A 46-year-old female with dyspnoea, stridor and chronic cough.
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Cough↗
Biomedical subjects
D Hwang
Publications and source records attributed to D Hwang.
Induction of potent Th1-type immune responses from a novel DNA vaccine for West Nile virus New York isolate (WNV-NY1999).
West Nile virus (WNV) is a vectorborne pathogen that induces brain inflammation and death. Recently, confirmed cases of infection and deaths have occurred in the United States Mid-Atlantic region. In this study, a DNA vaccine encoding the WNV capsid protein was constructed, and the in vivo immune responses generated were investigated in DNA vaccine-immunized mice. Antigen-specific humoral and cellular immune responses were observed, including a potent induction of antigen-specific Th1 and cytotoxic T lymphocyte responses. Strong induction of Th1-type immune responses included high levels of antigen-specific elaboration of the Th1-type cytokines interferon-gamma and interleukin-2 and beta-chemokines RANTES (regulated upon activation, normal T cell-expressed and secreted) and macrophage inflammatory protein-1beta. Dramatic infiltration of CD4 and CD8 T cells and macrophages also was observed at the muscle injection site. These results support the potential utility of this method as a tool for developing immunization strategies for WNV and other emerging pathogens.
Animals↗
Synthesis of potent and selective dopamine D(4) antagonists as candidate radioligands.
A series of dopamine D(4) antagonists was synthesized and evaluated as potential candidates for development as positron emission tomography (PET) radioligands. All new compounds display high affinity and selectivity for the D(4) receptors and compounds 5b, 5d, and 5e were identified as candidates for radioligand development.
Binding Sites↗
Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4.
Results from our previous studies demonstrated that activation of Toll-like receptor 4 (Tlr4), the lipopolysaccharide (LPS) receptor, is sufficient to induce nuclear factor kappaB activation and expression of inducible cyclooxygenase (COX-2) in macrophages. Saturated fatty acids (SFAs) acylated in lipid A moiety of LPS are essential for biological activities of LPS. Thus, we determined whether these fatty acids modulate LPS-induced signaling pathways and COX-2 expression in monocyte/macrophage cells (RAW 264.7). Results show that SFAs, but not unsaturated fatty acids (UFAs), induce nuclear factor kappaB activation and expression of COX-2 and other inflammatory markers. This induction is inhibited by a dominant-negative Tlr4. UFAs inhibit COX-2 expression induced by SFAs, constitutively active Tlr4, or LPS. However, UFAs fail to inhibit COX-2 expression induced by activation of signaling components downstream of Tlr4. Together, these results suggest that both SFA-induced COX-2 expression and its inhibition by UFAs are mediated through a common signaling pathway derived from Tlr4. These results represent a novel mechanism by which fatty acids modulate signaling pathways and target gene expression. Furthermore, these results suggest a possibility that propensity of monocyte/macrophage activation is modulated through Tlr4 by different types of free fatty acids, which in turn can be altered by kinds of dietary fat consumed.
Adenocarcinoma↗
Characterization of microsatellite markers adjacent to AP-4 on chromosome 16p13.3.
The 1400 kb genomic sequence between the markers D16S406 and D16S423 on chromosome 16p13.3 has been recently sequenced and the interval contains a transcription factor, AP-4, that was identified as a ligand for immunoglobulin-kappa promoter E-box elements,(1)suggesting that AP-4 may be related to immunodeficiency diseases. In addition, chromosome 16p13.3 includes a number of genes including the PKD1 gene,(2,3)the autosomal dominant polycystic kidney disease (ADPKD) gene. ADPKD is characterized by progressive development and enlargement of renal cysts.(4)The size and genomic complexity of the PKD1 gene makes it impractical to detect mutations for prenatal diagnosis. Therefore, pedigree-based linkage analysis remains useful for diagnosis of ADPKD. To increase the number of polymorphic markers in the region around AP-4 gene, we performed database searches of 1400 kb of genomic sequence (from contig NT000677 to NT001573: http://www.ncbi.gov/genome/seq.cgi) across the 16p13.3. A number of dinucleotide or tetranucleotide repeats were found, and 20 microsatellites that contain more than 15 contiguous repeats were chosen for further investigation.
Adult↗
Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans.
Augmentation of selective serotonin reuptake inhibitors (SSRIs) therapy by the 5-HT(1A) receptor agent pindolol may reduce the delay between initiation of antidepressant treatment and clinical response. This hypothesis is based on the ability of pindolol to block 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN) and to potentiate the increase in 5-HT transmission induced by SSRIs. However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT(1A) receptors during treatment with pindolol controlled release (CR) in nine healthy volunteers with Positron Emission Tomography and [11C]WAY 100635. Subjects were studied four times: at baseline, following one week of pindolol CR 7.5 mg/day (4 and 10 hrs post dose), and following one dose of pindolol CR 30 mg(4 hrs post dose). Occupancy of the DRN was 40 +/- 29% on scan 2, 38 +/- 26% on scan 3, and 64 +/- 15% on scan 4. The average occupancy in all other regions was significantly lower at each doses (18 +/- 5% on scan 2, 12 +/- 3% on scan 3, and 42 +/- 4% on scan 4). These results suggest that the blockade in the DRN reached in clinical studies (7.5 mg/day) might be too low and variable to consistently augment the therapeutic effect of SSRIs. However, these data indicate that pindolol exhibits in vivo selectivity for the DRN 5-HT(1A) autoreceptors. As DRN selectivity is desirable for potentiation of 5-HT function, this observation represents an important proof of concept for the development of 5-HT(1A) agents in this application.
Adult↗
Modulation of the expression of cyclooxygenase-2 by fatty acids mediated through toll-like receptor 4-derived signaling pathways.
Genetic evidence that Toll-like receptor 4 (Tlr4) is the lipopolysaccharide (LPS) receptor and biochemical evidence that Tlr4 confers LPS responsiveness as determined by activation of NF-kappaB and expression of inducible cyclooxygenase 2 have been demonstrated. Saturated fatty acids (SFAs) acylated in lipid A moiety of LPS are essential for biological activities of LPS. It is now demonstrated that SFAs, but not unsaturated fatty acids (UFAs), induce NF-kappaB activation and expression of COX-2 and other inflammatory markers in macrophages. UFAs inhibit COX-2 expression induced by SFAs and LPS. Additional evidence suggests that both SFA-induced COX-2 expression and its inhibition by UFAs are mediated through a common signaling pathway derived from Tlr4. These results represent a novel mechanism by which fatty acids modulate signaling pathways and target gene expression. Whether fatty acids also modulate signaling pathways and target gene expression derived from the activation of other Tlrs remains to be determined.-Hwang, D. Modulation of the expression of cyclooxygenase 2 by fatty acids mediated through Toll-like receptor 4-derived signaling pathways.
Animals↗
Effect of donor age on morphologic variation of cultured human corneal endothelial cells.
PURPOSE: To examine the effect of donor age on the morphologic variation of cultured human corneal endothelial cells (HCEC). METHODS: HCEC were obtained from the remaining corneoscleral rims of seven human corneas used for penetrating keratoplasty. The donor age ranged from 2 to 75 years. Primary cultures were established from explants of the endothelial cell layer, including the Descemet's membrane, and were propagated on culture dishes coated with bovine corneal endothelial extracellular matrix. At the fourth passage, frequency distribution of cell area in the confluent monolayer was calculated and the effect of donor age on cell area was analyzed. RESULTS: The percentage of HCEC with cell area over 2000 microm2 significantly increased with donor age (r = 0.935, p = 0.0007). CONCLUSION: Cultured HCEC established from older donor tissue display greater heterogeneity. The use of HCEC from younger donors may be preferable to maximize the benefits of HCEC transplantation.
Adolescent↗
Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase.
Genetic evidence indicating that TOLL-like receptor 4 (Tlr4) is the lipopolysaccharide (LPS) receptor in mice was reported. However, biochemical evidence that murine Tlr4 confers LPS responsiveness has not been convincingly demonstrated. Inducible cyclooxygenase (COX-2) is selectively expressed in LPS-stimulated macrophages in part mediated through the activation of NF kappa B. Thus, we determined whether murine Tlr4 confers LPS responsiveness as evaluated by the activation of NF kappa B and COX-2 expression. Transfection of a murine macrophage-like cell line (RAW264.7) with the constitutively active form (delta Tlr4) of Tlr4 is sufficient to activate NF kappa B and COX-2 expression. However, the truncated form (delta Tlr4(P712H)) of the missense mutant Tlr4(P712H) found in LPS-hyporesponsive mouse strain (C3H/HeJ) inhibits LPS-induced NF kappa B activation and COX-2 expression. The inability of delta Tlr4(P712H) to activate NF kappa B and induce COX-2 expression is rescued by a constitutively active adapter protein myeloid differentiation factor 88 (MyD88), which interacts directly with the cytoplasmic domain of Tlr proteins. Furthermore, MyD88 is co-immunoprecipitated with the wild-type delta Tlr4 but not with the delta Tlr4(P712H) mutant. Together, these results indicate that Tlr4 confers LPS responsiveness in RAW264.7 cells and suggest that hyporesponsiveness of C3H/HeJ mice to LPS is attributed to the disruption of Tlr4-mediated signaling pathways that results from the inability of the mutant Tlr4(P712H) to interact with MyD88.
Animals↗
Association of the vitamin D receptor start codon polymorphism (FokI) with bone mineral density in postmenopausal Korean women.
We undertook this study in order to examine the association between bone mineral density (BMD) and a polymorphism at the first of two potential translation initiation codons in the vitamin D receptor (VDR) gene. This polymorphism was detected by restriction fragment length polymorphism analysis, using polymerase chain reaction (PCR) and the restriction endonuclease FokI. The f allele indicates the presence of the FokI site, and the F allele its absence. The FokI genotype was determined in 174 postmenopausal Korean women, aged 43-71 years. The distribution of FokI genotypes in Koreans was found not to differ significantly from those found in Caucasians and Japanese, although it does differ significantly from that found in the black American population. We observed a significant association between the FokI polymorphism and lumbar BMD; P = 0.048, analysis of covariance [ANCOVA], but no association with femoral neck BMD (P = 0.505, ANCOVA). Those with the ff genotype had a 13.3% lower BMD in the lumbar spine than the FF subjects. In addition, a significantly higher prevalence of the ff genotype was observed in osteoporotic compared with osteopenic or normal women (P = 0.036, chi2 test). These data suggest that the ff genotype of the VDR gene correlates with decreased BMD in the lumbar spine in postmenopausal Korean women.
Base Sequence↗
Carrier detection and prenatal diagnosis of hemophilia A in a Korean population by PCR-based analysis of the BclI/intron 18 and St14 VNTR polymorphisms.
We have undertaken this study to identify the usefulness of polymerase chain reaction (PCR)-based analysis of DNA polymorphisms in the BclI/intron 18 and St14 variable number of tandem repeats (VNTR) loci for carrier detection and prenatal diagnosis of hemophilia A in the Korean population. We have analyzed these polymorphisms in members of 105 unrelated Korean families with severe hemophilia A. The observed heterozygosity rates for the BclI/intron 18 and St14 VNTR polymorphisms were 21.0% and 71.3%, respectively. The BclI/intron 18 polymorphism was less informative in Koreans when compared with Caucasians and Japanese. The allele frequencies for St14 VNTR in Koreans were different from those in Caucasians. Compared with Caucasians, there was a markedly higher occurrence of low molecular weight alleles in Koreans. The observed heterozygosity for the St14 VNTR polymorphism in combination with the BclI/intron 18 polymorphism was 81.9%. These two polymorphisms were applied to determine the carrier status of 107 women from 65 unrelated families, and to assess fetal status in 37 pregnancies. So far, we have experienced one case of misdiagnosis of carriership. Our study demonstrated that the PCR-based analysis of the BclI/intron 18 and St14 VNTR polymorphisms was useful in the carrier detection and prenatal diagnosis of hemophilia A in the Korean population.
DNA↗
Human lung morphology models for particle deposition studies.
Knowledge of human lung morphology is of paramount importance in calculating deposition patterns of inhaled particulate matter (PM) to be used in the definition of ambient air quality standards. Due to the inherently complex nature of the branching structure of the airway network, practical assumptions must be made for modeling purposes. The most commonly used mathematical models reported in the literature that describe PM deposition use Weibel's model A morphology. This assumes the airways of the lung to be a symmetric, dichotomously branching system. However, computer simulations of this model, when compared to scintigraphy images, have shown it to lack physiological realism (Martonen et al., 1994a). Therefore, a more physiologically realistic model of the lung is needed to improve the current PM dosimetry models. Herein, a morphological model is presented that is based on laboratory data from planar gamma camera and single-photon emission computed tomography (SPECT) images. Key elements of this model include: The parenchymal wall of the lung is defined in mathematical terms, the whole lung is divided into distinct left and right components, a set of branching angles is derived from experimental measurements, and the branching network is confined within the discrete left and right components (i.e., there is no overlapping of airways). In future work, this new, more physiologically realistic morphological model can be used to calculate PM deposition patterns for risk assessment protocols.
Algorithms↗
Fatty acids and immune responses--a new perspective in searching for clues to mechanism.
Dietary essential fatty acids are the precursors for eicosanoids. Among the eicosanoids derived from arachidonic acid, prostaglandin (PG) E2 is known to possess immunosuppressive actions. Thus, it has been a prevailing hypothesis that the immuno-modulatory roles of dietary fatty acids are mediated at least in part through the alteration of PG biosynthesis. PGs exert their biological effects through their cognate receptors. There are four subtypes of PGE receptors (EP1, EP2, EP3, and EP4) so far identified. Although the association of EP receptors with G proteins coupled to adenylate cyclase and the mobilization of intracellular calcium are well documented, downstream signaling pathways for these receptors are virtually unknown. Identification of downstream signaling pathways for each subtype of EP receptors and target genes regulated by the activation of the receptor will help with our understanding of the mechanism by which dietary fatty acids affect immune responses through the modulation of PGE2 biosynthesis. Emerging evidence suggests that fatty acids can additionally act as second messengers, regulators of signal transducing molecules or transcription factors. Acylation with long-chain fatty acids can occur on a variety of signaling molecules and can affect their membrane translocation and functions. Dietary fatty acids can alter functional properties of lipid mediators by changing the composition of acyl moieties of these molecules. Evidence accumulated recently indicates that long-chain unsaturated fatty acids and their metabolites bind and activate peroxisome proliferator-activated receptors (PPARs). PPARs are nuclear hormone receptors and transcription factors that regulate the expression of broad arrays of genes involved not only in lipid and glucose metabolism, but also in immune and inflammatory responses. PPARs may therefore be important cellular targets that mediate modulation of immune responses by dietary fatty acids. Together, it becomes clear now that multiple steps in various receptor-mediated signaling pathways can be modulated by dietary fatty acids. It will be a challenging task to quantitatively determine how different fatty acids alter functional properties of multitude of signaling components and final cellular responses. Elucidating the mechanism of actions of fatty acids on receptor-mediated signaling pathways in immuno-competent cells will provide a new insight for understanding the immuno-modulatory roles of dietary fatty acids.
Animals↗
Seasonal cell proliferation in the chemosensory epithelium and brain of red-backed salamanders, Plethodon cinereus.
The chemosensory epithelium of vertebrates retains the ability to produce new receptor neurons throughout life, presumably as a mechanism to replace aging or damaged receptors. We examined cell division in the main olfactory and vomeronasal epithelia of red-backed salamanders (Plethodon cinereus) because previous studies had shown that the volume of sensory epithelia changes seasonally. Cell division was compared throughout the year by injecting salamanders once with 5-bromo-2'-deoxyuridine (BrdU), which is incorporated into the DNA of cells during DNA synthesis, and sacrificing them one hour after injection. We used immunocytochemistry to locate cells that had arisen from cell division since BrdU injection and compared the number of labeled cells per area among animals. Animals collected in May had significantly more labeled nuclei than animals collected in any other month. However, proliferation rates among the other months were not significantly different and were quite low. Labeled nuclei also were found around the cerebral ventricles of salamanders collected in May, but rarely in any other month, although other tissues in the head often were heavily labeled. Cell proliferation appears to be up-regulated in the chemosensory epithelia and in the telencephalon during May, and we hypothesize that new receptors, and perhaps their interneurons in the telencephalon, are being generated in anticipation of seasonal events that are mediated by chemoreception.
Animals↗
Lung models: strengths and limitations.
The most widely used particle dosimetry models are those proposed by the National Council on Radiation Protection, International Commission for Radiological Protection, and the Netherlands National Institute of Public Health and the Environment (the RIVM model). Those models have inherent problems that may be regarded as serious drawbacks: for example, they are not physiologically realistic. They ignore the presence and commensurate effects of naturally occurring structural elements of lungs (eg, cartilaginous rings, carinal ridges), which have been demonstrated to affect the motion of inhaled air. Most importantly, the surface structures have been shown to influence the trajectories of inhaled particles transported by air streams. Thus, the model presented herein by Martonen et al may be perhaps the most appropriate for human lung dosimetry. In its present form, the model's major "strengths" are that it could be used for diverse purposes in medical research and practice, including: to target the delivery of drugs for diseases of the respiratory tract (eg, cystic fibrosis, asthma, bronchogenic carcinoma); to selectively deposit drugs for systemic distribution (eg, insulin); to design clinical studies; to interpret scintigraphy data from human subject exposures; to determine laboratory conditions for animal testing (ie, extrapolation modeling); and to aid in aerosolized drug delivery to children (pediatric medicine). Based on our research, we have found very good agreement between the predictions of our model and the experimental data of Heyder et al, and therefore advocate its use in the clinical arena. In closing, we would note that for the simulations reported herein the data entered into our computer program were the actual conditions of the Heyder et al experiments. However, the deposition model is more versatile and can simulate many aerosol therapy scenarios. For example, the core model has many computer subroutines that can be enlisted to simulate the effects of aerosol polydispersity, aerosol hygroscopicity, patient ventilation, patient lung morphology, patient age, and patient airway disease.
Aerosols↗
A unified and quantitative receptor model for the microtubule binding of paclitaxel and epothilone.
[formula: see text] Paclitaxel and epothilone represent the two major classes of antimicrotubule agents that promote tubulin polymerization and, presumably, mitotic arrest during cell division. A common minireceptor binding site model at beta-tubulin has been constructed for these structurally divergent compounds. Utilizing 20 amino acids identified in photoaffinity labeling experiments, the 3-D model correlates measured and predicted Ki's with r = 0.99 and rms(delta Gcalc-delta Gexp) = 0.2 kcal/mol. In addition, the model predicts the affinity of compounds not used in the training set and explains much of the SAR for the paclitaxel and epothilone families.
Antineoplastic Agents↗
A comparison of the dynamics of simple (Fourier) and complex (non-Fourier) mechanisms in texture segregation.
Models of texture segregation frequently feature two processing mechanisms: simple, linear channels (1st-order, Fourier mechanisms) and complex channels (2nd-order, non-Fourier mechanisms). Using texture patterns designed to segregate primarily as a result of activity in one set of channels or the other, we employed the method of cued response to obtain speed-accuracy tradeoff (SAT) functions measuring the time course of texture segregation processing in simple and complex channels. Here, both simple-channel and complex-channel patterns are composed of Gabor-patch texture elements, thus equating input to simple channels and the first stage of complex channels. Subjects were required to identify the orientation of a rectangular texture-region embedded in a background field of a different texture. SAT functions were obtained by requiring subjects to respond within 200 ms after an auditory cue. We found that: (1) when segregation depended primarily on activity in simple channels, performance was faster and better than when it depended primarily on complex channels; (2) in contrast to a previous study (Sutter, A., & Graham, N. (1995). Investigating simple and complex mechanisms in texture segragation using the speed-accuracy tradeoff method. Vision Research, 35, 2825-2843), simple-channel (Fourier) patterns composed of two textured regions were just as easily segregated as simple-channel patterns in which one of the regions was blank instead of textured; (3) performance with complex-channel patterns composed of diagonally oriented Gabor-patches was considerably worse than performance with complex-channel patterns composed of vertically and/or horizontally oriented Gabor-patches; (4) among simple-channel patterns containing only one region of texture (background-only or rectangle-only), there were minimal differences in performance; and (5) as in previous experiments, there were large individual differences in the segregation of complex-channel (non-Fourier) patterns. All of the above results can be explained within the framework of the simple- and complex-channels model of texture segregation.
Adult↗
Activation and inactivation of cyclo-oxygenase in rat alveolar macrophages by aqueous cigarette tar extracts.
Cyclo-oxygenase (COX) activity and its level of expression, the release of arachidonic acid (AA), and the accumulation of prostaglandins (PGs) were determined in isolated rat pulmonary alveolar macrophages (PAM) exposed to aqueous cigarette tar (ACT) extracts. COX activity increased 3-fold above the initial activity within 2 h of incubation with ACT extracts and gradually decreased below the initial activity after 8 h of incubation. The increased COX activity after 2 h of incubation did not lead to increased accumulation of PGE2. Accumulated levels of PGE2 increased dramatically after 12 h of incubation despite decreased COX activity in cells incubated with ACT extracts. This increased accumulation of PGE2 was greater in cells derived from vitamin E deficient rats compared with control rats. Release of AA from cells was dramatically increased in cells incubated with ACT extracts in parallel to PG accumulation. Thus increased accumulation of PGE2 despite decreased COX activity after 12 h of incubation is likely the result of increased substrate availability. These results suggest that, contrary to earlier reports, cigarette smoke stimulates the formation of PGs in alveolar macrophages. Increased PG production may lead to suppressed immune response and enhanced risk of tumorigenesis in smokers' lungs.
Animals↗