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PubMed2006

Plasma adipokines and body composition in response to modest dietary manipulations in the mouse.

OBJECTIVE: The relationship between adipokine levels and body composition has not been carefully examined. Most studies in humans are cross-sectional, and the few studies in mice have been restricted to a comparison of control animals with markedly obese, insulin-resistant mice. Our objective was to study changes in adipokine levels and body composition in response to modest dietary intervention. RESEARCH METHODS AND PROCEDURES: Plasma resistin, adiponectin, and leptin levels were examined in mice fed ad libitum, a 75% restricted diet, or a diet supplemented with 10% sucrose. Body composition was determined by whole-body DXA. RESULTS: The percentage body fat was reduced in mice subjected to the restricted diet and increased in mice supplemented with 10% dextrose. Adipokine levels were not different in either of these groups compared with the control mice. A significant inverse correlation was observed between resistin levels and total body fat, whereas there was no significant correlation between body fat and adiponectin levels. Positive correlations were observed between leptin levels and percentage body fat, total body fat, and abdominal fat. Leptin levels correlated with plasma glucose, but multivariate analysis revealed that this correlation was the result of a strong positive correlation between leptin and insulin levels. There were no correlations between glycemia and resistin or glycemia and adiponectin levels, and no correlation was observed between any of the adipokine levels and bone mineral content or density. DISCUSSION: These data suggest that in the mouse, modest dietary perturbations have little effect on resistin and adiponectin levels despite significant effects on glycemia, insulin levels, and bone parameters.

Adiponectin↗
PubMed2005

A metabolomic approach to ionotropic glutamate receptor subtype function: a nuclear magnetic resonance in vitro investigation.

A range of behaviours are elucidated via ionotropic glutamate receptors (iGluR). In this work, we examined the acute activation of iGluRs by a range of receptor ligands and effectors to see whether distinguishable metabolic sequelae were elucidated by the activity. We used a guinea-pig brain cortical tissue slice model using targeted receptor ligands ((RS)-(tetrazol-5-yl)glycine (TZG), (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801, dizocilpine), cis-4-[phosphomethyl]-piperidine-2-carboxylic acid (CGS 19755), (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, (2S, 3S, 4S)-2-carboxy-4-(1-methylethenyl)-3-pyrrolidineacetic acid (kainate) and D-serine (D-Ser), as well as compounds (quinolinic acid and kynurenic acid (KynA)) involved in some neuroinflammatory responses. The data were derived using 13C and 1H NMR spectroscopy, and analysed by metabolomic approaches and multivariate statistics. The metabolic effects of agonists at the three major classes of iGluR were easily separated from each other using this method. The classical N-methyl-D-aspartate receptor agonist TZG and the antagonist CGS 19755 produced excitatory and inhibitory metabolic responses, respectively, while the blocker MK-801 resulted in a significant decrease in net metabolism and produced the largest decrease in all metabolite pool sizes seen by any glutamatergic ligand we have studied. Quinolinic acid and KynA produced similar acute metabolic responses, which were unlike those to TZG or CGS 19755, but similar to that of D-Ser. D-Ser was highly stimulatory of net flux into the Krebs cycle. These data show that the metabolic response to iGluR perturbation in vitro is a sensitive discriminator of function.

Animals↗
PubMed2002

Retroviral transfer and expression of human MDR-1 in a murine haemopoietic stem cell line does not alter factor dependence, growth or differentiation characteristics.

In view of the recent report of a myeloproliferative syndrome in mice that had received an MDR-1-transduced haemopoietic graft, we have investigated the potential effects of MDR-1 expression on primitive haemopoietic cell growth and differentiation. Retroviral gene transfer was used to achieve exogenous expression of either MDR-1 or truncated nerve growth factor receptor (tNGFR) in the multipotent murine haemopoietic progenitor cell line, FDCP-mix. Following gene transfer, clonal lines were derived and FACS analysis confirmed appropriate expression of each transgene. MDR-1 (but not tNGFR) expression was associated with verapamil-sensitive rhodamine efflux and resistance to killing by etoposide. When growth factor responsiveness, proliferative capacity and differentiation capacity were examined, MDR-1 expressing FDCP-mix cells exhibited a normal phenotype and mimicked the response of tNGFR-expressing or untransduced FDCP-mix cells. Thus, in the model system we have used, MDR-1 does not perturb haemopoietic cell growth and development and our data do not support a myeloproliferative role for MDR-1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

A model of ocular dominance column development by competition for trophic factor.

Recent experimental evidence has shown that application of certain neurotrophic factors (NTs) to the developing primary visual cortex prevents the development of ocular dominance (OD) columns. One interpretation of this result is that afferents from the lateral geniculate nucleus compete for postsynaptic trophic factor in an activity-dependent manner. Application of excess trophic factor eliminates this competition, thereby preventing OD column formation. We present a model of OD column development, incorporating Hebbian synaptic modification and activity-driven competition for NT, which accounts for both normal OD column development as well as the prevention of that development when competition is removed. In the "control" situation, when available NT is below a critical amount, OD columns form normally. These columns form without weight normalization procedures and in the presence of positive inter-eye correlations. In the "experimental" case, OD column development is prevented in a local neighborhood in which excess NT has been added. Our model proposes a biologically plausible mechanism for competition between neural populations that is motivated by several pieces of experimental data, thereby accounting for both normal and experimentally perturbed conditions.

Animals↗
PubMed1997

Intracellular association between UDP-glucose:glycoprotein glucosyltransferase and an incompletely folded variant of alpha1-antitrypsin.

Genetic variants of human alpha1-antitrypsin unable to fold into the native structural conformation are poorly secreted from hepatocytes. The molecular chaperone calnexin coimmunoprecipitates with secretion-incompetent variant null(Hong Kong) retained in stably transfected mouse hepatoma cells (Le, A., Steiner, J. L., Ferrell, G. A., Shaker, J. F., and Sifers, R. N. (1994) J. Biol. Chem. 269, 7514-7519). Mobilization of intracellular Ca2+ stores with metabolic poisons diminished interaction with calnexin and coincided with coimmuoprecipitation of a 150-kDa protein (p150). Mobilization of endoplasmic reticulum lumenal Ca2+ with thapsigargin, an inhibitor of the microsomal Ca2+ATPase, gave a similar result. Coimmunoprecipitation of p150 was specifically disrupted in response to incubation of the cell lysate with exogenous CaCl2. Finally, in ECL Western blotting, p150 was recognized by polyclonal antiserum against UDP-glucose:glycoprotein glucosyltransferase that likely functions in glycoprotein folding and quality control (Sousa, M. C., Ferrero-Garcia, M. A., and Parodi, A. J. (1992) Biochemistry 31, 97-105). The data are consistent with a model in which perturbation of endoplasmic reticulum Ca2+ results in a stable physical association between unfolded human alpha1-antitrypsin and UDP-glucose:glycoprotein glucosyltransferase.

Animals↗
PubMed2000

Solution structure of the E200K variant of human prion protein. Implications for the mechanism of pathogenesis in familial prion diseases.

Prion propagation in transmissible spongiform encephalopathies involves the conversion of cellular prion protein, PrP(C), into a pathogenic conformer, PrP(Sc). Hereditary forms of the disease are linked to specific mutations in the gene coding for the prion protein. To gain insight into the molecular basis of these disorders, the solution structure of the familial Creutzfeldt-Jakob disease-related E200K variant of human prion protein was determined by multi-dimensional nuclear magnetic resonance spectroscopy. Remarkably, apart from minor differences in flexible regions, the backbone tertiary structure of the E200K variant is nearly identical to that reported for the wild-type human prion protein. The only major consequence of the mutation is the perturbation of surface electrostatic potential. The present structural data strongly suggest that protein surface defects leading to abnormalities in the interaction of prion protein with auxiliary proteins/chaperones or cellular membranes should be considered key determinants of a spontaneous PrP(C) --> PrP(Sc) conversion in the E200K form of hereditary prion disease.

Base Sequence↗
PubMed2000

Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas.

Chromosomal translocations in human lipomas frequently create fusion transcripts encoding high mobility group (HMG) I-C DNA-binding domains and C-terminal sequences from different presumed transcription factors, suggesting a potential role for HMG I-C in the development of lipomas. To evaluate the role of the HMG I-C component, the three DNA-binding domains of HMG I-C have now been expressed in transgenic mice. Despite the ubiquitous expression of the truncated HMG I-C protein, the transgenic mice develop a selective abundance of fat tissue early in life, show marked adipose tissue inflammation, and have an abnormally high incidence of lipomas. These findings demonstrate that the DNA-binding domains of HMG I-C, in the absence of a C-terminal fusion partner, are sufficient to perturb adipogenesis and predispose to lipomas. We provide data supporting the central utility of this animal model as a tool to understand the molecular mechanisms underlying the development of one of the most common kind of human benign tumors.

Adipocytes↗
PubMed1983

Physical studies on a nucleoprotein from the ribosome of E. coli.

Bacterial 5S RNA and its cognate proteins constitute an attractive system to study nucleoprotein interactions. The molecular weights of the components involved are modest and they can be prepared in the quantities necessary to permit the application of material-intensive techniques like NMR and X-ray crystallography. 5S RNA is being examined by proton NMR at 500 MHz with special attention paid to the downfield NH proton region. A substantial number of assignments can be suggested in this region based on nuclear Overhauser results. The binding of protein L25 (E. coli) to the RNA gives rise to a highly characteristic set of perturbations in the spectrum of the RNA. The data suggest a localized and assignable alteration in RNA structure upon formation of the complex. In addition we have grown large crystals of RNAs related to 5S RNA and their complexes with a cognate protein. The properties of these crystals and the progress made in analyzing their structure are discussed.

Base Sequence↗
PubMed1995

Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros.

Several lines of evidence suggest that hepatocyte growth factor/scatter factor (HGF/SF), a soluble protein secreted by embryo fibroblasts and several fibroblast lines, may elicit morphogenesis in adjacent epithelial cells. We investigated the role of HGF/SF and its membrane receptor, the product of the c-met protooncogene, in the early development of the metanephric kidney. At the inception of the mouse metanephros at embryonic day 11, HGF/SF was expressed in the mesenchyme, while met was expressed in both the ureteric bud and the mesenchyme, as assessed by reverse transcription PCR, in situ hybridization, and immunohistochemistry. To further investigate the expression of met in renal mesenchyme, we isolated 13 conditionally immortal clonal cell lines from transgenic mice expressing a temperature-sensitive mutant of the SV-40 large T antigen. Five had the HGF/SF+/met+ phenotype and eight had the HGF/SF-/met+ phenotype. None had the HGF/SF+/met- nor the HGF/SF-/met- phenotypes. Thus the renal mesenchyme contains cells that express HGF/SF and met or met alone. When metanephric rudiments were grown in serum-free organ culture, anti-HGF/SF antibodies (a) inhibited the differentiation of metanephric mesenchymal cells into the epithelial precursors of the nephron; (b) increased cell death within the renal mesenchyme; and (c) perturbed branching morphogenesis of the ureteric bud. These data provide the first demonstration for coexpression of the HGF/SF and met genes in mesenchymal cells during embryonic development and also imply an autocrine and/or paracrine role for HGF/SF and met in the survival of the renal mesenchyme and in the mesenchymal-epithelial transition that occurs during nephrogenesis. They also confirm the postulated paracrine role of HGF/SF in the branching of the ureteric bud.

Animals↗
PubMed2000

Sensitivity of mouse oocytes to nicotine-induced perturbations during oocyte meiotic maturation and aneuploidy in vivo and in vitro.

Oocyte meiosis is sensitive to endogenous and exogenous perturbations that upset the temporal sequence of biochemical reactions during oocyte maturation (OM) and predispose oocytes to aneuploidy. Nicotine is an alkaloid that has been reported to disrupt the rate of OM, reduce ovulation and fertilization rates, and increase diploidy. The objective of this study was to test the hypothesis that nicotine perturbs the rate of OM and induces aneuploidy in mouse oocytes in vivo and in vitro. Female mice were given 7.5 IU pregnant mare's serum and either 0, 5.0, 7.5, or 10 mg/kg nicotine in vivo at -3, 0, and +3 h relative to a 5 IU injection of HCG. Oocytes were also cultured in vitro in the presence of 0, 1.0, 5.0, or 10.0 mmol/l nicotine. In vivo, significant (P < 0.05) differences in the proportions of oocytes with premature centromere separation and premature anaphase were found at 10.0 mg/kg nicotine suggesting that the rate of OM was advanced. Also, at this dose the proportion of ovulated oocytes was reduced by approximately 50% relative to controls. In vitro, only non-significant differences were found among the parameters measured. Although nicotine reduced the ovulation rate and perturbed the rate of OM in vivo, these data show that the rate of aneuploidy was not significantly elevated.

Aneuploidy↗
PubMed2000

Muscle damage and resting metabolic rate after acute resistance exercise with an eccentric overload.

PURPOSE: The purpose of this investigation was to determine whether muscle damage caused from acute resistance exercise with an eccentric overload would influence resting metabolic rate (RMR) up to 72 h postexercise in resistance-trained (RT) and untrained (UT) subjects. METHODS: Nine RT and 9 UT male subjects (mean +/- SD; age = 20.7 +/- 2.1 yr; body mass = 79.0 +/- 1.4 kg; height = 178.4 +/- 3.1 cm; and body fat = 10.2 +/- 1.6%) were measured for RMR, creatine kinase concentration ([CK]), and rating of perceived muscle soreness (RPMS) on five consecutive mornings. To induce muscle damage, after the measurements on day 2, each subject performed leg presses that emphasized the eccentric movement for 8 sets at his six-repetition maximum (6-RM). RESULTS: Compared with baseline, the RMR (kJ x d(-1) and kJ x kg FFM(-1) x h(-1) was significantly elevated for RT and UT at 24 h and 48 h postexercise. From 24 h to 48 h to 72 h postexercise, RMR significantly decreased within both groups. The UT group had a significantly higher RMR at 24 h (9,705.4 +/- 204.5 kJ x d(-1)) and 48 h postexercise (8,930.9 +/- 104.4 kJ x d(-1)) when compared with the RT group (9,209.3 +/- 535.3 and 8,601.7 + 353.7 kJ x d(-1)). Both [CK] and RPMS showed a similar time course. CONCLUSION: There was a significantly higher [CK] for the UT group at 24 h postexercise (320.4 +/- 20.1 U x L(-1)) and for both [CK] and RPMS at 48 h (1,140.3 +/- 37.1 U x L(-1) and 4.4 +/- 0.5, respectively) and 72 h postexercise (675.9 +/- 41.7 U x L(-1) and 1.67 +/- 0.5, respectively) when compared with the RT group (24 h, 201.9 +/- 13.4 U x L(-1); 48 h, 845.4 +/- 30.7 U x L(-1) and 3.7 +/- 0.5: and 72 h postexercise, 420.2 +/- 70.2 U x L(-1) and 0.89 +/- 0.3). These data indicate that eccentrically induced muscle damage causes perturbations in RMR up to 48 h postexercise.

Adolescent↗
PubMed2025

A double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules.

Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases offer a novel approach to interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF-targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT-signaling dependent AR-negative CRPC (CRPC-WNT). The CRPC-WNT subgroup represents 11% of around 400,000 cases of CRPC worldwide who die yearly of CRPC. We discovered that SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT. Functionally, TCF7L2 maintains proliferation via the MAPK signaling axis in this subtype of CRPC. These data suggest a mechanistic rationale for interventions that perturb the DNA binding of the pro-proliferative TCF7L2 transcription factor (TF) and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.

Journal Article↗
PubMed2001

Entropy-enthalpy compensation: fact or artifact?

The phenomenon of entropy-enthalpy (S-H) compensation is widely invoked as an explanatory principle in thermodynamic analyses of proteins, ligands, and nucleic acids. It has been suggested that this compensation is an intrinsic property of either complex, fluctuating, or aqueous systems. The questions examined here are whether the observed compensation is extra-thermodynamic (i.e., reflects anything more than the well-known laws of statistical thermodynamics) and if so, what does it reveal about the system? Compensation is rather variably defined in the literature and different usages are discussed. The most precise and interesting one, which is considered here, is a linear relationship between DeltaH and DeltaS for some series of perturbations or changes in experimental variable. Some recent thermodynamic data on proteins purporting to show compensation is analyzed and shown to be better explained by other causes. A general statistical mechanical model of a complex system is analyzed to explore whether and under what conditions extra-thermodynamic compensation can occur and what it reveals about the system. This model shows that the most likely behavior to be seen is linear S-H compensation over a rather limited range of perturbations with a compensation temperature Tc = dDeltaH/dDeltaS within 20% of the experimental temperature. This behavior is insensitive to the details of the model, thus revealing little extra-thermodynamic or causal information about the system. In addition, it will likely be difficult to distinguish this from more trivial forms of compensation in real experimental systems.

Artifacts↗
PubMed2005

Effects of aging on early B- and T-cell development.

Lymphocyte production in the bone marrow and the thymus is reduced during aging, but why this decline occurs has not been fully elucidated. The ability to isolate hematopoietic stem and progenitor cells using sophisticated flow cytometric strategies and to manipulate them in vitro and in vivo has provided insights into the effects of aging on primary lymphopoiesis. These analyses have showed that intrinsic changes in hematopoietic precursors that affect their proliferative potential are one factor that contributes to the age-related decline in B- and T-cell production. This and other age-related defects may be exacerbated by changes in the lymphopoietic support potential of the bone marrow and thymic microenvironments as well as by age-induced fluctuations in the production of various endocrine hormones. Particular attention with regard to the latter point has focused on changes in the production of sex steroids, growth hormone, and insulin-like growth factor-I. The present review summarizes recent studies of how age-related perturbations affect primary lymphopoiesis and highlights how the data necessitate the reevaluation of a number of existing paradigms.

Aging↗
PubMed1988

Post-translational processing of the murine third component of complement.

The biosynthesis and secretion of the third component of complement (C3) has been studied with the macrophage cell line J774.2. C3 is initially synthesized as a single polypeptide chain precursor termed pro-C3, of relative molecular weight (Mr) 170,000 that is post-translationally modified by proteolytic cleavage into two polypeptides linked by disulphide bonds. The larger polypeptide, termed the alpha chain, has an Mr of 110,000-115,000, while the smaller beta chain has an Mr of 55,000-60,000. Pulse-chase experiments indicate that the proteolytic processing of pro-C3 occurs intracellularly, just prior to secretion. Unlike human C3, which has carbohydrate on both the alpha and beta chains, only the alpha chain of murine C3 is glycosylated. The carboxylic ionophores monensin and nigericin totally inhibit the proteolytic processing of pro-C3 at a concentration of approximately 10(-6) M. This block on proteolytic processing was shown not to be mediated by changes in intracellular pH induced by the disruption of proton gradients. Rather, data from experiments using carboxylic ionophores and other perturbants of cellular physiology indicated that the enzyme(s) responsible for the proteolytic cleavage of pro-C3 either reside in a cellular compartment with a neutral pH or are proteinases active over a relatively broad pH range.

Ammonium Chloride↗
PubMedDate not supplied

A differential method for inhomogeneity correction on dose in a photon beam.

For a uniform slab of inhomogeneity in a supervoltage beam, correction factors can be calculated from the Batho equation. In this report, we present a method for calculating the effect of an annular inhomogeneity, concentric about the beam axis, upon the dose at a point on the axis and below the annulus. A derivation of the equation required in the calculation for supervoltage radiation is given. Results from measurements made in 60Co beams for polystyrene foam, cedar, and aluminum annuli, all having 3.0 x 2.0 cm2 in cross section but with different inside diameters, are compared with correction values calculated by the method. For situations where the annulus is just submerged in the phantom, measured and calculated values are in good agreement. For a general situation, two calculation types are proposed and the data show that in general the measured scatter perturbation lies between the calculated values of the two types. Application of our technique predicts a sign reversal in the scatter perturbation due to an inhomogeneity. This reversal has previously been observed and reported and is also demonstrated in our measurements.

Cobalt Radioisotopes↗
PubMed2002

A genomic regulatory network for development.

Development of the body plan is controlled by large networks of regulatory genes. A gene regulatory network that controls the specification of endoderm and mesoderm in the sea urchin embryo is summarized here. The network was derived from large-scale perturbation analyses, in combination with computational methodologies, genomic data, cis-regulatory analysis, and molecular embryology. The network contains over 40 genes at present, and each node can be directly verified at the DNA sequence level by cis-regulatory analysis. Its architecture reveals specific and general aspects of development, such as how given cells generate their ordained fates in the embryo and why the process moves inexorably forward in developmental time.

Animals↗