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Search Results: 1 - 10 of 56833 matches for " Sonia Y. Lam "
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A Rigidifying Salt-Bridge Favors the Activity of Thermophilic Enzyme at High Temperatures at the Expense of Low-Temperature Activity
Sonia Y. Lam,Rachel C. Y. Yeung,Tsz-Ha Yu,Kong-Hung Sze,Kam-Bo Wong
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001027
Abstract: Thermophilic enzymes are often less active than their mesophilic homologues at low temperatures. One hypothesis to explain this observation is that the extra stabilizing interactions increase the rigidity of thermophilic enzymes and hence reduce their activity. Here we employed a thermophilic acylphosphatase from Pyrococcus horikoshii and its homologous mesophilic acylphosphatase from human as a model to study how local rigidity of an active-site residue affects the enzymatic activity.
A Rigidifying Salt-Bridge Favors the Activity of Thermophilic Enzyme at High Temperatures at the Expense of Low-Temperature Activity
Sonia Y. Lam,Rachel C. Y. Yeung,Tsz-Ha Yu,Kong-Hung Sze,Kam-Bo Wong
PLOS Biology , 2011, DOI: 10.1371/journal.pbio.1001027
Abstract: Background Thermophilic enzymes are often less active than their mesophilic homologues at low temperatures. One hypothesis to explain this observation is that the extra stabilizing interactions increase the rigidity of thermophilic enzymes and hence reduce their activity. Here we employed a thermophilic acylphosphatase from Pyrococcus horikoshii and its homologous mesophilic acylphosphatase from human as a model to study how local rigidity of an active-site residue affects the enzymatic activity. Methods and Findings Acylphosphatases have a unique structural feature that its conserved active-site arginine residue forms a salt-bridge with the C-terminal carboxyl group only in thermophilic acylphosphatases, but not in mesophilic acylphosphatases. We perturbed the local rigidity of this active-site residue by removing the salt-bridge in the thermophilic acylphosphatase and by introducing the salt-bridge in the mesophilic homologue. The mutagenesis design was confirmed by x-ray crystallography. Removing the salt-bridge in the thermophilic enzyme lowered the activation energy that decreased the activation enthalpy and entropy. Conversely, the introduction of the salt-bridge to the mesophilic homologue increased the activation energy and resulted in increases in both activation enthalpy and entropy. Revealed by molecular dynamics simulations, the unrestrained arginine residue can populate more rotamer conformations, and the loss of this conformational freedom upon the formation of transition state justified the observed reduction in activation entropy. Conclusions Our results support the conclusion that restricting the active-site flexibility entropically favors the enzymatic activity at high temperatures. However, the accompanying enthalpy-entropy compensation leads to a stronger temperature-dependency of the enzymatic activity, which explains the less active nature of the thermophilic enzymes at low temperatures.
Scientific Challenges and Implementation Barriers to Translation of Pharmacogenomics in Clinical Practice
Y. W. Francis Lam
ISRN Pharmacology , 2013, DOI: 10.1155/2013/641089
Abstract:
Scientific Challenges and Implementation Barriers to Translation of Pharmacogenomics in Clinical Practice
Y. W. Francis Lam
ISRN Pharmacology , 2013, DOI: 10.1155/2013/641089
Abstract: The mapping of the human genome and subsequent advancements in genetic technology had provided clinicians and scientists an understanding of the genetic basis of altered drug pharmacokinetics and pharmacodynamics, as well as some examples of applying genomic data in clinical practice. This has raised the public expectation that predicting patients’ responses to drug therapy is now possible in every therapeutic area, and personalized drug therapy would come sooner than later. However, debate continues among most stakeholders involved in drug development and clinical decision-making on whether pharmacogenomic biomarkers should be used in patient assessment, as well as when and in whom to use the biomarker-based diagnostic tests. Currently, most would agree that achieving the goal of personalized therapy remains years, if not decades, away. Realistic application of genomic findings and technologies in clinical practice and drug development require addressing multiple logistics and challenges that go beyond discovery of gene variants and/or completion of prospective controlled clinical trials. The goal of personalized medicine can only be achieved when all stakeholders in the field work together, with willingness to accept occasional paradigm change in their current approach. 1. Introduction Variability in clinical response to standard therapeutic dosage regimen was reported in the 1950s by many pioneers in the field. Since then, the association between monogenic polymorphisms and variations of drugs’ metabolism, transport, or target had been identified and the vision of personalized drug therapy in health care envisioned [1, 2]. Pharmacogenomic-guided drug therapy for patient is based on the premise that a large portion of interindividual variability in drug response (efficacy and/or toxicity) is genetically determined. Despite the widespread recognition of the scientific rationale and the clinical implementation of pharmacogenomic tests at several major academic medical institutions [3–7], most clinicians and researchers engaged in the discipline would agree that the early vision of achieving personalized therapy in the form of therapeutic regimens tailored to an individual’s genetic profile remains some years away. Broadly speaking, the development and implementation pathways for pharmacogenomic tests consist of several stages (Figure 1): first, discovery of pharmacogenomic biomarkers and validation in well-controlled studies with independent populations; second, replication of drug-gene(s) association and demonstration of utility in at-risk patients;
Bass's Work in Ring Theory and Projective Modules
T. Y. Lam
Mathematics , 2000,
Abstract: The early papers of Hyman Bass in the late 50s and the early 60s leading up to his pioneering work in algebraic K-theory have played an important and very special role in ring theory and the theory of projective (and injective) modules. In this article, we give a general survey of Bass's fundamental contributions in this early period of his work, and explain how much this work has influenced and shaped the thinking of subsequent researchers in the area.
Unit regular elements in corner rings
T. Y. Lam,Will Murray
Mathematics , 2014,
Abstract: For any ring \(R\), some characterizations are obtained for unit regular elements in a corner ring \(eRe\) in terms of unit regular elements in \(R\). \noindent {\bf Key Words}: von Neumann regular rings, unit regular rings, corner rings, idempotents \noindent {\bf AMS Classification}: 16A30
Combinatorial Auction-Based Pricing for Multi-tenant Autonomous Vehicle Public Transportation System
Albert Y. S. Lam
Computer Science , 2015,
Abstract: A smart city provides its people with high standard of living through advanced technologies and transport is one of the major foci. With the advent of autonomous vehicles (AVs), an AV-based public transportation system has been proposed recently, which is capable of providing new forms of transportation services with high efficiency, high flexibility, and low cost. For the benefit of passengers, multitenancy can increase market competition leading to lower service charge and higher quality of service. In this paper, we study the pricing issue of the multi-tenant AV public transportation system and three types of services are defined. The pricing process for each service type is modeled as a combinatorial auction, in which the service providers, as bidders, compete for offering transportation services. The winners of the auction are determined through an integer linear program. To prevent the bidders from raising their bids for higher returns, we propose a strategy-proof Vickrey-Clarke-Groves-based charging mechanism, which can maximize the social welfare, to settle the final charges for the customers. We perform extensive simulations to verify the analytical results and evaluate the performance of the charging mechanism.
The Low Column Density Lyman-alpha Forest
Nickolay Y. Gnedin,Lam Hui
Physics , 1996, DOI: 10.1086/310366
Abstract: We develop an analytical method based on the lognormal approximation to compute the column density distribution of the Lyman-alpha forest in the low column density limit. We compute the column density distributions for six different cosmological models and found that the standard, COBE-normalized CDM model cannot fit the observations of the Lyman-alpha forest at z=3. The amplitude of the fluctuations in that model has to be lowered by a factor of almost 3 to match observations. However, the currently viable cosmological models like the lightly tilted COBE-normalized CDM+Lambda model, the CHDM model with 20% neutrinos, and the low-amplitude Standard CDM model are all in agreement with observations, to within the accuracy of our approximation, for the value of the cosmological baryon density at or higher than the old Standard Bing Bang Nucleosynthesis value of 0.0125 for the currently favored value of the ionizing radiation intensity. With the low value for the baryon density inferred by Hogan & Rugers (1996), the models can only marginally match observations.
Equation of State of the Photoionized Intergalactic Medium
Lam Hui,Nickolay Y. Gnedin
Physics , 1996, DOI: 10.1093/mnras/292.1.27
Abstract: We develop an efficient method to study the effects of reionization history on the temperature-density relation of the intergalactic medium in the low density limit (overdensity less than 5). It is applied to the study of photo-reionization models in which the amplitude, spectrum and onset epoch of the ionizing flux, as well as the cosmology, are systematically varied. We find that the mean temperature-density relation at z=2-4 is well approximated by a power-law equation of state for uniform reionization models. We derive analytical expressions for its evolution and exhibit its asymptotic behavior: it is found that for sufficiently early reionization, imprints of reionization history prior to z=10 on the temperature-density relation are washed out. In this limit the temperature at cosmic mean density is proportional to (\Omega_b h/\sqrt\Omega_0)^{1/1.7}. While the amplitude of the radiation flux at the ionizing frequency of HI is found to have a negligible effect on the temperature-density relation as long as the universe reionizes before z=5, the spectrum can change the overall temperature by about 20%, through variations in the abundances of helium species. However the slope of the mean equation of state is found to lie within a narrow range for all reionization models we study, where reionization takes place before z=5. We discuss the implications of these findings for the observational properties of the Lyman-alpha forest. In particular, uncertainties in the temperature of the intergalactic medium, due to the uncertain reionization history of our universe, introduces a 30% scaling in the amplitude of the column density distribution while the the slope of the distribution is only affected by about 5%. Finally, we discuss how a fluctuating ionizing field affects the above results. We argue that under
Probing the Universe with the Lyman-alpha Forest: I. Hydrodynamics of the Low Density IGM
Nickolay Y. Gnedin,Lam Hui
Physics , 1997, DOI: 10.1046/j.1365-8711.1998.01249.x
Abstract: We introduce an efficient and accurate alternative to full hydrodynamic simulations, Hydro-PM (HPM), for the study of the low column density Lyman-alpha forest. It consists of a Particle-Mesh solver, modified to compute, in addition to the gravitational potential, an effective potential due to the gas pressure. Such an effective potential can be computed from the density field because of a tight correlation between density and pressure in the low density limit, which can be calculated for any photo-reionization history by a method outlined in Hui & Gnedin (1997). Such a correlation exists, in part, because of minimal shock-heating in the low density limit. We compare carefully the density and velocity fields as well as absorption spectra, computed using HPM versus hydrodynamic simulations, and find good agreement. We show that HPM is capable of reproducing measurable quantities, such as the column density distribution, computed from full hydrodynamic simulations, to a precision comparable to that of observations. We discuss how, by virtue of its speed and accuracy, HPM can enable us to use the Lyman-alpha forest as a cosmological probe. We also discuss in detail the smoothing of the gas (or baryon) fluctuation relative to that of the dark matter on small scales due to finite gas pressure. It is shown the conventional wisdom that the linear gas fluctuation is smoothed on the Jeans scale is incorrect for general reionization (or reheating) history; the correct linear filtering scale is in general smaller than the Jeans scale after reheating, but larger prior to it. (abridged)
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