bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug Safety during Pregnancy and in Infants: Lack of Mortality Related to Mitochondrial Dysfunction among Perinatally HIV‐Exposed Children in Pediatric HIV Surveillance
Authors: LINDEGREN MARY LOU , RHODES PHILIP , GORDON LAURA , FLEMING PATRICIA ,   STATE AND LOCAL HEALTH DEPARTMENT HIV/AIDS SURVEILLANCE PROGRAMS, AND THE PERINATAL SAFETY REVIEW WORKING GROUP
Published: July 2010

Abstract: The objectives were to assess whether any deaths reported among perinatally exposed, uninfected, or indeterminate children were consistent with mitochondrial dysfunction. and to characterize perinatal exposure to antiretrovirals among children born in the last five years and reported to perinatal HIV surveillance. Population‐based HIV/AIDS surveillance data on perinatally exposed children born in 1993 through 1998 from 32 states with HIV reporting and from a special HIV surveillance project in Los Angeles County and in 22 hospitals in New York City were used. The classifications of exposure and deaths were consistent with the investigation of deaths across all US cohorts. Deaths were ascertained from recent matches with death registries in each state. Causes of death were ascertained from death certificates, autopsy records when available, and medical records. None of the 98 deaths (1.1%) among 9067 perinatally exposed uninfected or indeterminate children born from 1993 through 1998 and reported through pediatric HIV surveillance died of conditions that were consistent with mitochondrial dysfunction. This included 679 children exposed to zidovudine (ZDV) and 3TC, 277 exposed to other antiretroviral combinations, 4512 exposed to ZDV alone, 927 with no antiretroviral exposure, and 2672 with unknown exposure‐1128 of whom were born before March 1994 and were unlikely to have been exposed to ZDV. No deaths attributable to mitochondrial dysfunction were found through this evaluation of population‐based HIV surveillance data. Long‐term follow‐up of antiretroviral‐exposed children has been recommended by the Public Health Service. This evaluation highlights the contribution of population‐based surveillance to the evaluation of potential toxicities associated with maternal antiretroviral use.
A Comparision of Genetic Mitochondrial Disease and Nucleoside Analogue Toxicity: Does Fetal Nucleoside Toxicity Underlie Reports of Mitochondrial Disease in Infants Born to Women Treated for HIV Infection?
Authors: HAAS RICHARD H.
Published: July 2010

Abstract: Recent reports of mitochondrial disease in infants whose mothers were treated in pregnancy with nucleoside analogues are of concern. Chronic nucleoside analogue treatment of adults has long been known to cause mitochondrial DNA depletion with the risk of multisystem disease. Combination nucleoside analogue treatment regimens may have the greatest risk of toxicity. This paper briefly presents the underlying biochemical etiologies and phenotypes of some common genetic mitochondrial diseases in order to provide a comparison with reports of infant toxicity. A standardized method for the diagnosis and evaluation of mitochondrial disease is discussed. A hypothesis, with predictions of the effects of antenatal nucleoside analogue treatment on the fetus, is presented and future directions for research on this problem are suggested.
Incorporation of Zidovudine into Cord Blood DNA of Infants and Peripheral Blood DNA of Their HIV‐1‐Positive Mothers
Authors: OLIVERO OFELIA A. , SHEARER GENE M. , CHOUGNET CLAIRE A. , KOVACS ANDREA A.S. , BAKER ROBIN , STEK ALICE M. , KHOURY MARGARET M. , POIRIER MIRIAM C.
Published: July 2010

Abstract:The nucleoside analogue 3′‐azido‐3′‐deoxythymidine (AZT) is a weak carcinogen in adult female mice and a moderately strong carcinogen in the offspring of female mice given the drug during gestation. In addition, incorporation of AZT into DNA was observed in multiple organs of transplacentally exposed newborn mice. Here we investigate the incorporation of AZT into peripheral leukocyte DNA of HIV‐1‐positive adult pregnant women given AZT for variable times during gestation and cord blood of infants exposed to AZTin utero. The length of treatment varied between 10 days and 9 months. High molecular weight DNA was extracted from maternal peripheral blood mono‐nuclear cells (PBMC) and infant cord blood. A specific AZT‐DNA radioimmunoassay was used to determine the amount of AZT incorporated into leukocyte DNA. Incorporation of AZT into DNA ranged up to 183.3 and 344.5 molecules of AZT/106nucleotides in the mothers and infants, respectively, and was detected in about 70% of samples. Therefore, AZT‐induced mutagenic events are possible in the majority of adults and infants. No correlation was found between level of incorporation and length of AZT treatment, suggesting that the differences observed among the individuals arise from variability in AZT metabolism. These data support previous observations that a high degree of inter‐individual variability in AZT phosphorylation occurs in primates.
Fetal Patas Monkeys Sustain Mitochondrial Toxicity As a Result of in Utero Zidovudine Exposure
Authors: GERSCHENSON MARIANA , POIRIER MIRIAM C.
Published: July 2010

Abstract: Mitochondrial toxicity was examined in near‐term fetuses of pregnant Erythrocebus patas monkeys given human equivalent doses of 3′‐azido‐3′ deoxythymidine (AZT) during the second half of gestation. Pregnant monkeys were dosed daily with 10 or 40 mg AZT, equivalent to about 21% and 86% of the daily AZT dose (500 mg) given to HIV‐1‐positive pregnant women to prevent maternal‐fetal virus transmission. The fetal tissues examined include heart and skeletal muscle, which have high energy requirements, and placenta, which is less dependent on mitochondrial integrity. Slot blot quantitation of mitochondrial DNA (mtDNA) levels showed dose‐dependent depletion in heart, skeletal muscle, and placenta from AZT‐exposed fetuses compared to unexposed controls. Furthermore, mtDNA degradation, observed by Southern blot analysis, appeared more extensive in AZT‐exposed tissues compared to unexposed controls. Mitochondrial functional integrity, as determined by oxidative phosphorylation (OXPHOS) enzyme assays, was also examined in heart, skeletal muscle, and placenta. All three tissues showed strong dose‐related decreases in Complex I. In placenta, dose‐related increases for Complexes II and IV and a decrease for Complex III were observed. Dose‐related increases for Complexes II and IV observed in heart and skeletal muscle have been reported. 1 The increase in Complex IV (cytochrome c oxidase) activity in heart and skeletal muscle tissue from patas fetuses exposed to 40 mg AZT/day has been confirmed here by histochemical staining. Overall, data demonstrate that mitochondrial toxicity, evidenced by depletion in mtDNA and OXPHOS enzyme abnormalities, is manifested similarly in heart, skeletal muscle, and placenta of AZT‐exposed monkey fetuses. It is therefore possible that the placenta, which is a readily accessible tissue, might be an indicator of potential mitochondrial toxicity in human pregnancies involving nucleoside analog drug exposure.
Evaluation of Immune Survival Factors in Pediatric HIV‐1 Infection
Authors: SHEARER WILLIAM T. , EASLY KIRK A. , GOLDFARB JOHANNA , JENSON HAL B. , ROSENBLATT HOWARD M. , KOVACS ANDREA , MCINTOSH KENNETH ,   THE PC HIV STUDY GROUP
Published: July 2010

Abstract: Peripheral blood CD4+ and CD8+ T cells, CD19+/20+ B cells, and serum immunoglobulins (Igs) have been implicated as survival factors for pediatric HIV‐1 infection. To determine which of these immune factors might be important in predicting survival, we studied HIV‐1 vertically infected (HIV‐1+) children over a 5‐year period. Peripheral blood lymphocytes and Igs were measured in 298 HIV‐1+ children, who were classified as survivors or nonsurvivors, and in 463 HIV‐1 vertically exposed and noninfected (HIV‐1−) children. Measurements of other possible survival factors were included in this study: albumin, hemoglobin, lactic dehydrogenase (LDH), and HIV‐1 RNA levels. Survivors had significantly higher CD4+ T‐cell, CD8+ T‐cell, and CD19+/CD20+ B‐cell counts and serum IgG levels, but lower serum IgA and IgM levels than nonsurvivors. Serum albumin and blood hemoglobin levels were higher, but serum LDH and HIV‐1 RNA levels were lower in the survivors compared to non‐survivors. In univariable analysis, factors affecting survival were baseline CD4+ T‐cell and CD8+ T‐cell counts, IgG, albumin, hemoglobin, LDH, and HIV‐1 RNA (all p < 0.001). In multivariable analysis, high baseline CD4+ T‐cell count, IgG and albumin levels, and low baseline HIV‐1 RNA load remained important factors for survival. Serum IgG level has been identified as an immune factor that independently predicts survival, in addition to the already established CD4+ T‐cell count. The HIV‐1 RNA and serum albumin levels also predicted survival.
Gene Therapy for Pediatric AIDS
Authors: BAUER GERHARD , SELANDER DAVID , ENGEL BARBARA , CARBONARO DENISE , CSIK SUSIE , RAWLINGS STEVE , CHURCH JOSEPH , KOHN DONALD B.
Published: July 2010

Abstract: Gene therapy is an experimental treatment modality under investigation for applications to HIV‐1 infection. We have developed retroviral vectors carrying anti‐HIV‐1 genes, demonstrated that these genes cause significant suppression of HIV‐1 replication in cultures of primary hematopoietic cells, and performed a clinical trial in pediatric AIDS patients. Four HIV‐1‐infected children and adolescents underwent bone marrow harvest from which CD34+ cells were isolated and transduced by a retroviral vector carrying an RRE decoy gene. The cells were reinfused into the subjects, without complications, showing that gene transfer in pediatric AIDS patients is safe and feasible. However, gene‐containing leukocytes in the peripheral blood were seen only at a low level and only in the first months following cell infusion. To attain some degree of efficacy, it will be necessary to achieve a higher level of gene transfer and to obtain sustained gene expression. We are currently developing new gene transfer methods and vectors designed to improve the results in future trials. If it becomes possible to reach the ideal goal of producing high percentages of T lymphocytes and monocytic cells that are resistant to HIV‐1 infection, gene therapy could serve as a complement to antiretroviral drug therapy and help to sustain immunologic function.
The Discovery of Uteroglobin and Its Significance for Reproductive Biology and Endocrinology
Authors: BEIER HENNING M.
Published: July 2010

Abstract: The discovery of uteroglobin resulted from investigations on the biochemical composition of oviductal and uterine secretions of the rabbit and other mammals. These determinations about physiological composition were urgently requested to prepare culture media for research on early mammalian development in vitro. Discovery of significant proteins during the sixties reflected the laboratory skills of that time. Protein characterization was achieved by isolation via Sephadex gels, electrophoresis on polyacrylamide gels, and finally immunoprecipitation using classical polyclonal antibodies. The molecular biology was not yet established. Uteroglobin could be found as the major protein component of rabbit uterine secretion. From the beginning, it was already identified as an unusually small, spheric uterine secretory molecule without any carbohydrates‐hence its name. Uteroglobin was the first mammalian protein that turned out to be progesterone‐regulated and, at the same time, released in mg amounts actually in one organ compartment. Moreover, uteroglobin and its gene proved to be a reliable model for the description of progesterone/progesterone receptor complex action at the DNA level. After its original observation in the uterus, however, uteroglobin was detected also in several other organs, for example, the epididymis, the seminal vesicle, and the lung. Initially, it could not be found in the blood, which challenged the hypothesis that uteroglobin specifically should operate by local activation rather than by a humoral or endocrine effect. Later, though, the human uteroglobin molecule, isolated from blood filtrate, was used for detailed structural analyses. The rabbit uteroglobin model certainly was beneficial for reproductive biological research. Experimental interference with steroid hormone regulation during preimplantation presented surprising effects, which led to the discovery of the transposition of the implantation window. The uterine secretion protein patterns, in particular the uteroglobin fraction and the β‐glycoprotein fraction, served as decisive marker profiles to identify the biological stage of the intrauterine microenvironment during preimplantation. This diagnostic procedure, using only protein parameters, enabled us to precisely predict the receptive stage of the endometrium for donated blastocysts to achieve implantation successfully.
All Human Genes of the Uteroglobin Family Are Localized on Chromosome 11q12.2 and Form a Dense Cluster
Authors: NI JIAN , KALFF‐SUSKE MARTHA , GENTZ REINER , SCHAGEMAN JEOFFREY , BEATO MIGUEL , KLUG JÖRG
Published: July 2010

Abstract:Rabbit uteroglobin is the founder member of a family of mammalian proteins that has expanded to more than 20 members within the last few years. All members are small, secretory, rarely glycosylated dimeric proteins with unclear physiological functions and are mainly expressed in mucosal tissues. A phylogenetic analysis shows that the family can be grouped into five subfamilies, A to E. Subfamily A contains rabbit uteroglobin and its orthologues from various species; most of these have been described to form antiparallel homodimers via two intermolecular disulfide bonds. All other subfamily members contain a third conserved cysteine and, from existing biochemical data, it can be predicted that a member of subfamily B or C will likely form heterodimers with a partner from subfamily E or D, respectively. Besides the mentioned cysteines, only one central lysine is conserved in all family members. In the known uteroglobin structures, this lysine forms an exposed salt bridge with an aspartate side chain, which is conserved in almost all sequences. Using radiation hybrid mapping and P1 clone analysis and utilizing data from the human genome project, we show that all known five human family members (Clara cell 10‐kDa protein, lipophilins A and B, lacryglobin, mammaglobin) and a new member, we call lymphoglobin, are localized on chromosome 11q12.2 in a dense cluster spanning not more than approximately 400 kbp.
Clara Cell Secretory Protein (CC16): Features as a Peripheral Lung Biomarker
Authors: BROECKAERT F. , CLIPPE A. , KNOOPS B. , HERMANS C. , BERNARD A.
Published: July 2010

Abstract: Clara cell protein (CC16 or CC10) is a 15.8‐kDa protein secreted all along the tracheobronchial tree and especially in the terminal bronchioles where Clara cells are localized. Even though the exact in vivo function of CC16 remains to be clarified, evidence is accumulating that CC16 plays an important protective role in the respiratory tract against oxidative stress and inflammatory response. CC16, however, presents also a major interest as a peripheral lung marker for assessing the cellular integrity or the permeability of the lung epithelium. The serum concentrations of CC16 are decreased in subjects with chronic lung damage caused by tobacco smoke and other air pollutants as a consequence of the destruction of Clara Icells. By contrast, serum CC16 increases in acute or chronic lung disorders characterized by an increased airways permeability. The sensitivity of serum CC16 to an increased leakiness of the lung allows for the detection of defects of the epithelial barrier at ozone levels below current air‐quality guidelines. Although the clinical significance of these early epithelial changes detected by serum CC16 remains to be determined, these results clearly show that the assay in serum of lung secretory proteins such as CC16 represents a new noninvasive approach to evaluate the integrity of the respiratory tract.
Antiflammin Peptides in the Regulation of Inflammatory Response
Authors: MORENO JUAN J.
Published: July 2010

Abstract:This review focuses on the role of antiflammins in the regulation of the inflammatory response, in particular acute inflammation. The results show that antiflammins were effective on several classical models of inflammation. Preliminary data suggest that antiflammin action may be due to their ability to suppress leukocyte trafficking to the lesion.
Synaptic Structure and Function in Transgenic APP Mice
Authors: ASHE KAREN HSIAO
Published: July 2010

Abstract: Efforts using transgenic mice are being made to understand the molecular and structural basis for dementia in Alzheimer's disease. Transgenic mice 12 to 18 months of age with amyloid plaques and impaired cognition show no neuronal or synaptic loss in the CA1 hippocampal subfield. Electrophysiological studies may yield new insights.
A Plasticity‐Based Theory of the Pathogenesis of Alzheimer's Disease
Authors: MESULAM M.‐MARSEL
Published: July 2010

Abstract: Amyloid plaques (APs) and neurofibrillary tangles (NFTs) are the two diagnostic markers of Alzheimer's disease (AD). The neuropsychological features of AD are closely correlated with the distribution of the NFTs and therefore favor a disease process revolving around neurofibrillary degeneration. The genetics, however, favor a disease process revolving around the APs, principally because mutations in the amyloid precursor protein (AβPP) are sufficient to cause AD. The inability to reconcile these two aspects of AD has prevented the formulation of a unified theory of pathogenesis. It is interesting to note that all genetic causes and risk factors of AD can increase the physiological burden of neuroplasticity. My hypothesis is that the resultant intensification of the plasticity burden leads to an initially adaptive upregulation of tau phosphorylation and AβPP turnover, to the subsequent formation of NFTs and APs as independent consequences of excessive plasticity‐related cellular activity, and to the eventual loss of neurons, dendrites, and synapses as the ultimate expression of plasticity failure. The two pathological markers of AD are therefore independent manifestations of a more fundamental process through which the many different genotypes of AD trigger an identical clinical and neuropathological phenotype.
Vulnerability of Select Neuronal Types to Alzheimer's Disease
Authors: BRAAK HEIKO , DEL TREDICI KELLY , SCHULTZ CHRISTIAN , BRAAK EVA
Published: July 2010

Abstract: From a morphological perspective, Alzheimer's disease (AD) is primarily a degenerative disorder of the neuronal cytoskeleton involving lipofuscin‐laden cortical projection neurons with long, thin, and sparsely myelinated axons. The neocortical primary fields, relatively small in extent but functionally sophisticated, exhibit an early and brief myelination cycle, whereas the much more expansive but relatively simply organized association areas undergo a late and prolonged myelination process. The greater the degree of myelination and the less intense the pigmentation, the more resistant a given projection neuron may be to oxidative stress as well as to the development of AD‐related neurofibrillary changes and vice versa. The neurofibrillary pathology commences from those cortical areas that are less completely myelinated and gradually progresses to the most functionally developed cortical fields that display the highest degree of myelination, thereby reflecting a hierarchy in the susceptibility of diverse cortical areas to the evolution of the AD‐associated cytoskeletal pathology.
“Fatal Attractions” of Proteins: A Comprehensive Hypothetical Mechanism Underlying Alzheimer's Disease and Other Neurodegenerative Disorders
Authors: TROJANOWSKI JOHN Q. , LEE VIRGINIA M.‐Y.
Published: July 2010

Abstract: Abnormal protein‐protein interactions that result in the formation of intracellular and extracellular aggregates of proteinacious fibrils are common neuropathological features of many, albeit diverse, neurodegenerative disorders, such as sporadic and familial Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and prion encephalopathies. Indeed, increasing evidence suggests that abnormal protein‐protein interactions and/or the lesions that result from the aggregation of pathological protein fibrils could play a mechanistic role in the dysfunction and death of neurons or glial cells in neurodegenerative diseases. Here we propose that “fatal attractions” between brain proteins are the key pathological events underlying Alzheimer's disease and a large number of other seemingly diverse neurodegenerative disorders. This hypothesis predicts that the abnormal interaction between normal brain proteins alters their conformation and promotes the assembly of these pathological conformers into filaments that progressively accumulate as intracellular or extracellular fibrous deposits in the central nervous system. Further, the transformation of the normal proteins into pathological conformers is predicted to result in losses of critical functions, and the disease proteins or their progressive accumulation into filamentous aggregates are predicted to acquire neurotoxic properties, all of which culminate in the dysfunction and death of affected brain cells. Thus, the “fatal attractions” hypothesis describes a plausible unifying mechanism that accounts for the onset/progression of Alzheimer's disease and a large number of other seemingly unrelated neurodegenerative disorders characterized neuropathologically by filamentous brain lesions formed by different proteins.
Alzheimer's Disease and Some Speculations about the Evolution of Its Modifiers
Authors: SAPOLSKY ROBERT M. , FINCH CALEB E.
Published: July 2010

Abstract: In this paper we consider the evolution of Alzheimer's‐like neuropathology in the aging primate brain. In particular, we examine the evolutionary pressures that have likely selected for the neuroprotective effects of estrogen and of the apolipoprotein E2 and E3 isoforms. We analyze this in the context of the altricial nature of newborn primates, their long period of dependency on competent maternal care, and the requirement of cognitive intactness for such competency.
A Perspective on Inflammation in Alzheimer's Disease
Authors: ROGERS JOSEPH , SHEN YONG
Published: July 2010

Abstract: Although there have been hundreds of recent papers that document a role for innate inflammatory responses in Alzheimer's disease (AD), several global issues and organizational points are still worth emphasizing. These include etiologic versus pathogenic roles for AD inflammation, the potency of AD inflammation, the sources of AD inflammation, and the highly interactive nature of AD inflammatory responses.
Hearing Where We're Coming From‐Ethically and Professionally
Authors: FOX RICHARD G.
Published: July 2010

Abstract:Anthropologists concerned about the discipline's ability to cope ethically and ethnographically with a globalized world should not dismiss too hastily the methodology‐and the ethics built into it‐that anthropology developed over the last century. This methodology of making “displacing” translations, based on ethnographic experience and a politics of translation, can still provide a workable ethics and a viable labor of ethnography even in the world at present.
HIV, Cytokines and Programmed Cell Death: A Subtle Interplay
Authors: GOUGEON MARIE‐LISE , LEDRU ERIC , NAORA HONAMI , BOCCHINO MARIALUISA , LECOEUR HERVÉ
Published: July 2010

Abstract: HIV infection is marked by the progressive destruction of the CD4 T lymphocyte subset, an essential component of the immune system and a vital source of cytokines required for differentiation of natural killer (NK) and γδ T cells, for maturation of B lymphocytes into plasmocytes, and for differentiation of CD8+ T cells into virus‐specific cytotoxic T lymphocytes. CD4 T lymphocytes are also a source of chemokines which control migration of lymphocytes to the site of infection and which also inhibit HIV entry into CD4‐expressing targets. Continuous production of viral proteins leads to an unbalanced immune activation and to the triggering of apoptotic programs, turning mononuclear cells, including CD4 T cells, CD8 T cells and APC, into effectors of apoptosis, leading to fratricidal destruction of healthy uninfected cells expressing the death receptors. Inappropriate PCD is also responsible for the disappearance of T helper cells primed for type‐1 cytokine synthesis, thus contributing to the lack of survival factors which could prevent spontaneous lymphocyte apoptosis. Under potent anti‐retroviral therapies, a significant decrease in spontaneous, TCR‐ and CD95‐induced lymphocyte apoptosis is observed, concomitant with a partial quantitative and qualitative restoration of the immune system in treated patients. However, owing to the suppressive effect of anti‐retroviral drugs on physiological apoptosis, these therapies are associated with alteration of TNF‐α‐regulated T cell homeostasis, leading to an accumulation in the blood of T cells primed for TNF‐α synthesis, and contributing to the development of a new syndrome associated with these treatments, the lipodystrophy syndrome.
The Complexity of TNF‐Related Apoptosis‐Inducing Ligand
Authors: ABE KARON , KURAKIN ALEXEI , MOHSENI‐MAYBODI MEHRDAD , KAY BRIAN , KHOSRAVI‐FAR ROYA
Published: July 2010

Abstract: One of the major goals of researchers in the field of apoptosis is to understand the molecular mechanisms of the various components of the apoptotic pathways, with the hope to identify targets for novel cancer therapies. The discovery of a TNF‐related, apoptosis‐inducing ligand, TRAIL, that kills transformed cells with great specificity in vitro, has provided the hope that TRAIL may be used to induce cell death in tumor cells without affecting normal tissues. However, TRAIL signaling is very complex and a clear understanding of its function is necessary before it can be used in cancer therapy. Complexity of TRAIL‐induced signaling is apparent from its ubiquitous expression, its ability to interact with five receptors, and its tumor‐selective induction of apoptosis. The signaling events that mediate the tumor selectivity of TRAIL‐induced apoptosis and the biological functions of each of the TRAIL receptors are not well characterized. This review will focus on the complexity of TRAIL and the role of c‐FLIP in mediating TRAIL function.
Evolution of Functions within the p53/p63/p73 Family
Authors: DE LAURENZI VINCENZO , MELINO GERRY
Published: July 2010

Abstract: Even though the tumor suppressor gene p53 is highly important in human cancer, as indicated by the fact that it is mutated in about 50% of cases, up to a few years ago no similar proteins had been identified. Recently, two p53 homologues have been identified, p73 and p63, with high aminoacid identity suggesting similar functions. Indeed, like p53, p73 as well (i) can bind mdmx, mdm2, p300/CAF and adenovirus E4‐ORF6 proteins, (ii) can trigger several promoters including p21, bax, mdm2, gadd45, cyclin G, IGFBP3, 14–3–3σ, (iii) is able to trigger cell death, (iv) is involved in the DNA damage response, although through a different pathway. Here we analyze the data present in the literature in search of diverging pathways among the p53, p63, p73 family. Both p63 and p73 present two significant structural peculiarities: the presence of an extended non‐conserved C‐terminus containing a sterile alpha motive (SAM), typical of developmental proteins, and the presence of number of different splicing isoforms differing in the N‐terminus or in the absence of the transactivation domain (ΔN forms), acting as dominant negative. The mouse knockout of p63 and p73, unlike the ones for p53, shows developmental abnormalities; p63 and p73 are rarely mutated in human cancers; both genes are regulated in different differentiation models. This strongly suggests the involvement of p63 and p73 in development. A picture is emerging showing a gradient of function among p53, p73, p63 ranging from tumor suppression to development.
The Interaction of HSP27 with Daxx Identifies a Potential Regulatory Role of HSP27 in Fas‐Induced Apoptosis
Authors: CHARETTE STEVE J. , LANDRY JACQUES
Published: July 2010

Abstract: The heat shock protein HSP27 protects cells against a wide variety of toxic treatments and blocks apoptosis induced by exposures to anticancer drugs and activation of the death receptor fas. The molecular mechanisms of protection are unknown but appear to be regulated by phosphorylation of HSP27. Two apoptotic pathways can be activated downstream of Fas. The Fas‐adaptor FADD mediates a caspase‐dependent pathway. Fas also activates a caspase‐independent pathway which correlates with fas‐induced translocation of Daxx from the nucleus to the cytoplasm and involves the interaction of Daxx with Fas and Ask1. We found that phosphorylated dimers of HSP27 interact with Daxx, preventing its interaction with Ask1 and Fas and blocking Daxx‐mediated apoptosis. Expression of HSP27 also prevents the translocation of Daxx from the nucleus to the cytoplasm which is induced upon expression of Ask1 or stimulation of Fas. The observations reveal a new level of regulation of the Fas pathway. Whereas the FADD axis can be modulated by expression of FLIP, a natural inhibitor of FADD, our results show that HSP27 can accomplish a similar function for the Daxx axis.
Convection in Slab and Spheroidal Geometries
Authors: PORTER DAVID H. , WOODWARD PAUL R. , JACOBS MICHAEL L.
Published: July 2010

Abstract: Three‐dimensional numerical simulations of compressible turbulent thermally driven convection, in both slab and spheroidal geometries, are reviewed and analyzed in terms of velocity spectra and mixing‐length theory. The same ideal gas model is used in both geometries, and resulting flows are compared. The piecewise‐parabolic method (PPM), with either thermal conductivity or photospheric boundary conditions, is used to solve the fluid equations of motion.

Fluid motions in both geometries exhibit a Kolmogorov‐like k−5/3 range in their velocity spectra. The longest wavelength modes are energetically dominant in both geometries, typically leading to one convection cell dominating the flow. In spheroidal geometry, a dipolar flow dominates the largest scale convective motions. Downflows are intensely turbulent and up drafts are relatively laminar in both geometries. In slab geometry, correlations between temperature and velocity fluctuations, which lead to the enthalpy flux, are fairly independent of depth. In spheroidal geometry this same correlation increases linearly with radius over the inner 70 percent by radius, in which the local pressure scale heights are a sizable fraction of the radius. The effects from the impenetrable boundary conditions in the slab geometry models are confused with the effects from non‐local convection. In spheroidal geometry nonlocal effects, due to coherent plumes, are seen as far as several pressure scale heights from the lower boundary and are clearly distinguishable from boundary effects.
Plumes in Stellar Convection Zones
Authors: ZAHN J.‐P.
Published: July 2010

Abstract: All numerical simulations of compressible convection reveal the presence of strong downward directed flows. Thanks to helioseismology, such plumes have now also been detected at the top of the solar convection zone, on supergranular scales. Their properties may be crudely described by adopting Taylor's turbulent entrainment hypothesis, whose validity is well established under various conditions. Using this model, one finds that the strong density stratification does not prevent the plumes from traversing the whole convection zone, and that they carry upward a net energy flux. They penetrate to some extent in the adjacent stable region, where they establish an almost adiabatic stratification when there is little radiative diffusion. These plumes have a strong impact on the dynamics of stellar convection zones, and they probably play a key role in the dynamo mechanism.
Fingering Convection: the Interplay of Small and Large Scales
Authors: PAPARELLA FRANCESCO
Published: July 2010

Abstract: Direct numerical simulations of two‐dimensional fingering convection are presented. They show the growth of a finger‐zone from a region of high gradients of temperature and salinity set in the initial conditions and the appearance of large‐scale convective cells in the homogeneous layers above and below it. The interaction between the finger‐zone and the convection is described and the vertical fluxes are compared with a theoretical scaling law.
Human Limits for Hypoxia: The Physiological Challenge of Climbing Mt. Everest
Authors: WEST JOHN B.
Published: July 2010

Abstract: Climbing Mt. Everest without supplementary oxygen presents a fascinating physiological challenge because, at the summit, humans are very near the limit of tolerance to hypoxia. It was not until 1978 that the feat was accomplished, and this was after many unsuccessful attempts over a period of more than 50 years, and several physiological studies that suggested that it would be impossible. An analysis shows that the critical factors for reaching the summit are the enormous hyperventilation which is necessary to maintain the alveolar Po2 at viable levels, the fact that the barometric pressure is substantially higher than predicted by the Standard Atmosphere, and the severe respiratory alkalosis that assists loading of oxygen by the blood in the lung. Even so the maximal oxygen consumption on the summit is extremely low with the result that climbers are critically vulnerable to unexpected setbacks such as changes in the weather.
Post‐Transcriptional Regulation of Lung Antioxidant Enzyme Gene Expression
Authors: CLERCH LINDA BIADASZ
Published: July 2010

Abstract:It is an honor, and indeed fitting, to have a chapter on pulmonary oxygen toxicity included in a Festschrift for Dan Gilbert, whose contributions to the free radical theory of oxygen toxicity have been a catalyst to the last half‐century of investigation in this field. There is cellular damage that results in pulmonary edema and even death if the increase in reactive oxygen species produced in the lung during exposure to hyperoxia is not counterbalanced by an increase in the cell's antioxidant defense systems. In this chapter experimental evidence will substantiate the importance of post‐transcriptional regulation of antioxidant enzyme gene expression in animal models of pulmonary oxygen toxicity and tolerance to hyperoxia with special emphasis given to the role of manganese superoxide dismutase (MnSOD) synthesis, specific activity, and RNA half‐life and to a proposed function of a MnSOD RNA‐binding protein as a positive regulator in the control of translational efficiency.
Reflections on the Role of the Thiol Group in Biology
Authors: HAUGAARD NIELS
Published: July 2010

Abstract: This essay is concerned with the role of the thiol or sulfhydrvl group in cellular function and metabolism and with the important investigations over many years that have led us to a better understanding of the importance of this molecular moiety that plays such a vital role in biology. The tools for measuring the SH group and for inhibiting or regenerating it will be discussed as will its essential role in the actions of many enzymes. The importance of the thiol group in glycolysis and in energy production by mitochondria will be emphasized. Of special interest at present is the fact that certain low molecular weight SH‐containing substances can mimic some of the actions of insulin and may become of benefit in the treatment of diabetes mellitus. Finally, the toxic effects of oxygen on metabolism and function will be discussed with particular reference to the possibility that oxidation of thiol groups may play a role in the manifestations of oxygen toxicity.
Enzyme‐Like Activity of Glycated Cross‐Linked Proteins in Free Radical Generation
Authors: YIM MOON B. , KANG SA‐OUK , CHOCK P. BOON
Published: July 2010

Abstract: The structure and property of cross‐linked amino acids and proteins produced by a three‐carbon α‐dicarbonyl methylglyoxal in glycation reaction were investigated. Our results showed that these reactions generated yellow fluorescent products and several free radical species. From the reaction with alanine, three types of free radicals were identified by EPR spectroscopy: 1) the cross‐linked radical cation, methylglyoxal diaklylimine cation radical; 2) the methylglyoxal radical anion as the counterion; 3) the superoxide radical anion produced only in the presence of oxygen. Glycation of bovine serum albumin by methylglyoxal also generated the protein‐bound, cross‐linked free radical, probably the cation radical of the cross‐linked Schiff base as observed with alanine. The glycated protein reduced ferricytochrome c to ferrocytochrome c in the absence of oxygen or added metal ions. This reduction of cytochrome c was accompanied by a large increase in the amplitude of the electron paramagnetic resonance signal originated from the protein‐bound free radical. In addition, the glycated protein catalyzed the oxidation of ascorbate in the presence of oxygen while the protein‐free radical signal disappeared. These results indicate that glycation of protein generates active centers for catalyzing one‐electron oxidation‐reduction reactions. This active center, which exhibits enzyme‐like character, was suggested to be the cross‐linked Schiff base/the cross‐linked Schiff base radical cation of the protein. It mimics the characteristics of metal‐catalyzed oxidation system. These results together indicate that glycated proteins accumulated in vivo provide stable active‐sites for catalyzing the formation of free radicals.
Molecular Markers of Oxidative Stress Vulnerability
Authors: HANBAUER INGEBORG , SCORTEGAGNA MARZIA
Published: July 2010

Abstract:In astrocyte primary cultures of trisomy 16 mice, an animal model for Down's syndrome, protein oxidation was 50% higher than in diploid littermates. Exposure to 10 μM H2O2or 50 μM kainic acid incremented protein oxidation in trisomic but not in diploid cultures. Studies on stress response genes showed that metallothionein (MT) level was 2–3 times higher in trisomy 16 than in diploid cultures. Kainic acid or H2O2exposure increased the MT protein level in diploid cultures but failed to increase it in trisomy 16 mouse beyond its elevated basal level. The reduced responsiveness of MT to simulated oxidative stress may result in insufficient removal of ROS, which could partially explain the further increase of protein oxidation in trisomy 16 cultures. In contrast, Pb exposure increased MT in trisomy 16 and diploid primary cultures to a similar extent. The similar metal responsiveness of MT in both phenotypes indicated that MT in trisomic glial cultures was not yet maximally stimulated. The flawed redox sensitivity in trisomy 16 mouse suggests possible alterations in the binding activity of ROS‐sensitive transcription factors on the MT promoter.
Mechanisms of Cell Death Governed by the Balance between Nitrosative and Oxidative Stress
Authors: ESPEY MICHAEL GRAHAM , MIRANDA KATRINA M. , FEELISCH MARTIN , FUKUTO JON , GRISHAM MATHEW B. , VITEK MICHAEL P. , WINK DAVID A.
Published: July 2010

Abstract:Many cellular functions in physiology are regulated by the direct interaction of NO with target biomolecules. In many pathophysiologic and toxicologic mechanisms, NO first reacts with oxygen, superoxide or other nitrogen oxides to subsequently elicit indirect effects. The balance between nitrosative stress and oxidative stress within a specific biological compartment can determine whether the presence of NO will be ultimately deleterious or beneficial. Nitrosative stress can be defined primarily through reactions mediated by N2O3, a reactive nitrogen oxide species generated by high fluxes of NO in an aerobic environment. In contrast, oxidative stress is mediated primarily by superoxide and peroxides. In addition to reactive oxygen species, several reactive nitrogen oxide species such as peroxynitrite, nitroxyl, and nitrogen dioxide can also impose oxidative stress to a cell. We here describe how the mechanisms of cell death are interwoven in the balance between the different chemical intermediates involved in nitrosative and oxidative stress.
Antioxidant Status and Human Health: Use of Cyclic Voltammetry for the Evaluation of the Antioxidant Capacity of Plasma and of Edible Plants
Authors: CHEVION SHLOMIT , CHEVION MORDECHAI
Published: July 2010

Abstract: The low molecular weight antioxidants (LMWA) play a major role in protecting biological systems against reactive oxygen‐derived species (ROS), and reflect the antioxidant capacity of the system. The cyclic voltammetry (CV) has been conveniently used and validated for the quantitation of the antioxidant capacity of the LMWA of blood plasma, tissue homogenates, and plant extracts. The CV tracing provides the biological oxidation potential (E and E1/2 which relate to the nature of the molecule(s)), the intensity of the anodic current wave (Ia), and its area S (both relate to the concentration of the molecule(s)). The components of the first anodic wave of plasma were identified by comparison with HPLC‐electrochemical detection. CV together with another plasma parameter R, which reflects the level of oxidized ascorbate, were used for the evaluation of the antioxidant status and the oxidative stress in healthy subjects and in chronic (diabetes mellitus) and acute patients (subjected to total body irradiation prior to bone marrow transplantation).These methodologies could be widely employed for rapid evaluation of subjects, in health and disease, for monitoring of their response to treatment and nutritional supplementation, and for screening of specific populations.
Free Radical Intermediates in Sonodynamic Therapy
Authors: MIŠÍK VLADIMÍR , RIESZ PETER
Published: July 2010

Abstract: Current understanding of the mechanism of sonodynamic action (i.e. the ultrasound‐dependent enhancement of the cytotoxic action of certain drugs ‐ sonosensitizers) with potential applications for cancer therapy is presented. The experimental evidence suggests that sonosensitization is due to the chemical activation of sonosensitizers inside or in the close vicinity of hot collapsing cavitation bubbles to form sensitizer‐derived free radicals either by direct pyrolysis or due to reactions with ·H and ·OH radicals, formed by pyrolysis of water. These free radicals (mostly carbon‐centered) react with oxygen to form peroxyl and alkoxyl radicals. Unlike ·OH and ·H, which are also formed by pyrolysis inside cavitation bubbles, the reactivity of alkoxyl and peroxyl radicals with organic components dissolved in biological media is lower and hence have higher probability of reaching critical cellular sites. Sonodynamic therapy appears to be a promising modality for cancer treatment since ultrasound can penetrate deep within the tissue and can be focused in a small region of tumor to chemically activate relatively non‐toxic molecules (e.g. porphyrins) thus minimizing undesirable side effects.
Glucose Deprivation‐Induced Oxidative Stress in Human Tumor Cells: A Fundamental Defect in Metabolism?
Authors: SPITZ DOUGLAS R. , SIM JULIA E. , RIDNOUR LISA A. , GALOFORO SANDRA S. , LEE YONG J.
Published: July 2010

Abstract: Recently, glucose deprivation‐induced oxidative stress has been shown to cause cytotoxicity, activation of signal transduction (i.e., ERK1, ERK2, JNK, and Lyn kinase), and increased expression of genes associated with malignancy (i.e., bFGF and c‐Myc) in MCF‐7/ADR human breast cancer cells. These results have led to the proposal that intracellular oxidation/reduction reactions involving hydroperoxides and thiols may provide a mechanistic link between metabolism, signal transduction, and gene expression in these human tumor cells. The current study shows that several other transformed human cell types appear to be more susceptible to glucose deprivation‐induced cytotoxicity and oxidative stress than untransformed human cell types. In a matched pair of normal and SV40‐transformed human fibroblasts the cytotoxic process is shown to be dependent upon ambient O2 concentration. A theoretical model to explain the results is presented and implications to unifying modern theories of cancer are discussed.
Cytomegalovirus Gene Regulation by Reactive Oxygen Species: Agents in Atherosclerosis
Authors: SPEIR EDITH
Published: July 2010

Abstract: Oxidative stress is implicated in the pathogenesis of atherosclerosis, and of viral infections caused by sendai virus, influenza and HIV. Vascular oxidative stress is due to inflammatory and immune responses of vascular cells, and to reperfusion after recanalization of blocked arteries. Because human cytomegalovirus (CMV) may contribute to atherogenesis by several mechanisms, and coronary artery smooth nuscle cells (SMC) are permissive for the virus, we examined CMV interactions with SMC. Infection causes generation of intracellular reactive oxygen species (ROS) which activate NF‐κB, a cellular transcription factor. NF‐κB mediates expression of the CMV promoter and of genes involved in the immune and inflammatory responses. Antioxidants or aspirin inhibit ROS, NF‐κB and CMV.
Progesterone Is an Autocrine/Paracrine Regulator of Human Granulosa Cell Survival in Vitro
Authors: MAKRIGIANNAKIS A. , COUKOS G. , CHRISTOFIDOU‐SOLOMIDOU M. , MONTAS S. , COUTIFARIS C.
Published: July 2010

Abstract: Ovarian follicles are composed of granulosa cells (GC), which undergo apoptosis within 24 hours of culture in serum‐free medium. The present study was designed to assess the role of progesterone in regulating human GC survival. Human GC were isolated from follicular aspirates of women undergoing in vitro fertilization. GC were then cultured for 24 hours in serum‐free media supplemented with progesterone and/or the progesterone antagonist RU486 and dexamethasone. Cells were then fixed and assessed for apoptosis by in situ end labeling of DNA fragments, cell cycle analysis of DNA content, and electron microscopy. When compared with controls, progesterone reduced and RU486 increased the percentage of apoptotic GC (p <0.05), whereas dexamethasone had no effect. In addition, RU486 inhibited the protective effect of progesterone on GC survival (p <0.05). Taken together, these data indicate that progesterone inhibits human GC apoptosis, and this effect is mediated through the progesterone receptor.
Molecular Defects Causing Ovarian Dysfunction
Authors: KALANTARIDOU SOPHIA N. , CHROUSOS GEORGE P.
Published: July 2010

Abstract: The functions of the hypothalamic‐pituitary‐ovarian and ‐adrenal axes are intertwined, and molecular defects in either axis may cause ovarian dysfunction. Advances in molecular genetics have allowed new insights into the pathophysiology of ovarian disorders. Specific gene mutations causing delayed puberty and/or ovarian failure, and heterosexual or isosexual precocious puberty have recently been described. The molecular insights gained into ovarian dysfunction have already led to rational therapies for some of these conditions.