bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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

ObjectiveThere 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.MethodsIn 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.ResultsCompared 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.ConclusionsSupplementation 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

AbstractTo 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

AbstractFor 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

AbstractIn 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

AbstractFrom 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

ABSTRACTThe 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

Abstract
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 &lt; 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 &lt; 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

Abstract
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

Abstract
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

AbstractGlutamate 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

AbstractThree 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.