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author:("Yang, chaohu")
1.  The myosin X motor is optimized for movement on actin bundles 
Nature Communications  2016;7:12456.
Myosin X has features not found in other myosins. Its structure must underlie its unique ability to generate filopodia, which are essential for neuritogenesis, wound healing, cancer metastasis and some pathogenic infections. By determining high-resolution structures of key components of this motor, and characterizing the in vitro behaviour of the native dimer, we identify the features that explain the myosin X dimer behaviour. Single-molecule studies demonstrate that a native myosin X dimer moves on actin bundles with higher velocities and takes larger steps than on single actin filaments. The largest steps on actin bundles are larger than previously reported for artificially dimerized myosin X constructs or any other myosin. Our model and kinetic data explain why these large steps and high velocities can only occur on bundled filaments. Thus, myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles.
Myosin X is a molecular motor unique in its ability to generate filopodia, but the mechanism explaining this behaviour is not known. Here, through a combination of structure, single-molecule assays and modelling the authors show that myosin X is optimized for transport along actin bundles.
doi:10.1038/ncomms12456
PMCID: PMC5025751  PMID: 27580874
2.  A smart temperature and magnetic-responsive gating carbon nanotube membrane for ion and protein transportation 
Scientific Reports  2016;6:32130.
Carbon nanotube (CNT) nanoporous membranes based on pre-aligned CNTs have superior nano-transportation properties in biological science. Herein, we report a smart temperature- and temperature-magnetic-responsive CNT nanoporous membrane (CNM) by grafting thermal-sensitive poly(N-isopropylacrylamide) (PNIPAM) and Fe3O4 nanoparticles (Fe3O4-NPs) on the open ends of pre-aligned CNTs with a diameter around 15 nm via surface-initiated atom transfer radical polymerization (SI-ATRP) method. The inner cavity of the modified CNTs in the membrane is designed to be the only path for ion and protein transportation, and its effective diameter with a variation from ~5.7 nm to ~12.4 nm can be reversible tuned by temperature and magnetic field. The PNIPAM modified CNM (PNIPAM-CNM) and PNIPAM magnetic nanoparticles modified CNM (PNIPAM-MAG-CNM) exhibit excellent temperature- or temperature-magnetic-responsive gating property to separate proteins of different sizes. The PNIPAM-CNMs and PNIPAM-MAG-CNMs have potential applications in making artificial cells, biosensors, bioseparation and purification filters.
doi:10.1038/srep32130
PMCID: PMC4989442  PMID: 27535103
3.  A Genetic Mechanism for Convergent Skin Lightening during Recent Human Evolution 
Molecular Biology and Evolution  2016;33(5):1177-1187.
Skin lightening among Eurasians is thought to have been a convergence occurring independently in Europe and East Asia as an adaptation to high latitude environments. Among Europeans, several genes responsible for such lightening have been found, but the information available for East Asians is much more limited. Here, a genome-wide comparison between dark-skinned Africans and Austro-Asiatic speaking aborigines and light-skinned northern Han Chinese identified the pigmentation gene OCA2, showing unusually deep allelic divergence between these groups. An amino acid substitution (His615Arg) of OCA2 prevalent in most East Asian populations—but absent in Africans and Europeans—was significantly associated with skin lightening among northern Han Chinese. Further transgenic and targeted gene modification analyses of zebrafish and mouse both exhibited the phenotypic effect of the OCA2 variant manifesting decreased melanin production. These results indicate that OCA2 plays an important role in the convergent skin lightening of East Asians during recent human evolution.
doi:10.1093/molbev/msw003
PMCID: PMC4839214  PMID: 26744415
OCA2; East Asians; skin lightening; pigmentation genes; adaptation; natural selection
4.  Y-chromosome diversity suggests southern origin and Paleolithic backwave migration of Austro-Asiatic speakers from eastern Asia to the Indian subcontinent 
Scientific Reports  2015;5:15486.
Analyses of an Asian-specific Y-chromosome lineage (O2a1-M95)—the dominant paternal lineage in Austro-Asiatic (AA) speaking populations, who are found on both sides of the Bay of Bengal—led to two competing hypothesis of this group’s geographic origin and migratory routes. One hypothesis posits the origin of the AA speakers in India and an eastward dispersal to Southeast Asia, while the other places an origin in Southeast Asia with westward dispersal to India. Here, we collected samples of AA-speaking populations from mainland Southeast Asia (MSEA) and southern China, and genotyped 16 Y-STRs of 343 males who belong to the O2a1-M95 lineage. Combining our samples with previous data, we analyzed both the Y-chromosome and mtDNA diversities. We generated a comprehensive picture of the O2a1-M95 lineage in Asia. We demonstrated that the O2a1-M95 lineage originated in the southern East Asia among the Daic-speaking populations ~20–40 thousand years ago and then dispersed southward to Southeast Asia after the Last Glacial Maximum before moving westward to the Indian subcontinent. This migration resulted in the current distribution of this Y-chromosome lineage in the AA-speaking populations. Further analysis of mtDNA diversity showed a different pattern, supporting a previously proposed sex-biased admixture of the AA-speaking populations in India.
doi:10.1038/srep15486
PMCID: PMC4611482  PMID: 26482917
5.  Myosin VI Must Dimerize and Deploy Its Unusual Lever Arm in Order to Perform Its Cellular Roles 
Cell reports  2014;8(5):1522-1532.
It is unclear if the reverse-direction myosin, myosin VI, functions as a monomer or dimer in cells and how it generates large movements on actin. We deleted a stable, single α-helix (SAH) domain that has been proposed to function as part of a lever arm to amplify movements, without impact on in vitro movement or in vivo functions. A myosin VI construct that used this SAH domain as part of its lever arm was able to take large steps in vitro, but did not rescue in vivo functions. It was necessary for myosin VI to internally dimerize, triggering unfolding of a three-helix bundle and calmodulin binding in order to step normally in vitro and rescue endocytosis and Golgi morphology in myosin VI-null fibroblasts. A model for myosin VI emerges in which cargo binding triggers dimerization and unfolds the three-helix bundle to create a lever arm essential for in vivo functions.
Graphical Abstract
doi:10.1016/j.celrep.2014.07.041
PMCID: PMC4476653  PMID: 25159143
unconventional myosin; processivity; calmodulin; single stable α-helix
6.  Optimization of 6-Heterocyclic-2-(1H-pyrazol-1-yl)-N-(pyridin-2-yl)pyrimidin-4-amine as Potent Adenosine A2A Receptor Antagonists for the Treatment of Parkinson’s Disease 
ACS Chemical Neuroscience  2014;5(8):674-682.
Parkinson’s disease is a neurodegenerative disease characterized by the motor symptoms of bradykinesia, tremor, and rigidity. Current therapies are based mainly on dopaminergic replacement strategies by administration of either dopamine agonists or dopamine precursor levodopa (L-Dopa). These treatments provide symptomatic relief without slowing or stopping the disease progression, and long-term usage of these drugs is associated with diminished efficacy, motor fluctuation, and dyskinisia. Unfortunately, there had been few novel treatments developed in the past decades. Among nondopaminergic strategies for the treatment of Parkinson’s disease, antagonism of the adenosine A2A receptor has emerged to show great potential. Here we report the optimization of a new chemical scaffold, which achieved exceptional receptor binding affinity and ligand efficiency against adenosine A2A receptor. The leading compounds demonstrated excellent efficacy in the haloperidol induced catalepsy model for Parkinson’s disease.
doi:10.1021/cn5000716
PMCID: PMC4140592  PMID: 24922583
Adenosine receptor; antagonist; GPCR; Parkinson’s disease; lead optimization
7.  An Updated Phylogeny of the Human Y-Chromosome Lineage O2a-M95 with Novel SNPs 
PLoS ONE  2014;9(6):e101020.
Though the Y-chromosome O2a-M95 lineage is one of the major haplogroups present in eastern Asian populations, especially among Austro-Asiatic speaking populations from Southwestern China and mainland Southeast Asia, to date its phylogeny lacks structure due to only one downstream SNP marker (M88) assigned to the lineage. A recent array-capture-based Y chromosome sequencing of Asian samples has yielded a variety of novel SNPs purportedly belonging to the O2a-M95 lineage, but their phylogenetic positions have yet to be determined. In this study, we sampled 646 unrelated males from 22 Austro-Asiatic speaking populations from Cambodia, Thailand and Southwestern China, and genotyped 12 SNP makers among the sampled populations, including 10 of the newly reported markers. Among the 646 males, 343 belonged to the O2a-M95 lineage, confirming the supposed dominance of this Y chromosome lineage in Austro-Asiatic speaking populations. We further characterized the phylogeny of O2a-M95 by defining 5 sub-branches: O2a1*-M95, O2a1a-F789, O2a1b*-F1252, O2a1b1*-M88 and O2a1b1a -F761. This updated phylogeny not only improves the resolution of this lineage, but also allows for greater tracing of the prehistory of human populations in eastern Asia and the Pacific, which may yield novel insights into the patterns of language diversification and population movement in these regions.
doi:10.1371/journal.pone.0101020
PMCID: PMC4074153  PMID: 24972021
8.  RNAi-mediated silencing of the Skp-2 gene causes inhibition of growth and induction of apoptosis in human renal carcinoma cells 
Renal cancer ranks one of the most frequent causes of cancer death in the world. S-phase kinase-associated protein 2 (SKP 2) is overexpressed in human tumors and has prognostic value in many cancers including renal cancer, indicating its potential as a therapeutic target. In this study, we investigated the therapeutic potential of Skp-2 in renal cancer using the technique of RNA silencing via short hairpin RNA (shRNA). Synthetic shRNA duplexes against Skp-2 were introduced to down-regulate the expression of Skp-2 in a highly malignant renal carcinoma cell line, ACHN. The results indicated that siRNA targeting of Skp-2 could lead to an efficient and specific inhibition of endogenous Skp-2 activity. Furthermore, we found that depletion of Skp-2 caused a dramatic cell cycle arrest, followed by massive apoptotic cell death, and eventually resulted in a significant decrease in growth, viability and tumor formation in renal cancer cell lines studied.
PMCID: PMC4128996  PMID: 25120761
Renal carcinoma; Skp-2; RNA silencing; cell cycle; apoptosis
9.  The expression and clinical significance of matrix metalloproteinase 7 and tissue inhibitor of matrix metalloproteinases 2 in clear cell renal cell carcinoma 
Renal cell carcinoma (RCC) is one of the most common malignant neoplasms in the urinary system, and has a high frequency of local invasion and distant metastasis. This study assessed the expression and clinical significance of matrix metalloproteinase 7 (MMP-7) and tissue inhibitor of matrix metalloproteinases 2 (TIMP-2) in human clear cell renal cell carcinoma (CCRCC) by tissue microarray, immunohistochemistry and RT-PCR analysis. The expression of MMP-7 in CCRCC tissues was significantly higher compared with that in the control group (CG) and TIMP-2 expression in CCRCC, by contrast, was lower compared with that in the CG. The expression of MMP-7 and TIMP-2 in the CCRCC tissues was significantly correlated with the pathological grade and clinical stage. Log-rank analyses indicated that upregulation of MMP-7 and downregulation of TIMP-2 expression may occur during the progression of CCRCC, and Cox multivariate survival rate analysis demonstrated that there was also a positive correlation between the pathological grade, clinical stage, MMP-7 expression and survival rate. Thus, MMP-7 is an independent prognostic factor and MMP-7 and TIMP-2 may serve as useful molecular markers for evaluating prognosis in CCRCC patients.
doi:10.3892/etm.2012.859
PMCID: PMC3570258  PMID: 23408109
clear cell renal cell carcinoma; matrix metalloproteinase 7; tissue inhibitor of matrix metalloproteinases 2; prognosis; tissue microarray
10.  Single Endemic Genotype of Measles Virus Continuously Circulating in China for at Least 16 Years 
PLoS ONE  2012;7(4):e34401.
The incidence of measles in China from 1991 to 2008 was reviewed, and the nucleotide sequences from 1507 measles viruses (MeV) isolated during 1993 to 2008 were phylogenetically analyzed. The results showed that measles epidemics peaked approximately every 3 to 5 years with the range of measles cases detected between 56,850 and 140,048 per year. The Chinese MeV strains represented three genotypes; 1501 H1, 1 H2 and 5 A. Genotype H1 was the predominant genotype throughout China continuously circulating for at least 16 years. Genotype H1 sequences could be divided into two distinct clusters, H1a and H1b. A 4.2% average nucleotide divergence was found between the H1a and H1b clusters, and the nucleotide sequence and predicted amino acid homologies of H1a viruses were 92.3%–100% and 84.7%–100%, H1b were 97.1%–100% and 95.3%–100%, respectively. Viruses from both clusters were distributed throughout China with no apparent geographic restriction and multiple co-circulating lineages were present in many provinces. Cluster H1a and H1b viruses were co-circulating during 1993 to 2005, while no H1b viruses were detected after 2005 and the transmission of that cluster has presumably been interrupted. Analysis of the nucleotide and predicted amino acid changes in the N proteins of H1a and H1b viruses showed no evidence of selective pressure. This study investigated the genotype and cluster distribution of MeV in China over a 16-year period to establish a genetic baseline before MeV elimination in Western Pacific Region (WPR). Continuous and extensive MeV surveillance and the ability to quickly identify imported cases of measles will become more critical as measles elimination goals are achieved in China in the near future. This is the first report that a single endemic genotype of measles virus has been found to be continuously circulating in one country for at least 16 years.
doi:10.1371/journal.pone.0034401
PMCID: PMC3332093  PMID: 22532829
11.  Retrospective seroepidemiology indicated that human enterovirus 71 and coxsackievirus A16 circulated wildly in central and southern China before large-scale outbreaks from 2008 
Virology Journal  2010;7:300.
Background
Large nationwide outbreaks of hand, foot, and mouth disease (HFMD) occurred in China from 2008; most of the cases were in children under 5 years. This study aims to identify the situation of natural human enterovirus 71 (HEV71) and coxsackievirus A16 (CVA16) infections in children before 2008 in China.
Results
Retrospective seroepidemiologic studies of HEV71 and CVA16 were performed with 900 serum samples collected from children ≤5 years of age in 2005. The samples were collected from 6 different geographical areas (Anhui, Guangdong, Hunan, Xinjiang, Yunnan, and Heilongjiang provinces) in mainland China. Of the 900 samples, 288 were positive for HEV71; the total positive rate was 32.0% and the geometric mean titer (GMT) was 1:8.5. Guangdong (43.7% and 1:10.8), Xinjiang (45.4% and 1:11.1), and Yunnan (43.4% and 1:12.0) provinces had relatively high rates of infection, while Heilongjiang province (8.1% and 1:4.9) had the lowest rate of infection. On the other hand, 390 samples were positive for CVA16; the total positive rate was 43.4% and the GMT was 1:9.5. Anhui (62.2% and 1:16.0) and Hunan (61.1% and 1:23.1) had relatively high rates, while Heilongjiang (8.0% and 1:4.6) had the lowest rate. Although there is a geographical difference in HEV71 and CVA16 infections, low neutralizing antibody positive rate and titer of both viruses were found in all 6 provinces.
Conclusions
This report confirmed that HEV71 and CVA16 had wildly circulated in a couple provinces in China before the large-scale outbreaks from 2008. This finding also suggests that public health measures to control the spread of HEV71 and CVA16 should be devised according to the different regional characteristics.
doi:10.1186/1743-422X-7-300
PMCID: PMC2989968  PMID: 21050463
12.  Genomic Analyses of Recombinant Adenovirus Type 11a in China▿  
Journal of Clinical Microbiology  2009;47(10):3082-3090.
Whole-genome sequencing of human adenovirus type 11 (HAdV-11) strain QS, isolated in China, was conducted, and its sequence was compared with the sequences of strains within the species of HAdVs. The HAdV-11 QS genome contains 34,755 nucleotides. Similar to the other HAdV subgenus B sequences, the HAdV-11 QS genome coded 37 functional proteins and could be divided into four early, two intermediate, and five late transcription regions. The amino acid sequences of the fiber and the hypervariable regions (HVRs) within the hexon gene of HAdV-11 QS were identical to the corresponding sequences of the HAdV-11a strain; further analyses that compared those amino acid sequences with the amino acid sequences of the HAdV species subgenus B:2 strains revealed that the highest degree of homology (>99.2%) existed between HAdV-11 QS and the prototypical HAdV-14 strain, except for a few coding sequences of HVRs within the hexon gene, DNA polymerase, pVI, and pre-terminal protein. This indicate that HAdV-11 strain QS, isolated in China, is a recombinant adenovirus of HAdV-14, and the recombination analyses also confirmed this finding. It is difficult to clarify the time and manner of the recombination, and further investigations are required to determine whether the emergence of recombination between HAdV-11a and HAdV-14 might increase virulence, thereby posing a new global challenge with regard to acute respiratory diseases in the near future.
doi:10.1128/JCM.00282-09
PMCID: PMC2756911  PMID: 19675212
13.  Outbreak of Acute Respiratory Disease in China Caused by B2 Species of Adenovirus Type 11▿  
Journal of Clinical Microbiology  2008;47(3):697-703.
An outbreak of acute respiratory tract infection occurred in Shanxi Province, China, from March to April 2006. Of the 254 patients affected by this outbreak, 247 patients were students of a senior high school; 1 of these patients died during the outbreak. Serological tests and blood culture revealed no evidence of bacterial infection. The results of direct reverse transcription-PCR or PCR performed with clinical specimens collected from the patients, including the sole patient who died, were positive for human adenoviruses (HAdVs) but negative for influenza virus, measles virus, rubella virus, mumps virus, parainfluenza virus, respiratory syncytial virus, and human enteroviruses. These findings were confirmed by enzyme-linked immunosorbent assay for HAdV immunoglobulin A, the conventional neutralization test, and viral isolation and identification. Sequencing of the entire hexon gene revealed that HdAV type 11a (HAdV-11a) belonging to the B2 species of HAdV was the etiological agent responsible for the outbreak. However, both the analysis of the phylogenetic relationship and the similarity plot indicated that the sequence of the 3′ end of the hexon gene outside the hypervariable regions the HAdV-11a strain isolated in this outbreak may be a recombinant with the sequence of the HAdV-14 strain of species B2. Although isolates of HAdV species B2 seldom cause respiratory infections, they may pose a new global challenge with regard to acute respiratory diseases; this possibility cannot be overlooked and should be carefully considered. Hence, the need to establish and improve both epidemiological and virological surveillance of HAdV infections in China should be emphasized.
doi:10.1128/JCM.01769-08
PMCID: PMC2650960  PMID: 19109466
14.  Association of bone morphogenetic protein-2 gene polymorphisms with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity in Chinese patients 
European Spine Journal  2008;17(7):956-964.
A case–control study was conducted to examine the association between two single nucleotide polymorphisms (SNPs) in exon 2 of the bone morphogenetic protein-2 gene (BMP-2) and ossification of the posterior longitudinal ligament (OPLL), and to investigate whether SNPs of the Ser37Ala (T/G) and the Ser87Ser (A/G) in the BMP-2 gene are associated with genetic susceptibility to OPLL and its severity in Chinese subjects. The Ser87Ser (A/G) SNP has been implicated in bone mineral density (BMD) and increases the risk of OA in women. The Ser37Ala (T/G) SNP is associated with BMD and the rate of bone loss in osteoporosis and osteoporosis fractures. A total of 57 OPLL patients and 135 non-OPLL controls were studied. Radiographs of the cervical spine were analyzed to determine the presence and the severity of OPLL. The association of two SNPs with the occurrence and the extent of OPLL were statistically evaluated. There was a significant association between the Ser37Ala (T/G) polymorphism and the occurrence of OPLL in the cervical spine. However, no significant association was found between the Ser37Ala (T/G) polymorphism and the more number of ossified cervical vertebrae in OPLL patients. There was a significant association between the Ser87Ser (A/G) polymorphism and the more number of ossified cervical vertebrae in OPLL patients. However, there was no statistical difference between the Ser87Ser (A/G) SNP and the occurrence of OPLL in the cervical spine. In addition, the Ser87Ser (A/G) polymorphism in male patients and in female patients showed no statistical difference between cases and controls. The present results demonstrate that BMP-2 Gene is not only a factor associated with the occurrence of OPLL, but also a factor related to more extensive OPLL. The “G” allele in the Ser37Ala (T/G) polymorphism is associated with the occurrence of OPLL, but not more extensive OPLL in the cervical spine. The “G” allele in the Ser87Ser (A/G) polymorphism promotes the extent of OPLL, whereas the “A” allele in the Ser87Ser (A/G) polymorphism restricts ectopic ossification in the cervical spine at least in Chinese subjects.
doi:10.1007/s00586-008-0651-8
PMCID: PMC2443260  PMID: 18389292
OPLL; BMP-2 gene; PCR; Polymorphism; Case–control study

Results 1-14 (14)