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Detecting genetic hypermutability of gastrointestinal tumor by using a forensic STR kit

Anqi Chen, Suhua Zhang, Jixi Li, Chaoneng Ji, Jinzhong Chen, Chengtao Li

《医学前沿（英文）》 2020年 第14卷 第1期   页码 101-111 doi: 10.1007/s11684-019-0698-4

摘要： Growing evidence suggests that somatic hypermutational status and programmed cell death-1 overexpression are potential predictive biomarkers indicating treatment benefits from immunotherapy using immune checkpoint inhibitors. However, biomarker-matched trials are still limited, and many of the genomic alterations remain difficult to target. To isolate the potential somatic hypermutational tumor from microsatellite instability low/microsatellite stability (MSI-L/MSS) cases, we employed two commercial kits to determine MSI and forensic short tandem repeat (STR) alternations in 250 gastrointestinal (GI) tumors. Three types of forensic STR alternations, namely, allelic loss, Aadd, and Anew, were identified. 62.4% (156/250) of the patients with GI exhibited STR alternation, including 100% (15/15) and 60% (141/235) of the microsatellite high instability and MSI-L/MSS cases, respectively. 30% (75/250) of the patients exhibited STR instability with more than 26.32% (26.32%–84.21%) STR alternation. The cutoff with 26.32% of the STR alternations covered all 15 MSI cases and suggested that it might be a potential threshold. Given the similar mechanism of the mutations of MSI and forensic STR, the widely used forensic identifier STR kit might provide potential usage for identifying hypermutational status in GI cancers.

关键词： mismatch repair protein deficiency (MMR-D)     microsatellite instability (MSI)     short tandem repeats (STR)     gastrointestinal tumor     hypermutability    

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Expression status of GATA3 and mismatch repair proteins in upper tract urothelial carcinoma

Yue Wang, Jinxia Zhang, Yunfan Wang, Shufang Wang, Yu Zhang, Qi Miao, Fei Gao, Huiying He

《医学前沿（英文）》 2019年 第13卷 第6期   页码 730-740 doi: 10.1007/s11684-019-0687-7

摘要： GATA binding protein 3 (GATA3) and mismatch repair (MMR) deficiency contribute to the development of urothelial carcinoma. However, the combined expression of GATA3 and microsatellite instability (MSI) in upper tract urothelial carcinoma (UTUC) and its prognostic value have not been investigated. Here, we immunohistochemically stained GATA3 and MMR proteins in 108 UTUC samples. GATA3 was positive in 74 cases, and its expression was significantly lower than in adjacent benign urothelium ( <0.001). Loss of GATA3 expression was statistically associated with adverse clinicopathologic parameters, such as advanced stage, lymphovascular invasion, neural invasion, lymph node metastasis, and extensive necrosis. Cancer-specific survival (CSS, =0.028) and disease-free survival (DFS, =0.024) were significantly shorter in patients with GATA3 negative tumors than in patients with GATA3 positive tumors. The absence of MMR proteins was observed in 8.3% of the cases, and focal staining was identified in 13.0%. When using “lax criteria” which resulted in counting cases as negative where MMR staining was in fact focally positive (<5%), we found that GATA3 was inversely associated with MSI ( =0.005). Moreover, GATA3 /microsatellite stability (MS) tumors were correlated with advanced pT stage ( <0.001) and poor outcome ( =0.019 for CSS, =0.016 for DFS) compared with GATA3 /MSI ones. The GATA3 /MSI cases had unfavorable clinical outcomes compared with GATA3 /MSI cases ( =0.008 for CSS, =0.023 for DFS). This finding raises a question as to whether GATA3 interacts with MSI through the TGF- signaling pathway and regulates UTUC progression.

关键词： upper tract urothelial carcinoma     GATA binding protein 3     mismatch repair     microsatellite instability     prognosis    

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Antithrombin deficiency and decreased protein C activity in a young man with venous thromboembolism:

null

《医学前沿（英文）》 2018年 第12卷 第3期   页码 319-323 doi: 10.1007/s11684-017-0553-4

摘要：

Antithrombin and protein C are two crucial members in the anticoagulant system and play important roles in hemostasis. Mutations in and lead to deficiency or dysfunction of the two proteins, which could result in venous thromboembolism (VTE). Here, we report a Chinese 22-year-old young man who developed recurrent and serious VTE in cerebral veins, visceral veins, and deep veins of the lower extremity. Laboratory tests and direct sequencing of and were conducted for the patient and his family members. Coagulation tests revealed that the patient presented type I antithrombin deficiency combined with decreased protein C activity resulting from a small insertion mutation c.848_849insGATGT in and a short deletion variant c.572_574delAGA in . This combination of the two mutations was absent in 400 healthy subjects each from southern and northern China. Then, we summarized all the mutations of the and gene reported in the Chinese Han population. This study demonstrates that the combination of antithrombin deficiency and decreased protein C activity can result in severe VTE and that the coexistence of different genetic factors may increase the risk of VTE.

关键词： antithrombin deficiency     protein C activity     mutation     variant     venous thromboembolism     anticoagulants    

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Prevalence of vitamin D deficiency in girls with idiopathic central precocious puberty

null

《医学前沿（英文）》 2018年 第12卷 第2期   页码 174-181 doi: 10.1007/s11684-017-0544-5

摘要：

The relationship between vitamin D deficiency and idiopathic central precocious puberty (ICPP) has been recently documented. In this study, 280 girls diagnosed with ICPP and 188 normal puberty control girls of similar ages were enrolled and retrospectively studied. The ICPP group had significantly lower serum 25-hydroxyvitamin D (25[OH]D) levels than the control group. Furthermore, a nonlinear relationship was found between serum 25[OH]D and ICPP, and a cut-off point for serum 25[OH]D was found at 31.8 ng/ml for ICPP with and without adjusting the different confounding factors. Girls with serum 25[OH]D≥31.8 ng/ml had a lower odds ratio (unadjusted: OR 0.36, 95% CI 0.15 to 0.83, <0.05; height and weight adjusted: OR 0.44, 95% CI 0.18 to 1.08, = 0.072; BMI adjusted: OR 0.36, 95% CI 0.16 to 0.84, <0.05). The ICPP subjects with 25[OH]D deficiency had a higher body mass index (BMI) than the subjects from the two other subgroups. Correlation analysis showed that vitamin D level is correlated with BMI and some metabolic parameters in the ICPP group. Our study suggested that vitamin D status may be associated with ICPP risk and may have a threshold effect on ICPP.

关键词： idiopathic central precocious puberty     threshold effects     vitamin D status    

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Correlativity study between expression of DNA double-strand break repair protein and radiosensitivity

Liang ZHUANG, Shiying YU, Xiaoyuan HUANG, Yang CAO, Huihua XIONG

《医学前沿（英文）》 2009年 第3卷 第1期   页码 26-29 doi: 10.1007/s11684-009-0008-7

摘要： DNA double-strand break (DSB) is generally regarded as the most lethal of all DNA lesions after radiation. Ku80, DNA-PK catalytic subunit (DNA-PKcs) and ataxia telangiectasia mutated (ATM) proteins are major DSB repair proteins. In this study, survival fraction at 2Gy (SF2) values of eight human tumor cell lines (including four human cervical carcinoma cell lines HeLa, SiHa, C33A, Caski, three human breast carcinoma cell lines MCF-7, MDA-MB-231, MDA-MB-453, and one human lung carcinoma cell line A549) were acquired by clone formation assay, and western blot was applied to detect the expressions of Ku80, DNA-PKcs and ATM protein. The correlativity of protein expression with SF2 value was analyzed by Pearson linear correlation analysis. We found that the expression of same protein in different cell lines and the expression of three proteins in the same cell line had a significant difference. The SF2 values were also different in eight tumor cell lines and there was a positive correlativity between the expression of DNA-PKcs and SF2 ( ＝0.723, = 0.043), but Ku80 and ATM expression had no correlation with SF2 ( >0.05). These findings suggest that the expression level of DNA-PKcs protein can be an indicator for predicting the radiosensitivity of tumor cells.

关键词： Ku80     DNA-PK(cs)-binding protein     human     ataxia telangiectasia mutated protein     tumor cell lines     radiosensitivity    

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Decellularized extracellular matrix mediates tissue construction and regeneration

《医学前沿（英文）》 2022年 第16卷 第1期   页码 56-82 doi: 10.1007/s11684-021-0900-3

摘要： Contributing to organ formation and tissue regeneration, extracellular matrix (ECM) constituents provide tissue with three-dimensional (3D) structural integrity and cellular-function regulation. Containing the crucial traits of the cellular microenvironment, ECM substitutes mediate cell–matrix interactions to prompt stem-cell proliferation and differentiation for 3D organoid construction in vitro or tissue regeneration in vivo. However, these ECMs are often applied generically and have yet to be extensively developed for specific cell types in 3D cultures. Cultured cells also produce rich ECM, particularly stromal cells. Cellular ECM improves 3D culture development in vitro and tissue remodeling during wound healing after implantation into the host as well. Gaining better insight into ECM derived from either tissue or cells that regulate 3D tissue reconstruction or organ regeneration helps us to select, produce, and implant the most suitable ECM and thus promote 3D organoid culture and tissue remodeling for in vivo regeneration. Overall, the decellularization methodologies and tissue/cell-derived ECM as scaffolds or cellular-growth supplements used in cell propagation and differentiation for 3D tissue culture in vitro are discussed. Moreover, current preclinical applications by which ECM components modulate the wound-healing process are reviewed.

关键词： decellularized extracellular matrix     3D culture     organoids     tissue repair    

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PROTECTIVE ROLES OF D1 PROTEIN TURNOVER AND THE XANTHOPHYLL CYCLE IN TOMATO (SOLANUM LYCOPERSICUM) UNDER

《农业科学与工程前沿（英文）》 2021年 第8卷 第2期

摘要：

D1 protein turnover and the xanthophyll cycle (XC) are important photoprotective mechanisms in plants that operate under adverse conditions. Here, streptomycin sulfate (SM) and dithiothreitol (DTT) were used in tomato plants as inhibitors of D1 protein turnover and XC to elucidate their photoprotective impacts under sub-high temperature and high light conditions (HH, 35°C, 1000 µmol·m-2·s-1). SM and DTT treatments significantly reduced the net photosynthetic rate, apparent quantum efficiency, maximum photochemical efficiency, and potential activity of photosystem II, leading to photoinhibition and a decline in plant biomass under HH. The increase in reactive oxygen species levels resulted in thylakoid membrane lipid peroxidation. In addition, there were increased non-photochemical quenching and decreased chlorophyll pigments in SM and DTT application, causing an inhibition of D1 protein production at both transcriptional and translational levels. Overall, inhibition of D1 turnover caused greater photoinhibition than XC inhibition. Additionally, the recovery levels of most photosynthesis indicators in DTT-treated plants were higher than in SM-treated plants. These findings support the view that D1 turnover has a more important role than XC in photoprotection in tomato under HH conditions.

 

关键词： D1 turnover / photoinhibition / photoprotection / photosynthesis / tomato / xanthophyll cycle    

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PROTECTIVE ROLES OF D1 PROTEIN TURNOVER AND THE XANTHOPHYLL CYCLE IN TOMATO (

Tao LU, Jiazhi LU, Mingfang QI, Zhouping SUN, Yufeng LIU, Tianlai LI

《农业科学与工程前沿（英文）》   页码 262-279 doi: 10.15302/J-FASE-2021383

摘要： D1 protein turnover and the xanthophyll cycle (XC) are important photoprotective mechanisms in plants that operate under adverse conditions. Here, streptomycin sulfate (SM) and dithiothreitol (DTT) were used in tomato plants as inhibitors of D1 protein turnover and XC to elucidate their photoprotective impacts under sub-high temperature and high light conditions (HH, 35°C, 1000 µmol·m ·s ). SM and DTT treatments significantly reduced the net photosynthetic rate, apparent quantum efficiency, maximum photochemical efficiency, and potential activity of photosystem II, leading to photoinhibition and a decline in plant biomass under HH. The increase in reactive oxygen species levels resulted in thylakoid membrane lipid peroxidation. In addition, there were increased non-photochemical quenching and decreased chlorophyll pigments in SM and DTT application, causing an inhibition of D1 protein production at both transcriptional and translational levels. Overall, inhibition of D1 turnover caused greater photoinhibition than XC inhibition. Additionally, the recovery levels of most photosynthesis indicators in DTT-treated plants were higher than in SM-treated plants. These findings support the view that D1 turnover has a more important role than XC in photoprotection in tomato under HH conditions.

关键词： D1 turnover     photoinhibition     photoprotection     photosynthesis     tomato     xanthophyll cycle    

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Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice

《医学前沿（英文）》   页码 957-971 doi: 10.1007/s11684-023-0988-8

摘要： Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.

关键词： DNAH10     mice     motile cilia     mutation     primary ciliary dyskinesia    

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Generation and repair of AID-initiated DNA lesions in B lymphocytes

null

《医学前沿（英文）》 2014年 第8卷 第2期   页码 201-216 doi: 10.1007/s11684-014-0324-4

摘要：

Activation-induced deaminase (AID) initiates the secondary antibody diversification process in B lymphocytes. In mammalian B cells, this process includes somatic hypermutation (SHM) and class switch recombination (CSR), both of which require AID. AID induces U:G mismatch lesions in DNA that are subsequently converted into point mutations or DNA double stranded breaks during SHM/CSR. In a physiological context, AID targets immunoglobulin (Ig) loci to mediate SHM/CSR. However, recent studies reveal genome-wide access of AID to numerous non-Ig loci. Thus, AID poses a threat to the genome of B cells if AID-initiated DNA lesions cannot be properly repaired. In this review, we focus on the molecular mechanisms that regulate the specificity of AID targeting and the repair pathways responsible for processing AID-initiated DNA lesions.

关键词： class switch recombination     somatic hypermutation     activation-induced deaminase     DNA repair     genomic instability    

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Construction of a CaHPO4-PGUS1 hybrid nanoflower through protein-inorganic self-assembly, and its applicationin glycyrrhetinic acid 3-O-mono-β-D-glucuronide preparation

Tian Jiang, Yuhui Hou, Tengjiang Zhang, Xudong Feng, Chun Li

《化学科学与工程前沿（英文）》 2019年 第13卷 第3期   页码 554-562 doi: 10.1007/s11705-019-1834-z

摘要： Glycyrrhetinic acid 3- -mono- -D-glucuronide (GAMG), an important pharmaceutical intermediate and functional sweetener, has broad applications in the food and medical industries. A green and cost-effective method for its preparation is highly desired. Using site-directed mutagenesis, we previously obtained a variant of -glucuronidase from Li-3 (PGUS1), which can specifically transform glycyrrhizin (GL) into GAMG. In this study, a facile method was established to prepare a CaHPO -PGUS1 hybrid nanoflower for enzyme immobilization, based on protein-inorganic hybrid self-assembly. Under optimal conditions, 1.2 mg of a CaHPO -PGUS1 hybrid nanoflower precipitate with 71.2% immobilization efficiency, 35.60 mg∙g loading capacity, and 118% relative activity was obtained. Confocal laser scanning microscope and scanning electron microscope results showed that the enzyme was encapsulated in the CaHPO -PGUS1 hybrid nanoflower. Moreover, the thermostability of the CaHPO -PGUS1 hybrid nanoflower at 55°C was improved, and its half-life increased by 1.3 folds. Additionally, the CaHPO -PGUS1 hybrid nanoflower was used for the preparation of GAMG through GL hydrolysis, with the conversion rate of 92% in 8 h, and after eight consecutive runs, it had 60% of its original activity.

关键词： β-glucuronidase     enzyme-inorganic hybrid nanoflower     biotransformation     glycyrrhizin     glycyrrtinic acid 3-O-mono-β-D-glucuronide    

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Bile duct injury repair — earlier is not better

null

《医学前沿（英文）》 2015年 第9卷 第4期   页码 508-511 doi: 10.1007/s11684-015-0418-7

摘要：

Bile duct injury is a common complication of cholecystectomy. The timing of bile duct injury repair remains controversial. A recent review conducted in France reported 39% complications and 64% failure after immediate repair in 194 patients compared with 14% complications and 8% failure after late repair in 133 patients. A national review of 139 consecutive early repairs conducted at five hepatopancreaticobiliary centers in Denmark reported 4% mortality, 36% morbidity, and 42 restrictures (30%) at a median follow-up of 102 months, and only 64 patients (46%) demonstrated uneventful short-term and long-term outcomes. Most patients with bile duct injury present with bile leak and sepsis; thus, early repair is not recommended. Percutaneous drainage of bile and endoscopic stenting are the mainstays of treatment of bile leak because they convert acute bile duct injury into a controlled external biliary fistula. The ensuing benign biliary stricture should be repaired by a biliary surgeon after a delay of 4–6 weeks once the external biliary fistula has closed.

关键词： bile duct injury     cholecystectomy     laparoscopic cholecystectomy    

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non-inferiority trial of intravenous ferric carboxymaltose versus iron sucrose in patients with iron deficiency

《医学前沿（英文）》 doi: 10.1007/s11684-023-1001-2

摘要： Iron deficiency (ID) and ID anemia (IDA) pose significant public health concerns in China. Although iron sucrose (IS) treatment is well-established in the country, ferric carboxymaltose (FCM) offers the advantage of higher doses and fewer infusions. This open label, randomized, controlled, non-inferiority trial was conducted at multiple sites in China to compare the outcomes of FCM (maximum of 2 doses, 500 or 1000 mg iron) and IS (up to 11 infusions, 200 mg iron) treatments in subjects with IDA. The primary endpoint was the achievement of hemoglobin (Hb) response (an increase of ≥2 g/dL from baseline) within 8 weeks, whereas secondary endpoints included changes in Hb, transferrin saturation, and serum ferritin levels. Among the 371 randomized subjects, a similar percentage of subjects treated with FCM and IS achieved Hb-response (FCM 99.4%, IS 98.3%), thereby confirming the non-inferiority of FCM compared with IS (difference 1.12 (−2.15, 4.71; 95% confidence interval (CI))). Furthermore, a significantly higher proportion of FCM-treated subjects achieved early Hb-response at Week 2 (FCM 85.2%, IS 73.2%; difference 12.1 (3.31, 20.65; 95% CI)). Additionally, the increase in TSAT and serum ferritin levels from baseline was significantly greater at all time points for FCM-treated subjects. The safety profiles of FCM and IS were comparable, with the exception of transient hypophosphatemia and pyrexia, which are consistent with FCM’s known safety profile. In conclusion, FCM proves to be an efficacious treatment for IDA, providing faster Hb-response and correction of ID with fewer administrations than IS.

关键词： iron deficiency     anemia     intravenous iron     ferric carboxymaltose     iron sucrose     Hb response     early response    

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Mobile platform for hydraulic turbine blade repair robot

GUI Zhongcheng, CHEN Qiang, SUN Zhenguo, ZHANG Wenzeng, LIU Kang

《机械工程前沿（英文）》 2008年 第3卷 第2期   页码 164-169 doi: 10.1007/s11465-008-0035-0

摘要： The wall-climbing mobile platform (MP) of a robot for repairing a hydraulic turbine blade onsite is developed. The MP is equipped with ferromagnetic adhesive devices and can work on a spatial curved surface. The contradiction between mobility and load-bearing ability is analyzed, and the problem of self-adaptation to the curved face is solved using differential-driven wheeled locomotion with ferromagnetic adhesive devices. The platform adheres to the blade surface through the force provided by the ferromagnetic devices, and a certain gap exists between the magnetic devices and the blade’s surface. A mechanism of three revolution degrees of freedom, which connects the magnetic devices with the platform’s chassis, is developed to make the platform self-adapt to the complex curved surface of the turbine blade. A proof-of-principle prototype has been manufactured, and experiments prove the success of the MP. The payload of the zero-turn-radius MP with excellent maneuverability exceeds 80 kg. The platform can automatically adapt to complex spatial surfaces, which satisfy the requirements of a hydraulic turbine blade in-situ repair robot.
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The effects of mismatch fracture properties in encapsulation-based self-healing concrete using cohesive-zone

Luthfi Muhammad MAULUDIN, Chahmi OUCIF, Timon RABCZUK

《结构与土木工程前沿（英文）》 2020年 第14卷 第3期   页码 792-801 doi: 10.1007/s11709-020-0629-0

摘要： Finite element analysis is developed to simulate the breakage of capsule in capsule-based self-healing concrete. A 2D circular capsule with different core-shell thickness ratios embedded in the mortar matrix is analyzed numerically along with their interfacial transition zone. Zero-thickness cohesive elements are pre-inserted into solid elements to represent potential cracks. This study focuses on the effects of mismatch fracture properties, namely fracture strength and energy, between capsule and mortar matrix into the breakage likelihood of the capsule. The extensive simulations of 2D specimens under uniaxial tension were carried out to investigate the key features on the fracture patterns of the capsule and produce the fracture maps as the results. The developed fracture maps of capsules present a simple but valuable tool to assist the experimentalists in designing appropriate capsule materials for self-healing concrete.

关键词： self-healing concrete     interfacial zone     capsule materials     cohesive elements     fracture maps    

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标题 作者 时间 类型 操作

Detecting genetic hypermutability of gastrointestinal tumor by using a forensic STR kit

Anqi Chen, Suhua Zhang, Jixi Li, Chaoneng Ji, Jinzhong Chen, Chengtao Li

期刊论文

Expression status of GATA3 and mismatch repair proteins in upper tract urothelial carcinoma

Yue Wang, Jinxia Zhang, Yunfan Wang, Shufang Wang, Yu Zhang, Qi Miao, Fei Gao, Huiying He

期刊论文

Antithrombin deficiency and decreased protein C activity in a young man with venous thromboembolism:

null

期刊论文

Prevalence of vitamin D deficiency in girls with idiopathic central precocious puberty

null

期刊论文

Correlativity study between expression of DNA double-strand break repair protein and radiosensitivity

Liang ZHUANG, Shiying YU, Xiaoyuan HUANG, Yang CAO, Huihua XIONG

期刊论文

Decellularized extracellular matrix mediates tissue construction and regeneration

期刊论文

PROTECTIVE ROLES OF D1 PROTEIN TURNOVER AND THE XANTHOPHYLL CYCLE IN TOMATO (SOLANUM LYCOPERSICUM) UNDER

期刊论文

PROTECTIVE ROLES OF D1 PROTEIN TURNOVER AND THE XANTHOPHYLL CYCLE IN TOMATO (

Tao LU, Jiazhi LU, Mingfang QI, Zhouping SUN, Yufeng LIU, Tianlai LI

期刊论文

Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice

期刊论文

Generation and repair of AID-initiated DNA lesions in B lymphocytes

null

期刊论文

Construction of a CaHPO4-PGUS1 hybrid nanoflower through protein-inorganic self-assembly, and its applicationin glycyrrhetinic acid 3-O-mono-β-D-glucuronide preparation

Tian Jiang, Yuhui Hou, Tengjiang Zhang, Xudong Feng, Chun Li

期刊论文

Bile duct injury repair — earlier is not better

null

期刊论文

non-inferiority trial of intravenous ferric carboxymaltose versus iron sucrose in patients with iron deficiency

期刊论文

Mobile platform for hydraulic turbine blade repair robot

GUI Zhongcheng, CHEN Qiang, SUN Zhenguo, ZHANG Wenzeng, LIU Kang

期刊论文

The effects of mismatch fracture properties in encapsulation-based self-healing concrete using cohesive-zone

Luthfi Muhammad MAULUDIN, Chahmi OUCIF, Timon RABCZUK

期刊论文