Instability of anti-de Sitter spacetime.
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Journal Article↗
Biomedical subjects
L Liu
Publications and source records attributed to L Liu.
Chiral derivatizing reagents for drug enantiomers bearing hydroxyl groups.
This review extensively summarizes and critically evaluates the recent research on the indirect resolution technique for enantiomeric alcohols. Twenty-one chiral derivatizing reagents divided in seven types, including chiral acids, activated acids, chloroformates, isocyanates, carbonyl nitriles, oxazolidin-2-ones and lactones, are described. The derivatization methods of the various chiral reagents, the liquid chromatography separation systems, the detection systems used for the diastereomeric derivatives of alcohols as well as their limitations and the prospects of the indirect resolution technique for the future are thoroughly discussed. This paper aims to instruct the application of a particular chiral reagent and the technical approach to be used and should be beneficial to the development of an indirect resolution method for enantiomeric alcohols as well as to the biomedical investigation of the differences between the antipodes of chiral alcohols.
Alcohols↗
Heat shock of vascular endothelial cells induces an up-regulatory transcriptional response of the thrombomodulin gene that is delayed in onset and does not attenuate.
Thrombomodulin is a vascular endothelial cell transmembrane protein that forms a 1:1 complex with thrombin, this interaction product forming the basis of a physiologically important natural anticoagulant system. Transcriptional down-regulation of thrombomodulin occurs following exposure of cultured endothelial cells to cytokines, while up-regulation is induced by retinoic acid and dibutyryl cyclic AMP. Thrombomodulin is also regulated developmentally, appearing in the parietal endoderm of 7.5-day-old mouse embryos. We determined that cell surface functional thrombomodulin in cultured human umbilical vein endothelial cells (HUVEC) and A549 cells increased 3.2- and 6.7-fold, respectively, in response to 24 h of continuous 42 degrees C heat shock stress. Northern analyses of thrombomodulin mRNA accumulation also showed a delayed response that was characterized by an augmentation in mRNA levels that started 12-18 h after the initiation of the stress, and continued to rise, without attenuation, during 48 h of continuous heat shock. Nuclear run-on studies confirmed that the predominant mechanism of augmentation was transcriptional. Furthermore, the heat shock-induced up-regulation of thrombomodulin in HUVEC abrogated the suppressive effect of tumor necrosis factor. Analysis of the 5' region of the thrombomodulin gene revealed six highly conserved tandem copies of the five base pair recognition unit that is the consensus sequence for a heat shock element. We hypothesize that the stress-induced augmentation in thrombomodulin gene transcription is mediated via heat shock factors binding to the heat shock element and that the stress response of thrombomodulin may have a biological role to protect the vascular endothelium during a variety of stresses, including inflammation, infection, and/or development.
Animals↗
Bioassay of procoagulant albumin in human plasma.
Procoagulant albumin (P-Al) is present in normal human plasma and increases monocyte and endothelial cell expression of tissue factor activity. To develop a bioassay for P-Al, we partially purified plasma from healthy volunteers and several patient groups using BaCl2 and (NH4)2SO4 precipitation. The samples were assayed for tissue factor (TF) inducing activity, expressed as a percentage increase compared to a serum-free media control. Over six months, the assay was reproducible in stored samples and in serial samples from normal volunteers. The plasma P-Al activities of 35 volunteers averaged 141 +/- 8.2% (SEM). There was no diurnal variation. There was no difference in the P-Al activity after a 12 hour fast and 2 hours after a large meal in 4 healthy volunteers. There was no increase in activity (r = 0.16) with the subject's age. The average activity from 16 poorly-controlled diabetics was 131 +/- 11% (SEM). No alteration in activity was seen with samples from patients with uremia, liver dysfunction, hemophilia, thrombotic events, or adenocarcinoma. These results indicate that P-Al activity can be bioassayed in individual patient samples; however, pathologic states associated with abnormal P-Al-induced tissue factor activity presently remain unidentified.
Adult↗
Rapid repair of O6-methylguanine-DNA adducts protects transgenic mice from N-methylnitrosourea-induced thymic lymphomas.
The methylating agent N-methylnitrosourea (MNU) is biased, surprisingly, in its carcinogenic potential toward the mouse thymus. Previous studies have shown that single doses of MNU administered to adult mice induced thymic lymphomas in over 80% of mice, while transgenic mice expressing high levels of the human O6-alkylguanine-DNA alkyltransferase gene in the thymus (MGMT-CD2 transgenics) were protected from developing MNU-induced lymphomas. The mechanism of this protection was examined in this report. In nontransgenic mice given a lymphomagenic dose of 80 mg/kg MNU, depletion of thymic alkyltransferase activity occurred within 3 h and remained undetectable for the subsequent 192 h; whereas in MGMT-CD2-transgenic mice, this dose of MNU did not deplete thymic alkyltransferase, and the lowest level of alkyltransferase was still 10-fold higher than the constitutive level of thymic alkyltransferase in nontransgenic mice. Likewise, the level of O6-methylguanine adducts detected in the thymus of nontransgenic mice was 96 pg/micrograms guanine 3 h after MNU compared to only 8 pg/micrograms guanine in transgenic mice. By 18 h, the level of O6-methylguanine in MGMT-CD2-transgenic mice was below 2 pg/micrograms guanine, compared to over 70 pg/micrograms guanine in nontransgenic mice. In contrast, no differences were noted in the liver between groups because the MGMT transgene is not expressed in the liver of this strain of mouse. Our data establish that rapid O6-methylguanine-DNA adduct repair due to enhanced levels of alkyltransferase in MGMT-CD2-transgenic mice blocks the initiation of MNU-induced carcinogenesis.
Animals↗
Platelet hyperfunction exists in both acute non-haemorrhagic and haemorrhagic stroke.
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Acute Disease↗
High extracellular GABA levels in hippocampus--as a mechanism of neuronal protection in cerebral ischemia in adrenalectomized gerbils.
Adrenalectomy protects the brain from delayed neuronal damage that occurs following transient forebrain ischemia in gerbils. Gamma-amino butyric acid (GABA) and GABA-mimetic drugs also have a neuro-protective effect. In this study we estimated the extracellular glutamate and GABA levels in the hippocampus during transient forebrain ischemia in adrenelectomized gerbils (n = 8) compared to controls (n = 6). Duration of ischemia was 10 min, and glutamate and GABA levels were measured with in vivo microdialysis. Microdialysis was started 2 h after the placement of a probe (to stabilise baseline) and samples were collected at 10-min intervals. The pattern of glutamate release did not show any difference between adrenelectomized animals and controls. Adrenelectomized animals showed marked increase in GABA levels during ischemia and upto 30 min after ischemia (P = 0.0287, 2-way ANOVA for repeated measurements). The enhanced GABA release may be one of the possible mechanisms of neuronal protection against ischemia in adrenelectomized gerbils.
Adrenalectomy↗
Steel factor stimulates the serine/threonine phosphorylation of the interleukin-3 receptor.
The murine interleukin-3 (IL-3) dependent cell line, B6SUtA1, which expresses high IL-3 receptor (IL-3R) numbers, was found to proliferate in a greater than additive fashion when grown in the presence of IL-3 and steel factor (SF). However, pretreatment of these cells with SF had no effect on the number of IL-3Rs expressed at the cell surface nor their affinity for IL-3. Interestingly, although, SF did induce the rapid and transient serine- and threonine-specific phosphorylation of the beta IL-3 subunit of the IL-3R. This serine/threonine phosphorylation was also observed with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, and both the 12-O-tetradecanoylphorbol-13-acetate- and SF-induced phosphorylation of the IL-3R could be inhibited with the highly specific protein kinase C inhibitor, bisindolylmaleimide (Compound 3), suggesting that SF might be stimulating this phosphorylation via protein kinase C. This SF-induced phosphorylation also occurred within 10 min of incubation at 4 degrees C, indicating that this might be a relatively early event in the c-kit signaling pathway. Last, this SF-induced phosphorylation of the IL-3R occurred in the presence of the tyrosine kinase inhibitor, genistein, at levels which blocked the autophosphorylation of c-kit. This suggests that c-kit might be capable of mediating this cross-talk phenomenon in the absence of its endogenous tyrosine kinase activity.
Animals↗
Identification of a new member of the protegrin family by cDNA cloning.
The porcine leukocyte protegrins are a family of cysteine-rich antimicrobial peptides the primary structures of which combine features of defensins and tachyplesins. We cloned three protegrins from porcine bone marrow mRNA by PCR, including one (PG-4) that was previously unknown. The 691 bp protegrin cDNAs were > 98.8% identical, and each was surrounded by highly conserved 5' and (in some instances) 3' sequences present in structurally dissimilar antimicrobial and LPS-binding peptides of animal leukocytes.
Amino Acid Sequence↗
Alkyltransferase transgenic mice: probes of chemical carcinogenesis.
Transgenic mice expressing DNA-repair genes are an instructive model with which to study the protective role of DNA-repair pathways in both spontaneous and chemical carcinogenesis. Of particular interest in chemical carcinogenesis is the DNA-repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase) which repairs O6-alkylguanine-DNA adducts. Transgenic mice carrying expression constructs for the alkyltransferase gene--either the human MGMT cDNA or the bacterial ada gene--express increased levels of alkyltransferase and have increased capacity to remove O6-methylguanine-DNA adducts. Protection from the DNA damaging effects of N-nitroso compounds occurs specifically in the cells and tissues in which the alkyltransferase transgene is expressed. For instance, mice carrying the PEPCKada construct have increased alkyltransferase in the liver and more rapid removal of O6methylguanine-DNA adducts. The protective effect is noted in hepatocytes, which express PEPCK-linked genes, not in nonparenchymal cells of the liver, which do not. Other tissues that express the transgene in the various models include the thymus, spleen, testes, muscle, stomach and brain. Mice expressing the human alkyltransferase in the thymus have a reduced incidence of thymic lymphomas following exposure to methyl nitrosourea (MNU), evidence of a role for this DNA-repair protein in protection from carcinogenesis due to N-nitroso compounds. Protection has also been observed in the induction of hepatic tumors by N-nitroso-dimethylamine (NDMA). These models will be used to identify whether overexpression of a single DNA-repair gene can block the carcinogenic process of N-nitroso compounds in many different tissues.
Actins↗
Interactions between laudanosine, GABA, and opioid subtype receptors: implication for laudanosine seizure activity.
We examined the interactions of D,L-laudanosine, a potentially epileptogenic metabolite of the neuromuscular relaxant atracurium besylate, with gamma-aminobutyric acid (GABA) and opioid binding sites, all of which have been implicated in seizure activity. Laudanosine was almost ineffective at [3H]muscimol binding to high-affinity GABA receptors (IC50 = 100 microM). However, laudanosine displayed an inhibitory effect at the low-affinity GABA receptors labeled by [3H]bicuculline methochloride, with an IC50 value of 10 microM. At the opioid receptor subtype, laudanosine lowered radiolabeled opioid binding at the mu 1, mu 2, delta, kappa 1, and kappa 3 receptors with Ki values of 2.7, 13, 5.5, 21, and 24 microM, respectively, concentrations seen clinically in blood and approaching those measured in cerebrospinal fluid. Saturation studies of mu 1, mu 2, delta, and kappa 3 sites in the presence of laudanosine revealed competitive interactions, with increases in the apparent Kd values but without significant changes in the maximal numbers of binding sites. In addition, we investigated whether the in vitro laudanosine-opioid receptor interaction would also be expressed by analgesic physiologic effects. We found that laudanosine elicited a dose-dependent analgesia in mouse tail-flick assay that was attenuated by coadministration of beta-funaltrexamine (mu 1- and mu 2-selective antagonist) and of naloxonazine (mu 1 antagonist), but not by nor-binaltorphimine (kappa 1-selective antagonist) or naltrindole (delta-selective antagonist), indicating a mu 1 mechanism for analgesia-mediated property of laudanosine. There is evidence suggesting mu 2 activity as well, but this is due to the ability of laudanosine to elicit analgesia when given intrathecally. We also observed cross-tolerance between laudanosine and morphine, as well as a partial effect of laudanosine on gastrointestinal transit. These results suggest an interaction between laudanosine and the low-affinity GABA receptor, as well as opioid mu 1 and mu 2 receptors.
Animals↗
Mapping of the genes encoding human inducible and endothelial nitric oxide synthase (NOS2 and NOS3) to the pericentric region of chromosome 17 and to chromosome 7, respectively.
Nitric oxide (NO) is an important molecular messenger regulating the functions of a wide variety of cells and tissues. NO is synthesized from L-arginine by a variety of isoforms of the enzyme nitric oxide synthase (NOS). We have used Southern blotting analysis on DNAs obtained from a panel of human-rodent hybrid cell lines to map the gene encoding the inducible NOS (NOS2) to chromosome 17cen-17q11 and the gene encoding the endothelial form of NOS (NOS3) to chromosome 7. Fluorescence in situ hybridization using a NOS2 probe gave several signals in the 17p11-q11 pericentromeric region.
Amino Acid Oxidoreductases↗
Direct measurements of room-temperature oxygen diffusion in YBa2Cu3Ox.
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Journal Article↗
Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria.
Phenylacetate, a deaminated metabolite of phenylalanine, has been implicated in damage to immature brain in phenylketonuria. Because primary brain tumors are highly reminiscent of the immature central nervous system, these neoplasms should be equally vulnerable. We show here that sodium phenylacetate can induce cytostasis and reversal of malignant properties of cultured human glioblastoma cells, when used at pharmacological concentrations that are well tolerated by children and adults. Treated tumor cells exhibited biochemical alterations similar to those observed in phenylketonuria-like conditions, including selective decline in de novo cholesterol synthesis from mevalonate. Because gliomas, but not mature normal brain cells, are highly dependent on mevalonate for production of sterols and isoprenoids vital for cell growth, sodium phenylacetate would be expected to affect tumor growth in vivo while sparing normal tissues. Systemic treatment of rats bearing intracranial gliomas resulted in significant tumor suppression with no apparent toxicity to the host. The data indicate that phenylacetate, acting through inhibition of protein prenylation and other mechanisms, may offer a safe and effective novel approach to treatment of malignant gliomas and perhaps other neoplasms as well.
Animals↗
Normal-state resistance fluctuations in high-Tc cuprate films.
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Journal Article↗
A rapid capsaicin-activated current in rat trigeminal ganglion neurons.
A subpopulation of pain fibers are activated by capsaicin, the ingredient in red peppers that produces a burning sensation when eaten or placed on skin. Previous studies on dorsal root ganglion neurons indicated that capsaicin activates sensory nerves via a single slowly activating and inactivating inward current. In rat trigeminal neurons, we identified a second capsaicin-activated inward current. This current can be distinguished from the slow one in that it rapidly activates and inactivates, requires Ca2+ for activation, and is insensitive to the potent capsaicin agonist resiniferatoxin. The rapid current, like the slower one, is inhibited by ruthenium red and capsazepine. The two capsaicin-activated inward currents share many similarities with the two inward currents activated by lowering the pH to 6.0. These similarities include kinetics, reversal potentials, responses to Ca2+, and inhibition by ruthenium red and capsazepine. These results suggest that acidic stimuli may be an endogenous activator of capsaicin-gated currents and therefore may rationalize why pain is produced when the plasma acidity is increased, as occurs during ischemia and inflammation.
Animals↗
Quantitative stereoscopic depth without binocular correspondence.
What features in a stereogram define the disparities that lead to stereoscopic depth? The usual answer is that luminance-defined edges from the two eyes are matched and produce depth perception. But parts of an object may be occluded by other objects and absent from one eye's view. It was suggested that unpaired monocular elements might signal occlusion in depth, and the qualitative perception of depth associated with unmatched elements has been shown to be consistent with the geometry of occlusion. We designed a stereogram that simulates a particular occlusion situation: an opaque white rectangle is stereoscopically in front of a large black rectangle pasted on a white background. The position of the occluder is adjusted so that its left edge obscures the left-hand edge of the black rectangle in the right eye view and its right edge obscures the right-hand edge of the black rectangle in the left eye view. We report here that quantitative stereopsis can be seen from this stereogram, even though there are no binocular corresponding luminance edges to match.
Depth Perception↗
Analysis of glioma cell lines for amplification and overexpression of MDM2.
Recently, amplification of the gene encoding a p53 binding protein, MDM2, was determined in 8% of the cases constituting a large series of glioblastomas. Here we have utilized Southern blot analysis to examine 30 cell lines established from such tumors, and our investigation has revealed large increases in MDM2 gene dosage in two cases, one of which showed coamplification of the CDK4 gene that resides in close proximity to MDM2 in chromosomal region 12q13-14. Northern analysis demonstrated overexpression of MDM2 mRNA in the two cell lines with gene amplification, and overexpression of MDM2 protein was evident in each of these by immunohistochemical and Western blot analysis. Analysis of TP53 cDNAs revealed normal TP53 sequences in the cell lines with MDM2 amplification; these results are consistent with those of previous studies suggesting that MDM2 amplification occurs only in tumors expressing wild-type p53. In total, these data suggest that MDM2 amplification in glioblastoma cell lines occurs at a frequency (6.7%) comparable to that determined in primary tumors; occurs in cell lines expressing wild-type p53; and can involve the coamplification of additional genes.
Gene Amplification↗