Stephen Tsai

All Publications

• Residual enhanced visual vector as a compact signature for mobile visual search SIGNAL PROCESSING Chen, D., Tsai, S., Chandrasekhar, V., Takacs, G., Vedantham, R., Grzeszczuk, R., Girod, B. 2013; 93 (8): 2316-2327

  View details for DOI 10.1016/j.sigpro.2012.06.005

  View details for Web of Science ID 000318581900021

• Rotation-invariant fast features for large-scale recognition and real-time tracking SIGNAL PROCESSING-IMAGE COMMUNICATION Takacs, G., Chandrasekhar, V., Tsai, S., Chen, D., Grzeszczuk, R., Girod, B. 2013; 28 (4): 334-344

  View details for DOI 10.1016/j.image.2012.11.004

  View details for Web of Science ID 000318142100004

• Blocking NRG1 and Other Ligand-Mediated Her4 Signaling Enhances the Magnitude and Duration of the Chemotherapeutic Response of Non-Small Cell Lung Cancer SCIENCE TRANSLATIONAL MEDICINE Hegde, G. V., de la Cruz, C. C., Chiu, C., Alag, N., Schaefer, G., Crocker, L., Ross, S., Goldenberg, D., Merchant, M., Tien, J., Shao, L., Roth, L., Tsai, S., Stawicki, S., Jin, Z., Wyatt, S. K., Carano, R. A., Zheng, Y., Sweet-Cordero, E. A., Wu, Y., Jackson, E. L. 2013; 5 (171)

  View details for Web of Science ID 000314810000006

• Genetic variation in the carbonyl reductase 3 gene confers risk of type 2 diabetes and insulin resistance: a potential regulator of adipogenesis JOURNAL OF MOLECULAR MEDICINE-JMM Chang, Y., Liu, P., Tsai, Y., Chiu, Y., Shih, S., Ho, L., Lee, W., Lu, C., Quertermous, T., Curb, J. D., Lee, W., Lee, P., He, Y., Yeh, J., Hwang, J., Tsai, S., Chuang, L. 2012; 90 (7): 847-858

  Abstract

  Prostaglandins are potent modulators of insulin sensitivity. We systemically evaluated the association of 61 tag single-nucleotide polymorphisms (SNP) in 14 genes involved in prostaglandin metabolism with type 2 diabetes. Among all genotyped SNPs, rs10483032 in the CBR3 (carbonyl reductase 3) gene, which encodes for an enzyme converting prostaglandin E(2) to prostaglandin F2(?), was associated with type 2 diabetes in 760 type 2 diabetic cases and 760 controls (stage-1 study) (P?=?2.0?×?10(-4)). The association was validated in 1,615 cases and 1,162 controls (stage-2 study) (P?=?0.009). The A allele at rs10483032 was associated with increased risk of type 2 diabetes (odds ratio?=?1.29; 95% confidence interval?=?1.14-1.47; combined P?

  View details for DOI 10.1007/s00109-012-0898-8

  View details for Web of Science ID 000305734700013

  View details for PubMedID 22527884

• Compressed Histogram of Gradients: A Low-Bitrate Descriptor INTERNATIONAL JOURNAL OF COMPUTER VISION Chandrasekhar, V., Takacs, G., Chen, D. M., Tsai, S. S., Reznik, Y., Grzeszczuk, R., Girod, B. 2012; 96 (3): 384-399

  View details for DOI 10.1007/s11263-011-0453-z

  View details for Web of Science ID 000299769400007

• Structural and Biochemical Studies of the Hedamycin Type II Polyketide Ketoreductase (HedKR): Molecular Basis of Stereo- and Regiospecificities BIOCHEMISTRY Javidpour, P., Das, A., Khosla, C., Shiou-Chuan Tsai, S. C. 2011; 50 (34): 7426-7439

  Abstract

  Bacterial aromatic polyketides that include many antibiotic and antitumor therapeutics are biosynthesized by the type II polyketide synthase (PKS), which consists of 5-10 stand-alone enzymatic domains. Hedamycin, an antitumor antibiotic polyketide, is uniquely primed with a hexadienyl group generated by a type I PKS followed by coupling to a downstream type II PKS to biosynthesize a 24-carbon polyketide, whose C9 position is reduced by hedamycin type II ketoreductase (hedKR). HedKR is homologous to the actinorhodin KR (actKR), for which we have conducted extensive structural studies previously. How hedKR can accommodate a longer polyketide substrate than the actKR, and the molecular basis of its regio- and stereospecificities, is not well understood. Here we present a detailed study of hedKR that sheds light on its specificity. Sequence alignment of KRs predicts that hedKR is less active than actKR, with significant differences in substrate/inhibitor recognition. In vitro and in vivo assays of hedKR confirmed this hypothesis. The hedKR crystal structure further provides the molecular basis for the observed differences between hedKR and actKR in the recognition of substrates and inhibitors. Instead of the 94-PGG-96 motif observed in actKR, hedKR has the 92-NGG-94 motif, leading to S-dominant stereospecificity, whose molecular basis can be explained by the crystal structure. Together with mutations, assay results, docking simulations, and the hedKR crystal structure, a model for the observed regio- and stereospecificities is presented herein that elucidates how different type II KRs recognize substrates with different chain lengths, yet precisely reduce only the C9-carbonyl group. The molecular features of hedKR important for regio- and stereospecificities can potentially be applied to biosynthesize new polyketides via protein engineering that rationally controls polyketide ketoreduction.

  View details for DOI 10.1021/bi2006866

  View details for Web of Science ID 000294083600012

  View details for PubMedID 21776967

• Mobile Visual Search [Linking the virtual and physical worlds] IEEE SIGNAL PROCESSING MAGAZINE Girod, B., Chandrasekhar, V., Chen, D. M., Cheung, N., Grzeszczuk, R., Reznik, Y., Takacs, G., Tsai, S. S., Vedantham, R. 2011; 28 (4): 61-76

  View details for DOI 10.1109/MSP.2011.940881

  View details for Web of Science ID 000291822000009

• Trends in menopausal hormone therapy use of US office-based physicians, 2000-2009 MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Tsai, S. A., Stefanick, M. L., Stafford, R. S. 2011; 18 (4): 385-392

  Abstract

  The aim of this study was to evaluate recent trends and the adoption of practice recommendations for menopausal hormone therapy (MHT) use from 2001 to 2009 by formulation, dose, woman's age, and characteristics of physicians reporting MHT visits.The IMS Health (Plymouth Meeting PA) National Disease and Therapeutic Index physician survey data from 2001 to 2009 were analyzed for visits in which MHT use was reported by US office-based physicians. Estimated national volume of visits for which MHT use was reported.MHT use declined each year since 2002. Systemic MHT use fell from 16.3 million (M) visits in 2001 to 6.1 M visits in 2009. Declines were greatest for women 60 years or older (64%) but were also substantial for women younger than 50 years (59%) and women 50 to 59 years old (60%). Women 60 years or older accounted for 37% of MHT use. Lower dose product use increased modestly, from 0.7 M (2001) to 1.3 M (2009), as did vaginal MHT use, from 1.8 M (2001) to 2.4 M (2009). Declines in continuing systemic MHT use (65%) were greater than for newly initiated MHT use (51%). Compared with other physicians, obstetrician/gynecologists changed their practices less, thereby increasing their overall share of total MHT visits from 72% (2001) to 82% (2009).Total MHT use has steadily declined. Increased use of lower dose and vaginal products reflects clinical recommendations. Uptake of these products, however, has been modest, and substantial use of MHT continues in older women.

  View details for DOI 10.1097/gme.0b013e3181f43404

  View details for Web of Science ID 000288781800009

  View details for PubMedID 21127439

• Direction-Adaptive Partitioned Block Transform for Color Image Coding IEEE TRANSACTIONS ON IMAGE PROCESSING Chang, C., Makar, M., Tsai, S. S., Girod, B. 2010; 19 (7): 1740-1755

  Abstract

  The direction-adaptive partitioned block transform (DA-PBT) is proposed to exploit the directional features in color images to improve coding performance. Depending on the directionality in an image block, the transform either selects one of the eight directional modes or falls back to the nondirectional mode equivalent to the conventional 2-D DCT. The selection of a directional mode determines the transform direction that provides directional basis functions, the block partitioning that spatially confines the high-frequency energy, the scanning order that arranges the transform coefficients into a 1-D sequence for efficient entropy coding, and the quantization matrix optimized for visual quality. The DA-PBT can be incorporated into image coding using a rate-distortion optimized framework for direction selection, and can therefore be viewed as a generalization of variable blocksize transforms with the inclusion of directional transforms and nonrectangular partitions. As a block transform, it can naturally be combined with block-based intra or inter prediction to exploit the directionality remaining in the residual. Experimental results show that the proposed DA-PBT outperforms the 2-D DCT by more than 2 dB for test images with directional features. It also greatly reduces the ringing and checkerboard artifacts typically observed around directional features in images. The DA-PBT also consistently outperforms a previously proposed directional DCT. When combined with directional prediction, gains are less than additive, as similar signal properties are exploited by the prediction and the transform. For hybrid video coding, significant gains are shown for intra coding, but not for encoding the residual after accurate motion-compensated prediction.

  View details for DOI 10.1109/TIP.2010.2044964

  View details for Web of Science ID 000278813800007

  View details for PubMedID 20215074

• A chromosome 16 quantitative trait locus regulates allogeneic bone marrow engraftment in nonmyeloablated mice BLOOD Cao, T. M., Thomas, A., Wang, Y., Tsai, S., Logronio, K., Shizuru, J. A. 2009; 114 (1): 202-210

  Abstract

  Identifying genes that regulate bone marrow (BM) engraftment may reveal molecular targets for overcoming engraftment barriers. To achieve this aim, we applied a forward genetic approach in a mouse model of nonmyeloablative BM transplantation. We evaluated engraftment of allogeneic and syngeneic BM in BALB.K and B10.BR recipients. This allowed us to partition engraftment resistance into its intermediate phenotypes, which are firstly the immune-mediated resistance and secondly the nonimmune rejection of donor BM cells. We observed that BALB.K and B10.BR mice differed with regard to each of these resistance mechanisms, thereby providing evidence that both are under genetic control. We then generated a segregating backcross (n = 200) between the BALB.K and B10.BR strains to analyze for genetic linkage to the allogeneic BM engraftment phenotype using a 127-marker genome scan. This analysis identified a novel quantitative trait locus (QTL) on chromosome 16, termed Bmgr5 (logarithm of odds 6.4, at 11.1 cM). The QTL encodes susceptibility alleles, from the BALB.K strain, that are permissive for allogeneic BM engraftment. Further identification of Bmgr5 genes by positional cloning may reveal new and effective approaches for overcoming BM engraftment obstacles.

  View details for DOI 10.1182/blood-2009-03-208801

  View details for Web of Science ID 000267789800031

  View details for PubMedID 19417206

• Identification of a Major Susceptibility Locus for Lethal Graft-versus-Host Disease in MHC-Matched Mice JOURNAL OF IMMUNOLOGY Cao, T. M., Lazzeroni, L. C., Tsai, S., Pang, W. W., Kao, A., Camp, N. J., Thomas, A., Shizuru, J. A. 2009; 183 (1): 462-469

  Abstract

  Graft-vs-host disease (GVHD) is the major cause of morbidity and mortality after allogeneic hemopoietic cell transplantation. From a genetic perspective, GVHD is a complex phenotypic trait. Although it is understood that susceptibility results from interacting polymorphisms of genes encoding histocompatibility Ags and immune regulatory molecules, a detailed and integrative understanding of the genetic background underlying GVHD remains lacking. To gain insight regarding these issues, we performed a forward genetic study. A MHC-matched mouse model was used in which irradiated recipient BALB.K and B10.BR mice demonstrate differential susceptibility to lethal GHVD when transplanted using AKR/J donors. Assessment of GVHD in (B10.BR x BALB.K)F(1) mice revealed that susceptibility is a dominant trait and conferred by deleterious alleles from the BALB.K strain. To identify the alleles responsible for GVHD susceptibility, a genome-scanning approach was taken using (B10.BR x BALB.K)F(1) x B10.BR backcross mice as recipients. A major susceptibility locus, termed the Gvh1 locus, was identified on chromosome 16 using linkage analysis (logarithm of the odds, 9.1). A second locus was found on chromosome 13, named Gvh2, which had additive but protective effects. Further identification of Gvh genes by positional cloning may yield new insight into genetic control mechanisms regulating GVHD and potentially reveal novel approaches for effective GVHD therapy.

  View details for DOI 10.4049/jimmunol.0900454

  View details for Web of Science ID 000275119400051

  View details for PubMedID 19525392

• Happy 40th anniversary JOURNAL OF COMPOSITE MATERIALS Tsai, S. W. 2008; 42 (18): 1821-1823

  View details for DOI 10.1177/0021998308093908

  View details for Web of Science ID 000258534000001

• Urodynamic responses to anal stretch in patients with detrusor sphincter dyssynergia ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION Huang, Y., Chen, S., Tsai, S., Bih, L., Lew, H. L. 2008; 89 (9): 1748-1752

  Abstract

  To evaluate the urodynamic responses to anal stretch in patients with detrusor sphincter dyssynergia (DSD).Descriptive study.Rehabilitation hospital affiliated with a medical university.Patients (N=36) with suprasacral spinal cord injury who had DSD confirmed on cystometrography.Not applicable.Detrusor pressure, urethral pressure, and summated electromyogram of external urethral sphincter on cystometrography.The urodynamic responses to anal stretch were evaluated in the first half (time 1, 1-15s) and the second half (time 2, 16-30s) of the evaluation time period. The activity of external urethral sphincter was reduced significantly in both times 1 and 2 (P<0.5). The medians of reduction percentages were 33% and 35% for times 1 and 2, respectively. The change of detrusor pressure was not significant in either time 1 or time 2.Anal stretch can reduce the activity of external urethral sphincter without significant change in detrusor pressure.

  View details for DOI 10.1016/j.apmr.2007.12.051

  View details for Web of Science ID 000259057300016

  View details for PubMedID 18760159

• Specific tumor suppressor function for E2F2 in Myc-induced T cell lymphomagenesis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Opavsky, R., Tsai, S., Guimond, M., Arora, A., Opavska, J., Becknell, B., Kaufmann, M., Walton, N. A., Stephens, J. A., Fernandez, S. A., Muthusamy, N., Felsher, D. W., Porcu, P., Caligiuri, M. A., Leone, G. 2007; 104 (39): 15400-15405

  Abstract

  Deregulation of the Myc pathway and deregulation of the Rb pathway are two of the most common abnormalities in human malignancies. Recent in vitro experiments suggest a complex cross-regulatory relationship between Myc and Rb that is mediated through the control of E2F. To evaluate the functional connection between Myc and E2Fs in vivo, we used a bitransgenic mouse model of Myc-induced T cell lymphomagenesis and analyzed tumor progression in mice deficient for E2f1, E2f2, or E2f3. Whereas the targeted inactivation of E2f1 or E2f3 had no significant effect on tumor progression, loss of E2f2 accelerated lymphomagenesis. Interestingly, loss of a single copy of E2f2 also accelerated tumorigenesis, albeit to a lesser extent, suggesting a haploinsufficient function for this locus. The combined ablation of E2f1 or E2f3, along with E2f2, did not further accelerate tumorigenesis. Myc-overexpressing T cells were more resistant to apoptosis in the absence of E2f2, and the reintroduction of E2F2 into these tumor cells resulted in an increase of apoptosis and inhibition of tumorigenesis. These results identify the E2f2 locus as a tumor suppressor through its ability to modulate apoptosis.

  View details for DOI 10.1073/pnas.0706307104

  View details for Web of Science ID 000249806900042

  View details for PubMedID 17881568

• The use of the Gaussian curve fitting method for scintigraphic measurements of the swallowing process in healthy subjects: implications for evaluation of dysphagia ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION Huang, Y., Tseng, F., Tsai, S., Lin, C., Chou, Y., Lew, H. L. 2006; 87 (11): 1526-1529

  Abstract

  To present the results of scintigraphic evaluation, using the Gaussian curve fitting method, via 3 parameters of oropharyngeal swallow: (1) pharyngeal transit time, (2) premature pharyngeal entry, and (3) postswallow pharyngeal stasis while ingesting liquid.A descriptive study.A rehabilitation hospital affiliated with a medical university.Eighteen healthy subjects.All 18 subjects received scintigraphic swallow examination to evaluate dynamic swallow process of 5 mL of liquid.The Gaussian curve fitting method was used to calculate the pharyngeal transit time, premature pharyngeal entry, and postswallow pharyngeal stasis.The mean pharyngeal transit time was .71 seconds. The maximal percentage of premature pharyngeal entry was 3%. The maximal percentage of postswallow pharyngeal stasis was 9%.The Gaussian curve fitting can be used as an objective and time-saving method to calculate the parameters in scintigraphic swallowing examination. Our results approximate other researchers' reports.

  View details for DOI 10.1016/j.apmr.2006.08.324

  View details for Web of Science ID 000242143500017

  View details for PubMedID 17084130

• Smart cure of thick composite filament wound structures to minimize the development of residual stresses Lee, D. H., Kim, S. K., Lee, W. I., Ha, S. K., Tsai, S. W. ELSEVIER SCI LTD. 2006: 530-537

  View details for DOI 10.1016/j.compositesa.2005.05.017

  View details for Web of Science ID 000236338500003

• Three decades of composites activities at US Air Force Materials Laboratory COMPOSITES SCIENCE AND TECHNOLOGY Tsai, S. W. 2005; 65 (15-16): 2295-2299

  View details for DOI 10.1016/j.compscitech.2005.05.017

  View details for Web of Science ID 000233076100003

• Prediction of fatigue S-N curves of composite laminates by Super Mic-Mac COMPOSITES PART A-APPLIED SCIENCE AND MANUFACTURING Sihn, S., Tsai, S. W. 2005; 36 (10): 1381-1388

  View details for DOI 10.1016/j.compositesa.2004.11.016

  View details for Web of Science ID 000232199000008

• Crystal structure of the beta-subunit of Acyl-CoA carboxylase: Structure-based engineering of substrate specificity BIOCHEMISTRY Diacovich, L., Mitchell, D. L., Pham, H., Gago, G., Melgar, M. M., Khosla, C., Gramajo, H., Tsai, S. C. 2004; 43 (44): 14027-14036

  Abstract

  Acetyl-CoA carboxylase (ACC) and propionyl-CoA carboxylase (PCC) catalyze the carboxylation of acetyl- and propionyl-CoA to generate malonyl- and methylmalonyl-CoA, respectively. Understanding the substrate specificity of ACC and PCC will (1) help in the development of novel structure-based inhibitors that are potential therapeutics against obesity, cancer, and infectious disease and (2) facilitate bioengineering to provide novel extender units for polyketide biosynthesis. ACC and PCC in Streptomyces coelicolor are multisubunit complexes. The core catalytic beta-subunits, PccB and AccB, are 360 kDa homohexamers, catalyzing the transcarboxylation between biotin and acyl-CoAs. Apo and substrate-bound crystal structures of PccB hexamers were determined to 2.0-2.8 A. The hexamer assembly forms a ring-shaped complex. The hydrophobic, highly conserved biotin-binding pocket was identified for the first time. Biotin and propionyl-CoA bind perpendicular to each other in the active site, where two oxyanion holes were identified. N1 of biotin is proposed to be the active site base. Structure-based mutagenesis at a single residue of PccB and AccB allowed interconversion of the substrate specificity of ACC and PCC. The di-domain, dimeric interaction is crucial for enzyme catalysis, stability, and substrate specificity; these features are also highly conserved among biotin-dependent carboxyltransferases. Our findings enable bioengineering of the acyl-CoA carboxylase (ACCase) substrate specificity to provide novel extender units for the combinatorial biosynthesis of polyketides.

  View details for DOI 10.1021/bi049065v

  View details for Web of Science ID 000224939400016

  View details for PubMedID 15518551

• Crystal structure of an Acyl-ACP dehydrogenase from the FK520 polyketide Biosynthetic pathway: Insights into extender unit biosynthesis JOURNAL OF MOLECULAR BIOLOGY Watanabe, K., Khosla, C., Stroud, R. M., Tsai, S. C. 2003; 334 (3): 435-444

  Abstract

  Polyketide synthases (PKSs) synthesize the polyketide cores of pharmacologically important natural products such as the immunosuppressants FK520 and FK506. Understanding polyketide biosynthesis at atomic resolution could present new opportunities for chemo-enzymatic synthesis of complex molecules. The crystal structure of FkbI, an enzyme involved in the biosynthesis of the methoxymalonyl extender unit of FK520, was solved to 2.1A with an R(crys) of 24.4%. FkbI has a similar fold to acyl-CoA dehydrogenases. Notwithstanding this similarity, the surface and substrate-binding site of FkbI reveal key differences from other acyl-CoA dehydrogenases, suggesting that FkbI may recognize an acyl-ACP substrate rather than an acyl-CoA substrate. This structural observation coincided the genetic experiment done by Carroll et al. J. Am. Chem. Soc., 124 (2002) 4176. Although an in vitro assay for FkbI remains elusive, the structural basis for the substrate specificity of FkbI is analyzed by a combination of sequence comparison, docking simulations and structural analysis. A biochemical mechanism for the role of FkbI in the biosynthesis of methoxymalonyl-ACP is proposed.

  View details for DOI 10.1016/j.jmb.2003.10.021

  View details for Web of Science ID 000186710600007

  View details for PubMedID 14623185

• Polyketide chain length control by chain length factor JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Tang, Y., Tsai, S. C., Khosla, C. 2003; 125 (42): 12708-12709

  Abstract

  Bacterial aromatic polyketides are pharmacologically important natural products. A critical parameter that dictates product structure is the carbon chain length of the polyketide backbone. Systematic manipulation of polyketide chain length represents a major unmet challenge in natural product biosynthesis. Polyketide chain elongation is catalyzed by a heterodimeric ketosynthase. In contrast to homodimeric ketosynthases found in fatty acid synthases, the active site cysteine is absent from the one subunit of this heterodimer. The precise role of this catalytically silent subunit has been debated over the past decade. We demonstrate here that this subunit is the primary determinant of polyketide chain length, thereby validating its designation as chain length factor. Using structure-based mutagenesis, we identified key residues in the chain length factor that could be manipulated to convert an octaketide synthase into a decaketide synthase and vice versa. These results should lead to novel strategies for the engineered biosynthesis of hitherto unidentified polyketide scaffolds.

  View details for DOI 10.1021/ja0378759

  View details for Web of Science ID 000185990300021

  View details for PubMedID 14558809

• Trends in the design, manufacture and evaluation of wind turbine blades WIND ENERGY Veers, P. S., Ashwill, T. D., Sutherland, H. J., Laird, D. L., Lobitz, D. W., Griffin, D. A., Mandell, J. F., Musial, W. D., Jackson, K., Zuteck, M., Miravete, A., Tsai, S. W., Richmond, J. L. 2003; 6 (3): 245-259

  View details for DOI 10.1002/we.90

  View details for Web of Science ID 000186355900005

• Applicability of time-temperature-water absorption superposition principle for flexural strength of CFRP laminates Fujieda, H., Sekine, N., Nakada, M., Miyano, Y., Kuraishi, A., Tsai, S. W. JAPAN SOC MECHANICAL ENGINEERS. 2003: 467-472

  View details for Web of Science ID 000185044600049

• Prediction of fatigue life for CFRP/metal bolted joint under temperature conditions Sekine, N., Nakada, M., Miyano, Y., Kuraishi, A., Tsai, S. W. JAPAN SOC MECHANICAL ENGINEERS. 2003: 484-489

  View details for Web of Science ID 000185044600052

• De Novo design and utilization of photolabile caged substrates as probes of hydrogen tunneling with horse liver alcohol dehydrogenase at sub-zero temperatures: a cautionary note BIOORGANIC CHEMISTRY Tsai, S. C., Klinman, J. P. 2003; 31 (2): 172-190

  Abstract

  In order to understand the influence of protein dynamics on enzyme catalysis and hydrogen tunneling, the horse liver alcohol dehydrogenase (HLADH) catalyzed oxidation of benzyl alcohol was studied at sub-zero temperatures. Previous work showed that wild type HLADH has significant kinetic complexity down to -50 degrees C due to slow binding and loss of substrate [S.-C. Tsai, J.P. Klinman, Biochemistry, 40 (2001) 2303]. A strategy was therefore undertaken to reduce kinetic complexity at sub-zero temperatures, using a photolabile (caged) benzyl alcohol that prebinds to the enzyme and yields the active substrate upon photolysis. By computer modeling, a series of caged alcohols were designed de novo, synthesized, and characterized with regard to photolysis and binding properties. The o-nitrobenzyl ether 15, with a unique long tail, was found to be most ideal. At sub-zero temperatures in 50% MeOH, a two-phase kinetic trace and a rate enhancement by the use of 15 were observed. Despite the elimination of substrate binding as a rate-limiting step, the use of caged benzyl alcohol does not produce a measurable H/D kinetic isotope effect. Unexpectedly, the observed fast phase corresponds to multiple enzyme turnovers, based on the stoichiometry of the substrate to enzyme. Possible side reactions and their effects, such as the re-oxidation of bound NADH and the dissipation of photo-excitation energy, may offer an explanation for the observed multiple-turnovers. The lack of observable deuterium isotope effects offers a cautionary note for the application of caged substrates to isolate and study chemical steps of enzyme reactions, particularly when NADH is involved in the reaction pathway.

  View details for DOI 10.1016/S0045-2068(03)00018-X

  View details for Web of Science ID 000182858500008

  View details for PubMedID 12729574

• Catalysis, specificity, and ACP docking site of Streptomyces coelicolor malonyl-CoA : ACP transacylase STRUCTURE Keatinge-Clay, A. T., Shelat, A. A., Savage, D. F., Tsai, S. C., Miercke, L. J., O'Connell, J. D., Khosla, C., Stroud, R. M. 2003; 11 (2): 147-154

  Abstract

  Malonyl-CoA:ACP transacylase (MAT), the fabD gene product of Streptomyces coelicolor A3(2), participates in both fatty acid and polyketide synthesis pathways, transferring malonyl groups that are used as extender units in chain growth from malonyl-CoA to pathway-specific acyl carrier proteins (ACPs). Here, the 2.0 A structure reveals an invariant arginine bound to an acetate that mimics the malonyl carboxylate and helps define the extender unit binding site. Catalysis may only occur when the oxyanion hole is formed through substrate binding, preventing hydrolysis of the acyl-enzyme intermediate. Macromolecular docking simulations with actinorhodin ACP suggest that the majority of the ACP docking surface is formed by a helical flap. These results should help to engineer polyketide synthases (PKSs) that produce novel polyketides.

  View details for Web of Science ID 000180905000006

  View details for PubMedID 12575934

• Interlocked composite grids design and manufacturing JOURNAL OF COMPOSITE MATERIALS Han, D. Y., Tsai, S. W. 2003; 37 (4): 287-316

  View details for DOI 10.1106/002199803028681

  View details for Web of Science ID 000181613000001

• Time- and temperature-dependent failures of a metal-to-composites bonded joint with PMMA adhesive material JOURNAL OF COMPOSITE MATERIALS Sihn, S., Miyano, Y., Nakada, M., Tsai, S. W. 2003; 37 (1): 35-54

  View details for DOI 10.1106/002199803028993

  View details for Web of Science ID 000180309200003

• Crystal structure of the priming beta-ketosynthase from the R1128 polyketide biosynthetic pathway STRUCTURE Pan, H., Tsai, S. C., Meadows, E. S., Miercke, L. J., Keatinge-Clay, A. T., O'Connell, J., Khosla, C., Stroud, R. M. 2002; 10 (11): 1559-1568

  Abstract

  ZhuH is a priming ketosynthase that initiates the elongation of the polyketide chain in the biosynthetic pathway of a type II polyketide, R1128. The crystal structure of ZhuH in complex with the priming substrate acetyl-CoA reveals an extensive loop region at the dimer interface that appears to affect the selectivity for the primer unit. Acetyl-CoA is bound in a 20 A-long channel, which placed the acetyl group against the catalytic triad. Analysis of the primer unit binding site in ZhuH suggests that it can accommodate acyl chains that are two to four carbons long. Selectivity and primer unit size appear to involve the side chains of three residues on the loops close to the dimer interface that constitute the bottom of the substrate binding pocket.

  View details for Web of Science ID 000179175300014

  View details for PubMedID 12429097

• Expression, site-directed mutagenesis, and steady state kinetic analysis of the terminal thioesterase domain of the methymycin/picromycin polyketide synthase BIOCHEMISTRY Lu, H. X., Tsai, S. C., Khosla, C., Cane, D. E. 2002; 41 (42): 12590-12597

  Abstract

  The thioesterase (TE) domain of the methymycin/picromycin synthase (PICS) was functionally expressed in Escherichia coli, and the optimal N-terminal boundary of the recombinant TE was determined. A series of diketide-N-acetylcysteamine (SNAC) thioesters were tested as substrates. PICS TE showed a strong preference for the 2-methyl-3-ketopentanoyl-SNAC substrate 5 over the stereoisomers of the reduced diketides 1-4, with an approximately 1.6:1 preference for the (2R,3S)-2-methyl-3-hydroxy diastereomer 2 over the (2S,3R)-diketide 1. The closely related DEBS TE, the thioesterase from the 6-deoxyerythronolide B synthase, showed a more marked 4.4:1 preference for 2 over 1, with only a slightly greater preference for the 3-ketoacyl-SNAC substrate 5. The roles of several active site residues in PICS TE were examined by site-directed mutagenesis. Serine 148, which is part of the apparent catalytic triad consisting of S148, H268, and D176, was found to be essential for thioesterase activity, while replacement of D176 with asparagine (D176N) gave a mutant thioesterase that retained substantial, albeit reduced, hydrolytic activity toward diketide-SNAC substrates. Mutation of E187 and R191, each of which is thought to play a role in substrate binding, had only minor effects on the relative specificity for diketide substrates 1, 2, and 5. Finally, when PICS TE was fused to the C-terminus of DEBS module 3, the resultant chimeric protein converted diketide 1 with methylmalonyl-CoA to triketide ketolactone 6 with improved catalytic efficiency compared to that of the previously developed DEBS module 3-(DEBS)TE construct.

  View details for DOI 10.1021/bi026006d

  View details for Web of Science ID 000178694000004

  View details for PubMedID 12379101

• Insights into channel architecture and substrate specificity from crystal structures of two macrocycle-forming thioesterases of modular polyketide synthases BIOCHEMISTRY Tsai, S. C., Lu, H. X., Cane, D. E., Khosla, C., Stroud, R. M. 2002; 41 (42): 12598-12606

  Abstract

  Modular polyketide synthases (PKSs) synthesize the polyketide cores of pharmacologically important natural products such as erythromycin and picromycin. Understanding PKSs at high resolution could present new opportunities for chemoenzymatic synthesis of complex molecules. The crystal structures of macrocycle-forming thioesterase (TE) domains from the picromycin synthase (PICS) and 6-deoxyerythronolide B synthase (DEBS) were determined to 1.8-3.0 A with an R(crys) of 19.2-24.4%, including three structures of PICS TE (crystallized at pH 7.6, 8.0, and 8.4) and a second crystal form of DEBS TE. As predicted by the previous work on DEBS TE [Tsai, S. C., et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14808-14813], PICS TE contains an open substrate channel and a hydrophobic dimer interface. Notwithstanding their similarity, the dimer interfaces and substrate channels of DEBS TE and PICS TE reveal key differences. The structural basis for the divergent substrate specificities of DEBS TE and PICS TE is analyzed. The size of the substrate channel increases with increasing pH, presumably due to electrostatic repulsion in the channel at elevated pH. Together, these structures support previous predictions that macrocycle-forming thioesterases from PKSs share the same protein fold, an open substrate channel, a similar catalytic mechanism, and a hydrophobic dimer interface. They also provide a basis for the design of enzymes capable of catalyzing regioselective macrocyclization of natural or synthetic substrates. A series of high-resolution snapshots of a protein channel at different pHs is presented alongside analysis of channel residues, which could help in the redesign of the protein channel architecture.

  View details for DOI 10.1021/bi0260177

  View details for Web of Science ID 000178694000005

  View details for PubMedID 12379102

• Treatment of detrusor-sphincter dyssynergia by pudendal nerve block in patients with spinal cord injury ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION Tsai, S. J., Lew, H. L., Date, E., Bih, L. I. 2002; 83 (5): 714-717

  Abstract

  To study the effects of pudendal nerve block with phenol on detrusor-sphincter dyssynergia in patients with spinal cord injury (SCI).Before-after trial performed by using a consecutive sample.Rehabilitation hospital affiliated with a medical school.Twenty-two male SCI patients (mean age, 46.3+/-11.9y; mean duration postinjury, 2.7y) with voiding dysfunction resulting from external urethral sphincter hypertonicity.Pudendal nerve block with 5% phenol solution under the guidance of electric stimulator.Outcomes were measured using (1) postvoid residual volume, maximal detrusor pressure, leak point pressure, bladder volume at the first uninhibited contraction, maximal bladder capacity, and urethral pressure profile; (2) rectoanal rest and squeeze pressures; and (3) quality of life measures for urination, quantified by the Quality of Life Index (QLI). Changes in bowel habit or autonomic dysreflexia were recorded.The mean decrease in postvoid residual volume was 242.8mL (mean decrease, 66%) after treatment (P<.001). The mean reduction in leak point pressure and maximal detrusor pressure were 37.1cmH(2)O and 43.3cmH(2)O, respectively (P<.05). The mean QLI significantly improved from -.74+/-.38 to.42+/-.47 (P<.001). The rectoanal pressures showed no significant difference. No complaints of fecal incontinence or other complications were noted after treatment.Pudendal nerve block performed by using 5% phenol solution was safe, easy to perform, and effective as a treatment for detrusor-sphincter dyssynergia in selected patients with SCI.

  View details for DOI 10.1053/apmr.2002.31609

  View details for Web of Science ID 000175494000019

  View details for PubMedID 11994813

• A progressive quadratic failure criterion, part B COMPOSITES SCIENCE AND TECHNOLOGY Kuraishi, A., Tsai, S. W., Liu, K. K. 2002; 62 (12-13): 1683-1695

  View details for Web of Science ID 000177970200013

• Modeling of mechanical property degradation by short-term aging at high temperatures COMPOSITES PART B-ENGINEERING Kim, J., Lee, W. I., Tsai, S. W. 2002; 33 (7): 531-543

  View details for Web of Science ID 000178837400004

• Crystal structure of the macrocycle-forming thioesterase domain of the erythromycin polyketide synthase: Versatility from a unique substrate channel PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Tsai, S. C., Miercke, L. J., Krucinski, J., Gokhale, R., Chen, J. C., Foster, P. G., Cane, D. E., Khosla, C., Stroud, R. M. 2001; 98 (26): 14808-14813

  Abstract

  As the first structural elucidation of a modular polyketide synthase (PKS) domain, the crystal structure of the macrocycle-forming thioesterase (TE) domain from the 6-deoxyerythronolide B synthase (DEBS) was solved by a combination of multiple isomorphous replacement and multiwavelength anomalous dispersion and refined to an R factor of 24.1% to 2.8-A resolution. Its overall tertiary architecture belongs to the alpha/beta-hydrolase family, with two unusual features unprecedented in this family: a hydrophobic leucine-rich dimer interface and a substrate channel that passes through the entire protein. The active site triad, comprised of Asp-169, His-259, and Ser-142, is located in the middle of the substrate channel, suggesting the passage of the substrate through the protein. Modeling indicates that the active site can accommodate and orient the 6-deoxyerythronolide B precursor uniquely, while at the same time shielding the active site from external water and catalyzing cyclization by macrolactone formation. The geometry and organization of functional groups explain the observed substrate specificity of this TE and offer strategies for engineering macrocycle biosynthesis. Docking of a homology model of the upstream acyl carrier protein (ACP6) against the TE suggests that the 2-fold axis of the TE dimer may also be the axis of symmetry that determines the arrangement of domains in the entire DEBS. Sequence conservation suggests that all TEs from modular polyketide synthases have a similar fold, dimer 2-fold axis, and substrate channel geometry.

  View details for Web of Science ID 000172848800016

  View details for PubMedID 11752428

• PECVD silicon carbide as a chemically resistant material for micromachined transducers Flannery, A. F., Mourlas, N. J., Storment, C. W., Tsai, S., Tan, S. H., Heck, J., Monk, D., Kim, T., Gogoi, B., Kovacs, G. T. ELSEVIER SCIENCE SA. 1998: 48-55

  View details for Web of Science ID 000075835900007

• Practical considerations for the design of composite structures MECHANICS OF COMPOSITE MATERIALS AND STRUCTURES Manne, P. M., Tsai, S. W. 1998; 5 (3): 227-255

  View details for Web of Science ID 000074152200002

• A progressive quadratic failure criterion for a laminate COMPOSITES SCIENCE AND TECHNOLOGY Liu, K. S., Tsai, S. W. 1998; 58 (7): 1023-1032

  View details for Web of Science ID 000076342100004

• Design optimization of composite plates: Part I - Design criteria for strength, stiffness, and manufacturing complexity of composite laminates JOURNAL OF COMPOSITE MATERIALS Manne, P. M., Tsai, S. W. 1998; 32 (6): 544-571

  View details for Web of Science ID 000072859800003

• Design optimization of composite plates: Part II - Structural optimization by plydrop tapering JOURNAL OF COMPOSITE MATERIALS Manne, P. M., Tsai, S. W. 1998; 32 (6): 572-598

  View details for Web of Science ID 000072859800004

• Obituary: Late Professor Tsuyoshi Hayashi ADVANCED COMPOSITE MATERIALS Hoff, R., Springer, G. S., Tsai, S. W. 1998; 7 (3): 217-218

  View details for Web of Science ID 000075585200004

• Manufacture and design of composite grids MATERIALES DE CONSTRUCCION Tsai, S. W., Liu, K. K., Manne, P. M. 1997; 47 (247-48): 59-71

  View details for Web of Science ID 000071677600005

• Analysis and behavior of grid structures COMPOSITES SCIENCE AND TECHNOLOGY Huybrechts, S., Tsai, S. W. 1996; 56 (9): 1001-1015

  View details for Web of Science ID A1996VR25500001

• Analysis and optimum design of composite grid structures JOURNAL OF COMPOSITE MATERIALS Chen, H. J., Tsai, S. W. 1996; 30 (4): 503-534

  View details for Web of Science ID A1996UH23700005

• Three-dimensional effective moduli of symmetric laminates JOURNAL OF COMPOSITE MATERIALS Chen, H. J., Tsai, S. W. 1996; 30 (8): 906-917

  View details for Web of Science ID A1996UQ48000003

• SCHOOLING TAIWAN WOMEN - EDUCATIONAL-ATTAINMENT IN THE MID-20TH CENTURY Tsai, S. L., Gates, H., Chiu, H. Y. AMER SOCIOLOGICAL ASSOC. 1994: 243-263

  View details for Web of Science ID A1994QY44300003

• 3-DIMENSIONAL EFFECTIVE MODULI OF ORTHOTROPIC AND SYMMETRICAL LAMINATES JOURNAL OF APPLIED MECHANICS-TRANSACTIONS OF THE ASME Roy, A. K., Tsai, S. W. 1992; 59 (1): 39-47

  View details for Web of Science ID A1992HP72000007