bluuebunny/crossref_metadata_2025 huggingface dataset:
All-trans-Retinoic Acid Ameliorates Hepatic Steatosis in Mice by a Novel Transcriptional Cascade
Authors: Kim Seong Chul , Kim Chun-Ki , Axe David , Cook Aaron , Lee Mikang , Li Tiangang , Smallwood Nicole , Chiang John Y.L. , Hardwick James P. , Moore David D. , Lee Yoon Kwang
Published: August 2013

Mice deficient in small heterodimer partner (SHP) are protected from diet-induced hepatic steatosis resulting from increased fatty acid oxidation and decreased lipogenesis. The decreased lipogenesis appears to be a direct consequence of very low expression of peroxisome proliferator-activated receptor gamma 2 (PPAR-γ2), a potent lipogenic transcription factor, in the SHP−/− liver. The current study focused on the identification of a SHP-dependent regulatory cascade that controls PPAR-γ2 gene expression, thereby regulating hepatic fat accumulation. Illumina BeadChip array (Illumina, Inc., San Diego, CA) and real-time polymerase chain reaction were used to identify genes responsible for the linkage between SHP and PPAR-γ2 using hepatic RNAs isolated from SHP−/− and SHP-overexpressing mice. The initial efforts identify that hairy and enhancer of split 6 (Hes6), a novel transcriptional repressor, is an important mediator of the regulation of PPAR-γ2 transcription by SHP. The Hes6 promoter is specifically activated by the retinoic acid receptor (RAR) in response to its natural agonist ligand, all-trans retinoic acid (atRA), and is repressed by SHP. Hes6 subsequently represses hepatocyte nuclear factor 4 alpha (HNF-4α)-activated PPAR-γ2 gene expression by direct inhibition of HNF-4α transcriptional activity. Furthermore, we provide evidences that atRA treatment or adenovirus-mediated RAR-α overexpression significantly reduced hepatic fat accumulation in obese mouse models, as observed in earlier studies, and the beneficial effect is achieved by the proposed transcriptional cascade.

Conclusions :

Our study describes a novel transcriptional regulatory cascade controlling hepatic lipid metabolism that identifies retinoic acid signaling as a new therapeutic approach to nonalcoholic fatty liver diseases. (Hepatology 2014;59:1750–1760)
Indocyanine Green Retention Test as a Noninvasive Marker of Portal Hypertension and Esophageal Varices in Compensated Liver Cirrhosis
Authors: Lisotti Andrea , Azzaroli Francesco , Buonfiglioli Federica , Montagnani Marco , Cecinato Paolo , Turco Laura , Calvanese Claudio , Simoni Patrizia , Guardigli Massimo , Arena Rosario , Cucchetti Alessandro , Colecchia Antonio , Festi Davide , Golfieri Rita , Mazzella Giuseppe
Published: August 2013

Noninvasive markers would be useful for the assessment of portal hypertension (PH) and esophageal varices (EV) in patients with cirrhosis. The aim of our study was to evaluate the performance of the indocyanine green (ICG) retention test as a noninvasive marker of PH and EV, measured against the gold standards (hepatic venous pressure gradient [HVPG] measurement and upper endoscopy). We prospectively enrolled patients with compensated cirrhosis referral to our unit. All patients underwent laboratory tests, abdominal ultrasound, upper gastrointestinal endoscopy, HVPG measurement, and the ICG 15-minute retention (ICG-r15) test. We evaluated the sensitivity and specificity of the ICG retention test and other noninvasive tools for the diagnosis of PH and EV. Ninety-six consecutive Child-Pugh A patients (67 male and 29 female; 60.3 ± 11.8 years of age) were enrolled. Seventy-four patients had clinically significant portal hypertension (CSPH), of whom 59 had severe portal hypertension (SPH). ICG-r15 and Lok index were independently related to the presence of both CSPH and SPH, whereas ICG-r15 and INR were related to EV. ICG-r15 values (<6.7% and <6.9%, respectively) were able to rule out the presence of CSPH and SPH (LR− 0.15 and 0.14); ICG-r15 <10% provided a 97.8% sensitivity (LR− 0.042) for the exclusion of EV and a 100% sensitivity (LR− 0.0) for large EV.

Conclusion

: The ICG-r15 test is an effective tool for assessment of PH in patients with compensated cirrhosis. Although this would not replace endoscopy, the ICG-r15 appears able to identify patients with advanced liver disease in which endoscopy is mandatory as well as rule out the presence of EV in patients with compensated cirrhosis. (Hepatology 2014;59:643–650)
CD8 T Cells Primed in the Gut-Associated Lymphoid Tissue Induce Immune-Mediated Cholangitis in Mice
Authors: Seidel Daniel , Eickmeier Ira , Kühl Anja A. , Hamann Alf , Loddenkemper Christoph , Schott Eckart
Published: August 2013

The pathogenesis of primary sclerosing cholangitis (PSC) remains poorly understood. Since PSC predominantly occurs in patients with inflammatory bowel disease, autoimmunity triggered by activated T cells migrating from the gut to the liver is a possible mechanism. We hypothesized that T cells primed in the gut-associated lymphoid tissue (GALT) by a specific antigen migrate to the liver and cause cholangitis when they recognize the same antigen on cholangiocytes. We induced ovalbumin-dependent colitis in mice that express ovalbumin in biliary epithelia (ASBT-OVA mice) and crossed ASBT-OVA mice with mice that express ovalbumin in enterocytes (iFABP-OVA mice). We analyzed T-cell activation in the GALT and crossreactivity to the same antigen in the liver as well as the effects of colitis

per se

on antigen-presentation and T-cell activation in the liver. Intrarectal application of ovalbumin followed by transfer of CD8 OT-I T cells led to antigen-dependent colitis. CD8 T cells primed in the GALT acquired effector function and the capability to migrate to the liver, where they caused cholangitis in a strictly antigen-dependent manner. Likewise, cholangitis developed in mice expressing ovalbumin simultaneously in biliary epithelia and enterocytes after transfer of OT-I T cells. Dextran sodium sulfate colitis led to increased levels of inflammatory cytokines in the portal venous blood, induced activation of resident liver dendritic cells, and promoted the induction of T-cell-dependent cholangitis.

Conclusion

: Our data strengthen the notion that immune-mediated cholangitis is caused by T cells primed in the GALT and provide the first link between colitis and cholangitis in an antigen-dependent mouse model. (Hepatology 2014;59:601–611)
Evaluation of Abdominal Ultrasonography Mass Screening for Hepatocellular Carcinoma in Taiwan
Authors: Yeh Yen-Po , Hu Tsung-Hui , Cho Po-Yuan , Chen Hsiu-Hsi , Yen Amy Ming-Fang , Chen Sam Li-Sheng , Chiu Sherry Yueh-Hsia , Fann Jean Ching-Yuan , Su Wei-Wen , Fang Yi-Jen , Chen Shih-Tien , San Hsiao-Ching , Chen Hung-Pin , Liao Chao-Sheng
Published: August 2013

Mass screening with abdominal ultrasonography (AUS) has been suggested as a tool to control adult hepatocellular carcinoma (HCC) in individuals, but its efficacy in reducing HCC mortality has never been demonstrated. This study aimed to assess the effectiveness of reducing HCC mortality by mass AUS screening for HCC based on a program designed and implemented in the Changhua Community-based Integrated Screening (CHCIS) program with an efficient invitation scheme guided by the risk score. We invited 11,114 (27.0%) of 41,219 eligible Taiwanese subjects between 45 and 69 years of age who resided in an HCC high-incidence area to attend a risk score-guided mass AUS screening between 2008 and 2010. The efficacy of reducing HCC mortality was estimated. Of the 8,962 AUS screening attendees (with an 80.6% attendance rate), a total of 16 confirmed HCC cases were identified through community-based ultrasonography screening. Among the 16 screen-detected HCC cases, only two died from HCC, indicating a favorable survival. The cumulative mortality due to HCC (per 100,000) was considerably lower in the invited AUS group (17.26) compared with the uninvited AUS group (42.87) and the historical control group (47.51), yielding age- and gender-adjusted relative mortality rates of 0.69 (95% confidence interval [CI]: 0.56-0.84) and 0.63 (95% CI: 0.52-0.77), respectively.

Conclusion :

The residents invited to community-based AUS screening for HCC, compared with those who were not invited, showed a reduction in HCC mortality by ˜31% among subjects aged 45-69 years who had not been included in the nationwide vaccination program against hepatitis B virus infection. (Hepatology 2014;59:1840–1849)
Ductular reaction in hereditary hemochromatosis: The link between hepatocyte senescence and fibrosis progression
Authors: Wood Marnie J. , Gadd Victoria L. , Powell Lawrie W. , Ramm Grant A. , Clouston Andrew D.
Published: August 2013

The development of portal fibrosis following the iron loading of hepatocytes is the first stage of fibrogenesis in hereditary hemochromatosis. In other chronic liver diseases it has been shown that a ductular reaction (DR) appears early, correlates with fibrosis progression, and is a consequence of activation of an alternative pathway of hepatocyte replication. This study was designed to investigate the presence of the DR in hemochromatosis and describe its associations. Liver biopsies from 63 C282Y homozygous patients were assessed for hepatic iron concentration (HIC) and graded for iron loading, fibrosis stage, steatosis, and inflammation. Immunostaining allowed quantification of the DR, hepatocyte senescence and proliferation, and analysis incorporated clinical data. Hepatocyte senescence was positively correlated with HIC, serum ferritin, and oxidative stress. A DR was demonstrated and occurred prior to histological fibrosis. HIC, age, hepatocyte senescence and proliferation, portal inflammation, and excessive alcohol consumption all had significant associations with the extent of the DR. In multivariate analysis, iron loading, hepatocyte replicative arrest, and portal inflammation remained independently and significantly associated with the DR. Of factors associated with fibrosis progression, the DR (odds ratio [OR] 10.86 P < 0.0001) and the presence of portal inflammation (OR 4.31, P = 0.028) remained significant after adjustment for cofactors. The extent of the DR regressed following therapeutic venesection. Conclusion: Iron loading of hepatocytes leads to impaired replication, stimulating the development of the DR in hemochromatosis and this correlates strongly with hepatic fibrosis. Portal inflammation occurs in hemochromatosis and is independently associated with the DR and fibrosis, and thus its role in this disease should be evaluated further. (HEPATOLOGY 2014;59:848–857)
Numerical Study of Heat and Mass Transfer MHD Viscous Flow Over a Moving Wedge in the Presence of Viscous Dissipation and Heat Source/Sink with Convective Boundary Condition
Authors: Ahmad Rashid , Khan Waqar Ahmed
Published: August 2013

In this article, the effects of viscous dissipation and internal heat generation/absorption on combined heat and mass transfer MHD viscous fluid flow over a moving wedge in the presence of mass suction/injection with the convective boundary condition are carried out numerically for the various values of dimensionless parameters. With the help of similarity transformation, the momentum, energy, and concentration equations are reduced to a set of dimensionless non‐linear ordinary differential equations. The significance of the dimensionless velocity, temperature, mass profiles, and their gradients are presented in graphical form. Three types of flows—particularly the flat plate, vertical wedge, and stagnation point flows—in favorable and unfavorable regimes are analyzed. The obtained results confirm that the flow field is substantially influenced by the magnetic, stretching/shrinking, pressure, Prandtl number, heat generation/dissipation, and mass suction/injection parameters. Current results indicate that stretching a wall boundary causes an increase in velocity, temperature, shear stress, temperature, and mass gradients while shrinking causes a decreasing trend with these profiles. The special modified form of the current problem is found to be in good agreement with the other published data. © 2013 Wiley Periodicals, Inc. Heat Trans Asian Res, 43(1): 17–38, 2014; Published online in Wiley Online Library (wileyonlinelibrary.com/journal/htj). DOI 10.1002/htj.21063
Enhanced suppressive capacity of tumor‐infiltrating myeloid‐derived suppressor cells compared with their peripheral counterparts
Authors: Maenhout Sarah K. , Van Lint Sandra , Emeagi Perpetua U. , Thielemans Kris , Aerts Joeri L.
Published: August 2013

Although the main site of action for myeloid‐derived suppressor cells (MDSCs) is most likely the tumor microenvironment, so far the study of these cells has been largely restricted to spleen‐derived MDSCs. In this study, we compared the suppressive capacity of splenic and tumor‐derived MDSCs in different subcutaneous mouse tumor models. We investigated which suppressive mechanisms were involved. Finally, we investigated whether MDSCs and regulatory T cells (Treg) cooperate in the suppression of T‐cell responses. In all models, splenic granulocytic MDSCs (grMDSC) strongly suppress CD4+ T‐cell proliferation while the suppressive effect on CD8+ T cells is less pronounced. Splenic monocytic MDSCs (moMDSC) have a lower suppressive capacity, compared to grMDSC, on both CD4+ and CD8+ T‐cell proliferation. Both grMDSC and moMDSC isolated from the tumor have a much stronger suppressive activity compared to MDSCs isolated from the spleen of tumor‐bearing mice, associated with a higher NO2− production by the tumor‐derived moMDSC and arginase activity for both subsets. The expression of CD80 is also elevated on tumor‐derived grMDSC compared with their peripheral counterparts. Direct contact with tumor cells is required for the upregulation of CD80 and CD80+ MDSCs are more suppressive than CD80− MDSCs. Coculture of Treg and MDSCs leads to a stronger suppression of CD8+ T‐cell proliferation compared to the suppression observed by Treg or MDSCs alone. Thus, we showed that tumor‐infiltrating MDSCs possess a stronger suppressive capacity than their peripheral counterparts and that various suppressive mechanisms account for this difference.
Lymphokine‐activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites
Authors: Jennings V.A. , Ilett E.J. , Scott K.J. , West E.J. , Vile R. , Pandha H. , Harrington K. , Young A. , Hall G.D. , Coffey M. , Selby P. , Errington‐Mais F. , Melcher A.A.
Published: August 2013

Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus‐induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine‐activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus‐loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand‐off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNɣ, IL‐12, IFNα and TNFα) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune‐mediated tumor cell killing.
Sleep duration and breast cancer risk: A meta‐analysis of observational studies
Authors: Qin Yingyi , Zhou Yuhao , Zhang Xiao , Wei Xin , He Jia
Published: August 2013

Studies on the association of short or long sleep duration with breast cancer risk have reported inconsistent results. We quantitatively assessed this association by conducting a meta‐analysis based on the evidence from observational studies. In April 2013, we performed electronic searches in PubMed, EmBase and the Cochrane Library to identify studies examining the effect of sleep duration on breast cancer incidence. The odds ratio (OR) was used to measure any such association in a random‐effects model. The analysis was further stratified by confounding factors that could bias the results. A total of six studies (two case–control and four cohort studies) involving 159,837 individuals were included in our meta‐analysis. Our study did not show an association between either short or long sleep duration and breast cancer risk (short sleep duration data: pooled OR = 1.01, 95% confidence interval (CI) = 0.90–1.14, p = 0.853; long sleep duration data: pooled OR = 0.95, 95% CI = 0.86–1.04, p = 0.251). Moreover, we did not identify any statistically significant association between sleep duration and breast cancer risk in all the subgroup analyses. In conclusion, our findings indicate that sleep duration has no effect on breast cancer risk.
Late morbidity leading to hospitalization among 5‐year survivors of young adult cancer: A report of the childhood, adolescent and young adult cancer survivors research program
Authors: Zhang Yang , Lorenzi Maria F. , Goddard Karen , Spinelli John J. , Gotay Carolyn , McBride Mary L.
Published: August 2013

To estimate the risk of late morbidity leading to hospitalization among young adult cancer 5‐year survivors compared to the general population and to examine the long‐term effects of demographic and disease‐related factors on late morbidity, a retrospective cohort of 902 five‐year survivors of young adult cancer diagnosed between 1981 and 1999 was identified from British Columbia (BC) Cancer Registry. A matched comparison group (N = 9020) was randomly selected from the provincial health insurance plan. All hospitalizations until the end of 2006 were determined from the BC health insurance plan hospitalization records. The Poisson regression model was used to estimate the rate ratios for late morbidity leading to hospitalization except pregnancy after adjusting for sociodemographic and clinical risk factors. Overall, 455 (50.4%) survivors and 3,419 (37.9%) individuals in the comparison group had at least one type of late morbidity leading to hospitalization. The adjusted risk of this morbidity for survivors was 1.4 times higher than for the comparison group (95% CI = 1.22–1.54). The highest risks were found for hospitalization due to blood disease (RR = 4.2; 95% CI = 1.98–8.78) and neoplasm (RR = 4.3; 95% CI = 3.41–5.33). Survivors with three treatment modalities had three‐fold higher risk of having any type of late morbidity (RR = 3.22; 95% CI = 2.09–4.94) than the comparators. These findings emphasize that young adult cancer survivors still have high risks of a wide range of late morbidities.
XPF protein levels determine sensitivity of malignant melanoma cells to oxaliplatin chemotherapy: Suitability as a biomarker for patient selection
Authors: Hatch Stephanie B. , Swift Lonnie P. , Caporali Simona , Carter Rebecca , Hill Esme J. , MacGregor Thomas P. , D'Atri Stefania , Middleton Mark R. , McHugh Peter J. , Sharma Ricky A.
Published: August 2013

As the options for systemic treatment of malignant melanoma (MM) increase, the need to develop biomarkers to identify patients who might benefit from cytotoxic chemotherapy becomes more apparent. In preclinical models, oxaliplatin has activity in cisplatin‐resistant cells. In this study, we have shown that oxaliplatin forms interstrand crosslinks (ICLs) in cellular DNA and that loss of the heterodimeric structure‐specific endonuclease XPF‐ERCC1 causes hypersensitivity to oxaliplatin in mammalian cells. XPF deficiency resulted in late S‐phase arrest and persistence of double‐strand breaks following oxaliplatin treatment. In a panel of 12 MM cell lines, oxaliplatin sensitivity correlated with XPF and ERCC1 protein levels. The knockdown of ERCC1 and XPF protein levels by RNA interference increased sensitivity of cancer cells to oxaliplatin; overexpression of exogenous ERCC1 significantly decreased drug sensitivity. Following immunohistochemical optimization, XPF protein levels were quantified in MM tissue samples from 183 patients, showing variation in expression and no correlation with prognosis. In 57 patients with MM treated with cisplatin or carboplatin, XPF protein levels did not predict the likelihood of clinical response. We propose that oxaliplatin should not be discarded as a potential treatment for MM on the basis of the limited activity of cisplatin in unselected patients. Moreover, we show that XPF‐ERCC1 protein levels are a key determinant of the sensitivity of melanoma cells to oxaliplatin in vitro. Immunohistochemical detection of XPF appears suitable for development as a tissue biomarker for potentially selecting patients for oxaliplatin treatment in a prospective clinical trial.
Complete regression of glioblastoma by mesenchymal stem cells mediated prodrug gene therapy simulating clinical therapeutic scenario
Authors: Altaner Cestmir , Altanerova Veronika , Cihova Marina , Ondicova Katarina , Rychly Boris , Baciak Ladislav , Mravec Boris
Published: August 2013

Suicide gene therapy mediated by mesenchymal stem cells with their ability to engraft into tumors makes these therapeutic stem cells an attractive tool to activate prodrugs directly within the tumor mass. In this study, we evaluated the therapeutic efficacy of human mesenchymal stem cells derived from bone marrow and from adipose tissue, engineered to express the suicide gene cytosine deaminase::uracil phosphoribosyltransferase to treat intracerebral rat C6 glioblastoma in a simulated clinical therapeutic scenario. Intracerebrally grown glioblastoma was treated by resection and subsequently with single or repeated intracerebral inoculations of therapeutic stem cells followed by a continuous intracerebroventricular delivery of 5‐fluorocytosine using an osmotic pump. Kaplan–Meier survival curves revealed that surgical resection of the tumor increased the survival time of the resected animals depending on the extent of surgical intervention. However, direct injections of therapeutic stem cells into the brain tissue surrounding the postoperative resection cavity led to a curative outcome in a significant number of treated animals. Moreover, the continuous supply of therapeutic stem cells into the brain with growing glioblastoma by osmotic pumps together with continuous prodrug delivery also proved to be therapeutically efficient. We assume that observed curative therapy of glioblastoma by stem cell‐mediated prodrug gene therapy might be caused by the destruction of both tumor cells and the niche where glioblastoma initiating cells reside.
Cytocompatibility assessment of chemical surface treatments for phosphate glass to improve adhesion between glass and polyester
Authors: S. Hasan M. , Ahmed I. , Parsons A. J. , Walker G. S. , Scotchford C. A.
Published: August 2013

Fully resorbable phosphate glass fiber reinforced polymer composites have shown real potential for replacing some of the existing metallic bone fracture fixation devices. However, some of these composites have not provided suitable mechanical strength profiles over the required healing period for bone. Typically, it has been seen that these composites can lose up to 50% or more of their strength within the first week of degradation. Functionalizing the glass surface to promote polymer adhesion or to introduce hydrophobicity at the glass surface could potentially introduce control over the mechanical properties of the composite and their retention. In this study eight chemical agents namely, Glycerol 2‐phosphate disodium salt; 3‐phosphonopropionic acid; 3‐aminopropyltriethoxy silane; etidronic acid; hexamethylene diisocyanate; sorbitol/sodium ended PLA oligomers and amino phosphonic acid, were selected to functionalise the bulk phosphate glass surface. Selected chemical agents had one functional group (—OH or O C N) to react with the glass and another functionality (either —OH, NH2,or Na) to react with the polymer matrix and/or produce hydrophobicity at the fiber surface. Bulk phosphate glass surface‐treated with the above agents were assessed for the cytotoxicity of degradation products cell‐material interaction in short‐ and long‐term direct cytocompatibility studies. Results obtained from these cytocompatibility studies (using human osteosarcoma (MG63) and primary human osteoblast cell lines) revealed no cytotoxicity from the degradation products and a response comparable to controls in terms of cell functions (attachment, viability, metabolic activity, proliferation, and differentiation) and morphology. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 3301–3310, 2013.
Preparation and characterization of hydrophilic composites AA/EPMA loaded with hydroxyapatite
Authors: Campos Yaima , Fuentes Gastón , Delgado José A. , Almirall Amisel
Published: August 2013

Copolymeric composites of acrylamide (AA) and 2,3‐epoxypropyl methacrylate (EPMA) with hydroxyapatite (HA) load were studied. Swelling studies reports an anomalous or non‐Fickian behavior following a good fitting to a pseudo second order mathematical treatment (α = 0.05, p < 0.0001). The composites showed a strong dependence on pH, related with the variations in the swelling behavior. The addition of load induces a diminution of swelling capacity and an increase of diametric tensile strength (DTS) ranging between 20 and 90 kPa. The calorimetric experiments showed two steps at 78°C and 255°C assigned to water loss and samples Tg. The drug control released was adjusted to a two‐term equation obtaining a diffusion coefficient around 10−5 cm2/s. The samples showed a significant bioactivity in vitro and it was certified by SEM, EDS and surface area calculus. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 3607–3615, 2013.
Insulin Resistance and Bone Strength: Findings From the Study of Midlife in the United States
Authors: Srikanthan Preethi , Crandall Carolyn J , Miller-Martinez Dana , Seeman Teresa E , Greendale Gail A , Binkley Neil , Karlamangla Arun S
Published: August 2013

Although several studies have noted increased fracture risk in individuals with type 2 diabetes mellitus (T2DM), the pathophysiologic mechanisms underlying this association are not known. We hypothesize that insulin resistance (the key pathology in T2DM) negatively influences bone remodeling and leads to reduced bone strength. Data for this study came from 717 participants in the Biomarker Project of the Midlife in the United States Study (MIDUS II). The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from fasting morning blood glucose and insulin levels. Projected 2D (areal) bone mineral density (BMD) was measured in the lumbar spine and left hip using dual-energy X-ray absorptiometry (DXA). Femoral neck axis length and width were measured from the hip DXA scans, and combined with BMD and body weight and height to create composite indices of femoral neck strength relative to load in three different failure modes: compression, bending, and impact. We used multiple linear regressions to examine the relationship between HOMA-IR and bone strength, adjusted for age, gender, race/ethnicity, menopausal transition stage (in women), and study site. Greater HOMA-IR was associated with lower values of all three composite indices of femoral neck strength relative to load, but was not associated with BMD in the femoral neck. Every doubling of HOMA-IR was associated with a 0.34 to 0.40 SD decrement in the strength indices (p < 0.001). On their own, higher levels of fasting insulin (but not of glucose) were independently associated with lower bone strength. Our study confirms that greater insulin resistance is related to lower femoral neck strength relative to load. Further, we note that hyperinsulinemia, rather than hyperglycemia, underlies this relationship. Although cross-sectional associations do not prove causality, our findings do suggest that insulin resistance and in particular, hyperinsulinemia, may negatively affect bone strength relative to load. © 2014 American Society for Bone and Mineral Research.
Roles of Parathyroid Hormone (PTH) Receptor and Reactive Oxygen Species in Hyperlipidemia‐Induced PTH Resistance in Preosteoblasts
Authors: Li Xin , Garcia Jamie , Lu Jinxiu , Iriana Sidney , Kalajzic Ivo , Rowe David , Demer Linda L. , Tintut Yin
Published: August 2013

Bioactive lipids initiate inflammatory reactions leading to pathogenesis of atherosclerosis. Evidence shows that they also contribute to bone loss by inhibiting parathyroid hormone receptor (PTH1R) expression and differentiation of osteoblasts. We previously demonstrated that bone anabolic effects of PTH(1–34) are blunted in hyperlipidemic mice and that these PTH effects are restored by antioxidants. However, it is not clear which osteoblastic cell developmental stage is targeted by bioactive lipids. To investigate the effects of hyperlipidemia at the cellular level, hyperlipidemic Ldlr−/− mice were bred with Col3.6GFPtpz mice, in which preosteoblasts/osteoblasts carry a topaz fluorescent label, and with Col2.3GFPcyan mice, in which more mature osteoblasts/osteocytes carry a cyan fluorescent label. Histological analyses of trabecular bone surfaces in femoral as well as calvarial bones showed that intermittent PTH(1–34) increased fluorescence intensity in WT‐Tpz mice, but not in Tpz‐Ldlr−/− mice. In contrast, PTH(1–34) did not alter fluorescence intensity in femoral cortical envelopes of either WT‐Cyan or Ldlr−/−‐Cyan mice. To test the mechanism of PTH1R downregulation, preosteoblastic MC3T3‐E1 cells were treated with bioactive lipids and the antioxidant Trolox. Results showed that inhibitory effects of PTH1R levels by bioactive lipids were rescued by pretreatment with Trolox. The inhibitory effects on expression of PTH1R as well as on PTH‐induced osteoblastic genes were mimicked by xanthine/xanthine oxidase, a known generator of reactive oxygen species. These findings suggest an important role of the preosteoblastic development stage as the target and downregulation of PTH receptor expression mediated by intracellular oxidant stress as a mechanism in hyperlipidemia‐induced PTH resistance. J. Cell. Biochem. 115: 179–188, 2014. © 2013 Wiley Periodicals, Inc.
Role of SPARC in Bone Remodeling and Cancer‐Related Bone Metastasis
Authors: Ribeiro Nilza , Sousa Susana R. , Brekken Rolf A. , Monteiro Fernado J.
Published: August 2013

There is a growing socioeconomic recognition that clinical bone diseases such as bone infections, bone tumors and osteoporotic bone loss mainly associated with ageing, are major issues in today's society. SPARC (secreted protein, acidic and rich in cysteine), a matricellular glycoprotein, may be a promising therapeutic target for preventing or treating bone‐related diseases. In fact, SPARC is associated with tissue remodeling, repair, development, cell turnover, bone mineralization and may also participate in growth and progression of tumors, namely cancer‐related bone metastasis. Yet, the function of SPARC in such biological processes is poorly understood and controversial. The main objective of this work is to review the current knowledge related to the activity of SPARC in bone remodeling, tumorigenesis, and bone metastasis. Progress in understanding SPARC biology may provide novel strategies for bone regeneration and the development of anti‐angiogenic, anti‐proliferative, or counter‐adhesive treatments specifically against bone metastasis. J. Cell. Biochem. 115: 17–26, 2014. © 2013 Wiley Periodicals, Inc.
Porting ONETEP to graphical processing unit‐based coprocessors. 1. FFT box operations
Authors: Wilkinson Karl , Skylaris Chris‐Kriton
Published: August 2013

We present the first graphical processing unit (GPU) coprocessor‐enabled version of the Order‐N Electronic Total Energy Package (ONETEP) code for linear‐scaling first principles quantum mechanical calculations on materials. This work focuses on porting to the GPU the parts of the code that involve atom‐localized fast Fourier transform (FFT) operations. These are among the most computationally intensive parts of the code and are used in core algorithms such as the calculation of the charge density, the local potential integrals, the kinetic energy integrals, and the nonorthogonal generalized Wannier function gradient. We have found that direct porting of the isolated FFT operations did not provide any benefit. Instead, it was necessary to tailor the port to each of the aforementioned algorithms to optimize data transfer to and from the GPU. A detailed discussion of the methods used and tests of the resulting performance are presented, which show that individual steps in the relevant algorithms are accelerated by a significant amount. However, the transfer of data between the GPU and host machine is a significant bottleneck in the reported version of the code. In addition, an initial investigation into a dynamic precision scheme for the ONETEP energy calculation has been performed to take advantage of the enhanced single precision capabilities of GPUs. The methods used here result in no disruption to the existing code base. Furthermore, as the developments reported here concern the core algorithms, they will benefit the full range of ONETEP functionality. Our use of a directive‐based programming model ensures portability to other forms of coprocessors and will allow this work to form the basis of future developments to the code designed to support emerging high‐performance computing platforms.Copyright © 2013 Wiley Periodicals, Inc.
A high‐level ab initio study of the N2 + N2 reaction channel
Authors: Pacifici Leonardo , Verdicchio Marco , Lago Noelia Faginas , Lombardi Andrea , Costantini Alessandro
Published: August 2013

A new six‐dimensional (6D) global potential energy surface (PES) is proposed for the full range description of the interaction of the
system governing collisional processes, including N atom exchange. The related potential energy values were determined using high‐level ab initio methods. The calculations were performed at a coupled‐cluster with single and double and perturbative triple excitations level of theory in order to have a first full range picture of the PES. Subsequently, in order to accurately describe the stretching of the bonds of the two interacting N2 molecules by releasing the constraints of being considered as rigid rotors, for the same molecular geometries higher level of theory multi reference calculations were performed. Out of the calculated values a 6D 4‐atoms global PES was produced for use in dynamical calculations. The ab initio calculations were made possible by the combined use of High Throughput Computing and High Performance Computing techniques within the frame of a computing grid empowered molecular simulator. © 2013 Wiley Periodicals, Inc.
Computational protein design: The proteus software and selected applications
Authors: Simonson Thomas , Gaillard Thomas , Mignon David , Schmidt am Busch Marcel , Lopes Anne , Amara Najette , Polydorides Savvas , Sedano Audrey , Druart Karen , Archontis Georgios
Published: August 2013

We describe an automated procedure for protein design, implemented in a flexible software package, called Proteus. System setup and calculation of an energy matrix are done with the XPLOR modeling program and its sophisticated command language, supporting several force fields and solvent models. A second program provides algorithms to search sequence space. It allows a decomposition of the system into groups, which can be combined in different ways in the energy function, for both positive and negative design. The whole procedure can be controlled by editing 2–4 scripts. Two applications consider the tyrosyl‐tRNA synthetase enzyme and its successful redesign to bind both O‐methyl‐tyrosine and D‐tyrosine. For the latter, we present Monte Carlo simulations where the D‐tyrosine concentration is gradually increased, displacing L‐tyrosine from the binding pocket and yielding the binding free energy difference, in good agreement with experiment. Complete redesign of the Crk SH3 domain is presented. The top 10000 sequences are all assigned to the correct fold by the SUPERFAMILY library of Hidden Markov Models. Finally, we report the acid/base behavior of the SNase protein. Sidechain protonation is treated as a form of mutation; it is then straightforward to perform constant‐pH Monte Carlo simulations, which yield good agreement with experiment. Overall, the software can be used for a wide range of application, producing not only native‐like sequences but also thermodynamic properties with errors that appear comparable to other current software packages.Copyright © 2013 Wiley Periodicals, Inc.
Punishing and cardiovascular effects of intravenous histamine in rats: Pharmacological selectivity
Authors: Podlesnik Christopher A. , Jimenez‐Gomez Corina
Published: August 2013

Although drugs may serve as reinforcers or punishers of operant behavior, the punishing function has received much less experimental attention than the reinforcing function. A sensitive method for studying drug‐induced punishment is to assess choice for a punished response over an unpunished response. In these experiments, rats chose between pressing one lever and receiving a sucrose pellet or pressing another lever and receiving a sucrose pellet plus an intravenous injection of histamine. When sucrose was delivered equally frequently for either the punished or the unpunished response, rats selected the unpunished lever consistently, but decreases in the punished response did not differ as a function of intravenous histamine dose (0.1–1 mg/kg/inj). Changing the procedure so that sucrose was delivered on the unpunished lever with p = .5 increased the rats' responding on the punished lever with saline injections. In addition, the same range of histamine doses produced a much larger range of responses on the punished lever that was dose dependent. Using these procedures to assess the receptors mediating histamine's effects, the histamine H1‐receptor antagonists, pyrilamine and ketotifen, antagonized the punishing effect of histamine, but the histamine H2‐receptor antagonist ranitidine did not. However, ranitidine pretreatments reduced histamine‐induced heart‐rate increases to a greater extent than did the histamine H1‐receptor antagonists when administered at the same doses examined under conditions of histamine punishment. Overall, the present findings extend the general hypothesis that activation of histamine H1‐receptors mediates the punishing effects of histamine. They also introduce methods for rapidly assessing pharmacological mechanisms underlying drug‐induced punishment.
An investigation of the characteristics of the convection reversal boundary under southward interplanetary magnetic field
Authors: Bristow W. A. , Spaleta J.
Published: August 2013

The characteristics of the Convection Reversal Boundary (CRB) as determined from Super Dual Auroral Radar Network (SuperDARN) observations of convection are examined and modeled. Convection patterns were calculated for all intervals within the 11 year period 2000–2010 when the interplanetary magnetic field met a restrictive set of criteria. When there were sufficient observations, the CRB was determined and binned as a function of latitude and magnetic local time. There were over 90,000 determinations of the CRB included in the study. Distributions of CRB locations were formed for each hour of magnetic local time. The distributions varied in average latitude and in variance, with the lowest latitude and broadest widths occurring near midnight. The distributions were skewed toward high latitudes on the dayside and toward low latitudes on the night side. The CRB was modeled as a linear sum of terms dependent on the interplanetary magnetic field, the solar wind, and the SymH indices. Finally, the dynamic behavior of the boundary is discussed and modeled in an attempt to reproduce the observed distributions.
An evaluation of author productivity in international radiography journals 2004–2011
Authors: Snaith Beverly A.
Published: August 2013

Introduction

Radiography, the allied health profession, has changed beyond recognition over the last century; however, in academic terms radiography is a relatively young profession. It is therefore still establishing its professional knowledge base. This article uses peer‐review author productivity distribution to evaluate its scholarly maturity.

Methods

Four peer‐reviewed journals in medical radiation sciences were examined over an 8‐year period (2004–2011) and author productivity was compared to Lotka's law. Further analysis of the most prolific authors provided an evaluation of their characteristics.

Results

The 1306 unique authors contributed 835 articles during the study period. Of these, 1012 (77.5%) contributed only one article to the journals studied, with an inverse power relationship of author productivity. At the 0.1 level of significance, radiography does not fit Lotka's law (n = −2.334; c = 0.712; Dmax = 0.0627; Critical threshold = 0.0337). There was a significant correlation between the most prolific authors and collaboration (P = 0.002), although variation was noted in author discipline and location.

Conclusions

The results of this study add to the discussion of radiography scholarship and demonstrate that the radiography authors have similar productivity distribution to other professions, but do not follow Lotka's law.
μ‐Raman spectroscopy of prehistoric paintings from the Abrigo Remacha rock shelter (Villaseca, Segovia, Spain)
Authors: Iriarte Mercedes , Hernanz Antonio , Ruiz‐López Juan F. , Martín Santiago
Published: August 2013

The composition of the materials present in prehistoric paintings discovered on the walls of the Abrigo Remacha rock shelter (Villaseca, Segovia, Spain) has been characterised by micro‐Raman spectroscopy. In addition, scanning electron microscopy and energy dispersive X‐ray microanalysis have been used as auxiliary techniques. The results show that haematite (α‐Fe2O3) is the main component of the red pigment. Amorphous carbon and paracoquimbite (Fe2(SO4)3.9H2O) have been detected in the bluish black pigment used in a significant bi‐colour pictograph. This is the first time that this mineral has been discovered in a prehistoric painting. Accretions of whewellite and weddellite form crusts covering most of the painting panel. Different carbonates are the main components of the rocky substrate. The detection of gypsum on the surface of the panel is associated to the flaking process that is affecting the painting panel. Copyright © 2013 John Wiley & Sons, Ltd.
Measurements of the Kinetics of the Reaction of OH Radicals with 3‐Methylfuran at Low Pressure
Authors: Liljegren Jennifer A. , Stevens Philip S.
Published: August 2013

The rate constant for the reaction of OH with 3‐methylfuran was measured at 2, 4, and 6 Torr using discharge‐flow techniques coupled with laser‐induced fluorescence detection of OH. The measured rate constant (k) at 298 ± 2 K was (9.1 ± 0.3) × 10−11 cm3 molecule−1 s−1, where the quoted uncertainty reflects twice the standard error of the measurements. This result is in good agreement with previously reported relative rate constant measurements at atmospheric pressure and room temperature. An Arrhenius expression of k = (3.2 ± 0.4) × 10−11 e(310 ± 40)/T cm3 molecule−1 s−1 was determined from measurements of the rate constant between 273 and 368 K. The negative temperature dependence agrees with previously reported theoretical calculations for the reaction of OH with 3‐methylfuran and previously reported measurements of the temperature dependences of the rate constants for the reaction of OH with similar heterocyclic organics such as furan and thiophene.
Relatively Short Poly(D‐lactide) Segments as Intra‐Crystallization‐Accelerating Moieties in Stereo Diblock Poly(lactide)s
Authors: Tsuji Hideto , Tajima Tomohiko
Published: August 2013

The homo‐crystallization of stereo diblock poly(lactide)s with high number‐average molecular weight () values of ca. 105 g mol−1 is accelerated by the incorporated relatively short poly(D‐lactide) (PDLA) segments with  = 2.0–7.7 × 103 g mol−1 during heating and PDLA segments with  = 3.5 and 7.7 × 103 g mol−1 during cooling. The relatively short PDLA segments linked to PLLA segments, which have sufficient lengths to form stereocomplex crystallites, are very effective to shorten a crystallization timeand to increase the productivity and thermal stability.
A Combined NMR Relaxometry and Surface Instability Detection System for Polymer Melt Extrusion
Authors: Ratzsch Karl‐Friedrich , Kádár Roland , Naue Ingo F. C. , Wilhelm Manfred
Published: August 2013

A combined system for solidification and instability detection during the forced extrusion of polymers is constructed and first investigations are presented. The system comprises a home built Halbach‐type NMR magnet, monitoring the NMR relaxation at different positions along the extrudate length, and a highly sensitive transducer in the die recording mechanical pressure fluctuations. The system is complemented by an optical extrudate visualization setup. First results are shown for low density and high density polyethylene (LDPE and HDPE), which have different branching structures. Three relevant processing parameters were varied during the investigations, i.e., extruder rotation speed, draw ratio and extrusion temperature. Overall, the characteristics of NMR relaxation show a clear dependence on the magnet position along the extrudate length, which can be related to the cooling, onset and propagation of crystallization, and solidification of the polymer melt. The coupling of a low‐field NMR with a high sensitivity instability detection system shows the potential of creating a versatile tool for a unique online control method in polymer processing. In the future, this combination could provide insight into the influence of branching structures on polymer processing of polyethylene, for example.
Some scales of equivalent conditions to characterize the Stieltjes inequality: the case
Authors: Gogatishvili Amiran , Persson Lars‐Erik , Stepanov Vladimir D. , Wall Peter
Published: August 2013

We prove that the weighted Stieltjes inequality

urn:x-wiley:dummy:mana201200118:equation:mana201200118-math-0003can be characterized by four different scales of conditions also for the case , . In particular, a new proof of a result of G. Sinnamon  is given, which also covers the case . Moreover, for the situation at hand a new gluing theorem and also an equivalence theorem of independent interest are proved and discussed. By applying our new equivalence theorem to weighted inequalities for the Stieltjes transform we obtain the four new scales of conditions for characterization of Stieltjes inequality.