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Biomedical subjects

A T Lee

Publications and source records attributed to A T Lee.

At least 19 recordsLinked to original sources
PubMed2002

Estimate of the cosmological bispectrum from the MAXIMA-1 cosmic microwave background map.

We use the measurement of the cosmic microwave background taken during the MAXIMA-1 flight to estimate the bispectrum of cosmological perturbations. We propose an estimator for the bispectrum that is appropriate in the flat sky approximation, apply it to the MAXIMA-1 data, and evaluate errors using bootstrap methods. We compare the estimated value with what would be expected if the sky signal were Gaussian and find that it is indeed consistent, with a chi(2) per degree of freedom of approximately unity. This measurement places constraints on models of inflation.

Journal Article↗
PubMed2001

Tests for Gaussianity of the MAXIMA-1 cosmic microwave background map.

Gaussianity of the cosmological perturbations is one of the key predictions of standard inflation, but it is violated by other models of structure formation such as cosmic defects. We present the first test of the Gaussianity of the cosmic microwave background (CMB) on subdegree angular scales, where deviations from Gaussianity are most likely to occur. We apply the methods of moments, cumulants, the Kolmogorov test, the chi(2) test, and Minkowski functionals in eigen, real, Wiener-filtered, and signal-whitened spaces, to the MAXIMA-1 CMB anisotropy data. We find that the data, which probe angular scales between 10 arcmin and 5 deg, are consistent with Gaussianity. These results show consistency with the standard inflation and place constraints on the existence of cosmic defects.

Journal Article↗
PubMed2001

Cosmology from MAXIMA-1, BOOMERANG, and COBE DMR cosmic microwave background observations.

Recent results from BOOMERANG-98 and MAXIMA-1, taken together with COBE DMR, provide consistent and high signal-to-noise measurements of the cosmic microwave background power spectrum at spherical harmonic multipole bands over 2<l less similar to 800. Analysis of the combined data yields 68% (95%) confidence limits on the total density, Omega(tot) approximately 1.11+/-0.07 (+0.13)(-0.12), the baryon density, Omega(b)h(2) approximately 0.032(+0.005)(-0.004) (+0.009)(-0.008), and the scalar spectral tilt, n(s) approximately 1.01(+0.09)(-0.07) (+0.17)(-0.14). These data are consistent with inflationary initial conditions for structure formation. Taken together with other cosmological observations, they imply the existence of both nonbaryonic dark matter and dark energy in the Universe.

Journal Article↗
PubMed2001

Fibrinogen and factor VII levels improve with glycemic control in patients with type 1 diabetes mellitus who have microvascular complications.

To determine whether the hypercoagulable state of patients with complications of diabetes can be reversed toward normal, a group of insulin-dependent individuals with proteinuria was treated with intensive insulin protocols. A statistically significant (P<.001) improvement in control of diabetes was achieved (mean +/- SEM glycosylated hemoglobin, 9.51% +/- 0.35% at baseline to 8.36% +/- 0. 39% at 12 months; and mean +/- SEM advanced glycosylated end products, 14.8 +/- 2.8 U/mL at baseline to 8.4 +/- 1.5 U/mL at 12 months). There were statistically significant decreases in 2 procoagulant factors: mean +/- SEM baseline elevated plasma factor VII, 128.69% +/- 5.63% at baseline to 106.24% +/- 3.43% at 12 months (P =.002); and mean +/- SEM plasma fibrinogen, 12.3 +/- 0.7 micromol/L (417.3 +/- 24.7 mg/dL) at baseline to 10.2 +/- 0.7 micromol/L (348.8 +/- 22.6 mg/dL) at 12 months (P =.04). Throughout the study, lipid fractions did not change significantly. Because plasma factor VII and fibrinogen concentrations were elevated while cholesterol and triglyceride concentrations were not, more attention should be paid to procoagulants as markers for thromboembolic complications in diabetic patients undergoing intensive insulin therapy.

Adult↗
PubMed2001

Mutant huntingtin enhances excitotoxic cell death.

Evidence suggests overactivation of NMDA-type glutamate receptors (NMDARs) contributes to selective degeneration of medium-sized spiny striatal neurons in Huntington's disease (HD). Here we determined whether expression of huntingtin containing the polyglutamine expansion augments NMDAR-mediated excitotoxicity. HEK293 cells coexpressing mutant huntingtin (htt-138Q) and either NR1A/NR2A- or NR1A/NR2B-type NMDARs exposed to 1 mM NMDA showed a significant increase in excitotoxic cell death compared to controls (cells coexpressing htt-15Q or GFP), but the difference was larger for NR1A/NR2B. Moreover, agonist-dependent cell death showed apoptotic features for cells coexpressing htt-138Q and NR1A/NR2B, but not for cells expressing htt-138Q and NR1A/NR2A. Further, NR1A/NR2B-mediated apoptosis was not seen with coexpression of an N-terminal fragment of mutant htt. Since NR1A/NR2B is the predominant NMDAR subtype in neostriatal medium-sized spiny neurons, enhancement of NMDA-induced apoptotic death in NR1A/NR2B-expressing cells by full-length mutant htt may contribute to selective neurodegeneration in HD.

Apoptosis↗
PubMed2001

Clinical studies of angiogenesis inhibitors: the University of Texas MD Anderson Center Trial of Human Endostatin.

Most solid-tumor malignancies remain incurable. Novel agents that target and counteract biologic mechanisms are now being developed. It is hoped that these drugs will allow for more effective, less toxic cancer treatments and long-term maintenance approaches. One important class of agents functions by an anti-angiogenic mechanism, targeting the blood vessel supply of the tumor and inhibiting tumor growth. Several principles are common to these new agents. First, because many of these agents are growth-inhibiting molecules that work exclusively against the tumor vasculature, single agents will have little effect on tumor size in advanced disease. Second, because these agents are relatively non-toxic, they are unlikely to induce the side effects associated with chemotherapy. Because endothelial cells seldom divide in a human host, anti-angiogenic compounds are expected to produce little toxicity. Third, most of these agents work synergistically with chemotherapy and/or radiotherapy. Ironically, combining these relatively non-toxic agents with chemotherapy often produces the toxicities usually associated with anticancer regimens. Anti-angiogenic agents might ultimately be studied in minimal disease. Clinical studies must demonstrate that these agents affect tumor vasculature, and phase I trials should include built-in surrogate endpoints. This article defines the general principles of anti-angiogenic drug action and explains how these principles have been used to design a phase I trial of human endostatin.

Angiogenesis Inhibitors↗
PubMed2001

From the lab to full-scale SBR operation: treating high strength and variable industrial wastewaters.

This paper describes the path taken from client objectives through laboratory studies and detailed design to full-scale SBR operation and current research. Conventional municipal design principles have often been used to develop treatment processes for industrial wastewaters. The use of scientific trials to test design criteria offers the client a "tailor made" design fir for their particular wastewater character. In this project, a waste management company wished to upgrade their physical-chemical treatment plant to incorporate a biological reactor for treating a range of industrial wastewaters. Laboratory-scale trials were undertaken to determine appropriate design criteria for a full-scale biological process. These laboratory studies indicated that conventional design criteria were not appropriate and that a SBR configuration was optimal compared with an IDAR configuration. It was also found that a novel fungal:bacterial mixed liquor consortium developed, resulting in good effluent quality and settling properties. The treatment plant was able to be constructed and operational within a tight timeframe and budget, allowing the client to take advantage of a commercial opportunity. The plant has been operating since 1997 and meets its discharge conditions. By combining scientific studies with engineering principles, the end-user obtained a complete treatment plant to meet their specific needs. A further benefit of the laboratory trials is current research into the development of a fungal:bacterial SBR to treat industrial wastewaters. This offers ongoing knowledge to the operational full-scale SBR.

Bioreactors↗
PubMed2000

beta(2)-glycoprotein I-dependent alterations in membrane properties.

beta(2)-Glycoprotein I (beta(2)GP1), a 50 kDa serum glycoprotein, binds anionic phospholipids and plays a role in phosphatidylserine (PS)-dependent coagulation and apoptotic processes. To characterize the molecular consequences that occur to target membranes upon binding of beta(2)GP1, the interaction between beta(2)GP1 and PS-containing vesicles was investigated by fluorescent spectroscopy. Membranes containing pyrene-labeled lipid showed that binding of beta(2)GP1 induced a decrease in excimer/monomor ratios (E/M) of the target membrane. Although these membrane alterations occurred in isotonic buffer, the effects were greater in low ionic strength buffer and were coincident to membrane precipitation. In contrast, increases in membrane polarization were only seen in low ionic strength buffer. Analysis of beta(2)GP1 binding kinetics by resonance energy transfer between fluorescein-labeled beta(2)GP1 and rhodamine-containing PS vesicles revealed a two-component process: (1) a primary and rapid binding via the C-terminus that occurred <2 s in both isotonic and low ionic strength buffers, and (2) a sequential binding of the N-terminus that was approximately 100-fold slower in low ionic strength solution. Taken together, these data suggest that beta(2)GP1 alters the fluidity and membrane polarization of its target membrane, which in low ionic strength buffer is of sufficient magnitude to induce precipitation.

Chemical Precipitation↗
PubMed2000

Improved glycemic control and platelet function abnormalities in diabetic patients with microvascular disease.

Patients with diabetes mellitus have a variety of platelet and coagulation system dysfunctions. At least theoretically, these can contribute to microvascular complications. Intensive glycemic control has been demonstrated to decrease microvascular complications in type 1 diabetics. We studied 16 patients with type 1 diabetes mellitus (11 men and five women; mean age, 39 years) with albuminuria greater than 0.1 g/d and/or proteinuria greater than 0.3 g/d and a creatinine clearance rate higher than 30 mL/min. They received a regimen including three to four injections of insulin per day with or without a weekly infusion of intravenous insulin, and were evaluated for 6 months. We compared the plasma level of von Willebrand factor, platelet aggregation responses to adenosine diphosphate (ADP), epinephrine, and collagen, and platelet adhesion at the beginning of the study and at follow-up intervals. Glycemic control improved significantly. There were no significant differences in the platelet aggregation responses to ADP (1.59 +/- 0.34 v 1.88 +/- 0.23 mmol/L, P = .3; normal, 4.6 +/- 0.2), epinephrine (0.50 +/- 0.20 v 1.11 +/- 0.31 mmol/L, P = .06; normal, 7.6 +/- 1.5), or collagen (92.4 +/- 6.61 v 82.60 +/- 3.78 seconds, P = .6; normal, 79.1 +/- 3.1) or in platelet adhesion (126.31 +/- 16.95 v 195.08 +/- 30.2 platelets, P = .34; normal, 68.6 +/- 1.4). Baseline von Willebrand factor increased, but not significantly (166.38% +/- 10.6% v 142.72% +/- 14.73%, P = .21; normal, 102.0% +/- 6.0%). In type 1 diabetic patients with established microvascular complications of nephropathy, a statistically significant improvement in glycemic control did not improve the in vitro platelet function abnormalities. Improved glycemic control delays the progression of microvascular disease through mechanisms not measured by tests of platelet function.

Adenosine Diphosphate↗
PubMed2000

Protection of the DNA during the exposure of Escherichia coli cells to a toxic metabolite: the role of the KefB and KefC potassium channels.

The effect of the toxic metabolite methylglyoxal on the DNA of Escherichia coli cells has been investigated. Exposure of E. coli cells to methylglyoxal reduces the transformability of plasmid DNA and results in the degradation of genomic DNA. The activity of the KefB and KefC potassium channels protects E. coli cells against methylglyoxal and limits the amount of DNA damage. In mutants lacking KefB and KefC, methylglyoxal-induced DNA damage was reduced by incubation with a weak acid that lowers the pHi to the same extent as through KefB and KefC activation. This provides evidence that acidification of the cytoplasm protects E. coli DNA against methylglyoxal. By the analysis of cells lacking UvrA, we demonstrate that this repair protein is required for the degradation of the DNA upon methylglyoxal exposure. However, protection by KefB and KefC occurred independently of UvrA. Although we present evidence that exposure of E. coli cells to methylglyoxal results in DNA degradation, our results suggest this event is not essential for methylglyoxal-induced death. The implications of these findings will be discussed.

Antiporters↗
PubMed1999

Phosphatidylserine externalization during differentiation-triggered apoptosis of erythroleukemic cells.

K562 erythroleukemia cells undergo apoptosis when induced to differentiate along the erythroid lineage with hemin. This event, characterized by DNA fragmentation, correlated with downregulation of the survival protein, BCL-xL, and decrease in mitochondrial transmembrane potential (deltapsi[m]) that ultimately resulted in cell death. Reorientation of phosphatidylserine (PS) from the cells inner-to-outer plasma membrane leaflet and inhibition of the aminophospholipid translocase was observed upon hemin-treatment. Constitutive expression of BCL-2 did not inhibit hemin-induced alterations in lipid asymmetry or decrease in deltapsi[m], and only moderately prevented DNA fragmentation. BCL-2, on the other hand, effectively inhibited actinomycin D-induced DNA fragmentation, the appearance of PS at the cells outer leaflet and the decrease in deltapsi[m]. The caspase inhibitor, z.VAD.fmk, blocked DNA fragmentation by both hemin and actinomycin D, but inhibited PS externalization only in the actinomycin D-treated cells. These results suggest that, unlike pharmacologically-induced apoptosis, PS externalization triggered by differentiation-induced apoptosis occurs by a mechanism that is associated with a decrease in deltapsi[m], but independent of BCL-2 and caspases.

Amino Acid Chloromethyl Ketones↗
PubMed1999

Aggregation and chimney formation during the solidification of ammonium chloride.

Experiments study large-scale pattern formation during the growth of ammonium chloride (NH4Cl) from solution in a thin (Hele-Shaw) geometry. In particular a solid-liquid mixture ("mushy layer") forms in which growing solid NH4Cl crystals form a solid network interspersed with liquid. There are different ways that the mushy layer can be formed, however. If the cell is heated from below and cooled from above, thermal convection generates large-scale recirculating flows that carry seed crystals from the upper (cold) boundary to the (warmer) side and bottom boundaries. Ballistic deposition of these seed crystals leads to aggregation patterns with significant voids (filled with liquid) with a wide range of length scales. If the cell is cooled from below with a warm environment, the solid NH4Cl grows dendritically without deposition, resulting in a compact mushy layer. Plume convection within this mushy layer produces one or two well-defined "chimneys." If the environment is cool (comparable to the liquidus temperature of the solution), the mushy layer forms by a combination of dendritic growth and ballistic deposition, resulting in a more permeable mushy layer and enhanced chimney formation. The effects of ballistic deposition are enhanced if the cell is tipped, in which case the voids reappear. Plume convection and chimney formation are dramatically enhanced in this case. Additional experiments are done in which fluid flows in the system are enhanced artificially to verify that enhancements in chimney formation are due primarily to the aggregation process, and not to the increases in fluid flows due to thermal and compositional convection.

Journal Article↗
PubMed1999

Hyperglycemia-induced embryonic dysmorphogenesis correlates with genomic DNA mutation frequency in vitro and in vivo.

Congenital malformations affecting multiple organ systems are at least three times more common in infants of mothers with IDDM than in infants born to nondiabetic mothers. Numerous studies have confirmed the teratogenic effect of hyperglycemia on the developing embryo, although no direct mechanism has been determined. In this study, we aimed to correlate the frequency of lacI mutations with degree of hyperglycemic exposure and severity of malformations in mouse embryos from in vitro cultures. Day 8 transgenic mouse embryos cultured in 30 or 50 mmol/l glucose for 48 h exhibited a higher incidence of morphological abnormalities, as well as an increase in lacI mutation frequency, compared with embryos cultured in 10 mmol/l glucose with no abnormalities and a lower frequency of lacI mutations. We also used a transgenic lacI rat system to evaluate the relationship between abnormal embryonic development and DNA mutation frequency in day 11 embryos of severely diabetic rats (serum glucose >20 mmol/l). Compared with control embryos, the embryos from diabetic rats displayed significantly more malformations, shorter crown-rump lengths, fewer somites, and more than six times greater genomic DNA mutation frequency. Genetic analysis of the mutated lacI gene from both in vitro cultured mouse embryos and in vivo developed rat embryos revealed that the majority of mutations were due to base substitutions (transitions and transversions), but that the rate of large DNA mutations tended to increase in embryos exposed to a diabetic environment. Our results support the interrelationship between increased rates of congenital malformations and DNA mutations in the offspring of diabetic pregnancy.

Animals↗
PubMed1998

Structure of the MscL homolog from Mycobacterium tuberculosis: a gated mechanosensitive ion channel.

Mechanosensitive ion channels play a critical role in transducing physical stresses at the cell membrane into an electrochemical response. The MscL family of large-conductance mechanosensitive channels is widely distributed among prokaryotes and may participate in the regulation of osmotic pressure changes within the cell. In an effort to better understand the structural basis for the function of these channels, the structure of the MscL homolog from Mycobacterium tuberculosis was determined by x-ray crystallography to 3.5 angstroms resolution. This channel is organized as a homopentamer, with each subunit containing two transmembrane alpha helices and a third cytoplasmic alpha helix. From the extracellular side, a water-filled opening approximately 18 angstroms in diameter leads into a pore lined with hydrophilic residues which narrows at the cytoplasmic side to an occluded hydrophobic apex that may act as the channel gate. This structure may serve as a model for other mechanosensitive channels, as well as the broader class of pentameric ligand-gated ion channels exemplified by the nicotinic acetylcholine receptor.

Amino Acid Sequence↗
PubMed1998

Retinoic acid induced mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase-dependent MAP kinase activation needed to elicit HL-60 cell differentiation and growth arrest.

Retinoic acid (RA) activated the extracellular signal-regulated kinase (ERK) 2 mitogen-activated protein kinase (MAPK) of HL-60 human myeloblastic leukemia cells before causing myeloid differentiation and cell cycle arrest associated with hypophosphorylation of the retinoblastoma (RB) tumor suppressor protein. ERK2 activation by mitogen-activated protein/ERK kinase (MEK) was necessary for RA-induced differentiation in studies using PD98059 to block MEK phosphorylation. G0 growth arrest and RB tumor suppressor protein hypophosphorylation (which is typically associated with induced differentiation and G0 arrest), two putatively RB-regulated processes, also depended on ERK2 activation by MEK. Activation of ERK2 by RA occurred within hours and persisted until the onset of RB hypophosphorylation, differentiation, and arrest. ERK2 activation was probably needed early, because delaying the addition of PD98059 relative to that of RA restored most of the RA-induced cellular response. In contrast to RA (which activates RA receptors (RARs) and retinoid X receptors in HL-60 cells with its metabolite retinoids), a retinoid that selectively binds RAR-gamma, which is not expressed in HL-60 cells, was relatively ineffective in causing ERK2 activation. This is consistent with the need for a nuclear retinoid receptor function in RA-induced ERK2 activation. RA reduced the amount of unphosphorylated RAR-alpha, whose activation is necessary for RA-induced differentiation and arrest. This shifted the ratio of phosphorylated:unphosphorylated RAR-alpha to predominantly the phosphorylated form. Unlike other steroid thyroid hormone receptors susceptible to phosphorylation and activation by MAPKs, RAR-alpha was not phosphorylated by the activated ERK2 MAPK. The results thus show that RA augments MEK-dependent ERK2 activation that is needed for subsequent RB hypophosphorylation, cell differentiation, and G0 arrest. The process seems to be nuclear receptor dependent and an early seminal component of RA signaling causing differentiation and growth arrest.

Antineoplastic Agents↗
PubMed1995

Three-point phase-contrast velocity measurements with increased velocity-to-noise ratio.

We describe a technique to increase the velocity-to-noise ratio (VNR) of phase-contrast magnetic-resonance velocity images based on making three measurements/flow encoding axis rather than the usual two. A phase-aliased high first moment data set and a nonaliased low first moment data set are acquired, and the high-moment data are phase unwrapped using the low-moment data. The VNR of the resulting measurement is given by that of the high-moment measurement and increases linearly with the first moment. A factor of 4 gain in VNR was observed with only a 50% increase in scan time. Thus, this method is a much more efficient way to increase VNR than simple averaging.

Cerebrospinal Fluid↗
PubMed1995

Motion artifacts in fMRI: comparison of 2DFT with PR and spiral scan methods.

Activation signals based on BOLD contrast changes consequent to neuronal stimulation typically produce cortical intensity differences of < 10% at 1.5T. Hemodynamically driven pulsation of the brain can cause highly pulsatile phase shifts, which in turn result in motion artifacts whose intensity is larger than the activation signals in 2DFT scan methods. This paper presents a theoretical and experimental comparison of the magnitude of such artifacts for 2DFT and two other methods using non-Cartesian k-space trajectories. It is shown that artifacts increase with TR for 2DFT methods, and that projection reconstruction (PR) and spiral methods have significantly reduced artifact intensities, because these trajectories collect low spatial frequencies with every view. The spiral technique is found to be superior in terms of efficiency and motion insensitivity.

Artifacts↗