bluuebunny/crossref_metadata_2025 huggingface dataset:
URBAN SAFETY MANAGEMENT: HOW TO DEAL WITH COMPLEXITY
Authors: FLEURY DOMINIQUE
Published: January 2008

Urban safety management remains a field of action in cities that is unanimously considered as being a necessity as well as being difficult to apprehend in its theoretical, disciplinary and spatial dimensions. The analysis frameworks that are today consensual are based on system approaches and on analyses of the complexity of urban dynamics and dysfunctional situations.

We propose a panorama of models that can be used for action and combined for effective interventions. Notably, the analysis of microregulation carried out in real time in driving situations uses psychoergonomic and cognitive psychology models, while the analysis of traffic accidents uses models developed for the more general diagnosis of safety.

Macroregulation of the travel system, carried out with a time delay by network managers, should work in favor of research for consistency among the various actions on the one hand, and the various levels of intervention on space on the other. Safety actions thus require a good understanding of the cognitive models at work in public policies.
GOVERNANCE OF URBAN MOBILITY: COMPLEX SYSTEMS AND INTEGRATED POLICIES
Authors: CASCETTA ENNIO , PAGLIARA FRANCESCA , PAPOLA ANDREA
Published: January 2008

Transportation systems are "internally" complex systems, made up of many elements influencing each other both directly and indirectly, often nonlinearly, with many feedback cycles. Apart from the internal complexity, transportation systems are closely interrelated with other systems, which can be defined as external. Transport projects may have implications for the economy, the location and intensity of the activities in a given area, the environment, the quality of life and social cohesion. Actually, today, in order to have a better view of the urban problems and mainly for better governance of mobility, the urban system per se is no longer studied, but rather the whole metropolitan area surrounding it. Transport and land use are clearly integrated. Each technological innovation in transport has encouraged both people and industry to change their location to take advantage of the improved mobility; similarly, each change in land development (e.g. houses, factories, offices and shops) has influenced the demand for travel and ultimately the provision of new transport infrastructures and services. An example of integrated land use and transport planning is the Regional Metro System (RMS) project, carried out in Campania, which is finally reported.
FROM SPATIALLY EXPLICIT TO MULTIAGENTS SIMULATION OF URBAN DYNAMIC
Authors: SEMBOLONI FERDINANDO
Published: January 2008

In the introduction a distinction is made between the macroscopic approach, which the spatially explicit method is connected with, and the microscopic approach. The spatially explicit method is considered in relation to the interactions between located variables: without and with transport of matter. It is compared with the microscopic approach and the main difference is highlighted: the long range interactions of the latter instead of the neighborhood-based interactions of the former. Finally, a comprehensive approach based on agents, goods and markets, considered as main classes, is proposed. In this approach, the basic actions — buy, produce and sell — are able to connect the main classes and to generate an economic system and an urban spatial pattern.
A COLLISION-AVOIDING MECHANISM BASED ON A THEORY OF MIND
Authors: ZANLUNGO FRANCESCO
Published: January 2008

We develop a collision-avoiding mechanism for a system of individual agents (pedestrians) that move in a crowd trying to reach their different goal points. The agents avoid collisions on the basis of a model of the other agents' behavior, a "theory of mind," which is realized at different levels through an iterative process (the first level, or level 0, corresponds to ignoring the other agents' behavior, level 1 to assuming that the other agents will ignore each other, and so on).

The model is conceived in order to perform an evolutionary simulation of some basic parameters that determine the agent's sensorial, cognitive and behavioral system (the perception of the agent's own size, the attraction to the goal, the radius and angle of the field of view and the level of the theory of mind).

In this preliminary work we present our model, show that it reproduces some of the simplest organized behaviors of a system of pedestrians, and focus on some features of the theory of mind, as the difference between odd and even levels.
UNIVERSALITY IN CITY MORPHOLOGY AND THE MORPHOLOGY OF A CITY AND ITS IMPLICATIONS FOR CITY EVACUATION PLANS
Authors: CIAMARRA MASSIMO PICA , CONIGLIO ANTONIO
Published: January 2008

Street networks play a crucial role in the emergence of vehicular traffic. Here we present an experimental analysis of the street networks of several European cities (London, Paris, Rome, Modena). This analysis evidences the existence of universal properties in the morphology of different cities, which is captured by a model for the dynamics of city growth. Then, we discuss the implications of our findings for the development of city evacuation plans, whose efficiency is of paramount importance for cities threatened by natural hazards, such as volcanoes.
EUV LITHOGRAPHY FOR SEMICONDUCTOR MANUFACTURING AND NANOFABRICATION
Authors: KINOSHITA HIROO
Published: January 2008

EUV lithography is the exposure technology in which even 15 nm node which is the limit of Si device can be achieved. Unlike the conventional optical lithography, this technology serves as a reflection type optical system, and a multilayer coated mirror is used. Development of manufacturing equipment is accelerated to aim at the utilization starting from 2011. The critical issues of development are the EUV light source which has the power over 115 W and resist with high sensitivity and low line edge roughness (LER).
NANOTECHNOLOGY AND HUMAN DISEASES
Authors: LEE GABRIEL YEW HOE , LIM CHWEE TECK
Published: January 2008

Tissues, cells and biomolecules can experience changes in their structural and mechanical properties during the occurrence of certain diseases. Recent advances in the fields of nanotechnology, biomechanics and cell and molecular biology have led to the development of state-of-the-art and novel biophysical and nanotechnological tools to probe the mechanical properties of individual living cells and biomolecules. Here we will review the basic principles and application of some of these nanotechnological tools used to relate changes in the elastic and viscoelastic properties of cells to alterations in the cellular and molecular structures induced by diseases such as malaria and cancer. Knowing the ways and the extent to which mechanical properties of living cells are altered with the onset of disease progression will be crucial for us to gain vital insights into the pathogenesis and pathophysiology of malaria and cancer, and potentially offers the opportunity to develop new and better methods of detection, diagnosis and treatment.
CHEMICAL INTERACTIONS AT NOBLE METAL NANOPARTICLE SURFACES — CATALYSIS, SENSORS AND DEVICES
Authors: NAIR A. SREEKUMARAN , TOM RENJIS T. , RAJEEV KUMAR V. R. , SUBRAMANIAM C. , PRADEEP T.
Published: January 2008

In this paper, a summary of some of the recent research efforts in our laboratory on chemical interactions at noble metal nanoparticle surfaces is presented. The article is divided into five sections, detailing with (i) interactions of simple halocarbons with gold and silver nanoparticle surfaces at room temperature by a new chemistry and the exploitation of this chemistry in the extraction of pesticides from drinking water, (ii) interaction of biologically important proteins such as Cyt c, hemoglobin and myoglobin as well as a model system, hemin with gold and silver nanoparticles and nanorods forming nano–bio conjugates and their surface binding chemistry, (iii) formation of polymer–nano composites with tunable optical properties and temperature sensing characteristics by single and multi-step methodologies, (iv) nanomaterials-based flow sensors and (v) composites of noble metal nanoparticles and metallic carbon nanotubes showing visible fluorescence induced by metal–semiconductor transition.
NANOSCALE CHARACTERIZATION BY SCANNING TUNNELING MICROSCOPY
Authors: XU HAI , XIE XIAN NING , ZILANI M. A. K. , CHEN WEI , WEE ANDREW THYE SHEN
Published: January 2008

Nanoscale characterization is a key field in nanoscience and technology as it provides fundamental understanding of the properties and functionalities of materials down to the atomic and molecular scale. In this article, we review the development and application of scanning tunneling microscope (STM) techniques in nanoscale characterization. We will discuss the working principle, experimental setup, operational modes, and tip preparation methods of scanning tunneling microscope. Selected examples are provided to illustrate the application of STM in the nanocharacterization of semiconductors. In addition, new developments in STM techniques including spin-polarized STM (SP-STM) and multi-probe STM (MP-STM) are discussed in comparison with conventional non-magnetic and single tip STM methods.
THEORETICAL STUDIES OF THE TETRACHLOROCUPRATE(II) ANION: ADF GEOMETRY OPTIMIZATION, AND CALCULATION OF THE PES, EPR PARAMETERS, AND VIBRATIONAL FREQUENCIES
Authors: RAHEMI H. , TAYYARI S. F. , RILEY M. J.
Published: January 2008

PES as functions of the trans-angle (θ) and the dihedral angle (ε) for optimized bond length is calculated. It is found that the most unstrained stable conformation of the [Formula: see text] is D2d at θ = 129.45° and ε = 90.0°. Calculated EPR g values change smoothly and in a logarithmic manner in the experimental range. The g33 value varies from 2.1287 (D4h) to 2.2836 (Td), and g11 = g22 from 2.035 to 2.1001. The Cu hyperfine values of the D4h are A11 = -196.455 and A22 = A33 = -17.533. At the most stable D2d conformation, the values are A11 = -177.606 and A22 = A33 = 2.6266, all in the 10-4 cm-1 unit.

The variation of EPR g values with molecular charge in the range of -2.0 to -2.8 were studied, and it was found that by increasing molecular charge, both components of g values are increased. For the D2d conformation with molecular charge of -2.6, g⊥ = 2.085 (expt. = 2.094) and g|| = 2.243 (expt. = 2.238). For the D4h conformation, calculated g|| values with increasing molecular charge improved, but g⊥ values deviated increasingly from experimental values. Frequencies are also calculated in the range of D2d to D4h.
INTRAMOLECULAR EXCITED ENERGY TRANSFER PATHWAYS IN PROTEINS
Authors: LAREO LEONARDO R. , GONZÁLEZ JANNETH
Published: January 2008

The transfer of energy perturbations within protein structure is an important phenomenon in many biological processes. In particular, the transfer of energy perturbations within a molecule in the absence of electron transfer is critical to the understanding of such processes as signaling involving receptors, channels, and enzymes among others, and to the design and development of relevant conducting materials. In this work, we have proposed a mechanism to explain this nonradiative, nonelectron energy transfer based on the π-orbital interactions of aromatic amino acids. Additionally, some theoretical background and possible computational approaches are presented as support for the proposal.
Two-dimensional kinetics of β2-integrin and ICAM-1 bindings between neutrophils and melanoma cells in a shear flow
Authors: Liang Shile , Fu Changliang , Wagner Desiree , Guo Huiguang , Zhan Dongying , Dong Cheng , Long Mian
Published: January 2008

Cell adhesion, mediated by specific receptor-ligand interactions, plays an important role in biological processes such as tumor metastasis and inflammatory cascade. For example, interactions between β2-integrin (lymphocyte function-associated antigen-1 and/or Mac-1) on polymorphonuclear neutrophils (PMNs) and ICAM-1 on melanoma cells initiate the bindings of melanoma cells to PMNs within the tumor microenvironment in blood flow, which in turn activate PMN-melanoma cell aggregation in a near-wall region of the vascular endothelium, therefore enhancing subsequent extravasation of melanoma cells in the microcirculations. Kinetics of integrin-ligand bindings in a shear flow is the determinant of such a process, which has not been well understood. In the present study, interactions of PMNs with WM9 melanoma cells were investigated to quantify the kinetics of β2-integrin and ICAM-1 bindings using a cone-plate viscometer that generates a linear shear flow combined with a two-color flow cytometry technique. Aggregation fractions exhibited a transition phase where it first increased before 60 s and then decreased with shear durations. Melanoma-PMN aggregation was also found to be inversely correlated with the shear rate. A previously developed probabilistic model was modified to predict the time dependence of aggregation fractions at different shear rates and medium viscosities. Kinetic parameters of β2-integrin and ICAM-1 bindings were obtained by individual or global fittings, which were comparable to respectively published values. These findings provide new quantitative understanding of the biophysical basis of leukocyte-tumor cell interactions mediated by specific receptor-ligand interactions under shear flow conditions.
CXCR2 agonists in ADPKD liver cyst fluids promote cell proliferation
Authors: Amura Claudia R. , Brodsky Kelley S. , Gitomer Berenice , McFann Kim , Lazennec Gwendal , Nichols Matthew T. , Jani Alkesh , Schrier Robert W. , Brian Doctor R.
Published: January 2008

Autosomal dominant polycystic kidney disease (ADPKD) is a highly prevalent genetic disease that results in cyst formation in kidney and liver. Cytokines and growth factors secreted by the cyst-lining epithelia are positioned to initiate autocrine/paracrine signaling and promote cyst growth. Comparative analyses of human kidney and liver cyst fluids revealed disparate cytokine/growth factor profiles. CXCR2 agonists, including IL-8, epithelial neutrophil-activating peptide (ENA-78), growth-related oncogene-α (GRO-α), are potent proliferative agents that were found at high levels in liver but not kidney cyst fluids. Liver cysts are lined by epithelial cells derived from the intrahepatic bile duct (i.e., cholangiocytes). In polarized pkd2(WS25/−) mouse liver cyst epithelial monolayers, CXCR2 agonists were released both apically and basally, indicating that they may act both on the endothelial and epithelial cells within or lining the cyst wall. IL-8 and human liver cyst fluid induced cell proliferation of HMEC-1 cells, a human microvascular endothelial cell line, and Mz-ChA1 cells, a human cholangiocyte cell model. IL-8 expression can be regulated by specific stresses. Hypoxia and mechanical stretch, two likely stressors acting on the liver cyst epithelia, significantly increased IL-8 secretion and promoter activity. AP-1, c/EBP, and NF-κB were required but not sufficient to drive the stress-induced increase in IL-8 transcription. An upstream element between −272 and −1,481 bp allowed for the stress-induced increase in IL-8 transcription. These studies support the hypothesis that CXCR2 signaling promotes ADPKD liver cyst growth.
Trauma-hemorrhage inhibits splenic dendritic cell proinflammatory cytokine production via a mitogen-activated protein kinase process
Authors: Kawasaki Takashi , Choudhry Mashkoor A. , Schwacha Martin G. , Fujimi Satoshi , Lederer James A. , Bland Kirby I. , Chaudry Irshad H.
Published: January 2008

Although splenic dendritic cell (DC) functions are markedly altered following trauma-hemorrhage, the mechanism(s) responsible for the altered DC functions remains unknown. We hypothesized that trauma-hemorrhage inhibits DC function via suppressing toll-like receptor 4 (TLR4) expression and mitogen-activated protein kinases (MAPKs). To examine this, male C3H/HeN (6–8 wk) mice were randomly assigned to sham operation or trauma-hemorrhage. Trauma-hemorrhage was induced by midline laparotomy and ∼90 min of hypotension [blood pressure (BP) 35 mmHg], followed by fluid resuscitation (4× the shed blood volume in the form of Ringer lactate). Two hours later, mice were euthanized, splenic DCs were isolated, and the changes in their MAPK activation, TLR4-MD-2 expression, and ability to produce cytokines were measured. The results indicate that trauma-hemorrhage downregulated the lipopolysaccharide (LPS)-induced MAPK activation in splenic DCs. In addition to the decrease in MAPK activation, surface expression of TLR4-MD-2 was suppressed following trauma-hemorrhage. Furthermore, LPS-induced cytokine production from splenic DCs was also suppressed following trauma-hemorrhage. These findings thus suggest that the decrease in TLR4-MD-2 and MAPK activation may contribute to the LPS hyporesponsiveness of splenic DCs following trauma-hemorrhage. Hyporesponsiveness of splenic DCs was also found after stimulation with the TLR2 agonist zymosan. Our results may thus explain the profound immunosuppression that is known to occur under those conditions.
A hyperpolarization-activated, cyclic nucleotide-gated, (Ih-like) cationic current and HCN gene expression in renal inner medullary collecting duct cells
Authors: Bolívar Juan J. , Tapia Dagoberto , Arenas Gabina , Castañón-Arreola Mauricio , Torres Haydee , Galarraga Elvira
Published: January 2008

The cation conductancein primary cultures of rat renal inner medullary collecting duct was studied using perforated-patch and conventional whole cell clamp techniques. Hyperpolarizations beyond −60 mV induced a time-dependent inward nonselective cationic current ( Ivti) that resembles the well-known hyperpolarization-activated, cyclic nucleotide-gated Ih and If currents. Ivti showed a half-maximal activation around −102 mV with a slope factor of 25 mV. It had a higher conductance (but, at its reversal potential, not a higher permeability) for K+ than for Na+ ( gK+/ gNa+ = 1.5), was modulated by cAMP and blocked by external Cd2+ (but not Cs+ or ZD-7288), and potentiated by a high extracellular K+ concentration. We explored the expression of the Ih channel genes (HCN1 to -4) by RT-PCR. The presence of transcripts corresponding to the HCN1, -2, and -4 genes was observed in both the cultured cells and kidney inner medulla. Western blot analysis with HCN2 antibody showed labeling of ∼90- and ∼120-kDa proteins in samples from inner medulla and cultured cells. Immunocytochemical analysis of cell cultures and inner medulla showed the presence of HCN immunoreactivity partially colocalized with the Na+-K+-ATPase at the basolateral membrane of collecting duct cells. This is the first evidence of an Ih-like cationic current and HCN immunoreactivity in either kidney or any other nonexcitable mammalian cells.
Flagellin is required for salmonella-induced expression of heat shock protein Hsp25 in intestinal epithelium
Authors: Petrof Elaine O. , Musch Mark W. , Ciancio Mae , Sun Jun , Hobert Michael E. , Claud Erika C. , Gewirtz Andrew , Chang Eugene B.
Published: January 2008

Flagellin is a bacterial protein responsible for activation of Toll-like receptor 5 (TLR5), which we hypothesize is involved in Salmonella's induction of cytoprotective heat shock proteins in intestinal epithelial cells. Flagellin induces the cytoprotective heat shock protein Hsp25 in different intestinal epithelial cell lines and in mouse intestine. Flagellin induces Hsp25 expression in a time-dependent manner in vitro. This effect is transcriptional, as confirmed by luciferase reporter assays and actinomycin D treatment. In addition, Hsp25 induction requires p38 MAPK activation and is only observed when flagellin is added to the basolateral side of polarized intestinal epithelial cells, consistent with the known location of TLR5. Flagellin-mediated Hsp25 induction is associated with increased protective effects against oxidant stress, an effect that is at least partially mediated by p38 MAPK. Use of small interfering RNA against Hsp25 demonstrates that flagellin-mediated protection against oxidant stress is to some degree mediated through Hsp25 induction. This suggests that, by protecting against oxidant injury, the induction of Hsp25 expression by flagellin may contribute to intestinal homeostasis. In a coculture cell model and in a mouse model of Salmonella enterica Serovar Typhimurium infection, not only does infection with wild-type and a flagellin-deletion mutant strain of Salmonella show that flagellin induces Hsp25 in vivo, but it also demonstrates that in the case of live Salmonella infection, flagellin serves as a major stimulus for the induction of Hsp25 expression. These data provide evidence that flagellin is required for Salmonella-mediated induction of Hsp25 expression in intestinal epithelium.
Fructose ingestion acutely elevates blood pressure in healthy young humans
Authors: Brown Clive M. , Dulloo Abdul G. , Yepuri Gayathri , Montani Jean-Pierre
Published: January 2008

Overconsumption of fructose, particularly in the form of soft drinks, is increasingly recognized as a public health concern. The acute cardiovascular responses to ingesting fructose have not, however, been well-studied in humans. In this randomized crossover study, we compared cardiovascular autonomic regulation after ingesting water and drinks containing either glucose or fructose in 15 healthy volunteers (aged 21–33 yr). The total volume of each drink was 500 ml, and the sugar content 60 g. For 30 min before and 2 h after each drink, we recorded beat-to-beat heart rate, arterial blood pressure, and cardiac output. Energy expenditure was determined on a minute-by-minute basis. Ingesting the fructose drink significantly increased blood pressure, heart rate, and cardiac output but not total peripheral resistance. Glucose ingestion resulted in a significantly greater increase in cardiac output than fructose but no change in blood pressure and a concomitant decrease in total peripheral resistance. Ingesting glucose and fructose, but not water, significantly increased blood pressure variability and decreased cardiovagal baroreflex sensitivity. Energy expenditure increased by a similar amount after glucose and fructose ingestion, but fructose elicited a significantly greater increase in respiratory quotient. These results show that ingestion of glucose and fructose drinks is characterized by specific hemodynamic responses. In particular, fructose ingestion elicits an increase in blood pressure that is probably mediated by an increase in cardiac output without compensatory peripheral vasodilatation.
Plasticity of muscle function in a thermoregulating ectotherm (Crocodylus porosus): biomechanics and metabolism
Authors: Seebacher Frank , James Rob S.
Published: January 2008

Thermoregulation and thermal sensitivity of performance are thought to have coevolved so that performance is optimized within the selected body temperature range. However, locomotor performance in thermoregulating crocodiles ( Crocodylus porosus) is plastic and maxima shift to different selected body temperatures in different thermal environments. Here we test the hypothesis that muscle metabolic and biomechanical parameters are optimized at the body temperatures selected in different thermal environments. Hence, we related indices of anaerobic (lactate dehydrogenase) and aerobic (cytochrome c oxidase) metabolic capacities and myofibrillar ATPase activity to the biomechanics of isometric and work loop caudofemoralis muscle function. Maximal isometric stress (force per muscle cross-sectional area) did not change with thermal acclimation, but muscle work loop power output increased with cold acclimation as a result of shorter activation and relaxation times. The thermal sensitivity of myofibrillar ATPase activity decreased with cold acclimation in caudofemoralis muscle. Neither aerobic nor anaerobic metabolic capacities were directly linked to changes in muscle performance during thermal acclimation, although there was a negative relationship between anaerobic capacity and isometric twitch stress in cold-acclimated animals. We conclude that by combining thermoregulation with plasticity in biomechanical function, crocodiles maximize performance in environments with highly variable thermal properties.
Sympathetic responses to vestibular activation in humans
Authors: Carter Jason R. , Ray Chester A.
Published: January 2008

Activation of sympathetic neural traffic via the vestibular system is referred to as the vestibulosympathetic reflex. Investigations of the vestibulosympathetic reflex in humans have been limited to the past decade, and the importance of this reflex in arterial blood pressure regulation is still being determined. This review provides a summary of sympathetic neural responses to various techniques used to engage the vestibulosympathetic reflex. Studies suggest that activation of the semicircular canals using caloric stimulation and yaw rotation do not modulate muscle sympathetic nerve activity (MSNA) or skin sympathetic nerve activity (SSNA). In contrast, activation of the otolith organs appear to alter MSNA, but not SSNA. Specifically, head-down rotation and off-vertical axis rotation increase MSNA, while sinusoidal linear accelerations decrease MSNA. Galvanic stimulation, which results in a nonspecific activation of the vestibule, appears to increase MSNA if the mode of delivery is pulse trained. In conclusion, evidence strongly supports the existence of a vestibulosympathetic reflex in humans. Furthermore, attenuation of the vestibulosympathetic reflex is coupled with a drop in arterial blood pressure in the elderly, suggesting this reflex may be important in human blood pressure regulation.
Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats
Authors: Piecha Grzegorz , Kokeny Gabor , Nakagawa Kumiko , Koleganova Nadezda , Geldyyev Aman , Berger Irina , Ritz Eberhard , Schmitt Claus Peter , Gross Marie-Luise
Published: January 2008

Patients with renal insufficiency develop secondary hyperparathyroidism. Monotherapy with active vitamin D or calcimimetics ameliorates secondary hyperparathyroidism. We compared kidney damage in subtotally nephrectomized (SNX) rats treated with active vitamin D (calcitriol) or the calcimimetic R-568. Male Sprague-Dawley SNX and sham-operated (sham-op) rats were randomized into the following treatment groups: SNX + R-568, SNX + calcitriol, SNX + vehicle, sham-op + R-568, sham-op + calcitriol, and sham-op + vehicle. Albuminuria and blood pressure were monitored and kidneys were examined using morphometry, immunohistochemistry, quantitative RT-PCR, and in situ hybridization. Parathyroid hormone concentrations were lowered to the same extent by the two interventions, although phosphorus and the calcium-phosphorus product were reduced only by R-568 treatment. SNX rats developed marked albuminuria, which was significantly reduced in ad libitum- and pair-fed animals treated with R-568 and animals treated with calcitriol. Mean glomerular volume (6.05 ± 1.46 vs. 2.70 ± 0.91 mm3), podocyte volume (831 ± 127 vs. 397 ± 67 μm3), the degree of foot process fusion (mean width of foot processes = 958 ± 364 vs. 272 ± 35 nm), and glomerular basement membrane thickness (244 ± 6 vs. 267 ± 23 nm), as well as desmin staining, were significantly higher in vehicle-treated SNX than sham-operated animals. These changes were ameliorated with R-568 and calcitriol. In SNX, as well as sham-operated, animals, expression of the calcium-sensing receptor (protein and mRNA) was upregulated by treatment with the calcimimetic, but not calcitriol. Calcitriol and R-568 were similarly effective in ameliorating kidney damage.
Vasopressin regulation of inner medullary collecting ducts and compensatory changes in mice lacking adenosine A1receptors
Authors: Rieg Timo , Pothula Kanishka , Schroth Jana , Satriano Joseph , Osswald Hartmut , Schnermann Jürgen , Insel Paul A. , Bundey Richard A. , Vallon Volker
Published: January 2008

Activation of adenosine A1receptors (A1R) can inhibit arginine vasopressin (AVP)-induced cAMP formation in isolated cortical and medullary collecting ducts. To assess the in vivo consequences of the absence of A1R, we performed experiments in mice lacking A1R (A1R−/−). We assessed the effects of the vasopressin V2receptor (V2R) agonist 1-desamino-8-d-arginine vasopressin (dDAVP) on cAMP formation in isolated inner medullary collecting ducts (IMCD) and on water excretion in conscious water-loaded mice. dDAVP-induced cAMP formation in isolated IMCD was significantly greater (∼2-fold) in A1R−/−compared with wild-type mice (WT) and, in contrast to WT, was not inhibited by the A1R agonist N6-cyclohexyladenosine. A1R−/−and WT had similar basal urinary excretion of vasopressin, expression of aquaporin-2 protein in renal cortex and medulla, and acute increases in urinary flow rate and electrolyte-free water clearance in response to the V2R antagonist SR121463 or acute water loading; the latter increased inner medullary A1R expression in WT. Dose dependence of dDAVP-induced antidiuresis after acute water loading was not different between the genotypes. However, A1R−/−had greater inner medullary expression of cyclooxygenase-1 under basal conditions and of the P2Y2and EP3receptor in response to water loading compared with WT mice. Thus vasopressin-induced cAMP formation is enhanced in isolated IMCD of mice lacking A1R, but the adenosine-A1R/V2R interaction demonstrated in vitro is likely compensated in vivo by multiple mechanisms, a number of which can be “uncovered” by water loading.
Glomerular hypertrophy precedes albuminuria and segmental loss of podoplanin in podocytes in Munich-Wistar-Frömter rats
Authors: IJpelaar D. H. T. , Schulz A. , Koop K. , Schlesener M. , Bruijn J. A. , Kerjaschki D. , Kreutz R. , de Heer E.
Published: January 2008

Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease. Albuminuria is a risk factor for FSGS and is influenced by environmental, genetic, and sex-specific factors. Podocytes play a central role in the development of albuminuria, but the precise relationship between early glomerular and podocyte-associated damage and albuminuria is unclear. Furthermore, experimental findings demonstrate a sex difference in development of albuminuria and FSGS. We investigated the early glomerular changes in male Munich-Wistar-Frömter (MWF) rats, which spontaneously develop albuminuria, and male albuminuria-resistant spontaneously hypertensive rats (SHR). In addition, since female MWF rats are protected from overt proteinuria and progressive renal disease, we compared the phenotypic changes in podocytes during early development of albuminuria in male and female MWF rats. In male MWF rats, glomerular hypertrophy preceded the onset of albuminuria and was greater than in male SHR. Albuminuria developed starting at 6 wk of age and coincided with focal and segmental loss of podoplanin, increased expression of desmin, entrapment of albumin in affected podocytes, and focal and segmental foot process effacement at the ultrastructural level. Other podocyte-associated molecules, such as nephrin and zonula occludens 1, were unaffected. Early glomerular hypertrophy and podocyte damage did not differ between male and female MWF rats. Our data show for the first time that albuminuria in male and female MWF rats is preceded by glomerular hypertrophy and accompanied by focal and segmental loss of podoplanin when FSGS was not yet present.
Acute responses in muscle mitochondrial and cytosolic enzyme activities during heavy intermittent exercise
Authors: Green H. J. , Bombardier E. B. , Duhamel T. A. , Holloway G. P. , Tupling A. R. , Ouyang J.
Published: January 2008

To examine the effects of repetitive bouts of heavy exercise on the maximal activities of enzymes representative of the major metabolic pathways and segments, 13 untrained volunteers [peak aerobic power (V̇o2 peak) = 44.3 ± 2.3 ml·kg−1·min−1] cycled at ∼91% V̇o2 peak for 6 min once per hour for 16 h. Maximal enzyme activities ( Vmax, mol·kg−1·protein·h−1) were measured in homogenates from tissue extracted from the vastus lateralis before and after exercise at repetitions 1 (R1), 2 (R2), 9 (R9), and 16 (R16). For the mitochondrial enzymes, exercise resulted in reductions ( P < 0.05) in cytochrome- c oxidase (COX, 14.6%), near significant reductions in malate dehydrogenase (4.06%; P = 0.06) and succinic dehydrogenase (4.82%; P = 0.09), near significant increases in β-hydroxyacyl-CoA dehydrogenase (4.94%; P = 0.08), and no change in citrate synthase (CS, 2.88%; P = 0.37). For the cytosolic enzymes, exercise reduced ( P < 0.05) Vmax in hexokinase (Hex, 4.4%), creatine phosphokinase (9.0%), total phosphorylase (13.5%), phosphofructokinase (16.6%), pyruvate kinase (PK, 14.1%) and lactate dehydrogenase (10.7%). Repetition-dependent reductions ( P < 0.05) in Vmax were observed for CS (R1, R2 > R16), COX (R1, R2 > R16), Hex (1R, 2R > R16), and PK (R9 > R16). It is concluded that heavy exercise results in transient reductions in a wide range of enzymes involved in different metabolic functions and that in the case of selected enzymes, multiple repetitions of the exercise reduce average Vmax.
Superoxide-Induced Potentiation in the Hippocampus Requires Activation of Ryanodine Receptor Type 3 and ERK
Authors: Huddleston A. Tara , Tang Wei , Takeshima Hiroshi , Hamilton Susan L. , Klann Eric
Published: January 2008

Reactive oxygen species (ROS) are required for the induction of long-term potentiation (LTP) and behave as signaling molecules via redox modifications of target proteins. In particular, superoxide is necessary for induction of LTP, and application of superoxide to hippocampal slices is sufficient to induce LTP in area CA1. Although a rise in postsynaptic intracellular calcium is necessary for LTP induction, superoxide-induced potentiation does not require calcium flux through N-methyl-d-aspartate (NMDA) receptors. Ryanodine receptors (RyRs) mediate calcium-induced calcium release from intracellular stores and have been shown to modulate LTP. In this study, we investigated the highly redox-sensitive RyRs and L-type calcium channels as calcium sources that might mediate superoxide-induced potentiation. In agreement with previous studies of skeletal and cardiac muscle, we found that superoxide enhances activation of RyRs in the mouse hippocampus. We identified a functional coupling between L-type voltage-gated calcium channels and RyRs and identified RyR3, a subtype enriched in area CA1, as the specific isoform required for superoxide-induced potentiation. Superoxide also enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) in area CA1, and ERK was necessary for superoxide-induced potentiation. Thus superoxide-induced potentiation requires the redox targeting of RyR3 and the subsequent activation of ERK.
Influence of Inhibitory Inputs on Rate and Timing of Responses in the Anteroventral Cochlear Nucleus
Authors: Gai Yan , Carney Laurel H.
Published: January 2008

Anatomical and physiological studies have shown that anteroventral cochlear nucleus (AVCN) neurons receive glycinergic and GABAergic inhibitory inputs. In this study, changes in the temporal responses of AVCN neurons to pure tones and complex sounds after blocking inhibition were analyzed. Blocking inhibition influenced the temporal responses of each type of AVCN neuron. Choppers showed more chopping peaks and shortened chopping cycles after blocking inhibition. Sustained and slowly adapting choppers showed increased regularity throughout the response duration after blocking inhibition, whereas most transient choppers showed increased regularity in the early part of the response. Diverse changes in temporal response patterns were observed in neurons with primary-like and unusual responses, with several neurons showing a large decrease in the first-spike latency after blocking inhibition. This result disagreed with previous findings that onset responses are less affected than sustained responses by manipulating inhibition. Although blocking inhibition had a greater effect on spontaneous activity than that on tone-evoked activity, the change in spontaneous activity was less significant because of larger variability. In addition, for relatively high level masker noises, blocking inhibition had similar effects on responses to noise-alone and noise-plus-tone stimuli, in contrast with previous studies with low-level background noise. In general, inhibition had an enhancing effect on temporal contrast only for responses to amplitude-modulated tones, for which envelope synchrony was enhanced. Results of this study contribute new information about the characteristics, functional roles, and possible sources of inhibitory inputs received by AVCN neurons.
Behavioral and Physiological Characterization of Sensorimotor Gating in the Goldfish Startle Response
Authors: Neumeister Heike , Szabo Theresa M. , Preuss Thomas
Published: January 2008

Prepulse inhibition (PPI) is typically associated with an attenuation of auditory startle behavior in mammals and is presumably mediated within the brainstem startle circuit. However, the inhibitory mechanisms underlying PPI are not yet clear. We addressed this question with complementary behavioral and in vivo electrophysiological experiments in the startle escape circuit of goldfish, the Mauthner cell (M-cell) system. In the behavioral experiments we observed a 77.5% attenuation (PPI) of startle escape probability following auditory prepulse–pulse stimulation. The PPI effect was observed for prepulse–pulse interstimulus intervals (ISIs) ranging from 20 to 600 ms and its magnitude depended linearly on prepulse intensity over a range of 14 dB. Electrophysiological recordings of synaptic responses to a sound pulse in the M-cell, which is the sensorimotor neuron initiating startle escapes, showed a 21% reduction in amplitude of the dendritic postsynaptic potential (PSP) and a 23% reduction of the somatic PSP following a prepulse. In addition, a prepulse evoked a long-lasting (500 ms) decrease in M-cell excitability indicated by 1) an increased threshold current, 2) an inhibitory shunt of the action potential (AP), and 3) by a linearized M-cell membrane, which effectively impedes M-cell AP generation. Comparing the magnitude and kinetics of inhibitory shunts evoked by a prepulse in the M-cell dendrite and soma revealed a disproportionately larger and longer-lasting inhibition in the dendrite. These results suggest that the observed PPI-type attenuation of startle behavior can be correlated to distinct postsynaptic mechanisms mediated primarily at the M-cell lateral dendrite.
Prenatal Morphine Exposure Attenuates the Maintenance of Late LTP in Lateral Perforant Path Projections to the Dentate Gyrus and the CA3 Region In Vivo
Authors: Villarreal D. M. , Derrick B. , Vathy I.
Published: January 2008

Previously we reported that prenatal exposure to morphine twice daily during gestation decreases proenkephalin levels in adult progeny within the brain, including the dentate gyrus, and alters μ and δ opioid receptors in the hippocampal CA3 region. The lateral aspect of the perforant path contains and releases enkephalin-derived opioid peptides, and induction of long-term potentiation (LTP) in lateral perforant path projections to both the dentate gyrus and the hippocampal CA3 region is blocked by antagonists of opioid receptors. Thus LTP induction at these synapses involves opioid receptor activation mediated by the release of proenkephalin-derived opioid peptides with lateral perforant path activation. Here we show in adult behaving animals, neither LTP induction nor the early phase of LTP (E-LTP) maintenance is altered by prenatal morphine exposure in the lateral perforant path projections to the dentate gyrus and the CA3 region. However, maintenance and longevity of late LTP (L-LTP), as reflected in the magnitude of LTP over days, was attenuated in animals prenatally exposed to morphine. In contrast, in medial perforant path projections to the dentate gyrus and CA3 region, both LTP induction and the maintenance of E- and L-LTP were unaffected by prenatal morphine treatment. Thus a brief prenatal exposure to the opiate morphine produces sustained, and possibly permanent, alterations in L-LTP in the opioidergic lateral perforant path projection. This suggests that prenatal morphine exposure disrupts LTP via disruption of opioid mechanisms involved in LTP maintenance or via disruption of opioid receptor activation during LTP induction, which can subsequently alter LTP maintenance.
Effect of Common Anesthetics on Dendritic Properties in Layer 5 Neocortical Pyramidal Neurons
Authors: Potez Sarah , Larkum Matthew E.
Published: January 2008

Understanding the impact of active dendritic properties on network activity in vivo has so far been restricted to studies in anesthetized animals. However, to date no study has been made to determine the direct effect of the anesthetics themselves on dendritic properties. Here, we investigated the effects of three types of anesthetics commonly used for animal experiments (urethane, pentobarbital and ketamine/xylazine). We investigated the generation of calcium spikes, the propagation of action potentials (APs) along the apical dendrite and the somatic firing properties in the presence of anesthetics in vitro using dual somatodendritic whole cell recordings. Calcium spikes were evoked with dendritic current injection and high-frequency trains of APs at the soma. Surprisingly, we found that the direct actions of anesthetics on calcium spikes were very different. Two anesthetics (urethane and pentobarbital) suppressed dendritic calcium spikes in vitro, whereas a mixture of ketamine and xylazine enhanced them. Propagation of spikes along the dendrite was not significantly affected by any of the anesthetics but there were various changes in somatic firing properties that were highly dependent on the anesthetic. Last, we examined the effects of anesthetics on calcium spike initiation and duration in vivo using high-frequency trains of APs generated at the cell body. We found the same anesthetic-dependent direct effects in addition to an overall reduction in dendritic excitability in anesthetized rats with all three anesthetics compared with the slice preparation.
Phytochemistry and pharmacogenomics of natural products derived from traditional chinese medicine and chinese materia medica with activity against tumor cells
Authors: Efferth Thomas , Kahl Stefan , Paulus Kerstin , Adams Michael , Rauh Rolf , Boechzelt Herbert , Hao Xiaojiang , Kaina Bernd , Bauer Rudolf
Published: January 2008

The cure from cancer is still not a reality for all patients, which is mainly due to the limitations of chemotherapy (e.g., drug resistance and toxicity). Apart from the high-throughput screening of synthetic chemical libraries, natural products represent attractive alternatives for drug development. We have done a systematic bioactivity-based screening of natural products derived from medicinal plants used in traditional Chinese medicine. Plant extracts with growth-inhibitory activity against tumor cells have been fractionated by chromatographic techniques. We have isolated the bioactive compounds and elucidated the chemical structures by nuclear magnetic resonance and mass spectrometry. By this strategy, we identified 25-O-acetyl-23,24-dihydro-cucurbitacin F as a cytotoxic constituent of Quisqualis indica. Another promising compound identified by this approach was miltirone from Salvia miltiorrhiza. The IC50 values for miltirone of 60 National Cancer Institute cell lines were associated with the microarray-based expression of 9,706 genes. By COMPARE and hierarchical cluster analyses, candidate genes were identified, which significantly predicted sensitivity or resistance of cell lines to miltirone. [Mol Cancer Ther 2008;7(1):152–61]
Suppression of VEGF secretion and changes in glioblastoma multiforme microenvironment by inhibition of Integrin-linked kinase (ILK)
Authors: Edwards Lincoln A. , Woo Janet , Huxham Lynsey A. , Verreault Maite , Dragowska Wieslawa H. , Chiu Gigi , Rajput Ashish , Kyle Alastair H. , Kalra Jessica , Yapp Donald , Yan Hong , Minchinton Andrew I. , Huntsman David , Daynard Tim , Waterhouse Dawn N. , Thiessen B. , Dedhar Shoukat , Bally Marcel B.
Published: January 2008

Integrin-linked kinase (ILK) was assesed as a therapeutic target in glioblastoma xenograft models through multiple endpoints including treatment related changes in the tumor microenvironment. Glioblastoma cell lines were tested in vitro for sensitivity toward the small-molecule inhibitors QLT0254 and QLT0267. Cell viability, cell cycle, and apoptosis were evaluated using MTT assay, flow cytometry, caspase activation, and DAPI staining. Western blotting and ELISA were used for protein analysis (ILK, PKB/Akt, VEGF, and HIF-1α). In vivo assessment of growth rate, cell proliferation, BrdUrd, blood vessel mass (CD31 labeling), vessel perfusion (Hoechst 33342), and hypoxia (EF-5) was done using U87MG glioblastoma xenografts in RAG2-M mice treated orally with QLT0267 (200 mg/kg q.d.). ILK inhibition in vitro with QLT0254 and QLT0267 resulted in decreased levels of phospho-PKB/Akt (Ser473), secreted VEGF, G2-M block, and apoptosis induction. Mice treated with QLT0267 exhibited significant delays in tumor growth (treated 213 mm3 versus control 549 mm3). In situ analysis of U87MG tumor cell proliferation from QLT0267-treated mice was significantly lower relative to untreated mice. Importantly, VEGF and HIF-1α expression decreased in QLT0267-treated tumors as did the percentage of blood vessel mass and numbers of Hoechst 33342 perfused tumor vessels compared with control tumors (35% versus 83%). ILK inhibition with novel small-molecule inhibitors leads to treatment-associated delays in tumor growth, decreased tumor angiogenesis, and functionality of tumor vasculature. The therapeutic effects of a selected ILK inhibitor (QLT0267) should be determined in the clinic in cancers that exhibit dysregulated ILK, such as PTEN-null glioblastomas. [Mol Cancer Ther 2008;7(1):59–70]
Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression
Authors: Aird Katherine M. , Ding Xiuyun , Baras Aris , Wei Junping , Morse Michael A. , Clay Timothy , Lyerly Herbert K. , Devi Gayathri R.
Published: January 2008

Inflammatory breast cancer (IBC) patients show poor survival and a significant incidence of epidermal growth factor receptor-2 (ErbB2) overexpression. A distinct mechanism involving increased expression of X-linked inhibitor of apoptosis protein (XIAP) and survivin, key members of the inhibitor of apoptosis protein (IAP) family, was observed post-trastuzumab (an ErbB2 monoclonal antibody) treatment in an ErbB2-overexpressing, estrogen receptor negative, IBC cellular model, SUM190PT, isolated from a primary IBC tumor. In contrast, a decrease in the IAP expression was observed in the non-IBC, ErbB2-overexpressing SKBR3 cells in which trastuzumab treatment also decreased p-AKT and cell viability. Further, in SUM190PT cells, therapeutic sensitivity to GW583340 (a dual epidermal growth factor receptor/ErbB2 kinase inhibitor) corresponded with XIAP down-regulation and abrogation of XIAP inhibition on active caspase-9 release. Specific small interfering RNA–mediated XIAP inhibition in combination with trastuzumab caused decrease in inactive procaspase-9 and inhibition of p-AKT corresponding with 45% to 50% decrease in cell viability in the SUM190PT cells, which have high steady-state p-AKT levels. Further, embelin, a small-molecule inhibitor that abrogates binding of XIAP to procaspase-9, caused significant decrease in SUM190PT viability. However, embelin in combination with trastuzumab failed to affect SUM190PT viability because it has no direct effect on XIAP, which is induced by trastuzumab treatment. These data have identified a novel functional link between ErbB2 signaling and antiapoptotic pathway mediated by XIAP. Blockade of the IAP antiapoptotic pathway alone or in combination would be an attractive strategy in IBC therapy. [Mol Cancer Ther 2008;7(1):38–47]