bluuebunny/crossref_metadata_2025 huggingface dataset:
The Fat Mouse: A Powerful Genetic Model to Study Hemostatic Gene Expression in Obesity/NIDDM
Authors: LOSKUTOFF DAVID J. , FUJISAWA KAZUHIKO , SAMAD FAHUMIYA
Published: July 2010

Abstract:In this chapter, we summarize our studies on plasminogen activator inhibitor 1 (PAI‐1), tissue factor, and transforming growth factor beta (TGF‐β) expression in obesity, using genetically obese mice as a model. These studies emphasize the key role played by the adipocyte, a cell whose numbers, size, and metabolic activity are grossly altered in obesity/NIDDM. They also implicate multiple cytokines, hormones, and growth factors in the abnormal expression of these and perhaps other hemostatic genes by adipocytes in obesity/NIDDM. These studies demonstrate that tumor necrosis factor alpha (TNF‐α) plays a central role in the expression of hemostatic genes in this disorder.
Inducible Expression of LOX‐1, a Novel Receptor for Oxidized LDL, in Macrophages and Vascular Smooth Muscle Cells
Authors: KUME NORIAKI , MORIWAKI HIDEAKI , KATAOKA HIROHARU , MINAMI MANABU , MURASE TAKATOSHI , SAWAMURA TATSUYA , MASAKI TOMOH , KITA TORU
Published: July 2010

Abstract: Macrophages appear to take up oxidized low density lipoprotein (Ox‐LDL) by multiple receptor‐mediated pathways. This study, therefore, has been performed to determine if LOX‐1, a novel receptor for Ox‐LDL, which was identified in vascular endothelial cells, is also expressed in macrophages. Expression of LOX‐1 can be induced after macrophage‐like differentiation in human peripheral blood monocytes as well as THP‐1 cells. Furthermore, expression of LOX‐1 in macrophages is also upregulated by an inflammatory cytokine TNF‐α, which was shown to be present in atherosclerotic arterial wall. Expression of this novel receptor LOX‐1 may play an important role in Ox‐LDL uptake and subsequent foam cell formation in macrophages.
In VivoDetermination of Body Composition of Rats Using Magnetic Resonance Imaging
Authors: TANG HAIYING , VASSELLI JOSEPH , WU ED , GALLAGHER DYMPNA
Published: July 2010

Abstract:Magnetic resonance imaging (MRI) has potential as an instrument to measure body composition because it can discriminate various soft tissuesin vivo. These soft tissues include adipose tissue, muscle, organs, and brain. We report on preliminary studies using a 4.2‐tesla MRI for measuring body composition in the mouse and rat. We employed image segmentation methods that include an image correction method, a necessary requirement when the images are taken in the presence of nonuniform radio‐frequency (RF) coil response. The software for 3‐D data segmentation, quantification, correction, image manipulation, and visualization has been developed as a research tool. This method currently is being validated.
Assessing Body Composition and Changes in Body Composition: Another Look at Dual‐Energy X‐ray Absorptiometry
Authors: LOHMAN TIMOTHY G. , HARRIS MARGARET , TEIXEIRA PEDRO J. , WEISS LAUREN
Published: July 2010

Abstract: Dual‐energy X‐ray absorptiometry (DXA) is selected with increasing frequency as a method for both assessing body composition and measuring the changes in body composition. Issues have been raised about hydration, software version, hardware (fan beam vs. pencil beam), and the subject population in relation to the validity of DXA‐derived estimates of body composition. This paper reviews validation studies of DXA to assess the impact of recent developments in its technology. Studies by Prior et al., 1 Kohrt et al., 2 Salamone et al., 3 Going et al., 4 and Pietrobelli et al.5 demonstrate the effectiveness of DXA estimates of changes in body composition. By contrast, Clasey et al., 6 Nelson et al., 7 and Friedl et al.8 found limitations in DXA estimates of body composition and its changes. These contradictory conclusions were explored for threats to internal validity in each research study. From this analysis, two validation guidelines are recommended for use when evaluating estimates of body composition. When multicomponent models are used, it is essential that estimates of body water as a fraction of fat‐free mass fall in the expected range (71 to 75%) and have a relatively small standard deviation (2 to 3%). For measuring changes in body composition, DXA estimates of total body mass must accurately reflect both baseline and posttreatment scale body weight estimates. Failure to meet these guidelines threatens the internal validity of the study and raises the likelihood of methodological discrepancies. Applying these criteria to DXA studies of body composition under review accounts for much of the contradictory conclusions among investigations.
Comparisons between Hologic QDR 1000W, QDR 4500A, and Lunar Expert Dual‐Energy X‐ray Absorptiometry Scanners Used for Measuring Total Body Bone and Soft Tissue
Authors: TOTHILL P. , HANNAN W. J.
Published: July 2010

Abstract: Measurements of total‐body bone and soft tissue were compared between two fan‐beam dual‐energy X‐ray absorptiometry (DXA) scanners, a Hologic QDR 4500A, a Lunar Expert, and a pencil‐beam Hologic QDR 1000W. Phantom studies showed that mass measurements were not compromised by magnification effects, but that the height of a bone within the body affected the measured bone mineral content (BMC) and, to a lesser extent, the bone mineral density (BMD). There were differences in calibration for fat proportion between the three instruments. Comparisons on volunteers demonstrated very high correlations of bone and soft tissue measurements, but regression coefficients differed from unity, and intercepts were significant. With all three scanners, wrapping lard around the limbs of a volunteer, to simulate weight change, changed the apparent BMC and BMD.
Comparison of Air‐Displacement Plethysmography, Hydrodensitometry, and Dual X‐ray Absorptiometry for Assessing Body Composition of Children 10 to 18 Years of Age
Authors: LOCKNER D. W. , HEYWARD V. H. , BAUMGARTNER R. N. , JENKINS K. A.
Published: July 2010

Abstract: Body density (Db) of 54 boys and girls 10–18 years of age (13.9 ± 2.4 years) was measured in an air‐displacement plethysmograph, the BOD POD®, and compared to Db determined by hydrodensitometry (HW). Both Db values were converted to percent body fat (%BF) using a two‐component model conversion formula and compared to %BF determined by dual energy X‐ray absorptiometry (DXA). Body density estimated from the BOD POD (1.04657 ± 0.01825 g/cc) was significantly higher than that estimated from HW (1.04032 ± 0.01872 g/cc). The relative body fat calculated from the BOD POD (23.12 ± 8.39 %BF) was highly correlated but, on average, 2.9% BF lower than %BF DXA. Average %BF estimates from HW and DXA were not significantly different. Despite consistently underestimating the %BF of children, the strong relationship between DXA and the BOD POD suggests that further investigation may improve the accuracy of the BOD POD for assessing body composition in children.
In Vivo Elemental Partition Analysis Using Fast Neutrons: A Tool for Testing the Efficacy of New Clinical Interventions
Authors: KEHAYIAS JOSEPH J. , VALTUEÑA SILVIA , WAITEKUS ANATHEA B. , SHEAHAN CHARLES A. , O'NEILL MEGAN
Published: July 2010

Abstract: The nutritional status of patients can be evaluated by monitoring changes in body composition, including depletion of protein and muscle; distribution of adipose tissue; and changes in hydration status, and bone or cell mass. Fast neutron activation (for N and P) and neutron inelastic scattering (for C and O) are used to assess in vivo elements characteristic of specific body compartments. Nonbone phosphorus for muscle is measured by the 31P(n,α)28Al reaction, and nitrogen for protein via the (n,2n) fast neutron reaction. The carbon‐to‐oxygen (C/O) ratio is used to measure distribution of fat and lean tissue in the body and to monitor small changes in lean mass and its quality. In addition to evaluating the efficacy of new treatments, the method is used to study the mechanisms of depletion of lean tissue with aging.
Modeling Leg Sections by Bioelectrical Impedance Analysis, Dual‐Energy X‐ray Absorptiometry, and Anthropometry: Assessing Segmental Muscle Volume Using Magnetic Resonance Imaging as a Reference
Authors: ELIA M. , FULLER N. J. , HARDINGHAM C. R. , GRAVES M. , SCREATON N. , DIXON A. K. , WARD L. C.
Published: July 2010

Abstract: This study aimed to assess the value of different DXA and BIA models for predicting muscle volume in mid‐thigh segments obtained by MRI. Three DXA models were used: in model A, muscle was taken to be equivalent to fat‐free soft tissue; in model B the thigh segment was divided into its constituent tissues using fixed assumptions about tissue composition; in model C the assumptions were similar to model B, but with variable distribution of fat and fat‐free soft tissue, depending on body mass index. The two BIA models (both parallel tissue resistance models) involved impedance measurements at 50 kHz, and assumptions about either the specific resistivities of all the constituent tissues (model A), or resistivities of only adipose tissue and muscle (model B). Anthropometric estimates (thigh circumference and skinfold thickness) assumed that both limb and muscle circumference were circular. Compared to MRI estimates of muscle mass, those obtained by DXA model A (fat‐free soft tissue) were not as good as those obtained using models B and C, although the standard deviations of the differences were similar with all three models. The BIA models were superior to the anthropometric estimates of muscle volume (relative to MRI) with respect to bias, but the standard deviations of the differences were large for both. The intraobserver repeatabilities for muscle volume were < 0.5% for MRI, <1% for DXA, 1.8% for BIA, and 1.7% for anthropometry (interobserver value for BIA was 3.8% and for anthropometry 3.5%). The study suggests that DXA modeling provides a promising approach for assessing muscle mass in thigh segments, and suggests the potential value of parallel BIA models for groups of individuals but not for individual subjects, possibly because muscle resistivity is influenced not only by its composition but also by the direction of current flow in muscle.
Cellular‐Level Body Composition Model: A New Approach to Studying Fat‐free Mass Hydration
Authors: WANG ZIMIAN , DEURENBERG PAUL , HEYMSFIELD STEVEN B.
Published: July 2010

Abstract: Fat‐free mass hydration, the ratio of total body water (TBW) to fat‐free mass (FFM), is stable at ∼0.73 in mammals, and this constancy provides a means of estimating total body fat in vivo. As there is no mechanistic theory to explain the magnitude and variability in TBW/FFM, the present investigation describes a cellular‐level model indicating that FFM hydration is determined by four factors: body cell mass hydration, extracellular fluid hydration, ratio of extracellular solids to TBW, and ratio of extracellular water to intracellular water. According to the model, TBW/FFM can be predicted for adult humans as a mean of 0.73, and a variation range 0.69–0.77. The suggested modeling approach provides a conceptual framework for TBW‐fat estimation method and identifies important areas that remain to be studied.
Epidemiological Applications of Body Composition: The Effects and Adjustment of Measurement Errors
Authors: GUO SHUMEI S. , SIERVOGEL ROGER M. , CHUMLEA WM. CAMERON
Published: July 2010

Abstract: The amounts of fat and fat‐free mass (FFM) are functions of life‐style, diseases, increasing age, and genetics. The levels of these body compartments are established risk factors for cardiovascular and related chronic diseases. Body composition can be assessed by several methods. The measurements for each method have inherent variations, which can be due to error in the measurement or biological variation. This presentation focuses on the reliability and precision of body composition measurements and the impact of these errors on epidemiological and population‐based studies. The effects of these errors in applying body composition to epidemiological studies include the following: (1) the association of cardiovascular risk factors with body composition in cross‐sectional studies; (2) changes in body composition in longitudinal or intervention studies; (3) association of changes in body composition with cardiovascular risk factors; and (4) comparison of levels of body composition among subgroups in cross‐sectional studies and in intervention studies.
Anthropometry in Body Composition: An Overview
Authors: WANG J. , THORNTON J. C. , KOLESNIK S. , PIERSON R. N.
Published: July 2010

Abstract: Anthropometry is a simple reliable method for quantifying body size and proportions by measuring body length, width, circumference (C), and skinfold thickness (SF). More than 19 sites for SF, 17 for C, 11 for width, and 9 for length have been included in equations to predict body fat percent with a standard error of estimate (SEE) range of ±3% to ±11% of the mean of the criterion measurement. Recent studies indicate that not only total body fat, but also regional fat and skeletal muscle, can be predicted from anthropometrics. Our Rosetta database supports the thesis that sex, age, ethnicity, and site influence anthropometric predictions; the prediction reliabilities are consistently higher for Whites than for other ethnic groups, and also by axial than by peripheral sites (biceps and calf). The reliability of anthropometrics depends on standardizing the caliper and site of measurement, and upon the measuring skill of the anthropometrist. A reproducibility of ± 2% for C and ± 10% for SF measurements usually is required to certify the anthropometrist.
Body Fat Content Influences the Body Composition Response to Nutrition and Exercise
Authors: FORBES GILBERT B.
Published: July 2010

Abstract: In most situations involving a significant change in body weight, both fat‐free body mass (FFM) and body fat participate, but the relative contribution of FFM and fat to the total weight change is influenced by the initial body fat content. Overfeeding: In experiments of at least 3‐weeks' duration, the weight gain of thin people comprises 60–70% lean tissues, whereas in the obese it is 30–40%. Underfeeding: In humans, there is an inverse curvilinear relationship between initial body fat content and the proportion of weight loss consisting of lean tissue. The same trend holds for animals and birds, including loss during hibernation. Another factor is the magnitude of the energy deficit: as energy intake is reduced, lean tissue makes up an increasing fraction of the total weight loss. Exercise: If individuals lose much weight with exercise, the result is usually some loss of lean tissue as well as fat, and once again the proportion of lean loss to total weight loss is greater in thin people than in those who have larger body fat burdens. Members of twin pairs often differ in weight. In thin individuals, lean accounts for about half of the intrapair weight difference, whereas in the obese it accounts for only one quarter. Body fat content must be taken into account in evaluating body composition changes induced by nutrition and exercise.
Value of Total Body Potassium in Assessing the Nutritional Status of Children with End‐Stage Liver Disease
Authors: TROCKI ORRAWIN , WOTTON MARITA J. , CLEGHORN GEOFF J. , SHEPHERD ROSS W.
Published: July 2010

Abstract: Malnutrition is a common problem in children with end‐stage liver disease (ESLD), and accurate assessment of nutritional status is essential in managing these children. In a retrospective study, we compared nutritional assessment by anthropometry with that by body composition. We analyzed all consecutive measurements of total body potassium (TBK, n= 186) of children less than 3 years old with ESLD awaiting transplantation found in our database. The TBK values obtained by whole body counting of 40K were compared with reference TBK values of healthy children. The prevalence of malnutrition, as assessed by weight (weight Z score <−2) was 28%, which was significantly lower (chi‐square test, p < 0.0001) than the prevalence of malnutrition (76%) assessed by TBK (<90% of expected TBK for age). These results demonstrated that body weight underestimated the nutritional deficit and stressed the importance of measuring body composition as part of assessing nutritional status of children with ESLD.
Smaller Organ Tissue Mass in the Elderly Fails to Explain Lower Resting Metabolic Rate
Authors: GALLAGHER DYMPNA , ALLEN AARON , WANG ZIMIAN , HEYMSFIELD STEVEN B. , KRASNOW NORMAN
Published: July 2010

Abstract: We previously reported our in vivo prediction of whole body resting energy expenditure (REE) using magnetic resonance imaging and echocardiography‐derived organ volumes combined with published organ tissue metabolic rates.1 The models, developed in young healthy persons from predicted and measured variables, were highly correlated (e.g., calculated vs. measured REE, r= 0.92, p < 0.001), with no significant differences (p= NS) between them. This study employed the same approach to determine whether possible age‐related decreases in organ tissue mass may account for the lower REE commonly reported in elderly persons. Measurements of REE (REEm) were acquired by indirect calorimetry. Calculated REE (REEc) models were developed from measured tissues and organs, and energy flux rates were assigned for each of the seven tissue/organ components, as reported by Elia.2 Older men (n= 6) and women (n= 7) had significantly lower REEm compared to REEc (p= 0.001). The magnitude of the differences were 13% and 9.5%, respectively, for men and women. These preliminary data suggest that factors other than organ atrophy may contribute to the lower metabolic rate of older persons. Further studies are required to investigate whether there is a reduction in the oxidative capacity of individual organs and tissues.
Reexamining the Sarcopenia Hypothesis: Muscle Mass versus Muscle Strength
Authors: VISSER M. , NEWMAN A. B. , NEVITT M. C. , KRITCHEVSKY S. B. , STAMM E. B. , GOODPASTER B. H. , HARRIS T. B. ,   FOR THE HEALTH, AGING, AND BODY COMPOSITION STUDY RESEARCH GROUP
Published: July 2010

Abstract:The association of muscle mass and muscle strength with lower‐extremity performance, as measured by timed repeated chair stands, was investigated using preliminary data from 3,075 Black and White participants (70–79 years old) in the Health, Aging, and Body Composition Study. Leg muscle mass (LM) was measured by dual‐energy X‐ray absorptiometry (Hologic QDR 4500). The maximal isokinetic torque of the leg extensors (LS) was measured at 60°/s using a Kin‐Com isokinetic dynamometer. Men were stronger, had greater LM, and better performance than women. As expected, low LS was associated with poorer performance after adjusting for race, study site, and body fat. Low LM was associated with poorer performance in men and women, with a potential threshold effect in women only. When LS and LM were modeled simultaneously, only LS remained independently associated with performance. In conclusion, muscle strength, but not muscle mass, is independently associated with lower‐extremity performance.
Body Water Spaces and Cellular Hydration during Healthy Aging
Authors: RITZ P. ,   INVESTIGATORS
Published: July 2010

Abstract: Age‐related changes in the proportions of intracellular or extracellular water to total body water and in the ratio of total body water to fat‐free mass are debatable. These are important issues both for medical reasons (dehydration is a threat in the diseased elderly) and for methodological reasons (most techniques for assessing of body composition assume constant hydration of the fat‐free mass). This study compared hydration in young and elderly (60 ears) people. In the first part of the study, we analyzed the literature and computed the ratio of total body water over fat‐free mass, Hf. Eligible studies involved independent measurements of fat‐free mass and total body water. Hf did not appear to change with age. The second part of this study computed Hf in 103 individuals studied in our laboratory. The mean values were not different in young (73.2 ± 2.4%) and elderly people (73.4 ± 2.4%). At all ages, the proportion of intracellular or extracellular water (as measured by bromide dilution) to total body water (as measured by oxygen 18 dilution) was similar. The same finding holds for the proportion of intracellular water to fat‐free mass. We conclude that hydration of fat‐free mass and cellular hydration are not affected in healthy aging.
Relative Overhydration of Fat‐free Mass in Postobese versus Never‐Obese Subjects
Authors: LEONE PATRICIA A. , GALLAGHER DYMPNA , WANG JACK , HEYMSFIELD STEVEN B.
Published: July 2010

Abstract: Obese subjects who undergo gastrointestinal surgery for weight reduction have relatively greater loss of body cell mass (BCM) than of extracellular fluid. Although the mechanism is uncertain, an implication is that weight‐reduced, surgically treated obese subjects are relatively overhydrated. The present investigation explored whether diet‐treated postobese (PO) subjects also are relatively overhydrated. Ten PO participants were recruited over a two‐year period and matched to never‐obese (NO) people by age (± 4 years), weight (± 3 kg), height (± 5 cm), race, and gender. PO participants had lost ≥ 18.5 kg and had maintained this loss for 2–16 years. Body density (Db), total body water (TBW), and bone mineral content (BMC) were measured by hydrodensitometry, tritium dilution, and dual‐energy X‐ray absorptiometry, respectively. Fat and fat‐free mass (FFM) were derived using a four‐compartment model. BCM was calculated from total body potassium (TBK) measured with a whole body counter. The results indicate that PO subjects were relatively overhydrated and had reduced BCM compared to NO subjects (p < 0.05). These observations are important for interpreting body weight, body composition, and metabolic data of obese subjects who lost weight and maintained their weight loss over the long term.
Group IV Cytosolic Phospholipase A2 Activation by Diacylglycerol Pyrophosphate in Murine P388D1 Macrophages
Authors: BALSINDE JESÚS , BALBOA MARÍA A. , DENNIS EDWARD A.
Published: July 2010

Abstract: Diacylglycerol pyrophosphate (DGPP) is a novel phospholipid identified in yeast, bacteria, and plants, but not yet in mammalian cells. Given its structural resemblance to other phospholipid‐activating molecules, such as lysophosphatidate, phosphatidate, and diacylglycerol, it was questioned whether DGPP was capable of activating macrophages to release arachidonic acid (AA) metabolites such as the prostaglandins. It has been found that DGPP is able to potently stimulate prostaglandin production in the murine cell line P388D1 by a mechanism that involves activation of the cytosolic Group IV phospholipase A2 (cPLA2). Our results demonstrate that DGPP possesses macrophage‐activating‐factor properties and suggest a role for this novel compound in the inflammatory response.
Sphingosine‐1‐Phosphate Signaling via the EDG‐1 Family of G‐Protein‐Coupled Receptors
Authors: HLA TIMOTHY , LEE MENQ‐JER , ANCELLIN NICOLAS , THANGADA SHOBHA , LIU CATHERINE H. , KLUK MICHAEL , CHAE SUNG‐SUK , WU MING‐TAO
Published: July 2010

Abstract: The bioactive lipid sphingosine‐1‐phosphate (SPP) is abundantly formed and released during the activation of platelets by thrombotic stimuli. Once exported, SPP interacts with the G‐protein‐coupled receptors (GPCR) of the EDG‐1 family. SPP binds to EDG‐1 with the dissociation constant of ∼8 nM and induces signal transduction events such as mitogen‐activated protein kinase (MAP kinase) activation, decrease of cAMP levels, remodeling of the actin cytoskeleton, among others. EDG‐1 is a prototypical member of a large family of GPCRs that interact with glycero‐ and sphingolysolipid phosphates, namely, SPP and lysophosphatidic acid (LPA). Three other GPCRs, trivially termed EDG‐3, EDG‐5, and EDG‐8, are also high‐affinity receptors for SPP. The four SPP receptor subtypes regulate different intracellular signal transduction pathways. In vascular endothelial cells, cooperative signaling between EDG‐1 and EDG‐3 subtypes of SPP receptors results in adherens junction assembly, cell survival, morphogenesis into capillary‐like networks, and angiogenesis. SPP acts distinctly, albeit cooperatively, with polypeptide angiogenic factors, resulting in the formation of mature neovessels. Thus SPP signaling as an extracellular mediator via the EDG‐1 family of GPCRs may be a heretofore unrecognized mechanism for the regulation of angiogenesis and vascular endothelial cell function.
Lysophosphatidic Acid Induction of Neuronal Apoptosis and Necrosis
Authors: STEINER MARION R. , HOLTSBERG FREDERICK W. , KELLER JEFFREY N. , MATTSON MARK P. , STEINER SHELDON M.
Published: July 2010

Abstract:Lysophosphatidic acid (LPA) elicits a unique response in primary hippocampal neurons and sympathetic neuron‐like cells, PC12 cells differentiated with nerve growth factor; LPA is cytotoxic. Treatment of rat hippocampal neurons with 50 μM LPA resulted in necrosis, as determined morphologically and by release of lactate dehydrogenase. Lower concentrations of LPA, 0.1, and 1 μM, induced neuronal apoptosis, as assessed by chromatin condensation, annexin V binding, TUNEL staining, and the caspase sensitivity of these events. In addition, 10 and 25 μM LPA induced apoptosis of PC12 cells. In order to define intracellular events associated with this neuronal apoptosis, protective agents were identified. Neurons and PC12 cells were protected against LPA‐induced apoptosis by pretreatment with the antioxidant, propyl gallate, or with nitric oxide synthase inhibitors. PC12 cells were protected by insulin and insulin‐like growth‐factor‐1 treatment. There is also evidence for mitochondrial participation in LPA‐mediated apoptosis, including cyclosporin A‐mediated protection. Thus, LPA‐induced neuronal apoptosis is associated with mitochondrial alterations, the generation of reactive oxygen species and nitric oxide, and protection by pretreatment with a serum constituent, insulin‐like growth factor 1.
LPA as a Paracrine Mediator of Adipocyte Growth and Function
Authors: PAGÈS CÉLINE , GIRARD ALEXIA , JEANNETON OLIVIER , BARBE PIERRE , WOLF CLAUDE , LAFONTAN MAX , VALET PHILIPPE , SAULNIER‐BLACHE JEAN SÉBASTIEN
Published: July 2010

Abstract: Adipogenesis corresponds to the recruitment of new adipocytes in adipose tissue, and results from the proliferation/differentiation of preadipocytes. Production of paracrine and autocrine factors by adipocytes plays an important role in adipogenesis. We recently demonstrated the existence of adipocyte production of lysophosphatidic acid (LPA) both in vitro and in situ. This production is modulated by catecholamines via α2‐adrenergic receptors. Adipocyte‐LPA present in conditioned media increases the growth of a preadipose cell line in culture. This growth is associated with an activation of mitogen‐activated protein kinases, and of the focal adhesion kinase. Because of the close proximity of preadipocytes and adipocytes within adipose tissue, adipocyte‐LPA could play an important role in autocrine/paracrine control of adipogenesis.
Structure‐Function Analyses of Eicosanoid Receptors: Physiologic and Therapeutic Implications
Authors: BREYER RICHARD M. , KENNEDY CHRISTOPHER R. J. , ZHANG YAHUA , BREYER MATTHEW D.
Published: July 2010

Abstract:Prostaglandins (PGs) are ubiquitous lipid mediators derived from cyclooxygenase (COX) metabolism of arachidonic acid that exert a broad range of physiologic activities including modulation of inflammation, ovulation, and arterial blood pressure. The physiologic actions of PGs are mediated in part by their interaction with specific G‐protein‐coupled PG receptors. Eight PG receptors have been cloned, including four for the major COX metabolite, PGE2. The physiologic roles of the PGE2receptors have been investigated utilizing subtype‐selective agonists, localization of receptor mRNA expression, and creation of mice with targeted disruption of PG receptor genes. These analyses have delineated discrete roles for the various PG receptor subtypes. Recent studies on mice lacking the PGE2EP2receptor have implicated the PGE2EP2receptor subtype in arterial dilatation and salt‐sensitive hypertension, and also indicate that this receptor plays a key role in female fertility. The EP2receptor may thus prove to be a productive target for pharmacological intervention in the treatment of hypertension and infertility.
Mutation Detection in K‐ras, BRCA1, BRCA2, and p53 Using PCR/LDR and a Universal DNA Microarray
Authors: FAVIS REYNA , BARANY FRANCIS
Published: July 2010

Abstract: We have developed a multiplex PCR/ligase detection reaction (PCR/LDR) that combines high sensitivity with the ability to simultaneously detect hundreds of mutations in a single‐tube reaction. To enable us to rapidly assay large numbers of samples, we have linked this mutation detection scheme with analysis on a Universal DNA microarray. We have successfully applied this approach to characterize K‐ras and p53 mutations in DNA derived from undissected colon tumors. The sensitivity of the assay has also facilitated detection of low‐frequency mutations in BRCA1 and BRCA2 in pooled samples of DNA; thus, PCR/LDR can rapidly screen large numbers of DNA samples required for population studies.
p53 and APC Mutations Are Detectable in the Plasma and Serum of Patients with Colorectal Cancer (CRC) or Adenomas
Authors: GOCKE CHRISTOPHER D. , BENKO FLOYD A. , KOPRESKI MICHAEL S. , McGARRITY THOMAS J.
Published: July 2010

Abstract: Background—A variety of tumor‐related DNA has been detected in the plasma and serum of cancer patients, including RAS, the BCL2‐IgH transgene, and p53. It is not known whether the APC gene, which is frequently mutated in colorectal cancer (CRC), can be identified in the plasma of CRC patients. Similarly, it is unknown whether another tumor suppressor gene altered in CRC, p53, is detectable in people with precursor lesions to CRC. Materials and Methods—The plasma of 240 colonoscopy patients was tested for mutations at two frequently altered sites (codons 175 and 248). A restriction enzyme‐mediated enrichment assay was used to detect these mutants. We also tested tumor tissue from 8 patients with CRC for mutations in the mutation cluster region of the APC gene using direct DNA sequencing. Corresponding plasma from any positive patient was then similarly sequenced. Results—Three plasma p53 mutations were identified. Two of these patients had adenomas at biopsy, and 1 had a hyperplastic polyp. All were tested for the same p53 mutations, and 1 of the adenomas was positive. One of the 8 CRC patients had a 5‐base‐pair deletion in the cancer and the same deletion was detectable in that patient's plasma, although at an amount that we estimate at 1–5% of the total APC DNA present. Conclusions—APC mutations are detectable in the plasma of CRC patients. p53 mutants are detectable in the plasma of colorectal adenoma patients. These may have important implications for cancer screening and diagnosis in the large intestine and suggest that all malignant and premalignant DNA alterations from the colon are identifiable in the blood.
Detection of DNA in the Plasma of Septic Patients
Authors: MARTINS GLORIA ADRIANA , KAWAMURA MARCIA TIE , CARVALHO MARIA DA GLORIA DA COSTA
Published: July 2010

Abstract: Small amounts of plasma‐free DNA have been observed both in healthy individuals and in patients with various diseases such as systemic lupus erythematosus, rheumatoid arthritis, viral hepatitis, and cancer. This communication demonstrates that septic patients also release DNA in plasma. After DNA extraction from plasma, exon 1 of the K‐ras gene was amplified by PCR and products were analyzed by dot‐blot hybridization. Plasmas from polytraumatic patients and control healthy individuals were used for comparisons with septic patients. Our results show that septic patients present DNA in their plasma. As far as we know, this is the first evidence of circulating DNA in septic patients.
Multiplex and Real‐Time Quantitative PCR on Fetal DNA in Maternal Plasma: A Comparison with Fetal Cells Isolated from Maternal Blood
Authors: HAHN SINUHE , ZHONG XIAO YAN , BÜRK MARTIN R. , TROEGER CAROLYN , HOLZGREVE WOLFGANG
Published: July 2010

Abstract: Fetal DNA has recently been detected in maternal plasma by PCR and has shown promise for the prenatal determination of fetal sex or rhesus D. In order to obtain the maximum amount of information from this fetal genetic material, we have devised a sensitive multiplex PCR method to permit simultaneous analysis for both the SRY locus and the rhesus D gene. Our studies show that this technique is very sensitive and specific. In the 22 cases from rhesus D negative women examined, we were able to determine both fetal genotypes correctly. In the parallel enrichment for fetal cells, fetal erythroblasts were only detected in 14 of the 19 cases. Our data also indicate that fetal DNA from rhesus D positive fetuses is present in maternal plasma even after prophylactic anti‐D treatment. Furthermore, since fetal cells have been reported to be elevated in pregnancies with aneuploid fetuses, we have quantified the amount of fetal DNA present in the maternal plasma of 10 such affected pregnancies by real‐time PCR. Our results indicate that fetal DNA is elevated under such circumstances when compared to gestationally matched normal pregnancies (mean of 7% in aneuploid samples versus 3.5% in normal pregnancies). These results indicate that the quantification of fetal DNA in maternal plasma may be an additional screening tool for pregnancies at risk of bearing an aneuploid fetus.
New Hypotheses on the Material Nature of Horizontally Mobile Genes
Authors: HEINEMANN JACK A. , ROUGHAN PAUL D.
Published: July 2010

Abstract:The evolutionary history of organisms is often assumed to be recorded in the structure of important molecules, such as DNA sequences. Whereas the structure of these molecules does sometimes affirm other evidence of ancestry, like fossil records, it sometimes does not. Horizontal gene transfer can distort perceptions of ancestry. Determining the impact of horizontal gene transfer on evolution has been limited by the crude tools available to detect it. Physical and genetic vectors are now known to conduct genes between organisms, even between biological kingdoms of organisms. The effects are being noticed in important molecules preserved in the genomes of organisms. This article will review the systematic bias in using molecular morphology, like DNA sequences, to infer ancestry and how this bias is the unavoidable result of the way that experimental genetics itself evolved. We present the novel hypothesis that genes usually called epigenes, like methylation patterns and prions, are infectiously transferred, sometimes using DNA as a vector, but not as a gene.
Evolutionary Psychology: Counting Babies or Studying Information‐Processing Mechanisms
Authors: CRAWFORD CHARLES
Published: July 2010

Abstract:Evolutionary psychology focuses on the study of adaptations. Its practitioners put little credence in the study of reproductive success in recent and current environments, and argue for an information‐processing, cost‐benefit conception of adaptation. Because ancestral and current environments differ, it is necessary to distinguish between innate and operational adaptations and between concurrently contingent and developmentally contingent behaviors. These distinctions lead to an evolutionary classification of behaviors into true pathologies, pseudopathologies, quasinormal behaviors, and adaptive‐culturally‐variable behaviors. I argue that a complete study of the functioning of a behavioral adaptation involves modeling ancestral selection pressures, cross‐cultural research, experimental studies of mental processes, and studies of the proximate biological correlates of information‐processing adaptations. Finally, I claim that evolutionary psychology can help us avoid making both naturalistic and moralistic fallacies.
Mental Traits as Fitness Indicators: Expanding Evolutionary Psychology's Adaptationism
Authors: MILLER GEOFFREY
Published: July 2010

Abstract:According to most evolutionary psychologists, human psychological adaptations can be recognized by criteria such as high efficiency, high complexity, high modularity, low phenotypic variance, low genotypic variance, low heritability, universality across cultures, and universality across individuals. These criteria are appropriate for adaptations that have been shaped through stabilizing selection for survival utility. However, they are often inappropriate for adaptations that have been shaped by sexual selection through mate choice as reliable signals of heritable fitness. If some psychological adaptations evolved as sexually selected fitness indicators of this type, we should expect them to violate many standard criteria used by evolutionary psychology to distinguish adaptations from non‐adaptations. This paper addresses the problems raised by new developments in sexual selection theory and animal signaling theory for evolutionary psychology's adaptationism. It suggests that our adaptationist criteria must recognize two typical kinds of psychological adaptations: naturally selected survival mechanisms and sexually selected fitness indicators.
Genomic Imprinting, Sex‐Biased Dispersal, and Social Behavior
Authors: HAIG DAVID
Published: July 2010

Abstract:Some genes carry a record of the sex of the gene's carrier in the previous generation that influences the gene's expression in this generation. This additional information can result in intragenomic conflicts between an individual's maternally and paternally derived alleles over behaviors that affect relatives with whom the individual has different degrees of maternal and paternal relatedness. Asymmetries of relatedness can arise because of sex‐biased dispersal. For example, if females remain in their natal group and males disperse, female members of a group will all be matrilineal relatives, but may have unrelated fathers. Sex‐linked inheritance creates an evolutionary bias in favor of social groups that trace descent through the homogametic sex. This bias has a positive and negative aspect. The positive aspect is increased relatedness among siblings of the homogametic sex. The negative aspect is the lack of sex‐linked relatedness between parents and offspring of the heterogametic sex.
On the Evolution of Misunderstandings about Evolutionary Psychology
Authors: YOUNG JASON , PERSELL ROGER
Published: July 2010

Abstract: Some of the controversy surrounding evolutionary explanations of human behavior may be due to cognitive information‐processing patterns that are themselves the result of evolutionary processes. Two such patterns are (1) the tendency to oversimplify information so as to reduce demand on cognitive resources and (2) our strong desire to generate predictability and stability from perceptions of the external world. For example, research on social stereotyping has found that people tend to focus automatically on simplified social‐categorical information, to use such information when deciding how to behave, and to rely on such information even in the face of contradictory evidence. Similarly, an undying debate over nature vs. nurture is shaped by various data‐reduction strategies that frequently oversimplify, and thus distort, the intent of the supporting arguments. This debate is also often marked by an assumption that either the nature or the nurture domain may be justifiably excluded at an explanatory level because one domain appears to operate in a sufficiently stable and predictable way for a particular argument. As a result, critiques inveighed against evolutionary explanations of behavior often incorporate simplified‐and erroneous‐assumptions about either the mechanics of how evolution operates or the inevitable implications of evolution for understanding human behavior. The influences of these tendencies are applied to a discussion of the heritability of behavioral characteristics. It is suggested that the common view that Mendelian genetics can explain the heritability of complex behaviors, with a one‐gene‐one‐trait process, is misguided. Complex behaviors are undoubtedly a product of a more complex interaction between genes and environment, ensuring that both nature and nurture must be accommodated in a yet‐to‐be‐developed post‐Mendelian model of genetic influence. As a result, current public perceptions of evolutionary explanations of behavior are handicapped by the lack of clear articulation of the relationship between inherited genes and manifest behavior.
Some New Directions for Research on the Biology of Aging
Authors: MARTIN GEORGE M.
Published: July 2010

Abstract: A highly selective, eclectic, and personal view of new directions and new opportunities for research on the biology of aging is briefly outlined. Some concern is raised regarding the present emphasis on the use of centenarians for the definition of genetic loci responsible for unusually robust retention of structure and function. More progress is likely to be made were we to focus on the genetic basis for “elite” aging in middle‐aged subjects examined for very specific phenotypes, as these are likely to be far less polygenic. Descriptive gerontology is entering a renaissance, given such new clinical tools as functional MRI and basic science tools such as functional genomics and proteomics. Advances in genomics should expedite answers to such questions as why some avian species have exceptionally long lifespans despite unusual loads of oxidative stress. One hopes to see renewed mechanistic studies, using such tools, at the systems levels. New methodologies are permitting the evaluation of stochastic alterations in gene structure and function in postreplicative cells. The exciting work on molecular misreading should prompt us to reexplore the Orgel hypothesis as it applies to such cell types. Epigenetic shifts in gene expression that occur in association with sexual maturation and the cessation of growth may have deleterious consequences late in the life course. It will therefore be important for gerontologists to investigate the molecular biology of pubescence. Finally, our community should investigate the impact of environmental “gerontogens,” agents that accelerate specific processes of aging and specific senescent phenotypes.
Mitochondrial Oxidative Stress and Aging in the Filamentous Fungus Podospora anserina
Authors: OSIEWACZ HEINZ D. , BORGHOUTS CORINA
Published: July 2010

Abstract: In the filamentous fungus Podospora anserina, mitochondrial oxidative stress is a major contributor to aging. Reactive oxygen species (ROS) generated as a result of electron leakage during respiration lead to damage of components of the electron transport chain. In aging wild‐type cultures, damaged proteins cannot be replaced because the mitochondrial genes encoding some of the corresponding subunits gradually become deleted from the mitochondrial DNA (mtDNA). Consequently, these defects result in an increased generation of reactive oxygen species and respiration deficits leading to cell death. Analyses of wild‐type strains and of different long‐lived mutants of P. anserina provide strong evidence that molecular mechanisms controlling aging processes in this fungus are complex and act at different levels. A basic mechanism (e.g., damage by ROS) appears to be overlaid by prominent instabilities of the mtDNA.
Molecular Genetic Mechanisms of Life Span Manipulation in Caenorhabditis elegans
Authors: MURAKAMI SHIN , TEDESCO PATRICIA M. , CYPSER JAMES R. , JOHNSON THOMAS E.
Published: July 2010

Abstract: Aging and a limited life span are fundamental biological realities. Recent studies have demonstrated that longevity can be manipulated and have revealed molecular mechanisms underlying longevity control in the soil nematode Caenorhabditis elegans. Signals from both neurons and the gonad appear to negatively regulate longevity. One tissue‐specific signal involves an insulin‐like phosphatidylinositol 3‐OH kinase pathway, dependent upon the DAF‐16 forkhead transcription factor. These signals regulate mechanisms determining longevity that include the OLD‐1 (formerly referred to as TKR‐1) receptor tyrosine kinase. Interestingly, increased resistance to environmental stress shows a strong correlation with life extension.
Poly(ADP‐Ribosyl)ation, Genomic Instability, and Longevity
Authors: BÜRKLE ALEXANDER
Published: July 2010

Abstract: Poly(ADP‐ribosyl)ation is a DNA strandbreak‐driven posttranslational modification of nuclear proteins that is catalyzed by poly(ADP‐ribose) polymerase‐1 (PARP‐1), with NAD+ serving as substrate. Recently, additional PARP isoforms were described that seem to account for a minor fraction of cellular poly(ADP‐ribose) synthesis. We have previously described a correlation between poly(ADP‐ribosyl)ation capacity of mononuclear leukocytes of various mammalian species and species‐specific life span. Likewise, lymphoblastoid cell lines derived from human centenarians display a higher poly(ADP‐ribosyl)ation capacity than do controls. At the functional level, recent data show that PARP‐1 is a key regulator of alkylation‐induced sister‐chromatid exchange, imposing a negative control commensurate with the enzyme activity. PARP‐1 activity may therefore be responsible for tuning the rate of genomic instability events that are provoked by the constant attack of endogenous and exogenous genotoxins to a level appropriate for the longevity potential of a given organism or species.
Protein Degradation by the Proteasome and Its Implications in Aging
Authors: FRIGUET BERTRAND , BULTEAU ANNE‐LAURE , CHONDROGIANNI NIKI , CONCONI MARIANGELA , PETROPOULOS ISABELLE
Published: July 2010

Abstract: Free radical damage to cellular components is believed to contribute to the aging process. Studies on proteins have shown both an age‐related decline in several enzyme activities and an age‐related accumulation of oxidized forms of protein. Oxidized forms of protein are generally degraded more rapidly than their native counterparts. Indeed, the normal functions of the cell involve the regular elimination of these altered molecules. The proteasome, a multienzymatic proteolytic complex, is the major enzymatic system in charge of cellular “cleansing” and plays a key role in the degradation of damaged proteins. Consequently, proteasome function is very important in controlling the level of altered proteins in eukaryotic cells. Because the steady‐state level of oxidized protein reflects the balance between the rate of protein oxidation and the rate of protein degradation, age‐related accumulation of altered protein can be due to an increase of free radical‐mediated damage, a loss of protease activity, or the combination of both mechanisms. One of the hypotheses put forward to explain the accumulation of altered proteins is the decrease of proteasome activity with age. In this paper, the importance of oxidative damage to proteins and that of their elimination by the proteasome are first described. Then, evidence for a decline of proteasome activity upon aging and upon oxidative stress is provided by studies from our and other laboratories.