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We prove continuity of certain cost functions arising from optimal control of affine control systems. We give sharp sufficient conditions for this continuity. As an application, we prove a version of weak KAM theorem and consider the Aubry–Mather problems corresponding to these systems.

XXY men (Klinefelter syndrome) are testosterone deficient, socially isolated, exhibit impaired gender identity, and may experience more homosexual behaviors. Here, we characterize social behaviors in a validated XXY mouse model to understand mechanisms. Sociability and gender preference were assessed by three-chambered choice tasks before and after castration and after testosterone replacement. Metabolomic activities of brain and blood were quantified through fractional synthesis rates of palmitate and ribose (GC-MS). XXY mice exhibit greater sociability than XY littermates, particularly for male mice. The differences in sociability disappear after matching androgen exposure. Intact XXY, compared with XY, mice prefer male mice odors when the alternatives are ovariectomized female mice odors, but they prefer estrous over male mice odors, suggesting that preference for male mice may be due to social, not sexual, cues. Castration followed by testosterone treatment essentially remove these preferences. Fractional synthesis rates of palmitate are higher in the hypothalamus, amygdala, and hippocampus of XXY compared with XY mice but not with ribose in these brain regions or palmitate in blood. Androgen ablation in XY mice increases fractional synthesis rates of fatty acids in the brain to levels indistinguishable from those in XXY mice. We conclude that intact XXY mice exhibit increased sociability, differences in gender preference for mice and their odors are due to social rather than sexual cues and, these differences are mostly related to androgen deficiency rather than genetics. Specific metabolic changes in brain lipids, which are also regulated by androgens, are observed in brain regions that are involved in these behaviors. aneuploidy; Klinefelter syndrome; testosterone; X-inactivation; brain lipids doi: 10.1152/ajpendo.00085.2010.

We prove a generalization of the Li-Yau estimate for a broad class of second order linear parabolic equations. As a consequence, we obtain a new Cheeger-Yau inequality and a new Harnack inequality for these equations. We also prove a Hamilton-Li-Yau estimate, which is a matrix version of the Li-Yau estimate, for these equations. This results in a generalization of Huisken's monotonicity formula for a family of evolving hypersurfaces. Finally, we also show that all these generalizations are sharp in the sense that the inequalities become equality for a family of fundamental solutions, which however different from the Gaussian heat kernels on which the equality was achieved in the classical case. [ABSTRACT FROM AUTHOR]

We prove sharp Harnack inequalities for a family of Kolmogorov-Fokker-Planck type hypoelliptic diffusions. [ABSTRACT FROM AUTHOR]

Background: Tracing stable isotopes, such as 13C using various mass spectrometry (MS) methods provides a valuable information necessary for the study of biochemical processes in cells. However, extracting such information requires special care, such as a correction for naturally occurring isotopes, or overlapping mass spectra of various components of the cell culture medium. Developing a method for a correction of overlapping peaks is the primary objective of this study. Results: Our computer program-MIDcor (free at https://github.com/seliv55/mid_correct) written in the R programming language, corrects the raw MS spectra both for the naturally occurring isotopes and for the overlapping of peaks corresponding to various substances. To this end, the mass spectra of unlabeled metabolites measured in two media are necessary: in a minimal medium containing only derivatized metabolites and chemicals for derivatization, and in a complete cell incubated medium. The MIDcor program calculates the difference (D) between the theoretical and experimentally measured spectra of metabolites containing only the naturally occurring isotopes. The result of comparison of D in the two media determines a way of deciphering the true spectra. (1) If D in the complete medium is greater than that in the minimal medium in at least one peak, then unchanged D is subtracted from the raw spectra of the labeled metabolite. (2) If D does not depend on the medium, then the spectrum probably overlaps with a derivatized fragment of the same metabolite, and D is modified proportionally to the metabolite labeling. The program automatically reaches a decision regarding the way of correction. For some metabolites/fragments in the case (2) D was found to decrease when the tested substance was 13C labeled, and this isotopic effect also can be corrected automatically, if the user provides a measured spectrum of the substance in which the 13C labeling is known a priori. Conclusion: Using the developed program improves the reliability of stable isotope tracer data analysis. [ABSTRACT FROM AUTHOR]

In this paper, we study the Ma-Trudinger-Wang (MTW) conditions for cost functions c which are of the form c = l o d, where d is a Riemannian distance function with constant sectional curvature. In this case, the MTW conditions are equivalent to some computable conditions on the function l. As a corollary, we give some new costs on Riemannian manifolds of constant negative curvature for which the MTW conditions are satisfied. [ABSTRACT FROM AUTHOR]

We give new computable necessary conditions for a class of optimal transportation problems to have smooth solutions. [ABSTRACT FROM AUTHOR]

Prenatal nutrient restriction with intrauterine growth restriction (IUGR) alters basal and glucose-stimulated insulin response and hepatic metabolic adaptation. The effect of early intervention with insulin-sensitizing peroxisome proliferator-activated receptor γ agonists was examined in the metabolically maladapted F1 pregestational IUGR offspring with a propensity toward pregnancy-induced gestational diabetes. The effect of rosiglitazone maleate ERG; 11 μmol/day from postnatal day (PN) 21 to PN60] vs. placebo (PL) on metabolic adaptations in 2-mo-old F1 female rats subjected to prenatal (IUGR), postnatal (PNGR), or pre- and postnatal (IUGR + PNGR) nutrient restriction was investigated compared with control (CON). RG vs. PL had no effect on body weight or plasma glucose concentrations but increased subcutaneous white and brown adipose tissue and plasma cholesterol concentrations in all three experimental groups. Glucose tolerance tests with a 1:1 mixture of [2-2H2]and [6,6-2H2]glucose in RG IUGR vs. PL IUGR revealed glucose tolerance with a lower glucose-stimulated insulin release (GSIR) and suppressed endogenous hepatic glucose production (HGP) with no difference in glucose clearance (GC) and recycling (GR). RG PNGR, although similar to PL CON, was hyperglycemic vs. PL PNGR with reduced GR but no difference in the existent low GSIR, HGP, and GC. RG IUGR + PNGR overall was no different from the PL counterpart. Insulin tolerance tests revealed perturbed recovery to baseline from the exaggerated hypoglycemia in RG vs. the PL groups with the only exception being RG PNGR where further worsening of hypoglycemia over PL PNGR was minimal with full recovery to baseline. These observations support that early intervention with RG suppressed HGP in IUGR vs. PL IUGR, without increasing GSIR similar to that seen in CON. Although RG reversed PNGR to the PL CON metabolic state, no such insulin-sensitizing effect was realized in IUGR + PNGR. [ABSTRACT FROM AUTHOR]

Background: Metabolic flux profiling based on the analysis of distribution of stable isotope tracer in metabolites is an important method widely used in cancer research to understand the regulation of cell metabolism and elaborate new therapeutic strategies. Recently, we developed software Isodyn, which extends the methodology of kinetic modeling to the analysis of isotopic isomer distribution for the evaluation of cellular metabolic flux profile under relevant conditions. This tool can be applied to reveal the metabolic effect of proapoptotic drug edelfosine in leukemia Jurkat cell line, uncovering the mechanisms of induction of apoptosis in cancer cells. Results: The study of 13C distribution of Jukat cells exposed to low edelfosine concentration, which induces apoptosis in ≤5% of cells, revealed metabolic changes previous to the development of apoptotic program. Specifically, it was found that low dose of edelfosine stimulates the TCA cycle. These metabolic perturbations were coupled with an increase of nucleic acid synthesis de novo, which indicates acceleration of biosynthetic and reparative processes. The further increase of the TCA cycle fluxes, when higher doses of drug applied, eventually enhance reactive oxygen species (ROS) production and trigger apoptotic program. Conclusion: The application of Isodyn to the analysis of mechanism of edelfosine-induced apoptosis revealed primary drug-induced metabolic changes, which are important for the subsequent initiation of apoptotic program. Initiation of such metabolic changes could be exploited in anticancer therapy. [ABSTRACT FROM AUTHOR]

We examined the effect of early exercise training (Ex) on glucose kinetics, basal, and insulin-stimulated skeletal muscle (SKM) plasma membrane (PM) GLUT4 in pre- and/or postnatal nutrient-restricted adult rat offspring compared with sedentary (Sed) state. Pregestational control female (Ex CON vs. Sed CON) and offspring exposed to prenatal (Ex IUGR vs. Sed IUGR), postnatal (Ex PNGR vs. Sed PNGR), or pre- and postnatal (Ex IUGR + PNGR vs. Sed IUGR + PNGR) nutrient restriction were studied. The combined effect of exercise and pre/postnatal nutrition in the Ex IUGR demonstrated positive effects on basal and glucose-stimulated plasma insulin response (GSIR) with suppression of endogenous hepatic glucose production (HOP) compared with sedentary state. Ex PNGR was hyperglycemic after glucose challenge with no change in glucose-stimulated insulin production or HGP compared with sedentary state. Ex IUGR + PNGR remained glucose tolerant with unchanged glucose-stimulated insulin production but increased endogenous HOP compared with sedentary state. Basal SKM PM-associated GLUT4 was unchanged by exercise in all four groups. Whereas Ex PNGR and Ex IUGR + PNGR insulin responsiveness was similar to that of Ex CON, Ex IUGR remained nonresponsive to insulin. Early introduction of regular Ex in the pregestational female offspring had a positive effect on hepatic adaptation to GSIR and HGP in IUGR and IUGR + PNGR, with no effect in PNGR. Change in insulin responsiveness of SKM GLUT4 translocation was observed in exercised IUGR + PNGR and PNGR but not in exercised IUGR. [ABSTRACT FROM AUTHOR]

To determine mechanisms underlying the transgenerational presence of metabolic perturbations in the intrauterine growth-restricted second-generation adult females (F2 IUGR) despite normalizing the in utero metabolic environment, we examined in vivo glucose kinetics and in vitro skeletal muscle postinsulin receptor signaling after embryo transfer of first generation (F1 IUGR) to control maternal environment. Female F2 rats, procreated by F1 pre- and postnatally nutrient- and growth-restricted (IUGR) mothers but embryo transferred to gestate in control mothers, were compared with similarly gestating age- and sex-matched control (CON) F2 progeny. Although there were no differences in birth weight or postnatal growth patterns, the F2 IUGR had increased hepatic weight, fasting hyperglycemia, hyperinsulinemia, and unsuppressed hepatic glucose production, with no change in glucose futile cycling or clearance, compared with F2 CON. These hormonal and metabolic aberrations were associated with increased skeletal muscle total GLUT4 and pAkt concentrations but decreased plasma membrane-associated GLUT4, total pPKCζ, and PKCζ enzyme activity, with no change in total SHP2 and PTP1B concentrations in IUGR F2 compared with F2 CON. We conclude that transgenerational presence of aberrant glucose/insulin metabolism and skeletal muscle insulin signaling of the adult F2 IUGR female offspring is independent of the immediate intrauterine environment, supporting nutritionally induced heritable mechanisms contributing to the epidemic of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

A current trend in neuroscience research is the use of stable isotope tracers in order to address metabolic processes in vivo. The tracers produce a huge number of metabolite forms that differ according to the number and position of labeled isotopes in the carbon skeleton (isotopomers) and such a large variety makes the analysis of isotopomer data highly complex. On the other hand, this multiplicity of forms does provide sufficient information to address cell operation in vivo. By the end of last millennium, a number of tools have been developed for estimation of metabolic flux profile from any possible isotopomer distribution data. However, although well elaborated, these tools were limited to steady state analysis, and the obtained set of fluxes remained disconnected from their biochemical context. In this review we focus on a new numerical analytical approach that integrates kinetic and metabolic flux analysis. The related computational algorithm estimates the dynamic flux based on the time-dependent distribution of all possible isotopomers of metabolic pathway intermediates that are generated from a labeled substrate. The new algorithm connects specific tracer data with enzyme kinetic characteristics, thereby extending the amount of data available for analysis: it uses enzyme kinetic data to estimate the flux profile, and vice versa, for the kinetic analysis it uses in vivo tracer data to reveal the biochemical basis of the estimated metabolic fluxes. [ABSTRACT FROM AUTHOR]

Metabolic control analysis (MCA) provides a quantitative description of substrate flux in response to changes in system parameters of complex enzyme systems. Medical applications of the approach include the following: understanding the threshold effect in the manifestation of metabolic diseases; investigating the gene dose effect of aneuploidy in inducing phenotypic transformation in cancer; correlating the contributions of individual genes and phenotypic characteristics in metabolic disease (e.g., diabetes); identifying candidate enzymes in pathways suitable as targets for cancer therapy; and elucidating the function of "silent" genes by identifying metabolic features shared with genes of known pathways. MCA complements current studies of genomics and proteomics, providing a link between biochemistry and functional genomics that relates the expression of genes and gene products to cellular biochemical and physiological events. Thus, it is an important tool for the study of genotype-phenotype correlations. It allows genes to be ranked according to their importance in controlling and regulating cellular metabolic networks. We can expect that MCA will have an increasing impact on the choice of targets for intervention in drug discovery. [ABSTRACT FROM AUTHOR]

Stearoyl-CoA desaturase (SCD) is a key enzyme in the conversion of stearate to oleate (C18:0 to C18:1), and palmitate to palmitoleate (C16:0 to C16:1). There are two mouse SCD genes (SCD1 and SCD2). While SCD 1 is the isoform of SCD highly expressed in the liver and adipose tissue, and its expression is induced during adipocyte differentiation with dexamethasone and insulin, SCD2 is constitutively expressed in preadipocytes. The objective of the study is to evaluate the effect of SCD inhibition on fatty acid composition and turnover in NIH3T3 preadipocytes. NIH3T3 preadipocytes were grown in culture for 72 hours with [U-[sup 13]C] stearate and [1, 2 [sup 13]C]-acetate with 1) DMSO or 2) 0.8 µM of SCD inhibitor 06811M1005 (generously provided by CompleGen, Inc.). Analysis of fatty acid mass isotopomers was performed by gas chromatography/mass spectroscopy (GCMS). Fatty acid composition and the desaturation indices were calculated from the gas chromatogram. In cells cultured with SCD inhibitor 06811M1005 in [U-[sup 13]C]-stearate and [1,2 [sup 13]C]-acetate, the desaturation index for C18:1 n-9 was significantly reduced by ∼30% (p<0.03). There was a reduction in the conversion of U-stearate to U-oleate from 64% to 38% (p<0.04) when SCD was inhibited. While 13C isotopomer enrichment of palmitate and stearate reached the same plateau levels in treated and untreated cells, 13C isotopomer enrichment of oleate in the treated cells was significantly lower than control suggesting reduced oleate turnover during the study period. We conclude: NIH3T3 preadipocytes differentiate either in the presence of dexamethasone and insulin or PPAR υ agonist into adipocytes with phenotypes having different expression of SCD1. SCD inhibitor 06811M 1005 probably acts equally on SCD1 and SCD2 in the preadipocytes resulting in a change in desaturation index. Contrary to the expectation of reduced de novo lipogenesis, SCD inhibition primarily reduced on the conversion of stearate to oleate and the turnover of oleate without affecting the uptake and de novo synthesis of palmitate or stearate. [ABSTRACT FROM AUTHOR]

Neurologists are worried about bleeding and complications from lumbar punctures in patients who use antiplatelet agents, such as aspirin and clopidogrel. We evaluated the bleeding risks of performing lumbar punctures in patients who are using or have recently used antiplatelet agents by retrospective review of lumbar punctures performed at the Johns Hopkins Hospital between 2004 and 2018 in patients who were actively using or recently used aspirin or clopidogrel, or both. Patients were stratified into time groups based on when the lumbar puncture was done relative to the time the antiplatelet drug was discontinued: <1 week, 1-4 weeks, >4 weeks. We recorded red blood cell counts for the earliest and latest spinal fluid collections to determine the risk of traumatic bleeding; we also noted any complications. Antiplatelet medication use within 1 week of lumbar puncture was associated with a 3% incidence of bloody tap and 4% incidence of traumatic tap that cleared. In the group of patients who waited for a lumbar puncture at least 4 weeks after discontinuation of antiplatelet drug, there was a 5% incidence of bloody or traumatic tap. There was no difference in rates of bleeding between aspirin versus aspirin plus clopidogrel. The rate of hematoma complications was highest in the group of patients on aspirin at the time of the procedure (0.7%). Aspirin or clopidogrel, or both, did not meaningfully increase hemorrhagic complications in patients undergoing lumbar punctures, regardless of when the antiplatelet drug was discontinued relative to the time of the procedure., (Copyright © 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Mitochondria are generally considered as a powerhouse in a cell where the majority of the cellular ATP and metabolite productions occur. Metabolic rewiring and reprogramming may be initiated and regulated by mitochondrial enzymes. The hypothesis that cellular metabolic rewiring and reprogramming processes may occur as cellular microenvironment is disturbed, resulting in alteration of cell phenotype, such as cancer cells resistant to therapeutics seems to be now acceptable. Cancer metabolic reprogramming regulated by mitochondrial enzymes is now one of the hallmarks of cancer. This chapter provides an overview of cancer metabolism and summarizes progress made in mitochondria-mediated metabolic regulation in cancer drug resistance.

Objective: Postnatal calorie and growth restriction (PNGR) in the first generation (F1) rat female offspring causes a lean and glucose tolerant phenotype associated with hypoinsulinemia and reduced glucose-stimulated insulin secretion (GSIS). Despite the absence of gestational hyperglycemia in the F1 PNGR female, naturally born second generation (F2) PNGR female adult offspring reportedly exhibit obesity, hyperglycemia with insulin resistance. The objective of this study was to determine the role of the intrauterine environment on the heritability of the trans-generational phenotypic expression in the F2 PNGR female adult offspring., Materials/methods: We performed embryo transfer (ET) of the F2 embryos from the procreating F1 pregnant PNGR or control (CON) females to gestate in control recipient rat mothers. Employing stable isotopes glucose metabolic kinetics was determined., Results: Birth weight, postnatal growth pattern and white adipose tissue in female F2 ET-PNGR were similar to ET-CON. Similarly, no differences in basal glucose and insulin concentrations, GSIS, glucose futile cycling and glucose clearance were seen. When compared to F2 ET-CON, F2 ET-PNGR showed no overall difference in glucose or hepatic glucose production (HGP) AUCs with minimal hyperglycemia (p<0.04) as a result of unsuppressed endogenous HGP (p<0.02) observed only during the first phase of IVGTT., Conclusions: We conclude that the lean, glucose tolerant and hypoinsulinemic phenotype with reduced GSIS in the F1 generation is nearly normalized when the embryo-transferred F2 offspring gestates in a normal metabolic environment. This observation supports a role for the intra-uterine environment in modifying the heritability of the trans-generational PNGR phenotype., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Prenatal nutrient restriction with intrauterine growth restriction (IUGR) alters basal and glucose-stimulated insulin response and hepatic metabolic adaptation. The effect of early intervention with insulin-sensitizing peroxisome proliferator-activated receptor gamma agonists was examined in the metabolically maladapted F(1) pregestational IUGR offspring with a propensity toward pregnancy-induced gestational diabetes. The effect of rosiglitazone maleate [RG; 11 micromol/day from postnatal day (PN) 21 to PN60] vs. placebo (PL) on metabolic adaptations in 2-mo-old F(1) female rats subjected to prenatal (IUGR), postnatal (PNGR), or pre- and postnatal (IUGR + PNGR) nutrient restriction was investigated compared with control (CON). RG vs. PL had no effect on body weight or plasma glucose concentrations but increased subcutaneous white and brown adipose tissue and plasma cholesterol concentrations in all three experimental groups. Glucose tolerance tests with a 1:1 mixture of [2-(2)H(2)]- and [6,6-(2)H(2)]glucose in RG IUGR vs. PL IUGR revealed glucose tolerance with a lower glucose-stimulated insulin release (GSIR) and suppressed endogenous hepatic glucose production (HGP) with no difference in glucose clearance (GC) and recycling (GR). RG PNGR, although similar to PL CON, was hyperglycemic vs. PL PNGR with reduced GR but no difference in the existent low GSIR, HGP, and GC. RG IUGR + PNGR overall was no different from the PL counterpart. Insulin tolerance tests revealed perturbed recovery to baseline from the exaggerated hypoglycemia in RG vs. the PL groups with the only exception being RG PNGR where further worsening of hypoglycemia over PL PNGR was minimal with full recovery to baseline. These observations support that early intervention with RG suppressed HGP in IUGR vs. PL IUGR, without increasing GSIR similar to that seen in CON. Although RG reversed PNGR to the PL CON metabolic state, no such insulin-sensitizing effect was realized in IUGR + PNGR.

Testosterone (T) and its metabolite dihydrotestosterone (DHT) are androgens with different biologic profiles. T and DHT measurements are required for assessment of patients with ambiguous genitalia, hirsutism, during 5 alpha reductase treatment of prostate disorders, and new androgen formulations. Our laboratory has developed and validated a method to simultaneously measure serum T and DHT with liquid chromatography tandem mass spectrometry (LC-MS/MS) for use in a clinical chemistry laboratory. Analysis of sera from blood collected in tubes containing clot activator gave results of T that were fourfold higher than blood collected in plain tubes. Changing the ion pair selected for monitoring eliminated this interference by clot activators. Blood collected in fluoride-coated tubes gave serum T and DHT levels that were 20 and 15% lower, respectively than levels measured in blood collected in plain tubes (no additives). Addition of T enanthate to blood collected in plain tubes caused a dose related increase serum T levels due to the action of non-specific esterases in the red cells. This esterase activity could be avoided by using fluoride tubes for blood collection. Serum DHT levels were consistently lower when measured by LC-MS/MS versus radioimmunoassay. The differences were concentration dependent and the variance for the difference was large when serum DHT concentration was low. Celite chromatograph prior to radioimmunoassay reduced the differences between the two methods, thus confirming that higher levels of DHT obtained by immunoassays were probably due to interfering substances which were partially removed by Celite chromatography.

Background: Recent reports have described inherent problems with androgen immunoassays compared with mass spectrometry analyses., Methods: We developed a method for measuring serum testosterone (T) and 5alpha-dihydrotestosterone (DHT) simultaneously via liquid-liquid extraction followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with positive-mode electrospray ionization., Results: The DHT and T calibrators showed a linear response from 0.069 nmol/L to 34.4 nmol/L and 69.3 nmol/L, respectively. T interference in the DHT assay and vice versa were negligible. Within- and between-run imprecision values were <5% for both analytes. Percent recoveries of T and DHT spiked into samples at concentrations spanning the calibration curve were 100%-113% and 98%-107%, respectively. The lower limit of quantification was 0.069 nmol/L for both steroids. Serum T concentrations measured by LC-MS/MS were different from those obtained by RIA, especially at lower T concentrations. Serum DHT concentrations measured by LC-MS/MS were markedly lower than those generated by RIA because of the nonselectivity of the RIA without chromatography. The reference intervals (mean +/- 2 SDs) determined for T and DHT were 9.2-33.7 nmol/L and 0.47-2.65 nmol/L, respectively, for 113 healthy adult men and 0.33-2.02 nmol/L and 0.09-0.91 nmol/L, respectively, for 133 healthy premenopausal women., Conclusions: We have developed and validated a selective and precise method for simultaneous measurements of serum T and DHT that can be adopted for routine measurements of these androgens in health and disease in men and women.

The metabolism of [1, 2 (13)C(2)] glucose via the tricarboxylic acid (TCA) cycle yields a number of key glutamate mass isotopomers whose formation is a function of pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH). Analysis of the isotopomer distribution patterns was used to determine the relative flux of glucose entry into the TCA cycle through anaplerotic and oxidative pathways in the cerebral cortex of both uninjured and traumatically injured adult male rats. In the cerebral cortex of uninjured animals the PC/PDH ratio showed greater metabolism of glucose via pyruvate carboxylase, which is consistent with the notion that the majority of glucose taken up at rest is used as a substrate for anaplerotic processes and not as an energy source. While traumatic brain injury did not change the overall (13)C enrichment of glutamate indicating a continued oxidation of glucose, the PC/PDH ratio was reduced in the injured cortex at 3.5 h after injury. This suggests that glucose metabolism is primarily directed through pathways associated with energy production in the early postinjury period. By 24 h, the anaplerotic flux decreased and the PC/PDH ratio increased in both the injured and non-injured cortex indicating a switch away from energy production to pathways associated with anabolic and/or regenerative processes.