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1.
Ken Katono Yuichi Sato Shi-Xu Jiang Makoto Kobayashi Ryo Nagashio Shinichiro Ryuge Eriko Fukuda Naoki Goshima Yukitoshi Satoh Makoto Saegusa Noriyuki Masuda 《PloS one》2015,10(3)
Introduction
Myosin-9 (MYH9) belongs to the myosin superfamily of actin-binding motor protein. Recently, MYH9 has been thought to be associated with cancer cell migration, invasion, and metastasis. The aims of this study were to immunohistochemically examine MYH9 expression in surgically resected non-small cell lung cancer (NSCLC), and evaluate its correlations with clinicopathological parameters and the prognosis of patients.Methods
MYH9 expression was immunohistochemically studied in 266 consecutive resected NSCLCs, and its associations with clinicopathological parameters were evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of MYH9 expression on survival.Results
MYH9 expression was detected in 102 of 266 (38.3%) NSCLCs. MYH9 expression was significantly correlated with the adenocarcinoma histology (P = 0.014), poorer differentiation ((P = 0.033), intratumoral vascular invasion and lymphatic invasion ((P = 0.013 and P = 0.045 respectively), and a poorer prognosis ((P = 0.032). In addition, multivariable analysis revealed that MYH9 expression independently predicted a poorer survival (HR, 2.15; 95%CI, 1.17-3.92; (P = 0.01).Conclusion
The present study revealed that MYH9 is expressed in a subset of NSCLC with a more malignant nature, and its expression is an indicator of a poorer survival probability. 相似文献2.
M. Carolina Gallego-Iradi Alexis M. Clare Hilda H. Brown Christopher Janus Jada Lewis David R. Borchelt 《PloS one》2015,10(11)
Background
Mutations in Matrin 3 [MATR3], an RNA- and DNA-binding protein normally localized to the nucleus, have been linked to amyotrophic lateral sclerosis (ALS) and distal myopathies. In the present study, we have used transient transfection of cultured cell lines to examine the impact of different disease-causing mutations on the localization of Matrin 3 within cells.Results
Using CHO and human H4 neuroglioma cell models, we find that ALS/myopathy mutations do not produce profound changes in the localization of the protein. Although we did observe variable levels of Matrin 3 in the cytoplasm either by immunostaining or visualization of fluorescently-tagged protein, the majority of cells expressing either wild-type (WT) or mutant Matrin 3 showed nuclear localization of the protein. When cytoplasmic immunostaining, or fusion protein fluorescence, was seen in the cytoplasm, the stronger intensity of staining or fluorescence was usually evident in the nucleus. In ~80% of cells treated with sodium arsenite (Ars) to induce cytoplasmic stress granules, the nuclear localization of WT and F115C mutant Matrin 3 was not disturbed. Notably, over-expression of mutant Matrin 3 did not induce the formation of obvious large inclusion-like structures in either the cytoplasm or nucleus.Conclusions
Our findings indicate that mutations in Matrin 3 that are associated with ALS and myopathy do not dramatically alter the normal localization of the protein or readily induce inclusion formation. 相似文献3.
Sang-il Lee Akiko Hida Shingo Kitamura Kazuo Mishima Shigekazu Higuchi 《Journal of physiological anthropology》2014,33(1):9
Background
In our previous studies, we found that the Ile394Thr SNP in the melanopsin gene (OPN4) was functionally associated with the pupillary light reflex. This indicates the possibility that OPN4*Ile394Thr is associated with other non-image forming responses. The aim of this study was therefore to determine whether OPN4*Ile394Thr is associated with sleep/wake timing.Methods
A total of 348 healthy Japanese university students participated in this study. Scalp hair was used to genotype the Ile394Thr SNP of OPN4. Sleep habits, including bedtime, wake time and sleep duration, were assessed separately for weekdays and weekends. A total of 328 samples, including 223 samples with TT genotype, 91 with TC genotype and 14 with CC genotype, were used for statistical analysis. No significant difference in age or male/female distribution was found among the three genotype groups.Results
There was no significant difference in circadian preference among the genotype groups. During weekdays, bedtime, wake time and midpoint of sleep for CC subjects were significantly later than those for TT and TC subjects. However, there was no difference between TT and TC subjects in any of their sleep habits. During weekends, bedtime of CC subjects was significantly later than those of TT and TC subjects, and the midpoint of sleep of CC subjects was significantly later than that of TC subjects.Conclusions
Our findings demonstrated that OPN4*Ile394Thr is associated with sleep/wake timing. We also found that the sleep/wake timing of subjects with the CC genotype was later than that of subjects with the TT or TC genotype. 相似文献4.
Elize Pietersen Jonny Peter Elizabeth Streicher Frik Sirgel Neesha Rockwood Barbara Mastrapa Julian Te Riele Malika Davids Paul van Helden Robin Warren Keertan Dheda 《PloS one》2015,10(4)
Background
There are limited data about the epidemiology and treatment-related outcomes associated with capreomycin resistance in patients with XDR-TB. Capreomycin achieves high serum concentrations relative to MIC but whether capreomycin has therapeutic benefit despite microbiological resistance remains unclear.Methods
We reviewed the susceptibility profiles and outcomes associated with capreomycin usage in patients diagnosed with XDR-TB between August 2002 and October 2012 in two provinces of South Africa. Patients whose isolates were genotypically tested for capreomycin resistance were included in the analysis.Results
Of 178 XDR-TB patients 41% were HIV-infected. 87% (154/178) isolates contained a capreomycin resistance-conferring mutation [80% (143/178) rrs A1401G and 6% (11/178) were heteroresistant (containing both the rrs A1401G mutation and wild-type sequences)]. Previous MDR-TB treatment, prior usage of kanamycin, or strain type was not associated with capreomycin resistance. 92% (163/178) of XDR-TB patients were empirically treated with capreomycin. Capreomycin resistance decreased the odds of sputum culture conversion. In capreomycin sensitive and resistant persons combined weight at diagnosis was the only independent predictor for survival (p=<0.001). By contrast, HIV status and use of co-amoxicillin/clavulanic acid were independent predictors of mortality (p=<0.05). Capreomycin usage was not associated with survival or culture conversion when the analysis was restricted to those whose isolates were resistant to capreomycin.Conclusion
In South Africa the frequency of capreomycin conferring mutations was extremely high in XDR-TB isolates. In those with capreomycin resistance there appeared to be no therapeutic benefit of using capreomycin. These data inform susceptibility testing and the design of treatment regimens for XDR-TB in TB endemic settings. 相似文献5.
6.
Fei-Feng Li Jing Zhou Dan-Dan Zhao Peng Yan Xia Li Ying Han Xian-Shu Li Gui-Yu Wang Kai-Jiang Yu Shu-Lin Liu 《PloS one》2015,10(6)
Background
Nodal/TGF signaling pathway has an important effect at early stages of differentiation of human embryonic stem cells in directing them to develop into different embryonic lineages. SMAD3 is a key intracellular messenger regulating factor in the Nodal/TGF signaling pathway, playing important roles in embryonic and, particularly, cardiovascular system development. The aim of this work was to find evidence on whether SMAD3 variations might be associated with ventricular septal defects (VSD) or other congenital heart diseases (CHD).Methods
We sequenced the SMAD3 gene for 372 Chinese Han CHD patients including 176 VSD patients and evaluated SNP rs2289263, which is located before the 5’UTR sequence of the gene. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0). The Hardy-Weinberg equilibrium test of the population was carried out using the online software OEGE.Results
Three heterozygous variants in SMAD3 gene, rs2289263, rs35874463 and rs17228212, were identified. Statistical analyses showed that the rs2289263 variant located before the 5’UTR sequence of SMAD3 gene was associated with the risk of VSD (P value=0.013 <0.05).Conclusions
The SNP rs2289263 in the SMAD3 gene is associated with VSD in Chinese Han populations. 相似文献7.
Renée N. Douville Yuriy Lissitsyn Aaron F. Hirschfeld Allan B. Becker Anita L. Kozyrskyj Joel Liem Nathalie Bastien Yan Li Rachel E. Victor Mehtab Sekhon Stuart E. Turvey Kent T. HayGlass 《PloS one》2010,5(8)
Background
A broad variety of natural environmental stimuli, genotypic influences and timing all contribute to expression of protective versus maladaptive immune responses and the resulting clinical outcomes in humans. The role of commonly co-segregating Toll-like receptor 4 (TLR4) non-synonymous single nucleotide polymorphisms Asp299Gly and Thr399Ile in this process remains highly controversial. Moreover, what differential impact these polymorphisms might have in at risk populations with respiratory dysfunction, such as current asthma or a history of infantile bronchiolitis, has never been examined. Here we determine the importance of these polymorphisms in modulating LPS and respiratory syncytial virus (RSV) - driven cytokine responses. We focus on both healthy children and those with clinically relevant respiratory dysfunction.Methodology
To elucidate the impact of TLR4 Asp299Gly and Thr399Ile on cytokine production, we assessed multiple immune parameters in over 200 pediatric subjects aged 7–9. Genotyping was followed by quantification of pro- and anti-inflammatory cytokine responses by fresh peripheral blood mononuclear cells upon acute exposure to LPS or RSV.Principal Findings
In contrast to early reports, neither SNP influenced immune responses evoked by LPS exposure or RSV infection, as measured by the intermediate phenotype of pro- and anti-inflammatory cytokine responses to these ubiquitous agents. There is no evidence of altered sensitivity in populations with “at risk” clinical phenotypes.Conclusions/Significance
Genomic medicine seeks to inform clinical practice. Determination of the TLR4 Asp299Gly/Thr399Ile haplotype is of no clinical benefit in predicting the nature or intensity of cytokine production in children whether currently healthy or among specific at-risk groups characterized by prior infantile broncholitis or current asthma. 相似文献8.
Background
Ventricular septal defects (VSDs) are the most common and simplest type of congenital heart diseases (CHDs). Animal studies have suggested that the downregulation of Yes-associated protein 1 (YAP1) during embryonic development causes VSD-associated CHDs. However, how YAP1 contributes to isolated VSD (iVSD) is unclear.Methods and Results
Twenty right atrial specimens were obtained from iVSD patients during routine congenital cardiac surgery and we assessed YAP1 expression in these specimens. For controls, six right atrial specimens were obtained from normal hearts of children without heart disease, three of whom died from cerebral palsy, and three who underwent heart transplants. YAP1 mRNA and protein levels and nuclear localization were significantly reduced in iVSD specimens compared to normal heart specimens. Concomitantly, mRNA levels of YAP1 downstream targets CTGF and AXL were also significantly decreased in iVSD specimens. Although Ki67-positive cardiomyocytes in iVSD specimens were comparable to normal heart specimens, Ki67-positive non-cardiomyocytes were significantly decreased.Conclusions
YAP1 expression was markedly decreased in hearts of iVSD children. Given the important role of YAP1 during heart development, downregulation of YAP1 expression may contribute to iVSD and affect the proliferation of non-cardiomyocytes. 相似文献9.
Neha Gupta Mercilena Benjamin Anjana Kar Sachin Dev Munjal Aditya N. Sarangi Ashwin Dalal Rakesh Aggarwal 《PloS one》2015,10(12)
Background
Mild unconjugated hyperbilirubinemia (UH), due to reduced activity of the enzyme uridine diphosphoglucuronate-glucuronosyltransferase family, polypeptide 1 (UGT1A1), is a common clinical condition. Most cases are caused by presence in homozygous form of an A(TA)7TAA nucleotide sequence instead of the usual A(TA)6TAA sequence in promoter region of the UGT1A1 gene. In some cases, other genetic variations have been identified which differ between populations. There is need for more data on such genetic variations from India.Methods
DNA from subjects with unexplained persistent or recurrent UH was tested for the presence of TA promoter insertions. In addition, all five exons and splicing site regions of UGT1A1 gene were sequenced. Several bioinformatics tools were used to determine the biological significance of the observed genetic changes. Functional analysis was done to look for effect of a splice site mutation in UGT1A1.Results
Of 71 subjects with UH (68 male; median age [range], 26 [16–63] years; serum bilirubin 56 [26–219] μM/L, predominantly unconjugated) studied, 65 (91.5%) subjects were homozygous for A(TA)7TAA allele, five (7.0%) were heterozygous, and one (1.4%) lacked this change. Fifteen subjects with UH had missense exonic single nucleotide changes (14 heterozygous, 1 homozygous), including one subject with a novel nucleotide change (p.Thr205Asn). Bioinformatics tools predicted some of these variations (p.Arg108Cys, p.Ile159Thr and p.Glu463Val) to be deleterious. Functional characterization of an exonic variation (c.1084G>A) located at a splice site revealed that it results in frameshift deletion of 31 nucleotides and premature truncation of the protein.Conclusion
Our study revealed several single nucleotide variations in UGT1A1 gene in Indian subjects with UH. Functional characterization of a splice site variation indicated that it leads to disordered splicing. These variations may explain UH in subjects who lacked homozygous A(TA)7TAA promoter alleles. 相似文献10.
Lei He Li Gao Zhe Shi Yuhong Li Lingyan Zhu Shiming Li Peng Zhang Guoying Zheng Qi Ren Yun Li Bo Hu Fumin Feng 《PloS one》2015,10(3)
Background
Anti-tuberculosis (anti-TB) drug-induced liver injury (ADLI) is one of the most common adverse effects associated with TB treatment. Cytochrome P450 (CYP) 1A1 and glutathione S-transferase (GST) P1 are important phase I/II metabolizing enzymes involved in drug metabolism and detoxification. Genetic polymorphism and CpG island methylation have been reported as factors influencing the expression of CYP1A1 and GSTP1.Objective
This study aimed to determine the potential relationships of CYP1A1 and GSTP1 polymorphisms and CpG island methylation with ADLI risk.Design
This was a population-based one-to-one matched case–control study.Setting
The subjects were patients with TB receiving treatment in China from December 2010 to June 2013.Patients
In total, 127 patients with TB and ADLI (case group) and 127 patients with TB but without liver injury (control group) were included in this study. Subjects were matched in terms of sex, age, and therapeutic regimen.Methods
The general condition of each patient was assessed using questionnaires. The CYP1A1 MspI and GSTP1 Ile105Val polymorphisms as well as methylation status were detected by polymerase chain reaction (PCR)–restriction fragment length polymorphism and the methylation-specific PCR method.Results
We found no significant difference in GSTP1 and CYP1A1 genotypes between the two groups, probably because the sample size was not large enough; however, patients with ADLI had significantly higher GSTP1 and CYP1A1 promoter methylation rates than control subjects [odds ratio (OR) = 2.467 and 2.000, respectively]. After adjusting for drinking, which significantly differed between the groups as per univariate analysis, we found that hypermethylation of GSTP1 and CYP1A1 promoters was associated with ADLI (OR = 2.645 and 2.090, respectively).Conclusion
Hypermethylation of CpG islands of GSTP1 and CYP1A1 promoters may thus play important roles in the development of ADLI and provide evidence of being used as novel markers for ADLI risk prediction. 相似文献11.
Yan Gao Yiming Lu Jianming Yi Zhihui Li Dawen Gao Zhoulong Yu Tongning Wu Chenggang Zhang 《PloS one》2016,11(1)
Objective
C. elegans has been used as a biomonitor for microwave-induced stress. However, the RF (radiofrequency) fields that have been used in previous studies were weak (≤1.8W/kg), and the bio-effects on C. elegans were mostly negative or ambiguous. Therefore, this study used more intense RF fields (SAR = 3W/kg) and longer time course of exposure (60h at 25°C, L1 stage through adult stage) to investigate the biological consequences of 1750 MHz RF fields in wild-type worms.Methods
The growth rates and lifespans of RF-exposure group and the control group were carefully recorded. RNA samples were collected at L4 (35h) and gravid adult (50h) stages for further high-throughput sequencing, focusing on differences between the RF-exposure and the sham control groups.Results
The RF-exposed and sham control groups developed at almost the same rate and had similar longevity curves. In L4 stage worms, 94 up-regulated and 17 down-regulated genes were identified, while 186 up-regulated and 3 down-regulated genes were identified in adult stage worms. GO analysis showed that the differentially expressed genes at 35h were associated with growth, body morphogenesis and collagen and cuticle-based development. Genes that were linked to growth rate and reproductive development were differentially expressed at 50h. Some embryonic and larval development genes in the offspring were also differentially expressed at 50h. Ten genes were differentially expressed at both 35h and 50h, most of which were involved in both embryonic and larval developmental processes. Although prolonged RF fields did not induce significant temperature increase in RF exposure groups, the temperature inside worms during exposure was unknown.Conclusions
No harmful effects were observed in prolonged exposure to 1750 MHz RF fields at SAR of 3W/kg on development and longevity of C. elegans. Although some differentially expressed genes were found after prolonged RF exposure, these differences were ascribed to oscillating gene expression patterns in L4 and gravid adult worms. It was also difficult to rule out a weak thermal effect caused by prolonged RF exposure inside the worms. 相似文献12.
Ron P. Dirks Remon van Geel Sanne M. M. Hensen Siebe T. van Genesen Nicolette H. Lubsen 《PloS one》2010,5(4)
Background
The aging related decline of heat shock factor-1 (HSF1) signaling may be causally related to protein aggregation diseases. To model such disease, we tried to cripple HSF1 signaling in the Xenopus tadpole.Results
Over-expression of heat shock factor binding protein-1 did not inhibit the heat shock response in Xenopus. RNAi against HSF1 mRNA inhibited the heat shock response by 70% in Xenopus A6 cells, but failed in transgenic tadpoles. Expression of XHSF380, a dominant-negative HSF1 mutant, was embryonic lethal, which could be circumvented by delaying expression via a tetracycline inducible promoter. HSF1 signaling is thus essential for embryonic Xenopus development. Surprisingly, transgenic expression of the XHSF380 or of full length HSF1, whether driven by a ubiquitous or a neural specific promoter, was not detectable in the larval brain.Conclusions
Our finding that the majority of neurons, which have little endogenous HSF1, refused to accept transgene-driven expression of HSF1 or its mutant suggests that HSF1 levels are strictly controlled in neuronal tissue. 相似文献13.
Peter U. Ardelt Jan Ebbing Fabian Adams Cora Reiss Wadih Arap Renata Pasqualini Alexander Bachmann Ulrich Wetterauer Hubertus Riedmiller Burkhard Kneitz 《PloS one》2015,10(3)
Background
To use combinatorial epitope mapping (“fingerprinting”) of the antibody response to identify targets of the humoral immune response in patients with transitional cell carcinoma (TCC) of the bladder.Methods
A combinatorial random peptide library was screened on the circulating pool of immunoglobulins purified from an index patient with a high risk TCC (pTa high grade plus carcinoma in situ) to identify corresponding target antigens. A patient cohort was investigated for antibody titers against ubiquitin.Results
We selected, isolated, and validated an immunogenic peptide motif from ubiquitin as a dominant epitope of the humoral response. Patients with TCC had significantly higher antibody titers against ubiquitin than healthy donors (p<0.007), prostate cancer patients (p<0.0007), and all patients without TCC taken together (p<0.0001). Titers from superficial tumors were not significantly different from muscle invasive tumors (p = 0.0929). For antibody response against ubiquitin, sensitivity for detection of TCC was 0.44, specificity 0.96, positive predictive value 0.96 and negative predictive value 0.41. No significant titer changes were observed during the standard BCG induction immunotherapy.Conclusions
This is the first report to demonstrate an anti-ubiquitin antibody response in patients with TCC. Although sensitivity of antibody production was low, a high specificity and positive predictive value make ubiquitin an interesting candidate for further diagnostic and possibly immune modulating studies. 相似文献14.
Patrick Horn Gülsüm Erkilet Verena Veulemans Patric Kr?pil Leon Schurgers Tobias Zeus Christian Heiss Malte Kelm Ralf Westenfeld 《PloS one》2016,11(3)
Background
Circulating microparticles (MPs) derived from endothelial cells and blood cells bear procoagulant activity and promote thrombin generation. Thrombin exerts proinflammatory effects mediating the progression of atherosclerosis. Aortic valve stenosis may represent an atherosclerosis-like process involving both the aortic valve and the vascular system. The aim of this study was to investigate whether MP-induced thrombin generation is related to coronary atherosclerosis and aortic valve calcification.Methods
In a cross-sectional study of 55 patients with severe aortic valve stenosis, we assessed the coronary calcification score (CAC) as indicator of total coronary atherosclerosis burden, and aortic valve calcification (AVC) by computed tomography. Thrombin-antithrombin complex (TATc) levels were measured as a marker for thrombin formation. Circulating MPs were characterized by flow cytometry according to the expression of established surface antigens and by measuring MP-induced thrombin generation.Results
Patients with CAC score below the median were classified as patients with low CAC, patients with CAC Score above the median as high CAC. In patients with high CAC compared to patients with low CAC we detected higher levels of TATc, platelet-derived MPs (PMPs), endothelial-derived MPs (EMPs) and MP-induced thrombin generation. Increased level of PMPs and MP-induced thrombin generation were independent predictors for the severity of CAC. In contrast, AVC Score did not differ between patients with high and low CAC and did neither correlate with MPs levels nor with MP-induced thrombin generation.Conclusion
In patients with severe aortic valve stenosis MP-induced thrombin generation was independently associated with the severity of CAC but not AVC indicating different pathomechanisms involved in coronary artery and aortic valve calcification. 相似文献15.
Betty Fumel Pascal Froment Martin Holzenberger Gabriel Livera Philippe Monget Sophie Fouchécourt 《PloS one》2015,10(3)
Background
In the testis, thyroid hormone (T3) regulates the number of gametes produced through its action on Sertoli cell proliferation. However, the role of T3 in the regulation of steroidogenesis is still controversial.Methods
The TRαAMI knock-in allele allows the generation of transgenic mice expressing a dominant-negative TRα1 (thyroid receptor α1) isoform restricted to specific target cells after Cre-loxP recombination. Here, we introduced this mutant allele in both Sertoli and Leydig cells using a novel aromatase-iCre (ARO-iCre) line that expresses Cre recombinase under control of the human Cyp19(IIa)/aromatase promoter.Findings
We showed that loxP recombination induced by this ARO-iCre is restricted to male and female gonads, and is effective in Sertoli and Leydig cells, but not in germ cells. We compared this model with the previous introduction of TRαAMI specifically in Sertoli cells in order to investigate T3 regulation of steroidogenesis. We demonstrated that TRαAMI-ARO males exhibited increased testis weight, increased sperm reserve in adulthood correlated to an increased proliferative index at P3 in vivo, and a loss of T3-response in vitro. Nevertheless, TRαAMI-ARO males showed normal fertility. This phenotype is similar to TRαAMI-SC males. Importantly, plasma testosterone and luteinizing hormone levels, as well as mRNA levels of steroidogenesis enzymes StAR, Cyp11a1 and Cyp17a1 were not affected in TRαAMI-ARO.Conclusions/Significance
We concluded that the presence of a mutant TRαAMI allele in both Leydig and Sertoli cells does not accentuate the phenotype in comparison with its presence in Sertoli cells only. This suggests that direct T3 regulation of steroidogenesis through TRα1 is moderate in Leydig cells, and that Sertoli cells are the main target of T3 action in the testis. 相似文献16.
Charles S. Berenson Ragina L. Kruzel Catherine T. Wrona Manoj J. Mammen Sanjay Sethi 《PloS one》2015,10(9)
Background
Dysfunctional innate responses of alveolar macrophages to nontypeable Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae contribute to morbidity in chronic obstructive pulmonary disease (COPD). Our earlier studies discovered impaired COPD alveolar macrophage responses to Toll-like receptor (TLR) ligands of nontypeable H. influenzae and provide rationale for further evaluation of TLR signaling. While the role of TLR single nucleotide polymorphisms is increasingly recognized in inflammatory diseases, TLR single nucleotide polymorphisms in COPD have only recently been explored. We hypothesized that specific TLR polymorphisms are associated with dysfunctional innate immune COPD alveolar macrophage responses and investigated polymorphisms of TLR2(Arg753Gln), TLR4(Thr399Ile; Asp299Gly), and TLR9(T1486C; T1237C).Methods
DNA was purified from cells of 1) healthy nonsmokers (n = 20); 2) COPD ex-smokers (n = 83); 3) COPD active smokers (n = 93). DNA amplifications (polymerase chain reaction) were performed for each SNP. Alveolar macrophages from each group were incubated with nontypeable H. influenzae, M. catarrhalis and S. pneumoniae. Cytokine induction of macrophage supernatants was measured and the association with TLR single nucleotide polymorphism expression was determined.Results
No significant inter-group differences in frequency of any TLR SNP existed. However both TLR9 single nucleotide polymorphisms were expressed in high frequency. Among COPD ex-smokers, diminished IL-8 responsiveness to nontypeable H. influenzae, M. catarrhalis and S. pneumoniae was strongly associated with carriage of TLR9(T1237C) (p = 0.02; p = 0.008; p = 0.02), but not TLR9(T1486C). Carriage of TLR9(T1237C), but not TLR9(T1486C), correlated with diminished FEV1%predicted (p = 0.037).Conclusion
Our results demonstrate a notable association of TLR9(T1237C) expression with dysfunctional innate alveolar macrophage responses to respiratory pathogens and with severity of COPD. 相似文献17.
18.
Background
About 9% of the offspring of a clinically healthy Piétrain boar named ‘Campus’ showed a progressive postural tremor called Campus syndrome (CPS). Extensive backcross experiments suggested a dominant mode of inheritance, and the founder boar was believed to be a gonadal mosaic. A genome-scan mapped the disease-causing mutation to an 8 cM region of porcine chromosome 7 containing the MHY7 gene. Human distal myopathy type 1 (MPD1), a disease partially resembling CPS in pigs, has been associated with mutations in the MYH7 gene.Results
The porcine MYH7 gene structure was predicted based on porcine reference genome sequence, porcine mRNA, and in comparison to the human ortholog. The gene structure was highly conserved with the exception of the first exon. Mutation analysis of a contiguous genomic interval of more than 22 kb spanning the complete MYH7 gene revealed an in-frame insertion within exon 30 of MYH7 (c.4320_4321insCCCGCC) which was perfectly associated with the disease phenotype and confirmed the dominant inheritance. The mutation is predicted to insert two amino acids (p.Ala1440_Ala1441insProAla) in a very highly conserved region of the myosin tail. The boar ‘Campus’ was shown to be a germline and somatic mosaic as assessed by the presence of the mutant allele in seven different organs.Conclusion
This study illustrates the usefulness of recently established genomic resources in pigs. We have identified a spontaneous mutation in MYH7 as the causative mutation for CPS. This paper describes the first case of a disorder caused by a naturally occurring mutation in the MYH7 gene of a non-human mammalian species. Our study confirms the previous classification as a primary myopathy and provides a defined large animal model for human MPD1. We provide evidence that the CPS mutation occurred during the early development of the boar ‘Campus’. Therefore, this study provides an example of germline mosaicism with an asymptomatic founder.19.
Pecci A Biino G Fierro T Bozzi V Mezzasoma A Noris P Ramenghi U Loffredo G Fabris F Momi S Magrini U Pirastu M Savoia A Balduini C Gresele P;Italian Registry for MYH-releated diseases 《PloS one》2012,7(4):e35986
Background
MYH9-related disease (MYH9-RD) is a rare autosomal dominant genetic syndrome characterized by congenital thrombocytopenia associated with the risk of developing progressive nephropathy, sensorineural deafness, and presenile cataract. During the collection of a large case-series of patients with MYH9-RD we noticed several cases with unexplained elevation of liver enzymes. Our aim was to evaluate if the alteration of liver tests is a feature of the MYH9-RD and to define its clinical significance.Methods and Findings
Data concerning liver tests, prospectively recorded in the Italian Registry for MYH9-RD, were collected and compared with those of three control populations: patients with autoimmune thrombocytopenia, patients with inherited thrombocytopenias other than MYH9-RD, and the participants to a large epidemiologic survey in an Italian geographic isolate. Thirty-eight of 75 evaluable MYH9-RD patients (50.7%) showed an elevation of ALT and/or AST, and 17 of 63 (27.0%) an increase of GGT. The increases ranged from 1.9±0.7 to 2.7±1.6 fold the upper normal limit. The prevalence of liver test alterations was significantly higher in MYH9-RD patients than in each of the control populations, with odds ratios ranging from 8.2 (95% CIs 2.2–44.8) to 24.7 (14.8–40.8). Clinical follow-up and more detailed liver studies of a subset of patients, including ultrasound liver scan, liver elastography and liver biopsy in one case, did not show any significant structural damage or evolution towards liver insufficiency.Conclusions
Elevation of liver enzymes is a frequent and previously unrecognized feature of the MYH9-RD syndrome; however, this defect does not appear to have poor prognostic value. 相似文献20.
Michael S. Donnenberg Tracy H. Hazen Tamer H. Farag Sandra Panchalingam Martin Antonio Anowar Hossain Inacio Mandomando John Benjamin Ochieng Thandavarayan Ramamurthy Boubou Tamboura Anita Zaidi Myron M. Levine Karen Kotloff David A. Rasko James P. Nataro 《PLoS neglected tropical diseases》2015,9(5)