bluuebunny/crossref_metadata_2025 huggingface dataset:
Light and shadow: the status of Italian geology around 1807
Authors: Vai Gian Battista
Published: August 2009

The stratigraphical approach and geological mapping of William Smith in England and Georges Cuvier in France gave birth to modern geology. However, before 1815 neither used the word ‘geology’, a term first coined by Ulisse Aldrovandi in 1603. At the turn of the nineteenth century most leading geoscientists were based in France and Germany, but those in Britain were poised to take over the lead. After three centuries of dominance in science and geology, was Italian geology in decline? A review of the works of Italian geologists and the role these played in disseminating Italian geological research has been undertaken to examine this question. The French Revolution and the Napoleonic wars shocked the Italian states, disrupted the economic order and discontinued the progress of science. Nevertheless, from 1759 to 1859 over 40 classic papers in geology were published in Italy. Among them, Gian Battista Brocchi's
Conchiologia Fossile
is the most renowned for having inspired Charles Lyell's work. In the middle decades of the nineteenth century Italian geoscientists made up the majority of foreign members of both the French and English geological societies. The Italian Geological Society was not formed until 1881. This was largely due to the earlier political fragmentation of Italy into many small states.
Practical geology and the early Geological Society
Authors: Veneer Leucha
Published: August 2009

Historical accounts of the interests and activities of the Geological Society of London have often portrayed the Society as indifferent to practical geology and as being focused instead on fieldwork and gentlemanly debate. However, the Society's founders displayed a wide range of interests in the applications of geology and mineralogy. The British Mineralogical Society had been established in 1799 to elucidate the mineral history of Britain and to amass practical information for the benefit of British mining, and the members of this society later brought with them into the Geological Society their practical and mineralogical interests. Close study of the early projects of the Geological Society shows that the membership at this time had a great interest in the practical applications of geology, and especially mining. However, it is clear that there was a significant change in the Society's programmatic activities in the late 1810s and 1820s, when the Society moved away from practical geology. These changes reflected a changing membership.
The Geological Society and its official recognition, 1824–1828
Authors: Boylan Patrick J.
Published: August 2009

Under the 1824–1826 presidency of William Buckland, the still young Geological Society negotiated with the Government a very important advance in terms of the official recognition of the Society and the emerging science of geology that the Society represented, by obtaining a prestigious new legal status in the form of a Royal Charter of Incorporation. Then, under William Fitton's presidency, in 1828 the government granted the Society rent-free accommodation for both its meetings and its rapidly growing library and museum in the government offices in Somerset House, London. The objectives behind these two related moves are considered, although it is unfortunate that little of the detailed background documentation to these developments seem to have been preserved within either Society or government records. A brief account of what might have been – the possibility of seeking a Coat of Arms for the newly Chartered Society – concludes the story.
The first female Fellows and the status of women in the Geological Society of London
Authors: Burek Cynthia V.
Published: August 2009

Women were first permitted to become Fellows of the Geological Society of London in 1919. Eight joined in May of that year and then in June a further two were admitted. By February 1922 there were 21 female Fellows. The Geological Society had opened its doors to women and, after an initial rush, there was a slow trickle. However, there were a number of highly regarded female geologists before this time, and several of them received grants, medals and, indeed, submitted papers, although they were not always permitted to read these themselves. Some of the first female Fellows have disappeared without trace, but the contributions of others are significant. As well as being educationalists, they were expert in many different areas of geology, with palaeontology and stratigraphy featuring strongly. Few, however, stayed on in this male-dominated arena once they married and had children. It seems there was no common reason for these women to seek membership of the Geological Society, other than their love of geology, but membership brought them recognition and status. They led the way as role models for future female Fellows and were the first of many women to play a significant role in the Geological Society's history.
Walk with the Founding Fathers
Authors: Rudwick Martin J. S.
Published: August 2009

Part of the History of Geology Group's Bicentenary celebrations included a field trip to the Isle of Wight entitled ‘Walk with the Founding Fathers’. It followed in the footsteps of Thomas Webster as he attempted to understand the island's complex geology almost 200 years ago. The material used for the field trip – prepared by Martin Rudwick – is reprinted here. The logistics of the weekend were organized by History of Geology Group committee members, John Mather and Dick Moody, and the trip was led by Professors Martin Rudwick and Hugh Torrens.
Chemists get down to Earth
Authors: Knight David
Published: August 2009

Four of the Founding Fathers of the Geological Society, Arthur Aikin, Richard Knight, William Hasledine Pepys and Humphry Davy, were chemists, coming to geology through mineralogy. The nature and status of chemistry in 1807 helps us to see why, and we note that chemists were down to earth and empirical minded in contrast to the speculative geologists of the eighteenth century. These four, a closely linked and coherent group, made various and important contributions to the scientific world in London generally, and to the Geological Society in particular. Nevertheless, Davy had very different expectations of the Society from the others: he wanted a dining club under the aegis of the Royal Society (of which he was Secretary), but they (successfully) sought a formal and separate body in which papers would be read and published. By the time of Davy's death in 1829, the Society was chartered and flourishing; and the rise of palaeontology had made chemistry much less central to geology.
The rise of geology as a science in Germany around 1800
Authors: Guntau Martin
Published: August 2009

Special attention was paid to geology and mineralogy in the German countries around 1800. Following the final decades of the eighteenth century, during which an essential understanding of the natural history of the Earth was gained, geology developed into an independent science. Mining was dependent on geological findings, which in turn promoted geology. This process was driven by lecturers in the mining academies founded at that time, mining civil servants, university professors and also by private scholars. In this process, the Mining Academy of Freiberg, at which German and foreign students took their degrees, was of great importance. Abraham Gottlob Werner worked there as a lecturer who combined geological findings – based on his theory of Neptunism – into one systematic doctrine, imparting his ideas to many students over decades. These students became successful mining and metallurgy officials in the first years of the nineteenth century, and professors of geology and mineralogy at universities in Germany and abroad. During the same period, Leopold von Buch and Alexander von Humboldt contributed to the consolidation of geology as a natural science in Germany. Leopold von Buch had not only recognized the task of developing historical geology; he himself made important contributions to the stratigraphy of the Mesozoic and to palaeontology. The term ‘guide fossil’ was established by him. His coloured geological map of Western and Central Europe, published in 1826 and with five editions up to 1843, met with great approval.
Intestinal cell kinase, a MAP kinase-related kinase, regulates proliferation and G1cell cycle progression of intestinal epithelial cells
Authors: Fu Zheng , Kim Jungeun , Vidrich Alda , Sturgill Thomas W. , Cohn Steven M.
Published: August 2009

Intestinal cell kinase (ICK), originally cloned from the intestine and expressed in the intestinal crypt epithelium, is a highly conserved serine/threonine protein kinase that is similar to mitogen-activated protein kinases (MAPKs) in the catalytic domain and requires dual phosphorylation within a MAPK-like TDY motif for full activation. Despite these similarities to MAPKs, the biological functions of ICK remain unknown. In this study, we report that suppression of ICK expression in cultured intestinal epithelial cells by short hairpin RNA (shRNA) interference significantly impaired cellular proliferation and induced features of gene expression characteristic of colonic or enterocytic differentiation. Downregulation of ICK altered expression of cell cycle regulators (cyclin D1, c-Myc, and p21Cip1/WAF1) of G1-S transition, consistent with the G1cell cycle delay induced by ICK shRNA. ICK deficiency also led to a significant decrease in the expression and/or activity of p70 ribosomal protein S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E), concomitant with reduced expression of their upstream regulators, the mammalian target of rapamycin (mTOR) and the regulatory associated protein of mTOR (Raptor). Furthermore, ICK interacts with the mTOR/Raptor complex in vivo and phosphorylates Raptor in vitro. These results suggest that disrupting ICK function may downregulate protein translation of specific downstream targets of eIF4E and S6K1 such as cyclin D1 and c-Myc through the mTOR/Raptor signaling pathway. Taken together, our findings demonstrate an important role for ICK in proliferation and differentiation of intestinal epithelial cells.
Impaired contractile function and calcium handling in hearts of cardiac-specific calcineurin b1-deficient mice
Authors: Schaeffer Paul J. , DeSantiago Jaime , Yang John , Flagg Thomas P. , Kovacs Attila , Weinheimer Carla J. , Courtois Michael , Leone Teresa C. , Nichols Colin G. , Bers Donald M. , Kelly Daniel P.
Published: August 2009

To define the necessity of calcineurin (Cn) signaling for cardiac maturation and function, the postnatal phenotype of mice with cardiac-specific targeted ablation of the Cn B1 regulatory subunit (Ppp3r1) gene (csCnb1−/−mice) was characterized. csCnb1−/−mice develop a lethal cardiomyopathy, characterized by impaired postnatal growth of the heart and combined systolic and diastolic relaxation abnormalities, despite a lack of structural derangements. Notably, the csCnb1−/−hearts did not exhibit diastolic dilatation, despite the severe functional phenotype. Myocytes isolated from the mutant mice exhibited reduced rates of contraction/relaxation and abnormalities in calcium transients, consistent with altered sarcoplasmic reticulum loading. Levels of sarco(endo) plasmic reticulum Ca-ATPase 2a (Atp2a2) and phospholamban were normal, but phospholamban phosphorylation was markedly reduced at Ser16and Thr17. In addition, levels of the Na/Ca exchanger (Slc8a1) were modestly reduced. These results define a novel mouse model of cardiac-specific Cn deficiency and demonstrate novel links between Cn signaling, postnatal growth of the heart, pathological ventricular remodeling, and excitation-contraction coupling.
A slowly inactivating sodium current contributes to spontaneous diastolic depolarization of atrial myocytes
Authors: Song Yejia , Shryock John C. , Belardinelli Luiz
Published: August 2009

Diastolic depolarization (DD) of atrial myocytes can lead to spontaneous action potentials (APs) and, potentially, atrial tachyarrhythmias. This study examined the hypotheses that 1) a slowly inactivating component of the Na+ current (referred to as late INa) may contribute to DD and initiate AP firing and that 2) blocking late INa will reduce spontaneous and induced firing of APs by atrial myocytes. Guinea pig atrial myocytes without or with DD and spontaneous AP firing were studied using the whole cell patch-clamp technique. In experiments using cells with a stable resting membrane potential (no spontaneous DD or firing), hydrogen peroxide (H2O2, 50 μmol/l) caused DD and AP firing. The H2O2-induced activity was suppressed by the late INa inhibitors tetrodotoxin (TTX, 1 μmol/l) and ranolazine (5 μmol/l). In cells with DD but no spontaneous APs, the late INa enhancer anemone toxin II (ATX-II, 10 nmol/l) accelerated DD and induced APs. In cells with DD and spontaneous AP firing, TTX and ranolazine (both, 1 μmol/l) significantly reduced the slope of DD by 81 ± 12% and 75 ± 11% and the frequency of spontaneous firing by 70 ± 15% and 74 ± 9%, respectively. Ramp voltage-clamp simulating DD elicited a slow inward current. TTX at 1, 3, and 10 μmol/l inhibited this current by 41 ± 4%, 73 ± 2%, and 91 ± 1%, respectively, suggesting that a slowly inactivating INa underlies the DD. ATX-II and H2O2 increased the amplitude of this current, and the effects of ATX-II and H2O2 were attenuated by ranolazine or TTX. In conclusion, late INa can contribute to the DD of atrial myocytes and the inhibition of this current suppresses atrial DD and spontaneous APs.
Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation
Authors: Cao Zeling , Bell Jeffrey B. , Mohanty Joy G. , Nagababu Enika , Rifkind Joseph M.
Published: August 2009

A role for nitric oxide (NO) produced during the reduction of nitrite by deoxygenated red blood cells (RBCs) in regulating vascular dilation has been proposed. It has not, however, been satisfactorily explained how this NO is released from the RBC without first reacting with the large pools of oxyhemoglobin and deoxyhemoglobin in the cell. In this study, we have delineated a mechanism for nitrite-induced RBC vasodilation that does not require that NO be released from the cell. Instead, we show that nitrite enhances the ATP release from RBCs, which is known to produce vasodilation by several different methods including the interaction with purinergic receptors on the endothelium that stimulate the synthesis of NO by endothelial NO synthase. This mechanism was established in vivo by measuring the decrease in blood pressure when injecting nitrite-reacted RBCs into rats. The observed decrease in blood pressure was not observed if endothelial NO synthase was inhibited by Nω-nitro-l-arginine methyl ester (l-NAME) or when any released ATP was degraded by apyrase. The nitrite-enhanced ATP release was shown to involve an increased binding of nitrite-modified hemoglobin to the RBC membrane that displaces glycolytic enzymes from the membrane, resulting in the formation of a pool of ATP that is released from the RBC. These results thus provide a new mechanism to explain nitrite-induced vasodilation.
Identification of the amino acid sequence that targets peroxiredoxin 6 to lysosome-like structures of lung epithelial cells
Authors: Sorokina Elena M. , Feinstein Sheldon I. , Milovanova Tatyana N. , Fisher Aron B.
Published: August 2009

Peroxiredoxin 6 (Prdx6), an enzyme with glutathione peroxidase and PLA2(aiPLA2) activities, is highly expressed in respiratory epithelium, where it participates in phospholipid turnover and antioxidant defense. Prdx6 has been localized by immunocytochemistry and subcellular fractionation to acidic organelles (lung lamellar bodies and lysosomes) and cytosol. On the basis of their pH optima, we have postulated that protein subcellular localization determines the balance between the two activities of Prdx6. Using green fluorescent protein-labeled protein expression in alveolar epithelial cell lines, we showed Prdx6 localization to organellar structures resembling lamellar bodies in mouse lung epithelial (MLE-12) cells and lysosomes in A549 cells. Localization within lamellar bodies/lysosomes was in the luminal compartment. Targeting to lysosome-like organelles was abolished by the deletion of amino acids 31–40 from the Prdx6 NH2-terminal region; deletion of the COOH-terminal region had no effect. A green fluorescent protein-labeled peptide containing only amino acids 31–40 showed lysosomal targeting that was abolished by mutation of S32 or G34 within the peptide. Studies with mutated protein indicated that lipid binding was not necessary for Prdx6 targeting. This peptide sequence has no homology to known organellar targeting motifs. These studies indicate that the localization of Prdx6 in acidic organelles and consequent PLA2activity depend on a novel 10-aa peptide located at positions 31–40 of the protein.
Abrogation of TGF-β1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition
Authors: Guo Weichao , Shan Bin , Klingsberg Ross C. , Qin Xiangmei , Lasky Joseph A.
Published: August 2009

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with no known effective pharmacological therapy. The fibroblastic foci of IPF contain activated myofibroblasts that are the major synthesizers of type I collagen. Transforming growth factor (TGF)-β1 promotes differentiation of fibroblasts into myofibroblasts in vitro and in vivo. In the current study, we investigated the molecular link between TGF-β1-mediated myofibroblast differentiation and histone deacetylase (HDAC) activity. Treatment of normal human lung fibroblasts (NHLFs) with the pan-HDAC inhibitor trichostatin A (TSA) inhibited TGF-β1-mediated α-smooth muscle actin (α-SMA) and α1type I collagen mRNA induction. TSA also blocked the TGF-β1-driven contractile response in NHLFs. The inhibition of α-SMA expression by TSA was associated with reduced phosphorylation of Akt, and a pharmacological inhibitor of Akt blocked TGF-β1-mediated α-SMA induction in a dose-dependent manner. HDAC4 knockdown was effective in inhibiting TGF-β1-stimulated α-SMA expression as well as the phosphorylation of Akt. Moreover, the inhibitors of protein phosphatase 2A and 1 (PP2A and PP1) rescued the TGF-β1-mediated α-SMA induction from the inhibitory effect of TSA. Together, these data demonstrate that the differentiation of NHLFs to myofibroblasts is HDAC4 dependent and requires phosphorylation of Akt.
The triterpenoid CDDO limits inflammation in preclinical models of cystic fibrosis lung disease
Authors: Nichols David P. , Ziady Assem G. , Shank Samuel L. , Eastman Jean F. , Davis Pamela B.
Published: August 2009

Excessive inflammation in cystic fibrosis (CF) lung disease is a contributor to progressive pulmonary decline. Effective and well-tolerated anti-inflammatory therapy may preserve lung function, thereby improving quality and length of life. In this paper, we assess the anti-inflammatory effects of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9( 11 )-dien-28-oic acid (CDDO) in preclinical models of CF airway inflammation. In our experiments, mice carrying the R117H Cftr mutation have significantly reduced airway inflammatory responses to both LPS and flagellin when treated with CDDO before inflammatory challenge. Anti-inflammatory effects observed include reduced airway neutrophilia, reduced concentrations of proinflammatory cytokines and chemokines, and reduced weight loss. Our findings with the synthetic triterpenoids in multiple cell culture models of CF human airway epithelia agree with effects previously described in other disease models (e.g., neoplastic cells). These include the ability to reduce NF-κB activation while increasing nuclear factor erythroid-related factor 2 (Nrf2) activity. As these two signaling pathways appear to be pivotal in regulating the net inflammatory response in the CF airway, these compounds are a promising potential anti-inflammatory therapy for CF lung disease.
Rev-erb-α: an integrator of circadian rhythms and metabolism
Authors: Duez Hélène , Staels Bart
Published: August 2009

The endogenous circadian clock ensures daily rhythms in diverse behavioral and physiological processes, including locomotor activity and sleep/wake cycles, but also food intake patterns. Circadian rhythms are generated by an internal clock system, which synchronizes these daily variations to the day/night alternance. In addition, circadian oscillations may be reset by the time of food availability in peripheral metabolic organs. Circadian rhythms are seen in many metabolic pathways (glucose and lipid metabolism, etc.) and endocrine secretions (insulin, etc.). As a consequence, misalignment of the internal timing system vs. environmental zeitgebers (light, for instance), as experienced during jetlag or shift work, may result in disruption of physiological cycles of fuel utilization or energy storage. A large body of evidence from both human and animal studies now points to a relationship between circadian disorders and altered metabolic response, suggesting that circadian and metabolic regulatory networks are tightly connected. After a review of the current understanding of the molecular circadian core clock, we will discuss the hypothesis that clock genes themselves link the core molecular clock and metabolic regulatory networks. We propose that the nuclear receptor and core clock component Rev-erb-α behaves as a gatekeeper to timely coordinate the circadian metabolic response.
Influence of hormone replacement therapy on eccentric exercise induced myogenic gene expression in postmenopausal women
Authors: Dieli-Conwright Christina M. , Spektor Tanya M. , Rice Judd C. , Sattler Fred R. , Schroeder E. Todd
Published: August 2009

Hormone replacement therapy (HRT) is used in postmenopausal women to relieve symptoms of menopause and prevent osteoporosis. We sought to evaluate changes in mRNA expression of key myogenic factors in postmenopausal women taking and not taking HRT following a high-intensity eccentric resistance exercise. Fourteen postmenopausal women were studied and included 6 control women not using HRT (59 ± 4 years, 63 ± 17 kg) and 8 women using traditional HRT (59 ± 4 yr, 89 ± 24 kg). Both groups performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on a Cybex dynamometer at 60°/s. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 h after the exercise bout. Gene expression was determined using RT-PCR for follistatin, forkhead box 3A (FOXO3A), muscle atrophy F-box (MAFbx), muscle ring finger-1 (MuRF-1), myogenic differentiation factor (MyoD), myogenin, myostatin, myogenic factor 5 (Myf5), and muscle regulatory factor 4 (MRF4). At rest, the HRT group expressed higher levels of MyoD, myogenin, Myf5, MRF4, and follistatin ( P < 0.05). In response to eccentric exercise, follistatin, MyoD, myogenin, Myf5, and MRF4 were significantly increased ( P ≤ 0.05) and FOXO3A, MAFbx, MuRF-1, and myostatin were significantly decreased in the control and HRT groups ( P ≤ 0.05). Significantly greater changes in mRNA expression of follistatin, FOXO3A, MAFbx, MuRF-1, MyoD, myogenin, myostatin, Myf5, and MRF4 (p≤0.05) occurred in the HRT group than in the control group after exercise. These data suggest that postmenopausal women using HRT express higher myogenic regulatory factor gene expression, which may reflect an attempt to preserve muscle mass. Furthermore, postmenopausal women using HRT experienced a greater myogenic response to maximal eccentric exercise.
Edward F. Adolph Distinguished Lecture: Muscle as an endocrine organ: IL-6 and other myokines
Authors: Pedersen Bente K.
Published: August 2009

Skeletal muscle is an endocrine organ that produces and releases myokines in response to contraction. Some myokines are likely to work in a hormone-like fashion, exerting specific endocrine effects on other organs such as the liver, the brain, and the fat. Other myokines will work locally via paracrine mechanisms, exerting, e.g., angiogenetic effects, whereas yet other myokines work via autocrine mechanisms and influence signaling pathways involved in fat oxidation and glucose uptake. The finding that muscles produce and release myokines creates a paradigm shift and opens new scientific, technological, and scholarly horizons. This finding represents a breakthrough within integrative physiology and contributes to our understanding of why regular exercise protects against a wide range of chronic diseases. Thus the myokine field provides a conceptual basis for the molecular mechanisms underlying, e.g., muscle-fat, muscle-liver, muscle-pancreas, and muscle-brain cross talk.
Vitamin C and E supplementation prevents mitochondrial damage of ileum myocytes caused by intense and exhaustive exercise training
Authors: Rosa Eloi F. , Ribeiro Rafael Ferreira , Pereira Felipe M. T. , Freymüller Edna , Aboulafia Jeannine , Nouailhetas Viviane L. A.
Published: August 2009

Intense and exhaustive exercise (IEE) is associated with oxidative stress in skeletal muscle, and we recently reported that intestine is sensitive to IEE. In the present study, we investigated the possible relationship between the effects of IEE on morphology and oxidative markers in the ileum and isolated mitochondria. C57BL/6 mice were ascribed either to a control group comprising two subgroups, one sedentary and another exercised for 10 days (E10), or to a corresponding supplemented control group again comprising two subgroups, one sedentary and another exercised for 10 days (E10-V). The IEE program consisted of a single daily treadmill running session at 85% of Vmax, until animal exhaustion. Vitamins C (10 mg/kg) and E (10 mg/kg) were concurrently intraperitoneally administered 2 h before the exercise sessions. IEE was shown to cause 1) impairment of ileum internal membrane mitochondria verified by ultramicrography analysis; 2) increase in ileum carbonyl content (117%) and reduction in antioxidant capacity (36%); 3) increase in mitochondria carbonyl content (38%), increase in the percentage of ruptured mitochondria (25.3%), increase in superoxide dismutase activity (186%), and reduction in citrate synthase activity (40.4%) compared with control animals. Observations in the vitamin-supplemented exercised animals (E10-V) were 1) healthy appearance of myocyte mitochondria; 2) decrease in ileum carbonyl content (66%) and increase in antioxidant capacity (53%); 3) decrease in mitochondria carbonyl content (43%), decrease in the percentage of ruptured mitochondria (30%), slight increase in superoxide dismutase activity (7%), and significant increase in citrate synthase activity (121%) compared with E10 animals. Therefore, the present results strongly corroborate the hypothesis that IEE leads to marked disturbances in intestinal mitochondria, mainly in redox status, and affects whole intestinal redox status.
Human diaphragm efficiency estimated as power output relative to activation increases with hypercapnic hyperpnea
Authors: Finucane Kevin E. , Singh Bhajan
Published: August 2009

Hyperpnea with exercise or hypercapnia causes phasic contraction of abdominal muscles, potentially lengthening the diaphragm at end expiration and unloading it during inspiration. Muscle efficiency in vitro varies with load, fiber length, and precontraction stretch. To examine whether these properties of muscle contractility determine diaphragm efficiency (Effdi) in vivo, we measured Effdiin six healthy adults breathing air and during progressive hypercapnia at three levels of end-tidal Pco2with mean values of 48 (SD 2), 55 (SD 2), and 61 (SD 1) Torr. Effdiwas estimated as the ratio of diaphragm power (W˙di) [the product of mean inspiratory transdiaphragmatic pressure, diaphragm volume change (ΔVdi) measured fluoroscopically, and 1/inspiratory duration (Ti−1)] to activation [root mean square values of inspiratory diaphragm electromyogram (RMSdi) measured from esophageal electrodes]. At maximum hypercapnea relative to breathing air, 1) gastric pressure and diaphragm length at end expiration (Pgeeand Ldiee, respectively) increased 1.4 (SD 0.2) and 1.13 (SD 0.08) times, ( P < 0.01 for both); 2) inspiratory change (Δ) in Pg decreased from 4.5 (SD 2.2) to −7.7 (SD 3.8) cmH2O ( P < 0.001); 3) ΔVdi·Ti−1, W˙di, RMSdi, and Effdiincreased 2.7 (SD 0.6), 4.9 (SD 1.8), 2.6 (SD 0.9), and 1.8 (SD 0.3) times, respectively ( P < 0.01 for all); and 4) net and inspiratory W˙di were not different ( P = 0.4). Effdiwas predicted from Ldiee( P < 0.001), Pgee( P < 0.001), ΔPg·Ti−1( P = 0.03), and ΔPg ( P = 0.04) ( r2= 0.52) (multivariate regression analysis). We conclude that, with hypercapnic hyperpnea, 1) ∼47% of the maximum increase of W˙di was attributable to increased Effdi; 2) Effdiincreased due to preinspiratory lengthening and inspiratory unloading of the diaphragm, consistent with muscle behavior in vitro; 3) passive recoil of the diaphragm did not contribute to inspiratory W˙di or Effdi; and 4) phasic abdominal muscle activity with hyperpnea reduces diaphragm energy consumption.
Gouty Arthritis in Acute Cerebrovascular Disease
Authors: Lin Ya-Hui , Hsu Huan-Lin , Huang Ying-Chih , Lee Meng , Huang Wen-Yi , Huang Yen-Chu , Lee Tsong-Hai , Lee Jiann-Der
Published: August 2009

Background: Gouty arthritis is a metabolic disorder associated with several medical diseases and is considered as a high-risk factor of acute myocardial infarction and cardiovascular mortality. Since no study has assessed the frequency of gout attack in acute-stroke patients, a retrospective analysis of gouty arthritis in stroke patients was performed to identify the frequency and characteristics of gouty arthritis in hospitalized stroke patients. Methods: We reviewed the data of 920 patients admitted to the neurology ward of the Chiayi Chang Gung Memorial Hospital between 2002 and 2005 with ischemic stroke. The frequency of gouty arthritis in these patients was evaluated. The severity of the risk factors was compared between the patients with gout and those without. Results: The frequency of gouty arthritis in the stroke patients was 6.5%. Most patients had an attack of gout within 9 days of admission. History of gout, uric acid level and hypercholesterolemia were independent risk factors of gout attack during acute stroke. The duration of acute-ward stay was longer in patients with gout than in those without (17.17 vs. 14.01 days, p = 0.016). Conclusions: Our retrospective study demonstrated that gout attack is not uncommon in acute-stroke patients and may result in longer duration of acute-ward stay.
Antihypertensive Agents and Risk of Parkinson’s Disease, Essential Tremor and Dementia: A Population-Based Prospective Study (NEDICES)
Authors: Louis Elan D. , Benito-León Julián , Bermejo-Pareja Félix
Published: August 2009

Background: Recent interest in antihypertensive agents, especially calcium channel blockers, has been sparked by the notion that these medications may be neuroprotective. A modest literature, with mixed results, has examined whether these medications might lower the odds or risk of Parkinson’s disease (PD) or dementia. There are no data for essential tremor (ET). Objective: To examine the association between antihypertensive use (defined broadly and by individual subclasses) and ET, PD and dementia. For each disorder, we used cross-sectional data (association with prevalent disease) and prospective data (association with incident disease). Methods: Prospective population-based study in Spain enrolling 5,278 participants at baseline. Results: Use of antihypertensive medications (aside from β-blockers) was similar in prevalent ET cases and controls. Baseline use of antihypertensive agents was not associated with reduced risk of incident ET. Antihypertensive medication use was not associated with prevalent or incident PD. Calcium channel blocker use was marginally reduced in prevalent dementia cases (ORadjusted = 0.63, p = 0.06) but was not associated with reduced risk of incident dementia (RRadjusted = 1.02, p = 0.95). Conclusions: We did not find evidence of a protective effect of antihypertensive medications in these three neurodegenerative disorders.
Cardio-Ankle Vascular Index as a Predictor of Cognitive Impairment in Community-Dwelling Elderly People: Four-Year Follow-Up
Authors: Yamamoto Naomune , Yamanaka Gaku , Ishikawa Motonao , Takasugi Emiko , Murakami Shougo , Yamanaka Takashi , Ishine Masayuki , Matsubayashi Kozo , Hanafusa Toshiaki , Otsuka Kuniaki
Published: August 2009

Background/Aim: The relation between markers of generalized atherosclerosis and cognitive impairment in old age is controversial. The aim of the study was to evaluate the cardio-ankle vascular index (CAVI) as a predictor of longitudinal changes in cognitive function in older individuals. Methods: We evaluated the cognitive function in elderly people with high (AS(+)) and low (AS(–)) values of CAVI each year over 4 years. Results: The changes in the Hasegawa Dementia Scale Revised (HDS-R) and the mini-mental state examination (MMSE) at 4 years were significantly larger in the AS(+) group (AS(+) vs. AS(–) = –1.8 ± 4.4 vs. 0.3 ± 2.8 points and –1.1 ± 3.0 vs. 0.1 ± 2.3 points, p = 0.008 and 0.03, respectively). The annual changes in the HDS-R were significantly decreased from baseline at 1 year later to 4 years later in AS(+) (baseline vs. 1, 2, 3, 4 years = 26.5 vs. 25.0, 25.5, 25.7, 24.8 points, p < 0.001); in comparison, the annual changes in MMSE significantly decreased from the baseline over the 4 years in AS (+) (baseline vs. 1, 2, 3, 4 years = 26.8 vs. 26.2, 25.8, 26.4, 25.7 points, p = 0.002). Conclusion: The results of this study suggest that elderly people with a high CAVI value are at a greater risk of cognitive decline.
A Videofluoroscopic Study of the Emphatic Consonants in Jordanian Arabic
Authors: Al-Tamimi Feda , Alzoubi Firas , Tarawnah Rama
Published: August 2009

In order to identify the nature of the emphatic consonants and the articulatory features accompanying their production, 384 videofluoroscopic images of 2 male and 2 female Jordanian speakers were analyzed. Analysis focused on the differences between nonemphatic and emphatic consonants in the pharyngeal length and width, the hyoid bone elevation and larynx raising. Results show that males and females produce emphatics as pharyngealized sounds with the tongue root retracting into the oropharynx and the hyoid bone elevating and the larynx raising as a result.
A PTP4A3 Peptide PIMAP39 Modulates TNF-Alpha Levels and Endotoxic Shock
Authors: Tang Xiaoren , Woodward Timothy , Amar Salomon
Published: August 2009

Lipopolysaccharide (LPS) stimulation of macrophages initiates intracellular signaling pathways leading to activation of MAPK and its subsequent influence on cytokine production. We recently identified a LITAF-STAT6(B) complex regulated by p38 MAPK in response to LPS stimulation. However, the LPS-induced cascade in the p38/LITAF/TNF signaling pathway remains unclear. Here, we identified PTP4A3, a protein tyrosine phosphotase, as a novel negative regulator of LPS-induced LITAF/TNF-α production. PTP4A3 exerts its negative role by dephosphorylating p38α MAPK in response to LPS stimulation of primary macrophages. PTP4A3 expression is upregulated in primary macrophages. Further structure-function analysis revealed that a unique short peptide (PIMAP39) derived from PTP4A3 is capable of mimicking the functionality of full-length PTP4A3 to selectively dephosphorylate p38α and indirectly suppress LPS-induced LITAF-STAT6B complex when it is translocated from the cytoplasmic region to the nucleus of the cell. Treatment of mice with PIMAP39 significantly attenuates the severity of adverse host responses to LPS stimulation, and in some cases provides complete resistance to a lethal dose of LPS due to suppression of TNF-α production. All together, these results reveal a previously unrecognized role for the PTP4A3 pathway in response to LPS.
Combination of Captopril and Allopurinol Retards Fructose-Induced Metabolic Syndrome
Authors: Roncal Carlos A. , Reungjui Sirirat , Sánchez-Lozada Laura Gabriela , Mu Wei , Sautin Yuri Y. , Nakagawa Takahiko , Johnson Richard J.
Published: August 2009

Background: Both ACE inhibitors and allopurinol have been shown to partially prevent metabolic syndrome induced by fructose. We tested the hypothesis that combined therapy might be more effective at blocking the metabolic syndrome induced with fructose. Methods: Male Sprague-Dawley rats were fed a high fructose diet with or without allopurinol, captopril, or the combination for 20 weeks. A control group received a normal diet. All groups were pair-fed to assure equivalent caloric intake. Results: Despite reduced energy intake, the fructose-fed rats developed features of metabolic syndrome including elevated blood pressure, abdominal obesity, hypertriglyceridemia, hyperuricemia and hyperinsulinemia. While both allopurinol and captopril alone tended to reduce features of the metabolic syndrome, the combined therapy was synergistic, with significant reduction in blood pressure, less accumulation of abdominal fat, an improvement in the dyslipidemia and a complete prevention of insulin resistance. Conclusion: A high fructose diet can induce metabolic syndrome even in the setting of caloric restriction. Captopril and allopurinol synergistically reduce features of the metabolic syndrome, especially hypertension, insulin resistance and dyslipidemia. Combination allopurinol and ACE inhibitor therapy might provide a superior means to prevent diabetes and cardiovascular disease.
Scavenger Receptors of Endothelial Cells Mediate the Uptake and Cellular Proatherogenic Effects of Carbamylated LDL
Authors: Apostolov Eugene O. , Shah Sudhir V. , Ray Debarti , Basnakian Alexei G.
Published: August 2009

Objective—

Carbamylated LDL (cLDL) has been recently shown to have robust proatherogenic effects on human endothelial cells in vitro, suggesting cLDL may have a significant role in atherosclerosis in uremia. The current study was designed to determine which receptors are used by cLDL and thus cause the proatherogenic effects.

Methods and Results—

In ex vivo or in vitro models as well as in intact animals, administration of cLDL was associated with endothelial internalization of cLDL and subendothelial translocation (transcytosis). In vitro recombinant LOX-1 and SREC-1 receptors showed the greatest cLDL binding. However, pretreatment of the endothelial cells with specific inhibiting antibodies demonstrated that cLDL binds mainly to LOX-1 and CD36 receptors. The transcytosis was dependent on SR-A1, SREC-1, and CD36 receptors whereas LOX-1 receptor was not involved. The cytotoxicity was mediated by several studied scavenger receptors, but cLDL-induced monocyte adhesion depended only on LOX-1. The cLDL-induced synthesis of LOX-1 protein significantly contributed to both cytotoxicity and accelerated monocyte adhesion to endothelial cells.

Conclusions—

Our data suggest that cLDL uses a unique pattern of scavenger receptors. They show that LOX-1 receptor, and partially CD36, SREC-1, and SR-A1 receptors, are essential for the proatherogenic effects of cLDL on human endothelial cells.
PPARβ/δ Agonists Modulate Platelet Function via a Mechanism Involving PPAR Receptors and Specific Association/Repression of PKCα–Brief Report
Authors: Ali Ferhana Y. , Hall Matthew G. , Desvergne Béatrice , Warner Timothy D. , Mitchell Jane A.
Published: August 2009

Objectives—Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a nuclear receptor found in platelets. PPARβ/δ agonists acutely inhibit platelet function within a few minutes of addition. As platelets are anucleated, the effects of PPARβ/δ agonists on platelets must be nongenomic. Currently, the particular role of PPARβ/δ receptors and their intracellular signaling pathways in platelets are not known.

Methods and Results—We have used mice lacking PPARβ/δ (PPARβ/δ−/−) to show the effects of the PPARβ/δ agonist GW501516 on platelet adhesion and cAMP levels are mediated specifically by PPARβ/δ, however GW501516 had no PPARβ/δ-specific effect on platelet aggregation. Studies in human platelets showed that PKCα, which can mediate platelet activation, was bound and repressed by PPARβ/δ after platelets were treated with GW501516.

Conclusions—These data provide evidence of a novel mechanism by which PPAR receptors influence platelet activity and thereby thrombotic risk.
CXCR4 Expression Determines Functional Activity of Bone Marrow–Derived Mononuclear Cells for Therapeutic Neovascularization in Acute Ischemia
Authors: Seeger Florian H. , Rasper Tina , Koyanagi Masamichi , Fox Henrik , Zeiher Andreas M. , Dimmeler Stefanie
Published: August 2009

Objective—

Bone marrow–derived mononuclear cells (BMCs) improve the functional recovery after ischemia. However, BMCs comprise a heterogeneous mixture of cells, and it is not known which cell types are responsible for the induction of neovascularization after cell therapy. Because cell recruitment is critically dependent on the expression of the SDF-1-receptor CXCR4, we examined whether the expression of CXCR4 may identify a therapeutically active population of BMCs.

Methods and Results—

Human CXCR4
+
and CXCR4
−
BMCs were sorted by magnetic beads. CXCR4
+
BMCs showed a significantly higher invasion capacity under basal conditions and after SDF-1 stimulation. Hematopoietic or mesenchymal colony-forming capacity did not differ between CXCR4
+
and CXCR4
−
BMCs. Injection of CXCR4
+
BMCs in mice after induction of hindlimb ischemia significantly improved the recovery of perfusion compared to injection of CXCR4
−
BMCs. Likewise, capillary density was significantly increased in CXCR4
+
BMC-treated mice. Because part of the beneficial effects of cell therapy were attributed to the release of paracrine effectors, we analyzed BMC supernatants for secreted factors. Importantly, supernatants of CXCR4
+
BMCs were enriched in the proangiogenic cytokines HGF and PDGF-BB.

Conclusion—

CXCR4
+
BMCs exhibit an increased therapeutic potential for blood flow recovery after acute ischemia. Mechanistically, their higher migratory capacity and their increased release of paracrine factors may contribute to enhanced tissue repair.
Bone Marrow Progenitor Cells Induce Endothelial Adherens Junction Integrity by Sphingosine-1-Phosphate–Mediated Rac1 and Cdc42 Signaling
Authors: Zhao Yidan D. , Ohkawara Hiroshi , Rehman Jalees , Wary Kishore K. , Vogel Stephen M. , Minshall Richard D. , Zhao You-Yang , Malik Asrar B.
Published: August 2009

Rationale:

Little is known about the contribution of bone marrow–derived progenitor cells (BMPCs) in the regulation endothelial barrier function as defined by microvascular permeability alterations at the level of adherens junctions (AJs).

Objective:

We investigated the role of BMPCs in annealing AJs and thereby in preventing lung edema formation induced by endotoxin (LPS).

Methods and Results:

We observed that BMPCs enhanced basal endothelial barrier function and prevented the increase in pulmonary microvascular permeability and edema formation in mice after LPS challenge. Coculture of BMPCs with endothelial cells induced Rac1 and Cdc42 activation and AJ assembly in endothelial cells. However, transplantation of BMPCs isolated from sphingosine kinase-1–null mice (
SPHK1
−/−
), having impaired S1P production, failed to activate Rac1 and Cdc42 or protect the endothelial barrier.

Conclusions:

These results demonstrate that BMPCs have the ability to reanneal endothelial AJs by paracrine S1P release in the inflammatory milieu and the consequent activation of Rac-1 and Cdc42 in endothelial cells.
Efficient Regulation of VEGF Expression by Promoter-Targeted Lentiviral shRNAs Based on Epigenetic Mechanism
Authors: Turunen Mikko P. , Lehtola Tiia , Heinonen Suvi E. , Assefa Genet S. , Korpisalo Petra , Girnary Roseanne , Glass Christopher K. , Väisänen Sami , Ylä-Herttuala Seppo
Published: August 2009

Rationale:

We studied a possibility that shRNAs can lead to transcriptional gene activation at the promoter level via epigenetic mechanism.

Objective:

The purpose of this study was to test the effects on vascular endothelial growth factor (VEGF-A) expression by promoter targeted small hairpin RNAs (shRNAs) in vitro and in experimental animals in vivo using stable local lentiviral gene transfer.

Methods and Results:

One shRNA was identified which strongly increased VEGF-A expression in C166 endothelial cells at mRNA and protein level whereas another shRNA decreased VEGF-A expression. Quantitative chromatin immunoprecipitation analysis revealed that the repressing shRNA caused epigenetic changes, which increased nucleosome density within the promoter and transcription start site and led to repression of VEGF-A expression. Epigenetic changes caused by the activating shRNA were opposite to those caused by the repressing shRNA. These results were confirmed in vivo in an ischemic mouse hindlimb model after local gene transfer where VEGF-A upregulation achieved by promoter-targeted shRNA increased vascularity and blood flow.

Conclusions:

We show that lentivirus-mediated delivery of shRNA molecules targeted to specific regions in the mVEGF-A promoter either induce or repress VEGF-A expression via epigenetic modulation. Thus, we describe a new approach of gene therapy, epigenetherapy, based on an epigenetic mechanism at the promoter level. Controlling transcription through manipulation of specific epigenetic marks provides a novel approach for the treatment of several diseases.
iPS Programmed Without c-MYC Yield Proficient Cardiogenesis for Functional Heart Chimerism
Authors: Martinez-Fernandez Almudena , Nelson Timothy J. , Yamada Satsuki , Reyes Santiago , Alekseev Alexey E. , Perez-Terzic Carmen , Ikeda Yasuhiro , Terzic Andre
Published: August 2009

Rationale
:

Induced pluripotent stem cells (iPS) allow derivation of pluripotent progenitors from somatic sources. Originally, iPS were induced by a stemness-related gene set that included the c-MYC oncogene.

Objective
:

Here, we determined from embryo to adult the cardiogenic proficiency of iPS programmed without c-MYC, a cardiogenicity-associated transcription factor.

Methods and Results
:

Transgenic expression of 3 human stemness factors SOX2, OCT4, and KLF4 here reset murine fibroblasts to the pluripotent ground state. Transduction without c-MYC reversed cellular ultrastructure into a primitive archetype and induced stem cell markers generating 3-germ layers, all qualifiers of acquired pluripotency. Three-factor induced iPS (3F-iPS) clones reproducibly demonstrated cardiac differentiation properties characterized by vigorous beating activity of embryoid bodies and robust expression of cardiac Mef2c, α-actinin, connexin43, MLC2a, and troponin I. In vitro isolated iPS-derived cardiomyocytes demonstrated functional excitation-contraction coupling. Chimerism with 3F-iPS derived by morula-stage diploid aggregation was sustained during prenatal heart organogenesis and contributed in vivo to normal cardiac structure and overall performance in adult tumor-free offspring.

Conclusions
:

Thus, 3F-iPS bioengineered without c-MYC achieve highest stringency criteria for bona fide cardiogenesis enabling reprogrammed fibroblasts to yield de novo heart tissue compatible with native counterpart throughout embryological development and into adulthood.