Department of Medical Genetics and Developmental Biology
The Department of Medical Genetics and Developmental Biology (MGDB) was established in 2012, originally as the Genetics Teaching and Research Section under the School of Basic Medical Sciences. In 2015, it underwent restructuring and expansion to form the current Department of Medical Genetics and Developmental Biology—an adjustment that reflects its broader academic focus and enhanced mission.
2. Staff Information of MGDB
The MGDB is chaired by Professor Haihong Ye. The department has 13 faculty members, all of whom hold doctoral degrees, including 3 professors (who also serve as doctoral supervisors), 8 associate professors, and 2 lecturers. Additionally, it is supported by 3 skilled laboratory technicians.
3. Departmental Teaching Activities, Including Course Offerings and Student Mentorship of MGDB
The MGDB provides a comprehensive portfolio of theoretical and practical courses tailored to undergraduate and graduate students in clinical medicine, basic medical sciences, and international students. Core courses include Medical Genetics, Medical Genetics B, Molecular Genetics, High-Throughput Sequencing, and Bioinformatics. Committed to continuous teaching innovation, the department has made significant strides in improving educational outcomes. It has also authored or compiled seven translated works and textbooks, with the English-language textbook Medical Genetics being a notable example.
4. Departmental research work, such as research directions, research projects, and paper publications.
Research directions
The department currently has three principal investigators (PIs) leading research programs in three key areas:
（1）Neurodevelopment and genetics
（2）Tumor genetics
（3）Tumor genetics and gene therapy
As an accredited degree-granting unit, the MGDB offers both doctoral and master’s programs in genetics. Over the past three years, it has enrolled 20 graduate students (12 master’s candidates and 8 doctoral candidates), with its alumni achieving a 100% post-graduation employment rate.
Research Achievements (2019–2024)
Competitive Grants: Led over 20 national and provincial-level projects, including the National Science and Technology Support Program, the National Natural Science Foundation of China, and the Beijing Municipal Natural Science Foundation.
（1）Research Funding: Secured a total of over ¥20 million RMB in research funding.
（2）Publications: Published 54 peer-reviewed articles in SCI-indexed journals.
（3）Intellectual Property: Filed 3 patent applications, 2 of which have been authorized.
ACADEMIC LEADER: PROFESSOR YE HAIHONG
Primary Research Focus: Developmental and Genetic Studies of Neurological and Psychiatric Disorders
The Ye Lab specializes in the developmental genetics of neurological and psychiatric disorders, with a focus on unraveling the genetic and molecular mechanisms underlying these conditions. Research has shown that abnormalities in neural development and function contribute significantly to various mental and neurological disorders, and genetic factors play a pivotal role in their pathogenesis.
The Ye Lab has made substantial contributions to understanding schizophrenia susceptibility genes (e.g., CHL1 and DISC1), clarifying a critical pathway that links neural adhesion molecules to the regulation of neurodevelopment-providing a neurodevelopmental framework for interpreting the etiology of schizophrenia. The team’s discovery that DSCAM deficiency induces severe congenital hydrocephalus in mouse models has established a valuable platform for studying disease mechanisms and developing therapeutic interventions.
Current research initiatives focus on 2–3 specific neuropsychiatric disorders (e.g., schizophrenia, congenital hydrocephalus, and autism spectrum disorders). Using both mouse genetic models and human genetic studies, the lab aims to identify novel disease-associated genes. These investigations explore the relationships between genetic variations, aberrant gene expression, epigenetic modifications, and disease phenotypes, with the ultimate goal of developing targeted therapeutic strategies.
The research group maintains strong clinical collaborations and leverages advanced high-throughput sequencing technologies to investigate disease mechanisms. A notable collaborative study with the Urology Department of Beijing Friendship Hospital revealed distinct clonal origins and evolutionary pathways in bilateral renal cell carcinomas—findings that not only provide clinical guidance for treatment but also establish novel research paradigms for studying bilateral organ pathologies. This multidisciplinary approach integrates fundamental genetic research with translational applications, bridging the gap between basic science and clinical practice.
The research team implemented a multidimensional bioinformatics analytical framework to systematically investigate the molecular mechanisms governing disease pathogenesis and progression. This integrated approach encompassed: (1) comprehensive analysis of high-throughput sequencing data sourced from public repositories; (2) systems-level integration of genomic, transcriptomic, and proteomic datasets; and (3) application of Mendelian randomization techniques utilizing genetic variants as instrumental variables to establish causal relationships between risk factors and disease phenotypes. This methodological framework significantly augments the mechanistic understanding of disease pathways while providing a robust, data-driven foundation for developing precision therapeutic interventions.
Recent Funded Research Projects
[1]2020.01 - 2023.12，Project Title: Mechanistic Study of NMDAR-FMRP Pathway in Regulating Schizophrenia-Related Endophenotypes in Animal Models
Funding Agency: NSFC General Program
Grant No.:31971116
PI: Ye haihong
[2]2020.01 - 2022.12
Project Title: Functional Role and Mechanisms of DISC1 in Neuronal Polarization
Funding Agency:Beijing Municipal Natural Science Foundation General Program
Grant No.: 5202005
PI: Ye haihong
[3] 2019.01 - 2022.12
Project Title: Pentamembrane Coupling of T-Tubule-Sarcoplasmic Reticulum-Mitochondria and the Excitation-Calcium-Metabolic Axis in Cardiomyocytes
Funding Agency: NSFC Major Program
Grant No.:91854209
Participant: Ye haihong
[4]2019.01 - 2021.12
Project Title: Mechanistic Study of CNTN6 in Autism Spectrum Disorder Pathogenesis via Regulation of Inhibitory Interneuron Development
Funding Agency: NSFC Youth Program
Grant No.:31801208
PI: Xu Yiliang
[5]2016.01 - 2017.12
Project Title:Pathogenic Mechanisms of Congenital Hydrocephalus Caused by DSCAM Deficiency
Funding Agency: NSFC General Program
Grant No.: 31571486
PI: Ye haihong
Publications in the Last Five Years
[1] Ren J, Xu Y, Yuan L, Liu Y, Chu Q, Zhao T, Zhang W, Tian J, Wang SQ#, Ye H#. Dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons via GSK3β. Sci China Life Sci, 2025 (Accepted)
[2] Xue L, Zhao J, Liu X, Zhao T, Zhang Y, Ye H#. MK-801-exposure induces increased translation efficiency and mRNA hyperacetylation of Grin2a in the mouse prefrontal cortex. Epigenetics. 2024 Dec;19(1):2417158.
[3] Zhang W, Huang H, Gui A, Mu D, Zhao T, Li H, Watanabe K, Xiao Z, Ye H#, Xu Y#. Contactin-6-deficient male mice exhibit the abnormal function of the accessory olfactory system and impaired reproductive behavior. Brain Behav. 2023 Apr;13(4):e2893.
[4] Liu X, Zhao J, Xue L, Zhao T, Ding W, Han Y, Ye H#. A comparison of transcriptome analysis methods with reference genome. BMC Genomics. 2022 Mar 25;23(1):232.
[5] Sun A, Qian D, Wang Z, Xu Y, Ye H#, Fang C#, Yan C. Protective effect of lipoic acid modification on brain dysfunctions of mice induced by mesoporous silica nanoparticles. Chemical Engineering Journal. 2021 Feb 415: 1289573.
[6] Han Y, Liu X, Ye H#, Tian Y#, Ji Z#. Lower mutant-allele tumor heterogeneity is a biomarker in FGFR3-mutant bladder cancer for better prognosis. World J Surg Oncol. 2020 Nov 26;18(1):310.
[7] Yang L, Li RC, Xiang B, Li YC, Wang LP, Guo YB, Liang JH, Wang XT, Hou T, Xing X, Zhou ZQ, Ye H, Feng RQ, Lakatta EG, Chai Z, Wang SQ#. Transcriptional regulation of intermolecular Ca2+ signaling in hibernating ground squirrel cardiomyocytes: The myocardin-junctophilin axis. Proc Natl Acad Sci U S A. 2021 Apr 6;118(14):e2025333118.
[8] Li LL, Guo QJ, Lou HY, Liang JH, Yang Y, Xing X, Li HT, Han J, Shen S, Li H, Ye H, Di Wu H, Cui B#, Wang SQ#. Nanobar Array Assay Revealed Complementary Roles of BIN1 Splice Isoforms in Cardiac T-Tubule Morphogenesis. Nano Lett. 2020 Sep 9;20(9):6387-6395.
ACADEMIC LEADER: PROFESSOR DU XIAOYANG
1. Discovery therapeutic targets for multiple diseases
In this field, we focus on finding new therapeutic targets for cancer, diabetes, atherosclerosis, and heart failure, as well as the genetic molecular mechanism of these diseases. (1) Epigenetic regulation in the development and multidrug resistance of small cell lung cancer (SCLC): Integrating cellular models, animal models, and multi-omics data to elucidate the epigenetic regulatory networks underlying in SCLC progression and multidrug resistance, identifying diagnostic biomarkers, and developing novel combination therapeutic strategies targeting key nodes to improve the prognosis of SCLC patients. (2) Molecular mechanisms of Helicobacter pylori (Hp) inducing gastric cancer and new target: Establishing long-term Hp infection animal and cell models to clarify the molecular mechanisms of gastric carcinogenesis and immune tolerance induced by Hp and its lysates. Furthermore, using metagenomic profiling to decipher the Hp–host–microbiota interaction network, identify key molecular targets, and propose new strategies for gastric cancer intervention. (3) Establishment of multiple metabolic animal models and develop new therapeutic targets: After breeding an inbred strain of spontaneously diabetic Mongolian gerbils, we discovered multiple new genes related diabetes, in which skeletal muscle eEF1A2 exacerbates a promising therapeutic value in diabetes and heart‑failure models we established by ourselves. We also found a novel epigenetic target and its clinical inhibitor of atherosclerosis.
2. Genetic Detection
In this field, we focus on two points: (1) Genomic stability: We conduct rigorous longitudinal studies to evaluate the genomic stability of CRISPR/Cas9-edited animals including CRISPR-edited mice (representing fundamental research models) and genetically engineered pigs designed for xenotransplantation (addressing critical safety concerns for clinical translation). (2) Genetic monitoring: We develop and implement high-throughput, multiplexed liquid chip-based genotyping platforms. These platforms utilize custom panels of SNP and microhaplotype markers to establish robust genetic monitoring systems across diverse laboratory species including mice, rats, Mongolian gerbils, miniature pigs, Chinese hamsters, and non-human primates.
Recent Funded Research Projects
[1] National Key R&D Program (2022-2026), Project Title: Study on Cerebral Ischemia-Reperfusion Injury and Establishment of Two Type 2 Diabetes Models in Inbred Mongolian Gerbils, along with Key Technological Research，Principal Investigator: Du Xiaoyan
[2] Natural Science Foundation of China (2022-2025), Project Title: Directed Breeding of Spontaneously Diabetic Mongolian Gerbil Obese and Non-obese Substrains and Molecular Mechanisms Targeting Adipose Tissue, Principal Investigator: Du Xiaoyan
[4] Natural Science Foundation of China (2020-2023), Project Title: Effects of CRISPR Gene Editing Technology on Genome Stability in Homologous Embryo Gene Knockout Mice Derived from Embryo Splitting, Principal Investigator: Du Xiaoyan
[5] Natural Science Foundation of China (Regional Joint Program, 2022-2026), Project Title: Establishment of a Spontaneous Type 2 Diabetes Animal Model in Chinese Hamsters and Functional Study of Key Genes, Principal Investigator: Chen Zhenwen
[6] Natural Science Foundation of China (2021-2024), Project Title: Establishment of Cerebral Ischemia/Reperfusion Neural Injury Model System in Mongolian gerbil, and Neuroprotective Effects and Molecular Mechanisms of Cystatin C, Principal Investigator: Chen Zhenwen
[7] National Key R&D Program for Youth (2021-2024), Project Title: Establishing Genetic Quality Assessment System for Common Laboratory Animals in China Based on SNP Technology, Task Leader: Huo Xueyun
[8] Natural Science Foundation of China (2018-2022), Project Title: Mechanism of Nedd4 Improving Insulin Sensitivity in Diabetic Skeletal Muscle through Ubiquitination of eEF1A2 in Mongolian Gerbils, Principal Investigator: Guo Meng
[9] Natural Science Foundation of China (2023-2026), Project Title: Establishment and Mechanism Study of Heart Failure Disease Model System in eEF1A2 Knockout Mice, Principal Investigator: Guo Meng
[10] Beijing Natural Science Foundation (2024-2026), Project Title: Genetic Quality Monitoring of Inbred and Closed Colony Mice Based on Microhaplotype, Principal Investigator: Lü Jianyi
[11] National Key Research and Development Program (2022-2026), Project Title: Research on Quality Assessment Technical Standards for Genetic Editing, SPF-level and Germ-free Experimental Animals, Principal Investigator: Li Changlong
[12] Natural Science Foundation of China (2021-2024), Project Title: Genetic Variations of Helicobacter pylori in Long-term Infected Mongolian Gerbils and Their Effects on Gastric Microbial Populations and Pathological Changes, Principal Investigator: Li Changlong
[13] National Key Research and Development Program (2021-2024), Project Title: Research on Quality Control of Experimental Animal Breeding, Husbandry, and Transportation, Task Leader: Liu Xin
Publications in the Last Five Years
[1] Sun M, Guo Y, Ren Z, Song A, Lu J, Li C, Lv J, Guo M, Liu X, Du X, Chen Z, Song G, He Y, Chen Z, Huo X. Development of a single-nucleotide polymorphism panel genotyping system for genetic analysis of Chinese hamsters. Animal Model Exp Med. 2025 May;8(5):916-921.
[2] Li S, Lv J, Li Z, Zhang Q, Lu J, Huo X, Guo M, Liu X, Li C, Wang J, Shi H, Deng L, Chen Z, Du X. Overcoming multi-drug resistance in SCLC: a synergistic approach with venetoclax and hydroxychloroquine targeting the lncRNA LYPLAL1-DT/BCL2/BECN1 pathway. Mol Cancer. 2024 Oct 31;23(1):243.
[3] Zhang X, He Y, Zhang X, Fu B, Song Z, Wang L, Fu R, Lu X, Xing J, Lv J, Guo M, Huo X, Liu X, Lu J, Du X, Ge Z, Chen Z, Li C. Sustained exposure to Helicobacter pylori induces immune tolerance by desensitizing TLR6. Gastric Cancer. 2024 27(2):324-342.
[4] He Y, Zhang X, Zhang X, Fu B, Xing J, Fu R, Lv J, Guo M, Huo X, Liu X, Lu J, Cao L, Du X, Ge Z, Chen Z, Lu X, Li C. Hypoxia exacerbates the malignant transformation of gastric epithelial cells induced by long-term H. pylori infection. Microbiol. Spectr. 2024 12(8):e0031124.
[5] Fang H, Li X, Lv J, Huo X, Guo M, Liu X, Li C, Chen Z, Du X. Adipocytokines and Inflammation in Patients and a Gerbil Model: Implications for Obesity-Related and Nonobese Diabetes. Journal of Diabetes Research, 2024:9683512.
[6] Li S, Lv J, Zhang X, Zhang Q, Li Z, Lu J, Huo X, Guo M, Liu X, Gao R, Gong J, Li C, Li W, Zhang T, Wang J, Chen Z, Du X. ELAVL4 promotes the tumorigenesis of small cell lung cancer by stabilizing LncRNA LYPLAL1-DT and enhancing profilin 2 activation. FASEB J. 2023 Oct;37(10):e23170.
[7] Lv J, Liu Y, Cui J, Fang H, Wu Y, Zhu X, Guo M, Li C, Dou J, Chen Z, Du X. Profile Screening of Differentially Expressed lncRNAs of Circulating Leukocytes in Type 2 Diabetes Patients and Differences From Type 1 Diabete. Front En docrinol (Lausanne), 2022, Jan 10;12:69055.
[8] Li S, Mao Q, Zhang Z, Wang Y, Chen D, Chen Z, Lv J. Identification of a five-gene panel to assess prognosis for gastric cancer. Biomed Res Int. 2022 Feb 9; 2022:5593619.
[9] Huo X, Zhang W, Zhao G, Chen Z, Dong P, Watari H, Narayana R, Tillmanns T, Pfeffer L, Yue J. FAK PROTAC inhibits ovarian tumor growth and metastasis by disrupting kinase dependent and independent pathways. Frontiers in Oncology. 28 April 2022.
[10] Li Z, Huo X, Chen K, Yang F, Tan W, Zhang Q, Yu H, Li C, Zhou D, Chen H, Zhao B, Wang Y, Chen Z, Du X. Profilin 2 and Endothelial Exosomal Profilin 2 Promote Angiogenesis and Myocardial Infarction Repair in Mice. Frontiers in Cardiovascular Medicine.2022 Apr 11;9:781753.
[11] Ma K, Li S, Huo X, Guo M, Du X, Li C, Liu X, Lv J, Chen Z. Exploring the mechanism of cisplatin resistance by transcriptome sequencing and reversing the chemoresistance by autophagy inhibition in small cell lung cancer, Biochem Biophys Res Commun, 2020, 533(3): 474-480.
[12] Guo Y, Cui Y, Sun M, Zhu X, Zhang Y, Lu J, Li C, Lv J, Guo M, Liu X, Chen Z, Du X, Huo X. Establishment and Application of a Novel Genetic Detection Panel for SNPs in Mongolian Gerbils. Genes (Basel). 2024 Jun 20;15(6):817.
[13] Wang Y, Zhao P, Song Z, Du X, Huo X, Lu J, Liu X, Lv J, Li C, Guo M, Chen Z. Generation of Gene-Knockout Mongolian Gerbils via CRISPR/Cas9 System, Front. Bioeng. Biotechnol., 2020, 8:780.
[14] Guo M, Li Y, Wang Y, Li X, Zhao P, Li C, Lv J, Liu X, Du X, Chen Z. Translation elongation factor eEF1A2 impairs insulin action in insulin-resistant skeletal muscle via PKC β & ER stress. J. Endocrinol., 2020, 244: 25-40.
ACADEMIC LEADER: Professor Ding Wei
Professor Ding Wei’s laboratory is dedicated to advancing gene therapy, with a particular emphasis on the genetic engineering, infection mechanisms, targeting properties, and immune responses of adeno-associated virus (AAV) vectors, aiming to enhance their efficiency and safety. Additionally, the lab investigates the stability and targeting of small nucleic acid delivery systems. Recently, the lab has expanded its scope into medical genetics, employing systems biology to integrate multi-omics data, elucidate the mechanisms of single-gene diseases and complex diseases, construct bioinformatics models, and identify novel biomarkers and therapeutic targets.
The core research areas of the laboratory are as follows: （1）Genetic engineering of recombinant adeno-associated virus (AAV) vectors, including their infection mechanisms, targeting characteristics, and immune responses. （2）Tumor cell invasion behavior, drug sensitivity, and epigenetic regulatory mechanisms. (3) Identification of molecular markers for genetic diseases and related mechanism studies, as well as the exploration of constructing artificial intelligence-assisted diagnostic models for congenital heart disease. Furthermore, the laboratory has extended its research direction to the systems biology of complex genetic diseases. Through high-throughput multi-omics and epigenetic analyses, the lab explores gene therapy intervention strategies and develops diagnostic and therapeutic approaches for complex diseases.
Recent Funded Research Projects
[1] 202101-202412, Mechanism of osteopontin splicing isoforms on the remodeling of tumor microenvironmental secretory signals and its role on the chemosensitivity in colorectal cancers, National Natural Science Foundation of China, General Program, Grant No. 82073215, Principal Investigator: Cheng Shan.
[2] 202201-202412, Study of endoplasmic reticulum stress on AAV-mediated RNAi gene therapy in Huntington's disease and methodology for specificity improvement of targeting molecules, Beijing Natural Science Foundation, General Program, Grant No. 7222001, Principal Investigator: Ding Wei.
[3] 202501-202812, The mechanism of CRKL gene copy number variation in the development of congenital heart disease, National Natural Science Foundation of China, General Program, Grant No. 82470313, Principal Investigator: Jing Wang.
Publications in the Last Five Years
[1] Xiaowei Sha, Jiaqian Li, Yunlong Fang, Jingjie Feng, Yasong Feng, Jing Wang Yang Si, Feng Li, Shan Cheng#, Wei Ding. Enhanced tumor suppression in patient-derived temozolomide-resistant glioblastoma cells using a combination treatment of Olaparib and FK866. BMC Cancer. 2025; 25(1):1174.
[2] Zicheng Ge, Jing Wang, Libing He, Meng Zhao, Yang Si, Siyuan Chang, Guoyan Zhang, Shan Cheng#, Wei Ding. Reconstruction of cancer marker analysis with holistic anatomical precision implicates heterogeneity development during breast tumor progression. Discov Oncol. 2024, 15(1):564.
[3] Qingfang Zhao*, Chenguang Zhang*#3, Xialu Zhang, Shanshan Wang, Ting Guo, Yuzhe Yin, Hui Zhang, Zhuo Li, Yang Si, Yabin Lu, Shan Cheng, Wei Ding#. ZNF281 inhibits mitochondrial biogenesis to facilitate metastasis of hepatocellular carcinoma. Cell Death Discov. 2023, 9(1):396.
[4] Xialu Zhang *, Chenguang Zhang *#, Qingfang Zhao, Shanshan Wang, Liyong Wang, Yang Si, Qiang Su, Shan Cheng, Wei Ding#. Inhibition of Annexin A10 Contributes to ZNF281 Mediated Aggressiveness of Hepatocellular Carcinoma. J Hepatocell Carcinoma, 2023, 10:553-571.
[5] Huan Niu, Meng Zhao, Jing Huang, Jing Wang, Yang Si, Shan Cheng#, Wei Ding. UHMK1-dependent phosphorylation of Cajal body protein coilin alters 5-FU sensitivity in colon cancer cells. Cell Commun Signal, 2022, 20(1):18. IF:6.153
[6] Mengtian Cui, Qingfang Zhao, Jing Wang, Yang Si, Shan Cheng#, Wei Ding#. ATF6-mediated unfolded protein response facilitates AAV2 transduction by releasing the suppression of AAV receptor on ER stress. J Virol, 2022, 96(3): e0110321. IF: 5.078
[7] Jing Wang*; Wanqing Xie*; Mingmei Cheng; Qun Wu; Fangyun Wang; Pei Li; Bo Fan; Xin Zhang#; Binbin Wang#; Xiongchang Liu#; Assessment of Transcatheter or Surgical Closure of Atrial Septal Defect using Interpretable Deep Keypoint Stadiometry, Research, 2022, 2022: 1-10
[8] Jing Huang, Mu Hu, Huan Niu, Jing Wang, Yang Si, Shan Cheng#, Wei Ding#. Osteopontin isoform c promotes the survival of cisplatin-treated NSCLC cells involving NFATc2-mediated suppression on calcium-induced ROS levels. BMC Cancer, 2021, 21(1):750. IF:4.372
[9] Jing Niu, Rui-Qi Gao, Meng-Tian Cui, Chen-Guang Zhang, Shen-Tao Li, Shan Cheng#, Wei Ding#. Suppression of TCAB1 expression induced cellular senescence by lessening proteasomal degradation of p21 in cancer cells. Cancer Cell Int, 2021, 21(1): 26. IF: 5.45
[10] Jing Wang*; Xiaofeng Liu*; Fangyun Wang; Lin Zheng; Fengqiao Gao; Hanwen Zhang; Xin Zhang#; Wanqing Xie#; Binbin Wang#; Automated interpretation of congenital heart disease from multi-view echocardiograms, Medical Image Analysis, 2021, 69:101942. doi:10.1016/j.media.2020.101942
[11] 1Siyuan Chang, Jing Huang, Huan Niu, Jing Wang, Yang Si, Zhigang Bai, Shan Cheng #, Wei Ding. Epigenetic regulation of osteopontin splicing isoform c defines its role as a microenvironmental factor to promote the survival of colon cancer cells from 5‑FU treatment. Cancer Cell Int, 2020, 20:452.
[12] Fenglian Yang*; Mu Hu*; Siyuan Chang, Jing Huang, Yang Si, Jinghui Wang, Shan Cheng#, Wenguo Jiang. Alteration in the sensitivity to crizotinib by Na+/H+ exchanger regulatory factor 1 is dependent to its subcellular localization in ALK-positive lung cancers, BMC Cancer, 2020, 20(1):202.
[13] Ran Zhang*, Lin Cao*, Mengtian Cui*, Zixian Sun, Mingxu Hu, Rouxuan Zhang, William Stuart, Xiaochu Zhao, Zirui Yang, Xueming Li, Yuna Sun, Shentao Li, Wei Ding#, Zhiyong Lou#, Zihe Rao. Adeno-associated virus 2 bound to its cellular receptor AAVR. Nat Microbiol, 2019, 4(4):675-682.