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Articles by J Huang
Total Records ( 19 ) for J Huang
  J Huang , J Gao , X Lv , G Li , D Hao , X Yao , L Zhou , D Liu and R. Wang
 

Glioma-specific transcription of tumor-killing genes has been exploited as a promising gene therapeutic modality in glioma patients. Musashi1 (Msi1) and GFAP gene promoters are both cancer-specific promoters. Optimized HIF-binding site (optHBS) sequence was newly found as efficient as EPO HREs used as enhancer in cancer gene therapy. We constructed 4optHBS-Msi1/GFAP promoters and tested their ability to mediate BAX expression to induce apoptosis in glioma cell lines. Our results demonstrated that 4optHBS-Msi1/GFAP promoters are apparently strong and glioma-selective promoters with potential application in targeted glioma gene therapy, and 4optHBS-Msi1/GFAP-BAX are valuable tools for glioma gene therapy.

  G Liu , M Ding , J Chen , J Huang , H Wang , Q Jing and B. Shen
 

Emerging evidence suggests that specific spatio-temporal microRNA (miRNA) expression is required for heart development. In recent years, hundreds of miRNAs have been discovered. In contrast, functional annotations are available only for a very small fraction of these regulatory molecules. In order to provide a global perspective for the biologists who study the relationship between differentially expressed miRNAs and heart development, we employed computational analysis to uncover the specific cellular processes and biological pathways targeted by miRNAs in mouse heart development. Here, we utilized Gene Ontology (GO) categories, KEGG Pathway, and GeneGo Pathway Maps as a gene functional annotation system for miRNA target enrichment analysis. The target genes of miRNAs were found to be enriched in functional categories and pathway maps in which miRNAs could play important roles during heart development. Meanwhile, we developed miRHrt (http://sysbio.suda.edu.cn/mirhrt/), a database aiming to provide a comprehensive resource of miRNA function in regulating heart development. These computational analysis results effectively illustrated the correlation of differentially expressed miRNAs with cellular functions and heart development. We hope that the identified novel heart development-associated pathways and the database presented here would facilitate further understanding of the roles and mechanisms of miRNAs in heart development.

  R. C Cooksey , D Jones , S Gabrielsen , J Huang , J. A Simcox , B Luo , Y Soesanto , H Rienhoff , E Dale Abel and D. A. McClain
 

Iron overload can cause insulin deficiency, but in some cases this may be insufficient to result in diabetes. We hypothesized that the protective effects of decreased iron would be more significant with increased β-cell demand and stress. Therefore, we treated the ob/ob mouse model of type 2 diabetes with an iron-restricted diet (35 mg/kg iron) or with an oral iron chelator. Control mice were fed normal chow containing 500 mg/kg iron. Neither treatment resulted in iron deficiency or anemia. The low-iron diet significantly ameliorated diabetes in the mice. The effect was long lasting and reversible. Ob/ob mice on the low-iron diet exhibited significant increases in insulin sensitivity and β-cell function, consistent with the phenotype in mouse models of hereditary iron overload. The effects were not accounted for by changes in weight or feeding behavior. Treatment with iron chelation had a more dramatic effect, allowing the ob/ob mice to maintain normal glucose tolerance for at least 10.5 wk despite no effect on weight. Although dietary iron restriction preserved β-cell function in ob/ob mice fed a high-fat diet, the effects on overall glucose levels were less apparent due to a loss of the beneficial effects of iron on insulin sensitivity. Beneficial effects of iron restriction were minimal in wild-type mice on normal chow but were apparent in mice on high-fat diets. We conclude that, even at "normal" levels, iron exerts detrimental effects on β-cell function that are reversible with dietary restriction or pharmacotherapy.

  J Huang , R. H Perlis , P. H Lee , A. J Rush , M Fava , G. S Sachs , J Lieberman , S. P Hamilton , P Sullivan , P Sklar , S Purcell and J. W. Smoller
  Objective:

Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia, bipolar disorder, and major depressive disorder. The purpose of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders.

Method:

The authors combined GWAS data from three large effectiveness studies of schizophrenia (CATIE, genotyped: N=741), bipolar disorder (STEP-BD, geno-typed: N=1,575), and major depressive disorder (STAR*D, genotyped: N=1,938) as well as from psychiatrically screened control subjects (NIMH-Genetics Repository: N=1,204). A two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups was applied, followed by a model selection step to identify the best-fitting model of allelic effects across disorders.

Results:

The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218), with the best-fitting model indicating that the effect was specific to bipolar II disorder. Findings also revealed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries, including variants in NPAS3 that showed pleiotropic effects across schizophrenia, bipolar disorder, and major depressive disorder.

Conclusions:

This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although genomewide signifi-cant evidence of cross-disorder effects was not detected, the results provide evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrate an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.

  R. H Perlis , J Huang , S Purcell , M Fava , A. J Rush , P. F Sullivan , S. P Hamilton , F. J McMahon , T Schulze , J. B Potash , P. P Zandi , V. L Willour , B. W Penninx , D. I Boomsma , N Vogelzangs , C. M Middeldorp , M Rietschel , M Nothen , S Cichon , H Gurling , N Bass , A McQuillin , M Hamshere , Craddock Wellcome Trust Case Control Consortium Bipolar Disorder Group , P Sklar and J. W. Smoller
  Objective:

Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts.

Method:

The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort.

Results:

Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety.

Conclusions:

The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.

  Z. x Duan , W Gu , L. y Zhang , D. y Du , P Hu , J Huang , Q Liu , Z. g Wang , J Hao and J. x. Jiang
 

Objective  To investigate the clinical relevance of the TLR4 11367 polymorphism in patients with major trauma.

Design  Genetic functional and association study.

Setting  Daping Hospital and Chongqing Emergency Medical Center, Chongqing, China.

Patients  A total of 132 patients with major trauma were prospectively recruited.

Main Outcome Measures  The TLR4 11367 polymorphism was genotyped using single-tube, bidirectional, allele-specific amplification method. Whole peripheral blood samples obtained within 24 hours after admission were stimulated with lipopolysaccharide and then tested for production of tumor necrosis factor and interleukin 6. Sepsis morbidity rate and multiple organ dysfunction scores were assessed.

Results  The 11367 polymorphism was shown to be strongly associated with less capacity of peripheral leukocytes to produce tumor necrosis factor and interleukin 6 in response to ex vivo lipopolysaccharide stimulation in patients with trauma at admission. Results from association study indicated that patients with trauma who carry the 11367C allele were less likely to have sepsis and multiple organ dysfunction.

Conclusions  Combined with our previous in vitro functional study, the results suggest that the TLR4 11367 polymorphism might be a good predictor of who is more likely to develop complications such as sepsis or multiple organ dysfunction syndrome, depending on genotype.

  Y Karpievitch , J Stanley , T Taverner , J Huang , J. N Adkins , C Ansong , F Heffron , T. O Metz , W. J Qian , H Yoon , R. D Smith and A. R. Dabney
 

Motivation: Quantitative mass spectrometry-based proteomics requires protein-level estimates and associated confidence measures. Challenges include the presence of low quality or incorrectly identified peptides and informative missingness. Furthermore, models are required for rolling peptide-level information up to the protein level.

Results: We present a statistical model that carefully accounts for informative missingness in peak intensities and allows unbiased, model-based, protein-level estimation and inference. The model is applicable to both label-based and label-free quantitation experiments. We also provide automated, model-based, algorithms for filtering of proteins and peptides as well as imputation of missing values. Two LC/MS datasets are used to illustrate the methods. In simulation studies, our methods are shown to achieve substantially more discoveries than standard alternatives.

  J Huang , S Ma , H Xie and C. H. Zhang
 

In multiple regression problems when covariates can be naturally grouped, it is important to carry out feature selection at the group and within-group individual variable levels simultaneously. The existing methods, including the lasso and group lasso, are designed for either variable selection or group selection, but not for both. We propose a group bridge approach that is capable of simultaneous selection at both the group and within-group individual variable levels. The proposed approach is a penalized regularization method that uses a specially designed group bridge penalty. It has the oracle group selection property, in that it can correctly select important groups with probability converging to one. In contrast, the group lasso and group least angle regression methods in general do not possess such an oracle property in group selection. Simulation studies indicate that the group bridge has superior performance in group and individual variable selection relative to several existing methods.

  M Taoudi Benchekroun , P Saintigny , S. M Thomas , A. K El Naggar , V Papadimitrakopoulou , H Ren , W Lang , Y. H Fan , J Huang , L Feng , J. J Lee , E. S Kim , W. K Hong , F. M Johnson , J. R Grandis and L. Mao
 

Leukoplakia is the most common premalignant lesion of the oral cavity. Epidermal growth factor receptor (EGFR) abnormalities are associated with oral tumorigenesis and progression. We hypothesized that EGFR expression and gene copy number changes are predictors of the risk of an oral premalignant lesion (OPL) progressing to oral squamous cell carcinoma (OSCC). A formalin-fixed, paraffin-embedded OPL biopsy specimen was collected from each of 162 patients in a randomized controlled clinical trial. We assessed EGFR expression by immunohistochemistry with two methods: a semiquantitative analysis (145 evaluable specimens) and an automated quantitative analysis (127 evaluable specimens). EGFR gene copy number was assessed by fluorescence in situ hybridization (FISH) in a subset of 49 OPLs with high EGFR expression defined by the semiquantitative analysis. We analyzed EGFR abnormalities for associations with OSCC development. High EGFR expression occurred in 103 (71%) of the 145 OPLs and was associated with a nonsignificantly higher risk of OSCC (P = 0.10). Twenty (41%) of 49 OPLs assessed by FISH had an increased EGFR gene copy number (FISH-positive). Patients with FISH-positive lesions had a significantly higher incidence of OSCC than did patients with FISH-negative (a normal copy number) lesions (P = 0.0007). Of note, 10 of 11 OSCCs that developed at the site of the examined OPL were in the FISH-positive group, leaving only one FISH-negative OPL that did so (P < 0.0001). Our data indicate that an increased EGFR gene copy number is common in and associated with OSCC development in patients with OPLs expressing high EGFR, particularly OSCC developing at the site of a high-expression OPL; they also suggest that EGFR inhibitors may prevent oral cancer in patients with OPLs having an increased EGFR gene copy number. Cancer Prev Res; 3(7); 800–9. ©2010 AACR.

  J Huang , M. I Che , Y. T Huang , M. K Shyu , Y. M Huang , Y. M Wu , W. C Lin , P. H Huang , J. T Liang , P. H Lee and M. C. Huang
 

Mucins play a key role in tumorigenesis. MUC15 is a membrane-bound mucin and the MUC15 messenger RNA (mRNA) has been detected in various organs. However, its role in tumor malignancy is still unclear. This study was to investigate the MUC15 expression in colorectal tumors and the role of MUC15 in colon cancer cells. We found that the mRNA expression of MUC15 was significantly higher in 70.8% (51/72) of colorectal tumors compared with their normal counterparts by real-time reverse transcription–polymerase chain reaction. Immunohistochemistry showed that MUC15 expression was increased in 82.6% (43/52) of colorectal tumors. MUC15 overexpression in HCT116 cells enhanced cell proliferation, cell–extracellular matrix adhesion, colony-forming ability and invasion. Furthermore, these effects were significantly reversed by knockdown of MUC15 with short-hairpin RNA. In nude mice models, MUC15 overexpression significantly (P < 0.01) enhanced tumor growth. In addition, treatment of PD98059 significantly (P < 0.01) inhibited MUC15-enhanced invasion, suggesting that the invasion induced by MUC15 in HCT116 cells was primarily mediated through activation of extracellular signal-regulated kinase 1/2. In conclusion, these results suggest that MUC15 is upregulated in colorectal tumors and its expression enhances the oncogenic potential of colon cancer cells.

  K Matsumoto , J Huang , N Viswakarma , L Bai , Y Jia , Y. T Zhu , G Yang , J Borensztajn , M.S Rao , Y. J Zhu and J. K. Reddy
 

Nuclear receptor coactivator [peroxisome proliferator-activated receptor-binding protein (PBP)/mediator subunit 1 (MED1)] is a critical component of the mediator transcription complex. Disruption of this gene in the mouse results in embryonic lethality. Using the PBP/MED1 liver conditional null (PBP/MED1Liv) mice, we reported that PBP/MED1 is essential for liver regeneration and the peroxisome proliferator-activated receptor ligand Wy-14,643-induced receptor-mediated hepatocarcinogenesis. We now examined the role of PBP/MED1 in genotoxic chemical carcinogen diethylnitrosamine (DEN)-induced and phenobarbital-promoted hepatocarcinogenesis. The carcinogenic process was initiated by a single intraperitoneal injection of DEN at 14 days of age and initiated cells were promoted with phenobarbital (PB) (0.05%) in drinking water. PBP/MED1Liv mice, killed at 1, 4 and 12 weeks, revealed a striking proliferative response of few residual PBP/MED1-positive hepatocytes that escaped Cre-mediated deletion of PBP/MED1 gene. No proliferative expansion of PBP/MED1 null hepatocytes was noted in the PBP/MED1Liv mouse livers. Multiple hepatocellular carcinomas (HCCs) developed in the DEN-initiated PBP/MED1fl/fl and PBP/MED1Liv mice, 1 year after the PB promotion. Of interest is that all HCC developing in PBP/MED1Liv mice were PBP/MED1 positive. None of the tumors was PBP/MED1 negative implying that hepatocytes deficient in PBP/MED1 are not susceptible to neoplastic conversion. HCC that developed in PBP/MED1Liv mouse livers were transplantable in athymic nude mice and these maintained PBP/MED1fl/fl genotype. PBP/MED1fl/fl HCC cell line derived from these tumors expressed PBP/MED1 and deletion of PBP/MED1fl/fl allele by adeno-Cre injection into tumors caused necrosis of tumor cells. These results indicate that PBP/MED1 is essential for the development of HCC in the mouse.

  A Ahmed , T Fujisawa , X. L Niu , S Ahmad , B Al Ani , K Chudasama , A Abbas , R Potluri , V Bhandari , C. M Findley , G. K.W Lam , J Huang , P. W Hewett , M Cudmore and C. D. Kontos
 

Atherosclerosis is promoted by a combination of hypercholesterolemia and vascular inflammation. The function of Angiopoietin (Ang)-2, a key regulator of angiogenesis, in the maintenance of large vessels is unknown. A single systemic administration of Ang-2 adenovirus (AdAng-2) to apoE–/– mice fed a Western diet significantly reduced atherosclerotic lesion size (40%) and oxidized LDL and macrophage content of the plaques. These beneficial effects were abolished by the inhibition of nitric oxide synthase (NOS). In endothelial cells, endothelial NOS activation per se inhibited LDL oxidation and Ang-2 stimulated NO release in a Tie2-dependent manner to decrease LDL oxidation. These findings demonstrate a novel atheroprotective role for Ang-2 when endothelial cell function is compromised and suggest that growth factors, which stimulate NO release without inducing inflammation, could offer atheroprotection.

  J Huang , E. C Davis , S. L Chapman , M Budatha , L. Y Marmorstein , R. A Word and H. Yanagisawa
 

Rationale: Loss of fibulin-4 during embryogenesis results in perinatal lethality because of aneurysm rupture, and defective elastic fiber assembly has been proposed as an underlying cause for the aneurysm phenotype. However, aneurysms are never seen in mice deficient for elastin, or for fibulin-5, which absence also leads to compromised elastic fibers.

Objective: We sought to determine the mechanism of aneurysm development in the absence of fibulin-4 and establish the role of fibulin-4 in aortic development.

Methods and Results: We generated germline and smooth muscle cell (SMC)-specific deletion of the fibulin-4 gene in mice (Fbln4GKO and Fbln4SMKO, respectively). Fbln4GKO and Fbln4SMKO aortic walls fail to fully differentiate, exhibiting reduced expression of SM-specific contractile genes and focal proliferation of SMCs accompanied by degenerative changes of the medial wall. Marked upregulation of extracellular signal-regulated kinase 1/2 signaling pathway was observed in the aneurysmal wall of Fbln4GKO and Fbln4SMKO mice and both mutants developed aneurysm predominantly in the ascending thoracic aorta. In vitro, Fbln4GKO SMCs exhibit an immature SMC phenotype with a marked reduction of SM-myosin heavy chain and increased proliferative capacity.

Conclusions: The vascular phenotype in Fbln4 mutant mice is remarkably similar to a subset of human thoracic aortic aneurysms caused by mutations in SMC contractile genes. Our study provides a potential link between the intrinsic properties of SMCs and aneurysm progression in vivo and supports the dual role of fibulin-4 in the formation of elastic fibers as well as terminal differentiation and maturation of SMCs in the aortic wall.

  J Huang , Z Xu , D Wang , C. M Ogata , K Palczewski , X Lee and N. M. Young
 

The Maclura pomifera agglutinin (MPA) recognizes the T-antigen disaccharide Galβ1,3GalNAc mainly through interaction of the -GalNAc moiety with its primary site, but the interactions of the two flanking subsites A and B with aglycones and substituents other than Gal, respectively, are not well understood. We therefore characterized the specificity of MPA in more detail by glycan microarray analysis and determined the crystal structures of MPA without ligand and in complexes with Galβ1,3GalNAc and p-nitrophenyl -GalNAc. In both sugar complexes, pairs of ligands created inter-tetramer hydrogen-bond bridging networks. While subsite A showed increased affinity for hydrophobic aglycones, it also accommodated several sugar substituents. Notably, a GalNAc-O-tripeptide, a Tn-antigen mimic, showed lower affinity than these compounds in surface plasmon resonance (SPR) experiments. The glycan array data that showed subsite B accepted compounds in which the O3 position of the GalNAc was substituted with various sugars other than Gal, but substitutions at O6 led to inactivity. Additions to the Gal moiety of the disaccharide also had only small effects on reactivity. These results are all compatible with the features seen in the crystal structures.

  C Li , Z Chen , Z Liu , J Huang , W Zhang , L Zhou , D. L Keefe and L. Liu
 

Mammalian parthenogenetic embryos (pE) are not viable due to placental deficiency, presumably resulting from lack of paternally expressed imprinted genes. Pluripotent parthenogenetic embryonic stem (pES) cells derived from pE could advance regenerative medicine by avoiding immuno-rejection and ethical roadblocks. We attempted to explore the epigenetic status of imprinted genes in the generation of pES cells from parthenogenetic blastocysts, and its relationship to pluripotency of pES cells. Pluripotency was evaluated for developmental and differentiation potential in vivo, based on contributions of pES cells to chimeras and development to day 9.5 of pES fetuses complemented by tetraploid embryos (TEC). Consistently, pE and fetuses failed to express paternally expressed imprinted genes, but pES cells expressed those genes in a pattern resembling that of fertilized embryos (fE) and fertilized embryonic stem (fES) cells derived from fE. Like fE and fES cells, but unlike pE or fetuses, pES cells and pES cell–fetuses complemented by TEC exhibited balanced methylation of Snrpn, Peg1 and U2af1-rs1. Coincidently, global methylation increased in pE but decreased in pES cells, further suggesting dramatic epigenetic reprogramming occurred during isolation and culture of pES cells. Moreover, we identified decreased methylation of Igf2r, Snrpn, and especially U2af1-rs1, in association with increased contributions of pES cells to chimeras. Our data show that in vitro culture changes epigenetic status of imprinted genes during isolation of pES cells from their progenitor embryos and that increased expression of U2af1-rs1 and Snrpn and decreased expression of Igf2r correlate with pluripotency of pES cells.

  X Zhang , B Han , J Huang , B Zheng , Q Geng , F Aziz and Q. Dong
  Objective

The purpose of this study was to detect the presence of cancer stem-like cells with bronchioalveolar stem cells (BASCs) properties and investigate the clinicopathological role of expression of OCT4 as well as the correlation with clinical outcomes in adenocarcinoma of the lung.

Methods

Specimens of 112 cases of Stage IB–IIIA lung adenocarcinoma after radical surgery were collected from June 1999 to June 2002. The putative cancer stem cells in tumor sections were visualized immunofluorescently by using the antibodies against three bronchioalveolar stem cells markers: surfactant protein C (SPC), Clara cell secretary protein (CCSP) and Octamer-4 (OCT4). Cancer stem-like cells with bronchioalveolar stem cell properties in human lung adenocarcinoma were subdivided into two phenotypes: OCT4+BASC (SPC+CCSP+OCT4+) and OCT4BASC (SPC+CCSP+OCT4).

Results

Cancer cells with CCSP+SPC+BASC phenotype were detected in 107 cases, 80 cases with OCT4+BASC phenotype (SPC+CCSP+OCT4+) and 27 cases with SPC+CCSP+OCT4. There was a correlation between differentiation and OCT4 expression (P = 0.047). The pattern of survival curves shows the expected trend of decreasing survival with increasing stage at diagnosis (P = 0.015) and with OCT4+BASC expression (P = 0.019). Multivariate Cox's analysis reveals that pathological stages of TNM (P = 0.008) and bronchioalveolar stem cells phenotypes (P = 0.015) are the independent prognostic factors.

Conclusions

The cancer cells with bronchioalveolar stem cells phenotype are detectable in adenocarcinoma of the lung and the expression of self-renewal regulatory gene OCT4 in these cells indicated the worse clinical outcomes.

  J Huang and J. Wang
 

In this paper, we develop an equilibrium model for stock market liquidity and its impact on asset prices when constant market presence is costly. We show that even when agents' trading needs are perfectly matched, costly market presence prevents them from synchronizing their trades and hence gives rise to endogenous order imbalances and the need for liquidity. Moreover, the endogenous liquidity need, when it occurs, is characterized by excessive selling of significant magnitudes. Such liquidity-driven selling leads to market crashes in the absence of any aggregate shocks. Finally, we show that illiquidity in the market leads to high expected returns, negative and asymmetric return serial correlation, and a positive relation between trading volume and future returns. We also propose new measures of liquidity based on its asymmetric impact on prices and demonstrate a negative relation between these measures and expected stock returns.

  Y. C Lin , J Huang , Q Zhang , J. M Hollander , J. C Frisbee , K. H Martin , C Nestor , R Goodman and H. G. Yu
 

Ca2+ entry is delicately controlled by inactivation of L-type calcium channel (LTCC) composed of the pore-forming subunit 1C and the auxiliary subunits β1 and 2. Calmodulin is the key protein that interacts with the COOH-terminal motifs of 1C, leading to the fine control of LTCC inactivation. In this study we show evidence that a hyperpolarization-activated cyclic nucleotide-gated channel, HCN2, can act as a nonchannel regulatory protein to narrow the L-type Ca2+ channel current-voltage curve. In the absence of LTCC auxiliary subunits, HCN2 can induce 1C inactivation. Without 2, HCN2-induced fast inactivation of 1C requires calmodulin. With 2, the 1C/HCN2/2 channel inactivation does not require calmodulin. In contrast, β1-subunit plays a relatively minor role in the interaction of 1C with HCN2. The NH2 terminus of HCN2 and the IQ motif of 1C subunit are required for 1C/HCN2 channel interaction. Ca2+ channel inactivation is significantly slowed in hippocampus neurons (HNs) overexpressing HCN2 mutant lacking NH2 terminus and accelerated in HNs overexpressing the wild-type HCN2 compared with HN controls. Collectively, these results revealed a potentially novel protection mechanism for achieving the LTCC inactivation via interaction with HCN2.

  J Huang , J. J Goedert , E. J Sundberg , T. D. H Cung , P. S Burke , M. P Martin , L Preiss , J Lifson , M Lichterfeld , M Carrington and X. G. Yu
 

A subset of HLA-B*35 alleles, B*35-Px, are strongly associated with accelerated HIV-1 disease progression for reasons that are not understood. Interestingly, the alternative set of B*35 subtypes, B*35-PY, have no detectable impact on HIV-1 disease outcomes, even though they can present identical HIV-1 epitopes as B*35-Px molecules. Thus, the differential impact of these alleles on HIV-1 disease progression may be unrelated to interactions with HIV-1–specific CD8+ T cells. Here, we show that the B*35-Px molecule B*3503 binds with greater affinity to immunoglobulin-like transcript 4 (ILT4), an inhibitory MHC class I receptor expressed on dendritic cells, than does the B*35-PY molecule B*3501, even though these two B*35 molecules differ by only one amino acid and present identical HIV-1 epitopes. The preferential recognition of B*3503 by ILT4 was associated with significantly stronger dendritic cell dysfunction in in vitro functional assays. Moreover, HIV-1–infected carriers of B*3503 had poor dendritic cell functional properties in ex vivo assessments when compared with carriers of the B*3501 allele. Differential interactions between HLA class I allele subtypes and immunoregulatory MHC class I receptors on dendritic cells thus provide a novel perspective for the understanding of MHC class I associations with HIV-1 disease progression and for the manipulation of host immunity against HIV-1.

 
 
 
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