bluuebunny/crossref_metadata_2025 huggingface dataset:
WriteSim TCExam - An open source text simulation environment for training novice researchers in scientific writing
Authors: Shah Jatin , Rajgor Dimple , Vaghasia Meenakshi , Phadtare Amruta , Pradhan Shreyasee , Carvalho Elias , Pietrobon Ricardo
Published: May 2010

Background

The ability to write clearly and effectively is of central importance to the scientific enterprise. Encouraged by the success of simulation environments in other biomedical sciences, we developed WriteSim TCExam, an open-source, Web-based, textual simulation environment for teaching effective writing techniques to novice researchers. We shortlisted and modified an existing open source application - TCExam to serve as a textual simulation environment. After testing usability internally in our team, we conducted formal field usability studies with novice researchers. These were followed by formal surveys with researchers fitting the role of administrators and users (novice researchers)

Results

The development process was guided by feedback from usability tests within our research team. Online surveys and formal studies, involving members of the Research on Research group and selected novice researchers, show that the application is user-friendly. Additionally it has been used to train 25 novice researchers in scientific writing to date and has generated encouraging results.

Conclusion

WriteSim TCExam is the first Web-based, open-source textual simulation environment designed to complement traditional scientific writing instruction. While initial reviews by students and educators have been positive, a formal study is needed to measure its benefits in comparison to standard instructional methods.
TGF-β1 blockade of microglial chemotaxis toward Aβ aggregates involves SMAD signaling and down-regulation of CCL5
Authors: Huang Wei-Chao , Yen Feng-Chang , Shie Feng-Shiun , Pan Chih-Ming , Shiao Young-Ji , Yang Cheng-Ning , Huang Fong-Lee , Sung Yen-Jen , Tsay Huey-Jen
Published: May 2010

Background

Overactivated microglia that cluster at neuritic plaques constantly release neurotoxins, which actively contribute to progressive neurodegeneration in Alzheimer's disease (AD). Therefore, attenuating microglial clustering can reduce focal neuroinflammation at neuritic plaques. Previously, we identified CCL5 and CCL2 as prominent chemokines that mediate the chemotaxis of microglia toward beta-amyloid (Aβ)aggregates. Although transforming growth factor-β1 (TGF-β1) has been shown to down-regulate the expression of chemokines in activated microglia, whether TGF-β1 can reduce the chemotaxis of microglia toward neuritic plaques in AD remains unclear.

Methods

In the present study, we investigated the effects of TGF-β1 on Aβ-induced chemotactic migration of BV-2 microglia using time-lapse recording, transwell assay, real-time PCR, ELISA, and western blotting.

Results

The cell tracing results suggest that the morphological characteristics and migratory patterns of BV-2 microglia resemble those of microglia in slice cultures. Using this model system, we discovered that TGF-β1 reduces Aβ-induced BV-2 microglial clustering in a dose-dependent manner. Chemotactic migration of these microglial cells toward Aβ aggregates was significantly attenuated by TGF-β1. However, these microglia remained actively moving without any reduction in migration speed. Pharmacological blockade of TGF-β1 receptor I (ALK5) by SB431542 treatment reduced the inhibitory effects of TGF-β1 on Aβ-induced BV-2 microglial clustering, while preventing TGF-β1-mediated cellular events, including SMAD2 phosphorylation and CCL5 down-regulation.

Conclusions

Our results suggest that TGF-β1 reduces Aβ-induced microglial chemotaxis via the SMAD2 pathway. The down-regulation of CCL5 by TGF-β1 at least partially contributes to the clustering of microglia at Aβ aggregates. The attenuating effects of SB431542 upon TGF-β1-suppressed microglial clustering may be mediated by restoration of CCL5 to normal levels. TGF-β1 may ameliorate microglia-mediated neuroinflammation in AD by preventing activated microglial clustering at neuritic plaques.
Degree sequences of geometric preferential attachment graphs
Authors: Jordan Jonathan
Published: May 2010

We investigate the degree sequence of the geometric preferential attachment model of Flaxman, Frieze and Vera (2006), (2007) in the case where the self-loop parameter α is set to 0. We show that, given certain conditions on the attractiveness function F, the degree sequence converges to the same sequence as found for standard preferential attachment in Bollobás et al. (2001). We also apply our method to the extended model introduced in van der Esker (2008) which allows for an initial attractiveness term, proving similar results.
Asymptotic independence for unimodal densities
Authors: Balkema Guus , Nolde Natalia
Published: May 2010

Asymptotic independence of the components of random vectors is a concept used in many applications. The standard criteria for checking asymptotic independence are given in terms of distribution functions (DFs). DFs are rarely available in an explicit form, especially in the multivariate case. Often we are given the form of the density or, via the shape of the data clouds, we can obtain a good geometric image of the asymptotic shape of the level sets of the density. In this paper we establish a simple sufficient condition for asymptotic independence for light-tailed densities in terms of this asymptotic shape. This condition extends Sibuya's classic result on asymptotic independence for Gaussian densities.
Kinematics of flight and the relationship to the vortex wake of a Pallas' long tongued bat (Glossophaga soricina)
Authors: Wolf Marta , Johansson L. Christoffer , von Busse Rhea , Winter York , Hedenström Anders
Published: May 2010

To obtain a full understanding of the aerodynamics of animal flight, the movement of the wings, the kinematics, needs to be connected to the wake left behind the animal. Here the detailed 3D wingbeat kinematics of bats, Glossophaga soricina, flying in a wind tunnel over a range of flight speeds (1–7 m s−1) was determined from high-speed video. The results were compared with the wake geometry and quantitative wake measurements obtained simultaneously to the kinematics. The wingbeat kinematics varied gradually with flight speed and reflected the changes observed in the wake of the bats. In particular, several of the kinematic parameters reflected the differences in the function of the upstroke at low and high flight speeds. At lower flight speeds the bats use a pitch-up rotation to produce a backward flick which creates thrust and some weight support. At higher speeds this mechanism disappears and the upstroke generates weight support but no thrust. This is reflected by the changes in e.g. angle of attack, span ratio, camber and downstroke ratio. We also determined how different parameters vary throughout a wingbeat over the flight speeds studied. Both the camber and the angle of attack varied over the wingbeat differently at different speeds, suggesting active control of these parameters to adjust to the changing aerodynamic conditions. This study of the kinematics strongly indicates that the flight of bats is governed by an unsteady high-lift mechanism at low flight speeds and points to differences between birds and bats.
Rotational behaviour of encapsulated pond snail embryos in diverse natural environments
Authors: Shartau Ryan B. , Harris Stephanie , Boychuk Evelyn C. , Goldberg Jeffrey I.
Published: May 2010

Encapsulated freshwater pond snail embryos display a cilia-driven rotation behaviour that is stimulated by artificially induced hypoxia. Previous studies have suggested that the mixing effect of this behaviour causes enhanced oxygen delivery to embryos within their egg capsules. Despite extensive laboratory-based studies describing this behaviour, it is unclear how this behaviour is used to cope with changes in oxygen concentration and other environmental factors in natural water bodies. We made field measurements of embryo rotation rates in laboratory-reared Helisoma trivolvis embryos placed in ponds of different trophic levels that ranged geographically from the southern Alberta prairie to the Rocky Mountains. Abiotic factors including temperature, pH, conductivity and water oxygen concentration were measured to understand how embryonic rotation is influenced by environmental conditions. Results showed that H. trivolvis embryos exhibit differences in rotational behaviour depending on the environmental conditions. Temperature and oxygen concentration were the primary factors significantly affecting rotation rates. The effect of oxygen concentration on rotation rates was not as widespread as observed under laboratory conditions, probably because the measured oxygen concentrations were above the range that influences embryonic rotation in the laboratory. The rotational behaviour of laboratory-reared Lymnaea stagnalis provided confirmation that embryos of other encapsulated pulmonates exhibit a similar rotational response in natural environments. These results suggest that embryo rotation is influenced by a complex interplay of environmental factors.
Design parameter to improve the suction performance of mixed-flow pump impeller
Authors: Oh H W
Published: May 2010

The effect of positive- and negative-curved blade stackings on the cavitation performance of a mixed-flow pump impeller has been investigated in the present study. To this end, two types of pump impellers with different blade stackings with no significant difference in the non-cavitating hydrodynamics were compared. A numerical simulation based on the validated computational fluid dynamics code has been carried out to analyse the detailed flow dynamic phenomena in the mixed-flow pump impeller. From the predicted characteristic curves pertaining to both the stacking conditions, superior suction performance of the mixed-flow pump impeller with the negative-curved blading has been demonstrated over the normal operating flow range. The computational analysis method and a design parameter presented herein can be effectively applied to the hydraulic design optimization process of general-purpose centrifugal and mixed-flow pump impellers.
Robust Position Control of Electro-Hydraulic Actuator Systems Using the Adaptive Back-Stepping Control Scheme
Authors: Kim H M , Park S H , Song J H , Kim J S
Published: May 2010

In general, the position control of electro-hydraulic actuator (EHA) systems is difficult because of system uncertainties such as Coulomb friction, viscous friction, and pump leakage coefficient. Even if the exact values of the friction and pump leakage coefficient may be obtained through experiment, the identification procedure is very complicated and requires much effort. In addition, the identified values may not guarantee the reliability of systems because of the variation of the operating condition. Therefore, in this paper, an adaptive back-stepping control (ABSC) scheme is proposed to overcome the problem of system uncertainties effectively and to improve the tracking performance of EHA systems. In order to implement the proposed control scheme, the system uncertainties in EHA systems are considered as only one term. In addition, in order to obtain the virtual controls for stabilizing the closed-loop system, the update rule for the system uncertainty term is induced by the Lyapunov control function (LCF). To verify the performance and robustness of the proposed control system, computer simulation of the proposed control system is executed first and the proposed control scheme is implemented for an EHA system by experiment. From the computer simulation and experimental results, it was found that the ABSC system produces the desired tracking performance and has robustness to the system uncertainties of EHA systems.
The Removal of 2-Phenylphenol from Aqueous Solution by Adsorption onto Organoclays
Authors: Seki Yoko , Ogawa Makoto
Published: May 2010

The adsorption of 2-phenylphenol onto organically pillared clays (a natural montmorillonite and a synthetic saponite) was investigated. Organoammonium salts used for the clay modification were trimethylphenylammonium bromide, 3-(trifluoromethyl)phenyltrimethylammonium bromide, and neostigmine bromide. All the organically pillared clays adsorbed 2-phenylphenol from water. The adsorbed amount of 2-phenylphenol was smaller as the cation-exchange capacity of host was larger, showing possible pore volume engineering.
Oppositane-Type Sesquiterpenoids from the Formosan Soft Coral Sinularia leptoclados
Authors: Huang Chiung-Yao , Su Jui-Hsin , Liu Yung-Chun , Wen Zhi-Hong , Hsu Chi-Hsin , Chiang Michael Y , Sheu Jyh-Horng
Published: May 2010

Two new natural products, the oppositane-type sesquiterpenoids leptocladolins A and B (1 and 2), along with two known compounds 1β-hydroxy-6α-acetoxyeudesm-4(15)-ene (3) and 1β,6α-dihydroxyeudesm-4(15)-ene (4) were obtained from a Formosan soft coral Sinularia leptoclados. The relative structures of 1 and 3 were confirmed by X-ray diffraction analysis. The absolute structures of 1 and 3 were determined by the Mosher’s method. It was found that 4 significantly inhibited the upregulation of pro-inflammatory iNOS protein in LPS-stimulated RAW264.7 macrophage cells.
Trans-Bilayer Ion Conduction by Proline Containing Cyclic Hexapeptides and Effects of Amino Acid Substitutions on Ion Conducting Properties
Authors: Taira Junichi , Osada Satoshi , Hayashi Ryo , Ueda Toshihisa , Jelokhani-Niaraki Masoud , Aoyagi Haruhiko , Kodama Hiroaki
Published: May 2010

Several ion channel forming cyclic peptides have been reported over the past two decades and various ion conducting mechanisms have been proposed. In this article, we report on amino acid substitutions in cyclic hexapeptides and their effects on the ion conducting properties of these peptides. Cyclic hexapeptides, cyclo(Pro–Xxx–Yyy)2, containing two Pro residues, were used as the main framework. The substitution is performed at the Xxx positions with cationic/hydrophilic Lys or hydrophobic Leu. Yyy positions were substituted with d-Phe, d-Ala, or Gly. The peptides which were absent Lys residues showed ion conducting profiles with clear transitions of electric currents, whereas the peptides containing Lys residues tended to exhibit spiky or burst-like profiles. These profiles were altered single state profiles by the protection of ε-amino groups with aromatic protecting groups. The protected analogs exhibited significant decrease in ion conductance. These results indicated that peptides containing Lys conduct ions without forming ring stacked tube-like structure. Ion channel properties were also affected by conformational changes of the cyclic peptides induced by substitution of the Yyy positions. Enhancement of intramolecular β-turn structures of cyclic peptides tended to decrease their ion conductance values.
Role of the Succinate Skeleton in the Disorder–Order Transition of AOT and Its Analogous Molecules: Detection by Infrared Absorption Spectra of the Configurations Arising from the Difference in Torsion Angles of the Succinate Skeleton
Authors: Okabayashi Hiro-Fumi , Izawa Ken-Ichi , Sumiya Akiko , Eastoe Julian , O’Connor Charmian J
Published: May 2010

The IR spectra in the 1300–1450 cm−1 region, which reflect the CH and CH2 deformation vibrational modes of the succinate skeleton, have been investigated in detail for sodium dialkylsulfonates (alkyl groups: ethyl, n-propyl, n-butyl, n-hexyl, n-heptyl, n-octyl, n-decyl, and n-dodecyl) and sodium 1,2-bis(2-ethylhexyl)sulfosuccinate (sodium 1,2-bis(2-ethylhexyloxycarbonyl)ethanesulfonate) (AOT). The results have provided clear evidence that two configurations, arising from the difference in the torsion angles of the succinate skeleton, are preferentially stabilized in aqueous solution as well as in the solid state, depending upon the concentration. Thus, the IR spectra of this region can be used as a powerful tool for elucidation of the mechanism of the disorder–order transition in aggregate systems of AOT or its homologs at the molecular level.
Half-Sandwich Rare Earth Metal Complexes as Novel Catalysts for Olefin Polymerization and Other Chemical Transformations
Authors: Nishiura Masayoshi , Hou Zhaomin
Published: May 2010

This article describes our recent studies on the synthesis and chemistry of mono(cyclopentadienyl)-ligated rare earth metal alkyl and hydride complexes. The half-sandwich mono- and dialkyl rare earth metal complexes are prepared either by alkane elimination reactions between trialkyl rare earth complexes and the neutral cyclopentadiene derivatives or by metathetical reactions of rare earth trichlorides with the alkali metal salts of the corresponding ligands. The reaction of the dialkyl complexes with an equivalent of a borate compound such as [Ph3C][B(C6F5)4] or [PhNMe2H][B(C6F5)4] generates easily the corresponding cationic monoalkyl species, which serve as excellent catalysts for the polymerization and copolymerization of a variety of olefins to yield a new family of polymer materials that show novel properties but are difficult to prepare by other catalysts. The half-sandwich monoalkyl rare earth complexes bearing the silylene-linked cyclopentadienyl–arylamido ligands act as excellent catalysts for the catalytic dimerization of terminal alkynes, cross coupling of terminal alkynes with isocyanides, and the catalytic addition of terminal alkyne C–H, amine N–H, and phosphine P–H bonds to carbodiimides. The hydrogenolysis of the dialkyl rare earth complexes with H2 affords a new class of polynuclear rare earth metal polyhydride complexes, which show unique features in both structure and reactivity.
Preparations and Photosensitizing Properties of 2,7,12,17-Tetra-n-propylporphycenatotin(IV) Dihalide Complexes
Authors: Taneda Masatsugu , Maeda Daisuke , Shimakoshi Hisashi , Abe Masaaki , Hisaeda Yoshio
Published: May 2010

2,7,12,17-Tetra-n-propylporphycenatodihalotin(IV) complexes ([Sn(TPrPc)X2], X = F, Cl, and Br) were synthesized and their photophysical properties were investigated. These complexes exhibit strong absorptions in the red region (600–630 nm). Strong quenching was observed during the fluorescence emission of the dibromotin(IV) complex, which is caused by an intramolecular heavy-atom effect. The complexes emit NIR phosphorescence in 1-iodopropane at room temperature and the intensity of the emission of the dibromotin(IV) complex is found to be smaller than that of the dichlorotin(IV) complex. The quantum efficiency (ΦΔ) of generation of singlet oxygen using the dibromotin(IV) complex is the highest among the porphycenatotin(IV) complexes (ΦΔ = 0.79). Photooxidation of 1,3-diphenylisobenzofuran catalyzed by the complexes upon irradiation with red light (over 600 nm) was studied and a rapid oxidation of the substrate was observed when using the dibromotin(IV) complex.
Influence of Calcination Temperatures on Iridium Dispersion and Hydrogenation Activity in Silica-Supported Iridium Catalysts
Authors: Shibuya Ryoji , Ohshima Masa-aki , Kurokawa Hideki , Miura Hiroshi
Published: May 2010

The influence of calcination temperatures on the dispersion of Ir/SiO2 catalysts has been studied. At low calcination temperatures, the chloride precursor was dispersed on the silica surface and formed highly dispersed Ir/SiO2 catalysts upon reduction. At high calcination temperatures, the formation of IrO2 was confirmed, which resulted in low dispersion after reduction.
Cardiac dysfunction in HgCl2-induced nephrotic syndrome
Authors: Moreira-Rodrigues Mónica , Henriques-Coelho Tiago , Moura Cláudia , Vasques-Nóvoa Francisco , Sampaio-Maia Benedita , Pestana Manuel , Leite-Moreira Adelino F
Published: May 2010

The experimental model of HgCl2injection is characterized by a systemic autoimmune disease which leads to the development of nephrotic syndrome (NS). NS seems to be accompanied by cardiovascular alterations, since patients with NS present an increased incidence in cardiac disease. The aim of our work was to study the effects of HgCl2-induced NS on myocardial function and morphometry. Normotensive Brown–Norway rats were injected with HgCl2(1 mg/kg, HgCl2group; n = 6, subcutaneous) or the vehicle (control group; n = 6, subcutaneous) on days 0, 2, 4, 7, 9 and 11. The animals were placed in metabolic cages for evaluation of urinary excretion of noradrenaline, sodium, total proteins, albumin and creatinine. Fourteen and 21 days after the first HgCl2injection, left ventricle (LV) hemodynamics was evaluated through pressure micromanometers in basal and isovolumetric heartbeats. The heart and gastrocnemius muscle weights and tibial length were also examined. In an additional group of animals cardiac dimensions and ejection fraction were assessed by echocardiography and LV apoptosis and fibrosis were studied. HgCl2-injected rats presented proteinuria, albuminuria, hyperlipidemia, anemia, sodium retention and ascites at day 14. These alterations were accompanied by LV hemodynamic changes only in isovolumetric heartbeats. Similarly, on day 21, HgCl2-injected rats presented proteinuria, albuminuria, hyperlipidemia, anemia, but no sodium retention or ascites. These animals presented LV systolic and diastolic dysfunction in both basal and isovolumetric heartbeats, as well as cardiac atrophy, LV fibrosis and an increase in myocyte apoptosis. In conclusion, HgCl2-induced NS is accompanied by LV dysfunction and can be a promising model for studying the link between NS and cardiac disease.
The influence of obstructive sleep apnea on the expression of glycerol-3-phosphate dehydrogenase1 gene
Authors: Guindalini Camila , Lee Kil S , Andersen Monica L , Santos-Silva Rogério , Bittencourt Lia Rita A , Tufik Sergio
Published: May 2010

Glycerol-3-phosphate dehydrogenase1 ( GPD1) is considered to be a key enzyme that connects carbohydrate and lipid metabolism. This gene is induced in response to sleep deprivation, suggesting a potential role for this enzyme in the manifestation of obstructive sleep apnea (OSA). This study aims to examine the effects of sleep apnea, obesity and other relevant clinical parameters on GPD1 expression in the peripheral blood of a rigorously selected sample population in order to identify a biological marker that would allow for early intervention and prevention of the disorder. Clinical and sleep parameters were assessed by a complete full-night polysomnography and the expression of GPD1 at the mRNA level was determined. The results were compared among 20 OSA patients and 20 controls, further classified into two subgroups according to their body mass index. The expression levels of the GPD1 gene did not differ between patients with OSA and their matched controls. The results were not affected by the clinical and biochemical measurements, the sleep parameters or the severity of nocturnal hypoxemia. On the other hand, individuals with OSA had higher levels of fasting glucose when compared with weight-matched controls ( P = 0.01). Moreover, higher very low-density lipoprotein (VLDL) was found in the over-weight OSA patient group, and higher cholesterol levels were found in the eutrophic OSA group when compared with their respective controls ( P < 0.05). Based on logistic regression analyses, fasting glucose levels emerged as an independent factor for OSA in both the eutrophic (odds ratio [OR] = 1.27; 95% confidence interval [CI] = 1.00–1.59) and over-weight groups (OR = 1.29; 95% CI = 1.04–1.59). Although the results from the current study corroborate the growing body of data connecting OSA to altered glucose metabolism, it does not provide evidence for the modulation of GPD1 transcription by either OSA or its related phenotypes. This suggests that GPD1 may not play a major role in the OSA manifestation.
Dietary factors and the risk for acute infant leukemia: evaluating the effects of cocoa-derived flavanols on DNA topoisomerase activity
Authors: Lanoue Louise , Green Kerri K , Kwik-Uribe Catherine , Keen Carl L
Published: May 2010

There is cumulative strong evidence that diets rich in flavanols can provide certain positive health benefits, particularly with respect to the cardiovascular system. Consequently, it has been suggested that increasing one's dietary intake of flavanols may be of benefit. Complicating this idea, there are reports that high intakes of certain flavonoids during pregnancy are associated with an increased risk for acute infant leukemia due to a poison effect of select polyphenolic compounds on DNA topoisomerase (topo) II activity that promotes aberrant chromosomal translocations. In the current study, we characterized the effects of select flavanols (epicatechin and catechin monomers), and select flavanol dimers and longer oligomers, on topo II activity, and on cellular toxicity in vitro. In contrast to the chemotherapeutic drug etoposide (VP16) and the flavonol quercetin, which strongly inhibited topo II activity and increased the formation of cleavage complexes demonstrating a poison effect, the flavanols epicatechin and catechin had little effect on topo II enzyme activity. Accordingly, several fold greater concentrations of the flavanols were required to achieve cellular toxicity similar to that of quercetin and VP16 in cultures of myeloid and lymphoid cells. Low cellular toxicity and limited topo II inhibition were also observed with a procyanidin-rich cocoa extract. Of all the flavanols tested, the dimers (B2, B5 and a mix of both) exerted the greatest inhibition of topo II and inhibited cellular proliferation rates at concentrations similar to quercetin. However, in contrast to quercetin, the dimers did not function as topo II poisons. Collectively, our in vitro data show that cocoa-derived flavanols have limited effects on topo II activity and cellular proliferation in cancer cell lines. We predict that these compounds are likely to have limited leukemogenic potential at physiological concentrations.
Maternal dietary chromium restriction programs muscle development and function in the rat offspring
Authors: Padmavathi Inagadapa J N , Rao Kalashikam Rajender , Venu Lagishetty , Ismail Ayesha , Raghunath Manchala
Published: May 2010

Intrauterine growth retardation programs the fetus to manipulated metabolic changes that lead to adult diseases. Considering that chromium (Cr) supplements influence lean body mass (LBM) in both humans and experimental animals, we have studied the effect of maternal Cr restriction on muscle development and function in the rat offspring. Female weanling Wistar/NIN rats received, for 12 weeks, a control or 65% Cr-restricted diet ad libitum and mated with control males. While control mothers/offspring received control diet throughout (CrC), some restricted mothers were switched to control diet from conception (CrRC) and parturition (CrRP) and their offspring were weaned on to control diet. Half of the remaining restricted pups were weaned on to control diet (CrRW) and the other half continued on restricted diet throughout (CrR). Maternal CrR significantly decreased the percent of LBM (LBM %) and fat-free mass (FFM %) in the offspring and this was associated with decreased expression of the myogenic genes: MyoD, Myf5 and MyoG. Surprisingly, expression of the muscle atrophy genes, Atrogin and MuRF 1, was also decreased in CrR offspring. Although basal glucose uptake by muscle was higher in CrR than in CrC offspring, the stimulation with insulin was comparable, implying no change in its insulin sensitivity. Rehabilitation partly corrected myogenic and atrophic gene expression but had no effect on LBM % or FFM % or glucose uptake by muscle. The results show that maternal Cr restriction in rats may irreversibly impair muscle development and glucose uptake by muscle. Modulation of muscle atrophy appears to be an adaptive mechanism to preserve muscle mass in CrR offspring.
Insulin inhibits human erythrocyte cAMP accumulation and ATP release: role of phosphodiesterase 3 and phosphoinositide 3-kinase
Authors: Hanson Madelyn S , Stephenson Alan H , Bowles Elizabeth A , Sprague Randy S
Published: May 2010

In non-erythroid cells, insulin stimulates a signal transduction pathway that results in the activation of phosphoinositide 3-kinase (PI3K) and subsequent phosphorylation of phosphodiesterase 3 (PDE3). Erythrocytes possess insulin receptors, PI3K and PDE3B. These cells release adenosine triphosphate (ATP) when exposed to reduced O2 tension via a signaling pathway that requires activation of the G protein, Gi, as well as increases in cAMP. Although insulin inhibits ATP release from human erythrocytes in response to Gi activation by mastoparan 7 (Mas 7), no effect on cAMP was described. Here, we investigated the hypothesis that insulin activates PDE3 in human erythrocytes via a PI3K-mediated mechanism resulting in cAMP hydrolysis and inhibition of ATP release. Incubation of human erythrocytes with Mas 7 resulted in a 62 ± 7% increase in cAMP ( n = 9, P < 0.05) and a 306 ± 69% increase in ATP release ( n = 9, P < 0.05), both of which were attenuated by pre-treatment with insulin. Selective inhibitors of PDE3 (cilostazol) or PI3K (LY294002) rescued these effects of insulin. These results support the hypothesis that insulin activates PDE3 in erythrocytes via a PI3K-dependent mechanism. Once activated, PDE3 limits Mas 7-induced increases in intracellular cAMP. This effect of insulin leads, ultimately, to decreased ATP release in response to Mas 7. Activation of Gi is required for reduced O2 tension-induced ATP release from erythrocytes and this ATP release has been shown to participate in the matching of O2 supply with demand in skeletal muscle. Thus, pathological increases in circulating insulin could, via activation of PDE3 in erythrocytes, inhibit ATP release from these cells, depriving the peripheral circulation of one mechanism that could aid in the regulation of the delivery of O2 to meet tissue metabolic need.
Acute circuit-resistance exercise increases expression of lymphocyte agouti-related protein in young women
Authors: Ghanbari-Niaki Abbass , Saghebjoo Marziyeh , Rashid-Lamir Amir , Fathi Rozita , Kraemer Robert R
Published: May 2010

Exercise-induced leukocytosis and lymphocytosis is accompanied by up-regulation and down-regulation of hundreds of genes in white blood cells (WBCs). Agouti-related protein (AgRP) is an orexigenic peptide secreted predominantly from the arcuate nucleus in the hypothalamus. AgRP affects feeding behavior and plays a role in energy and glucose homeostasis and adiposity. The purpose of the study was to determine effects of circuit resistance exercise (CRE) (9 exercises, 25 s per exercise) at different intensities on peripheral blood lymphocyte (PBL) AgRP mRNA expression and its concentrations in lymphocytes and plasma. Twenty-five young female college students were randomly divided into five groups: control, 40% 1-repetition maximum (1-RM), 60% 1-RM, 80% 1-RM and combined (40 + 60 + 80% 1-RM) loads. Peripheral blood mononuclear cells were isolated by a lymphocyte density gradient centrifugation method for AgRP mRNA expression. Lymphocyte ATP, glycogen, AgRP, growth hormone (GH), and plasma AgRP, GH and glucose concentrations were measured. CRE increased AgRP mRNA lymphocyte expression significantly ( P < 0.0001) at all intensities. A higher and significant ( P < 0.01) increase was found in the 60% 1-RM group when compared with the other groups. The CRE-induced lymphocyte AgRP expression was accompanied by elevations in plasma AgRP, glucose and GH levels as well as higher WBCs, lymphocytes and neutrophil counts. Lymphocyte AgRP and GH concentrations were significantly reduced ( P < 0.05). Lymphocyte ATP content was unchanged and glycogen was reduced in the combined group but not in the other groups. Data indicate that AgRP mRNA is expressed in PBLs and that CRE increases its expression. Data also reveal that the expression of AgRP was accompanied with higher plasma AgRP and GH concentrations. Findings suggest that AgRP may provide an important signal in the immune environment and that the lymphocyte may be considered as an extra-hypothalamic source of plasma AgRP following exercise stress.
Effects of Gum Arabic in rats with adenine-induced chronic renal failure
Authors: Ali Badreldin H , Al-Salam Suhail , Al Husseni Isehaq , Kayed Rana R , Al-Masroori Noura , Al-Harthi Thuriya , Al Zaabi Mohamed , Nemmar Abderrahim
Published: May 2010

Gum Arabic (GA [ Acacia senegal]) is reputed, in Arabian medicinal practices, to be useful in treating patients with chronic renal failure (CRF), albeit without strong scientific evidence. We have previously shown that GA had no significant effect in rats with CRF induced by surgical nephrectomy. Here, we used another animal model of human CRF (feeding adenine at a concentration of 0.75%w/wfor four weeks) to test the effect of GA on CRF. Renal morphology and measurements of plasma concentrations of urea and creatinine (Cr), and Cr clearance, in addition to urinary volume, osmolarity and protein concentrations, and N-acetylglucosamine and lactate dehydrogenase activities were performed. Interleukin-6 and the total antioxidant levels in urine, as well as the activity of superoxide dismutase in renal tissues, were estimated. Adenine feeding resulted in marked renal damage. GA (6%w/vand 12%w/vin drinking water for four consecutive weeks) significantly ameliorated the adverse biochemical alterations indicative of renal failure, abated the decrease in body weight and reduced the glomerular, tubular and interstitial lesions induced by adenine. Our study provides evidence that GA attenuated renal dysfunction in this model of CRF, suggesting a promising potential for it in protecting against renal failure progression. The mechanism(s) of this nephroprotection is uncertain but may involve anti-oxidant and/or anti-inflammatory actions.
Fenofibrate attenuates tubulointerstitial fibrosis and inflammation through suppression of nuclear factor-κB and transforming growth factor-β1/Smad3 in diabetic nephropathy
Authors: Li Lingyun , Emmett Nerimiah , Mann David , Zhao Xueying
Published: May 2010

Fibrates, the ligands of peroxisome proliferator-activated receptor- α, have been shown to have a renal protective action in diabetic models of renal disease, but the mechanisms underlying this effect are unknown. In the present study, we sought to investigate in greater detail the effect of fenofibrate and its mechanism of action on renal inflammation and tubulointerstitial fibrosis in an animal model of type 2 diabetes mellitus. Twelve-week-old non-diabetic Zucker lean (ZL) and Zucker diabetic fatty (ZD) rats were treated with vehicle or fenofibrate for 10 weeks. mRNA and protein analyses were performed by real-time polymerase chain reaction, Western blot and immunostaining. The diabetic condition of ZD rats was associated with an increase in collagen and α-smooth muscle actin accumulation in the kidney, which was significantly reduced by fenofibrate. Chronic treatment of ZD rats with fenofibrate attenuated renal inflammation and tubular injury as evidenced by a decrease in mRNA and protein expression of secreted phosphoprotein-1, monocyte chemotactic protein-1 and kidney injury molecule-1 in the kidneys. Renal interstitial macrophage infiltration was also significantly reduced in the kidneys of fenofibrate-treated diabetic animals. Moreover, renal nuclear factor (NF)- κB DNA-binding activity, transforming growth factor (TGF)- β1 and phospho-Smad3 proteins were significantly higher in ZD animals compared with ZL ones. This increase in NF- κB activity, TGF- β1 expression and Smad3 phosphorylation was greatly attenuated by fenofibrate in the diabetic kidneys. Taken together, fenofibrate suppressed NF- κB and TGF- β1/Smad3 signaling pathways and reduced renal inflammation and tubulointerstitial fibrosis in diabetic ZD animals.
Effect of prolonged phenytoin administration on rat brain gene expression assessed by DNA microarrays
Authors: Mariotti Veronica , Melissari Erika , Amar Shirly , Conte Angela , Belmaker Robert Haim , Agam Galila , Pellegrini Silvia
Published: May 2010

Preliminary clinical trials have recently shown that phenytoin, an antiepileptic drug, may also be beneficial for treatment of bipolar disorder. To examine molecular mechanisms of action of phenytoin as a potential mood stabilizer, DNA microarrays were used to study the effect of phenytoin on gene expression in the hippocampus and frontal cortex of Sprague–Dawley rats. While our particular interest is in bipolar disorder, this is the first DNA microarray study on the effect of phenytoin in brain tissue, in general. As compared with control rats, treated rats had 508 differentially expressed genes in the hippocampus and 62 in the frontal cortex. Phenytoin modulated the expression of genes which may affect neurotransmission, e.g. glutamate decarboxylase 1 ( Gad1) and γ-aminobutyric acid A receptor, alpha 5 ( Gabra5). Phenytoin also exerted an effect on neuroprotection-related genes, namely the survival-promoting and antioxidant genes v-akt murine thymoma viral oncogene homolog 1 ( Akt1), FK506 binding protein 12-rapamycin associated protein 1 ( Frap1), glutathione reductase ( Gsr) and glutamate cysteine ligase catalytic subunit ( Gclc). The expression of genes potentially associated with mechanisms of mood regulation such as adenylate cyclase-associated protein 1 ( Cap1), Glial Fibrillary Acidic Protein ( Gfap) and prodynorphin ( Pdyn) was also altered. Some of the above genes are regarded as targets of classical mood stabilizers and their modulation supports the clinical observation that phenytoin may have mood-stabilizing effects. The results may provide new insights regarding the mechanism of action of phenytoin and genes found differentially expressed following phenytoin administration may play a role in the pathophysiology of either bipolar disorder or epilepsy.
Short-term AMP-regulated protein kinase activation enhances insulin-sensitive fatty acid uptake and increases the effects of insulin on fatty acid oxidation in L6 muscle cells
Authors: Kelly Karen R , Abbott Marcia J , Turcotte Lorraine P
Published: May 2010

Evidence shows that exercise increases insulin-sensitive glucose uptake and that exercise-induced AMP-regulated protein kinase (AMPK) activation is a likely candidate to mediate this metabolic adaptation. The purpose of this study was to determine whether repeated AMPK activation can similarly enhance insulin-sensitive fatty acid (FA) metabolism. L6 myotubes were incubated under the following conditions: repeated plus acute 5-aminoimidazole-4-carboxamide-1- β-d-ribofuranoside (AICAR) treatment (RAA; 1 mmol/L AICAR for 5 h/d for 5 days plus 1 mmol/L AICAR for 60 min on day 6), repeated AICAR (RA; 1 mmol/L AICAR for 5 h/d for five days) or acute AICAR (AA; 1 mmol/L AICAR for 60 min) and were compared with control cells that were not treated with AICAR. On day six, cells from each group were incubated with or without 100 nmol/L insulin. AICAR treatment and insulin stimulation independently increased ( P < 0.05) palmitate uptake in all groups. RAA potentiated the insulin-induced increase in palmitate uptake by 97% ( P < 0.05) as compared with control cells. RA and AA treatments prevented the insulin-induced decrease in palmitate oxidation, while RAA treatment restored the sensitivity of the cells to insulin action on palmitate oxidation. Total peroxisome proliferator-activated receptor- γ co-activator-1 α, atypical protein kinase C- ζ, cytochrome C and CD36 protein content was increased ( P < 0.05) by RA treatment, but unaffected by insulin. These results indicate that repeated AMPK activation induces improvements in insulin-sensitive FA uptake and oxidation and that this occurs partly via changes in the expression of proteins linked to insulin signaling and FA uptake and oxidation capacity.
The iron chelator, desferrioxamine, reduces inflammation and atherosclerotic lesion development in experimental mice
Authors: Zhang Wei-Jian , Wei Hao , Frei Balz
Published: May 2010

Vascular inflammation and monocyte recruitment are initiating events in atherosclerosis that have been suggested to be caused, in part, by iron-mediated oxidative stress and shifts in the intracellular redox environment of vascular cells. Therefore, the objective of this study was to investigate whether the intracellular iron chelator, desferrioxamine (DFO), reduces inflammation and atherosclerosis in experimental mice. Treatment of C57BL/6J mice with DFO (daily intraperitoneal injection of 100 mg/kg body weight for two weeks) strongly inhibited lipopolysaccharide-induced increases of soluble cellular adhesion molecules and monocyte chemoattractant protein-1 (MCP-1) in the serum and activation of the redox-sensitive transcription factors, nuclear factor- κB and activator protein-1, in the aorta. Furthermore, treatment of apolipoprotein E-deficient (apoE−/−) mice with DFO (100 mg/kg, intraperitoneal, daily for 10 weeks) attenuated aortic atherosclerotic lesion development by 26% ( P < 0.05). DFO treatment of apoE−/− mice also lowered serum levels of MCP-1 and gene expression of proinflammatory and macrophage markers in the aorta and heart, in parallel with increased protein expression of the transferrin receptor in the heart and liver. In contrast, DFO treatment had no effect on serum cholesterol and triglyceride levels. These data show that DFO inhibits inflammation and atherosclerosis in experimental mice, providing the proof-of-concept for an important role of iron in atherogenesis. Whether eliminating excess iron is a useful adjunct for the prevention or treatment of atherosclerosis in humans remains to be investigated.
Knockdown of stromal interaction molecule 1 attenuates hepatocyte growth factor-induced endothelial progenitor cell proliferation
Authors: Shi Yankun , Song Mingbao , Guo Ruiwei , Wang Hong , Gao Pan , Shi Weibin , Huang Lan
Published: May 2010

Increased Ca2+entry through store-operated Ca2+channels (SOCCs) plays an essential role in the regulation of hepatocyte growth factor (HGF)-induced cell proliferation. Stromal interaction molecule 1 (STIM1) is thought to transmit endoplasmic reticulum (ER) Ca2+store depletion signals to the plasma membrane (PM), causing the opening of SOCCs in the PM. However, the relationship between HGF and STIM1 in endothelial progenitor cell (EPC) proliferation remains uncharacterized. The objective of this study was to evaluate the potential involvement of STIM1 in HGF-induced EPC proliferation. For this purpose, we used cultured rat bone marrow-derived EPCs and found that HGF-induced EPC proliferation at low concentrations. Store-operated Ca2+entry (SOCE) was elevated in HGF-treated EPCs, and the SOCC inhibitors 2-aminoethoxydiphenyl borate (2-APB) and BTP-2 inhibited the HGF-induced proliferation response. Moreover, STIM1 mRNA and protein expression levels were increased in response to HGF stimulation and knockdown of STMI1 decreased SOCE and prevented HGF-induced EPC proliferation. In conclusion, our data suggest that HGF-induced EPC proliferation is mediated partly via activation of STIM1.
Pathogenesis of alcoholic liver disease: the role of nuclear receptors
Authors: Gyamfi Maxwell Afari , Wan Yu-Jui Yvonne
Published: May 2010

Ethanol consumption causes fatty liver, which can lead to inflammation, fibrosis, cirrhosis and even liver cancer. The molecular mechanisms by which ethanol exerts its damaging effects are extensively studied, but not fully understood. It is now evident that nuclear receptors (NRs), including retinoid x receptor α and peroxisome proliferator-activated receptors, play key roles in the regulation of lipid homeostasis and inflammation during the pathogenesis of alcoholic liver disease (ALD). Given their pivotal roles in physiological processes, NRs represent potential therapeutic targets for the treatment and prevention of numerous metabolic and lipid-related diseases including ALD. This review summarizes the factors that contribute to ALD and the molecular mechanisms of ALD with a focus on the role of NRs.
Prediction of outcome in patients with acute respiratory distress syndrome by bronchoalveolar lavage inflammatory mediators
Authors: Lin Wei-Chieh , Lin Chiou-Feng , Chen Chia-Ling , Chen Chang-Wen , Lin Yee-Shin
Published: May 2010

Acute respiratory distress syndrome (ARDS) is characterized by overwhelming lung inflammation. This study explored the inflammatory mediators in bronchoalveolar lavage fluid (BALF) for prognostic relevance in patients with infection-induced ARDS. Thirty-nine patients with infection-induced ARDS (28 pneumonia and 11 extrapulmonary sepsis) and two patients with cardiogenic lung edema as the control were included. The expression profiles of inflammatory mediators in BALF were compared between ARDS and cardiogenic lung edema. A group of inflammatory mediators that showed higher expression in ARDS was analyzed for their relationships with clinical features and outcome. We found that 17 patients who died had higher levels of interleukin (IL)-6 ( P = 0.012), IL-8 ( P = 0.001) and monocyte chemoattractant protein-1 ( P = 0.036) in BALF compared with those who survived. Furthermore, there was an inverse relationship between the BALF levels of IL-6 ( P = 0.026), IL-8 ( P = 0.008) and macrophage inflammatory protein (MIP)-1 α ( P = 0.048) and the changes of lung compliance between days 1 and 4, whereas the BALF levels of IL-8 ( P = 0.033) and MIP-1 α ( P = 0.029) were positively correlated with the changes of sequential organ failure assessment scores between days 1 and 4. In multivariate logistic regression analysis, only IL-8 ( P = 0.013) and lung injury score (LIS) ( P = 0.017) independently predicted the mortality, and IL-8 ( P = 0.002) was most likely predictive of mortality in analysis of area under the receiver operating characteristic curve. In conclusion, we show the expression profiles of inflammatory mediators in BALF of infection-induced ARDS. Among the mediators, IL-8 is the most significant predictor for mortality, and several mediators are correlated with clinical severity. However, potential selection bias due to limited control subjects and lack of serum inflammatory mediator data suggest a necessity of further studies to confirm our findings.
Prophylactic treatment with Hypoxis hemerocallidea corm (African potato) methanolic extract ameliorates Brachyspira hyodysenteriae-induced murine typhlocolitis
Authors: Liu Zhiping , Wilson-Welder Jennifer H , Hostetter Jesse M , Jergens Albert E , Wannemuehler Michael J
Published: May 2010

Brachyspira hyodysenteriae is the causative agent of swine dysentery and induces a characteristic mucosal inflammation resulting in pronounced typhlocolitis in swine and mice. Hypoxis hemerocallidea corm (African potato) is a traditional medicine in southern Africa. An African potato methanolic extract (APME) and one of its major constituents, hypoxoside, have been shown in vitro to possess an anti-inflammatory property. The aim of this study is to evaluate the ability of APME to prevent or ameliorate B. hyodysenteriae-induced typhlocolitis. Mice were orally treated with APME for seven days prior to B. hyodysenteriae infection and the treatments continued daily for seven days postinfection (DPI). At the termination of the experiment, weight loss, gross and histological lesions, myeloperoxidase (MPO) activity, and intestinal epithelial proliferation were evaluated. In addition, the protein level of activated p65 subunit of nuclear factor- κB (NF- κB) and mRNA expression of NF- κB-associated genes were also measured. APME treatment significantly ( P < 0.05) reduced weight loss, the severity of typhlocolitis, mucosal MPO activity and intestinal epithelial proliferation subsequent to B. hyodysenteriae infection. Mucosal protein levels of active p65 and expression levels of NF- κB-associated genes following B. hyodysenteriae infection were also decreased by the oral treatment with APME. In conclusion, prophylactic treatment with APME ameliorated B. hyodysenteriae-induced typhlocolitis, suggesting H. hemerocallidea corm methanolic extract may have potential for ameliorating enteropathies that are mediated by overactive host inflammatory processes.