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AbstractWe performed a new series of measurements on samples that were part of early measurements on radiocarbon (14C) dating made in 1948–1949. Our results show generally good agreement to the data published in 1949–1951, despite vast changes in technology, with only two exceptions where there was a discrepancy in the original studies. Our new measurements give calibrated ages that overlap with the known ages. We dated several samples at four different laboratories, and so we were also able to make a small intercomparison at the same time. In addition, new measurements on samples from other Egyptian materials used by Libby and co-workers were made at UC Irvine. Samples of tree rings used in the original studies (from Broken Flute Cave and Centennial Stump) were obtained from the University of Arizona Laboratory of Tree-Ring Research archive and remeasured. New data were compared to the original studies and other records.

ABSTRACTACT-387042 and ACT-292706 are two novel bacterial topoisomerase inhibitors with broad-spectrum activity against Gram-positive and -negative bacteria, including methicillin-resistant Staphylococcus aureusand penicillin- and fluoroquinolone-resistant Streptococcus pneumoniae. We used the neutropenic murine thigh infection model to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of these investigational compounds against a group of 10 S. aureusand S. pneumoniaeisolates with phenotypic resistance to beta-lactams and fluoroquinolones. The in vitroactivities of the two compounds were very similar (MIC range, 0.03 to 0.125 mg/liter). Plasma pharmacokinetics were determined for each compound by using four escalating doses administered by the subcutaneous route. In treatment studies, mice had 107.4to 108CFU/thigh at the start of therapy with ACT-387042 and 106.7to 108.3CFU/thigh at the start of therapy with ACT-292706. A dose-response relationship was observed with all isolates over the dose range. Maximal kill approached 3 to 4 log10CFU/thigh compared to the burden at the start of therapy for the highest doses examined. There was a strong relationship between the PK/PD index AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) and therapeutic efficacy in the model (R2, 0.63 to 0.82). The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-387042 against S. aureusand S. pneumoniaewere 43 and 10, respectively. The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-292706 against S. aureusand S. pneumoniaewere 69 and 25, respectively. The stasis PD targets were significantly lower for S. pneumoniae(P< 0.05) for both compounds. The 1-log-kill AUC/MIC ratio targets were ∼2- to 4-fold higher than stasis targets. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy. These results should be helpful in the design of clinical trials for topoisomerase inhibitors.

Abstract:: We analyse theoretically the generation of second and higher harmonics for sodium clusters deposited on an insulating surface. To this end, we use the time-dependent local-density approximation solved on a three-dimensional grid. We explore the impact of the various laser parameters (intensity, frequency, polarisation) on the efficiency of second harmonic generation. The success sensitively depends on a proper tuning of these parameters. We find optimum conditions for which the laser frequency is half the resonance frequency of the system, if the polarisation is directed orthogonal to the surface of the substrate, and if the intensity is large but safely below the critical value for destruction of the electron cloud.

The mRNAs encoding mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mtHMG-CoA synthase), the rate limiting enzyme in ketone body production, are highly expressed in subcutaneous (SC) and, to a lesser extent, in peri-epididymal (PE) rat adipose tissues. This atypical mtHMG-CoA synthase gene expression is dependent on the age (from 9 weeks of age) and sex (higher in male than in female) of the rats. In contrast, the expression of mtHMG-CoA synthase in SC adipose deposit is independent of the nutritional state (fed versus starved) or of the thermic environment (24 degrees C versus 4 degrees C). The expression of mtHMG-CoA synthase is suppressed in SC fat pads of castrated male rats whereas treatment of castrated rats with testosterone restores a normal level of expression. Moreover, testosterone injection induces the expression mtHMG-CoA synthase in SC adipose tissue of age-matched females. The presence of the mtHMG-CoA synthase immunoreactive protein confers to mitochondria isolated from SC adipose deposits, the capacity to produce ketone bodies at a rate similar to that found in liver mitochondria (SC = 13.7 +/- 0.7, liver = 16.4 +/- 1.4 nmol/min/mg prot). mtHMG-CoA synthase is expressed in the stromal vascular fraction (SVF) whatever the adipose deposit considered. While acetyl-CoA carboxylase (ACC) is only expressed in mature adipocytes, the other lipogenic enzymes, fatty acid synthase (FAS) and citrate cleavage enzyme (CCE), are expressed both in SVF cells and mature adipocytes. The expression of lipogenic enzyme genes is markedly reduced in adipocytes but not in SVF cells isolated from 48-h starved male rats. When SVF is subfractionated, mtHMG-CoA synthase mRNAs are mainly recovered in two fractions containing poorly digested structures such as microcapillaries whereas the lowest expression is found in the pre-adipocyte fraction. Interestingly, FAS and CCE mRNAs co-segregate with mtHMG-CoA synthase mRNA. The possible physiological relevance of such atypical expression of mtHMG-CoA synthase is discussed.

We investigate spin modes in the ground state and the polarized first isomer of the Na₁₂ cluster describing the valence electrons in time-dependent local-spin-density approximation (TDLSDA) and the detailed ionic background using local pseudopotentials. The spin modes show a collective redshift compared to the unperturbed particle-hole excitations. They are strongly fragmented and the average energy of the modes along the principal axes are related to the underlying geometry (triaxial or axially symmetric). For the polarized isomer, we find significant cross talk between the spin modes and the dipole plasmon, which hints at a possible spectroscopic identification.

The formation of space charge layers by the action of surface states and the influence of more than one bulk impurity level are treated. Special attention is given to compound semiconductors. Recent experimental results are reported of subband spectroscopy, work function measurements, and metal semiconductor junction investigations. Requirements for simultaneous surface conductivity and LEED measurements are given. The contribution of various scattering processes to the dc conductivity is discussed. Finally the relations between surface reactions and space charge layers are considered.

Ohne Zusammenfassung:

In newborn-pig hepatocytes, the rate of oleate oxidation is extremely low, despite a very low malonyl-CoA concentration. By contrast, the sensitivity of carnitine palmitoyltransferase (CPT) I to malonyl-CoA inhibition is high, as suggested by the very low concentration of malonyl-CoA required for 50% inhibition of CPT I (IC50). The rates of oleate oxidation and ketogenesis are respectively 70 and 80% lower in mitochondria isolated from newborn-pig liver than from starved-adult-rat liver mitochondria. Using polarographic measurements, we showed that the oxidation of oleoyl-CoA and palmitoyl-L-carnitine is very low when the acetyl-CoA produced is channelled into the hydroxymethylglutaryl-CoA (HMG-CoA) pathway by addition of malonate. In contrast, the oxidation of the same substrates is high when the acetyl-CoA produced is directed towards the citric acid cycle by addition of malate. We demonstrate that the limitation of ketogenesis in newborn-pig liver is due to a very low amount and activity of mitochondrial HMG-CoA synthase as compared with rat liver mitochondria, and suggest that this could promote the accumulation of acetyl-CoA and/or beta-oxidation products that in turn would decrease the overall rate of fatty acid oxidation in newborn- and adult-pig livers.

The temporal changes in oleate oxidation, lipogenesis, malonyl-CoA concentration and sensitivity of carnitine palmitoyltransferase I (CPT 1) to malonyl-CoA inhibition were studied in isolated rabbit hepatocytes and mitochondria as a function of time after birth of the animal or time in culture after exposure to glucagon, cyclic AMP or insulin. (1) Oleate oxidation was very low during the first 6 h after birth, whereas lipogenesis rate and malonyl-CoA concentration decreased rapidly during this period to reach levels as low as those found in 24-h-old newborns that show active oleate oxidation. (2) The changes in the activity of CPT I and the IC50 (concn. causing 50% inhibition) for malonyl-CoA paralleled those of oleate oxidation. (3) In cultured fetal hepatocytes, the addition of glucagon or cyclic AMP reproduced the changes that occur spontaneously after birth. A 12 h exposure to glucagon or cyclic AMP was sufficient to inhibit lipogenesis totally and to cause a decrease in malonyl-CoA concentration, but a 24 h exposure was required to induce oleate oxidation. (4) The induction of oleate oxidation by glucagon or cyclic AMP is triggered by the fall in the malonyl-CoA sensitivity of CPT I. (5) In cultured hepatocytes from 24 h-old newborns, the addition of insulin inhibits no more than 30% of the high oleate oxidation, whereas it stimulates lipogenesis and increases malonyl-CoA concentration by 4-fold more than in fetal cells (no oleate oxidation). This poor effect of insulin on oleate oxidation seems to be due to the inability of the hormone to increase the sensitivity of CPT I sufficiently. Altogether, these results suggest that the malonyl-CoA sensitivity of CPT I is the major site of regulation during the induction of fatty acid oxidation in the fetal rabbit liver.

The phosphodiesterase (PDE) inhibitor isomazole increased the force of contraction to 278.3 ± 89.1 (n = 7) of the predrug value in ventricular trabeculae carneae isolated from nonfailing human hearts. This effect can be attributed mainly to a PDE III or a combined PDE III/IV inhibition since at the concentration of the maximal positive inotropic effect of isomazole, PDE III and PDE IV were completely inhibited. In explanted failing human hearts (end-stage myocardial failure, NYHA IV), isomazole increased the force of contraction only marginally to 110.1 ± 10.7 of the predrug value. The lack of a distinct positive inotropic efficacy of isomazole in failing human hearts could not be explained by an impairment of PDE inhibition since the properties of the PDE I-IV isoenzymes separated by DEAE-Sepharose chromatography and the inhibitory effects of isomazole did not differ in both preparations. The positive inotropic effect of the β-adrenoceptor agonist isoprenaline was also reduced in failing hearts. However, in the presence of isomazole, the diminished positive inotropic effect of isoprenaline was restored to values obtained with isoprenaline alone in nonfailing hearts. Thus, the decreased effect of inotropic drugs like isoprenaline or isomazole in preparations from failing human heart might be explained mainly by a diminished cAMP formation due to a defect in receptor-adenylate cyclase coupling.

The optical response of sodium clusters is studied using fully three-dimensional electronic dynamics, in real time, with an explicit ionic background. The obtained spectra are shown to come close to experimental results for free clusters. We use the approach also to compute the response of sodium clusters deposited on a NaCl(1 0 0) surface. The flattening of the clusters induced by the surface results in a shift and a large fragmentation of the plasmon resonance.

The positive inotropic effect of the alpha1-adrenoceptor agonist phenylephrine is accompanied by an increase in the presumed second messengers inositol 1,4,5-trisphosphate (1,4,5-IP3) and inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-IP4). Both 1,4,5-IP3and 1,3,4,5-IP4sensitize myocardial contractile proteins in chemically skinned fibers. In addition to the Ca++releasing effect of 1,4,5-IP3from the sarcoplasmic reticulum the Ca++-sensitizing effect of the inositol phosphates may play a role in alpha1-adrenergic positive inotropism. In isolated heart muscle preparations from patients with endstage heart failure (due to dilated cardiomyopathy) beta-adrenergic as well as alpha1-adrenergic effects are reduced compared to preparations from healthy hearts. The reduced beta-adrenergic effects can in part be explained by an increased content of signal transducing G1-proteins. It is tempting to investigate whether other G proteins are also altered in severe congestive heart failure.

The effects of pancreatic hormones and cyclic AMP on the induction of ketogenesis and long-chain fatty acid oxidation were studied in primary cultures of hepatocytes from fetal and newborn rabbits. Hepatocytes were cultivated during 4 days in the presence of glucagon (10(-6) M), forskolin (2 x 10(-5) M), dibutyryl cyclic AMP (10(-4) M), 8-bromo cyclic AMP (10(-4) M) or insulin (10(-7) M). Ketogenesis and fatty acid metabolism were measured using [1-14C]oleate (0.5 mM). In hepatocytes from fetuses at term, the rate of ketogenesis remained very low during the 4 days of culture. In hepatocytes from 24-h-old newborn, the rate of ketogenesis was high during the first 48 h of culture and then rapidly decreased to reach a low value similar to that measured in cultured hepatocytes from term fetuses. A 48 h exposure to glucagon, forskolin or cyclic AMP derivatives is necessary to induce ketone body production in cultured fetal hepatocytes at a rate similar to that found in cultured hepatocytes from newborn rabbits. In fetal liver cells, the induction of ketogenesis by glucagon or cyclic AMP results from changes in the partitioning of long-chain fatty acid from esterification towards oxidation. Indeed, glucagon, forskolin and cyclic AMP enhance oleate oxidation (basal, 12.7 +/- 1.6; glucagon, 50.0 +/- 5.5; forskolin, 70.6 +/- 5.4; cyclic AMP, 77.5 +/- 3.4% of oleate metabolized) at the expense of oleate esterification. In cultured fetal hepatocytes, the rate of fatty acid oxidation in the presence of cyclic AMP is similar to the rate of oleate oxidation present at the time of plating (85.1 +/- 2.6% of oleate metabolized) in newborn rabbit hepatocytes. In hepatocytes from term fetuses, the presence of insulin antagonizes in a dose-dependent fashion the glucagon-induced oleate oxidation. Neither glucagon nor cyclic AMP affect the activity of carnitine palmitoyltransferase I (CPT I). The malonyl-CoA concentration inducing 50% inhibition of CPT I (IC50) is 14-fold higher in mitochondria isolated from cultured newborn hepatocytes (0.95 microM) compared with fetal hepatocytes (0.07 microM), indicating that the sensitivity of CPT I decreases markedly in the first 24 h after birth. The addition of glucagon or cyclic AMP into cultured fetal hepatocytes decreased by 80% and 90% respectively the sensitivity of CPT I to malonyl-CoA inhibition. In the presence of cyclic AMP, the sensitivity of CPT I to malonyl-CoA inhibition in cultured fetal hepatocytes is very similar to that measured in cultured hepatocytes from 24-h-old newborns.

The m-cholinoceptor agonist carbachol elicits a negative inotropic effect in mammalian atria. Pretreatment with pertussis toxin converts the negative to a positive inotropic effect. In this study we investigated the time course of the effects of carbachol on force of contraction and phosphoinositide products in electrically driven left auricles from guinea pig hearts after pretreatment with pertussis toxin (180 micrograms/kg i.v.; 24 hr). Inositol phosphates and phosphatidylinositols were labeled with [3H]inositol and separated with high-performance liquid chromatography and thin-layer chromatography, respectively. All experiments were performed in the presence of LiCl (10 mmol/l). The positive inotropic effect of carbachol (10 mumol/l) began within 2 min and was maximal within 15 min. Inositol 1,4,5-trisphosphate rose within 1 min followed by an increase in inositol 1,3,4,5-tetrakisphosphate, inositol 1,3,4-trisphosphate, inositol 1,4-bisphosphate and inositol 1-phosphate beginning within 2 min. It is concluded that the carbachol-induced positive inotropic effect is associated with an increase in the presumed second messengers inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. Since the increase in inositol 1,4,5-trisphosphate precedes the increase in force of contraction, it may initiate the positive inotropic effect. The increase in inositol 1,3,4,5-tetrakisphosphate may be involved in maintaining the positive inotropic effect of carbachol.

The rat liver carnitine palmitoyltransferase 1 (L-CPT1), an integral outer mitochondrial membrane (OMM) protein, is the key regulatory enzyme of fatty acid oxidation and is inhibited by malonyl-CoA. In vitro import of L-CPT1 into the OMM requires the presence of mitochondrial receptors and is stimulated by ATP but is membrane potential-independent. Its N-terminal domain (residues 1-150), which contains two transmembrane segments, possesses all of the information for mitochondrial targeting and OMM insertion. Deletion of this domain abrogates protein targeting, whereas its fusion to non-OMM-related proteins results in their mitochondrial targeting and OMM insertion in a manner similar to L-CPT1. Functional analysis of chimeric CPTs expressed in Saccharomyces cerevisiae shows that this domain also mediates in vivo protein insertion into the OMM. When the malonyl-CoA-insensitive CPT2 was anchored at the OMM either by a specific OMM signal anchor sequence (pOM29) or by the N-terminal domain of L-CPT1, its activity remains insensitive to malonyl-CoA inhibition. This indicates that malonyl-CoA sensitivity is an intrinsic property of L-CPT1 and that its N-terminal domain cannot confer malonyl-CoA sensitivity to CPT2. Replacement of the N-terminal domain by pOM29 results in a less folded and less active protein, which is also malonyl-CoA-insensitive. Thus, in addition to its role in mitochondrial targeting and OMM insertion, the N-terminal domain of L-CPT1 is essential to maintain an optimal conformation for both catalytic function and malonyl-CoA sensitivity.

CH3CH2OD (deuterated ethanol) pulses (5 × 10-4 ML, 20 ms) are offered to polycrystalline ZnO under ultra high vacuum conditions. The reaction products are monitored with a rate of 1000 spectra per second by a time of flight mass spectrometer. D2O and CO2, both including lattice oxygen, are observed in desorption. The creation of surface oxygen vacancies destabilizes zinc atoms nearby which appear also in desorption. The rate constant ka (inverse relaxation time) increases below 900 K. Above this temperature ka decreases. The decrease may be due to bulk oxygen diffusing to the surface and refilling the surface oxygen vacancies.

The article discusses the history of the creation of the University Art Museum of the California State University in Long Beach, California. According to the author, the history of the museum involves a series of significant dates from the settlement of California in 1849, the creation of the campus in 1949, and to imagine the structure of the museum in the year 2049. The museum's history and future would lead people to learn about the culture that existed for the period of 200 years. The article also presents several maps of the museums along with their basic architectural patterns and combinations.