bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibited Phenol Ionization in Reverse Micelles: Confinement Effect at the Nanometer Scale
Authors: Silva O. Fernando , Fernández Mariana A. , Silber Juana J. , de Rossi Rita H. , Correa N. Mariano
Published: November 2011

We found that the absorption spectra of 2‐acetylphenol (2‐HAP), 4‐acetylphenol (4‐HAP), and p‐nitrophenol (p‐NPh) in water/sodium 1,4‐bis(2‐ethylhexyl)sulfosuccinate (AOT)/n‐heptane reverse micelles (RMs) at various W0 (W0=[H2O]/[surfactant]) values studied changed with time if −OH ions were present in the RM water pool. There is an evolution of ionized phenol (phenolate) bands to nonionized phenol absorption bands with time and this process is faster at low W0 values and with phenols with higher bulk water pKa values. That is, in bulk water and at the hydroxide anion concentration used, only phenolate species are observed, whereas in AOT RMs at this fixed hydroxide anion concentration, ionized phenols convert into nonionized phenol species over time. Furthermore, we demonstrate that, independent of the −OH concentration used to prepare the AOT RMs, the nonionized phenols are the more stable species in the RM media. We explain our results by considering that strong hydrogen‐bonding interactions between phenols and the AOT polar head groups result in the existence of only nonionized phenols at the AOT RM interface. The situation is quite different when the phenols are dissolved in cationic benzyl‐n‐hexadecyldimethylammonium chloride RMs. Therein, only phenolates species are present at the −OH concentrations used. The results clearly demonstrate that the classical definition of pH does not apply in a confined environment, such as in the interior of RMs and challenge the general idea that pH can be determined inside RMs.
Influence of defects and impurities on the deteriorated border region in multicrystalline silicon ingots
Authors: Wu Shanshan , Wang Lei , Li Xiaoqiang , Wang Peng , Yang Deren , You Da , Du Jiabin , Zhang Tao , Wan Yuepeng
Published: November 2011

The origin of the lower minority carrier lifetime in the border region of multicrystalline silicon (mc‐Si) ingots was investigated. Based on minority carrier lifetime measurements and chemical analyses, distributions of defects and impurities were studied. It is found that the content of oxygen, carbon and other metal impurities in the border region were almost at the same level as that in the bulk, while the concentration of Fe‐B pairs is significantly higher. More interestingly, the dislocation density in the border region was observed to be much lower than that in the adjacent part. It is elucidated that the lower dislocation density in the border region leads to more iron existing in the form of Fe‐B pairs, which could be responsible for the low lifetime. In addition, it is shown that the low minority carrier lifetime in the border region can be improved effectively by phosphorous gettering. (© 2012 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Assembling Nanostructures for Effective Catalysis: Supported Palladium Nanoparticle Multicores Coated by a Hollow and Nanoporous Zirconia Shell
Authors: Wang Yanfei , Biradar Ankush V. , Asefa Tewodros
Published: November 2011

We report the synthesis and catalytic activities of highly stable, hollow nanoreactors, called SiO2/Pd/h‐ZrO2, which consist of silica microsphere (SiO2)‐supported Pd nanoparticle multicores (Pd) that are encapsulated with a hollow and nanoporous ZrO2 shell (h‐ZrO2). The SiO2/Pd/h‐ZrO2 nanoreactors are fabricated by first synthesizing SiO2/Pd/SiO2/ZrO2 microspheres, and then etching the inner SiO2 shell with dilute NaOH solution. The hollow and nanoporous ZrO2 shell of the nanoreactors serves two important functions: 1) it provides reactants direct access to the Pd nanoparticle multicores inside the SiO2/Pd/h‐ZrO2 nanoreactors during catalysis, and 2) it stabilizes the Pd nanoparticles or protects them from aggregation/sintering. The fabrication of such structures capable of protecting the Pd nanoparticles from aggregation/sintering is of particular interest considering the fact that Pd nanoparticles generally have a high tendency to aggregate because of their high surface energies. Furthermore, the structures are interesting because the Pd nanoparticles are designed and synthesized here to have ‘naked’ surfaces or no organic surface‐passivating ligands—that are often necessary to stabilize metallic nanoparticles—in order to increase their catalytic efficiency. The resulting SiO2/Pd/h‐ZrO2 nanoreactors show excellent catalytic activity, as shown in the hydrogenation of olefins and nitro groups, even at room temperature under moderate hydrogen pressure. This stems from the SiO2/Pd/h‐ZrO2 microspheres’ high surface area and their small, stable, and bare Pd nanoparticles. Furthermore, the SiO2/Pd/h‐ZrO2 nanoreactor catalysts remain fairly stable after reaction and can be recycled multiple times without losing their high catalytic activities.
Olive oil protects against 2,4‐dichlorophenoxyacetic acid‐induced oxidative renal dysfunction in adult rats
Authors: Nakbi Amel , Tayeb Wafa , Dabbou Samia , Chargui Issam , Issaoui Manel , Ferih Ameur , Ali Zohra Ben , Alsaif Mohammed A. , Hammami Mohamed
Published: November 2011

This study was aimed to evaluate the protective effect of extra virgin olive oil (EVOO) and its fractions (hydrophilic (HF) and lipophilic (LF)) treatment on 2,4‐dichlorophenoxiacetic acid (2,4‐D)‐induced nephrotoxicity in rats. The Wistar rats (n = 80, 210–230 g) were divided into eight groups having ten animals, i.e., control group (C), (2,4‐D) group that received 2,4‐D (5 mg/kg b.w.), (2,4‐D/EVOO) group was treated with 2,4‐D plus EVOO, (2,4‐D/olive oil hydrophilic fraction, OOHF) group that received 2,4‐D plus HF, (2,4‐D/olive oil lipophilic fraction, OOLF) group was treated with 2,4‐D plus LF, (EVOO) group that received only EVOO, (OOHF) group was given HF and (OOLF) group was treated with the LF. These components were administered daily by gavage for 4 wk. 2,4‐D administration affected plasma urea and creatinine levels, which increased while uric acid significantly decreased. A marked increase of malondialdehyde level and with a significant decrease in enzymatic antioxidant's activities, were also observed in 2,4‐D treated rats. The co‐administration of EVOO and its fractions along with 2,4‐D resulted in a reversal of 2,4‐D induced biochemical changes in kidney accompanied by a significant decrease in lipid peroxidation and an increase in the level of the antioxidant defence system. Light microscopy investigations revealed that 2,4‐D exposure induced numerous histopathological alterations in the kidney. EVOO administration with 2,4‐D severely reduced the toxicity of 2,4‐D and preserved the normal histological architecture of the renal tissue. However, a milder histopathological improvement was observed in animals co‐treated with HF or LF plus 2,4‐D. In conclusion, the present study suggest that the nephroprotective potential of EVOO against 2,4‐D toxicity might be due to the synergic effect of the two fractions, which could be useful for achieving optimum effects in 2,4‐D‐induced renal damage.
Beta‐cell injury in Ncb5or‐null mice is exacerbated by consumption of a high‐fat diet
Authors: Guo Ying , Xu Ming , Deng Bin , Frontera Jennifer R. , Kover Karen L. , Aires Daniel , Ding Helin , Carlson Susan E. , Turk John , Wang WenFang , Zhu Hao
Published: November 2011

NADH‐cytochrome b5 oxidoreductase (Ncb5or) in endoplasmic reticulum (ER) is involved in fatty acid metabolism, and Ncb5or−/− mice fed standard chow (SC) are insulin‐sensitive but weigh less than wild‐type (WT) littermates. Ncb5or−/− mice develop hyperglycemia at about age 7 wk due to β‐cell dysfunction and loss in association with saturated fatty acid (SFA) accumulation and manifestations of ER and oxidative stress. Here we report that when Ncb5or−/− mice born to heterozygous mothers fed a high fat (HF) diet continue to ingest HF, they weigh as much as SC‐fed WT at age 5 wk. By age 7 wk, diabetes mellitus develops in all HF‐fed versus 68% of SC‐fed Ncb5or−/− mice. Islet β‐cell content in age 5‐wk Ncb5or−/− mice fed HF for 7 days is lower (53%) than for those fed SC (63%), and both are lower than for WT (75%, SC, vs. 69%, HF). Islet transcript levels for markers of mitochondrial biogenesis (PGC‐1α) and ER stress (ATF6α) are higher in Ncb5or−/− than WT mice but not significantly affected by diet. Consuming a HF diet exacerbates Ncb5or−/− β‐cell accumulation of intracellular SFA and increases the frequency of ER distention from 11% (SC) to 47% (HF), thus accelerates β‐cell injury in Ncb5or−/− mice.

Practical applications: Lipid‐induced beta‐cell injury plays a key role in the etiology of diabetes but its mechanism is poorly understood. We have established a lean diabetes mouse model lacking Ncb5or, a redox enzyme that functions in cellular fatty acid metabolism. Ncb5or‐null mice develop early‐onset diabetes as a result of beta‐cell dysfunction and loss, which is associated with intracellular accumulation of saturated free fatty acids and elevated markers of ER and oxidative stress in beta‐cells. Consumption of a high fat diet partially restores body weight of Ncb5or‐null mice but accelerates onset of diabetes by exacerbating beta‐cell lipid overload and ER stress. This mouse model allows us to elucidate the role of fatty acid metabolism in beta‐cell function and maintenance.
Electrocatalytic Performance of Pd Nanoparticles Supported on SiC Nanowires for Methanol Oxidation in Alkaline Media
Authors: Tong X. , Dong L. , Jin G. , Wang Y. , Guo X.‐Y.
Published: November 2011

Pd nanoparticles (NPs) with a mean size of 10–12 nm are dispersed on the surface of SiC nanowires (NWs) by a cyclic voltammetric deposition method, and employed as an electrocatalyst for methanol oxidation. The high dispersion and small size of supported Pd NPs enable the catalyst to have an electrochemical active surface area of 49.5 m2 g–1, which is larger than that of carbon nanotube supported Pd NPs (38.6 m2 g–1), and that of non‐supported Pd NPs (29.9 m2 g–1). Methanol oxidation measurements show that the supported Pd NPs possess a high electrocatalytic activity and an excellent stability. These results indicate that SiC NWs have great potentials as an advantageous supporting material in alcohol fuel cells.
Sulfonated Aromatic Polyethers Containing Pyridine Units as Electrolytes for High Temperature Fuel Cells
Authors: Kalamaras I. , Daletou M. K. , Gregoriou V. G. , Kallitsis J. K.
Published: November 2011

Novel sulfonated copolymers bearing main chain pyridine units have been synthesized for use as electrolytes in high temperature proton exchange membrane fuel cells (PEMFCs). The aim was to combine the excellent thermomechanical properties and high conductivity values after doping with phosphoric acid of these materials with the ability of the sulfonic groups to absorb and retain water and finally to examine the effect on the proton conduction ability. The resulted copolymers showed excellent film forming properties, mechanical integrity, and high glass transition temperatures (Tg > 300 °C). The Tg of the sulfonated copolymers is strongly affected by the sulfonated group content in the polymer backbone due to the acid base interactions of the pyridine and sulfonated groups. Furthermore, the membranes exhibited remarkable oxidative stability and presented proton conductivities in the range of 10–2 S cm–1.
Novel function of Niemann-Pick C1-like 1 as a negative regulator of Niemann-Pick C2 protein
Authors: Yamanashi Yoshihide , Takada Tappei , Shoda Jun-Ichi , Suzuki Hiroshi
Published: November 2011

The hepatic expression of Niemann-Pick C1-like 1 (NPC1L1), which is a key molecule in intestinal cholesterol absorption, is high in humans. In addition to NPC1L1, Niemann-Pick C2 (NPC2), a secretory cholesterol-binding protein involved in intracellular cholesterol trafficking and the stimulation of biliary cholesterol secretion, is also expressed in the liver. In this study, we examined the molecular interaction and functional association between NPC1L1 and NPC2.

In vitro

studies with adenovirus-based or plasmid-mediated gene transfer systems revealed that NPC1L1 negatively regulated the protein expression and secretion of NPC2 without affecting the level of NPC2 messenger RNA. Experiments with small interfering RNA against NPC1L1 confirmed the endogenous association of these proteins. In addition, endocytosed NPC2 could compensate for the reduction of NPC2 in NPC1L1-overexpressing cells, and this demonstrated that the posttranscriptional regulation of NPC2 was dependent on a novel ability of NPC1L1 to inhibit the maturation of NPC2 and accelerate the degradation of NPC2 during its maturation. Furthermore, to confirm the physiological relevance of NPC1L1-mediated regulation, we analyzed human liver specimens and found a negative correlation between the protein levels of hepatic NPC1L1 and hepatic NPC2.

Conclusion :

NPC1L1 down-regulates the expression and secretion of NPC2 by inhibiting its maturation and accelerating its degradation. NPC2 functions as a regulator of intracellular cholesterol trafficking and biliary cholesterol secretion; therefore, in addition to its role in cholesterol re-uptake from the bile by hepatocytes, hepatic NPC1L1 may control cholesterol homeostasis via the down-regulation of NPC2.
Homozygosity mapping identifies a bile acid biosynthetic defect in an adult with cirrhosis of unknown etiology
Authors: Molho-Pessach Vered , Rios Jonathan J. , Xing Chao , Setchell Kenneth D.R. , Cohen Jonathan C. , Hobbs Helen H.
Published: November 2011

The most common inborn error of bile acid metabolism is 3β-hydroxy-Δ5-C27-steroid oxidoreductase (3β-HSD) deficiency, a disorder that usually presents in early childhood with hepatic dysfunction. Timely diagnosis of this disorder is crucial because it can be effectively treated with primary bile acid replacement. Here we describe a 24-year-old woman from Iran with cirrhosis of unknown etiology. Her sister and a first cousin died of cirrhosis (ages 19 and 6 years) and another 32-year-old first cousin had a self-limited liver disorder in childhood that resolved at age 9 years. The family history suggested that the affected family members were homozygous for a mutant allele inherited identical-by-descent. A genome-wide analysis of 2.4 million single nucleotide polymorphisms was performed to identify regions of homozygosity that were present in the proband and the 32-year-old first cousin, but not in a healthy relative. One of these regions contained the gene encoding 3β-HSD (HSD3B7). Sequence analysis of HSD3B7 revealed that the proband and her 32-year-old cousin were homozygous for a frameshift mutation (c.45_46del AG, p.T15Tfsx27) in exon 1. The diagnosis of 3β-HSD deficiency was confirmed by documenting high levels of 3β-hydroxy-Δ5 bile acids in the serum of the proband and the 32-year-old first cousin using mass spectrometry. To our knowledge, the 32-year-old relative in this family represents the oldest asymptomatic patient with this disorder. Conclusion: This study highlights the clinical utility of homozygosity mapping in diagnosing autosomal recessive metabolic disorders. This family illustrates the wide variation in expressivity that occurs in 3β-HSD deficiency and underscores the need to consider a bile acid synthetic defect as a possible cause of liver disease in adults. (Hepatology 2012)
Hepatic ratio of phosphatidylcholine to phosphatidylethanolamine predicts survival after partial hepatectomy in mice
Authors: Ling Ji , Chaba Todd , Zhu Lin-Fu , Jacobs René L. , Vance Dennis E.
Published: November 2011

A major predictor of failed liver resection and transplantation is nonalcoholic fatty liver disease (NAFLD). NAFLD is linked to a wide spectrum of diseases including obesity and diabetes that are increasingly prevalent in Western populations. Thus, it is important to develop therapies aimed at improving posthepatectomy outcomes in patients with NAFLD, as well as to improve the evaluation of patients slated for hepatic surgery. Decreased hepatic phosphatidylcholine (PC) content and decreased ratio of hepatic PC to phosphatidylethanolamine (PE) have previously been linked to NAFLD. To determine if decreased hepatic PC/PE could predict survival after hepatectomy, we used mouse models lacking key enzymes in PC biosynthesis, namely, phosphatidylethanolamine N-methyltransferase and hepatic-specific CTP:phosphocholine cytidylyltransferase α. These mice were fed a high-fat diet to induce NAFLD. We then performed a 70% partial hepatectomy and monitored postoperative survival. We identified hepatic PC/PE to be inversely correlated with the development of steatosis and inflammation in the progression of NAFLD. Decreased hepatic PC/PE before surgery was also strongly associated with decreased rates of survival after partial hepatectomy. Choline supplementation to the diet increased hepatic PC/PE in Pemt
−/− mice with NAFLD, decreased inflammation, and increased the survival rate after partial hepatectomy. Conclusion: Decreased hepatic PC/PE is a predictor of NAFLD and survival following partial hepatectomy. Choline supplementation may serve as a potential therapy to prevent the progression of NAFLD and to improve postoperative outcome after liver surgery. (Hepatology 2012)
Lysine acetylation induced by chronic ethanol consumption impairs dynamin-mediated clathrin-coated vesicle release
Authors: Shepard Blythe D. , Tuma Dean J. , Tuma Pamela L.
Published: November 2011

The liver is the major site of ethanol metabolism and thus sustains the most injury from chronic alcohol consumption. Ethanol metabolism by the hepatocyte leads to the generation of reactive metabolites and oxygen radicals that can readily adduct DNA, lipids, and proteins. More recently, it has become apparent that ethanol consumption also leads to increased post-translational modifications of the natural repertoire, including lysine hyperacetylation. Previously, we determined that alcohol consumption selectively impairs clathrin-mediated internalization in polarized hepatocytes. However, neither the step at which the block occurs nor the mechanism responsible for the defect have been identified. To identify the specific step at which clathrin-mediated internalization is impaired, we examined the distributions, levels, and assembly of selected components of the clathrin machinery in control and ethanol-treated cells. To determine whether the impairment is caused by ethanol-induced lysine acetylation, we also examined the same coat components in cells treated with trichostatin A (TSA), a deacetylase inhibitor that leads to protein hyperacetylation in the absence of ethanol. Conclusion: We determined that both ethanol and TSA impair internalization at a late stage before vesicle fission. We further determined that this defect is likely the result of decreased dynamin recruitment to the necks of clathrin-coated invaginations resulting in impaired vesicle budding. These results also raise the exciting possibility that agents that promote lysine deacetylation may be effective therapeutics for the treatment of alcoholic liver disease. (Hepatology 2012)
Hepatitis C viral kinetics with the nucleoside polymerase inhibitor mericitabine (RG7128)
Authors: Guedj Jeremie , Dahari Harel , Shudo Emi , Smith Patrick , Perelson Alan S.
Published: November 2011

Mericitabine (RG7128) is a nucleoside polymerase inhibitor (NPI), which requires intracellular uptake and phosphorylation to two active triphosphates. Mathematical modeling has provided important insights for characterizing hepatitis C virus (HCV) RNA decline and estimating in vivo effectiveness of antiviral agents; however, it has not been used to characterize viral kinetics with NPIs. HCV RNA was frequently measured in 32 treatment-experienced patients infected with HCV genotype 1 during and after mericitabine monotherapy for 14 days with 750 mg or 1500 mg administered once (qd) or twice daily (bid). The initial decline of HCV RNA was typically slower than with interferon-α or protease inhibitors, and 12 patients presented a novel pattern of HCV RNA kinetics characterized by a monophasic viral decline. Viral kinetics could be well fitted by assuming that the effectiveness in blocking viral production gradually increased over time to reach its final value, ε2, consistent with previous accumulation time estimates of intracellular triphosphates. ε2 was high with bid dosing (mean 750 mg and 1500 mg: 98.0% and 99.8%, respectively; P = 0.018) and significantly higher than in patients treated qd (mean qd versus bid: 90% versus 99%, P < 10−7). Virus rebounded rapidly upon drug discontinuation, which was attributed to the elimination of active drug and the subsequent decline of drug effectiveness, with mean t1/2 = 13.9 hours in the bid regimens. Conclusion: The observed slower initial decline likely represents the time needed to accumulate intracellular triphosphates and is consistent with in vitro data. When administered bid, mericitabine reached a high, dose-dependent, final effectiveness in blocking viral production that rapidly dropped upon treatment cessation. Understanding HCV RNA kinetics with mericitabine could provide valuable insights for combining it with other direct-acting antiviral agents. (Hepatology 2012)
Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol
Authors: Chen Yu-Fan , Tseng Chien-Yu , Wang Hsei-Wei , Kuo Hung-Chih , Yang Vincent W. , Lee Oscar K.
Published: November 2011

Liver transplantation is the only definitive treatment for end-stage cirrhosis and fulminant liver failure, but the lack of available donor livers is a major obstacle to liver transplantation. Recently, induced pluripotent stem cells (iPSCs) derived from the reprogramming of somatic fibroblasts, have been shown to resemble embryonic stem (ES) cells in that they have pluripotent properties and the potential to differentiate into all cell lineages in vitro, including hepatocytes. Thus, iPSCs could serve as a favorable cell source for a wide range of applications, including drug toxicity testing, cell transplantation, and patient-specific disease modeling. Here, we describe an efficient and rapid three-step protocol that is able to rapidly generate hepatocyte-like cells from human iPSCs. This occurs because the endodermal induction step allows for more efficient and definitive endoderm cell formation. We show that hepatocyte growth factor (HGF), which synergizes with activin A and Wnt3a, elevates the expression of the endodermal marker Foxa2 (forkhead box a2) by 39.3% compared to when HGF is absent (14.2%) during the endodermal induction step. In addition, iPSC-derived hepatocytes had a similar gene expression profile to mature hepatocytes. Importantly, the hepatocyte-like cells exhibited cytochrome P450 3A4 (CYP3A4) enzyme activity, secreted urea, uptake of low-density lipoprotein (LDL), and possessed the ability to store glycogen. Moreover, the hepatocyte-like cells rescued lethal fulminant hepatic failure in a nonobese diabetic severe combined immunodeficient mouse model. Conclusion: We have established a rapid and efficient differentiation protocol that is able to generate functional hepatocyte-like cells from human iPSCs. This may offer an alternative option for treatment of liver diseases. (Hepatology 2012)
Glucokinase links Krüppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease
Authors: Bechmann Lars P. , Gastaldelli Amalia , Vetter Diana , Patman Gillian L. , Pascoe Laura , Hannivoort Rebekka A. , Lee Ursula E. , Fiel Isabel , Muñoz Ursula , Ciociaro Demetrio , Lee Young-Min , Buzzigoli Emma , Miele Luca , Hui Kei Y. , Bugianesi Elisabetta , Burt Alastair D. , Day Christopher P. , Mari Andrea , Agius Loranne , Walker Mark , Friedman Scott L. , Reeves Helen L.
Published: November 2011

The polymorphism, KLF6-IVS1–27A, in the Krüppel-like factor 6 (KLF6) transcription factor gene enhances its splicing into antagonistic isoforms and is associated with delayed histological progression of nonalcoholic fatty liver disease (NAFLD). To explore a potential role for KLF6 in the development of insulin resistance, central to NAFLD pathogenesis, we genotyped KLF6-IVS1–27 in healthy subjects and assayed fasting plasma glucose (FPG) and insulin sensitivities. Furthermore, we quantified messenger RNA (mRNA) expression of KLF6 and glucokinase (GCK), as an important mediator of insulin sensitivity, in human livers and in liver tissues derived from a murine Klf6 knockdown model (DeltaKlf6). Klf6 overexpression studies in a mouse hepatocyte line were utilized to mechanistically link KLF6 with Gck promoter activity. KLF6-IVS1–27Gwt (i.e., less KLF6 splicing) was associated with stepwise increases in FPG and insulin and reduced hepatic insulin sensitivity. KLF6 binds to the liver-specific Gck promoter and activates a GCK promoter-reporter, identifying GCK as a KLF6 direct transcriptional target. Accordingly, in DeltaKlf6 hepatocytes Gck expression was reduced and stable transfection of Klf6 led to up-regulation of Gck. GCK and KLF6 mRNAs correlate directly in human NAFLD tissues and immunohistochemistry studies confirm falling levels of both KLF6 and GCK in fat-laden hepatocytes. In contrast to full-length KLF6, splice variant KLF6-SV1 increases in NAFLD hepatocytes and inversely correlates with glucokinase regulatory protein, which negatively regulates GCK activity. Conclusion: KLF6 regulation of GCK contributes to the development of hepatic insulin resistance. The KLF6-IVS1–27A polymorphism, which generates more KLF6-SV1, combats this, lowering hepatic insulin resistance and blood glucose. (Hepatology 2011)
Hepatocyte growth factor/ c-met signaling is required for stem-cell–mediated liver regeneration in mice
Authors: Ishikawa Tsuyoshi , Factor Valentina M. , Marquardt Jens U. , Raggi Chiara , Seo Daekwan , Kitade Mitsuteru , Conner Elizabeth A. , Thorgeirsson Snorri S.
Published: November 2011

Hepatocyte growth factor (HGF)/c-Met supports a pleiotrophic signal transduction pathway that controls stem cell homeostasis. Here, we directly addressed the role of c-Met in stem-cell–mediated liver regeneration by utilizing mice harboring c-met floxed alleles and Alb-Cre or Mx1-Cre transgenes. To activate oval cells, the hepatic stem cell (HSC) progeny, we used a model of liver injury induced by diet containing the porphyrinogenic agent, 3,5-diethocarbonyl-1,4-dihydrocollidine (DDC). Deletion of c-met in oval cells was confirmed in both models by polymerase chain reaction analysis of fluorescence-activated cell-sorted epithelial cell adhesion molecule (EpCam)-positive cells. Loss of c-Met receptor decreased the sphere-forming capacity of oval cells in vitro as well as reduced oval cell pool, impaired migration, and decreased hepatocytic differentiation in vivo, as demonstrated by double immunofluorescence using oval- (A6 and EpCam) and hepatocyte-specific (i.e. hepatocyte nuclear factor 4-alpha) antibodies. Furthermore, lack of c-Met had a profound effect on tissue remodeling and overall composition of HSC niche, which was associated with greatly reduced matrix metalloproteinase (MMP)9 activity and decreased expression of stromal-cell–derived factor 1. Using a combination of double immunofluorescence of cell-type–specific markers with MMP9 and gelatin zymography on the isolated cell populations, we identified macrophages as a major source of MMP9 in DDC-treated livers. The Mx1-Cre-driven c-met deletion caused the greatest phenotypic impact on HSCs response, as compared to the selective inactivation in the epithelial cell lineages achieved in c-Metfl/fl; Alb-Cre+/− mice. However, in both models, genetic loss of c-met triggered a similar cascade of events, leading to the failure of HSC mobilization and death of the mice. Conclusion: These results establish a direct contribution of c-Met in the regulation of HSC response and support a unique role for HGF/c-Met as an essential growth-factor–signaling pathway for regeneration of diseased liver. (Hepatology 2012)
The effect of multivitamin supplementation on mood and stress in healthy older men
Authors: Harris Elizabeth , Kirk Joni , Rowsell Renee , Vitetta Luis , Sali Avni , Scholey Andrew B , Pipingas Andrew
Published: November 2011

Objective

There is a demonstrated association between poor mood and deficiency in several micronutrients. Multivitamin supplements contain a wide range of nutrients, suggesting that they may be effective in improving mood; however, few studies have investigated this potential in randomized, controlled trials. This study investigates the effects of a multivitamin, mineral, and herbal supplement on mood and stress in a group of healthy, older male volunteers.

Methods

In this randomized, double‐blind, placebo‐controlled trial, fifty men, aged 50–69 years, supplemented for a period of 8 weeks with a multivitamin formulation that contained vitamins (at levels above recommended daily intakes), minerals, antioxidants, and herbal extracts, or a placebo. They completed a series of mood and stress questionnaires at baseline and post‐supplementation.

Results

Compared with placebo, there was a significant reduction in the overall score on a depression anxiety and stress scale and an improvement in alertness and general daily functioning in the multivitamin group.

Conclusions

Supplementation with a multivitamin, mineral and herbal formulation may be useful in improving alertness and reducing negative mood symptoms and may also improve feelings of general day‐to‐day well‐being. Copyright © 2011 John Wiley & Sons, Ltd.
Gas–Surface Interactions on Quasicrystals
Authors: Curtarolo Stefano , Setyawan Wahyu , Diehl Renee D.
Published: November 2011

To commemorate the awarding of the Nobel Prize for Chemistry to Daniel Shechtman for his discovery of quasicrystals, this paper reviews our recent studies of the interaction of rare gases and hydrocarbon gases with the tenfold surface of quasicrystalline decagonal Al‐Co‐Ni.
So Useful, Those Quasicrystals
Authors: Dubois Jean‐Marie
Published: November 2011

For years, the community working on quasicrystals in many countries in the world was expecting the ultimate recognition of its contribution to the advancement of crystal chemistry, solid‐state physics, mathematics, and other fields. Nearly thirty years after the initial discovery, it was finally awarded in October 2011 to Prof. Danny Shechtman by the Nobel Committee for Physics and Chemistry. Many, most often independent, achievements contributed to this success. The purpose of this article is to chronicle the role played by the applications of quasicrystals and related compounds in the development of the field and its financing by governmental institutions as well as private companies. Those applications, potential or realized, have made the field of quasicrystals comprehensible to the general public and to decision makers all over the world, including in Stockholm, in spite of its rather complicated high‐dimensional crystallographic background, and in spite of the absolute opposition that a great chemist manifested against it in its infancy.
Challenges working with infants and their families: Symptoms and meanings—two approaches of infant–parent psychotherapy
Authors: Tuters Elizabeth , Doulis Sally , Yabsley Susan
Published: November 2011

In this article, the authors describe the rationale for the way they work with troubled infant–parent relationships. They focus on two approaches developed at the Hincks‐Dellcrest Children's Mental Health Centre (Toronto, Canada), a publically funded agency where they work and teach. One approach is Watch, Wait and Wonder, and the other is Infant–Parent Psychotherapy. The authors share a common philosophy that directs the way they think about the way they work. Two clinical case studies are presented to illustrate the treatment process of each approach. The presenting symptoms in both cases are similar (sleep difficulties), but the meaning, ages, and family compositions are different. The interventions unlocked the difficulties that each relationship was experiencing in a brief period of time.
Working here and now with the individual and family system: A case of a traumatized girl
Authors: Puura Kaija
Published: November 2011

From the moment of conception, each and every child lives and develops in connection with other people. Most children grow up in families formed by parent(s) and siblings, and relationships with them form an important part of the environment in which they develop. Interaction with parents and siblings affects brain development and the intrapsychic structures of the child. In the last few decades, knowledge of both normal and abnormal development of the human brain and mind has increased, revealing the complicated interplay of neurophysiology, emotions, and behavior within an individual as well as in interaction with others. In an attempt to address the challenge of working with various existing frameworks, in the Child Psychiatric Department of Tampere University Hospital, Professor Tuula Tamminen started a clinical philosophy called integrative child psychiatry. It includes looking at a child's situation from different perspectives and integrating data gathered into clinical understanding to choose the optimal treatment. In this article, I describe how I used individual child therapy, family therapeutic methods, psychoeducation, and some simple behavioral techniques in the treatment of a sexually abused girl.
Mrp2 is involved in the efflux and disposition of fosinopril
Authors: Green Benjamin R. , Bain Lisa J.
Published: November 2011

The multidrug‐resistance‐associated proteins 1 and 2 (MRP1/MRP2) are transporters responsible for the efflux of drugs and endogenous compounds. Madin Darby canine kidney (MDCK) cells transfected with the human MRP1 or MRP2 genes were used to assess whether several widely used pharmaceuticals are potential substrates by examining their differential toxicity, accumulation and efflux. Loratadine, an antihistamine, was 1.4‐fold less toxic to MRP1 cells and its retention was 1.3‐fold lower than that from MDCK control cells. Fosinopril, an angiotensin converting enzyme inhibitor, was 2.4‐fold less toxic and its retention was 4.5‐fold lower in MRP2‐transfected cells compared with control cells. To determine whether fosinopril contributed to a drug–drug interaction, fosinopril efflux was examined in vitro in combination with other known or suspected MRP2 substrates over a period of 20 min. When fosinopril was coincubated with desloratadine, loratadine or methotrexate, its retention was increased by 2‐, 4.7‐ and 2‐fold, respectively, which likely indicates that a drug–drug interaction is occurring. In vivo studies were conducted, in which FVB wild‐type and FVB/Mrp2−/− mice were dosed with fosinopril and the known MRP2 substrate methotrexate, and tissues collected after 1 h. In mice lacking Mrp2, drug levels were reduced in the intestine by 1.5‐fold, but increased in the liver, serum and kidneys, by 2.1‐, 2.9‐ and 3‐fold, respectively. These data suggest that, in the absence of Mrp2, fosinopril alters the retention of a second drug. These findings will help increase our understanding of the role that MRP2 plays in altering the retention and disposition of coadministered pharmaceuticals. Copyright © 2011 John Wiley & Sons, Ltd.
Age determines longitudinal changes in body composition better than menopausal and bone status: The OFELY study
Authors: Sornay-Rendu Elisabeth , Karras-Guillibert Caroline , Munoz Francoise , Claustrat Bruno , Chapurlat Roland D
Published: November 2011

Long-term body composition (BC) changes and their determinants have been rarely explored. We aimed to evaluate BC changes in French women from the Os des Femmes de Lyon (OFELY) cohort and to explore several determinants of those changes. At baseline, premenopausal (PreM) women (n = 145) had lower fat body mass (FM) and greater lean body mass (LM), relative skeletal muscle mass index (RASM), and total body bone mineral content (TBBMC) compared with untreated postmenopausal (PostM) women (n = 412). During a 6-year follow-up, LM and RASM did not change, whereas a significant increase of FM and a decrease of TBBMC were observed in PreM (n = 88) and PeriM women (n = 44; women who became PostM during the follow-up). In untreated PostM women, FM increased, whereas LM, RASM, and TBBMC decreased (p < 0.0001). Age was a significant determinant of the changes in BC. After controlling for age, menopausal status was still a significant determinant only for changes in TBBMC. FM, LM, RASM, and TBBMC were higher in women with normal bone mineral density (BMD) compared with women with osteopenia or osteoporosis (p < 0.0001), but after adjusting for age, changes of BC were not significantly different according to the bone status. After controlling for age and menopausal status, levels of P1NP in the highest quartile were associated with a greater decrease of LM and RASM compared with lower levels. In conclusion, BC changes in French women over a 6-year follow-up showed a high interindividual variability. Aging may be the most important determinant of changes in body composition, rather than menopausal and bone status. © 2012 American Society for Bone and Mineral Research
Low bone mass and high material bone density in two patients with Loeys-Dietz syndrome caused by transforming growth factor beta receptor 2 mutations
Authors: Ben Amor I Mouna , Edouard Thomas , Glorieux Francis H , Chabot Gilles , Tischkowitz Marc , Roschger Paul , Klaushofer Klaus , Rauch Frank
Published: November 2011

Loeys-Dietz syndrome (LDS) is a rare autosomal-dominant connective tissue disorder caused by heterozygous mutations in the genes encoding transforming growth factor beta receptor 1 or 2 (TGFBR1 or TGFBR2). Although an association between LDS and osteoporosis has been reported, the skeletal phenotype regarding bone mass is not well characterized. Here, we report on two LDS patients with mutations in TGFBR2. Patient 1 was a 24-year-old man who had a total of three fractures involving the left radius, the left metacarpal, and the right femur. At the age of 14 years, lumbar spine areal bone mineral density Z-score was −4.0 and iliac bone histomorphometry showed elevated bone turnover (bone formation rate per bone surface: 91 µm3/µm2/year; age-matched control values 37 [10], mean [SD]) and mildly low trabecular bone volume per tissue volume (17.2%; age-matched control values 25.7 [5.3]). Bone mineralization density distribution (BMDD) in trabecular bone was increased (CaPeak 22.70 wt% Ca; age-matched control values 21.66 [0.52]). Patient 2, a 17-year-old girl, suffered from diffuse bone pain but had not sustained fractures. At 14 years of age, her lumbar spine areal bone mineral density Z-score was −3.4. Iliac bone histomorphometry at that age confirmed low bone mass (bone volume to tissue volume 10.1%, same control values as above) and high bone turnover (bone formation rate per bone surface 70 µm3/µm2/year). BMDD in trabecular bone was significantly shifted toward increased mineralization (CaPeak 22.36 wt% Ca). Thus, it appears that LDS can be associated with low bone mass and high bone turnover but increased matrix mineralization of trabecular bone. © 2012 American Society for Bone and Mineral Research
PlexinA2 mediates osteoblast differentiation via regulation of Runx2
Authors: Oh Ji-Eun , Kim Hyung Joon , Kim Woo-Shin , Lee Zang Hee , Ryoo Hyun-Mo , Hwang Soon Jung , Lee Youngkyun , Kim Hong-Hee
Published: November 2011

The imbalance between bone-resorbing osteoclasts and bone-forming osteoblasts often leads to bone destructive diseases such as osteoporosis. In contrast to the development of several antiresorptive agents for osteoporosis therapy, discovery of anabolic drugs has been difficult because of an insufficient understanding of the complex mechanism of bone formation. In a microarray analysis with mouse preosteoblast cells, we found that PlexinA2 (PlxnA2), a molecule previously known to mediate axon guidance in neural development, was upregulated by the osteogenic factor BMP2. PlxnA2-specific siRNA decreased Runx2 expression, osteoblast differentiation, and mineralization. Runx2 overexpression restored osteoblastic differentiation of PlxnA2-knockdown cells. PlxnA2 was associated with both type 1 and 2 BMP receptors, and BMP2 increased the interaction between PlxnA2 and type 1 receptors. PlxnA2 also affected Smad and Akt signaling pathways downstream of BMP2. Taken together, the results of our study reveal that PlxnA2 has a pro-osteogenic function by modulating BMP2 signaling. Therefore, PlxnA2 may be a useful target for development of bone anabolic therapeutics. © 2012 American Society for Bone and Mineral Research
Hypothalamic action of glutamate leads to body mass reduction through a mechanism partially dependent on JAK2
Authors: Razolli Daniela S. , Solon Carina , Roman Erika A. , Ignacio‐Souza Letícia M. , Velloso Licio A.
Published: November 2011

Glutamate acts in the hypothalamus promoting region‐, and cell‐dependent effects on feeding. Part of these effects are mediated by NMDA receptors, which are up regulated in conditions known to promote increased food intake and thermogenesis, such as exposure to cold and consumption of highly caloric diets. Here, we hypothesized that at least part of the effect of glutamate on hypothalamic control of energy homeostasis would depend on the control of neurotransmitter expression and JAK2 signaling. The expression of NMDA receptors was co‐localized to NPY/AgRP, POMC, CRH, and MCH but not to TRH and orexin neurons of the hypothalamus. The acute intracerebroventricular injection of glutamate promoted a dose‐dependent increase in JAK2 tyrosine phosphorylation. In obese rats, 5 days intracerebroventricular treatment with glutamate resulted in the reduction of food intake, accompanied by a reduction of spontaneous motility and reduction of body mass, without affecting oxygen consumption. The reduction of food intake and body mass were partially restrained by the inhibition of JAK2. In addition, glutamate produced an increased hypothalamic expression of NPY, POMC, CART, MCH, orexin, CRH, and TRH, and the reduction of AgRP. All these effects on neurotransmitters were hindered by the inhibition of JAK2. Thus, the intracerebroventricular injection of glutamate results in the reduction of body mass through a mechanism, at least in part, dependent on JAK2, and on the broad regulation of neurotransmitter expression. These effects are not impaired by obesity, which suggest that glutamate actions in the hypothalamus may be pharmacologically explored to treat this disease. J. Cell. Biochem. 113: 1182–1189, 2012. © 2011 Wiley Periodicals, Inc.
Mutagenesis studies of the β I domain metal ion binding sites on integrin αVβ3 ligand binding affinity
Authors: Raborn Joel , Luo Bing‐Hao
Published: November 2011

Three divalent cation binding sites in the integrin β I domain have been shown to regulate ligand binding and adhesion. However, the degree of ligand binding and adhesion varies among integrins. The αLβ2 and α4β7 integrins show an increase in ligand binding affinity and adhesion when one of their ADMIDAS (adjacent to MIDAS, or the metal ion‐dependent adhesion site) residues is mutated. By contrast, the α2β1, α5β1, and αIIbβ3 integrins show a decrease in binding affinity and adhesion when their ADMIDAS is mutated. Our study here indicated that integrin αVβ3 had lower affinity when the ADMIDAS was mutated. By comparing the primary sequences of these integrin subunits, we propose that one residue associated with the MIDAS (β3 Ala252) may account for these differences. In the β1 integrin subunit, the corresponding residue is also Ala, whereas in both β2 and β7 integrin subunits, it is Asp. We mutated the β3 residue Ala252 to Asp and combined this mutant with mutations of one or two ADMIDAS residues. The mutant A252D showed reduced ligand binding affinity and adhesion. The ligand binding affinity and adhesion were increased when this A252D mutant was paired with mutations of one ADMIDAS residue. But when paired with mutations of two ADMIDAS residues the mutant nearly abolished ligand‐binding ability, which was restored by the activating glycosylation mutation. Our study suggests that the variation of this residue contributes to the different ligand binding affinities and adhesion abilities among different integrin families. J. Cell. Biochem. 113: 1190–1197, 2012. © 2011 Wiley Periodicals, Inc.
Cartilage oligomeric matrix protein enhances matrix assembly during chondrogenesis of human mesenchymal stem cells
Authors: Haleem‐Smith Hana , Calderon Raul , Song Yingjie , Tuan Rocky S. , Chen Faye H.
Published: November 2011

Cartilage oligomeric matrix protein/thrombospondin‐5 (COMP/TSP5) is an abundant cartilage extracellular matrix (ECM) protein that interacts with major cartilage ECM components, including aggrecan and collagens. To test our hypothesis that COMP/TSP5 functions in the assembly of the ECM during cartilage morphogenesis, we have employed mesenchymal stem cell (MSC) chondrogenesis in vitro as a model to examine the effects of COMP over‐expression on neo‐cartilage formation. Human bone marrow‐derived MSCs were transfected with either full‐length COMP cDNA or control plasmid, followed by chondrogenic induction in three‐dimensional pellet or alginate hydrogel culture. MSC chondrogenesis and ECM production was estimated based on quantitation of sulfated glycosaminoglycan (sGAG) accumulation, immunohistochemistry of the presence and distribution of cartilage ECM proteins, and real‐time RT‐PCR analyis of mRNA expression of cartilage markers. Our results showed that COMP over‐expression resulted in increased total sGAG content during the early phase of MSC chondrogenesis, and increased immuno‐detectable levels of aggrecan and collagen type II in the ECM of COMP‐transfected pellet and alginate cultures, indicating more abundant cartilaginous matrix. COMP transfection did not significantly increase the transcript levels of the early chondrogenic marker, Sox9, or aggrecan, suggesting that enhancement of MSC cartilage ECM was effected at post‐transcriptional levels. These findings strongly suggest that COMP functions in mesenchymal chondrogenesis by enhancing cartilage ECM organization and assembly. The action of COMP is most likely mediated not via direct changes in cartilage matrix gene expression but via interactions of COMP with other cartilage ECM proteins, such as aggrecan and collagens, that result in enhanced assembly and retention. J. Cell. Biochem. 113: 1245–1252, 2012. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.
Six common errors cause dangerous mistakes in interpretation of electron micrographs
Authors: Moradi Iman , Behjati Mohaddeseh
Published: November 2011

The highly complex techniques of electron microscopy made it bound to the sensitive and critical micrograph analysis. The accurately interpreted micrographs are of paramount values in basic investigations. Interpretation skills and quality of the micrographs are the two fundamental keys in accomplishment of these goals but there are many mistakes and errors that can happen during the sample preparation, sectioning, EM operation, and photo publishing. The mentioned mistakes and errors effect directly in the final result which is a micrograph and can lead the analyzer who can be a pathologist to an interpretation followed by serious danger for patient. Artifacts caused by any given stimuli expected to be bothersome for investigators. Even best qualified equipments can be regarded as source of artifact generation. In this article, seven serious errors in electron micrographs which usually occur in transmission electron microscopy are addressed. Microsc. Res. Tech., 2012. © 2011 Wiley Periodicals, Inc.