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1.  The Genomes of Oryza sativa: A History of Duplications 
Yu, Jun | Wang, Jun | Lin, Wei | Li, Songgang | Li, Heng | Zhou, Jun | Ni, Peixiang | Dong, Wei | Hu, Songnian | Zeng, Changqing | Zhang, Jianguo | Zhang, Yong | Li, Ruiqiang | Xu, Zuyuan | Li, Shengting | Li, Xianran | Zheng, Hongkun | Cong, Lijuan | Lin, Liang | Yin, Jianning | Geng, Jianing | Li, Guangyuan | Shi, Jianping | Liu, Juan | Lv, Hong | Li, Jun | Wang, Jing | Deng, Yajun | Ran, Longhua | Shi, Xiaoli | Wang, Xiyin | Wu, Qingfa | Li, Changfeng | Ren, Xiaoyu | Wang, Jingqiang | Wang, Xiaoling | Li, Dawei | Liu, Dongyuan | Zhang, Xiaowei | Ji, Zhendong | Zhao, Wenming | Sun, Yongqiao | Zhang, Zhenpeng | Bao, Jingyue | Han, Yujun | Dong, Lingli | Ji, Jia | Chen, Peng | Wu, Shuming | Liu, Jinsong | Xiao, Ying | Bu, Dongbo | Tan, Jianlong | Yang, Li | Ye, Chen | Zhang, Jingfen | Xu, Jingyi | Zhou, Yan | Yu, Yingpu | Zhang, Bing | Zhuang, Shulin | Wei, Haibin | Liu, Bin | Lei, Meng | Yu, Hong | Li, Yuanzhe | Xu, Hao | Wei, Shulin | He, Ximiao | Fang, Lijun | Zhang, Zengjin | Zhang, Yunze | Huang, Xiangang | Su, Zhixi | Tong, Wei | Li, Jinhong | Tong, Zongzhong | Li, Shuangli | Ye, Jia | Wang, Lishun | Fang, Lin | Lei, Tingting | Chen, Chen | Chen, Huan | Xu, Zhao | Li, Haihong | Huang, Haiyan | Zhang, Feng | Xu, Huayong | Li, Na | Zhao, Caifeng | Li, Shuting | Dong, Lijun | Huang, Yanqing | Li, Long | Xi, Yan | Qi, Qiuhui | Li, Wenjie | Zhang, Bo | Hu, Wei | Zhang, Yanling | Tian, Xiangjun | Jiao, Yongzhi | Liang, Xiaohu | Jin, Jiao | Gao, Lei | Zheng, Weimou | Hao, Bailin | Liu, Siqi | Wang, Wen | Yuan, Longping | Cao, Mengliang | McDermott, Jason | Samudrala, Ram | Wang, Jian | Wong, Gane Ka-Shu | Yang, Huanming
PLoS Biology  2005;3(2):e38.
We report improved whole-genome shotgun sequences for the genomes of indica and japonica rice, both with multimegabase contiguity, or almost 1,000-fold improvement over the drafts of 2002. Tested against a nonredundant collection of 19,079 full-length cDNAs, 97.7% of the genes are aligned, without fragmentation, to the mapped super-scaffolds of one or the other genome. We introduce a gene identification procedure for plants that does not rely on similarity to known genes to remove erroneous predictions resulting from transposable elements. Using the available EST data to adjust for residual errors in the predictions, the estimated gene count is at least 38,000–40,000. Only 2%–3% of the genes are unique to any one subspecies, comparable to the amount of sequence that might still be missing. Despite this lack of variation in gene content, there is enormous variation in the intergenic regions. At least a quarter of the two sequences could not be aligned, and where they could be aligned, single nucleotide polymorphism (SNP) rates varied from as little as 3.0 SNP/kb in the coding regions to 27.6 SNP/kb in the transposable elements. A more inclusive new approach for analyzing duplication history is introduced here. It reveals an ancient whole-genome duplication, a recent segmental duplication on Chromosomes 11 and 12, and massive ongoing individual gene duplications. We find 18 distinct pairs of duplicated segments that cover 65.7% of the genome; 17 of these pairs date back to a common time before the divergence of the grasses. More important, ongoing individual gene duplications provide a never-ending source of raw material for gene genesis and are major contributors to the differences between members of the grass family.
Comparative genome sequencing of indica and japonica rice reveals that duplication of genes and genomic regions has played a major part in the evolution of grass genomes
doi:10.1371/journal.pbio.0030038
PMCID: PMC546038  PMID: 15685292
3.  Cardioprotective effects of peroxisome proliferator activated receptor γ activators on acute myocarditis: anti-inflammatory actions associated with nuclear factor κB blockade 
Heart  2005;91(9):1203-1208.
Objective: To test the hypothesis that activation of peroxisome proliferator activated receptor γ (PPAR-γ) reduces experimental autoimmune myocarditis (EAM) associated with inhibitor κB (IκB) α induction, blockade of nuclear factor κB (NF-κB), and inhibition of inflammatory cytokine expression.
Methods: EAM was induced in Lewis rats by immunisation with porcine cardiac myosin. PPAR-γ activators 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and pioglitazone (PIO) were administered to rats with EAM.
Results: Enhanced PPAR-γ expression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. Administration of 15d-PGJ2 and PIO greatly reduced the severity of myocarditis and suppressed myocardial mRNA and protein expression of inflammatory cytokines in rats with EAM. In addition, treatment with PPAR-γ activators enhanced IκB concentrations in the cytoplasmic fractions and nuclear fractions from inflammatory myocardium. Concurrently, NF-κB was greatly activated in myocarditis; this activation was blocked in the 15d-PGJ2 treated and PIO treated groups.
Conclusions: PPAR-γ may have a role in the pathophysiology of EAM. Because an increase in IκB expression and inhibition of translocation of the NF-κB subunit p65 to the nucleus in inflammatory cells correlated with the protective effects of PPAR-γ activators, these results suggest that PPAR-γ activators act sequentially through PPAR-γ activation, IκB induction, blockade of NF-κB activation, and inhibition of inflammatory cytokine expression. These results suggest that PPAR-γ activators such as 15d-PGJ2 and PIO may have the potential to modulate human inflammatory heart diseases such as myocarditis.
doi:10.1136/hrt.2004.046292
PMCID: PMC1769084  PMID: 15774612
myocarditis; immunity; PPAR-γ; NF-κB; cytokine; inflammation
4.  SARS-CoV Infection in a Restaurant from Palm Civet 
Emerging Infectious Diseases  2005;11(12):1860-1865.
Contact with food animals was associated with SARS-CoV infection in the People’s Republic of China.
Epidemiologic investigations showed that 2 of 4 patients with severe acute respiratory syndrome (SARS) identified in the winter of 2003–2004 were a waitress at a restaurant in Guangzhou, China, that served palm civets as food and a customer who ate in the restaurant a short distance from animal cages. All 6 palm civets at the restaurant were positive for SARS-associated coronavirus (SARS-CoV). Partial spike (S) gene sequences of SARS-CoV from the 2 patients were identical to 4 of 5 S gene viral sequences from palm civets. Phylogenetic analysis showed that SARS-CoV from palm civets in the restaurant was most closely related to animal isolates. SARS cases at the restaurant were the result of recent interspecies transfer from the putative palm civet reservoir, and not the result of continued circulation of SARS-CoV in the human population.
doi:10.3201/eid1112.041293
PMCID: PMC3367621  PMID: 16485471
Severe acute respiratory syndrome; coronavirus; palm civet; research
5.  Human Bex2 interacts with LMO2 and regulates the transcriptional activity of a novel DNA-binding complex 
Nucleic Acids Research  2005;33(20):6555-6565.
Human Bex2 (brain expressed X-linked, hBex2) is highly expressed in the embryonic brain, but its function remains unknown. We have identified that LMO2, a LIM-domain containing transcriptional factor, specifically interacts with hBex2 but not with mouse Bex1 and Bex2. The interaction was confirmed both by pull-down with GST-hBex2 and by coimmunoprecipitation assays in vivo. Using electrophoretic mobility shift assay, we have demonstrated the physical interaction of hBex2 and LMO2 as part of a DNA-binding protein complex. We have also shown that hBex2 can enhance the transcriptional activity of LMO2 in vivo. Furthermore, using mammalian two-hybrid analysis, we have identified a neuronal bHLH protein, NSCL2, as a novel binding partner for LMO2. We then showed that LMO2 could up-regulate NSCL2-dependent transcriptional activity, and hBex2 augmented this effect. Thus, hBex2 may act as a specific regulator during embryonic development by modulating the transcriptional activity of a novel E-box sequence-binding complex that contains hBex2, LMO2, NSCL2 and LDB1.
doi:10.1093/nar/gki964
PMCID: PMC1298925  PMID: 16314316
6.  The Genome of Salmonella enterica Serovar Gallinarum: Distinct Insertions/Deletions and Rare Rearrangements 
Journal of Bacteriology  2005;187(14):4720-4727.
Salmonella enterica serovar Gallinarum is a fowl-adapted pathogen, causing typhoid fever in chickens. It has the same antigenic formula (1,9,12:—:—) as S. enterica serovar Pullorum, which is also adapted to fowl but causes pullorum disease (diarrhea). The close relatedness but distinct pathogeneses make this pair of fowl pathogens good models for studies of bacterial genomic evolution and the way these organisms acquired pathogenicity. To locate and characterize the genomic differences between serovar Gallinarum and other salmonellae, we constructed a physical map of serovar Gallinarum strain SARB21 by using I-CeuI, XbaI, and AvrII with pulsed-field gel electrophoresis techniques. In the 4,740-kb genome, we located two insertions and six deletions relative to the genome of S. enterica serovar Typhimurium LT2, which we used as a reference Salmonella genome. Four of the genomic regions with reduced lengths corresponded to the four prophages in the genome of serovar Typhimurium LT2, and the others contained several smaller deletions relative to serovar Typhimurium LT2, including regions containing srfJ, std, and stj and gene clusters encoding a type I restriction system in serovar Typhimurium LT2. The map also revealed some rare rearrangements, including two inversions and several translocations. Further characterization of these insertions, deletions, and rearrangements will provide new insights into the molecular basis for the specific host-pathogen interactions and mechanisms of genomic evolution to create a new pathogen.
doi:10.1128/JB.187.14.4720-4727.2005
PMCID: PMC1169526  PMID: 15995186
7.  Civets Are Equally Susceptible to Experimental Infection by Two Different Severe Acute Respiratory Syndrome Coronavirus Isolates 
Journal of Virology  2005;79(4):2620-2625.
Severe acute respiratory syndrome (SARS) was caused by a novel virus now known as SARS coronavirus (SARS-CoV). The discovery of SARS-CoV-like viruses in masked palm civets (Paguma larvata) raises the possibility that civets play a role in SARS-CoV transmission. To test the susceptibility of civets to experimental infection by different SARS-CoV isolates, 10 civets were inoculated with two human isolates of SARS-CoV, BJ01 (with a 29-nucleotide deletion) and GZ01 (without the 29-nucleotide deletion). All inoculated animals displayed clinical symptoms, such as fever, lethargy, and loss of aggressiveness, and the infection was confirmed by virus isolation, detection of viral genomic RNA, and serum-neutralizing antibodies. Our data show that civets were equally susceptible to SARS-CoV isolates GZ01 and BJ01.
doi:10.1128/JVI.79.4.2620-2625.2005
PMCID: PMC546564  PMID: 15681462
8.  Evaluation of Transcriptional Efficiency of Hepatitis B Virus Covalently Closed Circular DNA by Reverse Transcription-PCR Combined with the Restriction Enzyme Digestion Method†  
Journal of Virology  2005;79(3):1813-1823.
Virus persistence in chronic hepatitis B patients is due to the sustaining level of covalently closed circular DNA (cccDNA) within the nuclei of infected hepatocytes. In this study, we used a modified 1.3-fold hepatitis B virus (HBV) genome, with a BclI genetic marker embedded in the redundancy region, to examine the transcriptional activity of cccDNA and the effect of the HBx protein on transcriptional regulation. After harvesting total RNA from transfected cells or stable lines, we specifically identified and monitored the transcripts from cccDNA by using reverse transcription-PCR (RT-PCR) combined with the restriction enzyme digestion method. In this approach, we have found that (i) RT-PCR combined with detection of the BclI marker is a highly specific method for distinguishing cccDNA-derived transcripts from the original integrated viral genome, (ii) the transcriptional ability of cccDNA was less efficient than that from the integrated viral genome, and (iii) the transcriptional activity of cccDNA was significantly regulated by the HBx protein, a potential transcription activator. In conclusion, we provided a tool with which to elucidate the transcriptional regulation of cccDNA and clarified the transcriptional regulation mechanism of HBx on cccDNA. The results obtained may be helpful in the development of a clinical intervention for patients with chronic HBV infections.
doi:10.1128/JVI.79.3.1813-1823.2005
PMCID: PMC544084  PMID: 15650205
9.  Distinct Structural Domains within C19ORF5 Support Association with Stabilized Microtubules and Mitochondrial Aggregation and Genome Destruction 
Cancer research  2005;65(10):4191-4201.
C19ORF5 is a sequence homologue of microtubule-associated proteins MAP1A/MAP1B of unknown function, except for its association with mitochondria-associated proteins and the paclitaxel-like microtubule stabilizer and candidate tumor suppressor RASSF1A. Here, we show that when overexpressed in mammalian cells the recombinant 393-amino acid residue COOH terminus of C19ORF5 (C19ORF5C) exhibited four types of distribution patterns proportional to expression level. Although normally distributed throughout the cytosol without microtubular association, C19ORF5C specifically accumulated on stabilized microtubules in paclitaxel-treated cells and interacted directly with paclitaxel-stabilized microtubules in vitro. The native 113-kDa full-length C19ORF5 and a shorter 56-kDa form similarly associated with stabilized microtubules in liver cells and stabilized microtubules from their lysates. As C19ORF5 accumulated, it appeared on mitochondria and progressively induced distinct perinuclear aggregates of mitochondria. C19ORF5 overlapped with cytochrome c-deficient mitochondria with reduced membrane potential. Mitochondrial aggregation resulted in gross degradation of DNA, a cell death–related process we refer to as mitochondrial aggregation and genome destruction (MAGD). Deletion muta-genesis revealed that the C19ORF5 hyperstabilized microtubule-binding domain resides in a highly basic sequence of <100 residues, whereas the MAGD activity resides further downstream in a distinct 25-residue sequence (F967–A991). Our results suggest that C19ORF5 mediates communication between the microtubular cytoskeleton and mitochondria in control of cell death and defective genome destruction through distinct bifunctional structural domains. The accumulation of C19ORF5 and resultant MAGD signaled by hyperstabilized microtubules may be involved in the tumor suppression activity of RASSF1A, a natural microtubule stabilizer and interaction partner with C19ORF5, and the taxoid drug family.
doi:10.1158/0008-5472.CAN-04-3865
PMCID: PMC3225222  PMID: 15899810
10.  Putative tumor suppressor RASSF1 interactive protein and cell death inducer C19ORF5 is a DNA binding protein 
C19ORF5 is a homologue of microtubule-associated protein MAP1B that interacts with natural paclitaxel-like microtubule stabilizer and candidate tumor suppressor RASSF1A. Although normally distributed throughout the cytosol, C19ORF5 specifically associates with microtubules stabilized by paclitaxel or RASSF1A. At sufficiently high concentrations, C19ORF5 causes mitochondrial aggregation and genome destruction (MAGD). The accumulation on hyperstabilized microtubules coupled to MAGD has been proposed to mediate tumor suppression by the taxoid drug family and RASSF1A. Here, we show that the C-terminus of C19ORF5 (C19ORF5C) interacts with mitochondria-associated DNA binding protein, LRPPRC, in liver cells. Like LRPPRC, C19ORF5 also binds DNA with an affinity and specificity sufficient to be of utility in DNA affinity chromatography to purify homogeneous recombinant C19ORF5C from bacterial extracts. Homogeneous C19ORF5 exhibited no intrinsic DNase activity. Deletion mutagenesis indicated that C19ORF5 selectively binds double stranded DNA through its microtubule binding domain. These results suggest C19ORF5 as a DNA binding protein similar to microtubule-associated proteins tau and MAP2.
doi:10.1016/j.bbrc.2005.05.006
PMCID: PMC3225229  PMID: 15907802
Aneuploidy; Apoptosis; DNA binding; LRPPRC; MAP1B; Microtubule-associated proteins; Mitochondria; Mitotic spindle; Paclitaxel; RASSF1A; VCY2IP1
11.  Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys 
Nature medicine  2005;11(12):1295-1298.
We transplanted kidneys from α1,3-galactosyltransferase knockout (GalT-KO) pigs into six baboons using two different immunosuppressive regimens, but most of the baboons died from severe acute humoral xenograft rejection. Circulating induced antibodies to non-Gal antigens were markedly elevated at rejection, which mediated strong complement-dependent cytotoxicity against GalT-KO porcine target cells. These data suggest that antibodies to non-Gal antigens will present an additional barrier to transplantation of organs from GalT-KO pigs to humans.
doi:10.1038/nm1330
PMCID: PMC3018862  PMID: 16311604
12.  γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells 
Free radical biology & medicine  2005;40(8):1281-1292.
γ-Glutamyl transpeptidase (GGT) plays key roles in glutathione homeostasis and metabolism of glutathione S-conjugates. Rat GGT is transcribed via five tandemly arranged promoters into seven transcripts. The transcription of mRNAV is controlled by promoter 5. Previously we found that GGT mRNAV-2 was responsible for the induction of GGT in rat alveolar epithelial cells by 4-hydroxynonenal (HNE). In the current study, the underlying mechanism was investigated. Reporter deletion and mutation analysis demonstrated that an electrophile-response element (EpRE) in the proximal region of GGT promoter 5 (GP5) was responsible for the basal- and HNE-induced promoter activity. Gel-shift assays showed an increased binding activity of GP5 EpRE after HNE exposure. The nuclear content of NF-E2-related factor 2 (Nrf2) was significantly increased by HNE. The recruitment of Nrf2 to GP5 EpRE after HNE treatment was demonstrated by supershift and chromatin immunoprecipitation assays. The tissue expression pattern of GGT mRNA V was previously unknown. Using polymerase chain reaction, we found that GGT mRNAV-2 was expressed in many tissues in rat. Taken together, GGT mRNAV-2 is widely expressed in rat tissues and its basal and HNE-induced expression is mediated through EpRE/Nrf2 signaling.
doi:10.1016/j.freeradbiomed.2005.11.005
PMCID: PMC2702664  PMID: 16631518
γ-Glutamyl transpeptidase; 4-Hydroxy-2-nonenal; Glutathione; EpRE; Nrf2; Tissue distribution; Free radicals
13.  4-Hydroxynonenal Induces Rat γ-Glutamyl Transpeptidase through Mitogen-Activated Protein Kinase-Mediated Electrophile Response Element/Nuclear Factor Erythroid 2-Related Factor 2 Signaling 
γ-Glutamyl transpeptidase (GGT) plays critical roles in glutathione homeostasis and metabolism. Rat GGT is a single-copy gene from which seven types of GGT mRNA with a common protein encoding sequence, but different 5′-untranslated regions, may be transcribed. We previously showed that type V-2 was the predominant form of GGT mRNA in rat L2 epithelial cells, and that it could be induced by 4-hydroxynonenal (HNE) through the electrophile response element (EpRE) located in GGT promoter 5 (GP5). Here, we report transcription factors binding to GP5 EpRE and the involved signaling pathways. Immunodepletion gel shift assays demonstrated that GP5 EpRE bound JunB, c-Jun, FosB, and Fra2 from unstimulated cells, and that after exposure to HNE, EpRE binding complexes contained nuclear factor erythroid 2-related factor (Nrf) 1, Nrf2, JunB, c-Jun, FosB, c-Fos, Fra1, and Fra2. HNE-induced binding of Nrf2 and c-Jun in GP5 EpRE was confirmed by chromatin immunoprecipitation assays. Using reporter assays and specific inhibitors, we found that HNE induction of rat GGT mRNA V-2 was dependent on activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), but not protein kinase C or phosphatidylinositol 3-kinase. Pretreatment with ERK and p38MAPK inhibitors also blocked HNE-increased EpRE binding. HNE-increased nuclear content of Nrf1, Nrf2, and c-Jun in L2 cells was partially blocked by inhibition of either ERK1/2 or p38MAPK and completely blocked by simultaneous inhibition of both MAPKs. In conclusion, HNE induces GGT mRNA V-2 through altered EpRE transcription factor binding mediated by both ERK and p38MAPK.
doi:10.1165/rcmb.2005-0280OC
PMCID: PMC2696200  PMID: 16195535
electrophile response element; γ-glutamyl transpeptidase; glutathione; 4-hydroxynonenal; nuclear factor erythroid 2-related factor 2
14.  THE ROLE OF mPer1 IN MORPHINE DEPENDENCE IN MICE 
Neuroscience  2005;130(2):383-388.
Investigations using Drosophila melanogaster have shown that the circadian clock gene period can influence behavioral responses to cocaine, and the mouse homologues, mPer1 and mPer2, modulate cocaine sensitization and reward. In the present study, we applied DNAzyme targeting mPer1 to interfere the expression of mPer1 in CNS in mice and studied the role of mPer1 on morphine dependence. We found that the DNAzyme could attenuate the expression of mPer1 in CNS in mice. Mice treated with DNAzyme and morphine synchronously did not show preference to the morphine-trained side, whereas the control group did. In contrast, mice treated with DNAzyme after morphine showed preference to the morphine-trained side as well as the control group did. These results indicate that drug dependence seems to be influenced at least partially by mPer1, but mPer1 cannot affect morphine dependence that has been formed.
doi:10.1016/j.neuroscience.2004.09.012
PMCID: PMC2656444  PMID: 15664694
drug dependence; DNAzyme; learning and memory; circadian; i.c.v.
15.  CaM kinase II phosphorylation of slo Thr107 regulates activity and ethanol responses of BK channels 
Nature neuroscience  2005;9(1):41-49.
High-conductance, Ca2+-activated and voltage-gated (BK) channels set neuronal firing. They are almost universally activated by alcohol, leading to reduced neuronal excitability and neuropeptide release and to motor intoxication. However, several BK channels are inhibited by alcohol, and most other voltage-gated K+ channels are refractory to drug action. BK channels are homotetramers (encoded by Slo1) that possess a unique transmembrane segment (S0), leading to a cytosolic S0–S1 loop. We identified Thr107 of bovine slo (bslo) in this loop as a critical residue that determines BK channel responses to alcohol. In addition, the activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the cell controlled channel activity and alcohol modulation. Incremental CaMKII-mediated phosphorylation of Thr107 in the BK tetramer progressively increased channel activity and gradually switched the channel alcohol responses from robust activation to inhibition. Thus, CaMKII phosphorylation of slo Thr107 works as a ‘molecular dimmer switch’ that could mediate tolerance to alcohol, a form of neuronal plasticity.
doi:10.1038/nn1602
PMCID: PMC2574430  PMID: 16341213
16.  A survey of haplotype variants at several disease candidate genes: the importance of rare variants for complex diseases 
Liu, P | Zhang, Y | Lu, Y | Long, J | Shen, H | Zhao, L. | Xu, F | Xiao, P | Xiong, D | Liu, Y | Recker, R | Deng, H
Journal of Medical Genetics  2005;42(3):221-227.
Background: The haplotype based association method offers a powerful approach to complex disease gene mapping. In this method, a few common haplotypes that account for the vast majority of chromosomes in the populations are usually examined for association with disease phenotypes. This brings us to a critical question of whether rare haplotypes play an important role in influencing disease susceptibility and thus should not be ignored in the design and execution of association studies.
Methods: To address this question we surveyed, in a large sample of 1873 white subjects, six candidate genes for osteoporosis (a common late onset bone disorder), which had 29 SNPs, an average marker density of 13 kb, and covered a total of 377 kb of the DNA sequence.
Results: Our empirical data demonstrated that two rare haplotypes of the parathyroid hormone (PTH)/PTH related peptide receptor type 1 and vitamin D receptor genes (PTHR1 and VDR) with frequencies of 1.1% and 2.9%, respectively, had significant effects on osteoporosis phenotypes (p = 4.2 x 10–6 and p = 1.6 x 10–4, respectively). Large phenotypic differences (4.0∼5.0%) were observed between carriers of these rare haplotypes and non-carriers. Carriers of the two rare haplotypes showed quantitatively continuous variation in the population and were derived from a wide spectrum rather than from one extreme tail of the population phenotype distribution.
Conclusions: These findings indicate that rare haplotypes/variants are important for disease susceptibility and cannot be ignored in genetics studies of complex diseases. The study has profound implications for association studies and applications of the HapMap project.
doi:10.1136/jmg.2004.024752
PMCID: PMC1736011  PMID: 15744035
17.  Heterosexual Transmission of HIV in China 
Sexually transmitted diseases  2005;32(5):270-280.
Objective:
The objective of this study was to address the role of heterosexual transmission of HIV in China.
Goal:
The goal of this study was to explore the prevalence of unsafe sex and the likelihood of HIV spread heterosexually from core populations to others.
Study:
The authors conducted a review of behavioral studies.
Results:
Drug users were more likely to be involved in higher-risk sexual behaviors than were those who abstained from using drugs. Most female drug users (52-98%) reported having engaged in commercial sex. Most female sex workers (FSWs) and individuals with sexually transmitted diseases (STDs) had concurrent sexual partners. Many continued to have unprotected sex after noticing STD symptoms in themselves or their sexual partners. From 5% to 26% of rural-to-urban migrants had multiple sexual partners and 10% of males patronized FSWs during migration.
Conclusions:
Factors such as high rates of FSW patronage, low rates of condom use during commercial sex, having sex with both commercial and noncommercial sexual partners, and high rates of STD infection may promote a heterosexual epidemic in China.
PMCID: PMC1791011  PMID: 15849527
18.  Cooperative Interaction of Human XPA Stabilizes and Enhances Specific Binding of XPA to DNA Damage† 
Biochemistry  2005;44(19):7361-7368.
Human xeroderma pigmentosum group A (XPA) is an essential protein for nucleotide excision repair (NER). We have previously reported that XPA forms a homodimer in the absence of DNA. However, what oligomeric forms of XPA are involved in DNA damage recognition and how the interaction occurs in terms of biochemical understanding remain unclear. Using the homogeneous XPA protein purified from baculovirus-infected sf21 insect cells and the methods of gel mobility shift assays, gel filtration chromatography, and UV-cross-linking, we demonstrated that both monomeric and dimeric XPA bound to the DNA adduct of N-acetyl-2-aminofluorene (AAF), while showing little affinity for nondamaged DNA. The binding occurred in a sequential and protein concentration-dependent manner. At relatively low-protein concentrations, XPA formed a complex with DNA adduct as a monomer, while at the higher concentrations, an XPA dimer was involved in the specific binding. Results from fluorescence spectroscopic and competitive binding analyses indicated that the specific binding of XPA to the adduct was significantly facilitated and stabilized by the presence of the second XPA in a positive cooperative manner. This cooperative binding exhibited a Hill coefficient of 1.9 and the step binding constants of K1 = 1.4 × 106 M-1 and K2) = 1.8 × 107 M-1. When interaction of XPA and RPA with DNA was studied, even though binding of RPA-XPA complex to adducted DNA was observed, the presence of RPA had little effect on the overall binding efficiency. Our results suggest that the dominant form for XPA to efficiently bind to DNA damage is the XPA dimer. We hypothesized that the concentration-dependent formation of different types of XPA-damaged DNA complex may play a role in cellular regulation of XPA activity.
doi:10.1021/bi047598y
PMCID: PMC1475732  PMID: 15882075
19.  Men Who Have Sex with Men and Human Immunodeficiency Virus/Sexually Transmitted Disease Control in China 
Cell research  2005;15(11-12):858-864.
Objectives:
To address the role of men who have sex with men (MSM) in the human immunodeficiency virus (HIV)/sexually transmitted disease (STD) epidemic in China.
Goal:
To explore the prevalence of risky sexual behaviors and the existing prevention efforts among men who have sex with men (MSM) in China.
Study Design:
Review of behavioral and STD/HIV prevention studies addressing MSM in China.
Results:
Sexual risk behaviors including unprotected group sex, anal sex, casual sex, and commercial sex were prevalent among Chinese MSM. Many Chinese MSM also engaged in unprotected sex with both men and women. Most MSM either did not perceive that they were at risk of HIV/AIDS or underestimated their risk of infection. Surveillance and intervention research among these men are still in the preliminary stages.
Conclusions:
Chinese MSM are at risk for HIV/STD infection and potential transmission of HIV to the general population. In addition to sexual risk reduction among MSM, reduction of homosexualityrelated stigma should be part of effective intervention efforts. Volunteers from the MSM community and health care workers in primary health care system may serve as valuable resources for HIV/STD prevention and control among MSM.
doi:10.1038/sj.cr.7290359
PMCID: PMC1791010  PMID: 16354560
20.  TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells 
Nature medicine  2005;11(6):653-660.
Leprosy enables investigation of mechanisms by which the innate immune system contributes to host defense against infection, since in one form, the disease progresses, and in the other, the infection is limited. We report that Toll-like receptor (TLR) activation of human monocytes induces rapid differentiation into two distinct subsets: DC-SIGN+CD16+ macrophages and CD1b+DC-SIGN− dendritic cells. DC-SIGN+ phagocytic macrophages were expanded by TLR-mediated upregulation of IL-15/IL-15R. CD1b+ dendritic cells were expanded by TLR-mediated upregulation of GM-CSF/GM-CSFR, promoted T cell activation and secreted proinflammatory cytokines. While DC-SIGN+ macrophages were detected in lesions of all leprosy patients, CD1b+ dendritic cells were not detected in patients with the progressive lepromatous form, except during reversal reactions in which bacilli were cleared by Th1 responses. In T-lep lesions, DC-SIGN+ cells were positive for macrophage markers, but negative for dendritic cell markers. Thus, TLR-induced differentiation of monocytes into either macrophages or dendritic cells appears critically to influence effective host defenses in human infectious disease.
doi:10.1038/nm1246
PMCID: PMC1409736  PMID: 15880118
21.  IL-2 and Autocrine IL-4 Drive the In Vivo Development of Antigen-Specific Th2 T Cells Elicited by Nematode Parasites12 
The intestinal nematode parasite, Nippostrongylus brasiliensis, triggers potent type 2 immunity. Using OVA peptide as a model Ag, we have examined the adjuvant effects of this parasite on the in vivo development of Ag-specific Th2 cells from naive DO11.10 T cells. Our findings show that Th2 cells can develop from transferred naive OVA-specific DO11.10 T cells in recipient IL-4–/– mice inoculated with N. brasiliensis plus OVA. However, autocrine IL-4 is required for in situ Th2 cell differentiation since transferred IL-4Rα-deficient DO11.10 T cells showed greatly reduced Th2 cell development in inoculated IL-4–/– recipient mice. Surprisingly, we also found that IL-2 blockade promoted B7-dependent T cell cycling, but inhibited the development of OVA-specific Th2 cells. Furthermore, the effects of IL-2 occurred independently of CD25+ T regulatory cells. These studies establish a previously unrecognized requirement for autocrine IL-4 and IL-2 in Th2 responses elicited by nematode parasites.
PMCID: PMC1978543  PMID: 15699158
22.  Risk Factors for Sexually Transmitted Disease Among Rural-to-Urban Migrants in China: Implications for HIV/Sexually Transmitted Disease Prevention 
AIDS patient care and STDs  2005;19(1):49-57.
The objective of the study was to identify risk factors associated with sexually transmitted diseases (STDs) among rural-to-urban migrants in Beijing in 2002. Migrants with STDs consisted of 432 migrants who sought STD care in two public STD clinics. Migrants without STDs included 892 migrants recruited from 10 occupational clusters. Multiple logistic regression was used for data analysis. Compared to migrants without STDs, migrants with STDs were more likely to report having engaged in commercial sex (selling or buying sex) (odds ratio [OR] = 2.70, 95% confidence interval [CI]: 1.71–4.25), multiple sex partners in the previous month (OR = 6.50, 95% CI: 3.73–11.32) and higher perceived HIV-related stigma (OR = 1.89, 95% CI: 1.30–2.75). Being a migrant with an STD was also associated with female gender (OR = 4.10, 95% CI: 2.89–5.82), higher education (OR = 2.92, 95% CI: 1.40–6.06), and higher monthly salary (OR = 1.68. 95% CI: 1.23–2.29). Migrants with STDs visited their hometowns more frequently and had more stable jobs than migrants without STDs. Approximately 10% of the migrants with STDs and 7.7% of the migrants without STDs always used condoms. This study suggests that among migrants, acquisition of an STD is associated with higher participation in risk behaviors as would be expected, but also with higher perceived stigma, education, stable jobs, salary, and with female gender. Appropriate behavioral intervention programs are advocated to reduce the risk and stigma among the special population.
doi:10.1089/apc.2005.19.49
PMCID: PMC1935434  PMID: 15665635
23.  Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family 
Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disorder which is characterized by periodic attacks of muscle weakness associated with a decrease in the serum potassium level. The skeletal muscle calcium channel α-subunit gene CACNA1S is a major disease-causing gene for HypoPP, however, only three specific HypoPP-causing mutations, Arg528His, Arg1,239His and Arg1,239Gly, have been identified in CACNA1S to date. In this study, we studied a four-generation Chinese family with HypoPP with 43 living members and 19 affected individuals. Linkage analysis showed that the causative mutation in the family is linked to the CACNA1S gene with a LOD score of 6.7. DNA sequence analysis revealed a heterozygous C to G transition at nucleotide 1,582, resulting in a novel 1,582C→G (Arg528Gly) mutation. The Arg528Gly mutation co-segregated with all affected individuals in the family, and was not present in 200 matched normal controls. The penetrance of the Arg528Gly mutation was complete in male mutation carriers, however, a reduced penetrance of 83% (10/12) was observed in female carriers. No differences were detected for age-at-onset and severity of the disease (frequency of symptomatic attacks per year) between male and female patients. Oral intake of KCl is effective in blocking the symptomatic attacks. This study identifies a novel Arg528Gly mutation in the CACNA1S gene that causes HypoPP in a Chinese family, expands the spectrum of mutations causing HypoPP, and demonstrates a gender difference in the penetrance of the disease.
doi:10.1007/s00109-005-0638-4
PMCID: PMC1579762  PMID: 15726306
Hypokalemic periodic paralysis; Skeletal muscle calcium channel; Mutation; CACNA1S; Ion channel; CACNA1S: Skeletal muscle voltage-gated calcium channel α-subunit; HyperPP: Hyperkalemic periodic paralysis; HypoPP: Hypokalemic periodic paralysis; KCNE3: Voltage-gated potassium channel β subunit gene; PCR: Polymerase chain reaction; RFLP: Restriction fragment length polymorphism; SCN4A: Skeletal muscle voltage-gated sodium channel α-subunit
24.  Establishing a Web-Based DICOM Teaching File Authoring Tool Using Open-Source Public Software 
Journal of Digital Imaging  2005;18(3):169-175.
Online teaching files are an important source of educational and referential materials in the radiology community. The commonly used Digital Imaging and Communications in Medicine (DICOM) file format of the radiology community is not natively supported by common Web browsers. The ability of the Web server to convert and parse DICOM is important when the DICOM-converting tools are not available. In this paper, we describe our approach to develop a Web-based teaching file authoring tool. Our server is built using Apache Web server running on FreeBSD operating system. The dynamic page content is produced by Hypertext Preprocessor (PHP). Digital Imaging and Communications in Medicine images are converted by ImageMagick into Joint Photographic Experts Group (JPEG) format. Digital Imaging and Communications in Medicine attributes are parsed by dicom3tools and stored in PostgreSQL database. Using free software available from the Internet, we build a Web service that allows radiologists to create their own online teaching file cases with a common Web browser.
doi:10.1007/s10278-005-5171-z
PMCID: PMC3046713  PMID: 15924271
Teaching files; Web-based; Hypertext Preprocessor (PHP); Digital Imaging and Communications in Medicine (DICOM)
25.  Innate NKT lymphocytes confer superior adaptive immunity via tumor-capturing dendritic cells 
The Journal of Experimental Medicine  2005;202(11):1507-1516.
If irradiated tumor cells could be rendered immunogenic, they would provide a safe, broad, and patient-specific array of antigens for immunotherapies. Prior approaches have emphasized genetic transduction of live tumor cells to express cytokines, costimulators, and surrogate foreign antigens. We asked if immunity could be achieved by delivering irradiated, major histocompatibility complex–negative plasmacytoma cells to maturing mouse dendritic cells (DCs) within lymphoid organs. Tumor cells injected intravenously (i.v.) were captured by splenic DCs, whereas subcutaneous (s.c.) injection led only to weak uptake in lymph node or spleen. The natural killer T (NKT) cells mobilizing glycolipid α-galactosyl ceramide, used to mature splenic DCs, served as an effective adjuvant to induce protective immunity. This adjuvant function was mimicked by a combination of poly IC and agonistic αCD40 antibody. The adjuvant glycolipid had to be coadministered with tumor cells i.v. rather than s.c. Specific resistance was generated both to a plasmacytoma and lymphoma. The resistance afforded by a single vaccination lasted >2 mo and required both CD4+ and CD8+ T cells. Mature tumor capturing DCs stimulated the differentiation of P1A tumor antigen-specific, CD8+ T cells and uniquely transferred tumor resistance to naive mice. Therefore, the access of dying tumor cells to DCs that are maturing to activated NKT cells efficiently induces long-lived adaptive resistance.
doi:10.1084/jem.20050956
PMCID: PMC2213343  PMID: 16330814

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