Alopecia areata is a disease of the hair follicles, with strong evidence supporting autoimmune etiology. Alopecia areata is frequently associated with immune-medi- ated diseases with skin manifestations such as psoria...Alopecia areata is a disease of the hair follicles, with strong evidence supporting autoimmune etiology. Alopecia areata is frequently associated with immune-medi- ated diseases with skin manifestations such as psoriasis and lichen planus, or without skin manifestations such as autoimmune thyroiditis and idiopathic thrombocytopenic purpura. Helicobacter py/ori （H. pylorl） infection is present in around 50% of the world＇s population and has been associated with a variety of immune-mediated extra-digestive disorders including autoimmune thyroid- itis, idiopathic thrombocytopenic purpura, and psoriasis. A case of a 43-year old man with an 8-too history of alopecia areata of the scalp and beard is presented. The patient was being treated by a dermatologist and had psychiatric support, without any improvement. He had a history of dyspepsia and the urea breath test confirmed H. pylori infection. The patient went into remission from alopecia areata after H. pylori eradication. If such an association is confirmed by epidemiological studies designed for this purpose, new therapeutic options could be available for these patients, especially in areas where infection with H, pylori is highly prevalent.展开更多
The local structure and thermophysical behavior of Mg-La liquid alloys were in-depth understood using deep potential molecular dynamic(DPMD) simulation driven via machine learning to promote the development of Mg-La a...The local structure and thermophysical behavior of Mg-La liquid alloys were in-depth understood using deep potential molecular dynamic(DPMD) simulation driven via machine learning to promote the development of Mg-La alloys. The robustness of the trained deep potential(DP) model was thoroughly evaluated through several aspects, including root-mean-square errors(RMSEs), energy and force data, and structural information comparison results;the results indicate the carefully trained DP model is reliable. The component and temperature dependence of the local structure in the Mg-La liquid alloy was analyzed. The effect of Mg content in the system on the first coordination shell of the atomic pairs is the same as that of temperature. The pre-peak demonstrated in the structure factor indicates the presence of a medium-range ordered structure in the Mg-La liquid alloy, which is particularly pronounced in the 80at% Mg system and disappears at elevated temperatures. The density, self-diffusion coefficient, and shear viscosity for the Mg-La liquid alloy were predicted via DPMD simulation, the evolution patterns with Mg content and temperature were subsequently discussed, and a database was established accordingly. Finally, the mixing enthalpy and elemental activity of the Mg-La liquid alloy at 1200 K were reliably evaluated,which provides new guidance for related studies.展开更多
Mescaline,among the earliest identified natural hallucinogens,holds great potential in psychotherapy treatment.Nonetheless,despite the existence of a postulated biosynthetic pathway for more than half a century,the sp...Mescaline,among the earliest identified natural hallucinogens,holds great potential in psychotherapy treatment.Nonetheless,despite the existence of a postulated biosynthetic pathway for more than half a century,the specific enzymes involved in this process are yet to be identified.In this study,we investigated the cactus Lophophora williamsii(Peyote),the largest known natural producer of the phenethylamine mescaline.We employed a multi-faceted approach,combining de novo whole-genome and transcriptome sequencing with comprehensive chemical profiling,enzymatic assays,molecular modeling,and pathway engineering for pathway elucidation.We identified four groups of enzymes responsible for the six catalytic steps in the mescaline biosynthetic pathway,and an N-methyltransferase enzyme that N-methylates all phenethylamine intermediates,likely modulating mescaline levels in Peyote.Finally,we reconstructed the mescaline biosynthetic pathway in both Nicotiana benthamiana plants and yeast cells,providing novel insights into several challenges hindering complete heterologous mescaline production.Taken together,our study opens up avenues for exploration of sustainable production approaches and responsible utilization of mescaline,safeguarding this valuable natural resource for future generations.展开更多
Protoporphyrinogen oxidase （PPO, EC 1.3.3.4） is one of the most significant targets for a large family of in- hibitors that may be used as herbicide, bactericide, fungicide, or photosensitizing activator to treat ca...Protoporphyrinogen oxidase （PPO, EC 1.3.3.4） is one of the most significant targets for a large family of in- hibitors that may be used as herbicide, bactericide, fungicide, or photosensitizing activator to treat cancer through photodynamic therapy （PDT）. Molecular docking and CoMFA were combined in a multistep framework with the ultimate goal of identifying important factor contributing to the activity of PPO inhibitors. As a continuation of the previous research work on the development of new PPO inhibitors, the bioassay results indicated that good PPO in- hibitors were discovered in all of the three chemical series with ICs0 values ranging from 0.010 to 0.061 pmol·L ^-1. Using the crystal structure of tobacco mitochondrial PPO （mtPPO） as template, all the compounds were docked into the enzyme active site. The docking pose of each compound was subsequently used in a receptor-based alignment, leading to the development of a significant CoMFA model with r^2 value of 0.98 and q^2 （cross validation r^2） value of 0.63. This novel multistep framework gives insight into the and it can be extended to other classes of PPO inhibitors. In be particularly applicable in virtual screening procedures. structural characteristics for the binding of inhibitors, addition, the simplicity of the proposed approach may展开更多
It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb®) has been approve...It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb®) has been approved by the U.S. Food and Drug Administration (FDA) as a reversible HER2 inhibitor for treating breast cancer. However, HER2 L755S, T798I and T798M mutations confer drug resistance to lapatinib, restricting its efficacy toward HER2-positive breast cancer. Thus, novel therapy toward mutant HER2 is highly desired. Although several irreversible HER2 inhibitors have been developed to overcome these drug resistance problems, most of them were reported to cause severe side effects. In this study, three pharmacophore models based on HER2 L755S, T798I and T798M mutant structures were constructed and then validated through receiver operating characteristic (ROC) curve analysis and Güner-Henry (GH) scoring methods. Subsequently, these well-validated models were utilized as 3D queries to identify novel irreversible HER2 inhibitors from National Cancer Institute (NCI) database. Finally, two potential irreversible HER2 inhibitor candidates, NSC278329 and NSC718305, were identified and validated through molecular docking, molecular dynamics (MD) simulations and ADMET prediction. Furthermore, the analyses of binding modes showed that both NSC278329 and NSC718305 exhibit good binding interactions with HER2 L755S, T798I and T798M mutants. All together, the above results suggest that both NSC278329 and NSC718305 can serve as novel and effective irreversible HER2 inhibitors for treating breast cancers with HER2 L755S, T798I and T798M mutants. In addition, they may act as lead compounds for designing new irreversible HER2 inhibitors by carrying out structural modifications and optimizations in future studies.展开更多
The novelty and suitability of the mitochondrial gene CO1 in DNA barcoding as a reliable identification tool in animal species are undisputed. This is attributed to its standardized sequencing segment of the mitochond...The novelty and suitability of the mitochondrial gene CO1 in DNA barcoding as a reliable identification tool in animal species are undisputed. This is attributed to its standardized sequencing segment of the mitochondrial cytochrome c oxidase-1 gene (CO1) which has the necessary universality and variability making it a generally acceptable barcode region. CO1 is a haploid single locus that is uniparentally-inherited. Protein-coding regions are present in high-copy numbers making it an ideal barcode. The mitochondrial oxidase subunit I (COI) gene is a robust barcode with a suitable threshold for delineating animals and is not subject to drastic length variation, frequent mononucleotide repeats or microinversions. However, a low nucleotide substitution rate of plant mitochondrial genome [mtDNA] precludes the use of CO1 as a universal plant DNA barcode and makes the search for alternative barcode regions necessary. Currently, there exists no universal barcode for plants. The plastid region reveals leading candidate loci as appropriate DNA barcodes yet to be explored in biodiversity studies in Kenya. Four of these plastid regions are portions of coding genes (matK, rbcL, rpoB, and rpoC1), and three noncoding spacers (atpF-atpH, trnH-psbA, and psbK-psbL) which emerge as ideal candidate DNA loci. While different research groups propose various combinations of these loci, there exists no consensus;the lack thereof impedes progress in getting a suitable universal DNA barcode. Little research has attempted to investigate and document the applicability and extend of effectiveness of different DNA regions as barcodes to delineate cowpea at subspecies level. In this study we sought to test feasibility of the seven putative candidate DNA loci singly and in combination in order to establish a suitable single and multi-locus barcode regions that can have universal application in delineating diverse phylogeographic groups of closely related Kenyan cowpea variants. In this study, our focus was based on genetic parameters includin展开更多
The self-renewal and multipotent potentials in neural stem cells(NSCs)maintain the normal physiological functions of central nervous system(CNS).The ab-normal differentiation of NSCs would lead to CNS disorders.Howeve...The self-renewal and multipotent potentials in neural stem cells(NSCs)maintain the normal physiological functions of central nervous system(CNS).The ab-normal differentiation of NSCs would lead to CNS disorders.However,the mechanisms of how NSCs differentiate into astrocytes,oligodendrocytes(OLs)and neurons are still unclear,which is mainly due to the complexity of differentiation processes and the limita-tion of the cell separation method.In this study,we modeled the dynamics of neural cell interactions in a systemic approach by mining the high-throughput genomic and proteomic data,and identified 8615 genes that are involved in various biological processes and functions with significant changes during the differentiation processes.A total of 1559 genes are specifically expressed in neural cells,in which 242 genes are NSC specific,215 are astrocyte specific,551 are OL specific,and 563 are neuron specific.In addition,we proposed 57 transcriptional regulators specifically expressed in NSCs may play essential roles in the development courses.These findings provide more comprehensive analysis for better understanding the endogenous mechanisms of NSC fate determination.展开更多
对上海、南京地区的水杉赤枯病(Metasequoia red blight)的发生情况进行了调查和分析,并采用形态学和分子生物学结合的方法对该病的病原菌进行了鉴定。结果表明:单行种植和单棵零星分布的水杉感病程度相对于已经郁闭成林的水杉要严重得...对上海、南京地区的水杉赤枯病(Metasequoia red blight)的发生情况进行了调查和分析,并采用形态学和分子生物学结合的方法对该病的病原菌进行了鉴定。结果表明:单行种植和单棵零星分布的水杉感病程度相对于已经郁闭成林的水杉要严重得多;用作行道树的水杉抗病能力较弱,发病情况相对于农田中的水杉较为严重;生长势弱的水杉植株容易发生赤枯病,这一现象在行道树中表现尤为明显。通过对水杉赤枯病病原菌分离培养、人工接种试验、分离菌形态学观察及分子生物学分子鉴定,水杉赤枯病的病原菌被鉴定为细极链格孢(Alternaria tenuissima)和异角状拟盘多毛孢(Pestalotiopsis heterocornis)。展开更多
Mitochondrial DNA ND5/6 region was studied by PCR-RFLP analysis among ten representative strains belonging to three subspecies (Cyprinus carpio carpio, Cypri-nus carpio haematopterus and Cyprinus carpio rubrofuscus) o...Mitochondrial DNA ND5/6 region was studied by PCR-RFLP analysis among ten representative strains belonging to three subspecies (Cyprinus carpio carpio, Cypri-nus carpio haematopterus and Cyprinus carpio rubrofuscus) of common carp (Cyprinus carpio L.). A total of 2.4 kb frag-ment was amplified and subjected to restriction endonucle-ase analysis with nine restriction endonucleases subsequently.The results indicated that each subspecies owned one hyplo-type and four restriction enzymes (DdeⅠ, HaeⅢ, TaqⅠand MboⅠ) produced diagnostic restriction sites which could be used for discriminating the three subspecies and as molecu-lar genetic markers for assistant selective breeding of com-mon carp.展开更多
文摘Alopecia areata is a disease of the hair follicles, with strong evidence supporting autoimmune etiology. Alopecia areata is frequently associated with immune-medi- ated diseases with skin manifestations such as psoriasis and lichen planus, or without skin manifestations such as autoimmune thyroiditis and idiopathic thrombocytopenic purpura. Helicobacter py/ori （H. pylorl） infection is present in around 50% of the world＇s population and has been associated with a variety of immune-mediated extra-digestive disorders including autoimmune thyroid- itis, idiopathic thrombocytopenic purpura, and psoriasis. A case of a 43-year old man with an 8-too history of alopecia areata of the scalp and beard is presented. The patient was being treated by a dermatologist and had psychiatric support, without any improvement. He had a history of dyspepsia and the urea breath test confirmed H. pylori infection. The patient went into remission from alopecia areata after H. pylori eradication. If such an association is confirmed by epidemiological studies designed for this purpose, new therapeutic options could be available for these patients, especially in areas where infection with H, pylori is highly prevalent.
基金financially supported by the National Key R &D Program of China (No.2022YFB3709300)。
文摘The local structure and thermophysical behavior of Mg-La liquid alloys were in-depth understood using deep potential molecular dynamic(DPMD) simulation driven via machine learning to promote the development of Mg-La alloys. The robustness of the trained deep potential(DP) model was thoroughly evaluated through several aspects, including root-mean-square errors(RMSEs), energy and force data, and structural information comparison results;the results indicate the carefully trained DP model is reliable. The component and temperature dependence of the local structure in the Mg-La liquid alloy was analyzed. The effect of Mg content in the system on the first coordination shell of the atomic pairs is the same as that of temperature. The pre-peak demonstrated in the structure factor indicates the presence of a medium-range ordered structure in the Mg-La liquid alloy, which is particularly pronounced in the 80at% Mg system and disappears at elevated temperatures. The density, self-diffusion coefficient, and shear viscosity for the Mg-La liquid alloy were predicted via DPMD simulation, the evolution patterns with Mg content and temperature were subsequently discussed, and a database was established accordingly. Finally, the mixing enthalpy and elemental activity of the Mg-La liquid alloy at 1200 K were reliably evaluated,which provides new guidance for related studies.
基金fellowships from the Israel Ministry of Absorption and the Dean of the Plant Science Department in the Weizmann Institute.We thank Prof.David Nelson(University of Tennessee,USA)for the systematic naming of the cytochrome P450 enzymes characterized in this studyShmuel Regev and The Regev Nursery(Beit Elazari,Israel)for help in differentiating among Lophophora species+2 种基金Dr.Ziv Spiegelman for providing several N.benthamiana plantsXINTEZA(https://xinteza.com/)for funding this researchand the Adelis Foundation,the Leona M.and Harry B.Helmsley Charitable Trust,the Jeanne and Joseph Nissim Foundation for Life Sciences,Tom and Sondra Rykoff Family Foundation Research,Ron Sklare and the Raymond Burton Plant Genome Research Fund for supporting the A.A.laboratory。
文摘Mescaline,among the earliest identified natural hallucinogens,holds great potential in psychotherapy treatment.Nonetheless,despite the existence of a postulated biosynthetic pathway for more than half a century,the specific enzymes involved in this process are yet to be identified.In this study,we investigated the cactus Lophophora williamsii(Peyote),the largest known natural producer of the phenethylamine mescaline.We employed a multi-faceted approach,combining de novo whole-genome and transcriptome sequencing with comprehensive chemical profiling,enzymatic assays,molecular modeling,and pathway engineering for pathway elucidation.We identified four groups of enzymes responsible for the six catalytic steps in the mescaline biosynthetic pathway,and an N-methyltransferase enzyme that N-methylates all phenethylamine intermediates,likely modulating mescaline levels in Peyote.Finally,we reconstructed the mescaline biosynthetic pathway in both Nicotiana benthamiana plants and yeast cells,providing novel insights into several challenges hindering complete heterologous mescaline production.Taken together,our study opens up avenues for exploration of sustainable production approaches and responsible utilization of mescaline,safeguarding this valuable natural resource for future generations.
文摘Protoporphyrinogen oxidase （PPO, EC 1.3.3.4） is one of the most significant targets for a large family of in- hibitors that may be used as herbicide, bactericide, fungicide, or photosensitizing activator to treat cancer through photodynamic therapy （PDT）. Molecular docking and CoMFA were combined in a multistep framework with the ultimate goal of identifying important factor contributing to the activity of PPO inhibitors. As a continuation of the previous research work on the development of new PPO inhibitors, the bioassay results indicated that good PPO in- hibitors were discovered in all of the three chemical series with ICs0 values ranging from 0.010 to 0.061 pmol·L ^-1. Using the crystal structure of tobacco mitochondrial PPO （mtPPO） as template, all the compounds were docked into the enzyme active site. The docking pose of each compound was subsequently used in a receptor-based alignment, leading to the development of a significant CoMFA model with r^2 value of 0.98 and q^2 （cross validation r^2） value of 0.63. This novel multistep framework gives insight into the and it can be extended to other classes of PPO inhibitors. In be particularly applicable in virtual screening procedures. structural characteristics for the binding of inhibitors, addition, the simplicity of the proposed approach may
文摘It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb®) has been approved by the U.S. Food and Drug Administration (FDA) as a reversible HER2 inhibitor for treating breast cancer. However, HER2 L755S, T798I and T798M mutations confer drug resistance to lapatinib, restricting its efficacy toward HER2-positive breast cancer. Thus, novel therapy toward mutant HER2 is highly desired. Although several irreversible HER2 inhibitors have been developed to overcome these drug resistance problems, most of them were reported to cause severe side effects. In this study, three pharmacophore models based on HER2 L755S, T798I and T798M mutant structures were constructed and then validated through receiver operating characteristic (ROC) curve analysis and Güner-Henry (GH) scoring methods. Subsequently, these well-validated models were utilized as 3D queries to identify novel irreversible HER2 inhibitors from National Cancer Institute (NCI) database. Finally, two potential irreversible HER2 inhibitor candidates, NSC278329 and NSC718305, were identified and validated through molecular docking, molecular dynamics (MD) simulations and ADMET prediction. Furthermore, the analyses of binding modes showed that both NSC278329 and NSC718305 exhibit good binding interactions with HER2 L755S, T798I and T798M mutants. All together, the above results suggest that both NSC278329 and NSC718305 can serve as novel and effective irreversible HER2 inhibitors for treating breast cancers with HER2 L755S, T798I and T798M mutants. In addition, they may act as lead compounds for designing new irreversible HER2 inhibitors by carrying out structural modifications and optimizations in future studies.
文摘The novelty and suitability of the mitochondrial gene CO1 in DNA barcoding as a reliable identification tool in animal species are undisputed. This is attributed to its standardized sequencing segment of the mitochondrial cytochrome c oxidase-1 gene (CO1) which has the necessary universality and variability making it a generally acceptable barcode region. CO1 is a haploid single locus that is uniparentally-inherited. Protein-coding regions are present in high-copy numbers making it an ideal barcode. The mitochondrial oxidase subunit I (COI) gene is a robust barcode with a suitable threshold for delineating animals and is not subject to drastic length variation, frequent mononucleotide repeats or microinversions. However, a low nucleotide substitution rate of plant mitochondrial genome [mtDNA] precludes the use of CO1 as a universal plant DNA barcode and makes the search for alternative barcode regions necessary. Currently, there exists no universal barcode for plants. The plastid region reveals leading candidate loci as appropriate DNA barcodes yet to be explored in biodiversity studies in Kenya. Four of these plastid regions are portions of coding genes (matK, rbcL, rpoB, and rpoC1), and three noncoding spacers (atpF-atpH, trnH-psbA, and psbK-psbL) which emerge as ideal candidate DNA loci. While different research groups propose various combinations of these loci, there exists no consensus;the lack thereof impedes progress in getting a suitable universal DNA barcode. Little research has attempted to investigate and document the applicability and extend of effectiveness of different DNA regions as barcodes to delineate cowpea at subspecies level. In this study we sought to test feasibility of the seven putative candidate DNA loci singly and in combination in order to establish a suitable single and multi-locus barcode regions that can have universal application in delineating diverse phylogeographic groups of closely related Kenyan cowpea variants. In this study, our focus was based on genetic parameters includin
基金supported by the National Natural Science Foundation of China(Grant Nos.31070954,11172158 and 10832006)the Shanghai Commission of Science and Technology Basic Research Fund(No.09JC1406600)the Shanghai Education Committee and Shanghai Leading Academic Discipline Project(J50103,key discipline"Molecular Physiology").
文摘The self-renewal and multipotent potentials in neural stem cells(NSCs)maintain the normal physiological functions of central nervous system(CNS).The ab-normal differentiation of NSCs would lead to CNS disorders.However,the mechanisms of how NSCs differentiate into astrocytes,oligodendrocytes(OLs)and neurons are still unclear,which is mainly due to the complexity of differentiation processes and the limita-tion of the cell separation method.In this study,we modeled the dynamics of neural cell interactions in a systemic approach by mining the high-throughput genomic and proteomic data,and identified 8615 genes that are involved in various biological processes and functions with significant changes during the differentiation processes.A total of 1559 genes are specifically expressed in neural cells,in which 242 genes are NSC specific,215 are astrocyte specific,551 are OL specific,and 563 are neuron specific.In addition,we proposed 57 transcriptional regulators specifically expressed in NSCs may play essential roles in the development courses.These findings provide more comprehensive analysis for better understanding the endogenous mechanisms of NSC fate determination.
文摘对上海、南京地区的水杉赤枯病(Metasequoia red blight)的发生情况进行了调查和分析,并采用形态学和分子生物学结合的方法对该病的病原菌进行了鉴定。结果表明:单行种植和单棵零星分布的水杉感病程度相对于已经郁闭成林的水杉要严重得多;用作行道树的水杉抗病能力较弱,发病情况相对于农田中的水杉较为严重;生长势弱的水杉植株容易发生赤枯病,这一现象在行道树中表现尤为明显。通过对水杉赤枯病病原菌分离培养、人工接种试验、分离菌形态学观察及分子生物学分子鉴定,水杉赤枯病的病原菌被鉴定为细极链格孢(Alternaria tenuissima)和异角状拟盘多毛孢(Pestalotiopsis heterocornis)。
基金the Na-tional Natural Science Foundation of China (Grant No. 39830300) and the Key Laboratory of Freshwater Ecology and Biotechnology Institute of Hydrobiologythe Chinese Academy of Sciences
文摘Mitochondrial DNA ND5/6 region was studied by PCR-RFLP analysis among ten representative strains belonging to three subspecies (Cyprinus carpio carpio, Cypri-nus carpio haematopterus and Cyprinus carpio rubrofuscus) of common carp (Cyprinus carpio L.). A total of 2.4 kb frag-ment was amplified and subjected to restriction endonucle-ase analysis with nine restriction endonucleases subsequently.The results indicated that each subspecies owned one hyplo-type and four restriction enzymes (DdeⅠ, HaeⅢ, TaqⅠand MboⅠ) produced diagnostic restriction sites which could be used for discriminating the three subspecies and as molecu-lar genetic markers for assistant selective breeding of com-mon carp.
