The genetic transformation was achieved by pollen_mediated approach on maize ( Zea mays L.) inbred lines Tai 9101 and Zong 31. Plasmid DNA of pGLⅡ_RC_1 was mixed with fresh pollen of maize inbreds in sucrose ...The genetic transformation was achieved by pollen_mediated approach on maize ( Zea mays L.) inbred lines Tai 9101 and Zong 31. Plasmid DNA of pGLⅡ_RC_1 was mixed with fresh pollen of maize inbreds in sucrose solution. The pollens were treated by ultrasonication and collected, pollinated on silks of maize ears. Transformants were confirmed by dot blot hybridization, PCR amplification and PCR_Southern blot hybridization. The pollen_mediated transformation approach could circumvent the tedious tissue culture procedures like in particle bombardment and Agrobacterium infection, etc. This approach is simple, easy to operate, and could be widely used in practice.展开更多
Crop breeding aims to generate pure in bred lines with multiple desired traits. Doubled haploid (DH) and genome editing using CRISPR/Cas9 are two powerful game-changing technologies in crop breeding. However, both of ...Crop breeding aims to generate pure in bred lines with multiple desired traits. Doubled haploid (DH) and genome editing using CRISPR/Cas9 are two powerful game-changing technologies in crop breeding. However, both of them still fall short for rapid generation of pure elite lines with integrated favorable traits. Here, we report the development of a Haploid-Inducer Mediated Genome Editing (IMGE) approach, which utilizes a maize haploid inducer line carrying a CRISPR/Cas9 cassette targeting for a desired agronomic trait to pollinate an elite maize in bred line and to generate genome-edited haploids in the elite maize background. Homozygous pure DH lines with the desired trait improvement could be generated within two generations, thus bypassing the lengthy procedure of repeated crossing and backcrossing used in conventional breeding for integrating a desirable trait into elite commercial backgrounds.展开更多
Targeted genome modifications with the Cas9/gRNA system derived from the clustered regularly interspaced short palin- dromic repeat/CRISPR-associated （CRISPR/Cas） system have been successfully used in cultured human...Targeted genome modifications with the Cas9/gRNA system derived from the clustered regularly interspaced short palin- dromic repeat/CRISPR-associated （CRISPR/Cas） system have been successfully used in cultured human cells as well as in most model organisms, including zebrafish （Danio rerio）, mouse, and fruit fly （Chang et al., 2013; Cong et al., 2013; Gratz et al., 2013; Hwang et al., 2013; Jao et al., 2013; Shen et al., 2013; Wei et al., 2013）. Its application in zebrafish is particu- larly attractive due to the ease of handling this organism and the simple application of this method by direct injection of Cas9/ gRNA. However, the information about its specificity in this organism is very limited and needs further evaluation. In addition, it is conceivable that a Cas9 mRNA optimized for zebrafish codon preference could enhance its activity.展开更多
Development of tools for targeted modifications of specific DNA sequences in plants is of great importance to basic plant biology research as well as crop improvement.The ability to cut DNA at specific locations in th...Development of tools for targeted modifications of specific DNA sequences in plants is of great importance to basic plant biology research as well as crop improvement.The ability to cut DNA at specific locations in the genome to generate doublestrand breaks（DSBs）in vivo is a prerequisite for any genome editing efforts.展开更多
AIM To investigate whether immune mediated diseases(IMD) are more frequent in patients with inflammatory bowel disease(IBD).METHODS In this population based registry study,a total of 47325 patients with IBD were alive...AIM To investigate whether immune mediated diseases(IMD) are more frequent in patients with inflammatory bowel disease(IBD).METHODS In this population based registry study,a total of 47325 patients with IBD were alive and registered in the Danish National Patient Registry on December 16,2013. Controls were randomly selected from the Danish Civil Registration System(CRS) and matched for sex,age,and municipality. We used ICD 10 codes to identify the diagnoses of the included patients. The IBD population was divided into three subgroups: Ulcerative colitis(UC),Crohn's disease(CD) and Both the latter referring to those registered with both diagnoses. Subsequently,odds-ratios(OR) and 95%CI were obtained separately for each group and their respective controls. The use of Bonferoni post-test correction adjusted the significance level to P < 0.00125. P-values were estimated using Fisher's exact test.RESULTS There were significantly more women than men in the registry,and a greater percentage of comorbidity in the IBD groups(P < 0.05). Twenty different IMDs were all significantly more frequent in the IBD group. Sixteen were associated with UC versus twelve with CD. In both UC and CD ORs were significantly increased(P < 0.00125) for primary sclerosing cholangitis(PSC),celiac disease,type 1 diabetes(T1D),sarcoidosis,asthma,iridocyclitis,psoriasis,pyoderma gangrenosum,rheumatoid arthritis,and ankylosing spondylitis. Restricted to UC(P < 0.00125) were autoimmune hepatitis,primary biliary cholangitis,Grave's disease,polymyalgia rheumatica,temporal arteritis,and atrophic gastritis. Restricted to CD(P < 0.00125) were psoriatic arthritis and episcleritis. Restricted to women with UC(P < 0.00125) were atrophic gastritis,rheumatoid arthritis,temporal arteritis,and polymyalgia rheumatica. Restricted to women with CD were episcleritis,rheumatoid arthritis,and psoriatic arthritis. The only disease restricted to men(P < 0.00125) was sarcoidosis. CONCLUSION Immune mediated diseases were significantly more frequent in patients with IBD. 展开更多
AIM: To assess intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) for monitoring early efficacy of chemotherapy in a human gastric cancer mouse model.METHODS: IVIM-DWI was performed with 12 b-values (0...AIM: To assess intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) for monitoring early efficacy of chemotherapy in a human gastric cancer mouse model.METHODS: IVIM-DWI was performed with 12 b-values (0-800 s/mm<sup>2</sup>) in 25 human gastric cancer-bearing nude mice at baseline (day 0), and then they were randomly divided into control and 1-, 3-, 5- and 7-d treatment groups (n = 5 per group). The control group underwent longitudinal MRI scans at days 1, 3, 5 and 7, and the treatment groups underwent subsequent MRI scans after a specified 5-fluorouracil/calcium folinate treatment. Together with tumor volumes (TV), the apparent diffusion coefficient (ADC) and IVIM parameters [true water molecular diffusion coefficient (D), perfusion fraction (f) and pseudo-related diffusion coefficient (D<sup>*</sup>)] were measured. The differences in those parameters from baseline to each measurement (ΔTV%, ΔADC%, ΔD%, Δf% and ΔD<sup>*</sup>%) were calculated. After image acquisition, tumor necrosis, microvessel density (MVD) and cellular apoptosis were evaluated by hematoxylin-eosin (HE), CD31 and terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining respectively, to confirm the imaging findings. Mann-Whitney test and Spearman’s correlation coefficient analysis were performed.RESULTS: The observed relative volume increase (ΔTV%) in the treatment group were significantly smaller than those in the control group at day 5 (ΔTV<sub>treatment</sub>% = 19.63% ± 3.01% and ΔTV<sub>control</sub>% = 83.60% ± 14.87%, P = 0.008) and day 7 (ΔTV<sub>treatment</sub>% = 29.07% ± 10.01% and ΔTV<sub>control</sub>% = 177.06% ± 63.00%, P = 0.008). The difference in ΔTV% between the treatment and the control groups was not significant at days 1 and 3 after a short duration of treatment. Increases in ADC in the treatment group (ΔADC%<sub>treatment</sub>, median, 30.10% ±展开更多
Breakthroughs in the generation of programmable sequence-specific nucleases (SSNs), such as zinc finger nucleases (ZFNs),TAL effector nucleases (TALENs) and the RNA-directed nuclease CRISPR-associated protein 9 (Cas9)...Breakthroughs in the generation of programmable sequence-specific nucleases (SSNs), such as zinc finger nucleases (ZFNs),TAL effector nucleases (TALENs) and the RNA-directed nuclease CRISPR-associated protein 9 (Cas9), have greatly increased the ease of plant genome engineering (Voytas, 2013; Malzahn et al.,2017). Programmable SSNs introduce a DNA double-strand break展开更多
Samples of the Cambrian microbial dolomites were collected from Penglaiba section,a well-exposed stratigraphic section in the northwestern area of the Tarim Basin.This study provides an analogue for mediated dolomites...Samples of the Cambrian microbial dolomites were collected from Penglaiba section,a well-exposed stratigraphic section in the northwestern area of the Tarim Basin.This study provides an analogue for mediated dolomites that can precipitate in microbial mats and biofilms.The Cambrian stromatolitic dolomites were studied using high-resolution scanning electron microscopy.The results are as follows:(1)dolomites with 50 nm to 100 nm spherical nanostructures are aggregated into minerals of larger sphericities;(2)nanospherical dolomites of 50 nm to 170 nm diameter are densely arranged as dumbbell-shaped or chained aggregates;(3)silicified filaments,as well as dumbbell-shaped and chain arrangements,are preserved as important microstructures.On the basis of sedimentological,compositional,geochemical,and petrographic data,the microstructures were interpreted as nanoglobules that function as bacteria in the nucleation and filament mineralization stages.The microstructures function as such because they are wrapped in extracellular polymeric substance(EPS)or mucus and mineralized fossils.Silicification accounts for the exceptional preservation of microbial mat structures,including biofilms,as well as filamentous and coccoid microbes.In addition,EPS process is capable of binding different elements,with preference for Si,Mg,and Ca.Such suitable composition favors microbe mineralization and dolomite nucleation on organic substrates.These microscopic structures suggest bacterial mineralization and provide visual evidence for the origin of microbial dolomites.展开更多
ABO incompatible living donor liver transplantation has the potential to expand the donor pool for patients with end stage liver diseases on the expense of challenges to overcome immunological barriers across blood ty...ABO incompatible living donor liver transplantation has the potential to expand the donor pool for patients with end stage liver diseases on the expense of challenges to overcome immunological barriers across blood type.There is a profound impact of age on incidence and severity of antibody mediated rejection(AMR).Even children older than 1 year have chances of AMR;children aged 8 years or older have risks of hepatic necrosis similar to adult liver recipients.The mechanism of AMR is based on circulatory disturbances secondary to inflammation and injury of the vascular endothelium caused by an antibody-antigen-complement reaction.The strategy to overcome ABO blood type barrier is based on both pre-transplant desensitization and adequate treatment of this phenomenon.Nowadays,rituximab is the standard means of desensitization but unfortunately an insufficient aid to treat AMR.Because of low incidence(less than 5%in the rituximab era),in practice of AMR only some case reports about the treatment of clinical AMR are available in the literature.Initial experiences revealed that the proteasome inhibitor,bortezomib might be a promising treatment based on its capacity to deplete plasma cell agents.Although ABO blood type barrier has been counteracted in 95%of patients by applying“rituximab-desensitization”,many issues,such as prediction of high-risk patients of infection and AMR and secure treatment strategies for evoked AMR,remain to be resolved.展开更多
Hepatocyte nuclear factor 3γ(HNF3γ)is a hepatocyte nuclear factor,but its role and clinical significance in hepatocellular carcinoma(HCC)remain unclear.Herein,we report that HNF3γexpression is downregulated in pati...Hepatocyte nuclear factor 3γ(HNF3γ)is a hepatocyte nuclear factor,but its role and clinical significance in hepatocellular carcinoma(HCC)remain unclear.Herein,we report that HNF3γexpression is downregulated in patient HCC and inversely correlated with HCC malignancy and patient survival.Moreover,our data suggested that the HNF3γreduction in HCC could be mediated by METTL14-dependent m6A methylation of HNF3γmRNA.HNF3γexpression was increased during hepatic differentiation and decreased in dedifferentiated HCC cells.Interestingly,HNF3γdelivery promoted differentiation of not only HCC cells but also liver CSCs,which led to suppression of HCC growth.Mechanistic analysis suggested an HNF3γ-centered regulatory network that includes essential liver differentiation-associated transcription factors and functional molecules,which could synergistically facilitate HCC cell differentiation.More importantly,enforced HNF3γexpression sensitized HCC cells to sorafenib-induced growth inhibition and cell apoptosis through transactivation of OATP1B1 and OATP1B3 expression,which are major membrane transporters for sorafenib uptake.Clinical investigation showed that patient-derived HCC xenografts with high HNF3γexpression exhibited a sorafenib response and patients with high HCC HNF3γlevels benefited from sorafenib therapy.Together,these results suggest that HNF3γplays an essential role in HCC differentiation and may serve as a therapeutic target and predictor of sorafenib benefit in patients.展开更多
Dear Editor,RNA knockdown in vivo carries significant potential for dis-ease modeling and therapies.Despite the emerging approaches of CRISPR/Cas9-mediated permanent knock out of targeted genes,strategies targeting RN...Dear Editor,RNA knockdown in vivo carries significant potential for dis-ease modeling and therapies.Despite the emerging approaches of CRISPR/Cas9-mediated permanent knock out of targeted genes,strategies targeting RNA for disruption are advantageous in the treatment of acquired metabolic disorders when permanent modification of genome DNA is not appropriate,and RNA virus infection diseases when pathogenic DNA is not available(such as SARS-Cov-2 and MERS infections).展开更多
In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically ...In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically modified mice and highthroughput analyses, we demonstrate that prolonged HIF-1α signaling in B cells leads to enhanced RANKL production and osteoclast formation. In addition, deletion of HIF-1α in B cells prevents estrogen deficiency-induced bone loss in mice.Mechanistically, estrogen controls HIF-1α protein stabilization through HSP70-mediated degradation in bone marrow B cells.The stabilization of HIF-1α protein in HSP70-deficient bone marrow B cells promotes RANKL production and osteoclastogenesis.Induction of HSP70 expression by geranylgeranylacetone(GGA) administration alleviates ovariectomy-induced osteoporosis.Moreover, RANKL gene expression has a positive correlation with HIF1 A expression in human B cells. In conclusion, HIF-1αsignaling in B cells is crucial for the control of osteoclastogenesis, and the HSP70/HIF-1α axis may serve as a new therapeutic target for osteoporosis.展开更多
Although it has long been demonstrated that cytosolic DNA is a potent immune stimulant,it is only in recent years that the molecular mechanisms of DNA-stimulated innate immune responses have emerged.Studies have estab...Although it has long been demonstrated that cytosolic DNA is a potent immune stimulant,it is only in recent years that the molecular mechanisms of DNA-stimulated innate immune responses have emerged.Studies have established critical roles for the DNA sensor cyclic GMP–AMP synthase(cGAS)and the adapter protein MITA/STING in the innate immune response to cytosolic DNA or DNA viruses.Although the regulation of cGAS–MITA/STING-mediated signaling remains to be fully investigated,understanding the processes involved may help to explain the mechanisms of innate immune signaling events and perhaps autoinflammatory diseases and to provide potential therapeutic targets for drug intervention.In this review,we summarize recent progress on the regulation of the cGAS–MITA/STING-mediated innate immune response to DNA viruses at the organelle-trafficking,posttranslational and transcriptional levels.展开更多
Nitrogen （N） is one of most important nutrients for crop production, which makes up 1%-5% of total plant dry matter （Marschner, 2012）. Due to the limited availability of N in soil, application of N fertilizers has...Nitrogen （N） is one of most important nutrients for crop production, which makes up 1%-5% of total plant dry matter （Marschner, 2012）. Due to the limited availability of N in soil, application of N fertilizers has been an important agronomic practice to increase crop yield. However, over-application of N fertilizers has caused pollution of N in soil, water and air. It was estimated that the nitrogen use efficiency （NUE, the total biomass or grain yield produced per unit of applied fertilizer N） in cereal crops is as low as 33% （Raun and Johnson, 1999）. Therefore, improving NUE together with reducing application of N fertilizers is an important issue for environment and sustainable production of crops. This is especially important for rice, which is a staple food for half population in the world.展开更多
Capillary electrophoresis with many advantages plays an important role in pharmaceutical analysis and drug screening. This review gives an overview on the recent advances in the developments and applications of capill...Capillary electrophoresis with many advantages plays an important role in pharmaceutical analysis and drug screening. This review gives an overview on the recent advances in the developments and applications of capillary electrophoresis in the field of enzyme inhibitor screening. The period covers 2013 to 2017. Both the pre-capillary enzyme assays and in-capillary enzyme assays which include electrophoretically mediated microanalysis（EMMA） and immobilized enzyme microreactor（IMER） are summarized in this article.展开更多
In accordance with previous reports, the sequences related to phosporylated protein segments occur in conserved variable domains of immunoglobulins including first of all certain N-terminally located segments. Consequ...In accordance with previous reports, the sequences related to phosporylated protein segments occur in conserved variable domains of immunoglobulins including first of all certain N-terminally located segments. Consequently, we look here for the sequences 1) composing human and mouse proteins different from antigen receptors, 2) identical with or highly similar to nucleotide sequence representatives of conserved variable immunoglobulin segments and 3) identical with or closely related to phosphorylation sites. More precisely, we searched for the corresponding actual pairs of DNA and protein sequence segments using five-step bilingual approach employing among others a) different types of BLAST searches, b) two in-principle-different machine-learning methods predicting phosphorylated sites and c) two large databases recording existing phosphorylation sites. The approach identified seven existing phosphorylation sites and thirty-seven related human and mouse segments achieving limits for several predictions or phylogenic parameters. Mostly serines phosporylated with ataxia-telangiectasia-related kinase (involved in regulation of DNA-double-strand-break repair) were indicated or predicted in this study. Hypermutation motifs, located in effective positions of the selected sequence segments, occurred significantly less frequently in transcribed than non-transcribed DNA strands suggesting thus the incidence of mutation events. In addition, marked differences between the numbers and proportions of human and mouse cancer-related sequence items were found in different steps of selection process. The possible role of hypermutation changes within the selected segments and the observed structural relationships are discussed here with respect to DNA damage, carcinogenesis, cancer vaccination, ageing and evolution. Taken together, our data represent additional and sometimes perhaps complementary information to the existing databases of empirically proven phosphorylation sites or pathogenically important spots.展开更多
文摘The genetic transformation was achieved by pollen_mediated approach on maize ( Zea mays L.) inbred lines Tai 9101 and Zong 31. Plasmid DNA of pGLⅡ_RC_1 was mixed with fresh pollen of maize inbreds in sucrose solution. The pollens were treated by ultrasonication and collected, pollinated on silks of maize ears. Transformants were confirmed by dot blot hybridization, PCR amplification and PCR_Southern blot hybridization. The pollen_mediated transformation approach could circumvent the tedious tissue culture procedures like in particle bombardment and Agrobacterium infection, etc. This approach is simple, easy to operate, and could be widely used in practice.
基金National Key R&D Program of China (2016YFD0100303 and 2016YFD0101001)Beijing Natural Science Foundation (6172032).
文摘Crop breeding aims to generate pure in bred lines with multiple desired traits. Doubled haploid (DH) and genome editing using CRISPR/Cas9 are two powerful game-changing technologies in crop breeding. However, both of them still fall short for rapid generation of pure elite lines with integrated favorable traits. Here, we report the development of a Haploid-Inducer Mediated Genome Editing (IMGE) approach, which utilizes a maize haploid inducer line carrying a CRISPR/Cas9 cassette targeting for a desired agronomic trait to pollinate an elite maize in bred line and to generate genome-edited haploids in the elite maize background. Homozygous pure DH lines with the desired trait improvement could be generated within two generations, thus bypassing the lengthy procedure of repeated crossing and backcrossing used in conventional breeding for integrating a desirable trait into elite commercial backgrounds.
基金partially supported by the National Natural Science Foundation of China (No. 31110103904)the National Program on Key Basic Research Project (973 Program) of the Ministry of Science and Technology of China (Nos. 2011CBA01000 and 2012CB945101)
文摘Targeted genome modifications with the Cas9/gRNA system derived from the clustered regularly interspaced short palin- dromic repeat/CRISPR-associated （CRISPR/Cas） system have been successfully used in cultured human cells as well as in most model organisms, including zebrafish （Danio rerio）, mouse, and fruit fly （Chang et al., 2013; Cong et al., 2013; Gratz et al., 2013; Hwang et al., 2013; Jao et al., 2013; Shen et al., 2013; Wei et al., 2013）. Its application in zebrafish is particu- larly attractive due to the ease of handling this organism and the simple application of this method by direct injection of Cas9/ gRNA. However, the information about its specificity in this organism is very limited and needs further evaluation. In addition, it is conceivable that a Cas9 mRNA optimized for zebrafish codon preference could enhance its activity.
基金supported by a National Transgenic Science and Technology Program (2016ZX08010002)to R.W.a startup fund from the Huazhong Agricultural University
文摘Development of tools for targeted modifications of specific DNA sequences in plants is of great importance to basic plant biology research as well as crop improvement.The ability to cut DNA at specific locations in the genome to generate doublestrand breaks（DSBs）in vivo is a prerequisite for any genome editing efforts.
文摘AIM To investigate whether immune mediated diseases(IMD) are more frequent in patients with inflammatory bowel disease(IBD).METHODS In this population based registry study,a total of 47325 patients with IBD were alive and registered in the Danish National Patient Registry on December 16,2013. Controls were randomly selected from the Danish Civil Registration System(CRS) and matched for sex,age,and municipality. We used ICD 10 codes to identify the diagnoses of the included patients. The IBD population was divided into three subgroups: Ulcerative colitis(UC),Crohn's disease(CD) and Both the latter referring to those registered with both diagnoses. Subsequently,odds-ratios(OR) and 95%CI were obtained separately for each group and their respective controls. The use of Bonferoni post-test correction adjusted the significance level to P < 0.00125. P-values were estimated using Fisher's exact test.RESULTS There were significantly more women than men in the registry,and a greater percentage of comorbidity in the IBD groups(P < 0.05). Twenty different IMDs were all significantly more frequent in the IBD group. Sixteen were associated with UC versus twelve with CD. In both UC and CD ORs were significantly increased(P < 0.00125) for primary sclerosing cholangitis(PSC),celiac disease,type 1 diabetes(T1D),sarcoidosis,asthma,iridocyclitis,psoriasis,pyoderma gangrenosum,rheumatoid arthritis,and ankylosing spondylitis. Restricted to UC(P < 0.00125) were autoimmune hepatitis,primary biliary cholangitis,Grave's disease,polymyalgia rheumatica,temporal arteritis,and atrophic gastritis. Restricted to CD(P < 0.00125) were psoriatic arthritis and episcleritis. Restricted to women with UC(P < 0.00125) were atrophic gastritis,rheumatoid arthritis,temporal arteritis,and polymyalgia rheumatica. Restricted to women with CD were episcleritis,rheumatoid arthritis,and psoriatic arthritis. The only disease restricted to men(P < 0.00125) was sarcoidosis. CONCLUSION Immune mediated diseases were significantly more frequent in patients with IBD.
基金Supported by National Research Foundation of South Korea,No.NRF-2013R1A1A2013878 and No.2015R1A2A2A01007827
文摘AIM: To assess intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) for monitoring early efficacy of chemotherapy in a human gastric cancer mouse model.METHODS: IVIM-DWI was performed with 12 b-values (0-800 s/mm<sup>2</sup>) in 25 human gastric cancer-bearing nude mice at baseline (day 0), and then they were randomly divided into control and 1-, 3-, 5- and 7-d treatment groups (n = 5 per group). The control group underwent longitudinal MRI scans at days 1, 3, 5 and 7, and the treatment groups underwent subsequent MRI scans after a specified 5-fluorouracil/calcium folinate treatment. Together with tumor volumes (TV), the apparent diffusion coefficient (ADC) and IVIM parameters [true water molecular diffusion coefficient (D), perfusion fraction (f) and pseudo-related diffusion coefficient (D<sup>*</sup>)] were measured. The differences in those parameters from baseline to each measurement (ΔTV%, ΔADC%, ΔD%, Δf% and ΔD<sup>*</sup>%) were calculated. After image acquisition, tumor necrosis, microvessel density (MVD) and cellular apoptosis were evaluated by hematoxylin-eosin (HE), CD31 and terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining respectively, to confirm the imaging findings. Mann-Whitney test and Spearman’s correlation coefficient analysis were performed.RESULTS: The observed relative volume increase (ΔTV%) in the treatment group were significantly smaller than those in the control group at day 5 (ΔTV<sub>treatment</sub>% = 19.63% ± 3.01% and ΔTV<sub>control</sub>% = 83.60% ± 14.87%, P = 0.008) and day 7 (ΔTV<sub>treatment</sub>% = 29.07% ± 10.01% and ΔTV<sub>control</sub>% = 177.06% ± 63.00%, P = 0.008). The difference in ΔTV% between the treatment and the control groups was not significant at days 1 and 3 after a short duration of treatment. Increases in ADC in the treatment group (ΔADC%<sub>treatment</sub>, median, 30.10% ±
基金supported by a Collaborative Funding Grant from North Carolina Biotechnology Center and Syngenta Biotechnology (2016-CFG-8003)startup funds provided by East Carolina University and University of Maryland to Y.Q.a grant from the National Science Foundation (IOS-1339209)
文摘Breakthroughs in the generation of programmable sequence-specific nucleases (SSNs), such as zinc finger nucleases (ZFNs),TAL effector nucleases (TALENs) and the RNA-directed nuclease CRISPR-associated protein 9 (Cas9), have greatly increased the ease of plant genome engineering (Voytas, 2013; Malzahn et al.,2017). Programmable SSNs introduce a DNA double-strand break
基金financially supported by the National Natural Science Foundation of China(Grant No.41402102)Fundamental Research Funds for the Central Universities(Grant No.2652014001)+1 种基金the National Science and Technology Major Project of the Ministry of Science and Technology of China(Grant No.2011ZX05005–002–008HZ)National Basic Research Program of China(Grant No.2011CB201100–03)
文摘Samples of the Cambrian microbial dolomites were collected from Penglaiba section,a well-exposed stratigraphic section in the northwestern area of the Tarim Basin.This study provides an analogue for mediated dolomites that can precipitate in microbial mats and biofilms.The Cambrian stromatolitic dolomites were studied using high-resolution scanning electron microscopy.The results are as follows:(1)dolomites with 50 nm to 100 nm spherical nanostructures are aggregated into minerals of larger sphericities;(2)nanospherical dolomites of 50 nm to 170 nm diameter are densely arranged as dumbbell-shaped or chained aggregates;(3)silicified filaments,as well as dumbbell-shaped and chain arrangements,are preserved as important microstructures.On the basis of sedimentological,compositional,geochemical,and petrographic data,the microstructures were interpreted as nanoglobules that function as bacteria in the nucleation and filament mineralization stages.The microstructures function as such because they are wrapped in extracellular polymeric substance(EPS)or mucus and mineralized fossils.Silicification accounts for the exceptional preservation of microbial mat structures,including biofilms,as well as filamentous and coccoid microbes.In addition,EPS process is capable of binding different elements,with preference for Si,Mg,and Ca.Such suitable composition favors microbe mineralization and dolomite nucleation on organic substrates.These microscopic structures suggest bacterial mineralization and provide visual evidence for the origin of microbial dolomites.
基金a grant from Japan Agency for Medical Research and Developement(20317617).
文摘ABO incompatible living donor liver transplantation has the potential to expand the donor pool for patients with end stage liver diseases on the expense of challenges to overcome immunological barriers across blood type.There is a profound impact of age on incidence and severity of antibody mediated rejection(AMR).Even children older than 1 year have chances of AMR;children aged 8 years or older have risks of hepatic necrosis similar to adult liver recipients.The mechanism of AMR is based on circulatory disturbances secondary to inflammation and injury of the vascular endothelium caused by an antibody-antigen-complement reaction.The strategy to overcome ABO blood type barrier is based on both pre-transplant desensitization and adequate treatment of this phenomenon.Nowadays,rituximab is the standard means of desensitization but unfortunately an insufficient aid to treat AMR.Because of low incidence(less than 5%in the rituximab era),in practice of AMR only some case reports about the treatment of clinical AMR are available in the literature.Initial experiences revealed that the proteasome inhibitor,bortezomib might be a promising treatment based on its capacity to deplete plasma cell agents.Although ABO blood type barrier has been counteracted in 95%of patients by applying“rituximab-desensitization”,many issues,such as prediction of high-risk patients of infection and AMR and secure treatment strategies for evoked AMR,remain to be resolved.
基金supported by Ministry of Education(MOE)Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer and Shanghai Key Laboratory of Hepatobiliary Tumor Biologysupported by grants from the National Natural Science Foundation of China 81972222,81772582,and 81702736,National Key R&D Program of China(2017YFA0504503)Program of Shanghai Academic Research Leader(18XD1405400).
文摘Hepatocyte nuclear factor 3γ(HNF3γ)is a hepatocyte nuclear factor,but its role and clinical significance in hepatocellular carcinoma(HCC)remain unclear.Herein,we report that HNF3γexpression is downregulated in patient HCC and inversely correlated with HCC malignancy and patient survival.Moreover,our data suggested that the HNF3γreduction in HCC could be mediated by METTL14-dependent m6A methylation of HNF3γmRNA.HNF3γexpression was increased during hepatic differentiation and decreased in dedifferentiated HCC cells.Interestingly,HNF3γdelivery promoted differentiation of not only HCC cells but also liver CSCs,which led to suppression of HCC growth.Mechanistic analysis suggested an HNF3γ-centered regulatory network that includes essential liver differentiation-associated transcription factors and functional molecules,which could synergistically facilitate HCC cell differentiation.More importantly,enforced HNF3γexpression sensitized HCC cells to sorafenib-induced growth inhibition and cell apoptosis through transactivation of OATP1B1 and OATP1B3 expression,which are major membrane transporters for sorafenib uptake.Clinical investigation showed that patient-derived HCC xenografts with high HNF3γexpression exhibited a sorafenib response and patients with high HCC HNF3γlevels benefited from sorafenib therapy.Together,these results suggest that HNF3γplays an essential role in HCC differentiation and may serve as a therapeutic target and predictor of sorafenib benefit in patients.
文摘Dear Editor,RNA knockdown in vivo carries significant potential for dis-ease modeling and therapies.Despite the emerging approaches of CRISPR/Cas9-mediated permanent knock out of targeted genes,strategies targeting RNA for disruption are advantageous in the treatment of acquired metabolic disorders when permanent modification of genome DNA is not appropriate,and RNA virus infection diseases when pathogenic DNA is not available(such as SARS-Cov-2 and MERS infections).
文摘In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically modified mice and highthroughput analyses, we demonstrate that prolonged HIF-1α signaling in B cells leads to enhanced RANKL production and osteoclast formation. In addition, deletion of HIF-1α in B cells prevents estrogen deficiency-induced bone loss in mice.Mechanistically, estrogen controls HIF-1α protein stabilization through HSP70-mediated degradation in bone marrow B cells.The stabilization of HIF-1α protein in HSP70-deficient bone marrow B cells promotes RANKL production and osteoclastogenesis.Induction of HSP70 expression by geranylgeranylacetone(GGA) administration alleviates ovariectomy-induced osteoporosis.Moreover, RANKL gene expression has a positive correlation with HIF1 A expression in human B cells. In conclusion, HIF-1αsignaling in B cells is crucial for the control of osteoclastogenesis, and the HSP70/HIF-1α axis may serve as a new therapeutic target for osteoporosis.
基金The work in the authors’laboratory is supported by grants from the Ministry of Science and Technology of China(2014CB910103,2012CB910201 and 2016YFA0502100)the National Natural Science Foundation of China(3163000013,31521091 and 91429304).
文摘Although it has long been demonstrated that cytosolic DNA is a potent immune stimulant,it is only in recent years that the molecular mechanisms of DNA-stimulated innate immune responses have emerged.Studies have established critical roles for the DNA sensor cyclic GMP–AMP synthase(cGAS)and the adapter protein MITA/STING in the innate immune response to cytosolic DNA or DNA viruses.Although the regulation of cGAS–MITA/STING-mediated signaling remains to be fully investigated,understanding the processes involved may help to explain the mechanisms of innate immune signaling events and perhaps autoinflammatory diseases and to provide potential therapeutic targets for drug intervention.In this review,we summarize recent progress on the regulation of the cGAS–MITA/STING-mediated innate immune response to DNA viruses at the organelle-trafficking,posttranslational and transcriptional levels.
文摘Nitrogen （N） is one of most important nutrients for crop production, which makes up 1%-5% of total plant dry matter （Marschner, 2012）. Due to the limited availability of N in soil, application of N fertilizers has been an important agronomic practice to increase crop yield. However, over-application of N fertilizers has caused pollution of N in soil, water and air. It was estimated that the nitrogen use efficiency （NUE, the total biomass or grain yield produced per unit of applied fertilizer N） in cereal crops is as low as 33% （Raun and Johnson, 1999）. Therefore, improving NUE together with reducing application of N fertilizers is an important issue for environment and sustainable production of crops. This is especially important for rice, which is a staple food for half population in the world.
基金financial support from the National Natural Science Foundation of China (Grant nos. 81573384 and 21375101)
文摘Capillary electrophoresis with many advantages plays an important role in pharmaceutical analysis and drug screening. This review gives an overview on the recent advances in the developments and applications of capillary electrophoresis in the field of enzyme inhibitor screening. The period covers 2013 to 2017. Both the pre-capillary enzyme assays and in-capillary enzyme assays which include electrophoretically mediated microanalysis（EMMA） and immobilized enzyme microreactor（IMER） are summarized in this article.
文摘In accordance with previous reports, the sequences related to phosporylated protein segments occur in conserved variable domains of immunoglobulins including first of all certain N-terminally located segments. Consequently, we look here for the sequences 1) composing human and mouse proteins different from antigen receptors, 2) identical with or highly similar to nucleotide sequence representatives of conserved variable immunoglobulin segments and 3) identical with or closely related to phosphorylation sites. More precisely, we searched for the corresponding actual pairs of DNA and protein sequence segments using five-step bilingual approach employing among others a) different types of BLAST searches, b) two in-principle-different machine-learning methods predicting phosphorylated sites and c) two large databases recording existing phosphorylation sites. The approach identified seven existing phosphorylation sites and thirty-seven related human and mouse segments achieving limits for several predictions or phylogenic parameters. Mostly serines phosporylated with ataxia-telangiectasia-related kinase (involved in regulation of DNA-double-strand-break repair) were indicated or predicted in this study. Hypermutation motifs, located in effective positions of the selected sequence segments, occurred significantly less frequently in transcribed than non-transcribed DNA strands suggesting thus the incidence of mutation events. In addition, marked differences between the numbers and proportions of human and mouse cancer-related sequence items were found in different steps of selection process. The possible role of hypermutation changes within the selected segments and the observed structural relationships are discussed here with respect to DNA damage, carcinogenesis, cancer vaccination, ageing and evolution. Taken together, our data represent additional and sometimes perhaps complementary information to the existing databases of empirically proven phosphorylation sites or pathogenically important spots.
