bluuebunny/crossref_metadata_2025 huggingface dataset:
Hormetic Prevention of Molecular Damage during Cellular Aging of Human Skin Fibroblasts and Keratinocytes
Authors: RATTAN SURESH I. S. , ALI REHAB E.
Published: April 2007

Abstract:  Progressive accumulation of molecular damage is a hallmark of cellular aging, which is amenable to intervention and prevention by hormesis through mild stress. Our studies have shown that repeated mild heat stress (RMHS) has antiaging effects on growth and various other cellular and biochemical characteristics of normal human skin fibroblasts undergoing aging in vitro. RMHS at 41°C, for 1 h twice a week, increased the basal levels of various chaperones, reduced the accumulation of oxidatively and glycoxidatively damaged proteins, stimulated proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to ethanol, hydrogen peroxide, and UV‐B rays, enhanced the levels of various antioxidant enzymes, and increased the phosphorylation‐mediated activities of various stress kinases. RMHS‐exposed human fibroblasts are also better protected against glucose‐ and glyoxal‐induced growth inhibition and apoptosis. We have also observed various hormetic effects of RMHS on normal human epidermal keratinocytes, which include increased replicative life span, increased proteasomal activity, and enhanced levels of Na/K‐ATPase pump. We are also testing the above effects of RMHS in combination with potential hormetic molecules, such as curcumin, on aging, longevity, and differentiation of human cells in culture.
Beneficial Biochemical Outcomes of Late‐Onset Dietary Restriction in Rodents
Authors: GOTO SATARO , TAKAHASHI RYOYA , RADAK ZSOLT , SHARMA RAMESH
Published: April 2007

Abstract:  Dietary restriction (DR) or caloric restriction (CR) is the well‐established means to retard aging, leading to prolongation of mean and maximum life span in many animal models. We have been interested in the possibility of extending the span of health of elderly people rather than increasing longevity, and therefore studied the effects of DR/CR initiated late in life in rodent models. We restricted food for 2–3.5 months in mice or rats of middle or old ages, which would perhaps be equivalent to 50–70 years of age in humans. We found that: (1) Potentially harmful altered proteins were reduced in the animals' tissues. (2) Extended half‐life of protein in aged animals was shortened in mouse hepatocytes, suggesting improved protein turnover. (3) Reduced proteasome activity was upregulated in rat liver and skeletal muscle. (4) Protein carbonyls were decreased in rat liver mitochondria and skeletal muscle cytoplasm, and also oxidative DNA damage was reduced in rat liver nucleus, suggesting amelioration of oxidative stress. (5) Reduced apo A‐IV and C‐III metabolism in aged mouse was restored, suggesting increase in reduced fatty acid mobilization. (6) The carbonyl modification in histones that was paradoxically reduced in aged rat was increased to the level of a young animal, suggesting restoration of reduced transcription. These findings in rodents suggest a possibility that DR/CR is beneficial if applied in middle‐aged or early senescent obese people. We argue, however, that application of late life DR/CR can be harmful if practiced in people who are already eating modestly.
Prior Chronic in Vivo Glucocorticoid Excess Leads to an Anabolic Phenotype and an Extension of Cellular Life Span of Skin Fibroblasts in Vitro
Authors: KLETSAS DIMITRIS , PRATSINIS HARRIS , GIONI VASSILIKI , PILICHOS KONSTANTINOS , YIACOUMETTIS ANDREAS M. , TSAGARAKIS STYLIANOS
Published: April 2007

Abstract:  Intense stress can be detrimental for tissue homeostasis and accelerates aging. On the other hand, repeated mild stresses can have beneficial and even life‐prolonging effects. Hypersecretion of glucocorticoids (GCs) represents the major hormonal response to stress. However, besides its life‐sustaining role, GC excess can promote a “catabolic” phenotype. Accordingly, we have studied the effect of long‐lasting exposure to high GC levels in vivo on several parameters of tissue homeostasis, as well as cellular senescence, in cells removed from the high‐GC milieu in vivo and then cultured in vitro. To this end, we have used human skin fibroblasts from (a) Cushing's syndrome patients that are characterized by chronic endogenous GC excess and (b) patients treated with exogenous GC administration. Interestingly, when Cushing's syndrome fibroblasts were cultured in vitro under standard conditions they express an “anabolic” phenotype, i.e., they restore their ability for collagen synthesis, secrete reduced levels of metalloproteases, and have an increased proliferative capacity and contractility. Furthermore, these cells exhibit a significant extension of their proliferative life span, while they respond better to exogenous stress by producing significantly higher levels of heat‐shock protein‐70 (HSP70). In addition, preliminary results with fibroblasts from patients subjected to chronic exogenous GC administration indicate that they express a similar behavior in vitro, at least with regard to the restoration of collagen expression. These data suggest that prior exposure to elevated GC concentrations is not associated with persisting adverse effects on fibroblasts and may also have a beneficial outcome in some aspects of cell physiology, including longevity in vitro.
Glyoxal‐Induced Premature Senescence in Human Fibroblasts
Authors: SEJERSEN HENRIK , RATTAN SURESH I. S.
Published: April 2007

Abstract:  Mild stress‐induced hormesis is an effective strategy to intervene in the aging process. Repeated exposure of human skin fibroblasts to 41°C heat shock for 1 h twice a week is an example of mild stress that has many hormetic effects, including improved resistance to other stressors. We are now developing an experimental model system of sugar‐induced premature senescence, which can be useful to test the hormetic and antiaging effects of other stresses. Our present studies show that early‐passage human skin fibroblasts treated with 1 mM glyoxal for 72 h undergo premature senescence in terms of enlarged cell size, inhibition of cell division, slowing down of cell growth, a decrease in the number of DNA synthesizing cells, and increased resistance to apoptosis.
Sugar‐Induced Premature Aging and Altered Differentiation in Human Epidermal Keratinocytes
Authors: BERGE ULRICH , BEHRENS JULIANE , RATTAN SURESH I. S.
Published: April 2007

Abstract:  Normal human epidermal keratinocytes (NHEK) show both the Hayflick phenomenon and differentiation in vitro. The aim of this study was to induce senescence in keratinocytes using two sugars, glucose and glyoxal. Induction of senescence in early‐passage NHEK was characterized by monitoring cell morphology, short‐term growth characteristics, cell proliferation, and viability assay. In addition, apoptosis, senescence‐associated (SA) β‐gal activity, proteasomal activity and glycation, and glycoxidation of total proteins were determined. Our results show that a 3‐day treatment with 100 mM glucose or 0.1 mM glyoxal induces in early‐passage NHEK various cellular and biochemical characteristics comparable to those observed in serially subcultured late passage NHEK. Furthermore, sugar‐treated prematurely aged NHEK showed impaired differentiation, as measured by the quantification of involucrin. There is preliminary evidence that a preexposure of NHEK to mild heat shock (41°C, 1 h, 6 h in advance) can abrogate some of the sugar‐induced negative effects, which is an example of mild stress‐induced hormesis. This experimental model can be useful to study the effects of potential antiaging interventions.
Evidence for a Trade‐Off between Survival and Fitness Caused by Resveratrol Treatment of Caenorhabditis elegans
Authors: GRUBER JAN , TANG SOON YEW , HALLIWELL BARRY
Published: April 2007

Abstract:  Resveratrol is a naturally occurring polyphenolic compound commonly found in plant‐derived products, including red wine. A large number of beneficial effects including anticarcinogenic action and protection from atherosclerotic disease have been attributed to resveratrol. Increased resveratrol intake has been suggested as an explanation for the beneficial effects of moderate red wine consumption. Resveratrol also consistently extends the mean and maximum life span in model organisms including nematode worms. It has been suggested that resveratrol exerts its life‐span–extending effect through calorie restriction or hormesis mimetic effects. We have characterized the effect of resveratrol on stress resistance, developmental rate, growth, and fecundity in the nematode worm Caenorhabditis elegans in order to determine whether the beneficial effects of resveratrol on life span are associated with trade‐offs in terms of early life fitness in nematodes. We find that resveratrol treatment increases stress resistance, specifically to oxidative stress, and causes a small but significant decrease in fecundity early in life without affecting overall fecundity. Resveratrol increased mean and maximum life span by delaying the onset of the exponential increase in mortality characterizing the “dying phase” in C. elegans, but did not affect the dying phase itself, suggesting that it did not act by directly affecting metabolism.
High Radiosensitivity of Germ Cells in Human Male Fetus
Authors: Lambrot Romain , Coffigny Hervé , Pairault Catherine , Lécureuil Charlotte , Frydman René , Habert René , Rouiller-Fabre Virginie
Published: April 2007

Context: Germ cells formed during human fetal life are essential for fertility of the adult, and several studies have described an increasing frequency of male reproductive disorders, which may have a common origin in fetal life and which are hypothesized to be caused by endocrine disruptors. However, factors inducing a genotoxic stress may also be implicated.

Objectives: We investigated the effect of γ-irradiation on the functions of human fetal testis during the first trimester of gestation by using an organ culture system. Then we focused on the role of the p53 pathway in the observed effects.

Results: Germ cells were highly sensitive to irradiation even at doses as low as 0.1 and 0.2 Gy. Indeed, for these doses, one third of germ cells died by apoptosis. Other germ cells were blocked in their cycle, but no repair seemed to occur, and longer culture with the highest dose used showed that they were destined to die. Sertoli cells were less affected, although their proliferation and the level of anti-Müllerian hormone were reduced. Irradiation had no effect on testosterone secretion or on the expression of steroidogenic enzymes by Leydig cells. After irradiation, p53 phosphorylated on serine 15 was detected from 1–24 h in all cell types. This activation of p53 was accompanied by an increase in mRNA levels of proapoptotic factors Bax and Puma, whereas that of antiapoptotic Bcl-2 remained unchanged. P21, which is responsible for cell cycle arrest, was also up-regulated 6, 30, and 72 h after irradiation. Finally, when we added pifithrin-α, a specific inhibitor of p53 functions, a significant decrease in irradiation-induced apoptosis in both germ and Sertoli cells was observed, indicating the involvement of the p53 pathway in irradiation-induced apoptosis.

Conclusions: This study demonstrated here for the first time the great sensitivity of human fetal germ cells to genotoxic stress caused by ionizing radiation.
Monocyte Chemoattractant Protein-1 in Subcutaneous Abdominal Adipose Tissue: Characterization of Interstitial Concentration and Regulation of Gene Expression by Insulin
Authors: Murdolo Giuseppe , Hammarstedt Ann , Sandqvist Madeléne , Schmelz Martin , Herder Christian , Smith Ulf , Jansson Per-Anders
Published: April 2007

Context: The chemokine monocyte chemoattractant protein-1 (MCP-1) is implicated in obesity-associated chronic inflammation, insulin resistance, and atherosclerosis.

Objectives: The objectives of this study were to: 1) characterize the interstitial levels and the gene expression of MCP-1 in the sc abdominal adipose tissue (SCAAT), 2) elucidate the response of MCP-1 to acute hyperinsulinemia, and 3) determine the relationship between MCP-1 and arterial stiffness.

Design: Nine lean (L) and nine uncomplicated obese (OB) males were studied in the fasting state and during a euglycemic-hyperinsulinemic clamp combined with the microdialysis technique. Interstitial and serum MCP-1 (iMCP-1 and sMCP-1, respectively) levels, pulse wave analysis, and SCAAT biopsies were characterized at baseline and after hyperinsulinemia.

Results: OB showed elevated sMCP-1 (P < 0.01) but similar iMCP-1 levels as compared with L. Basal iMCP-1 concentrations were considerably higher than sMCP-1 (P < 0.0001), and a gradient between iMCP-1 and sMCP-1 levels was maintained throughout the hyperinsulinemia. At baseline, SCAAT gene expression profile revealed a “co-upregulation” of MCP-1, MCP-2, macrophage inflammatory protein-1α, and CD68 in OB, and whole-body glucose disposal inversely correlated with the MCP-1 gene expression. After hyperinsulinemia, MCP-1 and MCP-2 mRNA levels significantly increased in L, but not in OB. Finally, sMCP-1 excess in the OB positively correlated with the stiffer vasculature.

Conclusions: These observations demonstrate similar interstitial concentrations and a differential gene response to hyperinsulinemia of MCP-1 in the SCAAT from L and OB individuals. In human obesity, we suggest the SCAAT MCP-1 gene overexpression as a biomarker of an “inflamed” adipose organ and impaired glucose metabolism.
Dopamine Agonist Cabergoline Reduces Hemoconcentration and Ascites in Hyperstimulated Women Undergoing Assisted Reproduction
Authors: Álvarez Claudio , Martí-Bonmatí Luis , Novella-Maestre Edurne , Sanz Roberto , Gómez Raúl , Fernández-Sánchez Manuel , Simón Carlos , Pellicer Antonio
Published: April 2007

Context: Ovarian hyperstimulation syndrome (OHSS) results from increased vascular permeability (VP) caused by ovarian hypersecretion of vascular endothelial growth factor (VEGF), which activates its receptor-2. In animals, the dopamine receptor 2 agonist cabergoline (Cb2) inactivates VEGF receptor-2 and prevents increased VP.

Objective: Our objective was to test whether Cb2 reduces VP and prevents OHSS in humans.

Design: We conducted a prospective, randomized, double-blind study on oocyte donors at risk of developing OHSS (>20 follicles, >12 mm developed, and >20 oocytes retrieved).

Interventions: Cb2 0.5 mg/d (n = 37) or a placebo (n = 32) was administered from the day of human chorionic gonadotropin (d 0) until d 8. Ascites (a pocket of peritoneal fluid > 9 cm2 in lithotomy position), hemoconcentration, and serum prolactin were recorded. Pharmacokinetic studies with magnetic resonance employing the transfer constant rate (Ktrans, measure of permeability) and the extravascular extracellular space (υe, marker of cellular leakage) were performed to measure VP objectively.

Results: Hematocrit (P < 0.01), hemoglobin (P = 0.003), and ascites (P = 0.005) were significantly lower on d 4 and 6 after treatment with Cb2 as compared with placebo. The incidence of moderate OHSS was 20.0 and 43.8%, respectively (P = 0.04). Magnetic resonance studies showed an increase in VP and extravascular leakage of fluid 5 d after human chorionic gonadotropin injection that was significantly prevented with Cb2 (KtransP = 0.04 and υeP = 0.001, respectively).

Conclusions: Given that Cb2 is a well-established and safe medication, this study provides proof of concept for the use of dopamine agonists in the prevention of OHSS in women undergoing assisted reproduction.
Cellular Expression Levels of the Vitamin D Receptor Are Critical to Its Transcriptional Regulation by the Pituitary Transcription Factor Pit-1
Authors: Seoane Samuel , Ben Isabel , Centeno Viviana , Perez-Fernandez Roman
Published: April 2007

The biological role of 1,25-dihydroxyvitamin D3 has generally been related to calcium homeostasis, but this hormone also has fundamental effects on processes of cellular proliferation and differentiation. The genomic actions of 1,25-dihydroxyvitamin D3 are mediated by the vitamin D receptor (VDR) present in target cells. However, VDR transcriptional regulation is not well understood, probably attributable to the complexity of the VDR gene and its promoter. In the present study, it is demonstrated that administration of the pituitary transcription factor Pit-1 (originally found in the pituitary gland but also present in other nonpituitary cell types and tissues) to the MCF-7 (human breast adenocarcinoma) cell line induces a significant increase in VDR mRNA and protein levels. Conversely, Pit-1-targeted small interference RNA markedly reduced expression of VDR in MCF-7 cells. Reporter gene assays demonstrated that the effect of Pit-1 is mediated by its binding to a region located between −254 and −246 bp from the VDR transcription start site. Selective mutations of this site completely abolished VDR transcription. Chromatin immunoprecipitation analysis showed that binding of Pit-1 to the VDR promoter leads additionally to recruitment of cAMP response element-binding protein binding protein, acetylated histone H4, and RNA polymerase II. Surprisingly, Pit-1 binding also recruits VDR protein to the VDR promoter. Using several cell lines with different levels of VDR expression, it was demonstrated that up-regulation of VDR transcription by Pit-1 is dependent on the presence of VDR protein, suggesting that transcriptional expression of VDR in a given cell type is dependent on, among other factors, its own expression levels.
A numerical study of the use of pilot or split rate injection to reduce diesel engine noise
Authors: Ghaffarpour M R , Noorpoor A R
Published: April 2007

This paper investigates the effects of the various factors on combustion noise without increasing nitrogen oxides (NO x) in different operating conditions, especially at idle by using a combustion-simulation computer program (KIVA) and orthogonal array. Results indicated that the effects of pilot or split injection, compression ratio, and dynamic injection timing on combustion noise were strong at idle, while the effects of induction swirl ratio and number of injector holes were weak. Injection rate shaping, pilot or split injection, and double injections showed promising reduction in combustion noise and NO x simultaneously at the idle condition. The selected optimized injector (a split injection) for combustion noise reduction at the idle engine operating condition created different rate shapings from the baseline engine at medium speed and full load. This injector lowered combustion noise and NO x at medium speed and full load in comparison with the baseline injector. Generally, the pilot or split injection and double split injections are beneficial to reduce combustion noise and NO x at idle. Their effects are reduced as engine speed and load are increased such that no significant reduction in combustion noise occurs at high speeds and high loads.
Numerical simulation of homogeneous charge compression ignition combustion using a multi-dimensional model
Authors: Jia Ming , Xie Maozhao
Published: April 2007

A detailed chemical kinetics model was used in a computational fluid dynamics (CFD) code to study the combustion process of a homogeneous charge compression ignition (HCCI) engine fuelled with isooctane. The detailed chemical kinetics code CHEMKIN was implemented into the multi-dimensional CFD code KIVA-3V so that the chemical reactions and in-cylinder flow were coupled. The results indicate that the grid density and time step have little influence on the accuracy of the computational analysis of the HCCI combustion process; however, the initial temperature of the charge influences the burn point greatly. A comparative study on submodels indicates that the results calculated by the renormalization group k-ε turbulence model, the Han-Reitz heat transfer model, and the crevice flow model agree better with measurements than their counterparts, the standard k-ε turbulence model, the traditional heat transfer model, and the non-crevice flow model respectively. The modified multi-dimensional model predicts with good accuracy the pressure, heat release rate, and emissions under different equivalence ratios. The benefits and limits of four approaches extending the operation range of HCCI engines to higher load, i.e. retarded burn point by decreasing the intake temperature, enhanced thermal stratification by lowering the cylinder wall temperature and increasing the swirl ratio, and increasing the exhaust gas recirculation (EGR) ratio, were analysed by this model. The results indicate that proper combustion phasing retardation can reduce the ringing intensity significantly and maintain the performance and emissions level. Among these four methods, increasing the swirl ratio could reduce the ringing intensity most significantly, while EGR shows an excellent performance in all aspects.
A dynamic sliding-mode controller with fuzzy adaptive tuning for an active suspension system
Authors: Zhang Yun-Qing , Zhao Yong-Sheng , Yang Jingzhou , Chen Li-Ping
Published: April 2007

This paper introduces a controller consisting of two control loops for an active suspension system to improve the passenger comfort and manipulability of vehicles. The inner loop controls the hydraulic actuator to track a desired actuation force, and the outer loop provides the control force according to the external conditions. In order to alleviate the discontinuous jump in the inner loop, which is caused by the rate of change in the control force, a dynamic sliding-mode controller is proposed in the outer loop. A fuzzy adaptive tuning controller is adopted to improve the robustness and stability of the controller. The simulation results indicate that the proposed controller is more effective and robust in the vibration isolation of the vehicle body than is the linear quadratic Gaussian control approach, a type of conventional sliding-mode controller.
Investigation of the friction and surface degradation of innovative chondroplasty materials against articular cartilage
Authors: Northwood E , Fisher J , Kowalski R
Published: April 2007

Understanding the wear of the biomaterial-cartilage interface is for the development of innovative chondroplasty. The aim of this study was to investigate a number of biphasic materials as potential chondroplasty biomaterials. Simple geometry friction and wear studies were conducted using bovine articular cartilage pins loaded against a range of singlephase and biphasic materials. The frictions of each biomaterial was compared within simple and protein-containing lubricants. Longer-term continuous sliding tests within a protein containing lubricant were also conducted at various loading conditions to evaluate the friction and degradation for each surface. All single-phase materials showed a steady rise in friction, which was dependent on the loss of interstitial fluid load support from the opposing cartilage pin. All biphasic materials demonstrated a marked reduction in friction when compared with the single-phase materials. It is postulated that the biphasic nature of each material allowed an element of fluid load support to be maintained by fluid rehydration and expulsion. In the longer-term study, significant differences in the articular cartilage pin (surface damage) between the positive control (stainless steel) and the negative control (articular cartilage) was found. The potential biphasic chondroplasty materials produced a reduction in articular cartilage pin damage when compared with the single-phase materials. The changes in surface topography of the cartilage pin were associated with increased levels of friction achieved during the continuous wear test. The study illustrated the importance of the biphasic properties of potential chondroplasty materials, and future work will focus on the optimization of biphasic properties as well as long-term durability, such that materials will more closely mimic the biotribology of natural articular cartilage.
An analysis of the in vivo deterioration of Co-Cr-Mo implants through wear and corrosion
Authors: Hodgson A W , Mischler S , Von Rechenberg B , Virtanen S
Published: April 2007

The degradation of Co-Cr-Mo ASTM F75-92 hip implants after a harvesting period of 8 1/2 months in sheep was investigated. Hip prostheses and tissue samples were obtained from a medical study involving total hip arthroplasty of the cemented type in 12 sheep. Upon euthanasia, the explants were retrieved for analyses of the surfaces and evidence of degradation, while tissue samples from the interface regions were harvested for chemical analysis and evidence of Co, Cr, and Mo contents. Clear evidence of wear and corrosion was detected. Results also indicated that the modes of metal transport through the poly(methyl methacrylate) bone cement play an important role as the surface degradation mechanisms of the metal. The results are being discussed in terms of electrochemical and triboelectrochemical behaviour of the Co-Cr-Mo alloy.
The wear properties of CFR-PEEK-OPTIMA articulating against ceramic assessed on a multidirectional pin-on-plate machine
Authors: Scholes S C , Unsworth A
Published: April 2007

In an attempt to prolong the lives of rubbing implantable devices, several ‘new’ materials have been examined to determine their suitability as joint couplings. Tests were performed on a multidirectional pin-on-plate machine to determine the wear of both pitch and PAN (polyacrylonitrile)-based carbon fibre reinforced-polyetheretherketone (CFR-PEEK-OPTIMA) pins articulating against both BioLox Delta and BioLox Forte plates (ceramic materials). Both reciprocation and rotational motion were applied to the samples. The tests were conducted using 24.5 per cent bovine serum as the lubricant (protein concentration 15 g/l). Although all four material combinations gave similar low wear with no statistically significant difference ( p>0.25), the lowest average total wear of these pin-on-plate tests was provided by CFR-PEEK-OPTIMA pitch pins versus BioLox Forte plates. This was much lower than the wear produced by conventional joint materials (metal-on-polyethylene) and metal-on-metal combinations when tested on the pin-on-plate machine. This therefore indicates optimism that these PEEK-OPTIMA-based material combinations may perform well in joint applications.
Assuming exponential decay by incorporating viscous damping improves the prediction of the coeffcient of friction in pendulum tests of whole articular joints
Authors: Crisco J J , Blume J , Teeple E , Fleming B C , Jay G D
Published: April 2007

A pendulum test with a whole articular joint serving as the fulcrum is commonly used to measure the bulk coefficient of friction (COF). In such tests it is universally assumed that energy loss is due to frictional damping only, and accordingly the decay of pendulum amplitude is linear with time. The purpose of this work was to determine whether the measurement of the COF is improved when viscous damping and exponential decay of pendulum amplitude are incorporated into a lumped-parameter model.

Various pendulum models with a range of values for COF and for viscous damping were constructed. The resulting decay was fitted with an exponential function (including both frictional and viscous damping) and with a linear decay function (frictional damping only). The values predicted from the fit of each function were then compared to the known values.

It was found that the exponential decay function was able to predict the COF values within 2 per cent error. This error increased for models in which the damping coefficient was relatively small and the COF was relatively large. On the other hand, the linear decay function resulted in large errors in the prediction of the COF, even for small values of viscous damping. The exponential decay function including both frictional and constant viscous damping presented herein dramatically increased the accuracy of measuring the COF in a pendulum test of modelled whole articular joints.
A Paired-Vehicle Recourse Strategy for the Vehicle-Routing Problem with Stochastic Demands
Authors: Ak Aykagan , Erera Alan L.
Published: April 2007

This paper presents a paired-vehicle recourse strategy for the vehicle routing problem with stochastic demands (VRPSD). In the VRPSD, a fleet of homogeneous capacitated vehicles is dispatched from a terminal to serve single-period customer demands, which are known in distribution when planning, but only revealed with certainty upon vehicle arrival. While most existing research for this problem focuses on recourse strategies where each vehicle operates independently, this paper alternatively considers a strategy in which vehicles may be coordinated in pairs. A tabu search heuristic is developed to find good solutions to VRPSD instances with homogeneous customer demand distributions given this alternative recourse strategy. Finally, a computational study on a set of test problems with a variety of demand distributions reveals that the paired-recourse strategy may lead to expected travel cost savings of 3% to 25% on problems with 50 or more customers.
The Role of Vildagliptin in the Management of Type 2 Diabetes Mellitus
Authors: Kleppinger Erika L , Helms Kristen
Published: April 2007

Objective:

To highlight the role of incretin hormones in the management of type 2 diabetes mellitus with a focus on vildagliptin, a dipeptidyl peptidase IV (DPP IV) inhibitor currently in development.

Data Sources:

Searches were conducted in MEDLINE (1950–April 2007) and International Pharmaceutical Abstracts (1970–April 2007) using the key words vildagliptin, LAF237, and dipeptidyl peptidase IV inhibitor. Additional data were obtained from abstracts presented at the American Diabetes Association Scientific Sessions (2003–2006) and from the manufacturer.

Study Selection and Data Extraction:

Articles pertaining to the pharmacology, pharmacokinetics, safety, and efficacy of vildagliptin for the treatment of type 2 diabetes were reviewed for inclusion. When available, human trials were included over animal studies.

Data Synthesis:

Reduced incretin effect is thought to be associated with type 2 diabetes. Glucagon-like peptide-1 (GLP-1), an incretin hormone, stimulates postprandial insulin release; however, it is rapidly degraded by DPP IV. Studies evaluating the use of vildagliptin in patients with type 2 diabetes found significant decreases in DPP IV and increased GLP-1 activity 45 minutes after dosing. Glucagon levels were reduced, with little to no change in insulin levels. With vildagliptin doses ranging from 25 mg daily to 100 mg twice daily, researchers observed consistent reductions in fasting plasma glucose, 4 hour postprandial glucose, and hemoglobin A1c. Similar benefits were seen when vildagliptin was used in combination with metformin. Vildagliptin was well tolerated after 12 weeks; however, incidences of hypoglycemia increased with longer study duration. Optimal results with minimal adverse effects were achieved with 25 mg twice daily and 50 mg once daily doses.

Conclusions:

Vildagliptin represents a safe and effective new approach to targeting GLP-1 deficiencies in patients with type 2 diabetes by inhibiting DPP IV.
Subclinical delusional ideation and a self‐reference bias in everyday reasoning
Authors: Galbraith Niall , Manktelow Ken , Morris Neil
Published: April 2007

Previous studies (e.g.Moller & Husby, 2000;Blackwoodet al., 2004) have revealed that delusional thinking is accompanied by an exaggerated focus upon the self and upon stimuli that are perceived to be related to the self. The objective was to examine whether those high in subclinical delusional ideation exhibit a heightened tendency for self‐reference. Using a mixed design, healthy individuals, classified into high‐ and low‐scoring groups on the Peterset al.Delusions Inventory (Peters, Day, & Garety, 1996), were compared on everyday reasoning tasks across three experiments. High‐PDI scorers, in contrast to the low‐PDI group, rated self‐referent objections to everyday arguments as stronger than other‐referent objections and formulated more self‐referent assertion‐based objections to everyday arguments. The findings support the notion that subclinical delusional ideation is linked to a self‐reference bias, which is evident in the sort of everyday thinking that people engage in when forming or evaluating their beliefs and which may contribute to delusion formation.
Polarizing Avalon: The European virtuosity and global virtuality of Mamoru Oshii's filmic imaginary
Authors: Ingram Susan , Reisenleitner Markus
Published: April 2007

This article traces Asian and transnational imaginings of Europe in Avalon, Japanese anime director Mamoru Oshii's (Ghost in the Shell) ten-years-in-themaking feature film. Like The Matrix, which successfully combined video-game culture aesthetics with Asian anime and
martial-arts style, Oshii's film is similarly indebted to game culture and also spawned its own worldwide cult audience. What sets Avalon apart in this tradition is that it was filmed entirely in Poland and engages with one of the most pervasive European mythologies, the Arthurian legends.
The article pursues the traces of history and memory on which the film (literally) builds its computer graphics spaces, and explores how mythological images are mobilized as a response to the problems of place in game culture, rewarding success in the game with a particular grail, one with
an uncanny resemblance to a global consumerist version of the European Union.
Internal contrast and double decoding: Transitivity in Hughes's “On the Road”
Authors: Shen Dan
Published: April 2007

There have appeared, over the past thirty years or so, numerous stylistic investigations on transitivity, which tend to focus on the contrast between different types of transitivity process. This article, however, directs attention to how a literary writer creates a thematically-motivated contrast within the same (sub-)type of transitivity process. The case chosen for illustration is Langston Hughes's “On the Road” (1952). It is argued that such an internal contrast may, by way of semantic reorganization, change the nature of certain transitivity processes on a deeper level, and further, that the functioning of such context-determined deeper-level meaning, which interacts with the conventional surface meaning, depends on double decoding. Based on the analysis, the present study offers a comparison between stylistic analysis and literary criticism to help to show the usefulness of the former in advancing literary interpretation.
Differential Regulation of Action Potential- and Metabotropic Glutamate Receptor-Induced Ca2+Signals by Inositol 1,4,5-Trisphosphate in Dopaminergic Neurons
Authors: Cui Guohong , Bernier Brian E. , Harnett Mark T. , Morikawa Hitoshi
Published: April 2007

Ca2+signals associated with action potentials (APs) and metabotropic glutamate receptor (mGluR) activation exert distinct influences on neuronal activity and synaptic plasticity. However, it is not clear how these two types of Ca2+signals are differentially regulated by neurotransmitter inputs in a single neuron. We investigated this issue in dopaminergic neurons of the ventral midbrain using brain slices. Intracellular Ca2+was assessed by measuring Ca2+-sensitive K+currents or imaging the fluorescence of Ca2+indicator dyes. Tonic activation of metabotropic neurotransmitter receptors (mGluRs, α1 adrenergic receptors, and muscarinic acetylcholine receptors), attained by superfusion of agonists or weak, sustained (∼1 s) synaptic stimulation, augmented AP-induced Ca2+transients. In contrast, Ca2+signals elicited by strong, transient (50–200 ms) activation of mGluRs with aspartate iontophoresis were suppressed by superfusion of agonists. These opposing effects on Ca2+signals were both mediated by an increase in intracellular inositol 1,4,5-trisphosphate (IP3) levels, because they were blocked by heparin, an IP3receptor antagonist, and reproduced by photolytic application of IP3. Evoking APs repetitively at low frequency (2 Hz) caused inactivation of IP3receptors and abolished IP3facilitation of single AP-induced Ca2+signals, whereas facilitation of Ca2+signals triggered by bursts of APs (five at 20 Hz) was attenuated by less than half. We further obtained evidence suggesting that the psychostimulant amphetamine may augment burst-induced Ca2+signals via both depression of basal firing and production of IP3. We propose that intracellular IP3tone provides a mechanism to selectively amplify burst-induced Ca2+signals in dopaminergic neurons.
Conservation of Glutamate Receptor 2-Containing AMPA Receptors during Long-Term Potentiation
Authors: Adesnik Hillel , Nicoll Roger A.
Published: April 2007

Long-term potentiation (LTP) at hippocampal synapses is thought to involve the insertion of AMPA receptors into the postsynaptic membrane. Conflicting evidence exists as to whether calcium-permeable receptors are inserted during LTP and whether synaptic activity mediated by the newly inserted AMPA receptors is required to maintain the increase in synaptic strength. Here, we rigorously test these hypotheses and conclude that calcium-permeable AMPA receptors are not inserted during LTP nor does potentiation require ongoing activity to be maintained.
Prelimbic/Infralimbic Inactivation Impairs Memory for Multiple Task Switches, But Not Flexible Selection of Familiar Tasks
Authors: Rich Erin L. , Shapiro Matthew L.
Published: April 2007

Behavioral flexibility, in the form of strategy switching or set shifting, helps animals cope with changing contingencies in familiar environments. The prelimbic (PL) and infralimbic (IL) regions of the rat prefrontal cortex (PFC) contribute to this ability so that rats trained to use one strategy have difficulty learning a new one if the PL/IL is inactivated. Thus, the PL/IL mediates learning new tasks in place of old ones, but it may also be required to switch between familiar tasks. To test this hypothesis, we trained rats to perform multiple task switches on a plus-shaped maze, alternating between two familiar tasks. Muscimol inactivation of the PL/IL never impaired switch acquisition, but did impair memory for the recently acquired switch 24 h later. Additional experiments determined that control rats continued to perform the new task 24 h after a switch, but rats with PL/IL inactivation had impaired memory and performed the same task that was learned before inactivation. This impairment was observed in multiple switches, demonstrating that PL/IL activity was required to remember which of two familiar tasks was most recently successful. After many switches, however, muscimol no longer impaired performance, and both saline- and muscimol-infused rats appeared to use immediate task contingencies rather than memory to select among familiar tasks. This strategy may account for the decreased effect of PL/IL inactivation observed after extensive training. Thus, although PL/IL activity contributed to memory for multiple task switches, it was not required for flexibly selecting among highly familiar tasks.
Transient Synaptic Silencing of Developing Striate Cortex Has Persistent Effects on Visual Function and Plasticity
Authors: Caleo Matteo , Restani Laura , Gianfranceschi Laura , Costantin Laura , Rossi Chiara , Rossetto Ornella , Montecucco Cesare , Maffei Lamberto
Published: April 2007

Neural circuits in the cerebral cortex are shaped by experience during “critical periods” early in life. For example, visual cortex is immature at the time of eye opening and gradually develops its functional properties during a sensitive period. Very few reports have addressed the role of intrinsic neural activity in cortical maturation. Here we have exploited the bacterial enzyme botulinum neurotoxin E (BoNT/E) to produce a unilateral, reversible blockade of neural activity in rat visual cortex during the sensitive period. BoNT/E is a highly selective protease that interferes with transmitter release via cleavage of the synaptic protein SNAP-25 (synaptosomal-associated protein of 25 kDa). Unilateral, intracortical injections of BoNT/E were made at the time of eye opening and resulted in the silencing of the treated, but not contralateral, hemisphere for a period of 2 weeks. We found that visual acuity was permanently reduced in the blocked hemisphere, and the critical period for ocular dominance plasticity persisted into adulthood. Unexpectedly, these effects extended equally to the contralateral, uninjected side, demonstrating a fundamental role for interhemispheric connections in cortical maturation.
Phosphatidylinositol 3-Akt-Kinase-Dependent Phosphorylation of p21Waf1/Cip1as a Novel Mechanism of Neuroprotection by Glucocorticoids
Authors: Harms Christoph , Albrecht Katharina , Harms Ulrike , Seidel Kerstin , Hauck Ludger , Baldinger Tina , Hübner Denise , Kronenberg Golo , An Junfeng , Ruscher Karsten , Meisel Andreas , Dirnagl Ulrich , von Harsdorf Rüdiger , Endres Matthias , Hörtnagl Heide
Published: April 2007

The role of glucocorticoids in the regulation of apoptosis remains incongruous. Here, we demonstrate that corticosterone protects neurons from apoptosis by a mechanism involving the cyclin-dependent kinase inhibitor p21Waf1/Cip1. In primary cortical neurons, corticosterone leads to a dose- and Akt-kinase-dependent upregulation with enhanced phosphorylation and cytoplasmic appearance of p21Waf1/Cip1at Thr 145. Exposure of neurons to the neurotoxin ethylcholine aziridinium (AF64A) results in activation of caspase-3 and a dramatic loss of p21Waf1/Cip1preceding apoptosis in neurons. These effects of AF64A are reversed by pretreatment with corticosterone. Corticosterone-mediated upregulation of p21Waf1/Cip1and neuroprotection are completely abolished by glucocorticoid and mineralocorticoid receptor antagonists as well as inhibitors of PI3- and Akt-kinase. Both germline and somatically induced p21Waf1/Cip1deficiency abrogate the neuroprotection by corticosterone, whereas overexpression of p21Waf1/Cip1suffices to protect neurons from apoptosis. We identify p21Waf1/Cip1as a novel antiapoptotic factor for postmitotic neurons and implicate p21Waf1/Cip1as the molecular target of neuroprotection by high-dose glucocorticoids.
Differential Regulation of AMPA Receptor Trafficking by Neurabin-Targeted Synaptic Protein Phosphatase-1 in Synaptic Transmission and Long-Term Depression in Hippocampus
Authors: Hu Xiao-dong , Huang Qing , Yang Xian , Xia Houhui
Published: April 2007

Filamentous actin binding protein neurabin I (NrbI) targets protein phosphatase-1 (PP1) to specific postsynaptic microdomains, exerting critical control over AMPA receptor (AMPAR)-mediated synaptic transmission. NrbI-targeted synaptic PP1, which promotes synaptic depression upon long-term depression (LTD) stimuli, serves to prevent synaptic depression under basal conditions. The present studies investigate this opposite regulation of AMPAR trafficking during basal synaptic transmission and LTD by expressing NrbI or NrbI mutant, which is defective in PP1 binding, in hippocampal slice or neuron cultures. We find that expression of the NrbI mutant to interfere with PP1 targeting dramatically reduces basal synaptic transmission, which is correlated with the reduction in surface expression of AMPA subtype glutamate receptor (GluR) 1 and GluR2 subunits. Biochemical analysis demonstrates that the NrbI mutant selectively increases the phosphorylation of GluR2 at C-terminal consensus PKC site, serine 880, which is known to favor GluR2 interaction with PDZ (postsynaptic density 95/Discs large/zona occludens 1) protein PICK1 (protein interacting with C kinase-1). Inhibition of PKC activity or GluR2–PICK1 interaction completely reverses the synaptic depression in neurons expressing the NrbI mutant, suggesting that NrbI-targeted synaptic PP1 stabilizes the basal transmission by negatively controlling PKC phosphorylation of GluR2 and the subsequent PICK1-mediated decrease in GluR2-containing AMPAR surface expression. Distinct from basal transmission, blocking GluR2–PICK1 interaction or PKC activity produces minimal effects on LTD in NrbI-expressing neurons. Instead, NrbI-targeted PP1 facilitates LTD by dephosphorylating GluR1 at both serine 845 and serine 831, with GluR2 serine 880 phosphorylation unaltered. Our studies thus elucidate that NrbI-targeted PP1, in response to distinct synaptic activities, regulates the synaptic trafficking of specific AMPAR subunits.
Spinal Interneurons That Are Selectively Activated during Fictive Flexion Reflex
Authors: Berkowitz Ari
Published: April 2007

Behavioral choices in invertebrates are mediated by a combination of shared and specialized circuitry, including neurons that are inhibited during competing behaviors. Less is known, however, about the neural mechanisms of behavioral choice in vertebrates. The spinal cord can appropriately select among several types of limb movements, including limb withdrawal (flexion reflex), scratching, and locomotion, and thus is conducive to examination of vertebrate mechanisms of behavioral choice. Flexion reflex can interrupt and reset the rhythm of scratching and locomotion, suggesting that a combination of shared and specialized circuitry contributes to these behaviors, but little is known about the interneurons involved. Here, I usedin vivointracellular recording and dye injection to identify a group of spinal interneurons that are strongly activated during fictive flexion reflex but inhibited during fictive scratching and fictive swimming. These flexion-selective interneurons are typically rhythmically hyperpolarized during fictive scratching and fictive swimming. This hyperpolarization can be maximal during the ipsilateral hip flexor bursts of rhythmic limb motor patterns, although these cells are strongly activated during the ipsilateral hip flexor bursts of fictive flexion reflex. Thus, these interneurons are relatively specialized for fictive limb withdrawal, rather than contributing to the hip flexor phase of multiple types of limb movements. These flexion-selective cells are physiologically and morphologically distinguishable from a recently described group of spinal interneurons (transverse interneurons) that are strongly activated during both fictive flexion reflex and fictive scratching. Thus, spinal interneurons with distinct behavioral roles may to some extent be morphologically distinguishable.
Mashups: Strukturelle Eigenschaften und Herausforderungen von End-User Development im Web 2.0 (Mashups: Structural Characteristics and Challenges of End-User Development in Web 2.0)
Authors: Novak Jasminko , Voigt Benjamin J.J.
Published: April 2007

Mashups sind Web-basierte Anwendungen die Inhalte und Funktionalitäten von unterschiedlichen Onlinequellen über öffentlich verfügbare Schnittstellen verbinden (z.B. API, RSS). Mashup-Technologien versetzen Benutzer in die Lage, selbst neue Webseiten zu erstellen, die Daten und Dienste von unterschiedlichen Anbietern kombinieren. Die Webseite Programmable Web weist hin auf mehr als 800 solcher Anwendungen. Trotz der grossen Dynamik der “Mashup Bewegung”, gibt es bislang kaum Arbeiten, welche die strukturellen Eigenschaften, Designdimensionen und sozio-technischen Implikationen von Mashups analysieren. In diesem Beitrag wird ein konzeptuelles Rahmenwerk zur Analyse und Evaluierung von Mashups vorgeschlagen und in einer explorativen Studie angewandt. Die Studienergebnisse identifi-zieren die aktuellen Trends und ein dominantes Design-Modell erfolgreicher Mashups sowie kritische Aspekte, Limitationen und Chancen zukünftiger Entwicklung.
Modellbasierte Entwicklung von Web 2.0-Anwendungen mit MDA™ (Model-Based Development of Web 2.0 Applications with MDA)
Authors: Petrasch Roland
Published: April 2007

Modellbasierte Software-Entwicklung wie die Model Driven Architecture der OMG eignet sich für Anwendungssysteme, bei denen die fachliche Essenz von den technischen Details zu trennen und dabei ein hoher Grad an Automatisierung erwünscht ist, denn die Vermischung von fachlichen Aspekten (Anwendersicht) mit den implementationsspezifischen Details (Entwicklersicht) erschwert (nicht nur) bei Web 2.0 die Wartbarkeit, Wiederverwendbarkeit und Portabilität der Software. Modellbasierte Software-Entwicklung ermöglicht den Austausch von Technologien bzw. Plattformen – unter Beibehaltung der fachlichen Modelle. Dieser Beitrag zeigt an einem einfachen Beispiel, wie aus einer „alten” Web-Anwendung eine Software unter Verwendung von AJAX für das Web 2.0 entstehen kann, ohne dass eine komplette Neuentwicklung stattfindet.