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Articles by G Liu
Total Records ( 17 ) for G Liu
  Q Qiu , G Liu , W Li , Q Shi , F Zhu and G. Lu
 

Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first committed step of de novo triacylglycerol synthesis by converting glycerol-3-phosphate to lysophosphatidic acid (LPA). LPA is a mitogen that mediates multiple cellular processes including cell proliferation. Four GPAT isoforms have been cloned to date. GPAT4 is strongly expressed in the mouse testis. Reverse transcription–polymerase chain reaction (PCR), real-time PCR, and in situ hybridization (ISH) were used to analyze the GPAT4 expression and to localize the expressing cell types in the mouse testis during postnatal development. GPAT4 cDNA was inserted into pcDNA4/His to construct a recombinant vector, which was transfected into a mouse spermatogonial cell line (GC-1spg). GPAT4 was first expressed in mice at 2 weeks postnatally. Expression was abundant from the third week, plateaued at week 5–6 and then maintained at a high level in the adult. ISH revealed that GPAT4 gene was expressed abundantly in spermatocytes and around spermatids during meiosis but not in elongated spermatids during later spermiogenesis. GC-1spg cells showed a marked increase in proliferation after transfection with GPAT4; cell cycle analysis showed a decrease in the percentage of cells in the G0/G1 phase and an increase in the S phase. Thus, GPAT4 might play an important role in spermatogenesis, especially in mid-meiosis.

  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.

  Z Tian , T Ye , X Zhang , E Liu , W Wang , P Wang , G Liu , X Yang , G Hu and Z. Yu
 

Objective  To investigate the association between sleep duration and risk of hyperglycemia among preschool Chinese children.

Design  A population-based cross-sectional study.

Setting  Seventy-one randomly selected kindergartens in Tianjin, China.

Participants  Six hundred nineteen obese (body mass index z score ≥1.65) and 617 nonobese (body mass index z score <1.65) children aged 3 to 6 years were recruited and matched by age.

Main Exposure  Sleep duration.

Main Outcome Measures  Hyperglycemia, defined as a fasting glucose level of 100 mg/dL or higher.

Results  Obese children were more likely to have shorter sleep duration (≤8 hours) compared with their nonobese counterparts (P < .001). Compared with those who slept for 9 or 10 hours per night, those who slept for 8 hours or less had a significantly higher likelihood of having hyperglycemia, controlling for age and sex (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.12-2.45). After further adjustment for other potential confounders, the association still remained statistically significant (OR, 1.64; 95% CI, 1.09-2.46). In the stratified multivariable analyses, those who were obese and slept for 8 hours or less had an increased risk of having hyperglycemia (OR, 2.12; 95% CI, 1.06-4.21) compared with those who were nonobese and slept for 9 hours or more.

Conclusions  Shorter sleep duration is associated with an increased risk of having hyperglycemia among preschool Chinese children. Whether adequate sleep may help maintain euglycemia among children, especially for those who are overweight or obese, warrants further investigation.

  G Liu , L Wong and H. N. Chua
 

Motivation: Protein complexes are important for understanding principles of cellular organization and function. High-throughput experimental techniques have produced a large amount of protein interactions, which makes it possible to predict protein complexes from protein–protein interaction (PPI) networks. However, protein interaction data produced by high-throughput experiments are often associated with high false positive and false negative rates, which makes it difficult to predict complexes accurately.

Results: We use an iterative scoring method to assign weight to protein pairs, and the weight of a protein pair indicates the reliability of the interaction between the two proteins. We develop an algorithm called CMC (clustering-based on maximal cliques) to discover complexes from the weighted PPI network. CMC first generates all the maximal cliques from the PPI networks, and then removes or merges highly overlapped clusters based on their interconnectivity. We studied the performance of CMC and the impact of our iterative scoring method on CMC. Our results show that: (i) the iterative scoring method can improve the performance of CMC considerably; (ii) the iterative scoring method can effectively reduce the impact of random noise on the performance of CMC; (iii) the iterative scoring method can also improve the performance of other protein complex prediction methods and reduce the impact of random noise on their performance; and (iv) CMC is an effective approach to protein complex prediction from protein interaction network.

  Q Wang , A. h Wang , H. s Tan , N. n Feng , Y. j Ye , X. q Feng , G Liu , Y. x Zheng and Z. l. Xia
 

The base excision repair (BER) pathway is important in repairing DNA damage incurred from occupational exposure to 1,3-butadiene (BD). This study examines the relationship between inherited polymorphisms of the BER pathway (x-ray repair cross-complementing group 1 (XRCC1) Arg194Trp, Arg280His, Arg399Gln, T-77C, ADPRT Val762Ala, MGMT Leu84Phe and APE1 Asp148Glu) and chromosomal damage in BD-exposed workers, using the cytokinesis-blocked (CB) micronucleus (MN) assay in peripheral lymphocytes of 166 workers occupationally exposed to BD and 41 non-exposed healthy individuals. The MN frequency of exposed workers (3.39 ± 2.42) was higher than that of the non-exposed groups (1.48 ± 1.26) (P < 0.01). Workers receiving greater than median annual BD exposures had higher MN values than lower exposed workers: frequency ratio (FR) of 1.30, 95% confidence interval (CI) 1.14–1.53; P < 0.05. Workers who carried the following genotypes were associated with greater frequency of MN (P < 0.05 for each comparison, unless specified): XRCC1 -77 C/T genotype (FR = 1.28, 95% CI: 1.04–1.57; reference C/C), ADPRT 762 Ala/Ala (FR = 1.54, 95% CI: 1.17–2.03; P < 0.01), XRCC1 194 Arg/Trp (FR = 1.13, 95% CI: 0.87–1.27; reference, Arg/Arg), XRCC1 280 Arg/His (FR = 1.67, 95% CI: 1.10–2.42; reference, Arg/Arg), XRCC1 399 Arg/Gln and Gln/Gln genotypes (FR = 1.26, 95% CI: 1.03–1.53 and FR = 1.24, 95% CI 1.03–1.49; reference Arg/Arg, respectively). As XRCC1 polymorphisms were linked, workers carrying the XRCC1 (-77)-(194)-(280)-(399) diplotype, TCGA/TCGA, had a higher MN frequency compared with individuals carrying the wild-type CCGG/CCGG (FR = 1.57, 95% CI: 1.02–2.41; P < 0.05). In conclusion, CB-MN is a sensitive index of early damage among BD-exposed workers. In workers exposed to BD, multiple BER polymorphisms and a XRCC1 haplotype were associated with differential levels of chromosome damage.

  C. y Liu , M. C Wu , F Chen , M Ter Minassian , K Asomaning , R Zhai , Z Wang , L Su , R. S Heist , M. H Kulke , X Lin , G Liu and D. C. Christiani
 

The incidence of esophageal adenocarcinoma (EA) has been increasing rapidly, particularly among white males, over the past few decades in the USA. However, the etiology of EA and the striking male predominance is not fully explained by known risk factors. To identify susceptible genes for EA risk, we conducted a pathway-based candidate gene association study on 335 Caucasian EA cases and 319 Caucasian controls. A total of 1330 single-nucleotide polymorphisms (SNPs) selected from 354 genes were analyzed using an Illumina GoldenGate assay. The genotyped common SNPs include missense and exonic SNPs, SNPs within untranslated regions and 2 kb 5' of the gene, and tagSNPs for genes with little functional information available. Logistic regression adjusted for potential confounders was used to assess the genetic effect of each SNP on EA risk. We also tested gene–gender interactions using the likelihood ratio tests. We found that the genetic variants in the apoptosis pathway were significantly associated with EA risk after correcting for multiple comparisons. SNPs of rs3127075 in Caspase-7 (CASP7) and rs4661636 in Caspase-9 (CASP9) genes that play a critical role in apoptosis were found to be associated with an increased risk of EA. A protective effect of SNP rs572483 in the progesterone receptor (PGR) gene was observed among women carrying the variant G allele [adjusted odds ratio (OR) = 0.19; 95% confidence interval (CI) = 0.08–0.46] but was not observed among men (adjusted OR = 1.38; 95% CI = 0.95–2.00). In conclusion, this study suggests that the genetic variants of CASP7 and CASP9 in the apoptosis pathway may be important predictive markers for EA susceptibility and that PGR in the sex hormone signaling pathway may be associated with the gender differences in EA risk.

  Y Wu , L Yang , T Su , C Wang , G Liu and X. m. Li
 

Background and objectives: Although a renal biopsy is indispensable for depicting the severity of pathologic lesions in drug-induced tubulointerstitial nephritis (DTIN), it is not acceptable in some cases and cannot be performed serially because of its invasive nature. Therefore, the discovery of noninvasive markers that are closely related to the pathology of DTIN is of great value.

Design, setting, participants, & measurements: In this study, the urinary levels of monocyte chemotactic peptide-1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-d-glucosaminidase, and 1-microglobulin were measured in 40 DTIN subjects, and the performances of these parameters for distinguishing different pathologic lesions were compared.

Results: Linear correlation and receiver operating characteristic curve analyses showed that urinary MCP-1 levels were able to identify serious interstitial edema and inflammatory infiltration with greater accuracy than the other biomarkers (r = 0.501, P < 0.001 and r = 0.768, P < 0.001, respectively), whereas urinary NGAL levels showed the highest correlation coefficient with tubular atrophy (r = 0.692, P < 0.001).

Conclusions: These results suggest that these biomarker levels were higher in patients with DTIN than in controls. Urinary MCP-1 levels correlated and were predictive of the gradated severity of acute lesions in DTIN, whereas the roles of NGAL and 1-microglobulin in chronic alterations require further study.

  L Grumolato , G Liu , P Mong , R Mudbhary , R Biswas , R Arroyave , S Vijayakumar , A. N Economides and S. A. Aaronson
 

Wnt ligands signal through β-catenin and are critically involved in cell fate determination and stem/progenitor self-renewal. Wnts also signal through β-catenin-independent or noncanonical pathways that regulate crucial events during embryonic development. The mechanism of noncanonical receptor activation and how Wnts trigger canonical as opposed to noncanonical signaling have yet to be elucidated. We demonstrate here that prototype canonical Wnt3a and noncanonical Wnt5a ligands specifically trigger completely unrelated endogenous coreceptors—LRP5/6 and Ror1/2, respectively—through a common mechanism that involves their Wnt-dependent coupling to the Frizzled (Fzd) coreceptor and recruitment of shared components, including dishevelled (Dvl), axin, and glycogen synthase kinase 3 (GSK3). We identify Ror2 Ser 864 as a critical residue phosphorylated by GSK3 and required for noncanonical receptor activation by Wnt5a, analogous to the priming phosphorylation of low-density receptor-related protein 6 (LRP6) in response to Wnt3a. Furthermore, this mechanism is independent of Ror2 receptor Tyr kinase functions. Consistent with this model of Wnt receptor activation, we provide evidence that canonical and noncanonical Wnts exert reciprocal pathway inhibition at the cell surface by competition for Fzd binding. Thus, different Wnts, through their specific coupling and phosphorylation of unrelated coreceptors, activate completely distinct signaling pathways.

  S Ju , Y Ge , H Qiu , B Lu , Y Qiu , J Fu , G Liu , Q Wang , Y Hu , Y Shu and X. Zhang
 

Dendritic cells (DCs) are responsible for the initiation of immune responses. Our study demonstrates a new pathway for generating a large quantity of stimulatory monocyte-derived DCs (Mo-DCs) from human monocytes using anti-4-1BB ligand (4-1BBL) mAb to trigger reverse signaling. The anti-4-1BBL-driven Mo-DCs (DCs-4-1BBL) not only express higher levels of CD86, CD83 and HLA-DR, when compared with the Mo-DCs matured by tumor necrosis factor , but also exhibit a unique phenotype that expresses lower levels of PD-L1. High levels of GM-CSF, M-CSF and Flt3 ligand (FL) were found in the anti-4-1BBL-differentiation culture. Neutralizing M-CSF, GM-CSF and FL inhibited Mo-DC proliferation stimulated by anti-4-1BBL mAb, suggesting that M-CSF, GM-CSF and FL are involved in cell proliferation stimulated by anti-4-1BBL. Further analysis of the DCs-4-1BBL showed increased secretion of Th1-type cytokines IL-12 and IFN- and decreased secretion of IL-10. DCs-4-1BBL induced much stronger proliferative responses in the mixed lymphocyte reaction assay when compared with DCs derived by GM-CSF. Moreover, DCs-4-1BBL preferentially induced Th1 responses. We have further demonstrated that anti-4-1BBL antibody stimulated nuclear translocation of NF-B from the cytoplasm in monocytes, suggesting that reverse signaling by 4-1BBL is likely responsible for mediating DC differentiation. Collectively, we have found that reverse signaling of 4-1BBL promotes the differentiation of potent Th1-inducing DCs from human monocytes.

  T Truong , R. J Hung , C. I Amos , X Wu , H Bickeboller , A Rosenberger , W Sauter , T Illig , H. E Wichmann , A Risch , H Dienemann , R Kaaks , P Yang , R Jiang , J. K Wiencke , M Wrensch , H Hansen , K. T Kelsey , K Matsuo , K Tajima , A. G Schwartz , A Wenzlaff , A Seow , C Ying , A Staratschek Jox , P Nurnberg , E Stoelben , J Wolf , P Lazarus , J. E Muscat , C. J Gallagher , S Zienolddiny , A Haugen , H. F. M van der Heijden , L. A Kiemeney , D Isla , J. I Mayordomo , T Rafnar , K Stefansson , Z. F Zhang , S. C Chang , J. H Kim , Y. C Hong , E. J Duell , A. S Andrew , F Lejbkowicz , G Rennert , H Muller , H Brenner , L Le Marchand , S Benhamou , C Bouchardy , M. D Teare , X Xue , J McLaughlin , G Liu , J. D McKay , P Brennan and M. R. Spitz
  Background

Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies.

Methods

Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case–control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided.

Results

Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, Ptrend = 2 x 10–26), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, Ptrend = 1 x 10–10) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, Ptrend = 5 x 10–8) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, Ptrend = 2 x 10–5; rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, Ptrend = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer.

Conclusions

In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.

  A. N Freedman , L. B Sansbury , W. D Figg , A. L Potosky , S. R Weiss Smith , M. J Khoury , S. A Nelson , R. M Weinshilboum , M. J Ratain , H. L McLeod , R. S Epstein , G. S Ginsburg , R. L Schilsky , G Liu , D. A Flockhart , C. M Ulrich , R. L Davis , L. J Lesko , I Zineh , G Randhawa , C. B Ambrosone , M. V Relling , N Rothman , H Xie , M. R Spitz , R Ballard Barbash , J. H Doroshow and L. M. Minasian
 

Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled "Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation" on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice.

  S Li , B Han , G Liu , J Ouellet , F Labrie and G. Pelletier
 

The sex steroids, estrogens, progesterone, and androgens, all play a role in mammary development and function. To precisely identify the sites of action of these steroids, we studied the localization of the estrogen receptor (ER) and ERβ, the progesterone receptor A (PRA) and PRB, and androgen receptors (AR) in the normal human mammary gland. Immunocytochemical localization of ER, ERβ, PRA, PRB, and AR was performed with reduction mammoplasty specimens from premenopausal women. ER, PRA, PRB, and AR were localized mostly to the inner layer of epithelial cells lining acini and intralobular ducts, as well as to myoepithelial cells scattered in the external layer of interlobular ducts. AR was also found in some stromal cells. ERβ staining was more widespread, resulting in epithelial and myoepithelial cells being labeled in acini and ducts as well as stromal cells. These results suggest that all sex steroids can directly act on epithelial cells to modulate development and function of the human mammary gland. Estrogens and androgens can also indirectly influence epithelial cell activity by an action on stromal cells. (J Histochem Cytochem 58:509–515, 2010)

  X Zhang , P Sebastiani , G Liu , F Schembri , Y. M Dumas , E. M Langer , Y Alekseyev , G. T O'Connor , D. R Brooks , M. E Lenburg and A. Spira
 

Previous studies have shown that physiological responses to cigarette smoke can be detected via bronchial airway epithelium gene expression profiling and that heterogeneity in this gene expression response to smoking is associated with lung cancer. In this study, we sought to determine the similarity of the effects of tobacco smoke throughout the respiratory tract by determining patterns of smoking-related gene expression in paired nasal and bronchial epithelial brushings collected from 14 healthy nonsmokers and 13 healthy current smokers. Using whole genome expression arrays, we identified 119 genes whose expression was affected by smoking similarly in both bronchial and nasal epithelium, including genes related to detoxification, oxidative stress, and wound healing. While the vast majority of smoking-related gene expression changes occur in both bronchial and nasal epithelium, we also identified 27 genes whose expression was affected by smoking more dramatically in bronchial epithelium than nasal epithelium. Both common and site-specific smoking-related gene expression profiles were validated using independent microarray datasets. Differential expression of select genes was also confirmed by RT-PCR. That smoking induces largely similar gene expression changes in both nasal and bronchial epithelium suggests that the consequences of cigarette smoke exposure can be measured in tissues throughout the respiratory tract. Our findings suggest that nasal epithelial gene expression may serve as a relatively noninvasive surrogate to measure physiological responses to cigarette smoke and/or other inhaled exposures in large-scale epidemiological studies.

  A Friggeri , Y Yang , S Banerjee , Y. J Park , G Liu and E. Abraham
 

Phagocytosis of apoptotic cells is critical to resolution of inflammation. High mobility group box 1 protein (HMGB1), a mediator of inflammation, has been shown to diminish phagocytosis through binding to phosphatidylserine (PS) exposed on the surface of apoptotic neutrophils. However, it is currently unknown whether HMGB1 also modulates the activity of receptors involved in PS recognition on the surface of phagocytes. In the present studies, we found that preincubation of macrophages with HMGB1 decreased their ability to engulf apoptotic neutrophils or thymocytes. Preincubation of macrophages with HMGB1 prevented the enhancement of efferocytosis resulting from exposure to milk fat globule EGF factor 8 (MFG-E8), an opsonin that bridges PS and vβ3 as well as vβ5-integrins on the surface of phagocytes. The inhibitory effect of HMGB1 on the phagocytic activity of macrophages was prevented by preincubation of HMGB1 with soluble vβ3, but not with soluble vβ5. HMGB1 colocalized with the β3-integrin on the cell membrane of macrophages and bound to soluble vβ3, but not to soluble vβ5. HMGB1 suppressed the interaction between MFG-E8 and vβ3. HMGB1 also inhibited intracellular signaling events, including ERK phosphorylation and Rac-1 activation, which are activated in macrophages during phagocytosis of apoptotic cells. These results demonstrate that HMGB1 blocks vβ3-dependent recognition and uptake of apoptotic cells.

  H Li , G Liu , J Yu , W Cao , V. G Lobo and J. Xie
 

Alternative pre-mRNA splicing is often controlled by cell signals, for example, those activating the cAMP-dependent protein kinase (PKA) or the Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). We have shown that CaMKIV regulates alternative splicing through short CA repeats and hnRNP L. Here we use a splicing reporter that shows PKA/CaMKIV promotion of exon inclusion to select from exons containing random 13-nt sequences for RNA elements responsive to the kinases in cultured cells. This selection not only identified both PKA- and CaMKIV-responsive elements that are similar to the CaMKIV-responsive RNA element 1 (CaRRE1) or CA repeats, but also A-rich elements not previously known to respond to these kinases. Consistently, hnRNP L is identified as a factor binding the CA-rich elements. Analyses of the motifs in the highly responsive elements indicate that they are indeed critical for the kinase effect and are enriched in alternative exons. Interestingly, a CAAAAAA motif is sufficient for the PKA/CaMKIV-regulated splicing of the exon 16 of the CaMK kinase β1 (CaMKK2) transcripts, implying a role of this motif in signaling cross-talk or feedback regulation between these kinases through alternative splicing. Therefore, these experiments identified a group of RNA elements responsive to PKA and CaMKIV from in vivo selection. This also provides an approach for selecting RNA elements similarly responsive to other cell signals controlling alternative splicing.

  G Liu , A Friggeri , Y Yang , J Milosevic , Q Ding , V. J Thannickal , N Kaminski and E. Abraham
 

Uncontrolled extracellular matrix production by fibroblasts in response to tissue injury contributes to fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), a progressive and ultimately fatal process that currently has no cure. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in fibrotic lung diseases is unclear. In this study, we found up-regulation of miR-21 in the lungs of mice with bleomycin-induced fibrosis and also in the lungs of patients with IPF. Increased miR-21 expression was primarily localized to myofibroblasts. Administration of miR-21 antisense probes diminished the severity of experimental lung fibrosis in mice, even when treatment was started 5–7 d after initiation of pulmonary injury. TGF-β1, a central pathological mediator of fibrotic diseases, enhanced miR-21 expression in primary pulmonary fibroblasts. Increasing miR-21 levels promoted, whereas knocking down miR-21 attenuated, the pro-fibrogenic activity of TGF-β1 in fibroblasts. A potential mechanism for the role of miR-21 in fibrosis is through regulating the expression of an inhibitory Smad, Smad7. These experiments demonstrate an important role for miR-21 in fibrotic lung diseases and also suggest a novel approach using miRNA therapeutics in treating clinically refractory fibrotic diseases, such as IPF.

  G Liu , X Niu , R. S Wu , N Chudasama , Y Yao , X Jin , R Weinberg , S. I Zakharov , H Motoike , S. O Marx and A. Karlin
 

Large-conductance voltage- and calcium-activated potassium (BK) channels contain four pore-forming subunits and four modulatory β subunits. From the extents of disulfide cross-linking in channels on the cell surface between cysteine (Cys) substituted for residues in the first turns in the membrane of the S0 transmembrane (TM) helix, unique to BK , and of the voltage-sensing domain TM helices S1–S4, we infer that S0 is next to S3 and S4, but not to S1 and S2. Furthermore, of the two β1 TM helices, TM2 is next to S0, and TM1 is next to TM2. Coexpression of with two substituted Cys’s, one in S0 and one in S2, and β1 also with two substituted Cys’s, one in TM1 and one in TM2, resulted in two s cross-linked by one β. Thus, each β lies between and can interact with the voltage-sensing domains of two adjacent subunits.

 
 
 
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