bluuebunny/crossref_metadata_2025 huggingface dataset:
Blockade of hypoxia-reoxygenation-mediated collagen type I expression and MMP activity by overexpression of TGF-β1delivered by AAV in mouse cardiomyocytes
Authors: Hu Chang-Ping , Dandapat Abhijit , Liu Yong , Hermonat Paul L. , Mehta Jawahar L.
Published: June 2007

Transforming growth factor (TGF)-β1is one of the most pleiotropic and multifunctional peptides known. While the cardioprotective effect of TGF-β1during ischemia is well known, the specific role of TGF-β1in altering the cardiac remodeling process remains unclear. This study was designed to examine the regulation of hypoxia-reoxygenation-mediated collagen type I expression and activity of matrix metalloproteinases (MMPs) by overexpression of TGF-β1in cultured HL-1 mouse cardiomyocytes. TGF-β1was overexpressed in cardiomyocytes by transfection with adeno-associated virus (AAV)/TGF-β1Latentor with AAV/TGF-β1ACT(active TGF-β1). Twenty-four hours of hypoxia followed by 3 h of reoxygenation (H-R) markedly enhanced (pro)collagen type I expression and activity of MMPs concomitant with an increase in reactive oxygen species (ROS) release and LOX-1 expression. Overexpression of TGF-β1reduced these alterations induced by H-R. TGF-β1overexpression also blocked H-R-mediated p38 and p44/42 MAPK activation. Transfection with AAV/TGF-β1ACTwas superior to that with AAV/TGF-β1Latent. These data for the first time demonstrate that H-R induces signals for cardiac remodeling in cardiomyocytes and TGF-β1can modulate, possibly via antioxidant mechanism, these signals. These findings contribute to further understanding of the role of TGF-β1in the cardiac remodeling process.
Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance
Authors: Cooper Shawna A. , Whaley-Connell Adam , Habibi Javad , Wei Yongzhong , Lastra Guido , Manrique Camila , Stas Sameer , Sowers James R.
Published: June 2007

Hypertension commonly occurs in conjunction with insulin resistance and other components of the cardiometabolic syndrome. Insulin resistance plays a significant role in the relationship between hypertension, Type 2 diabetes mellitus, chronic kidney disease, and cardiovascular disease. There is accumulating evidence that insulin resistance occurs in cardiovascular and renal tissue as well as in classical metabolic tissues (i.e., skeletal muscle, liver, and adipose tissue). Activation of the renin-angiotensin-aldosterone system and subsequent elevations in angiotensin II and aldosterone, as seen in cardiometabolic syndrome, contribute to altered insulin/IGF-1 signaling pathways and reactive oxygen species formation to induce endothelial dysfunction and cardiovascular disease. This review examines currently understood mechanisms underlying the development of resistance to the metabolic actions of insulin in cardiovascular as well as skeletal muscle tissue.
Arterial shear stress regulates endothelial cell-directed migration, polarity, and morphology in confluent monolayers
Authors: Simmers Michael B. , Pryor Andrew W. , Blackman Brett R.
Published: June 2007

Hemodynamic regulation of directional endothelial cell (EC) migration implies an essential role of shear stress in governing EC polarity. Shear stress induces reorientation of the microtubule organizing center toward the leading edge of migrating cells in a Cdc42-dependent manner. We have characterized the global patterns of EC migration in confluent monolayers as a function of shear stress direction and exogenous pleiotropic factors. Results demonstrate the presence of mitogenic factors significantly affects the flow-induced dynamics of movement by prolonging the onset of monolayer quiescence up to 4 days, but not shear stress-induced morphology. In conjunction with increased motility, exogenous growth factors contributed to the directed migration of ECs in the flow direction. ECs exposed to arterial flow in serum/growth factor-free media and then supplemented with growth factors rapidly increased directional migration to 85% of cells migrating in the direction of flow and induced an increase in the distance traveled with the flow direction. This response was modulated by the directionality of flow and inhibited by the expression of dominant-negative Par6, a major downstream effector of Cdc42-induced polarity. Shear stress-induced directed migratory polarity is modulated by exogenous growth factors and dependent on Par6 activity and shear stress direction.
Characterizing the contribution of voltage- and calcium-dependent coupling to action potential stability: implications for repolarization alternans
Authors: Jordan Peter N. , Christini David J.
Published: June 2007

Experiments have provided suggestive but inconclusive insights into the relative contributions of transmembrane voltage and intracellular calcium handling to the development of cardiac electrical instabilities such as repolarization alternans. In this study, we applied a novel combination of techniques (action potential voltage clamping, calcium-transient clamping, and stability analysis) to cardiac cell models to more clearly determine the roles that voltage- and calcium-dependent coupling play in regulating action potential stability and the development of alternans subsequent to the loss of stability. Using these techniques, we are able to demonstrate that voltage- and calcium-dependent coupling exhibit varying degrees of influence on action potential stability across models. Our results indicate that cellular dynamic instabilities such as alternans may be initiated by either voltage- or calcium-dependent mechanisms or by some combination of the two. Based on these modeling results, we propose novel single-cell experiments that incorporate action-potential voltage clamping, calcium imaging, and real-time measurement of action potential stability. These experiments will make it possible to experimentally determine the relative contribution of voltage coupling to the regulation of action potential stability in real cardiac myocytes, thereby providing further insights into the mechanism of alternans.
Divergent immune responses to house dust mite lead to distinct structural-functional phenotypes
Authors: Johnson Jill R. , Swirski Filip K. , Gajewska Beata U. , Wiley Ryan E. , Fattouh Ramzi , Pacitto Stephanie R. , Wong Jonathan K. , Stämpfli Martin R. , Jordana Manel
Published: June 2007

Asthma is a chronic airway inflammatory disease that encompasses three cardinal processes: T helper (Th) cell type 2 (Th2)-polarized inflammation, bronchial hyperreactivity, and airway wall remodeling. However, the link between the immune-inflammatory phenotype and the structural-functional phenotype remains to be fully defined. The objective of these studies was to evaluate the relationship between the immunologic nature of chronic airway inflammation and the development of abnormal airway structure and function in a mouse model of chronic asthma. Using IL-4-competent and IL-4-deficient mice, we created divergent immune-inflammatory responses to chronic aeroallergen challenge. Immune-inflammatory, structural, and physiological parameters of chronic allergic airway disease were evaluated in both strains of mice. Although both strains developed airway inflammation, the profiles of the immune-inflammatory responses were markedly different: IL-4-competent mice elicited a Th2-polarized response and IL-4-deficient mice developed a Th1-polarized response. Importantly, this chronic Th1-polarized immune response was not associated with airway remodeling or bronchial hyperresponsiveness. Transient reconstitution of IL-4 in IL-4-deficient mice via an airway gene transfer approach led to partial Th2 repolarization and increased bronchial hyperresponsiveness, along with full reconstitution of airway remodeling. These data show that distinct structural-functional phenotypes associated with chronic airway inflammation are strictly dependent on the nature of the immune-inflammatory response.
Neutrophil elastase inhibition of cell cycle progression in airway epithelial cells in vitro is mediated by p27kip1
Authors: Fischer Bernard M. , Zheng Shuo , Fan Rongrong , Voynow Judith A.
Published: June 2007

Neutrophil elastase (NE), a serine protease present in high concentrations in the airways of cystic fibrosis patients, injures the airway epithelium. We examined the epithelial response to NE-mediated proteolytic injury. We have previously reported that NE treatment of airway epithelial cells causes a marked decrease in epithelial DNA synthesis and proliferation. We hypothesized that NE inhibits DNA synthesis by arresting cell cycle progression. Progression through the cell cycle is positively regulated by cyclin complexes and negatively regulated by cyclin-dependent kinase inhibitors (CKI). To test whether NE arrests cell cycle progression, we treated normal human bronchial epithelial (NHBE) cells with NE (50 nM) or control vehicle for 24 h and assessed the effect of treatment on the cell cycle by flow cytometry. NE treatment resulted in G1 arrest. Arrest in G1 phase may be the result of CKI inhibition of the cyclin E complex; therefore, we evaluated whether NE upregulated CKI expression and/or affected the interaction of CKIs with the cyclin E complex. Following NE or control vehicle treatment, expression of p27Kip1, a member of the Cip/Kip family, was evaluated. NE increased p27Kip1 gene and protein expression. NE increased the coimmunoprecipitation of p27Kip1 with cyclin E complex, suggesting that p27Kip1 inhibited cyclin E complex activity. Our results demonstrate that p27 is regulated by NE and is critical for NE-induced cell cycle arrest.
Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis
Authors: Poschet Jens F. , Timmins Graham S. , Taylor-Cousar Jennifer L. , Ornatowski Wojciech , Fazio Joseph , Perkett Elizabeth , Wilson Kari R. , Yu Hongwei D. , de Jonge Hugo R. , Deretic Vojo
Published: June 2007

The CFTR gene encodes a chloride channel with pleiotropic effects on cell physiology and metabolism. Here, we show that increasing cGMP levels to inhibit epithelial Na+channel in cystic fibrosis (CF) respiratory epithelial cells corrects several aspects of the downstream pathology in CF. Cell culture models, using a range of CF cell lines and primary cells, showed that complementary pharmacological approaches to increasing intracellular cGMP, by elevating guanyl cyclase activity though reduced nitric oxide, addition of cell-permeable cGMP analogs, or inhibition of phosphodiesterase 5 corrected multiple aspects of the CF pathological cascade. These included correction of defective protein glycosylation, bacterial adherence, and proinflammatory responses. Furthermore, pharmacological inhibition of phosphodiesterase 5 in tissues ex vivo or in animal models improved transepithelial currents across nasal mucosae from transgenic F508del Cftrtm1Eurmice and reduced neutrophil infiltration on bacterial aerosol challenge in Pseudomonas aeruginosa-susceptible DBA/2 mice. Our findings define phosphodiesterase 5 as a specific target for correcting a number of previously disconnected defects in the CF respiratory tract, now linked through this study. Our study suggests that phosphodiesterase 5 inhibition provides an opportunity for simultaneous and concerted correction of seemingly disparate complications in CF.
Phosphoinositide 3-kinase is activated by MUC1 but not responsible for MUC1-induced suppression of Toll-like receptor 5 signaling
Authors: Kato Kosuke , Lu Wenju , Kai Hirofumi , Kim K. Chul
Published: June 2007

MUC1 is a membrane-tethered mucin-like glycoprotein expressed on the surface of various mucosal epithelial cells as well as hematopoietic cells. Recently, we showed that MUC1 suppresses flagellin-induced Toll-like receptor (TLR) 5 signaling both in vivo and in vitro through cross talk with TLR5. In this study, we determined whether phosphoinositide 3-kinase (PI3K), a negative regulator of TLR5 signaling, is involved in the cross talk between MUC1 and TLR5 using various genetically modified epithelial cell lines. Our results showed 1) activation of MUC1 induced recruitment of the PI3K regulatory subunit p85 to the MUC1 cytoplasmic tail (CT) as well as Akt phosphorylation, 2) MUC1-induced Akt phosphorylation required the presence of Tyr20within the PI3K binding motif of the MUC1 CT, and 3) mutation of Tyr20or pharmacological inhibition of PI3K activation failed to block MUC1-induced suppression of TLR5 signaling. We conclude that whereas PI3K is downstream of MUC1 activation and negatively regulates TLR5 signaling, it is not responsible for MUC1-induced suppression of TLR5 signaling.
Contribution of alveolar macrophages to the response of the TIMP-3 null lung during a septic insult
Authors: Martin Erica L. , Sheikh Tanya A. , Leco Kevin J. , Lewis James F. , Veldhuizen Ruud A. W.
Published: June 2007

Mice deficient in tissue inhibitor of metalloproteinase-3 (TIMP-3) develop an emphysema-like phenotype involving increased pulmonary compliance, tissue degradation, and matrix metalloproteinase (MMP) activity. After a septic insult, they develop a further increase in compliance that is thought to be a result of heightened metalloproteinase activity produced by the alveolar macrophage, potentially modeling an emphysemic exacerbation. Therefore, we hypothesized that TIMP-3 null mice lacking alveolar macrophages would not be susceptible to the altered lung function associated with a septic insult. TIMP-3 null and wild-type (WT) mice were depleted of alveolar macrophages before the induction of a septic insult and assessed for alteration in lung mechanics, alveolar structure, metalloproteinase levels, and inflammation. The results showed that TIMP-3 null mice lacking alveolar macrophages were protected from sepsis-induced alterations in lung mechanics, particularly pulmonary compliance, a finding that was supported by changes in alveolar structure. Additionally, changes in lung mechanics involved primarily peripheral tissue vs. central airways as determined using the flexiVent system. From investigation into possible molecules that could cause these alterations, it was found that although several proteases and inflammatory mediators were increased during the septic response, only MMP-7 was attenuated after macrophage depletion. In conclusion, the alveolar macrophage is essential for the TIMP-3 null sepsis-induced compliance alterations. This response may be mediated in part by MMP-7 activity but occurs independently of inflammatory cytokine and/or chemokine concentrations.
Alveoli increase in number but not size from birth to adulthood in rhesus monkeys
Authors: Hyde Dallas M. , Blozis Shelley A. , Avdalovic Mark V. , Putney Lei F. , Dettorre Rachel , Quesenberry Nathanial J. , Singh Paramjit , Tyler Nancy K.
Published: June 2007

Postnatal developmental stages of lung parenchyma in rhesus monkeys is about one-third that of humans. Alveoli in humans are reported to be formed up to 8 yr of age. We used design-based stereological methods to estimate the number of alveoli ( Nalv) in male and female rhesus monkeys over the first 7 yr of life. Twenty-six rhesus monkeys (13 males ranging in age from 4 to 1,920 days and lung volumes from 41.7 to 602 cm3, 13 females ranging in age from 22 to 2,675 days and lung volumes from 43.5 to 380 cm3) were necropsied and lungs fixed, isotropically oriented, fractionated, sampled, embedded, and sectioned for alveolar counting. Parenchymal, alveolar, alveolar duct core air, and interalveolar septal tissue volumes increased rapidly during the first 2 yr with slowed growth from 2 to 7 yr. The rate of change was greater in males than females. Nalv also showed consistent growth throughout the study, with increases in Nalv best predicted by increases in lung volume. However, mean alveolar volume showed little relationship with age, lung volume, or body weight but was larger in females and showed a greater size distribution than in males. Alveoli increase in number but not volume throughout postnatal development in rhesus monkeys.
Improvement of insulin sensitivity by antagonism of the renin-angiotensin system
Authors: Henriksen Erik J.
Published: June 2007

The reduced capacity of insulin to stimulate glucose transport into skeletal muscle, termed insulin resistance, is a primary defect leading to the development of prediabetes and overt type 2 diabetes. Although the etiology of this skeletal muscle insulin resistance is multifactorial, there is accumulating evidence that one contributor is overactivity of the renin-angiotensin system (RAS). Angiotensin II (ANG II) produced from this system can act on ANG II type 1 receptors both in the vascular endothelium and in myocytes, with an enhancement of the intracellular production of reactive oxygen species (ROS). Evidence from animal model and cultured skeletal muscle cell line studies indicates ANG II can induce insulin resistance. Chronic ANG II infusion into an insulin-sensitive rat produces a markedly insulin-resistant state that is associated with a negative impact of ROS on the skeletal muscle glucose transport system. ANG II treatment of L6 myocytes causes impaired insulin receptor substrate (IRS)-1-dependent insulin signaling that is accompanied by augmentation of NADPH oxidase-mediated ROS production. Further critical evidence has been obtained from the TG(mREN2)27 rat, a model of RAS overactivity and insulin resistance. The TG(mREN2)27 rat displays whole body and skeletal muscle insulin resistance that is associated with local oxidative stress and a significant reduction in the functionality of the insulin receptor (IR)/IRS-1-dependent insulin signaling. Treatment with a selective ANG II type 1 receptor antagonist leads to improvements in whole body insulin sensitivity, enhanced insulin-stimulated glucose transport in muscle, and reduced local oxidative stress. In addition, exercise training of TG(mREN2)27 rats enhances whole body and skeletal muscle insulin action. However, these metabolic improvements elicited by antagonism of ANG II action or exercise training are independent of upregulation of IR/IRS-1-dependent signaling. Collectively, these findings support targeting the RAS in the design of interventions to improve metabolic and cardiovascular function in conditions of insulin resistance associated with prediabetes and type 2 diabetes.
Differences in response to corticotropin-releasing factor after short- and long-term consumption of a high-fat diet
Authors: Legendre Ariadne , Papakonstantinou Emilia , Roy Marie-Claude , Richard Denis , Harris Ruth B. S.
Published: June 2007

We previously reported an exaggerated endocrine and weight loss response to stress in rats fed a high-fat (HF) diet for 5 days. Others report blunted stress-induced anxiety in rats made obese on a HF diet. Experiments described here tested whether sensitivity to stress-related peptides was changed in obese and nonobese HF-fed rats. Third ventricle infusion of corticotropin-releasing factor (CRF) in rats made obese on HF diet (40% kcal fat) produced an exaggerated hypophagia, which is thought to be mediated by CRF2receptors. Obese rats responded to a lower dose of CRF for a longer time than rats fed a low-fat (LF) diet (12% kcal fat). CRF-induced release of corticosterone, which is thought to be mediated by CRF1receptors, was not exaggerated in obese HF-fed rats. In contrast, rats fed HF diet for 5 days showed the same food intake and corticosterone response to CRF as LF-fed rats. CRF mRNA expression in the paraventricular nucleus of the hypothalamus was stimulated by mild stress (ip saline injection and placement in a novel cage) in LF-fed rats but not in rats fed HF diet for 5 days because of a nonsignificant increase in expression in nonstressed HF-fed rats. In addition, nonstressed levels of urocortin (UCN) I mRNA expression in the Edinger-Westphal nucleus were significantly inhibited in HF-fed rats. These data suggest that rats that have become obese on a HF diet show a change in responsiveness to stress peptides, whereas the increased stress response in nonobese HF-fed rats may be associated with changes in basal CRF and UCN I mRNA expression.
Proteomics ofS-(1, 2-dichlorovinyl)-l-cysteine-induced acute renal failure and autoprotection in mice
Authors: Korrapati Midhun C. , Chilakapati Jaya , Witzmann Frank A. , Rao Chundury , Lock Edward A. , Mehendale Harihara M.
Published: June 2007

Previous studies (Vaidya VS, Shankar K, Lock EA, Bucci TJ, Mehendale HM. Toxicol Sci 74: 215–227, 2003; Korrapati MC, Lock EA, Mehendale HM. Am J Physiol Renal Physiol 289: F175–F185, 2005; Korrapati MC, Chilakapati J, Lock EA, Latendresse JR, Warbritton A, Mehendale HM. Am J Physiol Renal Physiol 291: F439–F455, 2006) demonstrated that renal repair stimulated by a low dose of S-(1,2-dichlorovinyl)l-cysteine (DCVC; 15 mg/kg ip) 72 h before administration of a normally lethal dose (75 mg/kg ip) protects mice from acute renal failure (ARF) and death (autoprotection). The present study identified the proteins indicative of DCVC-induced ARF and autoprotection in male Swiss Webster mice. Renal dysfunction and injury were assessed by plasma creatinine and histopathology, respectively. Whole-kidney homogenates were run on two-dimensional gel electrophoresis gels, and the expression of 18 common proteins was maximally changed (≥10-fold) in all the treatment groups and they were conclusively identified by liquid chromatography tandem mass spectrometry. These proteins were mildly downregulated after low dose alone and in autoprotected mice in contrast to severe downregulation with high dose alone. Glucose-regulated protein 75 and proteasome α-subunit type 1 were further investigated by immunohistochemistry for their localization in the kidneys of all the groups. These proteins were substantially higher in the proximal convoluted tubular epithelial cells in the low-dose and autoprotected groups compared with high-dose alone group. Proteins involved in energetics were downregulated in all the three groups of mice, leading to a compromise in cellular energy. However, energy is recovered completely in low-dose and autoprotected mice. This study provides the first report on proteomics of DCVC-induced ARF and autoprotection in mice and reflects the application of proteomics in mechanistic studies as well as biomarker development in a variety of toxicological paradigms.
Postnatal adrenalectomy impairs urinary concentrating ability by increased COX-2 and leads to renal medullary injury
Authors: Stubbe Jane , Madsen Kirsten , Nielsen Finn T. , Bonde Rasmus K. , Skøtt Ole , Jensen Boye L.
Published: June 2007

We hypothesized that aldosterone promotes development of the renal medulla in the postnatal period and that cyclooxygenase-2 (COX-2) activity contributes to renal dysfunction after impaired aldosterone signaling. To test these hypotheses, rat pups underwent either sham operation or adrenalectomy at postnatal day 10. Adrenalectomized rats were divided into no steroid substitution (ADX), corticosterone replacement (ADX-C), and corticosterone and DOCA substitution (ADX-CD) groups that received subcutaneous pellets with steroids. Without replacement, pups failed to thrive and exhibited impaired urinary-concentrating ability. The renal medulla was significantly smaller, and the medullary interstitial osmolality was lower in the ADX group, whereas COX-2 and PGE2tissue levels were significantly elevated compared with levels shown in sham animals. Substitution with DOCA and corticosterone corrected these changes, whereas corticosterone replacement alone improved survival but not weight gain and urinary-concentrating ability. Administration of a COX-2 inhibitor to ADX rats (parecoxib, 5 mg·kg−1·day−1, days 17–20) increased weight gain, urinary-concentrating ability, and papillary osmolality. After fluid deprivation, parecoxib attenuated weight loss and the increase in plasma Na+concentration and osmolality. It is concluded that mineralocorticoid is required for normal postnatal development of the renal medulla. COX-2 contributes to impaired urine-concentrating ability, NaCl loss, and extracellular volume depletion in postnatal mineralocorticoid deficiency.
Phosphate transporters: a tale of two solute carrier families
Authors: Virkki Leila V. , Biber Jürg , Murer Heini , Forster Ian C.
Published: June 2007

Phosphate is an essential component of life and must be actively transported into cells against its electrochemical gradient. In vertebrates, two unrelated families of Na+-dependent Pitransporters carry out this task. Remarkably, the two families transport different Pispecies: whereas type II Na+/Picotransporters (SCL34) prefer divalent HPO42−, type III Na+/Picotransporters (SLC20) transport monovalent H2PO4−. The SCL34 family comprises both electrogenic and electroneutral members that are expressed in various epithelia and other polarized cells. Through regulated activity in apical membranes of the gut and kidney, they maintain body Pihomeostasis, and in salivary and mammary glands, liver, and testes they play a role in modulating the Picontent of luminal fluids. The two SLC20 family members PiT-1 and PiT-2 are electrogenic and ubiquitously expressed and may serve a housekeeping role for cell Pihomeostasis; however, also more specific roles are emerging for these transporters in, for example, bone mineralization. In this review, we focus on recent advances in the characterization of the transport kinetics, structure-function relationships, and physiological implications of having two distinct Na+/Picotransporter families.
Muscarinic M2and M1Receptors Reduce GABA Release by Ca2+Channel Modulation Through Activation of PI3K/Ca2+-Independent and PLC/Ca2+-Dependent PKC
Authors: Salgado H. , Bellay T. , Nichols J. A. , Bose M. , Martinolich L. , Perrotti L. , Atzori M.
Published: June 2007

We measured pharmacologically isolated GABAergic currents from layer II/III neurons of the rat auditory cortex using patch-clamp recording. Activation of muscarinic receptors by muscarine (1 μM) or oxotremorine (10 μM) decreased the amplitude of electrically evoked inhibitory postsynaptic currents to about one third of their control value. Neither miniature nor exogenously evoked GABAergic currents were altered by the presence of muscarinic agonists, indicating that the effect was spike-dependent and not mediated postsynaptically. The presence of the N- or P/Q-type Ca2+channel blockers ω-conotoxin GVIA (1 μM) or ω-AgaTx TK (200 nM) greatly blocked the muscarinic effect, suggesting that Ca2+-channels were target of the muscarinic modulation. The presence of the muscarinic M2receptor (M2R) antagonists methoctramine (5 μM) or AF-DX 116 (1 μM) blocked most of the muscarinic evoked inhibitory postsynaptic current (eIPSC) reduction, indicating that M2Rs were responsible for the effect, whereas the remaining component of the depression displayed M1R-like sensitivity. Tissue preincubation with the specific blockers of phosphatidyl-inositol-3-kinase (PI3K) wortmannin (200 nM), LY294002 (1 μM), or with the Ca2+-dependent PKC inhibitor Gö 6976 (200 nM) greatly impaired the muscarinic decrease of the eIPSC amplitude, whereas the remaining component was sensitive to preincubation in the phospholipase C blocker U73122 (10 μM). We conclude that acetylcholine release enhances the excitability of the auditory cortex by decreasing the release of GABA by inhibiting axonal V-dependent Ca2+channels, mostly through activation of presynaptic M2Rs/PI3K/Ca2+-independent PKC pathway and—to a smaller extent—by the activation of M1/PLC/Ca2+-dependent PKC.
Precision, Reliability, and Information-Theoretic Analysis of Visual Thalamocortical Neurons
Authors: Kumbhani Romesh D. , Nolt Mark J. , Palmer Larry A.
Published: June 2007

High-order statistics of neural responses allow one to gain insight into neural function that may not be evident from firing rate alone. In this study, we compared the precision, reliability, and information content of spike trains from X- and Y-cells in the lateral geniculate nucleus (LGN) and layer IV simple cells of area 17 in the cat. To a stochastic, contrast-modulated Gabor patch, layer IV simple cells responded as precisely as their primary inputs, LGN X-cells, but less reliably. LGN Y-cells were more precise and reliable than LGN X-cells. Also, within each LGN cell type, 1) responses to the same stimulus were nearly identical if they shared the same center sign and 2) responses of neurons with the same center sign were nearly identical to the responses of neurons of opposite center sign if the stimulus' contrasts were inverted. These results suggest simple cells receive highly precise and synchronous LGN input, resulting in precise responses. Nonetheless, the response precision of simple cells was greater than expected. Finally, information-theoretic calculations of our cell responses revealed that 1) LGN X-cells encoded information at half the rate of LGN Y-cells but 2.5 times the rate of layer IV simple cells; 2) LGN cells encoded information in their responses using temporal patterns, whereas simple cells did not; and 3) simple cells used more of their information capacity than LGN X-cells. We propose mechanisms that simple cells might use to ensure high precision.
Role of Krüppel-Like Transcription Factors in Endothelial Biology
Authors: Atkins G. Brandon , Jain Mukesh K.
Published: June 2007

Krüppel-like factors are members of the zinc finger family of transcription factors that have been implicated as playing key roles in regulating cellular differentiation and tissue development. Studies over the past several years support an important role for this family of factors in vascular biology. This review summarizes the role of Krüppel-like factors in endothelial cell biology.
Adhesion Mechanisms in Platelet Function
Authors: Ruggeri Zaverio M. , Mendolicchio G. Loredana
Published: June 2007

Platelet adhesion is an essential function in response to vascular injury and is generally viewed as the first step during which single platelets bind through specific membrane receptors to cellular and extracellular matrix constituents of the vessel wall and tissues. This response initiates thrombus formation that arrests hemorrhage and permits wound healing. Pathological conditions that cause vascular alterations and blood flow disturbances may turn this beneficial process into a disease mechanism that results in arterial occlusion, most frequently in atherosclerotic vessels of the heart and brain. Besides their relevant role in hemostasis and thrombosis, platelet adhesive properties are central to a variety of pathophysiological processes that extend from inflammation to immune-mediated host defense and pathogenic mechanisms as well as cancer metastasis. All of these activities depend on the ability of platelets to circulate in blood as sentinels of vascular integrity, adhere where alterations are detected, and signal the abnormality to other platelets and blood cells. In this respect, therefore, platelet adhesion to vascular wall structures, to one another (aggregation), or to other blood cells, represent different aspects of the same fundamental biological process. Detailed studies by many investigators over the past several years have been aimed to dissect the complexity of these functions, and the results obtained now permit an attempt to integrate all the available information into a picture that highlights the balanced diversity and synergy of distinct platelet adhesive interactions.
The Limitations of Teacher Pay Incentive Programs Based on Inter-Cohort Comparisons: The Case of Chile's SNED
Authors: Carnoy Martin , Brodziak Iliana , Molina Andres , Socías Miguel
Published: June 2007

Since 1996, the Chilean government has awarded teachers pay bonuses based on school performance using a complex formula that combines absolute average student test scores and inter-cohort gains from test year to test year. In this paper, we compared the bonuses schools actually received on the basis of this formula to how they would have fared under a hypothetical alternative measure of school performance—intra-cohort gains between the 4th and 8th grades in 1996–2000. We show that schools that received monetary premiums for “good performance” under the SNED program were more likely to be schools that had scored higher on the 4th grade 1996 test, but, on average, they were not the schools that made the highest cohort gains as students progressed from 4th grade in 1996 to 8th grade in 2000. Given what we have found, to get more SNED awards, the wise school would do much better to raise 4th grade and 8th grade scores every two years (even years for 4th grade and odd years for 8th grade) and not focus on the more difficult task of helping students make greater progress from 4th to 8th grades. Although we have data on only one cohort's gain scores from 4th to 8th grades, our limited analysis demonstrates the possible constraints of a school-based incentive program when the available student performance data for awarding pay bonuses are inter-cohort rather than intra-cohort test score gains.
Money for Nothing? The Impact of Changes in the Pell Grant Program on Institutional Revenues and the Placement of Needy Students
Authors: Curs Bradley R. , Singell Larry D. , Waddell Glen R.
Published: June 2007

Using new institutional-level data, we assess the impact of changing federal aid levels on institutional-level Pell revenues. Using various policy instruments associated with Pell generosity, we quantify the sensitivity of institutional Pell revenues to the generosity of the Pell Grant program. In general, we find an elastic response of institutional Pell revenues with respect to the maximum Pell award, where other policy instruments associated with Pell generosity are found to have an inelastic or zero impact. We also document significant asymmetries across institutional selectivity, both in magnitude and in terms of which channel accounts for the measured sensitivity—award values directly or institutional enrollment. In the end, exogenous changes in the federal Pell Grant program are found to correlate strongly with changes in the distribution of needy students and revenues across institutional quality.
Facilitating the Teacher Quality Gap? Collective Bargaining Agreements, Teacher Hiring and Transfer Rules, and Teacher Assignment Among Schools in California
Authors: Koski William S. , Horng Eileen L.
Published: June 2007

Certain studies and the California legislature have recently concluded that seniority preference rules in teacher collective bargaining agreements facilitate a teacher ‘quality gap’ by permitting senior teachers to transfer to schools with higher-performing and more affluent children. This study examines the effects of such transfer rules on the distribution of teachers among and within school districts in California. The study finds that, when comparing California districts to each other, strong seniority preference rules are associated with a greater percentage of credentialed teachers in school districts. Employing hierarchical linear modeling, the study then finds that schools with higher percentages of minority students, within districts, have lower percentages of credentialed and experienced teachers. Contrary to certain previous research and conventional wisdom, however, this study finds no persuasive evidence that the seniority preference rules independently affect the distribution of teachers among schools or exacerbate the negative relationship between higher minority schools and uncredentialed and low-experience teachers.
Improving Lesion-Symptom Mapping
Authors: Rorden Chris , Karnath Hans-Otto , Bonilha Leonardo
Published: June 2007

Measures of brain activation (e.g., changes in scalp electrical potentials) have become the most popular method for inferring brain function. However, examining brain disruption (e.g., examining behavior after brain injury) can complement activation studies. Activation techniques identify regions involved with a task, whereas disruption techniques are able to discover which regions are crucial for a task. Voxel-based lesion mapping can be used to determine relationships between behavioral measures and the location of brain injury, revealing the function of brain regions. Lesion mapping can also correlate the effectiveness of neurosurgery with the location of brain resection, identifying optimal surgical targets. Traditionally, voxel-based lesion mapping has employed the chi-square test when the clinical measure is binomial and the Student's t test when measures are continuous. Here we suggest that the Liebermeister approach for binomial data is more sensitive than the chi-square test. We also suggest that a test described by Brunner and Munzel is more appropriate than the t test for nonbinomial data because clinical and neuropsychological data often violate the assumptions of the t test. We test our hypotheses comparing statistical tests using both simulated data and data obtained from a sample of stroke patients with disturbed spatial perception. We also developed software to implement these tests (MRIcron), made freely available to the scientific community.
Disentangling Sequential Effects of Stimulus- and Response-related Conflict and Stimulus-Response Repetition using Brain Potentials
Authors: Wendt Mike , Heldmann Marcus , Münte Thomas F. , Kluwe Rainer H.
Published: June 2007

Conflict monitoring theory holds that detection of conflicts in information processing by the anterior cingulate cortex (ACC) results in processing adaptation that minimizes subsequent conflict. Applying an Eriksen f lanker task with four stimuli mapped onto two responses, we investigated whether such modulation occurs only after response-related or also after stimulus-related conflict, focusing on the N2 component of the event-related potential. Contrasting with previous findings, both stimulus- and response-related conflict elicited enhancement of the N2, suggesting that the ACC is sensitive to conflict at both the stimulus and the response level. However, neither type of conflict resulted in reduced conflict effects on the following trial when stimulus-response (S-R) sequence effects were controlled by excluding identical S-R repetition trials. Identical S-R repetitions were associated with facilitated processing, thus demonstrating that inclusion of these trials in the analysis may mimic results predicted by the conflict adaptation hypothesis.
Neural Correlates of Promotion and Prevention Goal Activation: An fMRI Study using an Idiographic Approach
Authors: Eddington Kari M. , Dolcos Florin , Cabeza Roberto , R. Krishnan K. Ranga , Strauman Timothy J.
Published: June 2007

Regulatory focus theory [Higgins, E. T. Beyond pleasure and pain. American Psychologist, 52, 1280–1300, 1997] postulates two social-cognitive motivational systems, the promotion and prevention systems, for self-regulation of goal pursuit. However, the neural substrates of promotion and prevention goal activation remain unclear. Drawing on several literatures, we hypothesized that priming promotion versus prevention goals would activate areas in the left versus right prefrontal cortex (PFC), respectively, and that activation in these areas would be correlated with individual differences in chronic regulatory focus. Sixteen participants underwent functional magnetic resonance imaging while engaged in a depth-of-processing task, during which they were exposed incidentally to their own promotion and prevention goals. Task-related cortical activation was consistent with previous studies. At the same time, incidental priming of promotion goals was associated with left orbital PFC activation, and activation in this area was stronger for individuals with a chronic promotion focus. Findings regarding prevention goal priming were not consistent with predictions. The data illustrate the centrality of self-regulation and personal goal pursuit within the multilayered process of social cognition.
Disgust and Happiness Recognition Correlate with Anteroventral Insula and Amygdala Volume Respectively in Preclinical Huntington's Disease
Authors: Kipps C. M. , Duggins A. J. , McCusker E. A. , Calder A. J.
Published: June 2007

Patients with Huntington's disease (HD) can show disproportionate impairments in recognizing facial signals of disgust, but the neural basis of this deficit remains unclear. Functional imaging studies have implicated the anterior insula in the ability to recognize disgust, but have identified other structures as well, including the basal ganglia. In view of variable insula and basal ganglia volume changes in HD, we used voxel-based morphometry to map regional variations in gray matter (GM) volume in participants carrying the mutation for HD, and correlated this with their performance on a test of facial emotion recognition for six basic emotions (disgust, fear, anger, happiness, sadness, surprise). The volume of the anteroventral insula was strongly correlated with performance on the disgust recognition task. The amygdala volume (bilaterally) correlated with the ability to recognize happy facial expressions. There was marked specificity of the regional correlations for the emotion involved. Recognition of other emotion expressions, or more general cognitive or motor performance as measured by a standardized rating scale, did not correlate with regional brain volume in this group. Control participants showed no effect for any measure. The strong linear correlations for disgust and happiness recognition imply direct involvement of the anterior insula in disgust appreciation, and a similar role for the amygdala in recognizing happy facial expressions. The absence of a significant correlation with the basal ganglia suggests a less critical role for these structures in disgust recognition than has previously been suggested. The findings also highlight the role of neurodegenerative diseases combined with statistical imaging techniques in elucidating the brain basis of behavior and cognition.
The Temporal Theatres of Sculpture and Drama: Wole Soyinka and New York's Metropolitan Museum of Art
Authors: Clausius
Published: June 2007

To investigate the practices of evaluating and collecting African art is to expose the way in which modernism has dehistorized African art, globalizing it, universalizing it, rendering it timeless and thus 'modern.' In this way, modernism holds a mirror to itself, claiming for itself properties of truth and authenticity. The evolution of the New York art scene between 1957 and 1982 demonstrates a shift in museological praxis from anthropological to cultural theatre. In opposition to the neutralizing of history and the valorization of modernism, Wole Soyinka's tragic drama Death and the King's Horseman involves the spectator in a more interrogative instability. The synecdochal art object at the centre of the play, the egungun death mask, represents the extreme cultural negotiation of the imperialist stage. Unlike the passive, stoic nature of African sculpture, however, the ritual of the mask is aggressive and demanding, insisting as it does on its place in the terrifying vortex of post-colonial power politics.
Time is not fleeting: Thoughts of a Medieval Zen Buddhist
Authors: Steineck Christian
Published: June 2007

Awareness of impermanence is an attitude that permeates much of traditional Japanese culture. It is often seen to be grounded in Buddhist doctrine, which emphasizes the transiency of everything that exists. However, there are statements by the medieval Zen Master Dôgen (1200-1253) – a professedly orthodox Buddhist and arguably one of the most important religious minds from this country – that contradict this feeling. Arguing against over-emphasis on time's passage, Dôgen asserted the stationary aspects of time. Some of his modern readers took such statements as expressions of mystical insight into a world of timeless truth. A close reading of the sources suggests instead that Dôgen wanted to argue against eternalist as well as nihilist views. He developed a complex view of time, which accounts for its stable sequential order. This theory served to substantiate his claim that the Buddhist ideal could only be realized by continued religious practice.
Carl Schmitt, Political Theology, and Eschatology
Authors: Ostovich Steven
Published: June 2007

"Political Theology" is the rubric under which Carl Schmitt constructed his critique of liberalism and modern political culture. This critique remains influential even given the taint attached to Schmitt's name by his Nazi involvement. Schmitt's presupposition was that political concepts are secularized theological concepts, and his "political theology of the mortal god" was an attempt to formulate a political theological reason that could think through the paradox of sovereignty. This attempt founders on his inadequate understanding of the theological concept of time as eschatological. Reflecting on his failure provides a way to think anew about time as well as politics.
The Tyranny of Temporality: Edmund Spenser, Desire and the Already Written Text
Authors: Schmelzer Mary
Published: June 2007

This paper seeks to example the temporal dissonances between acts of imagination or creation and their representation in writing. What one can imagine in its synchronic fullness resists recovery in the diachronic, word by word act of writing, leading to frustration as well as the continued attempt and continued failure to get it right in writing. The artist/scientist tries to navigate this precarious space constantly. This seems to be precisely what Edmund Spenser is getting at in Canto X of Book VI of The Faerie Queene which describes Colin Clout's Vision on Mount Acidale, its interruption and interpretation. I offer it as a model of the tyranny of temporality.
Nowness and Loss of Meaning in Tensed Propositions
Authors: Riggs Peter
Published: June 2007

The debate over the ontological status of tense continues between A-theorists and B-theorists. Although it has been conceded by B-theorists that reference to tenses cannot be completely eliminated, they claim that this does not require a commitment to the existence of tensed facts. This article will seek to highlight an aspect of the meaning of tensed propositions that seems to have been overlooked, i.e. that tensed propositions retain their meaning only under certain circumstances.
Ambivalent Attitudes Towards Nature in the Early Poetry of Nāzik Al-Malā'ika
Authors: Husni Ronak
Published: June 2007

Nāzik al-Malā'ika's early collections of poetry are characterised by a love of nature. Like many English Romantic poets, she viewed the countryside as symbolic of innocence and beauty, while contrasting the purity and splendour of nature with the oppressiveness and artificiality of the city. The idea of nature as a moral guide often appears in her poetry; man can learn lessons of love, morality and forgiveness from nature more easily than from his fellow man or from books. Yet, she, at times, rejected an idealised picture of nature.
She is the Capital of the Soul: The Book of San'ā' by 'Abd Al-'Azīz Al-Maqālih
Authors: Huri Yair
Published: June 2007

The article discusses the idiosyncratic poetics of the Yemen's foremost modernist poet, ?Abd al-?Azız al-Maqālih, as reflected in his unique volume Kitāb San?ā? ("The Book of San?ā'", 2000). Though many critics regard the work merely as a tribute to his home city, I argue that this unique collection of poems primarily expresses al-Maqāslih's views regarding the essence of poetic language. Using San?ā''s extraordinary cityscape and establishing a sense of magical realism, al-Maqālih juxtaposes two cities—the "real" San?ā? and the "poetic" San?ā?. By fusing the two, the poet dexterously conveys his modernist notions about the demiurgic power of language and the necessity of dream-vision in constructing new realities within artistic creation.