bluuebunny/crossref_metadata_2025 huggingface dataset:
A Mixed Finite Element Implementation of a Gradient-enhanced Coupled Damage—Plasticity Model
Authors: Dorgan Robert J. , Voyiadjis George Z.
Published: June 2006

The numerical implementation of a gradient-enhanced continuum coupled damage—plasticity model as a constitutive framework to model the nonlocal response of materials is presented. By the introduction of “nonlocal, ” gradient-enhanced measures in the plasticity potential function and yield criterion and in the damage potential function and damage criterion, the proposed model introduces microstructural characteristic material length scales, which allow us to predict the size of localized zones based on material constants, as opposed to local models where the loss of ellipticity causes localized zones to be mesh dependent.

As numerical methods are used to compute the gradients of the hardening terms, no additional gradient internal state variables are introduced into the Helmholtz free energy. As opposed to previous theories that only incorporate linear hardening, the gradient model proposed here uses coupled nonassociative plasticity — nonassociative damage and can account for a wide range of material models because of the consistently expanded Laplacian evolution equations. However, due to the nonassociative material model, anisotropic hardening, and the corresponding gradients in plasticity, the model becomes highly complex as additional equations have to be introduced for the evolution of the gradients of plastic normal, plastic strains, damage normal, and damage tensor.

The numerical implementation uses a small deformation finite element formulation and includes the displacements, plastic multiplier, and damage multiplier as nodal degrees of freedom, thus allowing the three fields to have different interpolation functions. Higher-order elements are used for the plastic multiplier and damage multiplier to enforce continuity of the second gradients, which requires the introduction of additional boundary conditions.
Effective Elastoplastic Damage Mechanics for Fiber-reinforced Composites with Evolutionary Complete Fiber Debonding
Authors: Ju J. W. , Ko Y. F. , Ruan H. N.
Published: June 2006

A micromechanical damage mechanics framework is proposed to predict the overall elastoplastic behavior and interfacial damage evolution of fiberreinforced ductile composites. Progressively debonded fibers are replaced by equivalent voids. The effective elastic moduli of three-phase composites, composed of a ductile matrix, randomly located yet unidirectionally aligned circular fibers, and voids, are derived by using a rigorous micromechanical formulation. In order to characterize the homogenized elastoplastic behavior, an effective yield criterion is derived based on the ensemble area averaging process and the first-order effects of eigenstrains. The resulting effective yield criterion, together with the overall associative plastic flow rule and the hardening law, constitutes the analytical framework for the estimation of effective elastoplastic damage responses of ductile composites containing both perfectly bonded and completely debonded fibers. An evolutionary interfacial fiber debonding process, governed by the internal stresses of fibers and interfacial strength, is incorporated into the proposed framework. The Weibull's function is employed to describe the varying probability of fiber debonding. Further, comparison between predictions and available experimental data are presented to illustrate the potential of the proposed methodology.
Micromechanics-based Interfacial Debonding Model for Damage of Functionally Graded Materials with Particle Interactions
Authors: Paulino G. H. , Yin H. M. , Sun L. Z.
Published: June 2006

A micromechanical damage model is developed for two-phase functionally graded materials (FGMs) considering the interfacial debonding of particles and pair-wise interactions between particles. Given an applied mechanical loading on the upper and lower boundaries of an FGM, in the particle—matrix zones, interactions from all other particles over the representative volume element (RVE) are integrated to calculate the homogenized elastic fields. A transition function is constructed to solve the elastic field in the transition zone. The progressive damage process is dependent on the applied loading and is represented by the debonding angles which are obtained from the relation between particle stress and interfacial strength. In terms of the elastic equivalency, debonded, isotropic particles are replaced by perfectly bonded, orthotropic particles. Correspondingly, the effective elasticity distribution in the gradation direction is solved. The computational implementation is discussed and numerical simulations are provided to illustrate the capability of the proposed model.
The Role of Personality and Career Decision-Making Self-Efficacy in the Career Choice Commitment of College Students
Authors: Wang Naitian , Jome LaRae M. , Haase Richard F. , Bruch Monroe A.
Published: June 2006

This study investigated the effects of personality and career decision-making self-efficacy on progress in career choice commitment in a sample of 184 college students. It was hypothesized that self-efficacy would mediate the relationship between neuroticism and extraversion and career choice commitment. Results revealed significant differences between White students and a composite group of students of color on the study variables. For White students, self-efficacy fully mediated the relationship between extraversion and career choice commitment, whereas for students of color, a partially mediated model fit the data in which neuroticism and extraversion were related to career choice commitment directly and indirectly through self-efficacy. The results of this study are discussed in terms of the implications they might have for career theory and research.
Psychological Distress, Perceived Family Conflict, and Career Development Issues in College Students of Color
Authors: Constantine Madonna G. , Flores Lisa Y.
Published: June 2006

We tested a hypothesized path model that examined the relationships among psychological distress, perceived family conflict, and various career-related constructs in a sample of 329 African American, Asian American, and Latino/Latina American college students. Across each subsample of participants, we found that greater levels of psychological distress predicted higher levels of career indecision, which in turn was associated with lower career certainty and greater perceived family conflict. Lower levels of perceived family conflict predicted high career aspiration for all three subgroups. Higher career certainty predicted greater career aspiration for Asian American students, but this relationship was not significant for African American and Latino/Latina American students. Implications of the findings for career counseling practice and research are discussed.
The Factorial Validity of the Maslach Burnout Inventory–General Survey in Representative Samples of Eight Different Occupational Groups
Authors: Langballe Ellen Melbye , Falkum Erik , Innstrand Siw Tone , Aasland Olaf Gjerløw
Published: June 2006

The Maslach Burnout Inventory-General Survey (MBI-GS) is designed to measure the three subdimensions (exhaustion, cynicism, and professional efficacy) of burnout in a wide range of occupations. This article examines the factorial validity of the MBI-GS across eight different occupational groups in Norway: lawyers, physicians, nurses, teachers, church ministers, bus drivers, and people working within advertising and information technology ( N = 5,024). Separate confirmatory factor analyses using LISREL showed that the hypothesized three-factor model had sufficient fit in all occupational groups except for the group of people working in advertising. In a multigroup analysis including all occupations but the latter one and in an analysis of all individuals combined into one sample, the three-factor model had a clearly better fit than the alternative one-factor and two-factor models. The results support that MBI-GS provides a suitable measurement to assess burnout across a diversity of professions.
The Discursive Condition of Viagra
Authors: Grace Victoria , Potts Annie , Gavey Nicola , Vares Tiina
Published: June 2006

This research investigates the socio-cultural implications of Viagra as a biomedical solution to a medically defined problem. This New Zealand-based research involved interviews with 33 men, to examine how they discursively constituted meanings around masculinity, erections, and the role of Viagra. It is argued that the relationship between discourses of mechanistic functionality of erections, the primacy of the male as performer, and the partner's pleasure as measure of success, create the conditions of possibility for a pharmaceutical solution directed at the male. The problem is configured as the uncertainty accompanying the instability evident in the relationship between these discourses. The men's discourse on the solution, Viagra, confirms this analysis.
The New Sexual Technobody: Viagra in the Hyperreal World
Authors: Croissant Jennifer L.
Published: June 2006

This essay, based on the work of Baudrillard and other critical theorists of culture and technology, describes how Viagra and related products are creating not just new standards for men and women's sexual performance, but new forms of ‘hypersexual’ reality/hyperreal sexuality. Considering television advertisements and framed around metaphors of landscape, Internet ‘SPAM’ advertisements for sexual performance enhancing products (both mechanical and chemical), and bodybuilding magazine representations of the body and sexuality, it is apparent that sexual expression in these genres is both constrained and yet exceeds its boundaries. Sexuality is represented in these media as heterosexual, penetrative, and never to be imperfect in any way. The body itself, perhaps aging or flawed, is represented as incapable of achieving these ends reliably without pharmaceutical means. I argue that Viagra and other sexual pharmaceuticals are best understood as hyperreal or hypernatural (reflecting Baudrillard's 1994 work, Simulacra and Simulation), as simulacra that bear no relation to ‘reality’. Sexual pharmaceutical advertisements refer to an unmedicated imaginary that assumes a unity where there is diversity, and conflates the means and ends of sexual technique.
The ‘Pinking’ of Viagra Culture: Drug Industry Efforts to Create and Repackage Sex Drugs for Women
Authors: Hartley Heather
Published: June 2006

This essay will describe how the success of Viagra stimulated drug companies to create a women's sexual condition comparable to erectile problems in men for which they could market new sex drugs to women. The heart of the article focuses on two interrelated aspects of Viagra culture playing out in drug industry efforts to create and expand a market for sex drugs for women: (1) the industry's ‘Hunt for the Pink Viagra’ to treat the ‘disease’ of female sexual dysfunction (FSD), and (2) the prescription and promotion of off-label uses of men's sex drugs to women. In order to contextualize these two trends, the article outlines key activities and actions that have enabled the drug industry to consolidate power and build capacity in this area, including: mass dissemination of estimates of disease prevalence; the institutionalization of FSD in academic circles, which includes strategic revision of disease definitions as well as the creation of a legitimized infrastructure for dissemination of supporting research and education; and public-relations stimulated mainstream media coverage. The article concludes with a consideration of the ongoing challenges to the medicalization of women's sexuality as well as to harmful corporate practices more broadly.
Security and social ‘sorting’
Authors: Morgan Nigel , Pritchard Annette
Published: June 2006

The discourses of surveillance are central to international tourism, itself concerned with mobilities and flows between inter-modal facilities such as train stations, ferry ports and airports – where the most diverse forms of surveillance are found. This article puts surveillance under scrutiny, discussing the ‘new surveillance’ and (through an exploration of the nature of airport surveillance) reviewing the implications of the ‘panoptic sort’ for tourism experiences, practices, and studies. The article concludes that there is an opportunity to locate tourism studies in the vanguard of social science explorations of the ethical and socio-cultural relationships that characterize the dynamics between surveillance and the body. In suggesting an agenda for study of the surveillance–tourism dialectic, it also contends that such examinations could further broaden the theorization of the gaze(s) in tourism studies.
Tourism translations
Authors: Jóhannesson Gunnar Thór
Published: June 2006

This article discusses Actor–Network Theory (ANT) and its utility for tourism studies. It argues that ANT can be an effective methodological approach for studying tourism development due to two reasons. First, its ability to deal with relational materiality of the social world, immanent in the concept of translation which highlights the net- workpractices of different actors; and second, its willingness to grasp multiple relational orderings, thus drawing diverse forms of tourism spatiality into analysis. The article begins by briefly sketching out the discourse on tourism and tourism development in relation to ANT. It then discusses the origins and characteristics of ANT. Special attention is paid to the concept of translation and how the approach provides an alternative focus for tourism research. The last part of the article briefly illustrates ANT as a methodological orientation through discussion of a tourism development project in Iceland.
Adhesive properties of Enterobacter sakazakii to human epithelial and brain microvascular endothelial cells
Authors: Mange Jean-Philippe , Stephan Roger , Borel Nicole , Wild Peter , Kim Kwang Sik , Pospischil Andreas , Lehner Angelika
Published: June 2006

Background

Enterobacter sakazakii is an opportunistic pathogen that has been associated with sporadic cases and outbreaks causing meningitis, necrotizing enterocolitis and sepsis especially in neonates. However, up to now little is known about the mechanisms of pathogenicity in E. sakazakii. A necessary state in the successful colonization, establishment and ultimately production of disease by microbial pathogens is the ability to adhere to host surfaces such as mucous membranes, gastric and intestinal epithelial or endothelial tissue.

This study examined for the first time the adherence ability of 50 E. sakazakii strains to the two epithelial cell lines HEp-2 and Caco-2, as well as the brain microvascular endothelial cell line HBMEC. Furthermore, the effects of bacterial culture conditions on the adherence behaviour were investigated. An attempt was made to characterize the factors involved in adherence.

Results

Two distinctive adherence patterns, a diffuse adhesion and the formation of localized clusters of bacteria on the cell surface could be distinguished on all three cell lines. In some strains, a mixture of both patterns was observed. Adherence was maximal during late exponential phase, and increased with higher MOI. The adhesion capacity of E. sakazakii to HBMEC cells was affected by the addition of blood to the bacteria growth medium. Mannose, hemagglutination, trypsin digestion experiments and transmission electron microscopy suggested that the adhesion of E. sakazakii to the epithelial and endothelial cells is mainly non-fimbrial based.

Conclusion

Adherence experiments show heterogeneity within different E. sakazakii strains. In agreement with studies on E. cloacae, we found no relationship between the adhesive capacities in E. sakazakii and the eventual production of specific fimbriae. Further studies will have to be carried out in order to determine the adhesin(s) involved in the interaction of E. sakazakii with cells and to enhance knowledge of the pathogenesis of E. sakazakii infection.
Deviation of eyes and head in acute cerebral stroke
Authors: Fruhmann Berger M , Proß RD , Ilg UJ , Karnath H-O
Published: June 2006

Background

It is a well-known phenomenon that some patients with acute left or right hemisphere stroke show a deviation of the eyes (Prévost's sign) and head to one side. Here we investigated whether both right- and left-sided brain lesions may cause this deviation. Moreover, we studied the relationship between this phenomenon and spatial neglect. In contrast to previous studies, we determined not only the discrete presence or absence of eye deviation with the naked eye through clinical inspection, but actually measured the extent of horizontal eye-in-head and head-on-trunk deviation. In further contrast, measurements were performed early after stroke onset (1.5 days on average).

Methods

Eye-in-head and head-on-trunk positions were measured at the bedside in 33 patients with acute unilateral left or right cerebral stroke consecutively admitted to our stroke unit.

Results

Each single patient with spatial neglect and right hemisphere lesion showed a marked deviation of the eyes and the head to the ipsilesional, right side. The average spontaneous gaze position in this group was 46° right, while it was close to the saggital body midline (0°) in the groups with acute left- or right-sided stroke but no spatial neglect as well as in healthy subjects.

Conclusion

A marked horizontal eye and head deviation observed ~1.5 days post-stroke is not a symptom associated with acute cerebral lesions per se, nor is a general symptom of right hemisphere lesions, but rather is specific for stroke patients with spatial neglect. The evaluation of the patient's horizontal eye and head position thus could serve as a brief and easy way helping to diagnose spatial neglect, in addition to the traditional paper-and-pencil tests.
Polymorphisms of XRCC1 genes and risk of nasopharyngeal carcinoma in the Cantonese population
Authors: Cao Yun , Miao Xiao-Ping , Huang Ma-Yan , Deng Ling , Hu Li-Fu , Ernberg Ingemar , Zeng Yi-Xin , Lin Dong-Xin , Shao Jian-Yong
Published: June 2006

Background

Nasopharyngeal carcinoma (NPC) is one of the most common cancers in southern China. In addition to environmental factors such as Epstein-Barr virus infection and diet, genetic susceptibility has been reported to play a key role in the development of this disease. The x-ray repair cross-complementing group 1 (XRCC1) gene is important in DNA base excision repair. We hypothesized that two common single nucleotide polymorphisms of XRCC1 (codons 194 Arg→Trp and 399 Arg→Gln) are related to the risk of NPC and interact with tobacco smoking.

Methods

We sought to determine whether these genetic variants of the XRCC1 gene were associated with the risk of NPC among the Cantonese population in a hospital-based case control study using polymerase chain reaction-restriction fragment length polymorphism analysis. We conducted this study in 462 NPC patients and 511 healthy controls.

Results

After adjustment for sex and age, we found a reduced risk of developing NPC in individuals with the Trp194Trp genotype (OR = 0.48; 95% CI, 0.27–0.86) and the Arg194Trp genotype (OR = 0.79; 95% CI, 0.60–1.05) compared with those with the Arg194Arg genotype. Compared with those with the Arg399Arg genotype, the risk for NPC was not significantly different in individuals with the Arg399Gln genotype (OR = 0.82; 95% CI, 0.62–1.08) and the Gln399Gln genotype (OR = 1.20; 95% CI, 0.69–2.06). Further analyses stratified by gender and smoking status revealed a significantly reduced risk of NPC among males (OR = 0.32; 95% CI, 0.14–0.70) and smokers (OR = 0.34; 95% CI, 0.14–0.82) carrying the XRCC1 194Trp/Trp genotype compared with those carrying the Arg/Arg genotype. No association was observed between Arg399Gln variant genotypes and the risk of NPC combined with smoking and gender.

Conclusion

Our findings suggest that the XRCC1 Trp194Trp variant genotype is associated with a reduced risk of developing NPC in Cantonese population, particularly in males and smokers. Larger studies are needed to confirm our findings and unravel the underlying mechanisms.
Cancer during pregnancy alters the activity of rat placenta and enhances the expression of cleaved PARP, cytochrome-c and caspase 3
Authors: Toledo Mércia Tancredo , Ventrucci Gislaine , Marcondes Maria Cristina Cintra Gomes
Published: June 2006

Background

The presence of cancer makes it difficult to predict the progress of pregnancy and can be deleterious to the maternal-foetal relationship. Apoptosis may affect a range of placental functions and result in the retardation of foetal growth. In this work, we investigated the placental alterations produced by tumour growth and the effects on the expression of apoptotic factors in placental tissue.

Methods

Adult female Wistar rats (90 days old, n = 54) were allocated to control (C), tumour-bearing (W), or ascitic fluid-injected (A) groups and were killed on the 16th, 19thor 21stday of pregnancy. Placental tissues were analysed using biochemical and histochemical assays.

Results

The placental protein content and glutathione-S-transferase activity were decreased in groups W and A. Histochemical analysis showed an increase in the number of cells with cleaved PARP, caspase 3 and cytochrome-c in groups W and A, indicating that the tumour growth clearly damaged placental tissue and affected the levels of apoptotic factors. These results were confirmed by western blotting.

Conclusion

Since trophoblastic cells are responsible for maintaining a normal placental function, the uncontrolled death of these cells in response to tumour cell growth or substances derived from ascitic fluid could have a negative impact on foetal development. Further knowledge of these events may help to preserve the foetus and placenta during development.
Prospective screening study of 0.5 Tesla dedicated magnetic resonance imaging for the detection of breast cancer in young, high-risk women
Authors: Rubinstein Wendy S , Latimer Jean J , Sumkin Jules H , Huerbin Michelle , Grant Stephen G , Vogel Victor G
Published: June 2006

Background

Evidence-based screening guidelines are needed for women under 40 with a family history of breast cancer, a BRCA1 or BRCA2 mutation, or other risk factors. An accurate assessment of breast cancer risk is required to balance the benefits and risks of surveillance, yet published studies have used narrow risk assessment schemata for enrollment. Breast density limits the sensitivity of film-screen mammography but is not thought to pose a limitation to MRI, however the utility of MRI surveillance has not been specifically examined before in women with dense breasts. Also, all MRI surveillance studies yet reported have used high strength magnets that may not be practical for dedicated imaging in many breast centers. Medium strength 0.5 Tesla MRI may provide an alternative economic option for surveillance.

Methods

We conducted a prospective, nonrandomized pilot study of 30 women age 25–49 years with dense breasts evaluating the addition of 0.5 Tesla MRI to conventional screening. All participants had a high quantitative breast cancer risk, defined as ≥ 3.5% over the next 5 years per the Gail or BRCAPRO models, and/or a known BRCA1 or BRCA2 germline mutation.

Results

The average age at enrollment was 41.4 years and the average 5-year risk was 4.8%. Twenty-two subjects had BIRADS category 1 or 2 breast MRIs (negative or probably benign), whereas no category 4 or 5 MRIs (possibly or probably malignant) were observed. Eight subjects had BIRADS 3 results, identifying lesions that were "probably benign", yet prompting further evaluation. One of these subjects was diagnosed with a stage T1aN0M0 invasive ductal carcinoma, and later determined to be a BRCA1 mutation carrier.

Conclusion

Using medium-strength MRI we were able to detect 1 early breast tumor that was mammographically undetectable among 30 young high-risk women with dense breasts. These results support the concept that breast MRI can enhance surveillance for young high-risk women with dense breasts, and further suggest that a medium-strength instrument is sufficient for this application. For the first time, we demonstrate the use of quantitative breast cancer risk assessment via a combination of the Gail and BRCAPRO models for enrollment in a screening trial.
The visible touch: in planta visualization of protein-protein interactions by fluorophore-based methods
Authors: Bhat Riyaz A , Lahaye Thomas , Panstruga Ralph
Published: June 2006

Non-invasive fluorophore-based protein interaction assays like fluorescence resonance energy transfer (FRET) and bimolecular fluorescence complementation (BiFC, also referred to as "split YFP") have been proven invaluable tools to study protein-protein interactions in living cells. Both methods are now frequently used in the plant sciences and are likely to develop into standard techniques for the identification, verification and in-depth analysis of polypeptide interactions. In this review, we address the individual strengths and weaknesses of both approaches and provide an outlook about new directions and possible future developments for both techniques.
Tuberculous abdominal cocoon – a report of 6 cases and review of the Literature
Authors: Kaushik Robin , Punia RPS , Mohan Harsh , Attri Ashok K
Published: June 2006

The abdominal cocoon is a rare cause of intestinal obstruction that is usually diagnosed at the time of laparotomy. It is usually of unknown origin, although at times, it may be seen secondary to a variety of conditions. Tuberculosis is an infrequently implicated cause of abdominal cocoon, and has only occasionally been reported previously in the Literature. This paper presents our experience with tubercular cocoon as a cause of intestinal obstruction, and discusses the surgical implications of the same.
Aging is No Longer an Unsolved Problem in Biology
Authors: HOLLIDAY ROBIN
Published: June 2006

Abstract:  For much of the 20th century, the accumulation of a considerable amount of information about the processes of aging did not reveal the underlying mechanisms. Toward the end of that century, the biological basis for aging became very much clearer. It became apparent that the best strategy for animals' survival was to develop to an adult, but not to invest resources in maintaining the body, or soma, indefinitely. In their natural environment, animals do not survive environmental hazards (predators, disease, starvation, and drought) to reach a long life span. There is thus a trade‐off between the investment of resources in reproduction, and the survival time of the soma. At a stroke, this solves the problem of different rates of aging in different species, because those that develop and reproduce fast also have short life spans, and those that develop and reproduce slowly have long life spans. This difference is due to actual resources invested in the maintenance of the adult soma. There is now much evidence that long‐lived mammals have much more efficient maintenance mechanisms than short‐lived mammals. Thus, aging can be defined as the eventual failure of maintenance. It also became apparent that many different maintenance mechanisms exist, and that these depend on very many genes and a considerable investment in metabolic resources. Most individual theories of aging revolve around the failure of a given maintenance system, but as there are many of these, it is likely that most of the important theories have some degree of truth. A broad interpretation of the different degenerative changes during senescence should therefore be adopted, with the major conclusion that aging is multicausal. It is also evident that the evolved design of many components of complex animals is incompatible with indefinite survival. We can therefore conclude that this evolved design is intrinsically related to the fact of aging. This in turn means that aging cannot be reversed, although it may be modulated, as, for example, by calorie restriction.
Free Radical Theory of Aging: An Update
Authors: HARMAN DENHAM
Published: June 2006

Abstract:  Aging is the progressive accumulation of diverse, deleterious changes with time that increase the chance of disease and death. The basic chemical process underlying aging was first advanced by the free radical theory of aging (FRTA) in 1954: the reaction of active free radicals, normally produced in the organisms, with cellular constituents initiates the changes associated with aging. The involvement of free radicals in aging is related to their key role in the origin and evolution of life. Aging changes are commonly attributed to development, genetic defects, the environment, disease, and an inborn aging process (IAP). The latter produces aging changes at an exponentially increasing rate with age, becoming the major risk factor for disease and death for humans after the age of 28 years in the developed countries. In them the IAP limits human average life expectancy at birth (ALE‐B)—a rough measure of the healthy life span—to about 85 years; few reach 100 years and only one is known to have lived to 122 years. In these countries, improvements in living conditions (ILC) have gradually raised ALE‐Bs to 76–79 years, 6–9 years less than the limit imposed by aging, with no change in the maximum life span (MLS). The extensive studies based on the FRTA hold promise that ALE‐B and the MLS can be extended, the ALE‐B possibly by a few years, and the MLS somewhat less.
Catabolic Insufficiency and Aging
Authors: TERMAN ALEXEI
Published: June 2006

Abstract:  Cellular degradative processes, which include lysosomal (autophagic) and proteasomal degradation, as well as the activity of cytosolic and mitochondrial proteases, provide for a continuous turnover of damaged and obsolete biomolecules and organelles. Inherent insufficiency of these degradative processes results in progressive accumulation within long‐lived postmitotic cells of biological “garbage” (“waste” material), such as indigestible protein aggregates, defective mitochondria, and lipofuscin (age pigment), an intralysosomal, polymeric, undegradable material. Intracellular “garbage” is neither completely catabolized, nor exocytosed to any considerable extent. Heavy lipofuscin loading of lysosomes, typical of old age, seems to pronouncedly decrease autophagic potential. As postulated in the mitochondrial–lysosomal axis theory of aging, this occurs on account of the transport of newly synthesized lysosomal enzymes to lipofuscin‐loaded lysosomes rather than to active lysosomes/late endosomes, making the enzyme content of autophagolysosomes insufficient for proper degradation. Consequently, the turnover of mitochondria progressively declines, resulting in decreased ATP synthesis and enhanced formation of reactive oxygen species, inducing further mitochondrial damage and additional lipofuscin formation. With advancing age, lipofuscin‐loaded lysosomes and defective mitochondria occupy increasingly larger parts of long‐lived postmitotic cells, leaving less and less capability for normal turnover and ATP production, finally resulting in cell death.
Inadequate Intensity of Various Components of Total Environmental Signals Can Lead to Natural Aging
Authors: KHALYAVKIN ALEXANDER V. , YASHIN ANATOLI I.
Published: June 2006

Abstract:  We suppose that natural aging derives from an inevitable shift in certain parameters of physiological control systems under the influence of inadequate environmental conditions, which are not able to fully induce an organism's “optimal” existence in the self‐maintenance mode. In this case the rate of aging is proportional to the multidimensional difference between the cues from evolutionarily designed adequate habitat and signals from the real environment. The negative correlation between parameters of Gompertzian mortality (and some other published findings) is compatible with this view. Here we discuss examples from intracellular to organism level in order to show that adequate patterns of outer signals can reverse some aging manifestations.
Human Immunosenescence
Authors: PAWELEC G. , KOCH S. , FRANCESCHI C. , WIKBY A.
Published: June 2006

Abstract:  The rate of acceleration of the frequency of death due to cardiovascular disease or cancer increases with age from middle age up to around 75–80 years, plateauing thereafter. Mortality due to infectious disease, however, does not plateau, but continues to accelerate indefinitely. The elderly are particularly susceptible to novel infectious agents such as SARS, as well as to previously encountered pathogens. Why is this? The elderly commonly possess oligoclonal expansions of T cells, especially of CD8 cells, which, surprisingly, are associated with cytomegalovirus (CMV) seropositivity. This in turn is associated with many of the same phenotypic and functional alterations to T cell immunity that have been suggested as biomarkers of immune system aging. We suggest that, in fact, CMV, not age per se, is the prime driving force behind many or most of the oligoclonal expansions and altered phenotypes and functions of CD8 cells in the elderly. Thus, the manner in which CMV and the host immune system interact (over which period? on which genetic background? with which co‐infections?) is critical in determining the “age” of adaptive immunity and hence human longevity. In this respect, immunosenescence is infectious.
The Value of Life and the Value of Life Extension
Authors: HORROBIN STEVEN
Published: June 2006

Abstract:  Recent developments in aging research have added new urgency to the bioethical debate concerning life and death issues, the value of life, and the reasonable limits of medicine. This paper analyzes the basic structures of the liberal and conservative components of this debate, showing that there has hitherto been inadequate analysis on both sides concerning the nature and implications of the value of life, as well as, and as distinct from the value of life extension. Classic concepts of the intrinsic or extrinsic value of life are argued to be tangential or actually irrelevant to the value of life's continuance and so to the value of life extension. An analysis of personhood is proposed which focuses explicitly upon the value of life extension to persons. This analysis shows that persons may only intelligibly be understood as processes, for whom life extension is an inalienable and fundamental value. It is further proposed that, properly understood, such an analysis may significantly narrow the liberal/conservative divide in bioethics.
OXPHOS Supercomplexes
Authors: KRAUSE FRANK , SCHECKHUBER CHRISTIAN Q. , WERNER ALEXANDRA , REXROTH SASCHA , REIFSCHNEIDER NICOLE H. , DENCHER NORBERT A. , OSIEWACZ HEINZ D.
Published: June 2006

Abstract:  Recent biochemical evidence has indicated the existence of respiratory supercomplexes as well as ATP synthase oligomers in the inner mitochondrial membrane of different eukaryotes. We have studied the organization of the respiratory chain of a wild‐type strain and of two long‐lived mutants of the filamentous fungus Podospora anserina. This aging model is able to respire by either the standard or the alternative pathway. In the latter, electrons are directly transferred from ubiquinol to the alternative oxidase (AOX) and thus bypass complexes III and IV. We showed that the two pathways are composed of distinct respiratory supercomplexes. These data are of significance for the understanding of both respiratory pathways as well as of life‐span control and aging.
Using Caenorhabditis elegans as a Model for Aging and Age‐Related Diseases
Authors: OLSEN ANDERS , VANTIPALLI MAITHILI C. , LITHGOW GORDON J.
Published: June 2006

Abstract:  During the last three decades the soil nematode C. elegans has become a prominent model organism for studying aging. Initially research in the C. elegans aging field was focused on the genetics of aging and single gene mutations that dramatically increased the life span of the worm. Undoubtedly, the existence of such mutations is one of the main reasons for the popularity of the worm as model system for studying aging. However, today many different approaches are being used in the C. elegans aging field in addition to genetic manipulations that influence life span. For example, environmental manipulations such as caloric restriction and hormetic treatments, evolutionary studies, population studies, models of age‐related diseases, and drug screening for compounds that extend life span are now being investigated using this nematode. This review will focus on the most recent developments in C. elegans aging research with the aim of illustrating the diversity of the field.
Age‐Dependent Decrease in Renal Glucocorticoid Receptor Function Is Reversed by Dietary Restriction in Mice
Authors: SHARMA RAMESH , DUTTA DEBIPREETA
Published: June 2006

Abstract:  The effects of age and dietary restriction (alternate days of feeding for 3 months) on the concentration, activation, and DNase I digestion of nuclear‐bound glucocorticoid receptors (GRs) in the kidney of male mice at two different ages (5 months as adult and 20 months as old) were investigated. A significant decrease (30%) in the concentration of renal GRs was observed in older ad libitum (AL)‐fed mice as compared to the adult mice. Dietary restriction (DR) of older mice significantly increased (28%) the level of GRs as compared to the AL‐fed control animals. The affinity of the receptor for the hormone remained the same for both AL‐ and DR‐fed animals at both ages. Scatchard and slot blot analyses of the data confirmed the decreased level of renal GRs in older mice compared to the adult mice as well as an increased level of receptor in older DR mice. Activation studies of GRs by both salt and heat indicated a decreased (15–20%) activation of renal GRs in older animals compared to the adult mice in the AL‐fed group. It was further observed that DR significantly enhanced (30%) the degree of both salt‐ and heat‐dependent activation of GRs in older animals compared to the AL‐fed animals of the age‐matched group. DNase I digestion and extraction of nuclear‐bound GR complexes showed a lower degree (26%) of extraction in older AL‐fed animals compared to the adult animals. However, DR did not alter the pattern of digestibility of bound GR complexes. These above findings indicate that DR could reverse the decrease of GR function in older animals and may provide better adaptability of kidney in water and electrolyte balance.
Investigation of Differentially Expressed Genes in the Ventricular Myocardium of Senescent Rats
Authors: ISHIHATA AKIRA , KATANO YUMI
Published: June 2006

Abstract:  Aging alters a variety of physiological functions of the heart. The molecular basis of the age‐related functional changes has not been fully understood. Differential gene expression provides the basis for many fundamental cellular processes associated with development and aging. The identification and cloning of genes whose expression is modulated by aging can be of importance for our better understanding of these age‐related phenomena. In order to isolate and characterize gene products differentially expressed in senescent hearts, we applied a differential display method for screening those genes in rat ventricular myocardium. Total RNAs were isolated from 2‐month‐old (young) and 24‐month‐old rat (senescent) ventricles by the acid‐guanidium‐phenol‐chloroform method. The first‐strand synthesis of the cDNAs from each RNA was carried out with oligo‐d(T) primers. The differential display screening was performed with three arbitrary primers and eight anchor primers, and the products were isolated on a 6% denaturing polyacrylamide gel. The bands showing differential expression were excised and subcloned into T‐vector. We selected 19 upregulated clones and 66 downregulated clones in aged rat hearts. The differential expression of those candidate genes was confirmed by reverse Northern blot analysis. The selected genes were sequenced by dye‐terminator methods. Among 31 clones, 15 clones were unknown. The known products included alpha‐myosin heavy chain, cytochrome oxidase subunit, H+‐transporting ATP synthase F0 complex subunit c isoform 3 (ATP5G3), and Na+‐K+‐Cl− cotransporter. The RT‐PCR differential display method effectively identified genes differentially expressed in senescent hearts, and may be a useful tool for investigating factors responsible for age‐related physiological changes.
Naïve T Cells in the Elderly
Authors: PFISTER GERALD , WEISKOPF DANIELA , LAZUARDI LUTFAN , KOVAIOU RANIA D. , CIOCA DANIEL P. , KELLER MICHAEL , LORBEG BERND , PARSON WALTHER , GRUBECK‐LOEBENSTEIN BEATRIX
Published: June 2006

Abstract:  One of the most striking changes in the primary lymphoid organs during human aging is the progressive involution of the thymus. As a consequence, the rate of naïve T cell output dramatically declines with age and the peripheral T cell pool shrinks. These changes lead to increased incidence of severe infections and decreased protective effect of vaccinations in the elderly. Little is, however, known of the composition and function of the residual naïve T cell repertoire in elderly persons. To evaluate the impact of aging on the naïve T cell pool, we investigated the quantity, phenotype, function, composition, and senescence status of CD45RA+CD28+ human T cells—a phenotype generally considered as naïve cells—from both young and old healthy donors. We found a significant decrease in the number of CD45RA+CD28+ T cells in the elderly, whereas the proliferative response of these cells is still unimpaired. In addition to their reduced number, CD45RA+CD28+ T cells from old donors display significantly shorter telomeres and have a restricted TCR repertoire in nearly all 24 Vβ families. These findings let us conclude that naïve T cells cannot be classified with conventional markers in old age.
Mitochondria Damage Checkpoint, Aging, and Cancer
Authors: SINGH KESHAV K.
Published: June 2006

Abstract:  There is growing evidence supporting the progressing decline in mitochondrial function with age. Mitochondria are the major site of reactive oxygen species (ROS) production in the cell; therefore it is likely that progressive decline in mitochondrial function is due to the accumulation of oxidative damage with age. Despite this notion, a role for mitochondria in cellular senescence has been largely ignored. Our studies using mitochondrial gene knockout cells (ρ0) from a variety of tissue types demonstrate that loss of mitochondrial function leads to cell cycle arrest, cellular senescence, and tumorigenic phenotype. In light of these and earlier studies we hypothesize the existence of a mitochondria damage checkpoint (mitocheckpoint) in human cells. Mitocheckpoint permits cells to arrest in the cell cycle in order to repair/restore mitochondrial function to the normal level. Upon overwhelming, persistent, or severe damage to mitochondria, mitocheckpoint machinery may allow cells to undergo senescence. Thus cellular senescence may function as another checkpoint before cells decide to initiate programmed cell death resulting in aging of tissues and organs. Alternatively, mutations occur in the mitochondrial and/or nuclear DNA, resulting in tumorigenesis.
Effect of Lipid Restriction on Mitochondrial Free Radical Production and Oxidative DNA Damage
Authors: SANZ ALBERTO , CARO PILAR , SANCHEZ JOSE GOMEZ , BARJA GUSTAVO
Published: June 2006

Abstract:  Many studies have shown that caloric restriction (40%) decreases mitochondrial reactive oxygen species (ROS) generation in rodents
. Moreover, we have recently found that 7 weeks of 40% protein restriction without strong caloric restriction also decreases ROS production in rat liver. This is interesting since it has been reported that protein restriction can also extend longevity in rodents. In the present study we have investigated the possible role of dietary lipids in the effects of caloric restriction on mitochondrial oxidative stress. Using semipurified diets, the ingestion of lipids in male Wistar rats was decreased by 40% below controls, while the other dietary components were ingested at exactly the same level as in animals fed ad libitum. After 7 weeks of treatment the liver mitochondria of lipid‐restricted animals showed significant increases in oxygen consumption with complex I‐linked substrates (pyruvate/malate and glutamate/malate). Neither mitochondrial H2O2 production nor oxidative damage to mitochondrial or nuclear DNA was modified in lipid‐restricted animals. Oxidative damage to mitochondrial DNA was one order of magnitude higher than that of nuclear DNA in both dietary groups. These results deny a role for lipids and reinforce the possible role of dietary proteins as being responsible for the decrease in mitochondrial ROS production and DNA damage in caloric restriction.
Establishment of H2O2‐Induced Premature Senescence in Human Fibroblasts Concomitant with Increased Cellular Production of H2O2
Authors: ZDANOV STEPHANIE , REMACLE JOSE , TOUSSAINT OLIVIER
Published: June 2006

Abstract:  Premature senescence of human fibroblasts is established after exposure to an acute sublethal concentration of H2O2. Overexpression of transforming growth factor‐β1 (TGF‐β1) was shown to be responsible for the appearance of the biomarkers of senescence in these conditions. Other studies have shown that incubation of human fibroblasts with TGF‐β1 leads to overexpression of H2O2. In this work, we show an increased production of H2O2 by human fibroblasts as premature senescence is established after an initial exposure to H2O2.
Structural and Functional Differences between Mouse Mot‐1 and Mot‐2 Proteins That Differ in Two Amino Acids
Authors: DEOCARIS CUSTER C. , YAMASAKI KAZUHIKO , KAUL SUNIL C. , WADHWA RENU
Published: June 2006

Abstract:  Chaperone functions mediated by the heat‐shock protein (HSP) family constitute a fundamental mechanism that governs the life span of organisms. Here we investigated the chaperone activities of the mitochondrial HSP70 protein, mortalin, which is a heat‐uninducible stress protein involved in immortalization and tumorigenesis. There are two mortalin alleles, mot‐1 and mot‐2, in mouse, encoding two distinct proteins. Whereas an overexpression of mot‐1‐induced senescence in NIH 3T3 cells, overexpression of mot‐2 promoted their malignant properties. Here, we provide evidence that mot‐1 possesses very low chaperone activity as compared to mot‐2. A “lazy lid” hypothesis is proposed for their differential aging phenotypes.
Proteasomal Oscillation during Mild Heat Shock in Aging Human Skin Fibroblasts
Authors: KRAFT DAVID CHRISTIAN , DEOCARIS CUSTER C. , RATTAN SURESH I. S.
Published: June 2006

Abstract:  Augmentation of proteasome machinery is emerging as a significant gerontomodulatory consequence of hormetic stimulation, such as mild heat stress. This study describes the phenomenon we term hormetic proteasomal oscillation, wherein mildly heat‐stressed human fibroblasts (41°C, 1 h) display an adaptation response pattern in proteasome activity. Remarkably, such response appears to be diverse in severely heat‐stressed or senescent fibroblasts. This proteasomal oscillation, as an innate cellular reaction to heat and aging, however, is independent of 20S proteasome protein levels and nuclear factor‐E2‐related factor 2 (Nrf2) transactivation.