bluuebunny/crossref_metadata_2025 huggingface dataset:
Ursodeoxycholyl lysophosphatidylethanolamide improves steatosis and inflammation in murine models of nonalcoholic fatty liver disease
Authors: Pathil Anita , Mueller Jan , Warth Arne , Chamulitrat Walee , Stremmel Wolfgang
Published: December 2011

Hepatic fat accumulation and changes in lipid composition are hallmarks of nonalcoholic fatty liver disease (NAFLD). As an experimental approach for treatment of NAFLD, we synthesized the bile acid–phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE). Previous work demonstrated profound hepatoprotective properties of the conjugate

in vitro

and

in vivo

. Here we investigated the effects of UDCA-LPE in two nutritional mouse models of NAFLD. C57BL/6 mice were fed a high-fat diet (HFD) for 28 weeks, resulting in steatosis with hyperlipidemia. In a second model, mice received a methionin–choline-deficient (MCD) diet for up to 11 weeks, which induced advanced nonalcoholic steatohepatitis (NASH). Establishment of liver injury was followed by intraperitoneal injections of 30 mg/kg UDCA-LPE three times a week for different time periods. UDCA-LPE ameliorated both HFD- and MCD-induced increases in alanine aminotransferase (ALT) values near to normalization. As for metabolic parameters, UDCA-LPE reduced elevated serum triglyceride and cholesterol values in HFD mice. Liver histology showed improvement of steatosis in HFD and MCD mice concomitant with reductions in hepatic triglyceride and cholesterol levels. Additionally, the conjugate lowered serum caspase-8 activity in both models and decreased lipid hydroperoxides in MCD mice. Abundance of proinflammatory lysophosphatidylcholine (LPC), which was detectable in both HFD and MCD mice, was reduced by UDCA-LPE. Quantitative reverse transcriptase-polymerase chain reaction qRT-PCR of liver specimens revealed that UDCA-LPE strongly down-regulated inflammatory genes and modified the expression of genes involved in lipid metabolism.

Conclusion:

The current study demonstrates that UDCA-LPE improves hepatic injury at different stages of NAFLD. By concurrently lowering hepatic lipid overloading as well as susceptibility of hepatocytes toward inflammatory stimuli, the conjugate may be able to ameliorate disease progression. Thus, UDCA-LPE represents a promising compound suitable for the treatment of NAFLD. (Hepatology 2012 )
A cell-permeable hairpin peptide inhibits hepatitis C viral nonstructural protein 5A–mediated translation and virus production
Authors: Khachatoorian Ronik , Arumugaswami Vaithilingaraja , Ruchala Piotr , Raychaudhuri Santanu , Maloney Eden M. , Miao Edna , Dasgupta Asim , French Samuel W.
Published: December 2011

NS5A is a key regulator of the hepatitis C virus (HCV) life cycle including RNA replication, assembly, and translation. We and others have shown that NS5A augments HCV internal ribosomal entry site (IRES)-mediated translation. Furthermore, Quercetin treatment and heat shock protein (HSP) 70 knockdown inhibit the NS5A-driven augmentation of IRES-mediated translation and infectious virus production. We have also coimmunoprecipitated HSP70 with NS5A and demonstrated cellular colocalization, leading to the hypothesis that the NS5A/HSP70 complex formation is important for IRES-mediated translation. Here, we have identified the NS5A region responsible for complex formation through

in vitro

deletion analyses. Deletion of NS5A domains II and III failed to reduce HSP70 binding, whereas domain I deletion eliminated complex formation. NS5A domain I alone also bound HSP70. Deletion mapping of domain I identified the C-terminal 34 amino acids (C34) as the interaction site. Furthermore, addition of C34 to domains II and III restored complex formation. C34 expression significantly reduced intracellular viral protein levels, in contrast to same-size control peptides from other NS5A domains. C34 also competitively inhibited NS5A-augmented IRES-mediated translation, whereas controls did not. Triple-alanine scan mutagenesis determined that an exposed beta-sheet hairpin in C34 was primarily responsible for NS5A-augmented IRES-mediated translation. Moreover, treatment with a 10–amino acid peptide derivative of C34 suppressed NS5A-augmented IRES-mediated translation and significantly inhibited intracellular viral protein synthesis, with no associated cytotoxicity.

Conclusion:

These results support the hypothesis that the NS5A/HSP70 complex augments viral IRES-mediated translation, identify a sequence-specific hairpin element in NS5A responsible for complex formation, and demonstrate the functional significance of C34 hairpin–mediated NS5A/HSP70 interaction. Identification of this element may allow for further interrogation of NS5A-mediated IRES activity, sequence-specific HSP recognition, and rational drug design.
Probability of C282Y homozygosity decreases as liver transaminase activities increase in participants with hyperferritinemia in the hemochromatosis and iron overload screening study
Authors: Adams Paul C. , Speechley Mark , Barton James C. , McLaren Christine E. , McLaren Gordon D. , Eckfeldt John H.
Published: December 2011

Hemochromatosis is considered by many to be an uncommon disorder, although the prevalence of

HFE
(
High

Iron) 282 Cys → Tyr (C282Y) homozygosity is relatively high in Caucasians. Liver disease is one of the most consistent findings in advanced iron overload resulting from hemochromatosis. Liver clinics are often thought to be ideal venues for diagnosis of hemochromatosis, but diagnosis rates are often low. The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 99,711 primary care participants in North America for iron overload using serum ferritin and transferrin saturation measurements and

HFE

genotyping. In this HEIRS substudy, serum hepatic transaminases activities (e.g., alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) were compared between 162 C282Y homozygotes and 1,367 nonhomozygotes with serum ferritin levels >300 μg/L in men and >200 μg/L in women and transferrin saturation >45% in women and 50% in men. The probability of being a C282Y homozygote was determined for AST and ALT ranges. Mean ALT and AST activities were significantly lower in C282Y homozygotes than nonhomozygotes. The probability of being a C282Y homozygote increased as the ALT and AST activities decreased.

Conclusion:

Patients with hyperferritinemia are more likely to be C282Y homozygotes if they have normal liver transaminase activities. This paradox could explain the low yields of hemochromatosis screening reported by some liver clinics.
Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease
Authors: Lomonaco Romina , Ortiz-Lopez Carolina , Orsak Beverly , Webb Amy , Hardies Jean , Darland Celia , Finch Joan , Gastaldelli Amalia , Harrison Stephen , Tio Fermin , Cusi Kenneth
Published: December 2011

The role of adipose tissue insulin resistance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains unclear. To evaluate this, we measured in 207 patients with NAFLD (age = 51 ± 1, body mass index = 34.1 ± 0.3 kg/m2) and 22 controls without NAFLD (no NAFLD) adipose tissue insulin resistance by means of a validated index (Adipo-IRi = plasma free fatty acids [FFA] x insulin [FPI] concentration) and as the suppression of plasma FFA during an oral glucose tolerance test and by a low-dose insulin infusion. We also explored the relationship between adipose tissue insulin resistance with metabolic and histological parameters by dividing them based on quartiles of adipose tissue insulin resistance (Adipo-IRi quartiles: Q1 = more sensitive; Q4 = more insulin resistant). Hepatic insulin resistance, measured as an index derived from endogenous glucose production x FPI (HIRi), and muscle insulin sensitivity, were assessed during a euglycemic insulin clamp with 3-[3H] glucose. Liver fat was measured by magnetic resonance imaging and spectroscopy, and a liver biopsy was performed to assess liver histology. Compared to patients without steatosis, patients with NAFLD were insulin resistant at the level of adipose tissue, liver, and skeletal muscle and had higher plasma aspartate aminotransferase and alanine aminotransferase, triglycerides, and lower high-density lipoprotein cholesterol and adiponectin levels (all

P

< 0.01). Metabolic parameters, hepatic insulin resistance, and liver fibrosis (but not necroinflammation) deteriorated as quartiles of adipose tissue insulin resistance worsened (all

P

< 0.01).

Conclusion :

Adipose tissue insulin resistance plays a key role in the development of metabolic and histological abnormalities of obese patients with NAFLD. Treatment strategies targeting adipose tissue insulin resistance (e.g., weight loss and thiazolidinediones) may be of value in this population. (Hepatology 2012)
Patient safety and reprocessing: A usability test of the endoscope reprocessing procedure
Authors: Jolly Jonathan D. , Hildebrand Emily A. , Branaghan Russell J. , Garland T. B. , Epstein Dana , Babcock‐Parziale Judith , Brown Victoria
Published: December 2011

When endoscopes are reprocessed correctly, endoscopy is a safe procedure. Recent incidents of insufficient reprocessing, however, have resulted in public concern. Results of a usability test of the reprocessing procedure identified that none of 24 users, naïve to the procedure, could reprocess endoscopes correctly, nor could they correctly complete any of the component tasks in the procedure. Five of the 76 subtasks were identified as particularly critical. These were 1) brushing the instrument channel, 2) attaching the channel plug and injection tube, 3) identifying leaks, 4) blowing water out of the endoscope's internal channels during high‐level disinfection, and 5) aspirating solution through the endoscope to remove debris loosened by brushing. Additionally, three themes were identified as causes of the majority of problems: 1) lack of visibility, 2) high memory demands, and 3) insufficient user feedback. Design recommendations for these problems are discussed. © 2011 Wiley Periodicals, Inc.
Assessment of future stream flow over the Sesan catchment of the Lower Mekong Basin in Vietnam
Authors: Raghavan Srivatsan V. , Vu Minh Tue , Liong Shie‐Yui
Published: December 2011

This study used a regional climate model, driven at a resolution of 30 km, to derive climate estimates that were used as input to a hydrological model to determine stream flow in a changing climate. This regional climate model output was derived using the Weather Research and Forecasting model, which was used to downscale the general circulation model ECHAM5 T63 under the A2 greenhouse gas emission scenario for the future. Two river basins, Dakbla and Poko, over the Sesan catchment of the Lower Mekong region were considered for runoff modeling. A 10‐year climatology of the recent past, 1991–2000, was used as the baseline for the present‐day climate, and another 10‐year climate over the period 2091–2100 was chosen for the future time slice. The results from the simulation of future stream flow indicate that, over both Dakbla and Poko river basins, the stream flow is likely to increase, especially during the peak rainfall season. The Dakbla River Basin shows a substantial increase in stream flow when compared with the Poko River Basin. Copyright © 2011 John Wiley & Sons, Ltd.
A synthetic compound, 1,5‐bis(2‐methoxyphenyl)penta‐ 1,4‐dien‐3‐one (B63), induces apoptosis and activates endoplasmic reticulum stress in non‐small cell lung cancer cells
Authors: Xiao Jian , Wang Yi , Peng Jing , Guo Lu , Hu Jie , Cao Menghua , Zhang Xie , Zhang Hanqing , Wang Zhouguang , Li Xiaokun , Yang Shulin , Yang Huiling , Liang Guang
Published: December 2011

Endoplasmic reticulum (ER) stress‐induced cancer cell apoptosis has become a novel signaling target for the development of therapeutic drugs for cancer treatment. Curcumin, a dietary phytochemical, exhibits growth‐suppressive activity against cancer cells via multitarget mechanisms. However, the low stability and poor pharmacokinetics significantly limit its clinical applications. Thus, we designed and synthesized a novel monocarbonyl analog of curcumin, 1,5‐bis(2‐methoxyphenyl) penta‐1,4‐dien‐3‐one (B63). This compound exhibited a higher chemical stability in cultural medium and a better intracellular profile than curcumin. Treatment with B63 potently induced apoptosis of human non‐small cell lung cancer (NSCLC) cells in a dose‐responsive manner, while exhibiting no cytotoxicity in normal lung fibroblast cells. Its antitumor effect was associated with the ER stress‐mediated apoptotic pathway and, ultimately, the activation of the caspase cascades. However, curcumin at the same concentrations did not cause ER stress in H460 cells. Further, C/EBP homologous protein knockdown by siRNA attenuated B63‐induced cell apoptosis, indicating that the apoptotic pathway is ER stress‐dependent. In vivo, the volume and weight of the tumor were reduced significantly by pretreating the H460 tumor cells with B63 before implantation. Taken together, these insights on the novel compound B63, from both chemical and biological perspectives, may provide a novel anticancer candidate for the treatment of NSCLC.
Coffee consumption and risk of endometrial cancer: Findings from a large up‐to‐date meta‐analysis
Authors: Je Youjin , Giovannucci Edward
Published: December 2011

Several epidemiological studies have examined the association between coffee drinking and risk of endometrial cancer. To provide a quantitative assessment of this association, we conducted a meta‐analysis of observational studies published up to October 2011 through a search of MEDLINE and EMBASE databases and the reference lists of retrieved article. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random‐effects model, and generalized least square trend estimation was used to assess dose–response relationships. A total of 16 studies (10 case–control and six cohort studies) on coffee intake with 6,628 endometrial cancer cases were included in the meta‐analysis. The pooled RR of endometrial cancer for the highest versus lowest categories of coffee intake was 0.71 (95% CI: 0.62–0.81; p for heterogeneity = 0.13). By study design, the pooled RRs were 0.69 (95% CI: 0.55–0.87) for case–control studies and 0.70 (95% CI: 0.61–0.80) for cohort studies. By geographic region, the inverse association was stronger for three Japanese studies (pooled RR = 0.40; 95% CI: 0.25–0.63) than five studies from USA/Canada (pooled RR = 0.69; 95% CI: 0.60–0.79) or eight studies from Europe (pooled RR = 0.79; 95% CI: 0.63–0.99). An increment of one cup per day of coffee intake conferred a pooled RR of 0.92 (95% CI: 0.90–0.95). In conclusion, our findings suggest that increased coffee intake is associated with a reduced risk of endometrial cancer, consistently observed for cohort and case–control studies. More large studies are needed to determine subgroups to obtain more benefits from coffee drinking in relation to endometrial cancer risk.
Epicatechin‐rich cocoa polyphenol inhibits Kras‐activated pancreatic ductal carcinoma cell growth in vitro and in a mouse model
Authors: Siddique Hifzur Rahman , Liao D. Joshua , Mishra Shrawan Kumar , Schuster Todd , Wang Lei , Matter Brock , Campbell Paul M. , Villalta Peter , Nanda Sanjeev , Deng Yibin , Saleem Mohammad
Published: December 2011

Activated Kras gene coupled with activation of Akt and nuclear factor‐kappa B (NF‐κB) triggers the development of pancreatic intraepithelial neoplasia, the precursor lesion for pancreatic ductal adenocarcinoma (PDAC) in humans. Therefore, intervention at premalignant stage of disease is considered as an ideal strategy to delay the tumor development. Pancreatic malignant tumor cell lines are widely used; however, there are not relevant cell‐based models representing premalignant stages of PDAC to test intervention agents. By employing a novel Kras‐driven cell‐based model representing premalignant and malignant stages of PDAC, we investigated the efficacy of ACTICOA‐grade cocoa polyphenol (CP) as a potent chemopreventive agent under in vitro and in vivo conditions. It is noteworthy that several human intervention/clinical trials have successfully established the pharmacological benefits of cocoa‐based foods. The liquid chromatography (LC)–mass spectrometry (MS)/MS data confirmed epicatechin as the major polyphenol of CP. Normal, nontumorigenic and tumorigenic pancreatic ductal epithelial (PDE) cells (exhibiting varying Kras activity) were treated with CP and epicatechin. CP and epicatechin treatments induced no effect on normal PDE cells, however, caused a decrease in the (i) proliferation, (ii) guanosine triphosphate (GTP)‐bound Ras protein, (iii) Akt phosphorylation and (iv) NF‐κB transcriptional activity of premalignant and malignant Kras‐activated PDE cells. Further, oral administration of CP (25 mg/kg) inhibited the growth of Kras‐PDE cell‐originated tumors in a xenograft mouse model. LC–MS/MS analysis of the blood showed epicatechin to be bioavailable to mice after CP consumption. We suggest that (i) Kras‐driven cell‐based model is an excellent model for testing intervention agents and (ii) CP is a promising chemopreventive agent for inhibiting PDAC development.
Tumor‐induced changes in the phenotype of blood‐derived and tumor‐associated T cells of early stage breast cancer patients
Authors: Poschke I. , De Boniface J. , Mao Y. , Kiessling R.
Published: December 2011

Tumor‐induced immune suppression has mainly been studied in patients with advanced cancer. Despite the fact that they are most likely to benefit from immunotherapy, patients with early stage cancers were under‐represented in these studies. We analyzed blood and tumor‐derived T cells from patients with stage 1 (n = 20), stage 2 (n = 23) or stage 3 (n = 1) breast cancer and found that, even early stage tumors induced T cell differentiation. Breast cancer patients had significantly more circulating CD8+ memory and fewer CD8+ naïve T cells than healthy controls (n = 10). Up‐regulation of CD69 and PD1 on cancer patient T cells suggests previous activation, and increased expression of the chemokine receptors CCR5 and CXCR3 on CD8+ T cells indicates that their homing capacity differs from that of healthy individuals. Comparison of blood‐derived and tumor‐associated T cells from patients with different metastatic status and tumor grades revealed that tumor progression and aggressiveness seem to favor the expansion of memory T cells over naive T cells. We have previously shown that immunosuppression in this patient population is stronger in the tumor than in the blood. Here, we report signs of exhaustion, such as loss of CD28, on tumor‐associated as compared to blood‐derived CD8+ T cells, despite the fact that tumor‐associated T cells are predominantly effector memory cells and express high levels of CD69. The finding that the presence of a tumor potentially induces immunosenescence early during tumorigenesis indicates that efficient immunotherapy might be difficult even in patients with early stage cancer due to T cell exhaustion and tolerance.
Quasicrystal as a Reinforcement Material in Magnesium Alloys
Authors: Chang Hye Jung , Kim Won Tae , Kim Do Hyang
Published: December 2011

The existence of the two‐phase region (icosahedral phase (I‐phase) + α‐Mg) in the Mg‐rich corner of the Mg‐Zn‐Y system indicates that composites consisting of I‐phase and ductile α‐Mg can be fabricated by a simple solidification process. Alloys with a range of combined strength and ductility can be designed by changing the fraction of the I‐phase. Strengthening in proportion with increasing the volume fraction of I‐phase can be explained by the effect of dispersion hardening due to the presence of finely dispersed I‐phase particles. When quasicrystals exist in the α‐Mg matrix as a second phase in Mg‐Zn‐Y alloys, the quasicrystals are stable against coarsening during thermomechanical processes such as hot rolling and high‐temperature forming, due to the low interfacial energy of the quasicrystals with the α‐Mg crystalline matrix, which provides strong bonding properties at the I‐phase/matrix interface. Therefore, quasicrystal‐reinforced Mg‐Zn‐Y alloys exhibit a much better combination of mechanical properties and formability than commercially used alloys such as AZ31 and AZ 61.
OBSERVATIONS OF SALINITY PATTERNS IN SHALLOW GROUNDWATER AND DRAINAGE WATER FROM AGRICULTURAL LAND IN THE NORTHERN PART OF THE NETHERLANDS
Authors: Velstra J. , Groen J. , De Jong K.
Published: December 2011

In studies concerning rainwater lenses on a parcel scale in brackish polder areas it is assumed that infiltrated rainwater flows through the rainwater lens and seeps to the watercourses. This freshwater system is supposed to be superimposed on the brackish diffuse upward seepage system. This study investigates the influence of field drainage on the dynamic behaviour of fresh rainwater lenses and the risk of salinization of the root zone. Observations presented in this paper show that shallow water and salt movements in clayey polders are more complex and more dynamic than previously thought.

On 18 parcels 2D geo‐electrical resistivity imaging profiles were measured, which give a good spatial and temporal representation of the salinity distribution of the groundwater. It appears that during wet periods upconing of brackish groundwater appears under pipe drains and ditches, which drain a mixture of fresh meteoric water and deep brackish groundwater. Between drainpipes small rainwater lenses develop. During the dry season, when the groundwater table drops below the drainage level, brackish soil moisture stays behind. Transpiration of the crops rooted in the clayey polder soils result in strong capillary rise of salts, which may even reach the root zone in some places. Copyright © 2011 John Wiley & Sons, Ltd.
Tyrosine phosphorylation and liver regeneration: A glance at intracellular transducers
Authors: Pagano Mario Angelo , Tibaldi Elena , Gringeri Enrico , Brunati Anna Maria
Published: December 2011

Liver regeneration (LR) is a compensatory growth that occurs in response to resection or injury of the liver aimed at restoring the liver mass and maintaining body homeostasis. The activation of intracellular signaling pathways due to extracellular stimuli mainly reflects a highly coordinated spatial and temporal organization of phosphotyrosine‐based signals generated by the concerted action of three basic functional modules, namely protein tyrosine kinases, protein tyrosine phosphatases, and the Src homology 2 (SH2) domain. In this review, we have selected a set of signaling proteins downstream of activated cytokine and growth factor receptors that highlight the multifaceted aspects of tyrosine phosphorylation with their impact on the course of LR. Besides being a process of remarkable biological interest, LR has recently emerged as a model for dissecting molecular mechanisms underlying diverse pathophysiological states, offering new perspectives in primarily, but not only, managing life‐threatening liver diseases. © 2011 IUBMB IUBMB Life, 2011
Devastation of adult stem cell pools by irradiation precedes collapse of trabecular bone quality and quantity
Authors: Green Danielle E , Adler Benjamin J , Chan Meilin E , Rubin Clinton T
Published: December 2011

Stem cell depletion and compromised bone marrow resulting from radiation exposure fosters long-term deterioration of numerous physiologic systems, with the degradation of the skeletal system ultimately increasing the risk of fractures. To study the interrelationship of damaged bone marrow cell populations with trabecular microarchitecture, 8- and 16-week-old C57BL/6 male mice were sublethally irradiated with 5 Gy of 137Cs γ-rays, and adult stem cells residing in the bone marrow, as well as bone quantity and quality, were evaluated in the proximal tibia after 2 days, 10 days, and 8 weeks compared with age-matched controls. Total extracted bone marrow cells in the irradiated 8-week, young adult mice, including the hematopoietic cell niches, collapsed by 65% ± 11% after 2 days, remaining at those levels through 10 days, only recovering to age-matched control levels by 8 weeks. As early as 10 days, double-labeled surface was undetectable in the irradiated group, paralleled by a 41% ± 12% and 33% ± 4% decline in bone volume fraction (BV/TV) and trabecular number (Tb.N), respectively, and a 50% ± 10% increase in trabecular separation (Tb.Sp) compared with the age-matched controls, a compromised structure that persisted to 8 weeks postirradiation. Although the overall collapse of the bone marrow population and devastation of bone quality was similar between the “young adult” and “mature” mice, the impact of irradiation—and the speed of recovery—on specific hematopoietic subpopulations was dependent on age, with the older animals slower to restore key progenitor populations. These data indicate that, independent of animal age, complications arising from irradiation extend beyond the collapse of the stem cell population and extend toward damage to key organ systems. It is reasonable to presume that accelerating the recovery of these stem cell pools will enable the prompt repair of the skeletal system and ultimately reduce the susceptibility to fractures. © 2012 American Society for Bone and Mineral Research.
Thapsigargin down‐regulates protein levels of GRP78/BiP in INS‐1E cells
Authors: Rosengren Victoria , Johansson Henrik , Lehtiö Janne , Fransson Liselotte , Sjöholm Åke , Ortsäter Henrik
Published: December 2011

Pancreatic β‐cells have a well‐developed endoplasmic reticulum (ER) and express large amounts of chaperones and protein disulfide isomerases (PDI) to meet the high demand for synthesis of proteins. We have observed an unexpected decrease in chaperone protein level in the β‐cell model INS‐1E after exposure to the ER stress inducing agent thapsigargin. As these cells are a commonly used model for primary β‐cells and has been shown to be vulnerable to ER stress, we hypothesize these cells are incapable of mounting a chaperone defense upon activation of ER stress. To investigate the chaperone expression during an ER stress response, induced by thapsigargin in INS‐1E cells, we used quantitative mass spectrometry based proteomics. The results displayed a decrease of GRP78/BiP, PDIA3 and PDIA6. Decrease of GRP78/BiP was verified by Western blot and occurred in parallel with enhanced levels of p‐eIF2α and CHOP. In contrast to INS‐1E cells, GRP78/BiP was not decreased in MIN6 cell or rat and mouse islets after thapsigargin exposure. Investigation of the decreased protein levels of GRP78/BiP indicates that this is not a consequence of reduced mRNA expression. Rather the reduction results from the combined effect of reduced protein synthesis and enhanced proteosomal degradation and possibly also degradation via autophagy. Induction of ER stress with thapsigargin leads to lower protein levels of GRP78/BiP, PDIA3 and PDIA6 in INS‐1E cells which may contribute to the susceptibility of ER stress in this β‐cell model. J. Cell. Biochem. 113: 1635–1644, 2012. © 2011 Wiley Periodicals, Inc.
Umami taste receptor functions as an amino acid sensor via Gαs subunit in N1E‐115 neuroblastoma cells
Authors: Muroi Yoshikage , Ishii Toshiaki
Published: December 2011

The sensing of the nutritional level of the body fluid is pivotal for maintaining homeostasis in animals. However, it is not yet understood how the cells detect nutritional levels. In the present study, we examined the function of umami taste receptor, which has a dimeric protein structure composed of Tas1r1 and Tas1r3, as amino acid sensor in the cells. We found that deprivation of amino acids induced neurite outgrowth in N1E‐115 cells. The neurite outgrowth was inhibited by almost all of the amino acids tested. To investigate the involvement of the umami taste receptor, siRNA against each of Tas1r1 or Tas1r3 was administered, resulting in suppression of the inhibitory effects of amino acids on neurite outgrowth. In addition, inosine 5′‐monophosphate, which potentiates the response to amino acids in the taste cells, enhanced the inhibitory effect of glutamine on neurite outgrowth. These results suggest that Tas1r1 + 3 functions as an amino acid sensor in N1E‐115 cells. Because glutamine increased intracellular cAMP concentration, we investigated the involvement of the Gαs subunit of the heterotrimeric G protein in signal transduction. The treatments to inhibit the Gαs subunit significantly suppressed the increase of intracellular cAMP concentration induced by glutamine and the inhibitory effect of amino acids on neurite outgrowth. In addition, the reagents for increasing intracellular cAMP concentration inhibited neurite outgrowth induced by deprivation of amino acids. We concluded that Tas1r1 + 3 functions as an amino acid sensor and activates the intracellular signaling pathway through the Gαs subunit in N1E‐115 cells. J. Cell. Biochem. 113: 1654–1662, 2012. © 2011 Wiley Periodicals, Inc.
The hydroxylation activity of Jmjd6 is required for its homo‐oligomerization
Authors: Han Gang , Li Jiajia , Wang Yiqin , Li Xia , Mao Hailei , Liu Yifan , Chen Charlie Degui
Published: December 2011

Jumonji C‐terminal (JmjC) domain‐containing proteins are protein hydroxylases and histone demethylases that control gene expression. Jumonji domain‐containing protein 6 (Jmjd6) is indispensable for embryonic development and has both histone arginine demethylase and lysyl‐hydroxylase activities. The protein undergoes post‐translational homo‐oligomerization, but the underlying mechanism remains unknown. In this study, we examined the enzymatic activity of Jmjd6 and uncovered the mechanism underlying its homo‐oligomerization. An in vitro enzymatic assay monitored by matrix‐assisted laser desorption‐ionization time‐of‐flight (MALDI‐TOF) mass spectrometry indicates that Jmjd6 is unable to remove the methyl group from histone arginine residues but can hydroxylate the histone H4 tail at lysine residues in a 2‐oxoglutarate (2‐OG)‐ and Fe (II)‐dependent manner. A mutational analysis reveals that the homo‐oligomerization of Jmjd6 requires its enzymatic activity and the N‐ and C‐termini. Using an in vitro enzymatic assay, we further demonstrate that Jmjd6 can hydroxylate its N‐terminus but not its C‐terminus. In summary, we did not detect arginine demethylase activity for Jmjd6, but we did confirm that it could catalyze the lysyl‐hydroxylation of histone peptides. In addition, we demonstrated that the homo‐oligomerization of Jmjd6 requires its own enzymatic activity and the N‐ and C‐termini. We propose that Jmjd6 forms intermolecular covalent bonds between its N‐ and C‐termini via autohydroxylation. J. Cell. Biochem. 113: 1663–1670, 2012. © 2011 Wiley Periodicals, Inc.
Novel synthesis of some new pyrimido[1,6‐a]pyrimidine and pyrazolo[1,5‐a]pyrimidine derivatives
Authors: Hussein Ahmed M.
Published: December 2011

An easy and efficient route for synthesis of some pyrimido[1,6‐a]pyrimidine and pyrazolo[1,5‐a]pyrimidine derivatives was described through the reaction of sodium salts of formyl ketones with 6‐aminothiouracil and 5‐aminopyrazole derivatives, respectively. The characterization of the reaction products was confirmed by using elemental analysis and spectral data. J. Heterocyclic Chem., (2012).
Experimental evidence that pristanic acid disrupts mitochondrial homeostasis in brain of young rats
Authors: Busanello Estela Natacha Brandt , Amaral Alexandre Umpierrez , Tonin Anelise Miotti , Grings Mateus , Moura Alana Pimentel , Eichler Paula , Vargas Carmen Regla , Wajner Moacir
Published: December 2011

Patients affected by peroxisomal disorders commonly present neurologic dysfunction and brain abnormalities, whose neuropathology is poorly understood. Given that high sustained concentrations of pristanic acid (Prist) are found in the brain of these patients, it is conceivable that this complex branched‐chain fatty acid is neurotoxic. Therefore, the present work investigated the in vitro effects of Prist at similar concentrations found in plasma of affected patients with some peroxisomal disorders on important parameters of energy homeostasis, including respiratory parameters determined by oxygen consumption, membrane potential (ΔΨm), NAD(P)H content, and swelling in mitochondrial preparations obtained from brain of young rats using glutamate plus malate or succinate as respiratory substrates. Prist markedly increased state 4 respiration and decreased state 3 respiration, the respiratory control ratio (RCR), and the ADP/O ratio with both substrates. The mitochondrial ΔΨm and the matrix NAD(P)H content were also decreased by Prist, which was also able to provoke mitochondrial swelling. Furthermore, Prist‐induced mitochondrial swelling was dependent on oxidative damage to the permeability transition pore (PTP), because cyclosporine A and the thiol‐reducing agent N‐acetylcysteine totally prevented mitochondrial swelling. These data suggest that Prist impairs mitochondrial homeostasis, acting as an uncoupler of oxidative phosphorylation and as a metabolic inhibitor, besides causing mitochondrial swelling probably mediated by the permeability transition pore. It is proposed that these pathomechanisms may potentially be involved in the neurological abnormalities characteristic of the peroxisomal diseases in which Prist accumulates. © 2011 Wiley Periodicals, Inc.
Epigenetic regulation of self‐renewal and fate determination in neural stem cells
Authors: Mohamed Ariff Iqbal , Mitra Arinjay , Basu Anirban
Published: December 2011

Differentiation and self‐renewal are two primary properties that characterize stem cells. Differentiation of neural stem/precursor cells (NSPCs) gives rise to multiple neural lineages, including neurons, astrocytes, and oligodendrocytes. Self‐renewal, by definition, signifies the progressive growth of cells, while preserving an undifferentiated state. A large number of interdependent factors, including transcription factors, epigenetic control, and micro‐RNA regulators, modulate these opposing processes without disrupting the regular neural network. The epigenetic modification of developmental genes, including alterations in DNA methylation, histone modifications, polycomb gene group and noncoding RNA expression, which are passed on through successive cell divisions, has proved to be one of the major mechanisms determining the fate of neural stem cells. Here, we review the diverse epigenetic pathways that decide whether NSPCs undergo proliferation or differentiation into different neuronal cell lineages. © 2011 Wiley Periodicals, Inc.
Voltage‐dependent ionic channels in differentiating neural precursor cells collected from adult mouse brains six hours post‐mortem
Authors: Bellardita Carmelo , Bolzoni Francesco , Sorosina Melissa , Marfia Giovanni , Carelli Stephana , Gorio Alfredo , Formenti Alessandro
Published: December 2011

A novel type of adult neural precursor cells (NPCs) has been isolated from the subventricular zone of the mouse 6 hr after animal death (T6‐NPCs). This condition is supposed to select hypoxia‐resistant cells of scientific and clinical interest. Ionic channels are ultimately the expression of the functional maturation of neurons, so the aim of this research was to characterize the pattern of the main voltage‐dependent ionic channels in T6‐NPCs differentiating to a neuronal phenotype, comparing it with NPCs isolated soon after death (T0‐NPCs). T6‐ and T0‐NPCs grow in medium containing epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). Differentiation was performed in small wells without the addition of growth factors, in the presence of adhesion molecules, fetal bovine serum, and leukemia inhibitory factor. Ionic currents, recorded by means of whole‐cell patch‐clamp, namely, ICa2+ HVA, both L‐ and non‐L‐type, IK+ delayed rectifying, IK+ inward rectifier, transient IK+A, and TTX‐sensitive INa+ have been found, although Na+ currents were found in only a small percentage of cells and after the fifth week of differentiation. No significant differences in current types, density, orcell capacitance were observed between T6‐NPCs and T0‐NPCs. The sequence in which the markers appear in new neural cells is not necessarily a fixed program, but the discrepancies in morphological, biochemical, and electrophysiological maturation of mouse NPCs to neurons, possibly different in vivo, suggest that the various steps of the differentiation are independently regulated. Therefore, in addition to morphological and biochemical data, functional tests should be considered for characterizing the maturation of neurons. © 2011 Wiley Periodicals, Inc.
Neoadjuvant chemotherapy with FOLFOX: Improved outcomes in Chinese patients with locally advanced gastric cancer
Authors: Li Zi‐Yu , Koh Cherry E. , Bu Zhao‐De , Wu Ai‐Wen , Zhang Lian‐Hai , Wu Xiao‐Jiang , Wu Qi , Zong Xiang‐Long , Ren Hui , Tang Lei , Zhang Xiao‐Peng , Li Ji‐You , Hu Ying , Shen Lin , Ji Jia‐Fu
Published: December 2011

Background

Although the role of peri‐operative chemotherapy is established in the treatment of locally advanced gastric cancer, the optimal regime remains to be determined. FOLFOX has been used in palliative setting with good response rates but its role in a neoadjuvant setting is not well established.

Methods

This is a prospective non‐randomized study comparing peri‐operative FOLFOX versus adjuvant FOLFOX in patients with resectable locally advanced gastric cancer. Response to chemotherapy was assessed according to WHO criteria and pathological changes. Kaplan–Meier log rank test was used to calculate and compare survival differences.

Results

There were 73 patients (neoadjuvant = 36). Complete and partial response was observed in 2 (6%) and 21 (64%) patients, respectively. Four‐year overall survival (OS) in the neoadjuvant arm was 78% versus 51% in the adjuvant arm (P = 0.031). Subgroup analysis found R0 resection (86% vs. 55%, P = 0.011) and patients with proximal cancers (87% vs. 14%, P < 0.001) to have improved OS. The most common side effect was grade 1–2 leukopenia. There were no grade 3 neuropathies, grade 4 cytopaenias, or treatment related deaths.

Conclusion

Peri‐operative treatment with FOLFOX shows promise in patients with resectable locally advanced gastric cancer. It warrants further evaluation and should be considered an alternative to peri‐operative ECF. J. Surg. Oncol. 2012; 105:793–799. © 2011 Wiley Periodicals, Inc.
The decision criterion of histological mixed type in “T1/T2” gastric carcinoma—comparison between TNM classification and Japanese classification of gastric cancer
Authors: Shimizu Hiroki , Ichikawa Daisuke , Komatsu Shuhei , Okamoto Kazuma , Shiozaki Atsushi , Fujiwara Hitoshi , Murayama Yasutoshi , Kuriu Yoshiaki , Ikoma Hisashi , Nakanishi Masayoshi , Ochiai Toshiya , Kokuba Yukihito , Kishimoto Mitsuo , Yanagisawa Akio , Otsuji Eigo
Published: December 2011

Background

This study was designed to evaluate the clinical significance of undifferentiated component in differentiated T1/T2 gastric adenocarcinoma.

Methods

Two hundred thirty‐one patients who underwent curative gastrectomy were diagnosed pathologically as differentiated type T1/T2 gastric cancer according to Japanese Classification of Gastric Carcinoma (JCGC). The patients were divided into subgroups, pure differentiated type (pure D group, 181 patients) and differentiated‐predominant mixed type (D > U group, 51 patients). The clinicopathological features of D > U group were compared with those of pure D group, and also those of undifferentiated‐predominant type (U > D group).

Results

Patients in D > U group were more likely to have larger and deeper tumors with lymphatic invasion and metastases than pure D group. However, there was no significant difference in clinicopathological factors between D > U and U > D groups, except for depth of tumor invasion. The postoperative 5‐year survival rate of D > U group was significantly poorer than that of pure D group (88% and 98%, P = 0.011). Multivariate analysis revealed the presence of undifferentiated component was an independent prognostic factor.

Conclusions

The presence of undifferentiated component in differentiated T1/T2 gastric cancer is associated with tumor progression. Therefore, the decision criterion of histological mixed type in TNM classification is better suited than JCGC in T1/T2 gastric cancer. J. Surg. Oncol. 2012; 105:800–804. © 2012 Wiley Periodicals, Inc.
Factors that Affect the Levels of Tourists' Satisfaction and Loyalty towards Food Festivals: a Case Study of Macau
Authors: Wan Yim King Penny , Chan Sow Hup Joanne
Published: December 2011

The present study investigates the factors that affect tourists' satisfaction towards food festivals and explores whether tourists intend to revisit and/or recommend food festivals to others. Based on personal interviews with 40 study subjects, eight factors that affect their satisfaction levels were identified: location and accessibility, food, venue facility, environment/ambiance, service, entertainment, timing and festival size. The majority of tourists were satisfied with the Macau Food Festival and intended to revisit and recommend it to others. The presented findings have practical implications for food festival organizers to further attract food tourists. Copyright © 2011 John Wiley & Sons, Ltd.
Zinc Ion Uniquely Induced Triple Shape Memory Effect of Dipole–Dipole Reinforced Ultra‐High Strength Hydrogels
Authors: Han Yanjiao , Bai Tao , Liu Yuan , Zhai Xinyun , Liu Wenguang
Published: December 2011

In this study, we demonstrate that dipole–dipole interaction can be employed to not only tremendously enhance the mechanical properties of hydrogel, but also impart the gel to an amazing ability to memorize two temporary shapes. Cross‐linked hydrogels synthesized by copolymerization of acrylonitrile, a dipole–dipole containing monomer and hydrophilic comonomer are shown to exhibit triple shape memory (SM) triggered by the dynamic association and dissociation of dipole–dipole pairing between cynao groups uniquely responding to zinc ion species and concentration. This approach contributes to design and fabrication of novel SM hydrogels in a distinct way from conventional SM materials.
In utero and postnatal exposure to isoflavones results in a reduced responsivity of the mammary gland towards estradiol
Authors: Molzberger Almut F. , Vollmer Günter , Hertrampf Torsten , Möller Frank Josef , Kulling Sabine , Diel Patrick
Published: December 2011

Scope Exposure scenarios during different stages of development of an organism are discussed to trigger adverse and beneficial effects of isoflavones (ISO). The aim of this study was to investigate how in utero and postnatal ISO exposure modulates the estrogen sensitivity of the mammary gland and to identify the underlying molecular mechanisms.

Methods and results Therefore, rats were exposed to either ISO‐free (IDD), ISO‐rich (IRD) or genistein‐rich diet (GRD), up to young adulthood. Proliferative activity (PCNA expression) in the mammary gland at different ages and the estrogen sensitivity of the mammary gland to estradiol (E2) or genistein (GEN) in adult ovariectomized animals was determined and compared with different treatments. Treatment with E2 resulted in a significant lower proliferative and estrogenic response of the mammary gland in IRD and GRD compared with IDD. This correlates to a change in the gene expression pattern and a decrease in the ratio of estrogen receptor alpha (ERα) beta (ERβ

Conclusions Our results provide evidence that in utero and postnatal exposure to a diet rich in ISO but also to GEN reduces the sensitivity of the mammary gland toward estrogens and support the hypothesis that in utero and postnatal ISO exposure reduces the risk to develop breast cancer.
Patient Satisfaction with Postoperative Follow‐up by a Hand Therapist
Authors: Elnikety Sherif , El‐Husseiny Moataz , Kamal Tamer , Talawadekar Gautam D. , Richards Hayley , Smith Andrew M.
Published: December 2011

Purpose

There has been a move to reduce and, indeed, stop postoperative appointments for uncomplicated surgical procedures within the National Health Service. The purpose of this study was to measure patient satisfaction with postoperative follow‐up conducted by a hand therapist, with no routine postoperative follow‐up by the surgeon.

Methods

A total of 124 patients were recruited over two years. Fifty patients post‐simple trapeziectomy and 74 patients post‐single‐digit Dupuytren's fasciectomy were prospectively surveyed for their opinion on their postoperative care and whether or not they would have liked to be reviewed by the surgeon in a routine postoperative follow‐up appointment. All patients included in this study had their operations performed by one surgeon in one hospital. All patients were reviewed by a hand therapist within two weeks of surgery.

Results

A total of 116 patients completed the study, of whom 106 patients (91%) were satisfied with their postoperative management and 99 patients (85%) did not want to be reviewed by the surgeon in a postoperative outpatient follow‐up appointment.

Discussion

This study reflects the successful application of postoperative follow‐up by a hand therapist. Copyright © 2011 John Wiley & Sons, Ltd.
Racial differences in female urethral morphology and levator hiatal dimensions: An ultrasound study
Authors: Derpapas Alexandros , Ahmed Shahla , Vijaya Gopalan , Digesu Giuseppe Alessandro , Regan Lesley , Fernando Ruwan , Khullar Vik
Published: December 2011

Aim

To compare the urethral sphincter morphology and levator hiatal dimensions between white and black premenopausal nulliparous asymptomatic women using 3D/4D translabial ultrasonography.

Methods

Nulliparous black and white women were recruited in a tertiary gynecological center. All women were completely asymptomatic for pelvic floor dysfunction. Women were assessed with 3D/4D translabial ultrasound scan of the pelvic floor, at rest. Measurements of the total urethral sphincter volume (TSV), rhabdosphincter volume, (RSV) and levator hiatal dimensions (LH) were taken at rest, after voiding.

Results

Twenty‐three white and 14 black women (37 in total) were investigated. Subjects did not differ by age or body mass index (BMI). Black women were found to have significantly larger rhabdosphincters (RS) than their white counterparts (8.88 cm3 ± 1.65 vs. 5.97 cm3 ± 1.82, respectively, P = 0.000). With respect to levator hiatal dimensions at rest, black women had a significantly wider transverse diameter (LHt) than white women (mean difference of LHt = 0.43 cm, 95% CI 0.08–0.78, P < 0.05).

Conclusions

Asymptomatic black nulliparous women have significantly larger rhabdosphincters than their white counterparts. Racial differences in the female urethral morphology could provide an insight on the pathophysiology of stress urinary incontinence. Neurourol. Urodynam. 31:502–507, 2012. © 2011 Wiley Periodicals, Inc.
Improving volunteer retention efforts in public library systems: how communication and inclusion impact female and male volunteers differently
Authors: Waters Richard D. , Bortree Denise Sevick
Published: December 2011

Although volunteer levels are near all‐time highs, volunteer coordinators are increasingly spending more time on retention efforts. The purpose of this study is to measure the impact of organizational communication and inclusive behaviors on volunteers' intention to continue volunteering. Through a survey of 472 volunteers in three library systems, research revealed that two organizational communication theories can improve the effectiveness of volunteer coordinator efforts. Specifically, structural equation modeling revealed that social group inclusion and overall participation in organizational events were the strongest predictors of female volunteers' future intentions to volunteer whereas event participation, being included in the organization's information network, and participating in decision making were the strongest predictors for male volunteers. Relationship indicators successfully predicted which volunteers were most likely to continue volunteering. Copyright © 2011 John Wiley & Sons, Ltd.