The use of an Nd:YAG laser for thin plate magnesium alloy butt welding was optimized using the Ta... more The use of an Nd:YAG laser for thin plate magnesium alloy butt welding was optimized using the Taguchi analytical methodology. The welding parameters governing the laser beam in thin plate butt welding were evaluated by measuring of the ultimate tension stress. The e ectiveness of the Taguchi method lies in clarifying the factor that dominates complex interactions in laser welding. The factors can be the shielding gas, laser energy, convey speed of workpiece, point at which the laser is focused, pulse frequency, and pulse shape. Furthermore, 18 combinations of these six essential welding parameters were set and Taguchi's method followed exactly. The optimal result was conÿrmed with a superior ultimate tension stress of 169 MPa, 2.5 times larger to that from original set for laser welding.
International Journal of Radiation Oncology*Biology*Physics, 1995
Purpose: To analyze our experience treating soft tissue sarcomas of the head and neck in adults, ... more Purpose: To analyze our experience treating soft tissue sarcomas of the head and neck in adults, and to-patterns of failure and prognostic factors. Methods and Materials: The records of 57 patients with Stage MO disease treated by radiation with or without surgery between 1972 and 1993 were reviewed. Median foiiow-up time was 4.3 years (range, l.l-16.8 years). A group of potentiai prognostic factors was evaluated, inchulmg age at diagnosis, sex, initiai tumor presentation (p&nary vs. recurrent), grade, T-stage, direct tumor extension, tumor depth, duration of treatment, and radlatlon dose. Results: The subset of angiosarcomas (11 out of 57 patients) had a considerably adverse effect on treatment outcome for the total group of sarcomas, with actuariai 5-year overali survivai (OS), locoregional control (LRC), and freedom from distant metastasis (FDM) rates being 31%, 24%, and 42%, respectively. In contrast, for the remaining 46 patients with other histopathologicai tumor types, OS, LRC, and FDM rates were signliicantly higher (74 % ,69 % , and 83 % , respectively). For this group of patients, significant prognostic factors identllied by uni-and multivarlate analysis included tumor grade as a predictor of OS and Tstage as a predictor of LRC (p 5 0.050). Those patients who experienced a locoregional recurrence were at a signilicantly increased risk of dying (p = 0.004 in a multivariate model). All 17 patients without direct tumor extension to neurovascular structures, bone, contiguous organs, or skin remained free from distant failure. In contrast, 27% of 29 patients with dhect extension had develop& distant metastases at 5 years. In multivariate analysis, the absence of direct extension was a positive predictor of F'DM (p = 0.007) and of OS (g = 0.034). Conclusions: 1) Anglosarcomas of the head aud neck have a considerably poorer prognosis than other soft tissue sarcomas of this site. 2) In addltlon to tumor grade and sixe, direct tumor extension may be a usefui additionai staging parameter. 3) High rates of locoregional failure in the head and neck area, a potential cause of morbid@ and death, indicate a need for improved treatment strategies.
Angewandte Chemie (International ed. in English), Jan 17, 2014
The 6,6-quinolone scaffold of the viridicatin-type of fungal alkaloids are found in various quino... more The 6,6-quinolone scaffold of the viridicatin-type of fungal alkaloids are found in various quinolone alkaloids which often exhibit useful biological activities. Thus, it is of interest to identify viridicatin-forming enzymes and understand how such alkaloids are biosynthesized. Here an Aspergillal gene cluster responsible for the biosynthesis of 4'-methoxyviridicatin was identified. Detailed in vitro studies led to the discovery of the dioxygenase AsqJ which performs two distinct oxidations: first desaturation to form a double bond and then monooxygenation of the double bond to install an epoxide. Interestingly, the epoxidation promotes non-enzymatic rearrangement of the 6,7-bicyclic core of 4'-methoxycyclopenin into the 6,6-quinolone viridicatin scaffold to yield 4'-methoxyviridicatin. The finding provides new insight into the biosynthesis of the viridicatin scaffold and suggests dioxygenase as a potential tool for 6,6-quinolone synthesis by epoxidation of benzodiazepi...
Tetracyclines are aromatic polyketides biosynthesized by bacterial type II polyketide synthases. ... more Tetracyclines are aromatic polyketides biosynthesized by bacterial type II polyketide synthases. The amidated tetracycline backbone is biosynthesized by the minimal polyketide synthases and an amidotransferase homologue OxyD. Biosynthesis of the key intermediate 6-methylpretetramid requires two early tailoring steps, which are cyclization of the linearly fused tetracyclic scaffold and regioselective C-methylation of the aglycon. Using a heterologous host (CH999)/vector pair, we identified the minimum set of enzymes from the oxytetracycline biosynthetic pathway that is required to afford 6-methylpretetramid in vivo. Only two cyclases (OxyK and OxyN) are necessary to completely cyclize and aromatize the amidated tetracyclic aglycon. Formation of the last ring via C-1/C-18 aldol condensation does not require a dedicated fourth-ring cyclase, in contrast to the biosynthetic mechanism of other tetracyclic aromatic polyketides, such as daunorubicin and tetracenomycin. Acetylderived polyketides do not undergo spontaneous fourth-ring cyclization and form only anthracene carboxylic acids as demonstrated both in vivo and in vitro. OxyF was identified to be the C-6 C-methyltransferase that regioselectively methylates pretetramid to yield 6-methylpretetramid. Reconstitution of 6-methylpretetramid in a heterologous host sets the stage for a more systematic investigation of additional tetracycline downstream tailoring enzymes and is a key step toward the engineered biosynthesis of tetracycline analogs.
Proficient production of the antitumor agent triostin A was developed using engineered Escherichi... more Proficient production of the antitumor agent triostin A was developed using engineered Escherichia coli (E. coli). The bacterium played host to 15 genes that encode integral biosynthetic proteins which were identified and cloned from Streptomyces lasaliensis. In this study, triostin A production was dramatically increased by more than 20-fold, 13 mg/L, with the introduction of exogenous quinoxaline-2-carboxylic acid (QXC), the speculative starting unit for biosynthesis of triostin A. Conversely, de noVo production of triostin A by means of high cell density fedbatch fermentation that is exclusive of exogenous QXC bore a modest amount of the antitumor agent. Noteworthy production of the biologically active molecule was achieved with smallscale cultivation and quantitative analysis of the product was accomplished with a liquid chromatography-mass spectrometer. This simple and speedy system could easily provide us with valuable information for maximizing the production titer. Our entirely heterologous production system also establishes a basis for the future use of E. coli for generation of novel bioactive compounds through tolerable precursor-directed biosynthesis.
The use of an Nd:YAG laser for thin plate magnesium alloy butt welding was optimized using the Ta... more The use of an Nd:YAG laser for thin plate magnesium alloy butt welding was optimized using the Taguchi analytical methodology. The welding parameters governing the laser beam in thin plate butt welding were evaluated by measuring of the ultimate tension stress. The e ectiveness of the Taguchi method lies in clarifying the factor that dominates complex interactions in laser welding. The factors can be the shielding gas, laser energy, convey speed of workpiece, point at which the laser is focused, pulse frequency, and pulse shape. Furthermore, 18 combinations of these six essential welding parameters were set and Taguchi's method followed exactly. The optimal result was conÿrmed with a superior ultimate tension stress of 169 MPa, 2.5 times larger to that from original set for laser welding.
International Journal of Radiation Oncology*Biology*Physics, 1995
Purpose: To analyze our experience treating soft tissue sarcomas of the head and neck in adults, ... more Purpose: To analyze our experience treating soft tissue sarcomas of the head and neck in adults, and to-patterns of failure and prognostic factors. Methods and Materials: The records of 57 patients with Stage MO disease treated by radiation with or without surgery between 1972 and 1993 were reviewed. Median foiiow-up time was 4.3 years (range, l.l-16.8 years). A group of potentiai prognostic factors was evaluated, inchulmg age at diagnosis, sex, initiai tumor presentation (p&nary vs. recurrent), grade, T-stage, direct tumor extension, tumor depth, duration of treatment, and radlatlon dose. Results: The subset of angiosarcomas (11 out of 57 patients) had a considerably adverse effect on treatment outcome for the total group of sarcomas, with actuariai 5-year overali survivai (OS), locoregional control (LRC), and freedom from distant metastasis (FDM) rates being 31%, 24%, and 42%, respectively. In contrast, for the remaining 46 patients with other histopathologicai tumor types, OS, LRC, and FDM rates were signliicantly higher (74 % ,69 % , and 83 % , respectively). For this group of patients, significant prognostic factors identllied by uni-and multivarlate analysis included tumor grade as a predictor of OS and Tstage as a predictor of LRC (p 5 0.050). Those patients who experienced a locoregional recurrence were at a signilicantly increased risk of dying (p = 0.004 in a multivariate model). All 17 patients without direct tumor extension to neurovascular structures, bone, contiguous organs, or skin remained free from distant failure. In contrast, 27% of 29 patients with dhect extension had develop& distant metastases at 5 years. In multivariate analysis, the absence of direct extension was a positive predictor of F'DM (p = 0.007) and of OS (g = 0.034). Conclusions: 1) Anglosarcomas of the head aud neck have a considerably poorer prognosis than other soft tissue sarcomas of this site. 2) In addltlon to tumor grade and sixe, direct tumor extension may be a usefui additionai staging parameter. 3) High rates of locoregional failure in the head and neck area, a potential cause of morbid@ and death, indicate a need for improved treatment strategies.
Angewandte Chemie (International ed. in English), Jan 17, 2014
The 6,6-quinolone scaffold of the viridicatin-type of fungal alkaloids are found in various quino... more The 6,6-quinolone scaffold of the viridicatin-type of fungal alkaloids are found in various quinolone alkaloids which often exhibit useful biological activities. Thus, it is of interest to identify viridicatin-forming enzymes and understand how such alkaloids are biosynthesized. Here an Aspergillal gene cluster responsible for the biosynthesis of 4'-methoxyviridicatin was identified. Detailed in vitro studies led to the discovery of the dioxygenase AsqJ which performs two distinct oxidations: first desaturation to form a double bond and then monooxygenation of the double bond to install an epoxide. Interestingly, the epoxidation promotes non-enzymatic rearrangement of the 6,7-bicyclic core of 4'-methoxycyclopenin into the 6,6-quinolone viridicatin scaffold to yield 4'-methoxyviridicatin. The finding provides new insight into the biosynthesis of the viridicatin scaffold and suggests dioxygenase as a potential tool for 6,6-quinolone synthesis by epoxidation of benzodiazepi...
Tetracyclines are aromatic polyketides biosynthesized by bacterial type II polyketide synthases. ... more Tetracyclines are aromatic polyketides biosynthesized by bacterial type II polyketide synthases. The amidated tetracycline backbone is biosynthesized by the minimal polyketide synthases and an amidotransferase homologue OxyD. Biosynthesis of the key intermediate 6-methylpretetramid requires two early tailoring steps, which are cyclization of the linearly fused tetracyclic scaffold and regioselective C-methylation of the aglycon. Using a heterologous host (CH999)/vector pair, we identified the minimum set of enzymes from the oxytetracycline biosynthetic pathway that is required to afford 6-methylpretetramid in vivo. Only two cyclases (OxyK and OxyN) are necessary to completely cyclize and aromatize the amidated tetracyclic aglycon. Formation of the last ring via C-1/C-18 aldol condensation does not require a dedicated fourth-ring cyclase, in contrast to the biosynthetic mechanism of other tetracyclic aromatic polyketides, such as daunorubicin and tetracenomycin. Acetylderived polyketides do not undergo spontaneous fourth-ring cyclization and form only anthracene carboxylic acids as demonstrated both in vivo and in vitro. OxyF was identified to be the C-6 C-methyltransferase that regioselectively methylates pretetramid to yield 6-methylpretetramid. Reconstitution of 6-methylpretetramid in a heterologous host sets the stage for a more systematic investigation of additional tetracycline downstream tailoring enzymes and is a key step toward the engineered biosynthesis of tetracycline analogs.
Proficient production of the antitumor agent triostin A was developed using engineered Escherichi... more Proficient production of the antitumor agent triostin A was developed using engineered Escherichia coli (E. coli). The bacterium played host to 15 genes that encode integral biosynthetic proteins which were identified and cloned from Streptomyces lasaliensis. In this study, triostin A production was dramatically increased by more than 20-fold, 13 mg/L, with the introduction of exogenous quinoxaline-2-carboxylic acid (QXC), the speculative starting unit for biosynthesis of triostin A. Conversely, de noVo production of triostin A by means of high cell density fedbatch fermentation that is exclusive of exogenous QXC bore a modest amount of the antitumor agent. Noteworthy production of the biologically active molecule was achieved with smallscale cultivation and quantitative analysis of the product was accomplished with a liquid chromatography-mass spectrometer. This simple and speedy system could easily provide us with valuable information for maximizing the production titer. Our entirely heterologous production system also establishes a basis for the future use of E. coli for generation of novel bioactive compounds through tolerable precursor-directed biosynthesis.
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