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Optimized human factor IX expression cassettes for hepatic-directed gene therapy of hemophilia B

null

《医学前沿（英文）》 2015年 第9卷 第1期   页码 90-99 doi: 10.1007/s11684-015-0390-2

摘要：

Gene therapy provides a potential cure for hemophilia B, and significant progress has been achieved in liver-directed gene transfer mediated by adeno-associated viral vectors. Recent clinical trials involving the use of a self-complementary adeno-associated virus serotype 8-human codon-optimized factor IX (AAV8-hFIXco) vector demonstrated encouraging efficacy with hFIX expression stabilized at 1% to 6% of normal level in patients, but safety concerns related to high vector doses are still present. Thus, further improvement of AAV vectors and hFIX expression cassette may positively contribute to the ultimate success of hemophilia B gene therapy. In this study, to obtain a higher expression level of hFIX that potentiates the coagulant capacity of recipients, human FIX expression vector was optimized by upgrading the codon adaption index and adjusting the GC content, inserting a Kozak sequence (GCCACC), and introducing a gain-of-function mutation, R338L (FIX Padua). The efficiency of the published and the presently constructed cassettes was compared through in vivo screening. In addition, the regulatory elements that control the FIX gene expression in these cassettes were screened for liver-specific effectiveness. Among all the constructed cassettes, scAAV-Pre-hFIXco-SIH-R338L, which was the construct under the control of the prothrombin enhancer and prealbumin promoter, resulted in the highest level of coagulant activity, and the expression levels of two constructed cassettes (scAAV-Chi-hFIXco-SIH-R338L and scAAV-Pre-hFIXco-SIH-R338L) were also higher than that of the published cassette (scAAV-LP1-hFIXco-SJ). In summary, our strategies led to a substantial increase in hFIX expression at the protein level or a remarkably elevated coagulant activity. Thus, these reconstructs of hFIX with AAV vector may potentially contribute to the creation of an efficacious gene therapy of hemophilia B.

关键词： factor IX     hemophilia B     liver-specific regulatory elements     hydrodynamic gene transfer    

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662 A/G gene variation in human tumor necrosis factor receptor superfamily, member 9 (TNFRSF9)

QU Yanchun, YANG Ze, SUN Liang, JI Linong

《医学前沿（英文）》 2008年 第2卷 第3期   页码 283-285 doi: 10.1007/s11684-008-0053-7

摘要： The aim of this paper is to report a new coding variance of the gene, a candidate for autoimmune diseases. We found the variation in two families with type 2 diabetes mellitus by D-HPLC mutation screening method and confirmed our results by direct sequencing and PCR-RFLP. Although without changing the amino acid coding, the variance may have an effect on codon usage and play a role in disease development, such as type 2 diabetes mellitus. However, we cannot define the role of this variance because the frequency of the minor allele is low in the Chinese population and no homozygote of the variance was found. More research in multiple populations will be necessary to define the role of this variance.

关键词： D-HPLC mutation     development     autoimmune     PCR-RFLP     candidate    

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Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor

Wenjie Zhu, Binghe Xu

《医学前沿（英文）》 2021年 第15卷 第2期   页码 208-220 doi: 10.1007/s11684-020-0795-4

摘要： New targeted therapies have been developed to overcome resistance to endocrine therapy (ET) and improve the outcome of HR /HER2 advanced breast cancer (ABC). We conducted a meta-analysis and systemic review on randomized controlled trials evaluating various targeted therapies in combination with ET in HR /HER2 ABC. PUBMED and EMBASE databases were searched for eligible trials. Hazard ratios (HRs) for progression-free survival (PFS), odds ratios (ORs) for objective response rate (ORR), clinical benefit rate (CBR), and toxicity were meta-analyzed. Twenty-six studies with data on 10 347 patients were included and pooled. The addition of cyclin-dependent kinase 4/6 inhibitors to ET significantly improved median PFS (pooled HR= 0.547, <0.001), overall survival (pooled HR= 0.755, <0.001), and tumor response rates (ORR, pooled OR= 1.478, <0.001; CBR, pooled OR= 1.201, <0.001) with manageable toxicities (pooled OR= 3.280, <0.001). The mammalian targets of rapamycin inhibitors and exemestane were not clinically beneficial for this pooled population including ET-naïve and ET-resistant patients. Moderate improvement in PFS (pooled HR= 0.686, <0.001) yet pronounced toxicities (pooled OR= 2.154, <0.001) were noted in the combination of phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors with fulvestrant. Future studies are warranted to optimize the population and the dosing sequence of these available options.

关键词： endocrine-resistant     HR+/HER2- advanced breast cancer     randomized clinical trials     meta-analysis     targeted therapy    

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correction of hemorrhagic diathesis in hemophilia A mice by an AAV-delivered hybrid FVIII composed of the human

《医学前沿（英文）》 2022年 第16卷 第4期   页码 584-595 doi: 10.1007/s11684-021-0844-7

摘要： Conventional therapies for hemophilia A (HA) are prophylactic or on-demand intravenous FVIII infusions. However, they are expensive and inconvenient to perform. Thus, better strategies for HA treatment must be developed. In this study, a recombinant FVIII cDNA encoding a human/rat hybrid FVIII with an enhanced procoagulant potential for adeno-associated virus (AAV)-delivered gene therapy was developed. Plasmids containing human FVIII heavy chain (hHC), human light chain (hLC), and rat light chain (rLC) were transfected into cells and hydrodynamically injected into HA mice. Purified AAV viruses were intravenously injected into HA mice at two doses. Results showed that the hHC+ rLC protein had a higher activity than the hHC+ hLC protein at comparable expression levels. The specific activity of hHC+ rLC was about 4- to 8-fold higher than that of their counterparts. Hydrodynamic injection experiments obtained consistent results. Notably, the HA mice undergoing the AAV-delivered hHC+ rLC treatment exhibited a visibly higher activity than those treated with hHC+ hLC, and the therapeutic effects lasted for up to 40 weeks. In conclusion, the application of the hybrid FVIII (hHC+ rLC) via an AAV-delivered gene therapy substantially improved the hemorrhagic diathesis of the HA mice. These data might be of help to the development of optimized FVIII expression cassette for HA gene therapy.

关键词： hemophilia A     adeno-associated virus (AAV)     human/rat hybrid factor VIII     gene therapy     dual chain strategy    

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Effects of hypoxia inducible factor-1alpha siRNA on the invasion of human Hela cells and expression of

Bin YANG MS , Xianglin YUAN , Yanmei ZOU , Qingsong XI , Guoxian LONG , Qiang FU , Guangyuan HU MM ,

《医学前沿（英文）》 2009年 第3卷 第3期   页码 303-308 doi: 10.1007/s11684-009-0060-3

摘要： The effects of hypoxia on the invasion and the related protein expression of Hela cells and the role of hypoxia inducible factor-1α (HIF-1α) were investigated. The Hela cells were divided into three groups, namely, H (non-transfected Hela cells), H (pGenesil-1 empty plasmid-transfected Hela cells), and H (HIF-1α-shRNA plasmid-transfected Hela cells), and were cultured under hypoxia (1% O) and normoxia for 48h. The expression of HIF-1α, E-cadherin, β-catenin, and actin was detected using Western blot. The scratch test and the invasion assay were applied to examine the invasion in each group. The expression of HIF-1α, E-cadherin, and β-catenin in tumor grafts was assayed immunohistochemically. Western blot results revealed that the bands of HIF-1α, E-cadherin, β-catenin, and actin proteins were detected in the H and H groups under hypoxia for 48h. The expression of E-cadherin, β-catenin, and actin was detected in the H group under hypoxia for 48h, and normoxia. In the H, H, and H groups under normoxia, and the H group under hypoxia for 48h, no expression of HIF-1α was detectable. The scratch test showed that the invasive ability in the H group was significantly alleviated. Immunohistochemically, it was found that there was a significant difference in the expression of HIF-1α, E-cadherin, and β-catenin between the H and H groups (<0.05), but the difference was not significant between the H and H groups. It was concluded that the effects of hypoxia on the invasion of human cervical cancer Hela cells and the expression of related proteins (E-cadherin, β-catenin, and actin) depend on HIF-1α.

关键词： hypoxia     actin     β     -catenin     E-cadherin     invasion    

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Cloning of human XAF1 gene promoter and assay of its transcription activity in a variety of cell lines

Qiong CHEN, Qing YU, Yuhu SONG, Peiyuan Li, Ying CHANG, Zhijun WANG, Lifeng LIU, Wei WU, Jusheng LIN

《医学前沿（英文）》 2009年 第3卷 第2期   页码 148-152 doi: 10.1007/s11684-009-0032-7

摘要： To investigate the regulation of tumor suppressor XAF1 gene expression in digestive system cancers, we studied XAF1 gene promoter transcription activity and mRNA level in digestive system cancer cell lines (human hepatoma cell line HepG2, human colon cancer cell line LoVo, and human gastric cancer cell line AGS) and nontumor cell lines (human embryonic liver cell line L02 (L02 cells) and human embryonic kidney 293 cells [HEK293 cells]) as controls. 1395-bp-promoter fragment of XAF1 gene was amplified by polymerase chain reaction (PCR) and cloned into pGL3-basic vector and pEGFP-1 vector to assay its promoter transcription activity. The plasmids were transfected into a variety of cell lines by lipofectamine 2000. The promoter transcription activity was determined by dual-luciferase report assay, and enhanced green fluorescent protein (EGFP)-positive cells were detected by fluorescence microscope. The expression of XAF1 mRNA in HEK293 and L02 were significantly higher than that in any of the three digestive system cancer cell lines. The dual-luciferase reporter assay showed that the promoter transcription activity in digestive system tumor cell lines transfected with pGL3-XAF1p promoter was apparently lower than that of both HEK293 and L02 cells. Expression of green fluorescent protein (GFP) under the control of XAF1 promoter in the three digestive system cancer cell lines was lower than that of both HEK293 and L02 cells. The activities of pGL3-XAF1p in the three digestive system cancer cell lines after treatment with heat stress were significantly lower than those in the unstressed cells. The results suggested that remarkably down-regulated XAF1 mRNA expression in digestive system cancer cell lines may be due to loss of transcription activity of XAF1 promoter.

关键词： gene     X-linked inhibitor of apoptosis protein associated factor-1 (XAF1)     promoter     transcription regulation    

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System dynamics analytical modeling approach for construction project management research: A critical review and future directions

Xiaoxiao XU, Patrick X. W. ZOU

《工程管理前沿（英文）》 2021年 第8卷 第1期   页码 17-31 doi: 10.1007/s42524-019-0091-7

摘要： Building and infrastructure construction projects can be viewed as a complex system consisting of many subsystems. Over the last two decades, considerable researches that use system dynamics (SD) as an analytical and modeling approach exist to address construction project management issues. However, only few critical reviews have been conducted to provide an in-depth understanding of SD application in construction project management. Moreover, many studies have failed to apply SD accurately. Therefore, the present study aims to gain an understanding of the current state of play and future directions in applying SD method in construction project management research, by undertaking a comprehensive review of 105 relevant articles published from 1994 to 2018. These articles are analyzed in terms of annual publication rate, key papers and their contribution, critical issues in SD application, and research topics. A significant increase in the number of publications in the last five years has been observed. When applying SD method to model construction system, the following aspects must be carefully considered: Model boundary, model development, model test, and model simulation. In addition, SD has been applied in a wide range of research topics, including (1) sustainable construction; (2) design error, rework, and change management; (3) risk management; (4) resource management; (5) decision making; (6) hybrid modeling; (7) safety management; (8) PPP project; and (9) organization performance. Based on the review findings, this study discusses three future research directions, namely, integration of SD with other methods, uncertainty analysis, and human factor analysis. This study can help researchers gain an in-depth understanding of the critical issues in the application of SD in construction management and the state-of-the-art of SD research.

关键词： system dynamics     construction management     problem and recommendation     research directions     literature review     human factor    

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Common biases in client involved decision-making in the AEC industry

Sujesh F. SUJAN, Arto KIVINIEMI, Steve W. JONES, Jacqueline M. WHEATHCROFT, Eilif HJELSETH

《工程管理前沿（英文）》 2019年 第6卷 第2期   页码 221-238 doi: 10.1007/s42524-019-0026-3

摘要： Understanding of the constitution of client involved decisions is important for future improvements of the processes. Significant decisions in construction projects are reliant on heuristic processes where assumptions are developed from past experience. The paper presents a methodology to collect empirical data in an unstructured manner utilizing participant intuition and experience regarding project level collaboration, a term easily understood by practitioners. Empirical data collected from 6 focus group discussions in Norway and 18 individual interviews in Finland is associated with biases in decision making aimed at bridging the gap of understanding and literature’s insufficient coverage. An analytic framework was developed to suit the diverse emergence of concepts to allow application of psychological principles in a structured manner to empirical data. The paper contributes by identifying types of cognitive and motivational biases in client involved decisions. The biases are found to be alleviated by one another depending on the particular application of the decision. Findings suggest that normative beliefs exist developed from past experience and habitual thinking. A number of emerged biases in this domain are alleviated from normative beliefs which are discussed in this paper.

关键词： collaboration     construction industry     social science     decision-making     client     cognitive bias     motivational bias     holistic analysis     human factor    

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Challenges of human–machine collaboration in risky decision-making

《工程管理前沿（英文）》 2022年 第9卷 第1期   页码 89-103 doi: 10.1007/s42524-021-0182-0

摘要： The purpose of this paper is to delineate the research challenges of human–machine collaboration in risky decision-making. Technological advances in machine intelligence have enabled a growing number of applications in human–machine collaborative decision-making. Therefore, it is desirable to achieve superior performance by fully leveraging human and machine capabilities. In risky decision-making, a human decision-maker is vulnerable to cognitive biases when judging the possible outcomes of a risky event, whereas a machine decision-maker cannot handle new and dynamic contexts with incomplete information well. We first summarize features of risky decision-making and possible biases of human decision-makers therein. Then, we argue the necessity and urgency of advancing human–machine collaboration in risky decision-making. Afterward, we review the literature on human–machine collaboration in a general decision context, from the perspectives of human–machine organization, relationship, and collaboration. Lastly, we propose challenges of enhancing human–machine communication and teamwork in risky decision-making, followed by future research avenues.

关键词： human–machine collaboration     risky decision-making     human–machine team and interaction     task allocation     human–machine relationship    

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Zooming in and out of ferroptosis in human disease

《医学前沿（英文）》 2023年 第17卷 第2期   页码 173-206 doi: 10.1007/s11684-023-0992-z

摘要： Ferroptosis is defined as an iron-dependent regulated form of cell death driven by lipid peroxidation. In the past decade, it has been implicated in the pathogenesis of various diseases that together involve almost every organ of the body, including various cancers, neurodegenerative diseases, cardiovascular diseases, lung diseases, liver diseases, kidney diseases, endocrine metabolic diseases, iron-overload-related diseases, orthopedic diseases and autoimmune diseases. Understanding the underlying molecular mechanisms of ferroptosis and its regulatory pathways could provide additional strategies for the management of these disease conditions. Indeed, there are an expanding number of studies suggesting that ferroptosis serves as a bona-fide target for the prevention and treatment of these diseases in relevant pre-clinical models. In this review, we summarize the progress in the research into ferroptosis and its regulatory mechanisms in human disease, while providing evidence in support of ferroptosis as a target for the treatment of these diseases. We also discuss our perspectives on the future directions in the targeting of ferroptosis in human disease.

关键词： ferroptosis     human disease     iron metabolism     lipid peroxidation     antioxidation    

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Tackling global electricity shortage through human power: Technical opportunities from direct or indirectutilizations of the pervasive and green human energy

Dan DAI, Jing LIU

《能源前沿（英文）》 2012年 第6卷 第3期   页码 210-226 doi: 10.1007/s11708-012-0200-3

摘要： With the energy and environmental problems becoming increasingly serious, human power, as a pervasive, renewable, mobile and environment friendly energy, draws more and more attention over the world. In this paper, the most basic features of human power are presented. The currently available human power harvesting theories and devices are briefly reviewed and compared. Further, direct or indirect utilization of human power in daily life, especially transportation and home appliances, such as human-powered car, watercraft, aircraft, washing machine and television etc. are summarized. Considering that the total energy from an individual is rather limited, as previously focused by most of the former works, it is conceived in this paper that an important future for large scale use of human powers lies in the efficient conversion, collection and storage of such energy from discrete people and then use it later on as desired. With the huge amount of energy gathered, the application category of human power would be significantly expended. Starting from this point, three technical ways towards efficiently utilizing human power are sketched, which are termed as human-powered grid (HPG), human-powered charger (HPC) and human-powered storage (HPS), among which, HPG is capable of collecting the electric power produced by each individual at different regions and thus can supply unique and flexible power to the customers covered in the area, without relying on the conventional electricity grid. The HPC can then charge various kinds of electrical devices instantly by a human driven generator which converts human power into electricity. Finally, the HPS can store electricity in time for later use. In this way, even for the devices requiring electricity that is strong enough, the collected human power can also serve as its reliable energy source. Meanwhile, utilization of human power becomes rather convenient and timely which guarantees its practical value. It is expected that with further research and increasing applications, human power could partially relieve the current global electricity shortage and environmental issues via its pervasive contribution.

关键词： human energy harvesting     human-powered transportation     human-powered home appliances     human-powered grid (HPG)     human-powered charger (HPC)     human-powered storage (HPS)     biofuel    

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Role of the forkhead transcription factor FOXO-FOXM1 axis in cancer and drug resistance

null

《医学前沿（英文）》 2012年 第6卷 第4期   页码 376-380 doi: 10.1007/s11684-012-0228-0

摘要：

The forkhead transcription factors FOXO and FOXM1 have pivotal roles in tumorigenesis and in mediating chemotherapy sensitivity and resistance. Recent research shows that the forkhead transcription factor FOXM1 is a direct transcriptional target repressed by the forkhead protein FOXO3a, a vital downstream effector of the PI3K-AKT-FOXO signaling pathway. Intriguingly, FOXM1 and FOXO3a also compete for binding to the same gene targets, which have a role in chemotherapeutic drug action and sensitivity. An understanding of the role and regulation of the FOXO-FOXM1 axis will impact directly on our knowledge of chemotherapeutic drug action and resistance in patients, and provide new insights into the design of novel therapeutic strategy and reliable biomarkers for prediction of drug sensitivity.

关键词： FOXO3a     FOXM1     transcription factor     cancer     drug resistance     tumorigenesis    

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Implantation of human umbilical cord mesenchymal stem cells for ischemic stroke: perspectives and challenges

null

《医学前沿（英文）》 2015年 第9卷 第1期   页码 20-29 doi: 10.1007/s11684-014-0371-x

摘要：

Ischemic stroke is a focal cerebral insult that often leads to many adverse neurological complications severely affecting the quality of life. The prevalence of stroke is increasing throughout the world, while the efficacy of current pharmacological therapies remains unclear. As a neuroregenerative therapy, the implantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) has shown great possibility to restore function after stroke. This review article provides an update role of hUC-MSCs implantation in the treatment of ischemic stroke. With the unique “immunosuppressive and immunoprivilege” property, hUC-MSCs are advised to be an important candidate for allogeneic cell treatment. Nevertheless, most of the treatments are still at primary stage and not clinically feasible at the current time. Several uncertain problems, such as culture conditions, allograft rejection, and potential tumorigenicity, are the choke points in this cellular therapy. More preclinical researches and clinical studies are needed before hUC-MSCs implantation can be used as a routinely applied clinical therapy.

关键词： cellular therapy     transplantation     human umbilical cord     mesenchymal stem cells     ischemic stroke    

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Immunological and virological characteristics of human immunodeficiency virus type 1 superinfection:

null

《医学前沿（英文）》 2017年 第11卷 第4期   页码 480-489 doi: 10.1007/s11684-017-0594-8

摘要：

Superinfection is frequently detected among individuals infected by human immunodeficiency virus type I (HIV-1). Superinfection occurs at similar frequencies at acute and chronic infection stages but less frequently than primary infection. This observation indicates that the immune responses elicited by natural HIV-1 infection may play a role in curb of superinfection; however, these responses are not sufficiently strong to completely prevent superinfection. Thus, a successful HIV-1 vaccine likely needs to induce more potent and broader immune responses than those elicited by primary infection. On the other hand, potent and broad neutralization responses are more often detected after superinfection than during monoinfection. This suggests that broadly neutralizing antibodies are more likely induced by sequential immunization of multiple different immunogens than with only one form of envelope glycoprotein immunogens. Understanding why the protection from superinfection by immunity induced by primary infection is insufficient and if superinfection can lead to cross-reactive immune responses will be highly informative for HIV-1 vaccine design.

关键词： human immunodeficiency virus type I     superinfection     incidence     immune response    

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An experimental analysis of human straight walking

Tao LI, Marco CECCARELLI

《机械工程前沿（英文）》 2013年 第8卷 第1期   页码 95-103 doi: 10.1007/s11465-013-0357-4

摘要：

In this paper, an experimental analysis of human straight walking has been presented. Experiments on human walking were carried out by using Cassino tracking system which is a passive cable-based measuring system. This system is adopted because it is capable of both pose and wrench measurements with fairly simple monitoring of operation. By using experimental results, trajectories of a human limb extremity and its posture have been analyzed; forces that are exerted against cables by the limb of a person under test have been measured by force sensors as well. Furthermore, by using experimental tests, modeling and characterization of the human straight walking gait have been proposed.

关键词： human locomotion     walking gait     characterization     humanoid robot     biped robot    

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标题 作者 时间 类型 操作

Optimized human factor IX expression cassettes for hepatic-directed gene therapy of hemophilia B

null

期刊论文

662 A/G gene variation in human tumor necrosis factor receptor superfamily, member 9 (TNFRSF9)

QU Yanchun, YANG Ze, SUN Liang, JI Linong

期刊论文

Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor

Wenjie Zhu, Binghe Xu

期刊论文

correction of hemorrhagic diathesis in hemophilia A mice by an AAV-delivered hybrid FVIII composed of the human

期刊论文

Effects of hypoxia inducible factor-1alpha siRNA on the invasion of human Hela cells and expression of

Bin YANG MS , Xianglin YUAN , Yanmei ZOU , Qingsong XI , Guoxian LONG , Qiang FU , Guangyuan HU MM ,

期刊论文

Cloning of human XAF1 gene promoter and assay of its transcription activity in a variety of cell lines

Qiong CHEN, Qing YU, Yuhu SONG, Peiyuan Li, Ying CHANG, Zhijun WANG, Lifeng LIU, Wei WU, Jusheng LIN

期刊论文

System dynamics analytical modeling approach for construction project management research: A critical review and future directions

Xiaoxiao XU, Patrick X. W. ZOU

期刊论文

Common biases in client involved decision-making in the AEC industry

Sujesh F. SUJAN, Arto KIVINIEMI, Steve W. JONES, Jacqueline M. WHEATHCROFT, Eilif HJELSETH

期刊论文

Challenges of human–machine collaboration in risky decision-making

期刊论文

Zooming in and out of ferroptosis in human disease

期刊论文

Tackling global electricity shortage through human power: Technical opportunities from direct or indirectutilizations of the pervasive and green human energy

Dan DAI, Jing LIU

期刊论文

Role of the forkhead transcription factor FOXO-FOXM1 axis in cancer and drug resistance

null

期刊论文

Implantation of human umbilical cord mesenchymal stem cells for ischemic stroke: perspectives and challenges

null

期刊论文

Immunological and virological characteristics of human immunodeficiency virus type 1 superinfection:

null

期刊论文

An experimental analysis of human straight walking

Tao LI, Marco CECCARELLI

期刊论文