bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phosphoinositide 3-kinase γ plays a critical role in bleomycin-induced pulmonary inflammation and fibrosis in mice
Authors: Russo Remo C , Garcia Cristiana C , Barcelos Lucíola S , Rachid Milene A , Guabiraba Rodrigo , Roffê Ester , Souza Adriano L S , Sousa Lirlândia P , Mirolo Massimiliano , Doni Andrea , Cassali Geovanni D , Pinho Vanessa , Locati Massimo , Teixeira Mauro M 
Published: November 2010

ABSTRACTPI3Kγ is central in signaling diverse arrays of cellular functions and inflammation. Pulmonary fibrosis is associated with pulmonary inflammation, angiogenesis, and deposition of collagen and is modeled by instillation of bleomycin. The role of PI3Kγ in mediating bleomycin-induced pulmonary inflammation and fibrosis in mice and potential mechanisms involved was investigated here. WT or PI3Kγ KO mice were instilled with bleomycin and leukocyte subtype influx, cytokine and chemokine levels, and angiogenesis and tissue fibrosis evaluated. The activation of lung-derived leukocytes and fibroblasts was evaluated in vitro. The relevance of PI3Kγ for endothelial cell function was evaluated in HUVECs. PI3Kγ KO mice had greater survival and weight recovery and less fibrosis than WT mice after bleomycin instillation. This was associated with decreased production of TGF-β1 and CCL2 and increased production of IFN-γ and IL-10. There was reduced expression of collagen, fibronectin, α-SMA, and von Willebrand factor and decreased numbers and activation of leukocytes and phosphorylation of AKT and IκB-α. PI3Kγ KO mice had a reduced number and area of blood vessels in the lungs. In vitro, treatment of human endothelial cells with the PI3Kγ inhibitor AS605240 decreased proliferation, migration, and formation of capillary-like structures. AS605240 also decreased production of collagen by murine lung-derived fibroblasts. PI3Kγ deficiency confers protection against bleomycin-induced pulmonary injury, angiogenesis, and fibrosis through the modulation of leukocyte, fibroblast, and endothelial cell functions. Inhibitors of PI3Kγ may be beneficial for the treatment of pulmonary fibrosis.
The Involvement of Specific PKC Isoenzymes in Phorbol Ester-Mediated Regulation of Steroidogenic Acute Regulatory Protein Expression and Steroid Synthesis in Mouse Leydig Cells
Authors: Manna Pulak R. , Soh Jae-Won , Stocco Douglas M. 
Published: November 2010

AbstractProtein kinase C (PKC) is a multigene family of serine/threonine kinases. PKC is involved in regulating adrenal and gonadal steroidogenesis; however, the functional relevance of the different PKC isoenzymes remains obscure. In this study, we demonstrate that MA-10 mouse Leydig tumor cells express several PKC isoforms to varying levels and that the activation of PKC signaling, by phorbol 12-myristate 13-acetate (PMA) elevated the expression and phosphorylation of PKCα, -δ, -ε, and -μ/protein kinase D (PKD). These responses coincided with the expression of the steroidogenic acute regulatory (StAR) protein and progesterone synthesis. Targeted silencing of PKCα, δ, and ε and PKD, using small interfering RNAs, resulted in deceases in basal and PMA-mediated StAR and steroid levels and demonstrated the importance of PKD in steroidogenesis. PKD was capable of controlling PMA and cAMP/PKA-mediated synergism involved in the steroidogenic response. Further studies pointed out that the regulatory events effected by PKD are associated with cAMP response element-binding protein (CREB) and c-Jun/c-Fos-mediated transcription of the StAR gene. Chromatin immunoprecipitation studies revealed that the activation of phosphorylated CREB, c-Jun, and c-Fos by PMA was correlated with in vivo protein-DNA interactions and the recruitment of CREB-binding protein, whereas knockdown of PKD suppressed the association of these factors with the StAR promoter. Ectopic expression of CREB-binding protein enhanced the trans-activation potential of CREB and c-Jun/c-Fos in StAR gene expression. Using EMSA, a −83/−67-bp region of the StAR promoter was shown to bind PKD-transfected MA-10 nuclear extract in a PMA-responsive manner, targeting CREB and c-Jun/c-Fos proteins. These findings provide evidence for the presence of multiple PKC isoforms and demonstrate the molecular events by which selective isozymes, especially PKD, influence PMA/PKC signaling involved in the regulation of the steroidogenic machinery in mouse Leydig cells.
Identification of Adipocyte Genes Regulated by Caloric Intake
Authors: Franck Niclas , Gummesson Anders , Jernås Margareta , Glad Camilla , Svensson Per-Arne , Guillot Gilles , Rudemo Mats , Nyström Fredrik H. , Carlsson Lena M. S. , Olsson Bob 
Published: November 2010

abstract

Context:
Changes in energy intake have marked and rapid effects on metabolic functions, and some of these effects may be due to changes in adipocyte gene expression that precede alterations in body weight.

Objective:
The aim of the study was to identify adipocyte genes regulated by changes in caloric intake independent of alterations in body weight.

Research Design and Methods:
Obese subjects given a very low-caloric diet followed by gradual reintroduction of ordinary food and healthy subjects subjected to overfeeding were investigated. Adipose tissue biopsies were taken at multiple time-points, and gene expression was measured by DNA microarray. Genes regulated in the obese subjects undergoing caloric restriction followed by refeeding were identified using two-way ANOVA corrected with Bonferroni. From these, genes regulated by caloric restriction and oppositely during the weight-stable refeeding phase were identified in the obese subjects. The genes that were also regulated, in the same direction as the refeeding phase, in the healthy subjects after overfeeding were defined as being regulated by caloric intake. Results were confirmed using real-time PCR or immunoassay.

Results:
Using a significance level of P &lt; 0.05 for all comparisons, 52 genes were down-regulated, and 50 were up-regulated by caloric restriction and regulated in the opposite direction by refeeding and overfeeding. Among these were genes involved in lipogenesis (ACLY, ACACA, FASN, SCD), control of protein synthesis (4EBP1, 4EBP2), β-oxidation (CPT1B), and insulin resistance (PEDF, SPARC).

Conclusions:
Metabolic genes involved in lipogenesis, protein synthesis, and insulin resistance are central in the transcriptional response of adipocytes to changes in caloric intake.
TNF-α Antagonism with Etanercept Decreases Glucose and Increases the Proportion of High Molecular Weight Adiponectin in Obese Subjects with Features of the Metabolic Syndrome
Authors: Stanley Takara L. , Zanni Markella V. , Johnsen Stine , Rasheed Sarah , Makimura Hideo , Lee Hang , Khor Victor K. , Ahima Rexford S. , Grinspoon Steven K. 
Published: November 2010

Context and Objective: Obesity is associated with activation of the TNF-α system, increased inflammatory markers, and insulin resistance. Although studies in rodents suggest that attenuation of TNF activity improves glucose homeostasis, the effect of prolonged inhibition of TNF-α with etanercept on inflammation and glucose homeostasis in a human model of obesity is not known.
Design and Participants: Forty obese subjects with features of metabolic syndrome were randomized to etanercept or placebo, 50 mg twice weekly for 3 months, followed by 50 mg once weekly for 3 months.
Outcome Measures: Subjects underwent oral glucose tolerance testing and measurement of serum inflammatory biomarkers and adipokines. Subcutaneous fat biopsy was performed in a subset for measurement of adipokine and TNF-α mRNA expression.
Results: Visceral adiposity was significantly associated with serum concentrations of TNF receptor 1 (TNFR1), TNFR2, and vascular cell adhesion molecule-1 and adipose tissue expression of TNF-α and SOCS-3 (all P &lt; 0.05). Insulin resistance as assessed by homeostasis model assessment was significantly associated with TNFR1, C-reactive protein, IL-6, and soluble intracellular adhesion molecule-1 (sICAM-1) (all P &lt; 0.05). Etanercept significantly improved fasting glucose (treatment effect vs. placebo over 6 months, −10.8 ± 4.4%, P = 0.02). Etanercept also increased the ratio of high molecular weight adiponectin to total adiponectin (+22.1 ± 9.2% vs. placebo, P = 0.02), and decreased levels of sICAM-1 (−11 ± 2% vs. placebo, P &lt; 0.0001). In contrast, body composition, lipids, C-reactive protein, and IL-6 were unchanged after 6 months.
Conclusions: Prolonged therapy with etanercept improved fasting glucose, increased the ratio of high molecular weight to total adiponectin, and decreased sICAM-1 in obese subjects with abnormal glucose homeostasis and significant subclinical inflammation.
A new look at metaphorical creativity in cognitive linguistics
Authors: Kövecses Zoltán 
Published: November 2010

Abstract
Where do we recruit novel and unconventional conceptual materials from when we speak, think and act metaphorically, and why? This question has been partially answered in the cognitive linguistic literature but, in my view, a crucial aspect of it has been left out of consideration or not dealt with in the depth it deserves: it is the effect of various kinds of context on metaphorical conceptualization. Of these, I examine the following: (1) the immediate physical setting, (2) what we know about the major entities participating in the discourse, (3) the immediate cultural context, (4) the immediate social setting, and (5) the immediate linguistic context itself. I suggest that we recruit conceptual materials for metaphorical purposes not only from bodily experience but also from all of these various contexts. Since the contexts can be highly variable, the metaphors used will often be variable, novel, and unconventional. The phenomenon can be observed in both everyday forms of language and literary texts.
Does prosodic constituency signal relative predictability? A Smooth Signal Redundancy hypothesis
Authors: Turk Alice 
Published: November 2010

AbstractThis paper explores issues relating to signaling word boundaries from the perspective of Aylett's Smooth Signal Redundancy proposal (Aylett, Stochastic suprasegmentals: Relationships between redundancy, prosodic structure and care of articulation in spontaneous speech, University of Edinburgh, 2000, Aylett and Turk, Language and Speech 47: 31–56, 2004) that language has evolved to spread redundancy, i.e. recognition likelihood, evenly throughout utterances. In Aylett's proposal, information that enables listeners to identify sequences of elements in an utterance (signal redundancy) comes from two sources: a) language redundancy, recognition likelihood based on lexical, syntactic, semantic, pragmatic and other factors, and b) acoustic redundancy, recognition likelihood based on acoustic salience. Smooth signal redundancy is achieved by a complementary relationship between language redundancy and acoustic redundancy that is implemented via prosodic structure.While Aylett and Turk (Language and Speech 47: 31–56, 2004) present the case for prosodic prominence as a lever for modulating the acoustic salience of syllables, the current paper proposes that prosodic constituency also fulfils this function for words. The current paper proposes that the signal redundancy, or recognition likelihood, of words can be manipulated by signaling their boundaries, and that the occurrence and strength of these boundary markers correlates inversely with language redundancy. Prosodic constituency implements the complementary relationship between language redundancy and word boundary salience.Smooth Signal Redundancy provides an integrated explanation for a set of properties relating to prosodic constituent structure.
Talking about quantities in space: Vague quantifiers, context and similarity
Authors: Coventry Kenny R. , Cangelosi Angelo , Newstead Stephen E. , Bugmann Davi 
Published: November 2010

AbstractIn this paper we examine how vague quantifiers, such asfew, several, lots of, map onto non-linguistic number systems. In particular our focus is to examine how judgements about vague quantifiers are affected by the presence of objects in visual scenes other than those being referred to. An experiment is presented that manipulated the number of objects in a visual scene (men playing golf; the ‘focus’ objects) together with the number of other objects in those scenes and their similarity—in terms of form (women or crocodiles) and function (playing golf, not playing golf)—to the focus objects. We show that the number of other objects in a scene impacts upon quantifiers judgements even when those objects are in a different category to the focus objects. We discuss the results in terms of the mapping between the large approximate number (estimation) system and language.
Compound stress assignment by analogy: the constituent family bias
Authors: Plag Ingo 
Published: November 2010

Abstract
This paper tests the hypothesis that stress assignment to English compounds works on the basis of analogy. In particular, the role of the constituent family, i.e. the set of compounds that share the same right or left constituent with a given compound, is investigated. On the basis of large amounts of data from three different corpora it is shown that the tendency towards a certain kind of stress pattern within the constituent families of a given compound is a strong predictor for stress assignment. This challenges rule-based approaches to compound stress assignment and lends independent evidence to exemplar-based approaches to language structure.
Insulin Resistance, Defective Insulin-Mediated Fatty Acid Suppression, and Coronary Artery Calcification in Subjects With and Without Type 1 Diabetes
Authors: Schauer Irene E. , Snell-Bergeon Janet K. , Bergman Bryan C. , Maahs David M. , Kretowski Adam , Eckel Robert H. , Rewers Marian 
Published: October 2010

OBJECTIVE
To assess insulin action on peripheral glucose utilization and nonesterified fatty acid (NEFA) suppression as a predictor of coronary artery calcification (CAC) in patients with type 1 diabetes and nondiabetic controls.

RESEARCH DESIGN AND METHODS
Insulin action was measured by a three-stage hyperinsulinemic-euglycemic clamp (4, 8, and 40 mU/m2/min) in 87 subjects from the Coronary Artery Calcification in Type 1 Diabetes cohort (40 diabetic, 47 nondiabetic; mean age 45 ± 8 years; 55% female).

RESULTS
Peripheral glucose utilization was lower in subjects with type 1 diabetes compared with nondiabetic controls: glucose infusion rate (mg/kg FFM/min) = 6.19 ± 0.72 vs. 12.71 ± 0.66, mean ± SE, P &lt; 0.0001, after adjustment for age, sex, BMI, fasting glucose, and final clamp glucose and insulin. Insulin-induced NEFA suppression was also lower in type 1 diabetic compared with nondiabetic subjects: NEFA levels (μM) during 8 mU/m2/min insulin infusion = 370 ± 27 vs. 185 ± 25, P &lt; 0.0001, after adjustment for age, sex, BMI, fasting glucose, and time point insulin. Lower glucose utilization and higher NEFA levels, correlated with CAC volume (r = −0.42, P &lt; 0.0001 and r = 0.41, P &lt; 0.0001, respectively) and predicted the presence of CAC (odds ratio [OR] = 0.45, 95% CI = 0.22–0.93, P = 0.03; OR = 2.4, 95% CI = 1.08–5.32, P = 0.032, respectively). Insulin resistance did not correlate with GHb or continuous glucose monitoring parameters.

CONCLUSIONS
Type 1 diabetic patients are insulin resistant compared with nondiabetic subjects, and the degree of resistance is not related to current glycemic control. Insulin resistance predicts the extent of coronary artery calcification and may contribute to the increased risk of cardiovascular disease in patients with type 1 diabetes as well as subjects without diabetes.
Outstanding Scientific Achievement Award Lecture 2010: Deconstructing Leptin: From Signals to Circuits
Authors: Myers Martin G. 
Published: October 2010

Martin G. Myers Jr., MD, PhD, received the American Diabetes Association's prestigious 2010 Outstanding Scientific Achievement Award at the Association's 70th Scientific Sessions in Orlando, Florida, on 28 June 2010. The Outstanding Scientific Achievement Award recognizes outstanding scientific achievement in the field of diabetes, taking into consideration independence of thought and originality.
Currently the Marilyn H. Vincent Professor of Diabetes Research at the University of Michigan, Ann Arbor, and Associate Professor in internal medicine and in molecular and integrative physiology at the University of Michigan Medical School, Dr. Myers began his impressive track record in diabetes research as a graduate student in the laboratory of Dr. Morris White at the Joslin Diabetes Center/Harvard Medical School. There, Dr. Myers deciphered many of the insulin signaling pathways engaged by insulin receptor substrate proteins.
Following his graduation from the Harvard MD-PhD Program in 1997, Dr. Myers was promoted to instructor in medicine at the Joslin Diabetes Center/Harvard Medical School. He began his independent work by building a molecular framework for understanding the mechanisms of leptin signaling, including how individual phosphorylation sites on the leptin receptor recruit distinct signaling molecules. He was promoted to assistant professor at Harvard in 1999.
In 2004, Dr. Myers moved to the University of Michigan, where he built upon the molecular framework of leptin signaling to probe the regulation of metabolism by individual leptin signals. Dr. Myers' laboratory revealed the specificity of leptin signals in metabolic control, including the role for leptin-STAT3 signaling in the regulation of energy balance and glucose homeostasis. His group also defined roles for leptin receptor feedback inhibition and hypothalamic mTor signaling in metabolism.
Dr. Myers' laboratory has recently developed novel molecular approaches to elucidate the leptin-regulated brain circuits that contribute to metabolic control, enabling the discovery of novel brain systems and their functions.
In 1998, Dr. Myers received the American Diabetes Association's Career Development Award for his scientific abilities. Dr. Myers' current support includes the National Institute of Diabetes and Digestive and Kidney Diseases MERIT Award.
Glycated Hemoglobin and the Risk of Kidney Disease and Retinopathy in Adults With and Without Diabetes
Authors: Selvin Elizabeth , Ning Yang , Steffes Michael W. , Bash Lori D. , Klein Ronald , Wong Tien Y. , Astor Brad C. , Sharrett A. Richey , Brancati Frederick L. , Coresh Josef 
Published: October 2010

OBJECTIVE
Glycated hemoglobin was recently recommended for use as a diagnostic test for diabetes. We examined the association between 2010 American Diabetes Association diagnostic cut points for glycated hemoglobin and microvascular outcomes (chronic kidney disease, end-stage renal disease [ESRD], and retinopathy) and formally tested for the presence of risk thresholds in the relationships of glycated hemoglobin with these outcomes.

RESEARCH DESIGN AND METHODS
Prospective cohort and cross-sectional analyses of 11,357 participants (773 with a history of diagnosed diabetes) from the Atherosclerosis Risk in Communities (ARIC) Study.

RESULTS
During a median of 14 years of follow-up of individuals without diagnosed diabetes at baseline, clinical categories of glycated hemoglobin were associated with risk of chronic kidney disease, with adjusted hazard ratios (HRs) of 1.12 (0.94–1.34) and 1.39 (1.04–1.85) for glycated hemoglobin 5.7–6.4% and ≥6.5%, respectively, as compared with &lt;5.7% (P trend = 0.002). The corresponding HRs for ESRD were 1.51 (0.82–2.76) and 1.98 (0.83–4.73), respectively (P trend = 0.047). In the absence of diagnosed diabetes, glycated hemoglobin was cross sectionally associated with the presence of moderate/severe retinopathy, with adjusted odds ratios of 1.42 (0.69–2.92) and 2.91 (1.19–7.11) for glycated hemoglobin 5.7–&lt;6.5% and ≥6.5%, respectively, compared with &lt;5.7% (P trend = 0.011). Risk associations were stronger among individuals with a history of diabetes. We did not observe significant thresholds in the associations of glycated hemoglobin with kidney disease risk or retinopathy.

CONCLUSIONS
These data from a community-based, biracial population support the use of new 2010 American Diabetes Association glycated hemoglobin cut points for the diagnosis of diabetes.
Safety and Efficacy of Ranibizumab in Diabetic Macular Edema (RESOLVE Study)
Authors: Massin Pascale , Bandello Francesco , Garweg Justus G. , Hansen Lutz L. , Harding Simon P. , Larsen Michael , Mitchell Paul , Sharp Dianne , Wolf-Schnurrbusch U.E.K. , Gekkieva Margarita , Weichselberger Andreas , Wolf Sebastian 
Published: October 2010

OBJECTIVE
The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center.

RESEARCH DESIGN AND METHODS
This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age &gt;18 years, type 1 or 2 diabetes, central retinal thickness [CRT] ≥300 μm, and best corrected visual acuity [BCVA] of 73–39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n = 51 each) or sham (n = 49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n = 151, patients receiving ≥1 injection).

RESULTS
At month 12, mean ± SD BCVA improved from baseline by 10.3 ± 9.1 letters with ranibizumab and declined by 1.4 ± 14.2 letters with sham (P &lt; 0.0001). Mean CRT reduction was 194.2 ± 135.1 μm with ranibizumab and 48.4 ± 153.4 μm with sham (P &lt; 0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P &lt; 0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab.

CONCLUSIONS
Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety.
Vitamin D Deficiency and Coronary Artery Calcification in Subjects With Type 1 Diabetes
Authors: Young Kendra A. , Snell-Bergeon Janet K. , Naik Ramachandra G. , Hokanson John E. , Tarullo David , Gottlieb Peter A. , Garg Satish K. , Rewers Marian 
Published: October 2010

OBJECTIVE
The objective of this study is to examine the relationship among serum levels of 25-hydroxyvitamin D (25[OH]D), polymorphisms in vitamin D-associated genes, and the presence and progression of coronary artery calcification (CAC) in adults with type 1 diabetes.

RESEARCH DESIGN AND METHODS
This prospective study included 374 non-Hispanic white individuals with type 1 diabetes (mean age 40 ± 9 years; 46% were male). CAC was measured at the baseline and 3- and 6-year follow-up visits were determined by electron beam computed tomography. Serum 25[OH]D levels were measured by liquid chromatography tandem mass spectrometry at the 3-year visit.

RESULTS
Normal (&gt;30 ng/mL), insufficient (20–30 ng/mL), and deficient (&lt;20 ng/mL) 25-[OH]D levels were present in 65%, 25%, and 10% of the individuals with type 1 diabetes, respectively. 25[OH]D deficiency was associated with the presence of CAC at the 3-year visit, odds ratio (OR) = 3.3 (95% CI 1.6–7.0), adjusting for age, sex, and hours of daylight. In subjects free of CAC at the 3-year visit, 25[OH]D deficiency predicted the development of CAC over the next 3 years in those with the vitamin D receptor M1T CC genotype (OR = 6.5 [1.1–40.2], P = 0.04) than in those with the CT or TT genotype (OR = 1.6 [0.3–8.6], P = 0.57).

CONCLUSIONS
Vitamin D deficiency independently predicts prevalence and development of CAC, a marker of coronary artery plaque burden, in individuals with type 1 diabetes.