bluuebunny/crossref_metadata_2025 huggingface dataset:
Modelling cellular senescence as a result of telomere state
Authors: Proctor Carole J. , Kirkwood Thomas B. L.
Published: May 2003

Telomeres in mammalian cells end in large duplex T loops. These loops protect the single‐strand overhangs from degradation and/or interactions with signalling proteins. This protection is sometimes referred to as capping. At each cell division, telomeres shorten and there is a general consensus that telomere shortening triggers cell cycle exit. However, the exact mechanism by which telomere shortening causes cell cycle arrest is not known. Mathematical models of telomere shortening have been developed to help us understand the processes involved. Until now most models have assumed that the trigger for cell cycle arrest is the first telomere or a group of telomeres reaching a critically short length. However, there is evidence that cells stop cycling over a wide range of telomere lengths. This suggests that telomere length per se may not in fact be the trigger for cellular senescence. In this paper we develop a model which examines the hypothesis that uncapping of a telomere is the main trigger. By letting the probability of uncapping depend upon telomere length, we show that the hypothesized model provides a good fit to experimental data.
Age‐dependent change in reactive oxygen species and nitric oxide generation by rat alveolar macrophages*
Authors: Tasat Deborah Ruth , Mancuso Regina , O'Connor Silvia , Molinari Beatriz
Published: May 2003

Immunosenescence is an age‐associated dysregulation of the immune function, which contributes to increased susceptibility to disease in the elderly. Alveolar macrophages (AM) are known phagocytes that generate reactive oxygen species (ROS) and nitric oxide (NO), essential mediators for host defence. We studied phagocytosis, ROS and NO production in AM obtained from young, adult and senescent rats (1–2, 9–12 and 18–24 months old, respectively) after exposure to lipopolysaccharide (LPS, 0.1–10 µg mL−1), 12‐O‐tetradecanoylphorbol 13‐acetate (TPA, 0.1 µg mL−1) or LPS + TPA in culture. Phagocytosis was significantly lower in control AM from adult rats than in AM from young animals. Nevertheless, AM from adult animals pretreated with LPS exhibited higher phagocytic capacity than AM from younger animals. ROS was identified by the NBT test at single cell level and quantified by automated image analysis. When TPA was added to all three populations, AM from adult and senescent animals responded more than AM from young animals. All LPS‐stimulated AM produce more NO than controls. However, NO production increased three‐, four‐ and two‐fold in young, adult and senescent animals, respectively. Our results demonstrate that AM from young, adult and senescent animals display differential responsiveness to inflammatory mediators. Therefore, aging processes markedly affect AM metabolic functions and may further compromise the lung immune defence response, increasing adverse long‐term health effects.
Serum Hbv Dna As A Marker of Efficacy During Therapy for Chronic Hbv Infection: Analysis and Review of the Literature
Authors: Mommeja-Marin Herve , Mondou Elsa , Blum Robert M. , Rousseau Franck
Published: May 2003

Currently, compounds under evaluation for treatment of chronic hepatitis B virus (HBV) infection are evaluated with liver histology as the primary end point for efficacy. However, because of practical limitations in serial liver biopsies, there is a need for alternate markers to assess efficacy over shorter periods of time. Considering the direct correlation between viral replication and disease progression during human immunodeficiency virus and hepatitis C virus infection, we explored whether such a correlation exists for HBV infection. We reviewed the literature and conducted an analysis to investigate the relationship between absolute or treatment–induced changes in HBV DNA levels and other accepted markers of disease activity. A total of 26 prospective studies met our selection criteria, including 33 evaluable treatment arms. The study treatments consisted of nucleosides and/or interferon regimens and control arms. We found statistically significant and consistent correlations between viral load level or change and histologic grading and biochemical and serologic response. Our analysis suggests that a treatment–induced reduction in HBV DNA level can be used for assessing efficacy of treatment regimens. Further, we observed that quantitative HBV DNA has a broader dynamic range than histology, allowing demonstration of differences between 2 active treatments of unequal potency. The analysis showed stronger results in studies using nucleoside regimens and in hepatitis B e antigen (HBeAg)–positive patients. In conclusion, the goal of anti–HBV therapy should be profound and durable viral suppression, as defined by very sensitive assays. Additional prospective studies are needed to precisely determine the desirable level of viremia to attain.
A Role of Autoantibody–Mediated Platelet Destruction in Thrombocytopenia in Patients With Cirrhosis
Authors: Kajihara Mikio , Kato Shinzo , Okazaki Yuka , Kawakami Yutaka , Ishii Hiromasa , Ikeda Yasuo , Kuwana Masataka
Published: May 2003

Thrombocytopenia is a common manifestation in patients with liver cirrhosis (LC), but its underlying mechanism remains controversial. This study examined the role of anti–platelet autoimmunity in cirrhotic thrombocytopenia by determining the autoantibody response to GPIIb–IIIa, a major platelet surface autoantigen recognized by anti–platelet antibodies in patients with idiopathic thrombocytopenic purpura (ITP). Circulating B cells producing anti–GPIIb–IIIa antibodies as well as platelet–associated and plasma anti–GPIIb–IIIa antibodies were examined in 72 patients with LC, 62 patients with ITP, and 52 healthy controls. In vitro anti–GPIIb–IIIa antibody production was induced in cultures of peripheral blood mononuclear cells (PBMCs) by stimulation with GPIIb–IIIa. The frequency of anti–GPIIb–IIIa antibody–producing B cells in patients with LC was significantly greater than in healthy controls (10.9 ± 6.2 vs. 0.4 ± 0.3/105 PBMCs; P < .0001) and was even higher than the frequency in patients with ITP (8.2 ± 5.2; P = .007). Anti–GPIIb–IIIa antibodies in the patients with LC and ITP were mainly present on the surfaces of circulating platelets rather than in the plasma in an unbound form. Furthermore, PBMCs from patients with LC and ITP produced anti–GPIIb–IIIa antibodies on antigenic stimulation with GPIIb–IIIa in vitro, and the specific antibodies produced had the capacity to bind normal platelet surfaces. In conclusion, the similar profile of the anti–GPIIb–IIIa autoantibody response in patients with LC and ITP suggests that autoantibody–mediated platelet destruction may contribute at least in part to cirrhotic thrombocytopenia.
Propranolol Plus Placebo Versus Propranolol Plus Isosorbide–5–Mononitrate in the Prevention of A First Variceal Bleed: A Double–Blind Rct
Authors: García-Pagán Juan Carlos , Morillas Rosa , Bañares Rafael , Albillos Agustin , Villanueva Candido , Vila Carme , Genescà Joan , Jimenez Manuel , Rodriguez Manuel , Calleja Jose Luis , Balanzó Joaquin , Garcáa-Durán Fernando , Planas Ramón , Bosch Jaume
Published: May 2003

Nonselective β–blockers are very effective in preventing first variceal bleeding in patients with cirrhosis. Treatment with isosorbide–5–mononitrate (IS–MN) plus propranolol achieves a greater reduction in portal pressure than propranolol alone. The present multicenter, prospective, double–blind, randomized, controlled trial evaluated whether combined drug therapy could be more effective than propranolol alone in preventing variceal bleeding. A total of 349 consecutive cirrhotic patients with gastroesophageal varices were randomized to receive propranolol + placebo (n = 174) or propranolol + IS–MN (n = 175). There were no significant differences in the 1– and 2–year actuarial probability of variceal bleeding between the 2 groups (propranolol + placebo, 8.3% and 10.6%; propranolol + IS–MN, 5% and 12.5%). The only independent predictor of variceal bleeding was a variceal size greater than 5 mm. However, among patients with varices greater than 5 mm (n = 196), there were no significant differences in the incidence of variceal bleeding between the 2 groups. Survival was also similar. Adverse effects were significantly more frequent in the propranolol + IS–MN group due to a greater incidence of headache. There were no significant differences in the incidence of new–onset or worsening ascites or in impairment of renal function. In conclusion, propranolol effectively prevents variceal bleeding. Adding IS–MN does not further decrease the low residual risk of bleeding in patients receiving propranolol. However, the long–term use of this combination drug therapy is safe and may be an alternative in clinical conditions associated with a greater risk of bleeding.
Effect of Ribavirin on Hepatitis C Viral Kinetics in Patients Treated With Pegylated Interferon
Authors: Herrmann Eva , Lee Jung-Hun , Marinos George , Modi Marlene , Zeuzem Stefan
Published: May 2003

A dynamic equilibrium between viral production and clearance characterizes untreated chronic hepatitis C viral infection. After initiating antiviral treatment, a typical multiphasic decay of viremia can be observed and analyzed using mathematical models. To elucidate the antiviral mechanism of ribavirin when used in combination with (pegylated) interferon alfa, we investigated kinetic parameters in patients with chronic hepatitis C treated with either peginterferon α–2a with or without ribavirin and standard interferon α–2b plus ribavirin for 48 weeks. Serum HCV RNA was measured frequently before, during, and at the end–of–treatment and the follow–up period. By using an appropriate model for viral dynamics, kinetic parameters were derived from nonlinear, least square fitting of serum HCV RNA quantifications. The first phase of viral decay (day 1) and the second phase of viral decay (days 2 to 21) were similar for all treatment groups. After about 7 to 28 days, a third phase of viral decay was seen in several patients, and this phase of decay was significantly faster in patients treated with peginterferon α–2a plus ribavirin compared with those treated with peginterferon α–2a alone. The decay of this third phase was associated with the virologic end–of–treatment response and sustained virologic response. In conclusion, the third–phase decay of initial viral kinetics, which may represent a treatment–enhanced degradation of infected cells, was more pronounced in patients treated with peginterferon α–2a plus ribavirin. This finding suggests that combination treatment leads to a better restoration of the patient's immune response.
Triple Therapy With Amantadine in Treatment–Naive Patients With Chronic Hepatitis C: A Placebo–Controlled Trial
Authors: Berg Thomas , Kronenberger Bernd , Hinrichsen Holger , Gerlach Tilman , Buggisch Peter , Herrmann Eva , Spengler Ulrich , Goeser Tobias , Nasser Samer , Wursthorn Karsten , Pape Gerd R. , Hopf Uwe , Zeuzem Stefan
Published: May 2003

The antiviral efficacy of amantadine in patients with chronic hepatitis C is controversial. In this randomized, prospective, placebo–controlled, multicenter trial, triple therapy with interferon alfa (IFN–α)–2a plus ribavirin and amantadine (amantadine group) was compared with combination therapy IFN–α plus ribavirin (control group). Four hundred previously untreated patients with histologically proven chronic hepatitis C were randomly allocated to treatment with amantadine sulphate (100 mg twice daily orally) or a matched placebo together with IFN–α induction plus ribavirin (1,000–1,200 mg/day orally) for 48 weeks. The primary end point was sustained virologic response (SVR) defined as undetectable serum hepatitis C virus (HCV) RNA (<100 copies/mL) 24 weeks after the end of treatment. SVR was observed in 52% of the amantadine group and in 43.5% of the control group (P = .11). Among patients with HCV genotype 1 infection, the corresponding SVR rates were 39% and 31%, respectively. The virologic on–treatment response rate in week 24 was significantly higher in the amantadine group as compared with the control group (70% vs. 59%, respectively, P = .016). This beneficial effect was mainly related to HCV type 1–infected patients (63% vs. 47%, respectively, P = .012). Independent factors associated with SVR, according to multiple logistic regression analysis, were amantadine treatment, low baseline HCV RNA, platelet counts (≥250/nL), pretreatment ALT quotient ≥3, and GGT level (<28 U/L) as well as HCV genotypes other than 1. In conclusion, although we could not demonstrate a significant advantage of the triple regimen in univariate analysis, multivariate analysis offers arguments that amantadine should be considered as a potential anti–HCV drug in future studies.
Portal Cavernoma–Associated Cholangiopathy: A Clinical and Mr Cholangiography Coupled With Mr Portography Imaging Study
Authors: Condat Bertrand , Vilgrain Valérie , Asselah Tarik , O'Toole Dermot , Rufat Pierre , Zappa Magali , Moreau Richard , Valla Dominique
Published: May 2003

Although biliary symptoms appear to be uncommon in patients with portal cavernoma, almost all of them have endoscopic retrograde cholangiographic abnormalities. The mechanisms underlying the biliary changes are explained poorly. This study in patients with portal cavernoma had 3 aims: (1) to assess the manifestations related to biliary involvement; (2) to evaluate with magnetic resonance (MR) imaging the aspect and frequency of cholangiographic changes; and (3) to clarify the mechanisms underlying biliary involvement. From December 1999 to July 2001, 25 consecutive adults with portal cavernoma without cancer or cirrhosis were studied with MR cholangiography coupled with MR portography. Seven patients presented with clinical manifestations of biliary disease. MR cholangiography findings were stenosis in 21 patients, with upstream dilatation in 16 and displacement in 13. MR cholangiography coupled with MR portography showed in all cases that the biliary abnormalities were secondary to a mass effect directly related to pressure by the cavernoma. In conclusion, in patients with portal cavernoma, clinical manifestations of biliary disease are most frequent; the cholangiographic abnormalities are very common and usually are caused by a mass effect by pressure from the veins composing the cavernoma. MR cholangiography coupled with MR portography is an effective noninvasive examination for simultaneous visualization of bile ducts and their relationship to the cavernoma.
Hydrophilic But Not Hydrophobic Bile Acids Prevent Gallbladder Muscle Dysfunction in Acute Cholecystitis
Authors: Xiao Zuo-Liang , Biancani Piero , Carey Martin C. , Behar Jose
Published: May 2003

The pathogenesis of acute cholecystitis (AC) is controversial. Bile acids may be involved in the pathogenesis of AC because the hydrophobic chenodeoxycholic acid (CDCA) reproduced in vitro the muscle dysfunction observed in AC and was prevented by the hydrophilic ursodeoxycholic acid (UDCA). The present study examined the in vivo effects of UDCA or CDCA on gallbladder muscle dysfunction caused by AC. Guinea pigs were treated with placebo, UDCA, or CDCA for 2 weeks before sham operation or induction of AC by bile duct ligation (BDL) for 3 days. Pretreatment with oral UDCA prevented the defective contraction in response to agonists (acetylcholine [ACh], cholecystokinin 8 [CCK–8], and KCl) that occurs after BDL. Prostaglandin (PG) E2–induced contraction remained normal in the placebo and UDCA–treated groups but was impaired in the CDCA–treated group. Treatment with UDCA also prevented the expected increase in the levels of H2O2, lipid peroxidation, and PGE2 content in the placebo–treated AC group, whereas CDCA caused further increases in these oxidative stress markers. The binding capacity of PGE2 to its receptors and the activity of catalase were reduced after treatment with CDCA. Treatment with UDCA enriched gallbladder bile acids with its conjugates and reduced the percentage of CDCA conjugates. In contrast, treatment with CDCA significantly decreased the percentage of UDCA in bile. In conclusion, oral treatment with UDCA prevents gallbladder muscle damage caused by BDL, whereas oral treatment with CDCA worsens the defective muscle contractility and the oxidative stress.
Long–Term Expression of Angiostatin Suppresses Metastatic Liver Cancer in Mice
Authors: Xu Ruian , Sun Xueying , Tse Lai-Yin , Li Hua , Chan Pui-Chung , Xu Sue , Xiao Weidong , Kung Hsiang-Fu , Krissansen Geoffrey W. , Fan Sheung-Tat
Published: May 2003

Metastatic liver cancer has a very poor prognosis and lacks effective therapy. Anti–angiogenic therapies, which starve tumors of blood supply, have proven to be effective in preclinical models because tumor growth is angiogenesis dependent. However, long–term, high–level, and sustained expression of angiogenesis inhibitors, such as angiostatin, is necessary to prevent dormant tumors from becoming active again. To achieve this objective, we engineered a recombinant adeno–associated virus (AAV) vector encoding mouse angiostatin, an endogenous inhibitor of tumor vascularization. After intraportal delivery of this vector, high–level, stable transgene expression of angiostatin lasting for at least 6 months was observed locally in hepatocytes. Gene transfer of AAV–angiostatin via the portal vein led to significant suppression of the growth of both nodular and metastatic EL–4 lymphoma tumors established in the liver and prolonged the survival time of the mice. The growth of neovessels was inhibited significantly, and extensive apoptosis of tumor cells was observed. The anti–angiogenic activity of angiostatin was independent of vascular endothelial growth factor (VEGF). The AAV–angiostatin viruses did not appear to be toxic to mice, and there was no detectable apoptosis of hepatocytes. In conclusion, these encouraging results warrant future investigation of the use of AAV–mediated anti–angiogenic gene therapy for targeting unresectable liver metastases, especially after surgical removal of primary tumors.
Insulin Receptor Substrate–4 Signaling in Quiescent Rat Hepatocytes and in Regenerating Rat Liver
Authors: Escribano Oscar , Fernández-Moreno María Dolores , Zueco José Antonio , Menor Cesar , Fueyo Jesus , Ropero Rosa María , Diaz-Laviada Inés , Román Irene D. , Guijarro Luis G.
Published: May 2003

This study was designed to characterize insulin receptor substrate–4 (IRS–4) in isolated rat hepatocytes and to examine its role in liver regeneration. Subcellular fractionation revealed that 85% of IRS–4 is located at isolated hepatocyte plasma membranes. The distribution of IRS–4 among intracellular compartments remained unchanged in insulin–stimulated cells. Two bands corresponding to 145 and 138 kd were observed in immunoblotting experiments. Immunoprecipitation of hepatocyte lysates with a highly specific antibody against IRS–4 led to an insulin and insulin–like growth factor 1 (IGF–1)–dependent increase in phosphotyrosine residues of the 145–kd band. IRS–4 was found to be associated with Src homology 2 (SH2) domain–containing proteins (phosphatidylinositol 3–kinase [PI 3–kinase] and Src homology phosphatase [SHP–2]) and with protein kinase C ζ (PKC ζ). Insulin and IGF–1 elicited a rapid and dose–dependent binding of these 3 proteins to IRS–4. These data suggest that IRS–4 is insulin–/IGF–1–activated by phosphorylation and not by translocation, inducing the recruitment of SH2 domain–containing proteins and PKC ζ to the membrane. To evaluate the possible role of IRS–4 in liver regeneration, we also examined this system after partial hepatectomy (PH). One day after PH, IRS–1 expression increased, consistent with a stimulatory role in the regenerative process, whereas it decreased 7 days after liver resection. This drastic IRS–1 depletion occurred at the expense of increased IRS–2 and IRS–4 expression 7 days after PH. In addition, at this period of time after surgery, the in vivo insulin stimulation of remnant rat livers showed an increase in IRS–4/PI 3–kinase association. Given that 1 and 7 days after PH isolated hepatocytes responded similarly to insulin in terms of induced cell proliferation, a compensatory role is proposed for IRS–2/4 induction. In conclusion, IRS–4 is activated by insulin and IGF–1–like IRS–1 in rat hepatocytes, and the induced expression of IRS–4 is a compensatory mechanism that plays a role in conditions of liver regeneration.
Natural enemies of three mealybug species (Hemiptera: Pseudococcidae) found on citrus and effects of some insecticides on the mealybug parasitoid Coccidoxenoides peregrinus (Hymenoptera: Encyrtidae) in South Africa
Authors: Wakgari W.M. , Giliomee J.H.
Published: May 2003

The population density of mealybug species in some South African citrus orchards has increased to pest status in recent years. The characterization of the natural enemy complex and quantification of their contribution to the control of Planococcus citri (Risso), Pseudococcus longispinus (Targioni-Tozzetti) and Pseudococcus calceolariae (Maskell) on Citrus limon (L.) and Citrus reticulata (Blanco) was investigated through intensive sampling. Eight primary and four secondary parasitoids, and two predator species were identified from P. citri and P. calceolariae. Anagyrus pseudococci (Girault) and Coccidoxenoides peregrinus (Timberlake) were the most common species, accounting for 44% and 21% of the total. Of the five primary parasitoids reared from P. longispinus, A. pseudococci and Anagyrus sp. were predominant, comprising 41% and 30%. Nymphal and adult parasitism (range = 0–26% vs. 0–66%) and predation (range = 0–5.6% vs. 0–4.1%) varied significantly between host trees and mealybug species (P < 0.001). The numbers of nymphal instars and adult stages of P. calceolariae and P. longispinus and the nymphal stage of P. citri that were parasitized and killed by predators correlated significantly with the total number of hosts on which they acted (P < 0.01), suggesting a density-dependent association. Laboratory bioassay of nine contact insecticides (methidathion, methomyl, methyl-parathion, parathion, profenofos and prothiofos) against C. peregrinus indicated that all were highly toxic, causing 98–100% mortality in < 6 h of treatment. The IGRs fenoxycarb and triflumuron did not cause significant parasitoid mortality (P > 0.05). However, a mixture of pyriproxyfen and mineral oil caused a marginally significant mortality (P < 0.05).
Detecting Cacopsylla pyricola (Hemiptera: Psyllidae) in predator guts using COI mitochondrial markers
Authors: Agustí N. , Unruh T.R. , Welter S.C.
Published: May 2003

Cacopsylla pyricola (Förster) is one of the most important pests of pear in North America, where several native predators have been considered for integrated pest management (IPM) programmes. Two molecular markers of 271 and 188 bp were developed from C. pyricola cytochrome oxidase I (COI) fragments, in order to study the detection of this species in the gut of arthropod predators. Primer sensitivity and the detection period for pear psylla remains in the guts of Anthocoris tomentosus Pericart were determined. The sensitivity threshold was defined at 10-5 dilution of a C. pyricola fifth-instar nymph in all samples. Predator adults were evaluated immediately after ingestion of one to five C. pyricola nymphs (t = 0) and after 2, 4, 6, 8, 16, 24 and 32 h. Detection of the presence of C. pyricola DNA always lasted longer using the shorter fragment and was observed after 32 h of digestion using both markers. The primers amplifying the 188 bp fragment amplified all four psyllid species tested, whereas the primers designed to amplify the 271 bp fragment did so exclusively for C. pyricola and its close relative, Cacopsylla pyri (Linnaeus). Both primers failed to amplify DNA from representative species of the Coccinellidae, Chrysopidae, Hemerobiidae, Anthocoridae, Miridae, Salticidae, Aphididae, Tetranychidae and the Tortricidae, suggesting their suitability for general trophic studies.
Predation and prey size choice by the carabid beetle Pterostichus melanarius (Coleoptera: Carabidae): the dangers of extrapolating from laboratory to field
Authors: McKemey A.R. , Symondson W.O.C. , Glen D.M.
Published: May 2003

The impact of predation by the generalist carabid beetle Pterostichus melanarius (Illiger) on populations of the field slug Deroceras reticulatum (Müller), and the effects of prey size on the predator–prey interaction, were measured under semi-field conditions. It was hypothesized that environmental heterogeneity would lead to very different patterns of comparative mortality than might be deduced from size choice experiments conducted in the laboratory. Results from outdoor mini-plots, emulating conditions in a field of wheat, demonstrated that P. melanarius significantly reduced numbers of slugs from all size classes, with no apparent preferences. This was in marked contrast to results from earlier laboratory studies, where this beetle fed preferentially on the smallest slugs. The slugs in the mini-plots ranged in size from 2–100 mg and the numbers in the mini-plot reflected the size frequency distribution in the field. Beetles in mini-plots containing high densities of slugs increased significantly in weight, in contrast to beetles in mini-plots with low slug density or no added slugs, which did not. Enzyme-linked immunosorbent assays (ELISA), using anti-slug monoclonal antibodies, showed that where there was a higher density of slugs there was more slug protein in the guts of the beetles. It was concluded that environmental heterogeneity probably provided a greater number and diversity of refugia for smaller than for larger slugs, counteracting laboratory-measured size preferences measured in arenas without refugia. These results have implications for a range of ecological studies involving inter- and intra-specific prey size choice, and emphasize the dangers of extrapolating from the laboratory to the field.
Interaction of the Bullous Pemphigoid Antigen 1 (BP230) and Desmoplakin with Intermediate Filaments Is Mediated by Distinct Sequences within Their COOH Terminus
Authors: Fontao Lionel , Favre Bertrand , Riou Sara , Geerts Dirk , Jaunin Fabienne , Saurat Jean-Hilaire , Green Kathleen J. , Sonnenberg Arnoud , Borradori Luca
Published: May 2003

The bullous pemphigoid antigen 1 (BP230) and desmoplakin (DP) are members of the plakin protein family of cytolinkers. Despite their homology, their COOH termini selectively bind distinct intermediate filaments (IFs). We studied sequences within their COOH termini required for their interaction with the epidermal keratins K5/K14, the simple epithelial keratins K8/K18, and type III IF vimentin by yeast three-hybrid, cell transfection, and overlay assays. The results indicate that BP230 interacts with K5/K14 but not with K8/K18 or vimentin via a region encompassing both the B and C subdomains and the COOH extremity, including a COOH-terminal eight-amino-acid stretch. In contrast, the C subdomain with the COOH-terminal extremity of DP interacts with K5/K14 and K8/K18, and its linker region is able to associate with K8/K18 and vimentin. Furthermore, the potential of DP to interact with IF proteins in yeast seems to be regulated by phosphorylation of Ser 2849 within its COOH terminus. Strikingly, BP230 and DP interacted with cytokeratins only when both type I and type II keratins were present. The head and tail domains of K5/K14 keratins were dispensable for their interaction with BP230 or DP. On the basis of our findings, we postulate that (1) the binding specificity of plakins for various IF proteins depends on their linker region between the highly homologous B and C subdomains and their COOH extremity and (2) the association of DP and BP230 with both epidermal and simple keratins is critically affected by the tertiary structure induced by heterodimerization and involves recognition sites located primarily in the rod domain of these keratins.
XBX-1 Encodes a Dynein Light Intermediate Chain Required for Retrograde Intraflagellar Transport and Cilia Assembly inCaenorhabditis elegans
Authors: Schafer Jenny C. , Haycraft Courtney J. , Thomas James H. , Yoder Bradley K. , Swoboda Peter
Published: May 2003

Intraflagellar transport (IFT) is a process required for flagella and cilia assembly that describes the dynein and kinesin mediated movement of particles along axonemes that consists of an A and a B complex, defects in which disrupt retrograde and anterograde transport, respectively. Herein, we describe a novel Caenorhabditis elegans gene, xbx-1, that is required for retrograde IFT and shares homology with a mammalian dynein light intermediate chain (D2LIC). xbx-1 expression in ciliated sensory neurons is regulated by the transcription factor DAF-19, as demonstrated previously for genes encoding IFT complex B proteins. XBX-1 localizes to the base of the cilia and undergoes anterograde and retrograde movement along the axoneme. Disruption of xbx-1 results in cilia defects and causes behavioral abnormalities observed in other cilia mutants. Analysis of cilia in xbx-1 mutants reveals that they are shortened and have a bulb like structure in which IFT proteins accumulate. The role of XBX-1 in IFT was further confirmed by analyzing the effect that other IFT mutations have on XBX-1 localization and movement. In contrast to other IFT proteins, retrograde XBX-1 movement was detected in complex A mutants. Our results suggest that the DLIC protein XBX-1 functions together with the CHE-3 dynein in retrograde IFT, downstream of the complex A proteins.
A Novel Dynein Light Intermediate Chain Colocalizes with the Retrograde Motor for Intraflagellar Transport at Sites of Axoneme Assembly inChlamydomonasand Mammalian Cells
Authors: Perrone Catherine A. , Tritschler Douglas , Taulman Patrick , Bower Raqual , Yoder Bradley K. , Porter Mary E.
Published: May 2003

The assembly of cilia and flagella depends on bidirectional intraflagellar transport (IFT). Anterograde IFT is driven by kinesin II, whereas retrograde IFT requires cytoplasmic dynein 1b (cDHC1b). Little is known about how cDHC1b interacts with its cargoes or how it is regulated. Recent work identified a novel dynein light intermediate chain (D2LIC) that colocalized with the mammalian cDHC1b homolog DHC2 in the centrosomal region of cultured cells. To see whether the LIC might play a role in IFT, we characterized the gene encoding the Chlamydomonas homolog of D2LIC and found its expression is up-regulated in response to deflagellation. We show that the LIC subunit copurifies with cDHC1b during flagellar isolation, dynein extraction, sucrose density centrifugation, and immunoprecipitation. Immunocytochemistry reveals that the LIC colocalizes with cDHC1b in the basal body region and along the length of flagella in wild-type cells. Localization of the complex is altered in a collection of retrograde IFT and length control mutants, which suggests that the affected gene products directly or indirectly regulate cDHC1b activity. The mammalian DHC2 and D2LIC also colocalize in the apical cytoplasm and axonemes of ciliated epithelia in the lung, brain, and efferent duct. These studies, together with the identification of an LIC mutation, xbx-1(ok279), which disrupts retrograde IFT in Caenorhabditis elegans, indicate that the novel LIC is a component of the cDHC1b/DHC2 retrograde IFT motor in a variety of organisms.
Effects of Environmental Enrichment on Spatial Memory and Neurochemistry in Middle-Aged Mice
Authors: Frick Karyn M. , Stearns Nancy A. , Pan Jing-Yu , Berger-Sweeney Joanne
Published: May 2003

The present study compared the effects of environmental enrichment on
spatial memory, glutamic acid decarboxylase (GAD) activity, and synaptophysin
levels in middle-aged male and female mice. Prior to testing, a subset of
18-month-old male and female C57BL/6 mice was housed with two to three toys
and a running wheel in the home cage for up to 29 d. Adult mice (7 mo) of both
sexes and the remaining middle-aged mice were group (social) housed, but not
exposed to enriching objects. After the enrichment period, all mice were
tested in a 1-day version of the Morris water maze, in which both spatial and
nonspatial memory were assessed. Immediately after testing, the hippocampus
and frontoparietal cortex were dissected, and GAD activity and synaptophysin
levels were measured. Environmental enrichment reduced the age-related
impairment in spatial acquisition and retention; relative to adult social
controls, middle-aged enriched mice were unimpaired, whereas middle-aged
social controls were impaired. This reduction was similar in middle-aged males
and females. Enrichment did not affect cued memory in either sex. Although
hippocampal GAD activity was increased by enrichment in males, all other
neurochemical measurements were unaffected by enrichment or aging in either
sex. These data suggest that environmental enrichment initiated at middle age
can reduce age-related impairments in spatial memory in males and females,
although the underlying neurobiological mechanisms of this effect remain
unknown.
A Modified Version of the Unique Cue Theory Accounts for Olfactory Compound Processing in Honeybees
Authors: Deisig Nina , Lachnit Harald , Sandoz Jean-Christophe , Lober Klaus , Giurfa Martin
Published: May 2003

We investigated the capability of honeybees to discriminate between single odorants, binary olfactory mixtures, and ternary olfactory mixtures in olfactory conditioning of the proboscis extension reflex. In Experiment 1, three single odorants (A+, B+, and C+) and three binary mixtures of these odors (AB+, AC+, and BC+) were reinforced while the ternary compound, consisting of all three odors (ABC-), was nonreinforced. In Experiment 2, only one single odorant (A+) and one binary olfactory compound (BC+) were reinforced while the ternary compound (ABC-) consisting of the single odor and the binary compound was nonreinforced. We studied whether bees can solve these problems and whether the course of differentiation can be predicted by the unique cue theory, a modified unique cue theory, or Pearce's configural theory. Honeybees were not able to differentiate reinforced from nonreinforced stimuli in Experiment 1. However, summation to ABC observed at the beginning of training contradicts the predictions of Pearce's configural theory. In Experiment 2, differentiation between the single odorant A and the ternary compound developed more easily than between the binary compound BC and ABC. This pattern of differentiation is in line with a modified unique cue theory and Pearce's configural theory. Summation to ABC at the beginning of training, however, again was at odds with Pearce's configural theory. Thus, olfactory compound processing in honeybees can best be explained by a modified unique cue theory.
Neural Correlates of Pavlovian Conditioning in Components of the Neural Network Supporting Ciliary Locomotion inHermissenda
Authors: Crow Terry , Tian Lian-Ming
Published: May 2003

Pavlovian conditioning inHermissendaconsists of pairing light, the conditioned stimulus (CS) with activation of statocyst hair cells, the unconditioned stimulus (US). Conditioning produces CS-elicited foot shortening and inhibition of light-elicited locomotion, the two conditioned responses (CRs). Conditioning correlates have been identified in the primary sensory neurons (photoreceptors) of the CS pathway, interneurons that receive monosynaptic input from identified photoreceptors, and putative pedal motor neurons. While cellular mechanisms of acquisition produced by the synaptic interaction between the CS and US pathways are well-documented, little is known about the mechanisms responsible for the generation or expression of the CR. Here we show that in conditioned animals light reduced tonic firing of ciliary activating pedal neurons (VP1) below their pre-CS baseline levels. In contrast, pseudorandom controls expressed a significant increase in CS-elicited tonic firing of VP1 as compared to pre-CS baseline activity. Identified interneurons in the visual pathway that have established polysynaptic connections with VP1 were examined in conditioned animals and pseudorandom controls. Depolarization of identified type Ieinterneurons with extrinsic current elicited a significant increase in IPSPs recorded in VP1 pedal neurons of conditioned animals as compared with pseudorandom controls. Conditioning also enhanced intrinsic excitability of type Ieinterneurons of conditioned animals as compared to pseudorandom controls. Light evoked a modest increase in IPSP frequency in VP1 of conditioned preparations and a significant decrease in IPSP frequency in VP1 of pseudorandom controls. Our results show that a combination of synaptic facilitation and intrinsic enhanced excitability in identified components of the CS pathway may explain light-elicited inhibition of locomotion in conditioned animals.
A cognitive approach to understanding university image
Authors: Arpan Laura M. , Raney Arthur A. , Zivnuska Suzanne
Published: May 2003

This study employed a cognitive psychological approach to examining a little studied phenomenon – university image – among two groups of evaluators. The study found that different groups used different criteria when rating ten major US universities. Found to significantly predict the image of the universities among a sample of current university students were three factors: academic factors, athletic factors, and the extent of news coverage of the university. Found to significantly predict the image of the same universities among an adult, non‐student sample were four factors: a combined factor including all university attributes (including academic and athletic); the extent of news coverage; the education level of respondents; and the respondents’ level of sports fanship. Recent research in attitude structure is used to explain how different image criteria are recalled and employed by the different groups.
Communicating sensitive business issues: Part 2
Authors: Dickson David A. , Rainey Seanenne , Hargie Owen D.W.
Published: May 2003

This is the second of a two‐part article reporting the results of a study which investigated communication and relationships in the workplaces of four large organizations in Northern Ireland, two in the public sector and two in the private. A central purpose of the research was to evaluate suitable methods for auditing relationships among staff. Based on a review of the apposite literature on organizational and relational communication, the most promising techniques finally selected were the focus group approach, retrospective interview technique, social network analysis, and critical incident technique. In Part 1 the first two of these techniques were evaluated. Now, in Part 2 social network analysis and critical incident technique are similarly examined, in terms of their potential to generate quality data on the types of association that typify those who share a work environment. In a final conclusion to the two‐part article, recommendations for using qualitative and quantitative methods for auditing internal relationships are also offered.
Collaborative communication in sponsor relations
Authors: Farrelly Francis , Quester Pascale , Mavondo Felix
Published: May 2003

Despite increasing attention in the marketing literature devoted to market orientation and relationship marketing issues, the sponsorship relationship has not been examined according to these perspectives. In this study, a number of propositions linking market orientation, collaborative communications, trust and commitment are developed and examined empirically in a sponsorship context. The findings suggest that market orientation and collaborative communication are both important determinants of sponsorship commitment, defined as a sponsor’s preparedness to leverage the association. Results concerning trust are somewhat more ambiguous. The implications of these findings are discussed in conclusion, along with directions for future research.
Public relations writing – a genre‐based model
Authors: Tench Ralph
Published: May 2003

This paper attempts to establish the existence of a professional language genre for public relations by evaluating the history of genre analysis and its application in professional contexts. Bhatia’s work, in 1993, demonstrates professional language genre analysis in similar contexts to public relations writing, which make the mapping of the process both relevant and workable for this discipline. The application of Bhatia’s and Swale’s work, in 1990, on modelling the rhetorical moves behind communicative purposes of a genre has been successfully applied within the paper to the news release genre. The paper therefore proposes a model of professional language genre analysis, which may provide a useful guide to writing effective news releases for practitioners and students working in the fields of public relations and corporate communications.
Co‐operative education in the pulp and paper sector in Quebec
Authors: Savoie‐Zajc Lorraine , Dolbec André
Published: May 2003

Using the concept of “community of practice” and a typology developed by Guile and Griffiths, this article characterizes the quality and the nature of learning students achieved while studying in a newly‐implemented pulp and paper vocational program, structured as a co‐operative education program and offered by six school boards throughout the province of Quebec, Canada. The observations come from a five‐year long action research program involving registered students, trainers in vocational centers, and work supervisors in pulp and paper mills. The conclusion highlights the structural barriers in pulp and paper mills that limit students’ access to operations. This co‐op education program is traditional according to the Guile and Griffiths’ typology.
Innovation: examining workplace learning in new enterprises
Authors: Fenwick Tara
Published: May 2003

Innovation is argued here to be a significant and complex dimension of learning in work, involving a mix of rational, intuitive, emotional and social processes embedded in activities of a particular community of practice. Dimensions of innovative learning are suggested to include level (individual, group, organization), rhythm (episodic or continuous), and magnitude of creative change (adaptive or generative) involved in the learning process. Drawing from a study of women who leave organizational employment to develop an enterprise of self‐employment, this article explores these dimensions of innovative learning. Two questions guide the analysis: what conditions foster innovative learning; and what are the forms and processes of the innovative learning process? Findings suggest that innovative processes involve multiple strategies and demand conditions of freedom, patience, support, and recognition.
Short‐term interest rate models: valuing interest rate derivatives using a Monte‐Carlo approach
Authors: Treepongkaruna Sirimon , Gray Stephen
Published: May 2003

This paper provides an accessible description and several examples of how to use Monte‐Carlo simulation to value interest rate derivatives when the short rate follows an arbitrary time series process. We compare the values of various interest rate derivatives using closed‐form solutions (when available), the Hull and White (1994) trinomial tree procedure, and a Monte‐Carlo simulation technique. We show that the simulation technique can be applied to more complex short rate processes by examining short rate models where the dynamics are too complicated for any tree or lattice approach and closed‐form valuation formulae are unavailable. In a practical empirical setting, we weigh the advantages and disadvantages of the simulation approach against competing approaches.
On Conditional Density Estimation
Authors: De Gooijer Jan G. , Zerom Dawit
Published: May 2003

With the aim of mitigating the possible problem of negativity in the estimation of the conditional density function, we introduce a so‐called re‐weighted Nadaraya‐Watson (RNW) estimator. The proposed RNW estimator is constructed by a slight modification of the well‐known Nadaraya‐Watson smoother. With a detailed asymptotic analysis, we demonstrate that the RNW smoother preserves the superior large‐sample bias property of the local linear smoother of the conditional density recently proposed in the literature. As a matter of independent statistical interest, the limit distribution of the RNW estimator is also derived.
Some Methodological Aspects of Validation of Models in Nonparametric Regression
Authors: Dette Holger , Munk Axel
Published: May 2003

In this paper we describe some general methods for constructing goodness of fit tests in nonparametric regression models. Our main concern is the development of statisticial methodology for the assessment (validation) of specific parametric models ℳ as they arise in various fields of applications. The fundamental idea which underlies all these methods is the investigation of certain goodness of fit statistics (which may depend on the particular problem and may be driven by different criteria) under the assumption that a specified model (which has to be validated) holds true as well as under a broad range of scenaria, where this assumption is violated. This is motivated by the fact that outcomes of tests for the classical hypothesis: “The model ℳ holds true” (and their associated p values) bear various methodological flaws. Hence, our suggestion is always to accompany such a test by an analysis of the type II error, which is in goodness of fit problems often the more serious one. We give a careful description of the methodological aspects, the required asymptotic theory, and illustrate the main principles in the problem of testing model assumptions such as a specific parametric form or homoscedasticity in nonparametric regression models.
Integral Spirituality, Deep Science, and Ecological Awareness
Authors: Maxwell Thomas P.
Published: May 2003

There is a growing understanding that addressing the global crisis facing humanity will require new methods for knowing, understanding, and valuing the world. Narrow, disciplinary, and reductionist perceptions of reality are proving inadequate for addressing the complex, interconnected problems of the current age. The pervasive Cartesian worldview, which is based on the metaphor of the universe as a machine, promotes fragmentation in our thinking and our perception of the cosmos. This divisive, compartmentalized thinking fosters alienation and self‐focused behavior. I aim to show in this essay that healing the fragmentation that is at the root of the current world crises requires an integrated epistemology that embraces both the rational knowledge of scientific empiricism and the inner knowledge of spiritual experience. This “deep science” transcends the illusion of separateness to discern the unity, the unbroken wholeness, that underlies the diverse forms of the universe. Our perception of connectedness, of our integral place in the web of life, emerges as an attribute of our connection with the eternal, beatific source of all existence. This awakened spiritual vision “widens our circle of understanding and compassion, to embrace all living creatures in the whole of nature” (Einstein, quoted in Goldstein [1976] 1987). Our behavior, as it emerges naturally out of our perception of the sacredness of the natural world, will naturally embody love and respect for all life forms. This vision promotes the healing of our long‐standing alienation from the natural world and offers hope for renewal in the midst of widespread cultural deterioration and environmental destruction.