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Biomedical subjects

R Tsai

Publications and source records attributed to R Tsai.

At least 19 recordsLinked to original sources
PubMed2006

The 'metabolon,' CD47, and the 'phagocytic synapse': molecular co-localization and species divergence.

CD47 is a widely expressed integral membrane protein, found also on red blood cells where it reportedly has a key role in inhibiting phagocytic clearance of RBC by signaling within a multi-molecular 'phagocytic synapse'. Calreticulin is postulated to be on the RBC surface and stimulate phagocytosis, whereupon CD47 on the RBC binds SIRPalpha on the phagocyte and signals a block against phagocytosis. While studies of mouse suggest such an inhibitory role for CD47, CD47 seems to have distinct interactions in human RBC--particularly within a 'metabolon' complex of CD47, Rh proteins, and several other proteins. We have assessed the relative density, co-clustering, and mobility of some of the implicated proteins on human RBC versus murine RBC (hu-RBC and mu-RBC, respectively), and we find a few major differences. While RBC from both species express similar densities of CD47 and SIRPalpha interactions are measurably modest, the interactions prove species-specific. While RBC from both species also have detectable calreticulin, fresh hu-RBC are found to have 10-100-fold more calreticulin binding sites on their surface. Imaging of clusters of SIRPalpha-CD47 on both species of RBC show that RhD does co-localize with CD47 on hu-RBC, but neither calreticulin nor Glycophorin-A appear enriched in the metabolon complexes. Furthermore, mouse-cells alone tend to aggregate due to cross-bridging by SIRPalpha complexes, showing accumulation of CD47 in the adhesion zone, which is consistent with a high mobility of CD47 unique to mu-RBC.

Animals↗
PubMed2005

Molecular evolution of antibody affinity for sensitive detection of botulinum neurotoxin type A.

Botulism is caused by botulinum neurotoxin (BoNT), the most poisonous substance known. Potential use of BoNT as a biothreat agent has made development of sensitive assays for toxin detection and potent antitoxin for treatment of intoxication a high priority. To improve detection and treatment of botulism, molecular evolution and yeast display were used to increase the affinity of two neutralizing single chain Fv (scFv) antibodies binding BoNT serotype A (BoNT/A). Selection of yeast displayed scFv libraries was performed using methods to select for both increased association rate constant (k(on)) and decreased dissociation rate constants (k(off)). A single cycle of error prone mutagenesis increased the affinity of the 3D12 scFv 45-fold from a K(D) of 9.43x10(-10)M to a K(D) of 2.1x10(-11)M. Affinity of the HuC25 scFv was increased 37-fold from 8.44x10(-10)M to 2.26x10(-11)M using libraries constructed by both random and site directed mutagenesis. scFv variable region genes were used to construct IgG for use in detection assays and in vivo neutralization studies. While IgG had the same relative increases in affinity as scFv, (35-fold and 81-fold, respectively, for 3D12 and HuC25) higher solution equilibrium binding constants were observed for the IgG, with the 3D12 K(D) increasing from 6.07x10(-11)M to 1.71x10(-12)M and the HuC25 K(D) increasing from 4.51x10(-11)M to 5.54x10(-13)M. Affinity increased due to both an increase in k(on), as well as slowing of k(off). Higher affinity antibodies had increased sensitivity, allowing detection of BoNT/A at concentrations as low as 1x10(-13)M. The antibodies will also allow testing of the role of affinity in in vivo toxin neutralization and could lead to the generation of more potent antitoxin.

Antibody Affinity↗
PubMed2005

Sequence variation within botulinum neurotoxin serotypes impacts antibody binding and neutralization.

The botulinum neurotoxins (BoNTs) are category A biothreat agents which have been the focus of intensive efforts to develop vaccines and antibody-based prophylaxis and treatment. Such approaches must take into account the extensive BoNT sequence variability; the seven BoNT serotypes differ by up to 70% at the amino acid level. Here, we have analyzed 49 complete published sequences of BoNTs and show that all toxins also exhibit variability within serotypes ranging between 2.6 and 31.6%. To determine the impact of such sequence differences on immune recognition, we studied the binding and neutralization capacity of six BoNT serotype A (BoNT/A) monoclonal antibodies (MAbs) to BoNT/A1 and BoNT/A2, which differ by 10% at the amino acid level. While all six MAbs bound BoNT/A1 with high affinity, three of the six MAbs showed a marked reduction in binding affinity of 500- to more than 1,000-fold to BoNT/A2 toxin. Binding results predicted in vivo toxin neutralization; MAbs or MAb combinations that potently neutralized A1 toxin but did not bind A2 toxin had minimal neutralizing capacity for A2 toxin. This was most striking for a combination of three binding domain MAbs which together neutralized >40,000 mouse 50% lethal doses (LD(50)s) of A1 toxin but less than 500 LD(50)s of A2 toxin. Combining three MAbs which bound both A1 and A2 toxins potently neutralized both toxins. We conclude that sequence variability exists within all toxin serotypes, and this impacts monoclonal antibody binding and neutralization. Such subtype sequence variability must be accounted for when generating and evaluating diagnostic and therapeutic antibodies.

Animals↗
PubMed2002

Patterns of lung function in asymptomatic nonsmoking men and women in the People's Republic of China.

PURPOSE: To evaluate patterns of lung function in healthy, working Chinese men and women in different geographic areas of the People's Republic of China (PRC). METHODS: We conducted lung function tests on 2926 asymptomatic, never smoking Chinese men and women aged 35-56 years residing in or around Beijing and Guangzhou. Within each of these locations, separate urban and rural samples were recruited. RESULTS: Age and height adjusted lung function was greater in Beijing than in Guangzhou, and within each city for residents of rural vs. urban areas. Among women, estimated rates of lung aging were greater in Beijing than in Guangzhou, and in urban vs. rural areas. Both FEV(1) and FVC exhibited a curvilinear association with body mass index. CONCLUSIONS: Lung function data from this largely working cohort exhibited marked geographic and urban-rural differences in this never smoking, adult Chinese cohort. Such variation is not uncommon and may reflect differences in body size, diet, and environmental and occupational exposures across these different settings. Caution should be used in applying published reference equations to populations from different parts of the PRC.

Adult↗
PubMed1999

An approach for evaluating aerosol particle deposition from a natural convection flow onto a vertical flat plate.

An approach through numerical integration for evaluating aerosol particle deposition onto a vertical flat plate is proposed. The airflow was based on the assumption of a two-dimensional, incompressible and steady state laminar flow driven by a buoyancy force. The mechanisms of particle deposition were coupled from natural convection, Brownian diffusion, thermophoresis and electrophoresis due to constant electric strength. This approach demonstrated an easier method of prediction and produced a very good agreement with the thermophoresis exact solution. Results described the role of thermophoretic and electrophoretic forces on particle deposition. The thermophoresis effect was predicted to be particularly important for particles of d(p)>/=0.1 microm moving toward a cold surface or away from a hot surface at a given temperature gradient. The electrophoresis effect dominates the deposition of submicron particles.

Aerosols↗
PubMed1998

Synthesis of benzo[c]quinolizin-3-ones: selective non-steroidal inhibitors of steroid 5 alpha-reductase 1.

A short and efficient synthesis of novel benzo[c]quinolizin-3-one derivatives is described. The synthesis is based on the tandem Mannich-Michael cyclization between 2-silyloxy-1,3-butadienes and a N-t-Boc iminium ion. The prepared derivatives are selective inhibitors of human steroid 5 alpha-reductase isoenzyme 1, thus having potential application as drugs for treatment of male pattern baldness and other DHT-dependent skin disorders.

5-alpha Reductase Inhibitors↗
PubMed1998

Relationship between lung function and blood pressure in Chinese men and women of Beijing and Guangzhou. PRC-USA Cardiovascular and Cardiopulmonary Epidemiology Research Group.

BACKGROUND: Previous studies of western populations have shown an inverse association between lung function and blood pressure. METHODS: As part of a People's Republic of China-United States cardiopulmonary epidemiology study, we investigated the cross-sectional relationship between lung function and blood pressure in 6757 Chinese men and women, aged 35-54, from Beijing and Guangzhou, China. We also evaluated the longitudinal association between lung function and incident hypertension among 4818 initially normotensive subjects followed up between 2 and 4 years later. RESULTS: In our cross-sectional analyses of baseline data, lung function varied inversely with baseline systolic (SBP) and diastolic blood pressure (DBP) in all women and in Beijing men. This association held for absolute and height-standardized forced vital capacity (FVC) and one-second forced expiratory volume (FEV1) (correlations: 0.10, -0.18, P < 0.0001), but was weaker after adjustment for age (correlations: -0.02, -0.11). The longitudinal follow-up showed that lower initial lung function levels were associated with a higher incidence of hypertension (SBP > or = 140 mmHg or DBP > or = 90 mmHg or currently using antihypertensive medications), but only among women in Guangzhou. Relative risks for hypertension incidence for those in the two lowest quintiles for FEV1 and FVC, compared to those in the two highest quintiles, ranged from 1.9 to 2.3 for Guangzhou women and from 0.9 to 1.4 for all other gender-city subgroups. Logistic regression analyses adjusting for age, baseline SBP, body mass index, smoking, education, and urban versus rural setting generally confirmed these patterns. CONCLUSIONS: These results suggest a statistically significant, though weak, inverse relationship between lung function and blood pressure in Chinese men and women. This association is largely attributable to age and is present prospectively only in women.

Adult↗
PubMed1996

Automated utility assessment of global health.

The objective of this study was to characterize the performance of an automated utility assessment instrument for measuring preferences for overall health. The study population consisted of 83 subjects recruited from the cafeteria of a large tertiary care hospital. We assessed utilities for current health relative to perfect health and death using the rating scale, time tradeoff and standard gamble metrics. To validate the instrument, we compared utilities with the General Health subscale of the SF-36 Health Survey instrument, satisfaction with current health, and degree of bother due to current health. We evaluated interview failure rate based on irrational orderings of two practice assessments (monocular and binocular blindness) or inability to complete the interview. As expected, utility for overall health was statistically significantly associated with the General Health subscale score and measures of satisfaction with current health and degree of bother. There is substantial variation in utilities among patients with similarly severe overall health, and substantial overlap in utilities among subjects with different levels of overall health. The failure rate in the study was acceptable (9.6%). Automated assessment of utility for overall health provides a feasible means for estimating individual preferences.

Adult↗
PubMed1995

Effects of cigarette smoking on lung function in four population samples in the People's Republic of China. The PRC-US Cardiovascular and Cardiopulmonary Epidemiology Research Group.

As part of an ongoing study of cardiopulmonary risk factors in the People's Republic of China, we conducted lung function tests and obtained information about smoking habits on 6,765 Chinese men and women 35 to 56 yr of age residing in or around Beijing in the north and in or around Guangzhou in the south. Within each region, separate urban and rural populations were recruited. This study examined the relationship between tobacco consumption (both manufactured cigarettes and leaf tobacco) and lung function in a subset of current smokers and never smokers who had acceptable lung function data. All methods were strictly standardized. Overall, tobacco smoking was associated with a statistically significant mean difference in FEV1 among men (-89 ml) and women (-52 ml) relative to never smokers after adjusting for age, height, and residence. Differences between smokers of cigarettes and smokers of leaf tobacco were not significant. Among the subset of smokers who smoked only cigarettes, this decrement increased with increasing duration of cigarette smoking, but it was small (-4 ml/yr of smoking for FEV1 for both men and women) in comparison with the effects of smoking reported from western countries. Although the smoking effect tended to increase with increasing dose, these differences were small and generally not statistically significant. The relatively small smoking effect in this study may result from differences between developed and developing countries in the cumulative dose of tobacco products. Alternative explanations or contributing factors such as racial differences in susceptibility and differences in the form and delivery of tobacco cannot be discounted.

Adult↗
PubMed1994

A north-south comparison of blood pressure and factors related to blood pressure in the People's Republic of China: a report from the PRC-USA Collaborative Study of Cardiovascular Epidemiology.

OBJECTIVES: To compare blood pressures in northern (Beijing) and southern (Guangzhou) Chinese population samples aged 35-54 years, males and females, urban and rural, and to assess the role of blood pressure-related traits in explaining north-south differences. DESIGN: Cross-sectional surveys were conducted in 1983-1984 of northern and southern populations employed in industry (urban) or farming (rural). METHODS: In the north samples were selected from the Capital Iron and Steel Complex (urban) and Shijingshan district (rural); in the south samples from the Guangzhou Shipyard (urban) and Panyu County (rural) were used. RESULTS: The number of subjects surveyed in north and south were 4706 and 4179, respectively: 1500 and 1052 urban males, and 717 and 914 rural males; and 1300 and 1061 urban females, and 1189 and 1152 rural females, respectively. Average systolic (SBP) and diastolic (DBP) blood pressures, were consistently higher in the north than in the south. SBP and DBP were significantly and independently related to age, body mass index, heart rate, use of antihypertensive drugs, serum triglycerides level, alcohol use (males only) and inversely to cigarette smoking. Northerners were older, taller, heavier and had higher body mass index and triglycerides level than southerners. With adjustment of SBP and DBP for blood pressure-related traits, north-south blood pressure differences decreased, but remained significant for urban males, rural males and rural females, with sizeable differences for rural samples in particular. CONCLUSIONS: North-south differences in blood pressure in these samples are accounted for only partly by north-south differences in the cited blood pressure-related traits. The role of other traits requires assessment.

Adult↗
PubMed1992

Regulation of hepatic growth hormone receptors in coho salmon (Oncorhynchus kisutch).

Factors potentially regulating hepatic growth hormone (GH) receptors in coho salmon (Oncorhynchus kisutch) have been investigated. From December to June of the first year, relative changes in hepatic 125I-sGH binding and 35SO4 incorporation by ceratobranchial cartilage were similar. Stunted salmon, which in seawater have elevated plasma GH yet fail to grow, showed lower hepatic 125I-sGH binding than did normally growing seawater salmon. However, MgCl2 treatment of stunts' membranes to reveal total specific binding of 125I-sGH indicated receptor occupation by endogenous sGH. Total specific 125I-sGH binding was low in seawater stunts and remained low if these fish remained unfed after return to fresh water, but increased approximately twofold upon feeding. Total specific binding in fasted salmon in fresh water showed a trend toward decreased levels by 1 week; by 3 weeks, binding was 40% lower than in fed fish. There was a positive correlation (r = 0.600) between condition factor and total specific binding in fed and fasted salmon in fresh water. Two weeks after hypophysectomy total specific binding was 50% lower than in sham-operated control salmon, indicating pituitary regulation of GH receptors. GH treatment reduced both free and total 125I-sGH binding in salmon examined 24 hr after treatment. Treatment with recombinant bovine insulin-like growth factor I, thyroxine, or cortisol did not affect free 125I-sGH binding. Both the pituitary and nutrition appear to be prime regulators of hepatic GH receptors in coho salmon.

Analysis of Variance↗
PubMed1987

Dietary model for production of experimental zinc deficiency in man.

A semipurified diet based on soy protein was developed to induce mild zinc deficiency in five male volunteers. Each of seven daily menus provided (mean +/- SD) 2248 +/- 128 kcal, 56.6 +/- 5.7 protein, 261 +/- 30 g carbohydrate, 110 +/- 21 g fat, 8.5 +/- 1.4 g fiber, and 4.8 +/- 1.3 mg zinc. The analytical value for phytate:zinc molar ratio was 21 +/- 9. One subject, who received five of the menus for 28 wk, lost approximately 200 mg body zinc and 7% weight; zinc concentration declined 25% in plasma, 30% in lymphocytes, and 55% in neutrophils. This dietary model allowed simple formulation of new menus for subjects in diverse states of health. It caused no ill effects after prolonged consumption, and all deficiency symptoms were reversed by zinc supplementation of 30 mg/d for 20 wk. With simple manipulation, this dietary model may be used safely for gradual induction of zinc and/or other micronutrient deficiencies in humans.

Amino Acids↗
PubMed1984

Vasopressin as a possible contributor to hypertension.

The role of vasopressin as a pressor agent to the hypertensive process was examined. Vasopressin plays a major role in the pathogenesis of DOCA-salt hypertension, since the elevation of blood pressure was not substantial in the rats with lithium-treated diabetes insipidus after DOCA-salt treatment. Administration of DDAVP which has antidiuretic action but minimal vasopressor effect failed to increase blood pressure to the levels observed after administration of AVP. Furthermore, the pressor action of vasopressin appears to be important in the development of this model of hypertension, since the enhanced pressor responsiveness to the hormone was observed in the initial stage of hypertension. Increased secretion of vasopressin from neurohypophysis also promotes the function of the hormone as a pathogenetic factor in hypertension. An unproportional release of vasopressin compared to plasma osmolality may be induced by the absence of an adjusting control of angiotensin II forming and receptor binding capacity for sodium balance in the brain. However, the role of vasopressin remains to be determined in human essential hypertension.

Animals↗