NPs have the ability to target liver KCs and could function as promising active targeting drug delivery vectors.
Olig2 Lineage Cells Generate GABAergic Neurons in the Prethalamic Nuclei, Including the Zona Incerta, Ventral Lateral Geniculate Nucleus and Reticular Thalamic Nucleus
Authors: Inamura Naoko , Ono Katsuhiko , Takebayashi Hirohide , Zalc Bernard , Ikenaka Kazuhiro
Published: August 2011

Neuronal differentiation is a crucial event during neural development. Recent studies have characterized the development of the diencephalon; however, the origins of the primarily GABAergic prethalamic nuclei, including the zona incerta (ZI), ventral lateral geniculate nucleus (vLG) and reticular thalamic nucleus (RT), remain unclear. Here we characterize Olig2 lineage cells in the developing prethalamus using mice in which tamoxifen-induced recombination permanently labels Olig2-expressing cells. We show that GABAergic neurons in the prethalamic nuclei, including the RT, ZI and vLG, originate from prethalamic Olig2 lineage cells. Based on these data and on those derived from short-term lineage-tracing data using Olig3-lacZ mice and previous reports, we suggest that vLG cells originate from the ventricular zone of the thalamus, zona limitans intrathalamica and prethalamus.
Aggregates of cAMP-Dependent Kinase Isoforms Characterize Different Areas in the Developing Central Nervous System of the Chicken, Gallus gallus
Authors: Mucignat-Caretta Carla , Caretta Antonio
Published: August 2011

The intracellular second messenger adenosine 3′,5′-cyclic monophosphate (cAMP) acts mainly through cAMP-dependent protein kinases (PKA). In mammals and reptiles, the PKA regulatory isoforms (RI and RII) are differentially distributed among the various brain areas and cell types, according to the age of the animal. Since PKA distribution may be an additional marker for homologous areas, PKA regulatory subunit types RI and RII were examined in the chicken brain, a species not yet investigated. Chicken brains were examined from prehatching to adult age, by means of immunohistochemistry and biochemical characterization. Most PKA regulatory subunits were segregated in discrete non-soluble clusters that contained either RI or RII. While RII aggregates were present also in non-neuronal cells, RI aggregates were detected only in neurons of some brain areas that are mainly related to the telencephalon. They appeared later than RII aggregates; their presence and location varied during development. RI aggregates were detected first in the olfactory bulb, around embryonic day 14; within 3 days they appeared in the hyperpallium and nidopallium, where the most intense labeling was observed in the perihatching period. Fainter RI aggregates persisted up to 3 years in the olfactory bulb and nidopallium caudale. Less intense RI aggregates were present for a shorter time, from 2 weeks to 3 months, in the septal nuclei, thalamic medial nuclei, periventricular hypothalamus, optic tectum periventricular area, brainstem reticular formation and spinal cord substantia gelatinosa. RI aggregates were not detected in many brain areas including the arcopallium, striatum and cranial nerve nuclei. RII distribution showed less variation during development. From embryonic day 12, some insoluble RII aggregates were detected in the brain; however, only minor modifications were observed in positive structures once they started to harbor insoluble RII aggregates. The present results suggest that the distribution of PKA aggregates may assist in characterizing phylogenetically homologous structures of the vertebrate central nervous system and may also unravel biochemical differences among areas considered homologous.
The Use of S100B and Tau Protein Concentrations in the Cerebrospinal Fluid for the Differential Diagnosis of Bacterial Meningitis: A Retrospective Analysis
Authors: Jung Klaus , Goerdt Christoph , Lange Peter , Blocher Joachim , Djukic Marija , Gerber Joachim , Spreer Annette , Nau Roland , Otto Markus , Schmidt Holger
Published: August 2011

Background: Patients with meningitis are often difficult to classify into bacterial (BM) or benign viral (VM) meningitis. To facilitate the differential diagnosis, S100B and Tau protein in the cerebrospinal fluid (CSF) were measured and compared with standard laboratory parameters. Methods: S100BCSF, TauCSF, and routine parameters (CSF leukocyte count, proteinCSF, lactateCSF, serum C-reactive protein, blood leukocyte count and body temperature) were analyzed in 33 patients with microbiologically confirmed BM and in 19 with VM. Their classification accuracy, sensitivity and specificity were studied by receiver operating characteristic (ROC) curves. Results: S100BCSF concentrations were higher in BM than in VM patients (p = 0.03) and showed a promising accuracy (90%) for the differential diagnosis of BM versus VM. Its discriminative properties were comparable to routine parameters. Of all parameters, S100BCSF showed the highest specificity (100%) with an optimal cut-off of 3.1 ng/ml. TauCSF concentrations were useless for the discrimination (p = 0.64). Conclusions: In contrast to TauCSF, S100BCSF concentrations ≧3.1 ng/ml are promising to discriminate bacterial from viral meningitis.
Decolorizing Activity of Malachite Green and Its Mechanisms Involved in Dye Biodegradation by Achromobacter xylosoxidans MG1
Authors: Wang Ji’ai , Qiao Min , Wei Kangbi , Ding Junmei , Liu Zhongzhong , Zhang Ke-Qin , Huang Xiaowei
Published: August 2011

An Achromobacter xylosoxidans MG1 strainisolated from the effluent treatment plant of a textile and dyeing factory from Yunnan Province in China was found capable of decolorizing the malachite green dye at a high efficacy. Strain MG1 reduced 86% malachite green at the concentration of 2,000 mg/l within 1 h, representing a greater ability for decolorizing and a higher tolerance of this compound than all previously reported bacteria. Color removal was optimal at pH 6 and 38°C. Further experimental evidences demonstrated that both cytoplasmic and extracellular biodegradation contributed to the decolorization of malachite green. Nested PCR was employed to identify the candidate genes responsible for malachite green decolorization, and we identified a cytoplasmic triphenylmethane reductase gene with 100% amino acid similarity to the corresponding gene in Citrobacter sp. strain. In contrast to our expectation, the addition of metyrapone had little effect on the cytoplasmic biodegradation, suggesting that cytochrome P450 was not involved in the high-performance reduction. The extracellular biodegradation was likely attributable to the secretion of extracellular proteases and some heat-resistant compounds.
Prevention of Neural-Tube Defects with Periconceptional Folic Acid, Methylfolate, or Multivitamins?
Authors: Czeizel Andrew E. , Dudás István , Paput László , Bánhidy Ferenc
Published: August 2011

Background/Aims: To review the main results of intervention trials which showed the efficacy of periconceptional folic acid-containing multivitamin and folic acid supplementation in the prevention of neural-tube defects (NTD). Methods and Results: The main findings of 5 intervention trials are known: (i) the efficacy of a multivitamin containing 0.36 mg folic acid in a UK nonrandomized controlled trial resulted in an 83–91% reduction in NTD recurrence, while the results of the Hungarian (ii) randomized controlled trial and (iii) cohort-controlled trial using a multivitamin containing 0.8 mg folic acid showed 93 and 89% reductions in the first occurrence of NTD, respectively. On the other hand, (iv) another multicenter randomized controlled trial proved a 71% efficacy of 4 mg folic acid in the reduction of recurrent NTD, while (v) a public health-oriented Chinese-US trial showed a 41–79% reduction in the first occurrence of NTD depending on the incidence of NTD. Conclusions: Translational application of these findings could result in a breakthrough in the primary prevention of NTD, but so far this is not widely applied in practice. The benefits and drawbacks of 4 main possible uses of periconceptional folic acid/multivitamin supplementation, i.e. (i) dietary intake, (ii) periconceptional supplementation, (iii) flour fortification, and (iv) the recent attempt for the use of combination of oral contraceptives with 6S-5-methytetrahydrofolate (methylfolate), are discussed. Obviously, prevention of NTD is much better than the frequent elective termination of pregnancies after prenatal diagnosis of NTD fetuses.
Anti-thrombotic effects of selective estrogen receptor modulator tamoxifen
Authors: Nayak Manasa , Singh Sunil , Roy Arnab , Prakash Vivek , Kumar Anand , Dash Debabrata
Published: August 2011

Tamoxifen is a known anti-cancer drug and established estrogen receptor modulator. Few clinical studies have earlier implicated the drug in thrombotic complications attributable to lower anti-thrombin and protein S levels in plasma. However, action of tamoxifen on platelet signalling machinery has not been elucidated in detail. In the present report we show that tamoxifen is endowed with significant inhibitory property against human platelet aggregation. From a series of in vivo and in vitro studies tamoxifen was found to inhibit almost all platelet functions, prolong tail bleeding time in mouse and profoundly prevent thrombus formation at injured arterial wall in mice, as well as on collagen matrix perfused with platelet-rich plasma under arterial shear against the vehicle dimethylsulfoxide (DMSO). These findings strongly suggest that tamoxifen significantly downregulates platelet responses and holds potential as a promising anti-platelet / anti-thrombotic agent.
Mast cells in atherosclerosis
Authors: Biessen Erik , Bot Ilze
Published: August 2011

The mast cell, a potent inflammatory cell type, is widely distributed over several tissues, but particularly prominent at the interface exposed to the environment to act in the first line of defense against pathogens. Upon activation mast cells release granules, which contain a large panel of mediators, including neutral proteases (e.g. chymase and tryptase), cathepsins, heparin, histamine and a variety of cytokines and growth factors. While mast cells have been demonstrated to be critically involved in a number of Th2 dominated diseases such as asthma and allergy, recent investigations have now also implicated mast cells in the pathogenesis of atherosclerosis and acute cardiovascular syndromes. In this review, we will discuss the contribution of mast cells to the initiation and progression of atherosclerosis and gauge the therapeutic opportunities of mast cell targeted intervention in acute cardiovascular syndromes.
The Democratic Peace through an Interaction of Domestic Institutions and Norms
Authors: Choi Seung-Whan
Published: August 2011

In an attempt to explain the democratic peace phenomenon, existing studies postulate institutional and normative models but treat them as contending and mutually exclusive explanations. This approach is both theoretically and empirically flawed. Extant institutional models fail to acknowledge that institutional factors have an impact only in the presence of requisite normative factors. Similarly, normative models fail to acknowledge that normative factors have the hypothesized impact only in combination with institutional factors. Since the possibility of such an interaction effect is overlooked, existing empirical models of the democratic peace are misspecified. This study fills the gap by introducing a multiplicative interaction model. This study presents evidence that, ceteris paribus, for democratic dyads in which the interaction effect of institutional and normative constraints is high, the likelihood of interstate disputes is lower than for nondemocratic dyads. Consequently, the democratic peace phenomenon should be seen primarily as an outcome of institutional and normative constraints working together.
‘Mapping’ and ‘doing’ critical geographies of home
Authors: Brickell Katherine
Published: August 2011

This paper reviews the diverse literatures on negative experiences of home at the domestic scale and sets out an agenda to further ‘critical geographies of home’. Tying into broader debates in critical geography on the delineations between the ‘mapping’ of exclusionary landscapes versus the ‘doing’ of something to transform them, the paper finds that the line between these two modes should not always be dichotomously drawn. Now is the time that the burgeoning interest in, and catalogue of research on, home is capitalized upon by pushing towards a critical geography that simultaneously illuminates and catalyses the addressing of domestic injustice.
Treatment of Sydenham Chorea With Intravenous Immunoglobulin
Authors: Walker Kathleen , Brink Anita , Lawrenson John , Mathiassen Wendy , Wilmshurst Jo M.
Published: August 2011

Sydenham chorea is a post-streptococcal, autoimmune, neuropsychiatric, movement disorder. There is no effective treatment. In a randomized study, comparison was made of the outcomes of 10 children treated with standard management alone compared to 10 who received additional intravenous immunoglobulin. The outcomes were assessed using a clinical rating scale, brain single-photon emission computed tomography, and the duration of symptomatic treatment. All three outcome measurement tools found improved outcomes in the group that received intravenous immunoglobulin.
In the Midst of a Storm
Authors: George Miriam
Published: August 2011

For the past few decades, Kerala, India, has been heralded as the model of development and has attracted significant media and academic attention. Among its most noteworthy achievements are its literacy, life expectancy, and mortality rates and state government spending on social welfare. However, these macrorealities mask many unpleasant microrealities, such as subjugating cultural practices and violence against women. This article explores the social system of Kerala to identify the invisibility of highly literate women in Kerala. The objectives are to deconstruct the gender paradox in Kerala and to discuss strategies to transform the dominant discourse including social work.
Using proportion of similar response to evaluate correlates of protection for vaccine efficacy
Authors: Giacoletti Katherine ED , Heyse Joseph
Published: August 2011

A question of interest in many vaccine clinical development programmes is whether vaccine-induced serum antibody level can be used as a correlate of vaccine efficacy; that is, whether serum antibody levels induced by a candidate vaccine can reliably predict the risk of breakthrough disease. Traditionally, analyses to answer this question have been based on modelling the incidence of breakthrough disease as a function of antibody level, among vaccinated subjects in clinical trials. The Proportion of Similar Response (PSR) method will be described and explored, and compared to the Receive Operator Characteristics (ROC) curve as a graphical tool and the area under the ROC (AUROC) as a summary measure in the context of evaluating correlates of protection. A way to use PSR analysis as complementary to Youden's index as a simple and elegant method to determine the discriminatory ability of a test and to set an optimal threshold value will be presented. In addition, the relationships among PSR and other measures of overlap and discrimination will be described. An example based on a clinical trial from a development programme for a vaccine against human papillomavirus (HPV) will be presented.
Economia Aziendale and financial valuations in Italy: Some contradictions and insights
Authors: Alexander David , Servalli Stefania
Published: August 2011

This paper analyses the development of Economia Aziendale as a peculiar Italian theoretical construct, arguing that the current model — at least since Zappa’s ideas of 1927 — is not compatible with Italian practice, nor with the largely successful efforts of the legal profession to stifle government attempts to increase flexibility and relevance. More precisely, two key research questions are addressed. First, is the strong theoretical tradition of Economia Aziendale consistent with the prevalent adoption of the historical cost principle in Italian financial accounting in the twentieth century? Second, how has the historical cost principle achieved this prevalence? We show that the theoretical tradition is clearly inconsistent with the prevalence of the historical cost principle, and provide a coherent rationale explaining this outcome.
Large-eddy simulations for internal combustion engines – a review
Authors: Rutland C J
Published: August 2011

A review of using large-eddy simulation (LES) in computational fluid dynamic studies of internal combustion engines is presented. Background material on turbulence modelling, LES approaches, specifically for engines, and the expectations of LES results are discussed. The major modelling approaches for turbulence, combustion, scalars, and liquid sprays are discussed. In each of these areas, a taxonomy is presented for the various types of models appropriate for engines. Advantages, disadvantages, and examples of use in the literature are described for the various types of models. Several recent examples of engine studies using LES are discussed. Recommendations and future prospects are included.
Job Analysis Techniques for Distal Upper Extremity Disorders
Authors: Garg Arun , Kapellusch Jay M.
Published: August 2011

Distal upper extremity (DUE) work-related musculoskeletal disorders (WMSDs) are among the most costly injuries suffered in industry today. These WMSDs are reported in both office (computer use) and manufacturing environments. Job physical exposure analysis techniques for DUE WMSDs range from simple checklists to quantitative models. A summary of literature review of biomechanical, physiological, psychophysical and epidemiological bases for job physical exposure risk factors for DUE WMSDs is provided. Several job analysis methods suitable for manufacturing environments are reviewed and discussed. A comparative analysis of Rapid Upper Limb Assessment (RULA), Threshold Limit Value for Hand Activity Level (TLV for HAL), and the Strain Index is provided along with results from validation studies and advantages and disadvantages of each method. Three examples from industries are provided to demonstrate applications of RULA, TLV for HAL, and the Strain Index. Last, issues with current job analysis methods when a worker rotates to different jobs and/or when a job consists of several tasks are discussed as well as the need for more robust models to account for these variations in physical exposure in real-world environments.
Auditory Displays for In-Vehicle Technologies
Authors: Nees Michael A. , Walker Bruce N.
Published: August 2011

Modern vehicle cockpits have begun to incorporate a number of information-rich techno-logies, including systems to enhance and improve driving and navigation performance and also driving-irrelevant information systems. The visually intensive nature of the driving task requires these systems to adopt primarily nonvisual means of information display, and the auditory modality represents an obvious alternative to vision for interacting with in-vehicle technologies (IVTs). Although the literature on auditory displays has grown tremendously in recent decades, to date, few guidelines or recommendations exist to aid in the design of effective auditory displays for IVTs. This chapter provides an overview of the current state of research and practice with auditory displays for IVTs. The role of basic auditory capabilities and limitations as they relate to in-vehicle auditory display design are discussed. Extant systems and prototypes are reviewed, and when possible, design recommendations are made. Finally, research needs and an iterative design process to meet those needs are discussed.
Feeding Difficulties in Preterm Infants
Authors: Dodrill Pamela
Published: August 2011

Preterm infants often display difficulty establishing oral feeding in the weeks following birth. This article aims to provide an overview of the literature investigating the development of feeding skills in preterm infants, as well as of interventions aimed at assisting preterm infants to develop their feeding skills. Available research suggests that preterm infants born at a lower gestational age and/or with a greater degree of morbidity are most at risk of early feeding difficulties. Respiratory disease was identified as a particular risk factor. Mechanisms for feeding difficulty identified in the literature include immature or dysfunctional sucking skills and poor suck–swallow–breath coordination. Available evidence provides some support for therapy interventions aimed at improving feeding skills, as well as the use of restricted milk flow to assist with maintaining appropriate ventilation during feeds. Further research is needed to confirm these findings, as well as to answer remaining clinical questions.
Ontogeny stage-independent and high-level clonal expansion in vitro of mouse hematopoietic stem cells stimulated by an engineered NUP98-HOX fusion transcription factor
Authors: Sekulovic Sanja , Gasparetto Maura , Lecault Véronique , Hoesli Corinne A. , Kent David G. , Rosten Patty , Wan Adrian , Brookes Christy , Hansen Carl L. , Piret James M. , Smith Clayton , Eaves Connie J. , Humphries R. Keith
Published: August 2011

Achieving high-level expansion of hematopoietic stem cells (HSCs) in vitro will have an important clinical impact in addition to enabling elucidation of their regulation. Here, we couple the ability of engineered NUP98-HOXA10hd expression to stimulate > 1000-fold net expansions of murine HSCs in 10-day cultures initiated with bulk lin−Sca-1+c-kit+ cells, with strategies to purify fetal and adult HSCs and analyze their expansion clonally. We find that NUP98-HOXA10hd stimulates comparable expansions of HSCs from both sources at ∼ 60% to 90% unit efficiency in cultures initiated with single cells. Clonally expanded HSCs consistently show balanced long-term contributions to the lymphoid and myeloid lineages without evidence of leukemogenic activity. Although effects on fetal and adult HSCs were indistinguishable, NUP98-HOXA10hd–transduced adult HSCs did not thereby gain a competitive advantage in vivo over freshly isolated fetal HSCs. Live-cell image tracking of single transduced HSCs cultured in a microfluidic device indicates that NUP98-HOXA10hd does not affect their proliferation kinetics, and flow cytometry confirmed the phenotype of normal proliferating HSCs and allowed reisolation of large numbers of expanded HSCs at a purity of 25%. These findings point to the effects of NUP98-HOXA10hd on HSCs in vitro being mediated by promoting self-renewal and set the stage for further dissection of this process.
Simvastatin inhibits TGFβ1-induced fibronectin in human airway fibroblasts
Authors: Schaafsma Dedmer , McNeill Karol D , Mutawe Mark M , Ghavami Saeid , Unruh Helmut , Jacques Eric , Laviolette Michel , Chakir Jamila , Halayko Andrew J
Published: August 2011

Background

Bronchial fibroblasts contribute to airway remodelling, including airway wall fibrosis. Transforming growth factor (TGF)-β1 plays a major role in this process. We previously revealed the importance of the mevalonate cascade in the fibrotic response of human airway smooth muscle cells. We now investigate mevalonate cascade-associated signaling in TGFβ1-induced fibronectin expression by bronchial fibroblasts from non-asthmatic and asthmatic subjects.

Methods

We used simvastatin (1-15 μM) to inhibit 3-hydroxy-3-methlyglutaryl-coenzyme A (HMG-CoA) reductase which converts HMG-CoA to mevalonate. Selective inhibitors of geranylgeranyl transferase-1 (GGT1; GGTI-286, 10 μM) and farnesyl transferase (FT; FTI-277, 10 μM) were used to determine whether GGT1 and FT contribute to TGFβ1-induced fibronectin expression. In addition, we studied the effects of co-incubation with simvastatin and mevalonate (1 mM), geranylgeranylpyrophosphate (30 μM) or farnesylpyrophosphate (30 μM).

Results

Immunoblotting revealed concentration-dependent simvastatin inhibition of TGFβ1 (2.5 ng/ml, 48 h)-induced fibronectin. This was prevented by exogenous mevalonate, or isoprenoids (geranylgeranylpyrophosphate or farnesylpyrophosphate). The effects of simvastatin were mimicked by GGTI-286, but not FTI-277, suggesting fundamental involvement of GGT1 in TGFβ1-induced signaling. Asthmatic fibroblasts exhibited greater TGFβ1-induced fibronectin expression compared to non-asthmatic cells; this enhanced response was effectively reduced by simvastatin.

Conclusions

We conclude that TGFβ1-induced fibronectin expression in airway fibroblasts relies on activity of GGT1 and availability of isoprenoids. Our results suggest that targeting regulators of isoprenoid-dependent signaling holds promise for treating airway wall fibrosis.
Treatment of allergic asthma: Modulation of Th2 cells and their responses
Authors: Bosnjak Berislav , Stelzmueller Barbara , Erb Klaus J , Epstein Michelle M
Published: August 2011

Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.
Altered surfactant homeostasis and recurrent respiratory failure secondary to TTF-1 nuclear targeting defect
Authors: Peca Donatella , Petrini Stefania , Tzialla Chryssoula , Boldrini Renata , Morini Francesco , Stronati Mauro , Carnielli Virgilio P , Cogo Paola E , Danhaive Olivier
Published: August 2011

Background

Mutations of genes affecting surfactant homeostasis, such as SFTPB, SFTPC and ABCA3, lead to diffuse lung disease in neonates and children. Haploinsufficiency of NKX2.1, the gene encoding the thyroid transcription factor-1 (TTF-1) - critical for lung, thyroid and central nervous system morphogenesis and function - causes a rare form of progressive respiratory failure designated brain-lung-thyroid syndrome. Molecular mechanisms involved in this syndrome are heterogeneous and poorly explored. We report a novel TTF-1 molecular defect causing recurrent respiratory failure episodes in an infant.

Methods

The subject was an infant with severe neonatal respiratory distress syndrome followed by recurrent respiratory failure episodes, hypopituitarism and neurological abnormalities. Lung histology and ultrastructure were assessed by surgical biopsy. Surfactant-related genes were studied by direct genomic DNA sequencing and array chromatine genomic hybridization (aCGH). Surfactant protein expression in lung tissue was analyzed by confocal immunofluorescence microscopy. For kinetics studies, surfactant protein B and disaturated phosphatidylcholine (DSPC) were isolated from serial tracheal aspirates after intravenous administration of stable isotope-labeled 2H2O and 13C-leucine; fractional synthetic rate was derived from gas chromatography/mass spectrometry 2H and 13C enrichment curves. Six intubated infants with no primary lung disease were used as controls.

Results

Lung biopsy showed desquamative interstitial pneumonitis and lamellar body abnormalities suggestive of genetic surfactant deficiency. Genetic studies identified a heterozygous ABCA3 mutation, L941P, previously unreported. No SFTPB, SFTPC or NKX2.1 mutations or deletions were found. However, immunofluorescence studies showed TTF-1 prevalently expressed in type II cell cytoplasm instead of nucleus, indicating defective nuclear targeting. This pattern has not been reported in human and was not found in two healthy controls and in five ABCA3 mutation carriers. Kinetic studies demonstrated a marked reduction of SP-B synthesis (43.2 vs. 76.5 ± 24.8%/day); conversely, DSPC synthesis was higher (12.4 vs. 6.3 ± 0.5%/day) compared to controls, although there was a marked reduction of DSPC content in tracheal aspirates (29.8 vs. 56.1 ± 12.4% of total phospholipid content).

Conclusion

Defective TTF-1 signaling may result in profound surfactant homeostasis disruption and neonatal/pediatric diffuse lung disease. Heterozygous ABCA3 missense mutations may act as disease modifiers in other genetic surfactant defects.
An RNA interference screen for identifying downstream effectors of the p53 and pRB tumour suppressor pathways involved in senescence
Authors: Rovillain Emilie , Mansfield Louise , Lord Christopher J , Ashworth Alan , Jat Parmjit S
Published: August 2011

Background

Cellular senescence is an irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress and acts as an important tumour suppressor mechanism.

Results

To identify the downstream effectors of the p53-p21 and p16-pRB tumour suppressor pathways crucial for mediating entry into senescence, we have carried out a loss-of-function RNA interference screen in conditionally immortalised human fibroblasts that can be induced to rapidly undergo senescence, whereas in primary cultures senescence is stochastic and occurs asynchronously. These cells are immortal but undergo a rapid irreversible arrest upon activation of the p53-p21 and p16-pRB pathways that can be readily bypassed upon their inactivation. The primary screen identified 112 known genes including p53 and another 29 shRNAmirs targetting as yet unidentified loci. Comparison of these known targets with genes known to be up-regulated upon senescence in these cells, by micro-array expression profiling, identified 4 common genes TMEM9B, ATXN10, LAYN and LTBP2/3. Direct silencing of these common genes, using lentiviral shRNAmirs, bypassed senescence in the conditionally immortalised cells.

Conclusion

The senescence bypass screen identified TMEM9B, ATXN10, LAYN and LTBP2/3 as novel downstream effectors of the p53-p21 and p16-pRB tumour suppressor pathways. Although none of them has previously been linked to cellular senescence, TMEM9B has been suggested to be an upstream activator of NF-κB signalling which has been found to have a causal role in promoting senescence. Future studies will focus on determining on how many of the other primary hits also have a casual role in senescence and what is the mechanism of action.
The respiratory molybdo-selenoprotein formate dehydrogenases of Escherichia coli have hydrogen: benzyl viologen oxidoreductase activity
Authors: Soboh Basem , Pinske Constanze , Kuhns Martin , Waclawek Mandy , Ihling Christian , Trchounian Karen , Trchounian Armen , Sinz Andrea , Sawers Gary
Published: August 2011

Background

Escherichia coli synthesizes three membrane-bound molybdenum- and selenocysteine-containing formate dehydrogenases, as well as up to four membrane-bound [NiFe]-hydrogenases. Two of the formate dehydrogenases (Fdh-N and Fdh-O) and two of the hydrogenases (Hyd-1 and Hyd-2) have their respective catalytic subunits located in the periplasm and these enzymes have been shown previously to oxidize formate and hydrogen, respectively, and thus function in energy metabolism. Mutants unable to synthesize the [NiFe]-hydrogenases retain a H2: benzyl viologen oxidoreductase activity. The aim of this study was to identify the enzyme or enzymes responsible for this activity.

Results

Here we report the identification of a new H2: benzyl viologen oxidoreductase enzyme activity in E. coli that is independent of the [NiFe]-hydrogenases. This enzyme activity was originally identified after non-denaturing polyacrylamide gel electrophoresis and visualization of hydrogen-oxidizing activity by specific staining. Analysis of a crude extract derived from a variety of E. coli mutants unable to synthesize any [NiFe]-hydrogenase-associated enzyme activity revealed that the mutants retained this specific hydrogen-oxidizing activity. Enrichment of this enzyme activity from solubilised membrane fractions of the hydrogenase-negative mutant FTD147 by ion-exchange, hydrophobic interaction and size-exclusion chromatographies followed by mass spectrometric analysis identified the enzymes Fdh-N and Fdh-O. Analysis of defined mutants devoid of selenocysteine biosynthetic capacity or carrying deletions in the genes encoding the catalytic subunits of Fdh-N and Fdh-O demonstrated that both enzymes catalyze hydrogen activation. Fdh-N and Fdh-O can also transfer the electrons derived from oxidation of hydrogen to other redox dyes.

Conclusions

The related respiratory molybdo-selenoproteins Fdh-N and Fdh-O of Escherichia coli have hydrogen-oxidizing activity. These findings demonstrate that the energy-conserving selenium- and molybdenum-dependent formate dehydrogenases Fdh-N and Fdh-O exhibit a degree of promiscuity with respect to the electron donor they use and identify a new class of dihydrogen-oxidizing enzyme.
Combinatorial administration of insulin and vitamin C alleviates the cerebral vasospasm after experimental subarachnoid hemorrhage in rabbit
Authors: Li Shouchun , Xue Jinghui , Shi Jixin , Yin Hongxia , Zhang Zhiwen
Published: August 2011

Background

Cerebral vasospasm (CVS) is a common serious complication after the spontaneous subarachnoid hemorrhage (SAH). Despite recent advances in medical and surgical treatments, the 30-day mortality rate of SAH remains high, and there is lack of especially effective clinical treatment to alleviate and improve CVS. The present study has investigated the therapeutic effect of insulin and vitamin C on CVS after SAH.

Results

Five days after SAH, there is obvious basilar artery spasm in SAH group, whose average vascular cross-sectional area (233,099 ± 16,750 μm2) is significantly smaller than that in control group (462,128 ± 74,756 μm2), which is also significantly different from those in SAH + insulin group (221,114 ± 43,457 μm2) and SAH + vitamin C group (237,820 ± 21,703 μm2). SAH + insulin + vitamin C group shows no evident vasospasm and maintains a vascular cross-sectional area of 425,530 ± 45,503 μm2, which is significantly different from that in SAH group. Insulin receptor α (InRα) expression is significantly downregulated in the vascular endothelial cells of SAH, SAH + insulin, and SAH + vitamin C groups (P < 0.01) but remains unchanged in vascular endothelial cells of SAH + insulin + vitamin C group (P > 0.05). Five days after SAH, serum and cerebrospinal fluid NO levels in SAH, SAH + insulin, and SAH + vitamin C groups decrease significantly (P < 0.01) compared to that in control group, whereas the reduction is not evident in SAH + insulin + vitamin C group (P > 0.05).

Conclusion

Combinatorial treatment with insulin and vitamin C has effectively relieved the CVS after SAH in rabbit, possibly through increasing the InRα expression and NO level, whereas treatment with insulin or vitamin C alone fails to do so.