bluuebunny/crossref_metadata_2025 huggingface dataset:
IRS proteins and the common path to diabetes
Authors: White Morris F.
Published: February 2015

Although a full understanding of insulin/insulin-like growth factor (IGF) action is evolving, the discovery of insulin receptor substrate (IRS) proteins and their role to link cell surface receptors to the intracellular signaling cascades provided an important step forward. Moreover, Insulin/IGF receptors use common signaling pathways to accomplish many tasks, the IRS proteins add a unique layer of specificity and control. Importantly, the IRS-2 branch of the insulin/IGF-signaling pathway is a common element in peripheral insulin response and pancreatic β-cell growth and function. Failure of IRS-2 signaling might explain the eventual loss of compensatory hyperinsulinemia during prolonged periods of peripheral insulin resistance. Moreover, short-term inhibition of IRS protein functions by serine phosphorylation, or sustained inhibition by ubiquitin-targeted proteosome-mediated degradation suggests a common molecular mechanism for insulin resistance during acute injury or infection, or the sensitivity of β-cells to autoimmune destruction. The broad role of IRS-1 and IRS-2 in cell growth and survival reveals a common regulatory pathway linking development, somatic growth, fertility, neuronal proliferation, and aging to the core mechanisms used by vertebrates for nutrient sensing.
Gene expression profile of rat adipose tissue at the onset of high-fat-diet obesity
Authors: Li Jinping , Yu Xinxin , Pan Wentong , Unger Roger H.
Published: February 2015

Morbid obesity is the result of massive expansion of white adipose tissue (WAT) and requires recruitment of adipocyte precursor cells and their supporting infrastructure. To characterize the change in the expression profile of the preexisting WAT at the start of obesity, when adipocyte hypertrophy is present but hyperplasia is still minimal, we employed a cDNA subtraction screen for genes differentially expressed in epididymal fat pads harvested 1 wk after the start of a 60% fat diet. Ninety-six genes were upregulated by at least 50% above the WAT of control rats receiving a 4% fat diet. Of these genes, 30 had not previously been identified. Sixteen of the 96 genes, including leptin, adipocyte complement-related protein 30 kDa, and resistin, were predicted to encode a signal peptide. Ten of the 16 had been previously identified in other tissues and implicated in cell growth, proliferation, differentiation, cell cycle control, and angiogenesis. One was a novel gene. Twenty-nine novel fragments were identified. Thus, at the onset of high-fat-diet-induced obesity in rats, adipose tissue increases its expression of factors previously implicated in the expansion of nonadipocyte tissues and of several uncharacterized novel factors. The only one of these thus far characterized functionally was found to promote lipogenesis.
Immediate effects of an 8-h advance shift of the rest-activity cycle on 24-h profiles of cortisol
Authors: Caufriez Anne , Moreno-Reyes Rodrigo , Leproult Rachel , Vertongen Françoise , Van Cauter Eve , Copinschi Georges
Published: February 2015

To investigate the adaptation of plasma cortisol profiles to an abrupt phase advance of the rest-activity cycle, eight normal young subjects were submitted in a sleep laboratory to an 8-h advance shift of their sleep-wake and dark-light cycles. The shift was achieved by advancing bedtimes from 2300–0700 to 1500–2300. Blood samples were obtained at 20-min intervals for 68 consecutive hours. The shift resulted within 6–9 h in a 3- to 4-h advance of timings of the nadir of the cortisol profile and of the end of the quiescent period but had no immediate effect on the timing of cortisol acrophase. The quiescent period of cortisol secretion was shortened and fragmented. Thus a major advance shift achieved without enforcing sleep deprivation results in a rapid partial adaptation of the temporal profiles of cortisol but also in a marked disruption of the cortisol quiescent period. Sleep onset was consistently followed by a decrease in cortisol concentrations. Conversely, both sleep-wake and dark-light transitions were consistently associated with cortisol secretory pulses.
Site and mechanism of action of dynorphin A-(1–13) andN-methyl-d-aspartate on ACTH release in fetal sheep
Authors: Nardo Laura , Soong Yi , Wu Dunli , Young I. Ross , Walker David , Szeto Hazel H.
Published: February 2015

Dynorphin A (Dyn A) stimulates the release of ACTH in fetal sheep, a response that involves N-methyl-d-aspartate (NMDA) receptors but not the secretogogues corticotropin-releasing hormone or arginine vasopressin. We now find that neither Dyn A-(1–13) (0.5 mg/kg, iv) nor NMDA (4 mg/kg, iv) elicits ACTH release in postnatal lambs. This led us to hypothesize that Dyn A-(1–13) and NMDA might act to release placental ACTH. However, the ability of Dyn A-(1–13), NMDA, and the κ-opioid receptor agonist U-50488H (1 mg/kg, iv) to release ACTH was lost after either fetal hypophysectomy ( n = 4) or hypothalamo-pituitary disconnection ( n = 4). These results indicate that neither the placenta nor the fetal pituitary is the site of action for these agonists and suggest a hypothalamic or suprahypothalamic site of action. Furthermore, the release of ACTH by Dyn A-(1–13) and NMDA was abolished after pretreatment with indomethacin, suggesting that they might cause the release of a prostanoid, possibly from the placenta, that subsequently acts at the hypothalamus or serves as a permissive factor in the action of Dyn A-(1–13) and NMDA at the hypothalamus.
Epinephrine effects on insulin-glucose dynamics: the labeled IVGTT two-compartment minimal model approach
Authors: Vicini Paolo , Avogaro Angelo , Spilker Mary E. , Gallo Alessandra , Cobelli Claudio
Published: February 2015

The hyperglycemic effects of epinephrine (Epi) are established; however, the modulation of Epi-stimulated endogenous glucose production (EGP) by glucose and insulin in vivo in humans is less clear. Our aim was to determine the effect of exogenously increased plasma Epi concentrations on insulin and glucose dynamics. In six normal control subjects, we used the labeled intravenous glucose tolerance test (IVGTT) interpreted with the two-compartment minimal model, which provides not only glucose effectiveness (S[Formula: see text]), insulin sensitivity (S[Formula: see text]), and plasma clearance rate (PCR) at basal state, but also the time course of EGP. Subjects were randomly studied during either saline or Epi infusion (1.5 μg/min). Exogenous Epi infusion increased plasma Epi concentration to a mean value of 2,034 ± 138 pmol/l. During the stable-label IVGTT, plasma glucose, tracer glucose, and insulin concentrations were significantly higher in the Epi study. The hormone caused a significant ( P < 0.05) reduction in PCR in the Epi state when compared with the basal state. The administration of Epi has a striking effect on EGP profiles: the nadir of the EGP profiles occurs at 21 ± 7 min in the basal state and at 55 ± 13 min in the Epi state ( P < 0.05). In conclusion, we have shown by use of a two-compartment minimal model of glucose kinetics that elevated plasma Epi concentrations have profound effects at both hepatic and tissue levels. In particular, at the liver site, this hormone deeply affects, in a time-dependent fashion, the inhibitory effect of insulin on glucose release. Our findings may explain how even a normal subject may have the propensity to develop glucose intolerance under the influence of small increments of Epi during physiological stress.
Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance
Authors: Maheshwari Hiralal G. , Pezzoli Suzan S. , Rahim Asad , Shalet Stephen M. , Thorner Michael O. , Baumann Gerhard
Published: February 2015

Growth hormone (GH) secretion is regulated by GH-releasing hormone (GHRH), somatostatin, and possibly ghrelin, but uncertainty remains about the relative contributions of these hypophysiotropic factors to GH pulsatility. Patients with genetic GHRH receptor (GHRH-R) deficiency present an opportunity to examine GH secretory dynamics in the selective absence of GHRH input. We studied circadian GH profiles in four young men homozygous for a null mutation in the GHRH-R gene by use of an ultrasensitive GH assay. Residual GH secretion was pulsatile, with normal pulse frequency, but severely reduced amplitude (<1% normal) and greater than normal process disorder (as assessed by approximate entropy). Nocturnal GH secretion, both basal and pulsatile, was enhanced compared with daytime. We conclude that rhythmic GH secretion persists in an amplitude-miniaturized version in the absence of a GHRH-R signal. The nocturnal enhancement of GH secretion is likely mediated by decreased somatostatin tone. Pulsatility of residual GH secretion may be caused by oscillations in somatostatin and/or ghrelin; it may also reflect intrinsic oscillations in somatotropes.
Effects of cortisol on lipolysis and regional interstitial glycerol levels in humans
Authors: Djurhuus C. B. , Gravholt C. H. , Nielsen S. , Mengel A. , Christiansen J. S. , Schmitz O. E. , Møller N.
Published: February 2015

Cortisol's effects on lipid metabolism are controversial and may involve stimulation of both lipolysis and lipogenesis. This study was undertaken to define the role of physiological hypercortisolemia on systemic and regional lipolysis in humans. We investigated seven healthy young male volunteers after an overnight fast on two occasions by means of microdialysis and palmitate turnover in a placebo-controlled manner with a pancreatic pituitary clamp involving inhibition with somatostatin and substitution of growth hormone, glucagon, and insulin at basal levels. Hydrocortisone infusion increased circulating concentrations of cortisol (888 ± 12 vs. 245 ± 7 nmol/l). Interstitial glycerol concentrations rose in parallel in abdominal (327 ± 35 vs. 156 ± 30 μmol/l; P = 0.05) and femoral (178 ± 28 vs. 91 ± 22 μmol/l; P = 0.02) adipose tissue. Systemic [3H]palmitate turnover increased (165 ± 17 vs. 92 ± 24 μmol/min; P = 0.01). Levels of insulin, glucagon, and growth hormone were comparable. In conclusion, the present study unmistakenly shows that cortisol in physiological concentrations is a potent stimulus of lipolysis and that this effect prevails equally in both femoral and abdominal adipose tissue.
Insulin fails to alter plasma LCFA metabolism in muscle perfused at similar glucose uptake
Authors: Yee Alice J. , Turcotte Lorraine P.
Published: February 2015

Insulin has been shown to alter long-chain fatty acid (LCFA) metabolism and malonyl-CoA production in muscle. However, these alterations may have been induced, in part, by the accompanying insulin-induced changes in glucose uptake. Thus, to determine the effects of insulin on LCFA metabolism independently of changes in glucose uptake, rat hindquarters were perfused with 600 μM palmitate and [1-14C]palmitate and with either 20 mM glucose and no insulin (G) or 6 mM glucose and 250 μU/ml of insulin (I). As dictated by our protocol, glucose uptake was not significantly different between the G and I groups (10.3 ± 0.6 vs. 11.0 ± 0.5 μmol · g−1· h−1; P > 0.05). Total palmitate uptake and oxidation were not significantly different ( P > 0.05) between the G (10.1 ± 1.0 and 0.8 ± 0.1 nmol · min−1· g−1) and I (10.2 ± 0.6 and 1.1 ± 0.2 nmol · min−1· g−1) groups. Preperfusion muscle triglyceride and malonyl-CoA levels were not significantly different between the G and I groups and did not change significantly during the perfusion ( P > 0.05). Similarly, muscle triglyceride synthesis was not significantly different between groups ( P > 0.05). These results demonstrate that the presence of insulin under conditions of similar glucose uptake does not alter LCFA metabolism and suggest that cellular mechanisms induced by carbohydrate availability, but independent of insulin, may be important in the regulation of muscle LCFA metabolism.
Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling
Authors: Choi Cheol S. , Kim Young-Bum , Lee Felix N. , Zabolotny Janice M. , Kahn Barbara B. , Youn Jang H.
Published: February 2015

Elevation of plasma lactate levels induces peripheral insulin resistance, but the underlying mechanisms are unclear. We examined whether lactate infusion in rats suppresses glycolysis preceding insulin resistance and whether lactate-induced insulin resistance is accompanied by altered insulin signaling and/or insulin-stimulated glucose transport in skeletal muscle. Hyperinsulinemic euglycemic clamps were conducted for 6 h in conscious, overnight-fasted rats with or without lactate infusion (120 μmol · kg−1 · min−1) during the final 3.5 h. Lactate infusion increased plasma lactate levels about fourfold. The elevation of plasma lactate had rapid effects to suppress insulin-stimulated glycolysis, which clearly preceded its effect to decrease insulin-stimulated glucose uptake. Both submaximal and maximal insulin-stimulated glucose transport decreased 25–30% ( P < 0.05) in soleus but not in epitrochlearis muscles of lactate-infused rats. Lactate infusion did not alter insulin's ability to phosphorylate the insulin receptor, the insulin receptor substrate (IRS)-1, or IRS-2 but decreased insulin's ability to stimulate IRS-1- and IRS-2-associated phosphatidylinositol 3-kinase activities and Akt/protein kinase B activity by 47, 75, and 55%, respectively ( P < 0.05 for all). In conclusion, elevation of plasma lactate suppressed glycolysis before its effect on insulin-stimulated glucose uptake, consistent with the hypothesis that suppression of glucose metabolism could precede and cause insulin resistance. In addition, lactate-induced insulin resistance was associated with impaired insulin signaling and decreased insulin-stimulated glucose transport in skeletal muscle.
Mouse models of insulin resistance
Authors: Hribal Marta Letizia , Oriente Francesco , Accili Domenico
Published: February 2015

The hallmarks of type 2 diabetes are impaired insulin action in peripheral tissues and decreased pancreatic β-cell function. Classically, the two defects have been viewed as separate entities, with insulin resistance arising primarily from impaired insulin-dependent glucose uptake in skeletal muscle, and β-cell dysfunction arising from impaired coupling of glucose sensing to insulin secretion. Targeted mutagenesis and transgenesis involving components of the insulin action pathway have changed our understanding of these phenomena. It appears that the role of insulin signaling in the pathogenesis of type 2 diabetes has been overestimated in classic insulin target tissues, such as skeletal muscle, whereas it has been overlooked in liver, pancreatic β-cells, and brain, which had been thought not to be primary insulin targets. We review recent progress and try to reconcile areas of apparent controversy surrounding insulin signaling in skeletal muscle and pancreatic β-cells.
Changes in LPLa and reverse cholesterol transport variables during 24-h postexercise period
Authors: Zhang John Q. , Smith Bryan , Langdon Melissa M. , Messimer Heidi L. , Sun Grace Y. , Cox Richard H. , James-Kracke Marilyn , Thomas Tom R.
Published: February 2015

We investigated the time course of exercise-induced lipoprotein lipase activity (LPLa) and reverse cholesterol transport (RCT) during the 24-h postexercise period. Subjects were 10 sedentary normolipidemic males [NTG; fasting triglyceride (TG) = 89.1 ± 8.6 mg/dl] and 6 hyperlipidemic males (HTG; fasting TG = 296.8 ± 64.0 mg/dl). Each subject performed a control trial (no exercise) and 4 exercise trials. In the exercise trials, a subject jogged on a treadmill at 60% of his maximal O2consumption for 1 h. Pre- and postheparin blood samples were taken before exercise (baseline) and at 4, 8, 12, and 24 h after exercise. There was no group difference in LPLa ( P > 0.05) over the time points. When the LPLa data from the two groups were combined, LPLa at 24 h after exercise was higher than baseline or at 4, 8, 12 h after exercise ( P < 0.05). Plasma TG and lecithin-cholesterol acyltransferase activity (LCATa) were higher in HTG than in NTG, and the total high-density lipoprotein-cholesterol (HDLtot-Chol) was lower in HTG than in NTG ( P < 0.05). HDL2-Chol, LCATa, and cholesterol ester transfer protein activity did not differ during the 24-h postexercise period ( P > 0.05). These results suggest that LPLa is still increasing 24 h after an acute aerobic exercise and that the magnitude of the increase in exercise-induced LPLa in HTG was similar to that in NTG. Furthermore, in the sedentary population with or without HTG, the variables related to RCT do not change during the 24-h period after exercise.
Phenylalanine kinetics in healthy volunteers and liver cirrhotics: implications for the phenylalanine breath test
Authors: Tugtekin I. , Wachter U. , Barth E. , Weidenbach H. , Wagner D. A. , Adler G. , Georgieff M. , Radermacher P. , Vogt J. A.
Published: February 2015

Expired 13CO2recovery from an oral l-[1-13C]phenylalanine ([13C]Phe) dose has been used to quantify liver function. This parameter, however, does not depend solely on liver function but also on total CO2 production, Phe turnover, and initial tracer distribution. Therefore, we evaluated the impact of these factors on breath test values. Nine ethyl-toxic cirrhotic patients and nine control subjects received intravenously 2 mg/kg of [13C]Phe, and breath and blood samples were collected over 4 h. CO2 production was measured by indirect calorimetry. The exhaled 13CO2 enrichments were analyzed by isotope ratio mass spectrometry and the [13C]Phe and l-[1-13C]tyrosine enrichments by gas chromatography-mass spectrometry. The cumulative13CO2 recovery was significantly lower in cirrhotic patients (7 vs. 12%; P < 0.01), in part due to lower total CO2 production rates. Phe turnover in cirrhotic patients was significantly lower (33 vs. 44 μmol · kg−1 · h−1; P < 0.05). When these extrahepatic factors were considered in the calculation of the Phe oxidation rate, the intergroup differences were even more pronounced (3 vs. 7 μmol · kg−1 · h−1) than those for 13CO2 recovery data. Also, the Phe-to-Tyr conversion rate, another indicator of Phe oxidation, was significantly reduced (0.7 vs. 3.0 μmol · kg−1 · h−1).
Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus
Authors: Miyazaki Yoshinori , Glass Leonard , Triplitt Curtis , Wajcberg Estela , Mandarino Lawrence J. , DeFronzo Ralph A.
Published: February 2015

We examined the relationship between peripheral/hepatic insulin sensitivity and abdominal superficial/deep subcutaneous fat (SSF/DSF) and intra-abdominal visceral fat (VF) in patients with type 2 diabetes mellitus (T2DM). Sixty-two T2DM patients (36 males and 26 females, age = 55 ± 3 yr, body mass index = 30 ± 1 kg/m2) underwent a two-step euglycemic insulin clamp (40 and 160 mU · m−2· min−1) with [3-3H]glucose. SSF, DSF, and VF areas were quantitated with magnetic resonance imaging at the L4–5level. Basal endogenous glucose production (EGP), hepatic insulin resistance index (basal EGP × FPI), and total glucose disposal (TGD) during the first and second insulin clamp steps were similar in male and female subjects. VF (159 ± 9 vs. 143 ± 9 cm2) and DSF (199 ± 14 vs. 200 ± 15 cm2) were not different in male and female subjects. SSF (104 ± 8 vs. 223 ± 15 cm2) was greater ( P < 0.0001) in female vs. male subjects despite similar body mass index (31 ± 1 vs. 30 ± 1 kg/m2) and total body fat mass (31 ± 2 vs. 33 ± 2 kg). In male T2DM, TGD during the first insulin clamp step (1st TGD) correlated inversely with VF ( r = −0.45, P < 0.01), DSF ( r = −0.46, P < 0.01), and SSF ( r = −0.39, P < 0.05). In males, VF ( r = 0.37, P < 0.05), DSF ( r = 0.49, P < 0.01), and SSF ( r = 0.33, P < 0.05) were correlated positively with hepatic insulin resistance. In females, the first TGD ( r = −0.45, P < 0.05) and hepatic insulin resistance ( r = 0.49, P < 0.05) correlated with VF but not with DSF, SSF, or total subcutaneous fat area. We conclude that visceral adiposity is associated with both peripheral and hepatic insulin resistance, independent of gender, in T2DM. In male but not female T2DM, deep subcutaneous adipose tissue also is associated with peripheral and hepatic insulin resistance.
A role for matrix stiffness in the regulation of cardiac side population cell function
Authors: Qiu Yiling , Bayomy Ahmad F. , Gomez Marcus V. , Bauer Michael , Du Ping , Yang Yanfei , Zhang Xin , Liao Ronglih
Published: February 2015

The mechanical properties of the local microenvironment may have important influence on the fate and function of adult tissue progenitor cells, altering the regenerative process. This is particularly critical following a myocardial infarction, in which the normal, compliant myocardial tissue is replaced with fibrotic, stiff scar tissue. In this study, we examined the effects of matrix stiffness on adult cardiac side population (CSP) progenitor cell behavior. Ovine and murine CSP cells were isolated and cultured on polydimethylsiloxane substrates, replicating the elastic moduli of normal and fibrotic myocardium. Proliferation capacity and cell cycling were increased in CSP cells cultured on the stiff substrate with an associated reduction in cardiomyogeneic differentiation and accelerated cell ageing. In addition, culture on stiff substrate stimulated upregulation of extracellular matrix and adhesion proteins gene expression in CSP cells. Collectively, we demonstrate that microenvironment properties, including matrix stiffness, play a critical role in regulating progenitor cell functions of endogenous resident CSP cells. Understanding the effects of the tissue microenvironment on resident cardiac progenitor cells is a critical step toward achieving functional cardiac regeneration.
Matrix stiffness-modulated proliferation and secretory function of the airway smooth muscle cells
Authors: Shkumatov Artem , Thompson Michael , Choi Kyoung M. , Sicard Delphine , Baek Kwanghyun , Kim Dong Hyun , Tschumperlin Daniel J. , Prakash Y. S. , Kong Hyunjoon
Published: February 2015

Multiple pulmonary conditions are characterized by an abnormal misbalance between various tissue components, for example, an increase in the fibrous connective tissue and loss/increase in extracellular matrix proteins (ECM). Such tissue remodeling may adversely impact physiological function of airway smooth muscle cells (ASMCs) responsible for contraction of airways and release of a variety of bioactive molecules. However, few efforts have been made to understand the potentially significant impact of tissue remodeling on ASMCs. Therefore, this study reports how ASMCs respond to a change in mechanical stiffness of a matrix, to which ASMCs adhere because mechanical stiffness of the remodeled airways is often different from the physiological stiffness. Accordingly, using atomic force microscopy (AFM) measurements, we found that the elastic modulus of the mouse bronchus has an arithmetic mean of 23.1 ± 14 kPa (SD) (median 18.6 kPa). By culturing ASMCs on collagen-conjugated polyacrylamide hydrogels with controlled elastic moduli, we found that gels designed to be softer than average airway tissue significantly increased cellular secretion of vascular endothelial growth factor (VEGF). Conversely, gels stiffer than average airways stimulated cell proliferation, while reducing VEGF secretion and agonist-induced calcium responses of ASMCs. These dependencies of cellular activities on elastic modulus of the gel were correlated with changes in the expression of integrin-β1 and integrin-linked kinase (ILK). Overall, the results of this study demonstrate that changes in matrix mechanics alter cell proliferation, calcium signaling, and proangiogenic functions in ASMCs.
IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells
Authors: Sun Zhaojun , Fourcade Julien , Pagliano Ornella , Chauvin Joe-Marc , Sander Cindy , Kirkwood John M. , Zarour Hassane M.
Published: February 2015

Immune checkpoint inhibitors show great promise as therapy for advanced melanoma, heightening the need to determine the most effective use of these agents. Here, we report that programmed death-1high (PD-1high) tumor antigen (TA)–specific CD8+ T cells present at periphery and at tumor sites in patients with advanced melanoma upregulate IL10 receptor (IL10R) expression. Multiple subsets of peripheral blood mononucleocytes from melanoma patients produce IL10, which acts directly on IL10R+ TA-specific CD8+ T cells to limit their proliferation and survival. PD-1 blockade augments expression of IL10R by TA-specific CD8+ T cells, thereby increasing their sensitivity to the immunosuppressive effects of endogenous IL10. Conversely, IL10 blockade strengthened the effects of PD-1 blockade in expanding TA-specific CD8+ T cells and reinforcing their function. Collectively, our findings offer a rationale to block both IL10 and PD-1 to strengthen the counteraction of T-cell immunosuppression and to enhance the activity of TA-specific CD8+ T cell in advanced melanoma patients. Cancer Res; 75(8); 1635–44. ©2015 AACR.
Targeting MPS1 Enhances Radiosensitization of Human Glioblastoma by Modulating DNA Repair Proteins
Authors: Maachani Uday Bhanu , Kramp Tamalee , Hanson Ryan , Zhao Shuping , Celiku Orieta , Shankavaram Uma , Colombo Riccardo , Caplen Natasha J. , Camphausen Kevin , Tandle Anita
Published: February 2015

To ensure faithful chromosome segregation, cells use the spindle assembly checkpoint (SAC), which can be activated in aneuploid cancer cells. Targeting the components of SAC machinery required for the growth of aneuploid cells may offer a cancer cell–specific therapeutic approach. In this study, the effects of inhibiting Monopolar spindle 1, MPS1 (TTK), an essential SAC kinase, on the radiosensitization of glioblastoma (GBM) cells were analyzed. Clonogenic survival was used to determine the effects of the MPS1 inhibitor NMS-P715 on radiosensitivity in multiple model systems, including GBM cell lines, a normal astrocyte, and a normal fibroblast cell line. DNA double-strand breaks (DSB) were evaluated using γH2AX foci, and cell death was measured by mitotic catastrophe evaluation. Transcriptome analysis was performed via unbiased microarray expression profiling. Tumor xenografts grown from GBM cells were used in tumor growth delay studies. Inhibition of MPS1 activity resulted in reduced GBM cell proliferation. Furthermore, NMS-P715 enhanced the radiosensitivity of GBM cells by decreased repair of DSBs and induction of postradiation mitotic catastrophe. NMS-P715 in combination with fractionated doses of radiation significantly enhanced the tumor growth delay. Molecular profiling of MPS1-silenced GBM cells showed an altered expression of transcripts associated with DNA damage, repair, and replication, including the DNA-dependent protein kinase (PRKDC/DNAPK). Next, inhibition of MPS1 blocked two important DNA repair pathways. In conclusion, these results not only highlight a role for MPS1 kinase in DNA repair and as prognostic marker but also indicate it as a viable option in glioblastoma therapy.

Implications: Inhibition of MPS1 kinase in combination with radiation represents a promising new approach for glioblastoma and for other cancer therapies. Mol Cancer Res; 13(5); 852–62. ©2015 AACR.
Enhanced Interhemispheric Functional Connectivity Compensates for Anatomical Connection Damages in Subcortical Stroke
Authors: Liu Jingchun , Qin Wen , Zhang Jing , Zhang Xuejun , Yu Chunshui
Published: February 2015

Background and Purpose—

Motor recovery after stroke has been shown to be correlated with both the fractional anisotropy (FA) of the affected corticospinal tract (CST) and the interhemispheric resting-state functional connectivity (rsFC) of the primary motor cortex (M1). However, the role of the restoration or enhancement of the M1–M1 rsFC in motor recovery remains largely unknown. We aimed to clarify this issue by investigating the correlations between the M1–M1 rsFC and the integrity of the M1–M1 anatomic connection and the affected CST in chronic subcortical stroke patients with good motor outcomes.

Methods—

Twenty patients and 16 healthy controls underwent multimodal magnetic resonance imaging examinations. Diffusion tensor imaging was used to reconstruct the M1–M1 anatomic connection and bilateral CSTs. White matter integrity of these tracts was assessed using FA. Resting-state functional magnetic resonance imaging was used to calculate M1–M1 rsFC. Group differences in these measures were compared. Correlations between M1–M1 rsFC and FA of the M1–M1 anatomic connection and the affected CST were analyzed in patients with stroke.

Results—

Compared with healthy controls, patients with stroke exhibited significantly reduced FA in the affected CST and the M1–M1 anatomic connection and a significantly increased M1–M1 rsFC. The FA values of the affected CST were positively correlated with the M1–M1 anatomic connection, and these FA values were negatively correlated with the M1–M1 rsFC in these patients.

Conclusions—

Our findings suggest that the M1–M1 anatomic connection impairment is secondary to CST damage, and the M1–M1 rsFC enhancement may reflect compensatory or reactive neural plasticity in stroke patients with CST impairment.
Faith and Redemption in The Winter’s Tale
Authors: Benkert Lysbeth Em
Published: February 2015

As parishioners transformed church teachings into everyday practice during the late Tudor period, once doctrinally clear notions of faith, forgiveness, and grace became muddied. The Winter’s Tale reflects this complication in that Shakespeare both draws on the Catholic and Protestant understanding of these concepts, and underpins the action of the play with a notion of grace as flowing from faith that is both rational and emotional, scriptural and iconographic. The play represents this multivalent understanding of faith by disrupting audience expectations of genre and gender. The pastoral is not free from courtly corruption. Paulina’s admonitions issue from the mouth of a woman. Ultimately, Hermione does not simply intercede and offer comfort; she breaks the constraints genre would place on her, and becomes the source both of forgiveness and grace. Consequently, the source of Leontes’s greatest anxiety is also the source of his redemption, and that source is wife, mother, Mary, and Christ.
A Cross-Linguistic Perspective on the Acquisition of Causal Connectives and Relations
Authors: Zufferey Sandrine , Mak Willem M. , Sanders Ted J.M.
Published: February 2015

Causality is one of the most frequent coherence relations linking sentences together within texts and discourses, and mastering them is an essential part of acquiring a language. In this paper, we investigate the way French- and Dutch-speaking children acquire these relations depending on the way they are encoded in their mother tongue. From a cross-linguistic perspective, important differences exist in the communication of causal relations. While in some languages like Dutch, objective relations linking causes with consequences and subjective relations linking claims and conclusions are prototypically conveyed by a specific connective, in others like English and spoken French, a single connective is used in both cases. In this paper, we study the impact of these cross-linguistic differences for children’s ability to understand causal relations in a text. Our results indicate that French- and Dutch-speaking children have a similar ability to handle objective and subjective causal relations. In addition, subjective relations remain more difficult than objective relations even at the age of eight. We conclude that conceptual development sets the pace for lexical acquisition and discuss the causes for the acute difficulty of subjective relations.
On the Role of Inertial Instability in Stratosphere–Troposphere Exchange near Midlatitude Cyclones*
Authors: Rowe Shellie M. , Hitchman Matthew H.
Published: February 2015

In simulations of midlatitude cyclones with the University of Wisconsin Nonhydrostatic Modeling System (UWNMS), mesoscale regions with large negative absolute vorticity commonly occur in the upper troposphere and lower stratosphere (UTLS), overlying thin layers of air with stratospheric values of ozone and potential vorticity (PV). These locally enhanced stratosphere–troposphere exchange (STE) events are related to upstream convection by tracing negative equivalent potential vorticity (EPV) anomalies along back trajectories. Detailed agreement between the patterns of negative absolute vorticity, PV, and EPV—each indicators of inertial instability in the UTLS—is shown to occur in association with enhanced STE signatures. Results are presented for two midlatitude cyclones in the upper Midwest, where convection develops between the subpolar and subtropical jets.

Mesoscale regions of negative EPV air originate upstream in the boundary layer. As they are transported through convection, EPV becomes increasingly negative toward the tropopause. In association with the arrival of each large negative EPV anomaly, a locally enhanced poleward surge of the subpolar jet occurs, characterized by high turbulent kinetic energy and low Richardson number. Isosurfaces of wind speed show that gravity waves emanating from inertially unstable regions connect with and modulate the subpolar and subtropical jets simultaneously. Inertially unstable convective outflow surges can facilitate STE locally by fostering poleward acceleration in the UTLS, with enhanced folding of tropospheric air over stratospheric air underneath the poleward-moving jet.
3D Volumetric Analysis of Wind Turbine Wake Properties in the Atmosphere Using High-Resolution Doppler Lidar
Authors: Banta Robert M. , Pichugina Yelena L. , Brewer W. Alan , Lundquist Julie K. , Kelley Neil D. , Sandberg Scott P. , Alvarez II Raul J. , Hardesty R. Michael , Weickmann Ann M.
Published: February 2015

Wind turbine wakes in the atmosphere are three-dimensional (3D) and time dependent. An important question is how best to measure atmospheric wake properties, both for characterizing these properties observationally and for verification of numerical, conceptual, and physical (e.g., wind tunnel) models of wakes. Here a scanning, pulsed, coherent Doppler lidar is used to sample a turbine wake using 3D volume scan patterns that envelop the wake and simultaneously measure the inflow profile. The volume data are analyzed for quantities of interest, such as peak velocity deficit, downwind variability of the deficit, and downwind extent of the wake, in a manner that preserves the measured data. For the case study presented here, in which the wake was well defined in the lidar data, peak deficits of up to 80% were measured 0.6–2 rotor diameters (D) downwind of the turbine, and the wakes extended more than 11D downwind. Temporal wake variability over periods of minutes and the effects of atmospheric gusts and lulls in the inflow are demonstrated in the analysis. Lidar scanning trade-offs important to ensuring that the wake quantities of interest are adequately sampled by the scan pattern, including scan coverage, number of scans per volume, data resolution, and scan-cycle repeat interval, are discussed.
Public Perceptions of the Media Coverage of Irregular Immigration
Authors: Beyer Audun , Matthes Jörg
Published: February 2015

Irregular immigration has become a globally important topic. While there have been some studies on public opinion toward irregular immigration, virtually no studies have examined how audiences evaluate the media coverage of this issue. There is also a lack of comparative research. The aims of this article are to provide survey data on public opinion toward irregular immigration in the United States, France, and Norway as well as a comparative analysis of public perceptions of the news coverage. Findings suggest that irregular immigration remains a highly salient issue in public opinion in all three countries. Furthermore, public opinion is generally critical and skeptic toward irregular immigration and immigrants, and differences between countries regarding the coverage of the issue in national mainstream media do not necessarily seem to be mirrored in public opinion. The survey data also suggest that citizens in all three countries tend to believe that the negative aspects of irregular immigration such as crimes or border control receive too little coverage whereas perspectives more positive to irregular immigration receive too much. Implications for further comparative research on public opinion and media coverage are discussed.
Faces of an Invisible Population
Authors: Figenschou Tine Ustad , Thorbjørnsrud Kjersti
Published: February 2015

Based on a quantitative, comparative analysis of U.S., French, and Norwegian news media, this article examines the use of human interest stories in the coverage of irregular immigration. In an innovative design, it systematically analyzes how human interest framing is related to the frequency and complexity of dominant arguments and perspectives (issue-specific frames). In contrast to the extant literature, arguing that news on immigration reduces immigrants to dangerous and anonymous threats, the article finds that about half the news stories studied have a human face or example. Moreover, these human interest articles tend to frame the issue from the immigrants’ perspective, describing their personal stories and struggle. This result nuances the commonly held assumption that human interest frames signal declining news quality, as the number and range of arguments presented are not significantly reduced when human narratives are employed. The prevalence of human interest frames is highest in Norway, where we also identify a reduction in frame complexity in human interest stories, indicating the need to rethink the democratic corporatist model in media system theory.
Who Says What or Nothing at All? Speakers, Frames, and Frameless Quotes in Unauthorized Immigration News in the United States, Norway, and France
Authors: Benson Rodney , Wood Tim
Published: February 2015

Determining the speakers and arguments that dominate the news has long been a core task of media sociology. Yet systematic evidence linking the two—who says what or nothing at all—is lacking in news analysis, especially on the important issue of immigration. In this article, we analyze quoted sources and issue frames in U.S., French, and Norwegian news coverage of unauthorized immigration during 2011 and 2012. Supporting claims of transnational media homogenization, we find most quotes are “frameless,” that is, do not contain any substantial arguments addressing the problems, causes, or solutions associated with immigration. Of those quotes that do offer frames, problem frames are far more common than causes and solutions. Across nations and media types, government sources dominate the news, focusing on problems for society, while pro-immigration associations and unaffiliated individuals help account for overall greater attention to problems for immigrants. On the other hand, providing limited support for structural variation, less narrative-driven French media featured fewer frameless quotes and also tended to offer more cause and solution frames than U.S. or Norwegian media; dominant frames varied notably across nations; and elite right newspapers were more likely to quote anti-immigration speakers and emphasize problems for society than other types of outlets. We also find that the mediated immigration “debate” is often only a series of opposed monologues; even ideologically diverse groups such as unaffiliated citizens tend to be linked to a small range of frames, suggesting that “who says what” is not a reflection of society, but rather the outcome of journalistic practices and sources’ rhetorical tactics.
Human Interest Framing of Irregular Immigration
Authors: Aalberg Toril , Beyer Audun
Published: February 2015

The media have a strong tendency to frame political issues with a focus on personal and emotional cases. We do not, however, know if there is a close link between the news media’s use of these frames and the news preferences of the public. Such a close relationship may exist either because human interest news coverage is driven by audience demand or because the public might be influenced by the degree of individual news stories in the news. On the other hand, the audience’s news preferences may be unrelated to the actual media coverage on irregular immigration due to citizens’ selective media exposure, which may be driven by political predispositions. Based on a large quantitative content analysis conducted in the United States, France, and Norway and a following public opinion survey in the same countries, we find that the application of a human interest frame in a country’s news coverage of irregular immigration does not correspond with the public’s preferences for this type of news coverage. On the individual level, our findings demonstrate that liberal audience groups favor human interest–framed news coverage, while conservatives do not agree that individual news stories would provide a better understanding of the issue of irregular immigration.
The prevalence and correlates of childhood trauma in patients with early psychosis
Authors: Duhig Michael , Patterson Sue , Connell Melissa , Foley Sharon , Capra Carina , Dark Frances , Gordon Anne , Singh Saveena , Hides Leanne , McGrath John J , Scott James
Published: February 2015

Objective:

To describe the prevalence and demographic, clinical and functional correlates of childhood trauma in patients attending early psychosis clinics.

Method:

Participants were recruited from outpatients attending four early psychosis services. Exposure to childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Psychopathology was measured using the Positive and Negative Syndrome Scale and the Depression, Anxiety and Stress Scale. Social and vocational functioning and substance use were also assessed.

Results:

Over three-quarters of the 100 patients reported exposure to any childhood trauma. Emotional, physical and sexual abuse were reported by 54%, 23% and 28% of patients, respectively, while 49% and 42% of patients reported emotional and physical neglect, respectively. Female participants were significantly more likely to be exposed to emotional and sexual abuse. Exposure to childhood trauma was correlated with positive psychotic symptoms and higher levels of depressive, anxiety and stress symptoms; however, it had no impact on social or vocational functioning or recent substance use.

Conclusion:

Exposure to childhood trauma was common in patients with early psychosis, and associated with increased symptomatology. Existing recommendations that standard clinical assessment of patients with early psychosis should include inquiry into exposure to childhood trauma are supported.
Bioinspired neuromorphic module based on carbon nanotube/C60/polymer composite
Authors: Kim Kyunghyun , Tudor Andrew , Chen Chia-Ling , Lee Dongwon , Shen Alex M , Chen Yong
Published: February 2015

It is extremely challenging to imitate neural networks with their high-speed parallel signal processing, low power consumption, and intelligent learning capability. In this work, we report a spike neuromorphic module composed of “synapstors” made from carbon nanotube/C60/polyimide composite and “CMOS Somas” made from complementary metal-oxide semiconductor electronic circuits. The “synapstor” emulates a biological synapse with spike signal processing, plasticity, and memory; the “CMOS Soma” emulates a Soma in a biological neuron with analog parallel signal processing and spike generation. Spikes, short potential pulses, and input to the synapstors trigger postsynaptic currents and generate output spikes from the CMOS Somas in a parallel manner with low power consumption. The module can be modified dynamically on the basis of the synapstor plasticity. Spike neuromorphic modules could potentially be scaled up to emulate biologic neural networks and their functions.
Different Contexts, Different Effects?
Authors: Kleiner Sibyl , Schunck Reinhard , Schömann Klaus
Published: February 2015

This paper takes a comparative approach to the topic of work time and health, asking whether weekly work hours matter for mental health. We hypothesize that these relationships differ within the United States and Germany, given the more regulated work time environments within Germany and the greater incentives to work long hours in the United States. We further hypothesize that German women will experience greatest penalties to long hours. We use data from the German Socioeconomic Panel and the National Longitudinal Survey of Youth to examine hours effects on mental health score at midlife. The results support our initial hypothesis. In Germany, longer work time is associated with worse mental health, while in the United States, as seen in previous research, the associations are more complex. Our results do not show greater mental health penalties for German women and suggest instead a selection effect into work hours operating by gender.
Crafting ministers
Authors: Taylor Simon J.
Published: February 2015

Using Richard Sennett’s work on craftsmanship, three locations of ministerial formation are examined: the local church, the training minister and the denominational church. From this examination, the article suggests that issues around congregational involvement, vulnerability and fallibility, and vocation require attention in the process of formation.
Credibility and obedience: Memories of the Sheffield Industrial Mission
Authors: Atkinson Mike H.
Published: February 2015

This paper begins where I started my ministry in 1959, outlining the missionary nature of the Sheffield Industrial Mission from 1944 to 1966, and examines its missiological base and its problems with the Church of England’s hierarchy. It focuses particularly on the work of Bishops Leslie Hunter and Ted Wickham.
The ‘Bhojpuriya’ Mumbaikar
Authors: Shrivastava Madhusri
Published: February 2015

Using Cultural Studies as the framework, this study investigates how north Indian migrants living in Kandivali east, Mumbai, exercise agency and appropriate Bhojpuri media texts to maintain their regional identity. Bhojpuri, a dialect of Hindi, has emerged as the lingua franca of these migrants hailing from the Indian states of Uttar Pradesh and Bihar. Beleaguered by the identity politics of the host city, the migrants turn to the Bhojpuri media to sustain the shared cultural beliefs that permeate their social relations. Familiar images in the media texts ensure continuity with tradition, feeding the resurgent pride of the community. The migrants’ aggressive defence of all things Bhojpuri, as well as their desire to sanitise Bhojpuri media of its bawdiness, is a manifestation of their embattled identities seeking validation.

 This article examines how the Bhojpuri media are intertwined with the migrants’ everyday realities. The media reinforce gender roles, alleviate anxieties and gratify desires vicariously. Media representations meld cultural memory with the migrants’ newly acquired understanding of the metropolis. In the process, hybrid identities are being fashioned by people on different points of the socio-economic axis.
Virtue ethics – an old answer to a new dilemma? Part 1. Problems with contemporary medical ethics
Authors: Misselbrook David
Published: February 2015

The commonest practical model used in contemporary medical ethics is Principlism. Yet, while Principlism is a widely accepted consensus statement for ethics, the moral theory that underpins it faces serious challenges in its attempt to provide a coherent and accepted system of moral analysis. This inevitably challenges the stability of such a consensus statement and makes it vulnerable to attack by competitors such as preference consequentialism. This two-part paper proposes an inclusive version of virtue theory as a more grounded system of moral analysis.