Artemisinin-based combination therapy(ACT)forms the first line of malaria treatment.However,the yield fluctuation of artemisinin has remained an unsolved problem in meeting the global demand for ACT.This problem is ma...Artemisinin-based combination therapy(ACT)forms the first line of malaria treatment.However,the yield fluctuation of artemisinin has remained an unsolved problem in meeting the global demand for ACT.This problem is mainly caused by the glandular trichome(GT)-specific biosynthesis of artemisinin in all currently used Artemisia annua cultivars.Here,we report that non-GT cells of self-pollinated inbred A.annua plants can express the artemisinin biosynthetic pathway.Gene expression analysis demonstrated the transcription of six known pathway genes in GT-free leaves and calli of inbred A.annua plants.LC-qTOF-MS/MS analysis showed that these two types of GT-free materials produce artemisinin,artemisinic acid,and arteannuin B.Detailed IR-MALDESI image profiling revealed that these three metabolites and dihydroartemisinin are localized in non-GT cells of leaves of inbred A.annua plants.Moreover,we employed all the above approaches to examine artemisinin biosynthesis in the reported XL annua glandless(gl)mutant.The resulting data demonstrated that leaves of regenerated gl plantlets biosynthesize artemisinin.Codectively,these findings not only add new knowledge leading to a revision of the current dogma of artemisinin biosynthesis inannua but also may expedite innovation of novel metabolic engineering approaches for high and stable production of artemisinin in the future.展开更多
Photodynamic therapy （PDT） is a tumor treatment modality in which a tumor- localized photosensitizer is excited with light, which results in local production of reactive oxygen species, destruction of tumor vasculat...Photodynamic therapy （PDT） is a tumor treatment modality in which a tumor- localized photosensitizer is excited with light, which results in local production of reactive oxygen species, destruction of tumor vasculature, tumor hypoxia, tumor cell death, and induction of an anti-tumor immune response. However, pre-existing tumor hypoxia may desensitize tumors to PDT by activating the hypoxia-inducible factor 1 （HIF-1） survival pathway. Therefore, we hypothesized that inhibition of HIF-1 with acriflavine （ACF） would exacerbate cell death in human epidermoid carcinoma （A431） cells. PDT of A431 tumor cells was per- formed using newly developed and optimized PEGylated cationic liposomes containing the photosensitizer zinc phthalocyanine （ZnPC）. Molecular docking revealed that ACF binds to the dimerization domain of HIF-la, and confocal microscopy confirmed translocation of ACF from the cytosol to the nucleus under hypoxia. HIF-1 was stabilized in hypoxic, but not normoxic, A431 cells following PDT. Inhibition of HIF-1 with ACF increased the extent of PDT-induced cell death under hypoxic conditions and reduced the expression of the HIF-1 target genes VEGF, PTGS2, and EDN1. Moreover, co-encapsulation of ACF in the aqueous core of ZnPC-containing liposomes yielded an adjuvant effect on PDT efficacy that was comparable to non-encapsulated ACF. In conclusion, HIF-1 contributes to A431 tumor cell survival following PDT with liposomal ZnPC. Inhibition of HIF-1 with free or liposomal ACF improves PDT efficacy.展开更多
Product yield on carbohydrate feedstocks is a key performance indicator for industrial ethanol production with the yeast Saccharomyces cerevisiae.This paper reviews pathway engineering strategies for improving ethanol...Product yield on carbohydrate feedstocks is a key performance indicator for industrial ethanol production with the yeast Saccharomyces cerevisiae.This paper reviews pathway engineering strategies for improving ethanol yield on glucose and/or sucrose in anaerobic cultures of this yeast by altering the ratio of ethanol production,yeast growth and glycerol formation.Particular attention is paid to strategies aimed at altering energy coupling of alcoholic fermentation and to strategies for altering redox-cofactor coupling in carbon and nitrogen meta-bolism that aim to reduce or eliminate the role of glycerol formation in anaerobic redox metabolism.In addition to providing an overview of scientific advances we discuss context dependency,theoretical impact and potential for industrial application of different proposed and developed strategies.展开更多
Geoengineering is a proposed response to anthropogenic global warming (AGW). Conventionally it consists of two strands: Solar Radiation Management (SRM), which is fast-acting, incomplete but inexpensive, and Carbon Di...Geoengineering is a proposed response to anthropogenic global warming (AGW). Conventionally it consists of two strands: Solar Radiation Management (SRM), which is fast-acting, incomplete but inexpensive, and Carbon Dioxide Removal (CDR), which is slower acting, more expensive, and comprehensive. Pairing SRM and CDR offers a contractually complete solution for future emissions if effectively-scaled and coordinated. SRM offsets warming, while CDR takes effect. We suggest coordination using a blockchain, i.e. smart contracts and a distributed ledger. Specifically, we integrate CDR futures with time and volume-matched SRM orders, to address emissions contractually before release. This provides an economically and environmentally proportionate solution to CO2 emissions at the wellhead, with robust contractual transparency, and minimal overhead cost. Our proposal offers a 'polluter pays' implementation of Long & Shepherds SRM 'bridge' concept. This 'polluter geoengineers' approach mandates and verifies emissionslinked payments with minimal friction, delay, or cost. Finally, we compare alternative market designs against this proposal, finding that this proposal offers several advantages. We conclude that blockchain implementation of the 'polluter geoengineers' approach is attractive and feasible for larger wellhead contracts. We also identify a handful of advantages and disadvantages that merit further study.展开更多
Background:Data on epidemiology, costs, and outcomes of burn-related injuries presenting at emergency departments (EDs) are scarce. To obtain such information, a questionnaire study with an adequate response rate is i...Background:Data on epidemiology, costs, and outcomes of burn-related injuries presenting at emergency departments (EDs) are scarce. To obtain such information, a questionnaire study with an adequate response rate is imperative. There is evidence that optimized strategies can increase patient participation. However, it is unclear whether this applies to burn patients in an ED setting. The objective of this feasibility study was to optimize and evaluate patient recruitment strategy and follow-up methods in patients with burn injuries presenting at EDs. Methods:In a prospective cohort study with a 6-month follow-up, patients with burn-related injuries attending two large EDs during a 3-month study period were included. Eligible patients were quasi-randomly allocated to a standard or optimized recruitment strategy by week of the ED visit. The standard recruitment strategy consisted of an invitation letter to participate, an informed consent form, a questionnaire, and a franked return envelope. The optimized recruitment strategy was complemented by a stamped returned envelope, monetary incentive, sending a second copy of the questionnaire, and a reminder by telephone in non-responders. Response rates were calculated, and questionnaires were used to assess treatment, costs, and health-related quality of life. Results:A total of 87 patients were included of which 85 were eligible for the follow-up study. There was a higher response rate at 2 months in the optimized versus the standard recruitment strategy (43.6%vs. 20.0%;OR=3.1 (95%CI 1.1–8.8)), although overall response is low. Non-response analyses showed no significant differences in patient, burn injury or treatment characteristics between responders versus non-responders. Conclusions:This study demonstrated that response rates can be increased with an optimized, but more labor-intensive recruitment strategy, although further optimization of recruitment and follow-up is needed. It is feasible to assess epidemiology, treatment, and costs after burn-related ED conta展开更多
Background: Amyloidosis is a disease characterized by the deposition of fibrillar proteins in tissues. The nature of the protein defines the type of amyloidosis. Cardiac involvement is most often secondary to deposits...Background: Amyloidosis is a disease characterized by the deposition of fibrillar proteins in tissues. The nature of the protein defines the type of amyloidosis. Cardiac involvement is most often secondary to deposits of transthyretin and immunoglobulin light chains. Treatment depends on the type of amyloidosis. Cardiac light chain amyloidosis is a medical emergency. Aim: To highlight the importance of an early diagnosis of cardiac light chain amyloidosis. Case Presentation: We report the case of an 88-year-old hypertensive female patient with sustained atrial fibrillation and recurrent heart failure, in whom echocardiography showed concentric left ventricle hypertrophy with mildly reduced left ventricle ejection fraction (LVEF) to 45%. Bone scintigraphy was normal. Serum analysis showed increased lambda free light chains. Accessory salivary gland biopsy revealed weak Kappa light chain staining and clear overexpression of lambda light chain deposits. The diagnosis of stage 3B cardiac amyloidosis secondary to lambda light chain myeloma was made. After a multidisciplinary meeting, it was decided to start treatment with DARATUMUMAB + LENALIDOMIDE. Patient’s general condition deteriorated with the occurrence of febrile pancytopenia. Chemotherapy was stopped and management was limited to comfort care until the patient’s death. Conclusion: Cardiac light-chain amyloidosis must be diagnosed early as it can be rapidly fatal.展开更多
文摘Artemisinin-based combination therapy(ACT)forms the first line of malaria treatment.However,the yield fluctuation of artemisinin has remained an unsolved problem in meeting the global demand for ACT.This problem is mainly caused by the glandular trichome(GT)-specific biosynthesis of artemisinin in all currently used Artemisia annua cultivars.Here,we report that non-GT cells of self-pollinated inbred A.annua plants can express the artemisinin biosynthetic pathway.Gene expression analysis demonstrated the transcription of six known pathway genes in GT-free leaves and calli of inbred A.annua plants.LC-qTOF-MS/MS analysis showed that these two types of GT-free materials produce artemisinin,artemisinic acid,and arteannuin B.Detailed IR-MALDESI image profiling revealed that these three metabolites and dihydroartemisinin are localized in non-GT cells of leaves of inbred A.annua plants.Moreover,we employed all the above approaches to examine artemisinin biosynthesis in the reported XL annua glandless(gl)mutant.The resulting data demonstrated that leaves of regenerated gl plantlets biosynthesize artemisinin.Codectively,these findings not only add new knowledge leading to a revision of the current dogma of artemisinin biosynthesis inannua but also may expedite innovation of novel metabolic engineering approaches for high and stable production of artemisinin in the future.
文摘Photodynamic therapy （PDT） is a tumor treatment modality in which a tumor- localized photosensitizer is excited with light, which results in local production of reactive oxygen species, destruction of tumor vasculature, tumor hypoxia, tumor cell death, and induction of an anti-tumor immune response. However, pre-existing tumor hypoxia may desensitize tumors to PDT by activating the hypoxia-inducible factor 1 （HIF-1） survival pathway. Therefore, we hypothesized that inhibition of HIF-1 with acriflavine （ACF） would exacerbate cell death in human epidermoid carcinoma （A431） cells. PDT of A431 tumor cells was per- formed using newly developed and optimized PEGylated cationic liposomes containing the photosensitizer zinc phthalocyanine （ZnPC）. Molecular docking revealed that ACF binds to the dimerization domain of HIF-la, and confocal microscopy confirmed translocation of ACF from the cytosol to the nucleus under hypoxia. HIF-1 was stabilized in hypoxic, but not normoxic, A431 cells following PDT. Inhibition of HIF-1 with ACF increased the extent of PDT-induced cell death under hypoxic conditions and reduced the expression of the HIF-1 target genes VEGF, PTGS2, and EDN1. Moreover, co-encapsulation of ACF in the aqueous core of ZnPC-containing liposomes yielded an adjuvant effect on PDT efficacy that was comparable to non-encapsulated ACF. In conclusion, HIF-1 contributes to A431 tumor cell survival following PDT with liposomal ZnPC. Inhibition of HIF-1 with free or liposomal ACF improves PDT efficacy.
文摘Product yield on carbohydrate feedstocks is a key performance indicator for industrial ethanol production with the yeast Saccharomyces cerevisiae.This paper reviews pathway engineering strategies for improving ethanol yield on glucose and/or sucrose in anaerobic cultures of this yeast by altering the ratio of ethanol production,yeast growth and glycerol formation.Particular attention is paid to strategies aimed at altering energy coupling of alcoholic fermentation and to strategies for altering redox-cofactor coupling in carbon and nitrogen meta-bolism that aim to reduce or eliminate the role of glycerol formation in anaerobic redox metabolism.In addition to providing an overview of scientific advances we discuss context dependency,theoretical impact and potential for industrial application of different proposed and developed strategies.
文摘Geoengineering is a proposed response to anthropogenic global warming (AGW). Conventionally it consists of two strands: Solar Radiation Management (SRM), which is fast-acting, incomplete but inexpensive, and Carbon Dioxide Removal (CDR), which is slower acting, more expensive, and comprehensive. Pairing SRM and CDR offers a contractually complete solution for future emissions if effectively-scaled and coordinated. SRM offsets warming, while CDR takes effect. We suggest coordination using a blockchain, i.e. smart contracts and a distributed ledger. Specifically, we integrate CDR futures with time and volume-matched SRM orders, to address emissions contractually before release. This provides an economically and environmentally proportionate solution to CO2 emissions at the wellhead, with robust contractual transparency, and minimal overhead cost. Our proposal offers a 'polluter pays' implementation of Long & Shepherds SRM 'bridge' concept. This 'polluter geoengineers' approach mandates and verifies emissionslinked payments with minimal friction, delay, or cost. Finally, we compare alternative market designs against this proposal, finding that this proposal offers several advantages. We conclude that blockchain implementation of the 'polluter geoengineers' approach is attractive and feasible for larger wellhead contracts. We also identify a handful of advantages and disadvantages that merit further study.
文摘Background:Data on epidemiology, costs, and outcomes of burn-related injuries presenting at emergency departments (EDs) are scarce. To obtain such information, a questionnaire study with an adequate response rate is imperative. There is evidence that optimized strategies can increase patient participation. However, it is unclear whether this applies to burn patients in an ED setting. The objective of this feasibility study was to optimize and evaluate patient recruitment strategy and follow-up methods in patients with burn injuries presenting at EDs. Methods:In a prospective cohort study with a 6-month follow-up, patients with burn-related injuries attending two large EDs during a 3-month study period were included. Eligible patients were quasi-randomly allocated to a standard or optimized recruitment strategy by week of the ED visit. The standard recruitment strategy consisted of an invitation letter to participate, an informed consent form, a questionnaire, and a franked return envelope. The optimized recruitment strategy was complemented by a stamped returned envelope, monetary incentive, sending a second copy of the questionnaire, and a reminder by telephone in non-responders. Response rates were calculated, and questionnaires were used to assess treatment, costs, and health-related quality of life. Results:A total of 87 patients were included of which 85 were eligible for the follow-up study. There was a higher response rate at 2 months in the optimized versus the standard recruitment strategy (43.6%vs. 20.0%;OR=3.1 (95%CI 1.1–8.8)), although overall response is low. Non-response analyses showed no significant differences in patient, burn injury or treatment characteristics between responders versus non-responders. Conclusions:This study demonstrated that response rates can be increased with an optimized, but more labor-intensive recruitment strategy, although further optimization of recruitment and follow-up is needed. It is feasible to assess epidemiology, treatment, and costs after burn-related ED conta
文摘Background: Amyloidosis is a disease characterized by the deposition of fibrillar proteins in tissues. The nature of the protein defines the type of amyloidosis. Cardiac involvement is most often secondary to deposits of transthyretin and immunoglobulin light chains. Treatment depends on the type of amyloidosis. Cardiac light chain amyloidosis is a medical emergency. Aim: To highlight the importance of an early diagnosis of cardiac light chain amyloidosis. Case Presentation: We report the case of an 88-year-old hypertensive female patient with sustained atrial fibrillation and recurrent heart failure, in whom echocardiography showed concentric left ventricle hypertrophy with mildly reduced left ventricle ejection fraction (LVEF) to 45%. Bone scintigraphy was normal. Serum analysis showed increased lambda free light chains. Accessory salivary gland biopsy revealed weak Kappa light chain staining and clear overexpression of lambda light chain deposits. The diagnosis of stage 3B cardiac amyloidosis secondary to lambda light chain myeloma was made. After a multidisciplinary meeting, it was decided to start treatment with DARATUMUMAB + LENALIDOMIDE. Patient’s general condition deteriorated with the occurrence of febrile pancytopenia. Chemotherapy was stopped and management was limited to comfort care until the patient’s death. Conclusion: Cardiac light-chain amyloidosis must be diagnosed early as it can be rapidly fatal.
