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51.
Estimating synonymous and nonsynonymous substitution rates 总被引:8,自引:4,他引:4
Partitioning the total substitution rate into synnonymous and nonsynonymous
components is a key aspect of many analyses in molecular evolution.
Numerous methods exist for estimating these rates. However, until recently
none of the estimation procedures were based on a sound statistical
footing. In this paper, the evolutionary model of Muse and Gaut (1994) is
used as the basis for two sets of parameters quantifying silent and
replacement substitution rates. The parameters are shown to be equal when
the four nucleotides are equally frequent and unequal otherwise.
Maximum-likelihood estimation of these parameters is described, and the
performance of these estimates is compared to that of existing estimation
procedures. It is shown that the estimates of Nei and Gojobori (1986) are
not unbiased for either set of parameters, although they provide very good
estimates for one set as long as sequence divergence is not too high.
However, some disturbing properties are found for the Nei and Gojobori
estimates. In particular, it is shown that the expected value of the Nei
and Gojobori estimate of silent substitution rate is a function of both the
silent and replacement substitution rates. The maximum-likelihood estimates
have no such problems.
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52.
Subramanian V Krishnamurthy P Singh K Singh M 《American journal of physiology. Heart and circulatory physiology》2007,292(1):H673-H683
The purpose of this study was to investigate the role of osteopontin (OPN) in diabetic hearts. Diabetes was induced in wild-type (WT) and OPN knockout (KO) mice by using streptozotocin (150 mg/kg) injection. Left ventricular (LV) structural and functional remodeling was studied 30 and 60 days after induction of diabetes. Induction of diabetes increased OPN expression in cardiac myocytes. Heart weight-to-body weight ratio was increased in both diabetic (D) groups. Lung wet weight-to-dry weight ratio was increased only in the WT-D group. Peak left ventricular (LV) developed pressures measured using Langendorff perfusion analyses were reduced to a greater extent in WT-D versus KO-D group. LV end-diastolic pressure-volume curve exhibited a significant leftward shift in WT-D but not in KO-D group. LV end-diastolic diameter, percent fractional shortening, and the ratio of peak velocity of early and late filling (E/A wave) were significantly reduced in WT-D mice as analyzed by echocardiography. The increase in cardiac myocyte apoptosis and fibrosis was significantly higher in the WT-D group. Expression of atrial natriuretic peptide and transforming growth factor-beta1 was significantly increased in the WT-D group. Induction of diabetes increased protein kinase C (PKC) phosphorylation in both groups. However, phosphorylation of PKC-betaII was significantly higher in the WT-D group, whereas phosphorylation of PKC-zeta was significantly higher in the KO-D group. Levels of peroxisome proliferator-activated receptor-gamma were significantly decreased in the WT-D group but not in the KO-D group. Thus increased expression of OPN may play a deleterious role during streptozotocin-induced diabetic cardiomyopathy with effects on cardiac fibrosis, hypertrophy, and myocyte apoptosis. 相似文献
53.
Mountain DJ Singh M Menon B Singh K 《American journal of physiology. Cell physiology》2007,292(2):C867-C875
Matrix metalloproteinases (MMPs), a family of extracellular endopeptidases, are implicated in angiogenesis because of their ability to selectively degrade components of the extracellular matrix. Interleukin-1 (IL-1), increased in the heart post-myocardial infarction (post-MI), plays a protective role in the pathophysiology of left ventricular (LV) remodeling following MI. Here we studied expression of various angiogenic genes affected by IL-1 in cardiac microvascular endothelial cells (CMECs) and investigated the signaling pathways involved in the regulation of MMP-2. cDNA array analysis of 96 angiogenesis-related genes indicated that IL-1 modulates the expression of numerous genes, notably increasing the expression of MMP-2, not MMP-9. RT-PCR and Western blot analyses confirmed increased expression of MMP-2 in response to IL-1. Gelatin in-gel zymography and Biotrak activity assay demonstrated that IL-1 increases MMP-2 activity in the conditioned media. IL-1 activated ERK1/2, JNKs, and protein kinase C (PKC), specifically PKC/1, and inhibition of these cascades partially inhibited IL-1-stimulated increases in MMP-2. Inhibition of PKC/1 failed to inhibit ERK1/2. However, concurrent inhibition of PKC/1 and ERK1/2 almost completely inhibited IL-1-mediated increases in MMP-2 expression. Inhibition of p38 kinase and nuclear factor-B (NF-B) had no effect. Pretreatment with superoxide dismutase (SOD) mimetic, MnTMPyP, increased MMP-2 protein levels, whereas pretreatment with SOD and catalase mimetic, EUK134, partially inhibited IL-1-stimulated increases in MMP-2 protein levels. Exogenous H2O2 significantly increased MMP-2 protein levels, whereas superoxide generation by xanthine/xanthine oxidase had no effect. This in vitro study suggests that IL-1 modulates expression and activity of MMP-2 in CMECs. MMP-2; protein kinase C; ERK1/2; JNK 相似文献
54.
Mahipal Yadav Charles L. Liotta Ramanarayanan Krishnamurthy 《Bioorganic & medicinal chemistry letters》2018,28(16):2759-2765
Regioselective oxidation of unprotected and partially protected oligosaccharides is a much sought-after goal. Herein, we report a notable improvement in the efficiency of TEMPO-catalyzed oxidation by modulating the temperature of the reaction. Mono-, di-, and tri-saccharides are oxidized regioselectively in yields of 75 to 92%. The present method is simple to implement and is also applicable for selective oxidations of other mono- and poly-hydroxy compounds including unprotected and partially protected nucleosides. 相似文献
55.
Manokari M. Priyadharshini S. Shekhawat Mahipal S. 《Plant Cell, Tissue and Organ Culture》2021,145(2):321-331
Plant Cell, Tissue and Organ Culture (PCTOC) - Spathoglottis plicata Blume is a vulnerable orchid species in various parts of the world, and the conventional propagation provides limited success to... 相似文献
56.
β-Adrenergic receptor (β-AR) stimulation induces cardiac myocyte apoptosis and plays an important role in myocardial remodeling. Here we investigated expression of various apoptosis-related genes affected by β-AR stimulation, and examined first time the role of ataxia telangiectasia mutated kinase (ATM) in cardiac myocyte apoptosis and myocardial remodeling following β-AR stimulation. cDNA array analysis of 96 apoptosis-related genes indicated that β-AR stimulation increases expression of ATM in the heart. In vitro, RT-PCR confirmed increased ATM expression in adult cardiac myocytes in response to β-AR stimulation. Analysis of left ventricular structural and functional remodeling of the heart in wild-type (WT) and ATM heterozygous knockout mice (hKO) 28 days after ISO-infusion showed increased heart weight to body weight ratio in both groups. M-mode echocardiography showed increased percent fractional shortening (%FS) and ejection fraction (EF%) in both groups 28 days post ISO-infusion. Interestingly, the increase in %FS and EF% was significantly lower in the hKO-ISO group. Cardiac fibrosis and myocyte apoptosis were higher in hKO mice at baseline and ISO-infusion increased fibrosis and apoptosis to a greater extent in hKO-ISO hearts. ISO-infusion increased phosphorylation of p53 (Serine-15) and expression of p53 and Bax to a similar extent in both groups. hKO-Sham and hKO-ISO hearts exhibited reduced intact β1 integrin levels. MMP-2 protein levels were significantly higher, while TIMP-2 protein levels were lower in hKO-ISO hearts. MMP-9 protein levels were increased in WT-ISO, not in hKO hearts. In conclusion, ATM plays a protective role in cardiac remodeling in response to β-AR stimulation. 相似文献
57.
Cerrone R. Foster Laura L. Daniel Christopher R. Daniels Suman Dalal Mahipal Singh Krishna Singh 《PloS one》2013,8(12)
Ataxia telangiectasia mutated kinase (ATM) is a cell cycle checkpoint protein activated in response to DNA damage. We recently reported that ATM plays a protective role in myocardial remodeling following β-adrenergic receptor stimulation. Here we investigated the role of ATM in cardiac remodeling using myocardial infarction (MI) as a model. Methods and Results: Left ventricular (LV) structure, function, apoptosis, fibrosis, and protein levels of apoptosis- and fibrosis-related proteins were examined in wild-type (WT) and ATM heterozygous knockout (hKO) mice 7 days post-MI. Infarct sizes were similar in both MI groups. However, infarct thickness was higher in hKO-MI group. Two dimensional M-mode echocardiography revealed decreased percent fractional shortening (%FS) and ejection fraction (EF) in both MI groups when compared to their respective sham groups. However, the decrease in %FS and EF was significantly greater in WT-MI vs hKO-MI. LV end systolic and diastolic diameters were greater in WT-MI vs hKO-MI. Fibrosis, apoptosis, and α-smooth muscle actin staining was significantly higher in hKO-MI vs WT-MI. MMP-2 protein levels and activity were increased to a similar extent in the infarct regions of both groups. MMP-9 protein levels were increased in the non-infarct region of WT-MI vs WT-sham. MMP-9 protein levels and activity were significantly lower in the infarct region of WT vs hKO. TIMP-2 protein levels similarly increased in both MI groups, whereas TIMP-4 protein levels were significantly lower in the infarct region of hKO group. Phosphorylation of p53 protein was higher, while protein levels of manganese superoxide dismutase were significantly lower in the infarct region of hKO vs WT. In vitro, inhibition of ATM using KU-55933 increased oxidative stress and apoptosis in cardiac myocytes. 相似文献
58.
A nearly universal feature of intron sequences is that even closely related
species exhibit a large number of insertion/deletion differences. The goal
of the analysis described here is to test whether the observed pattern of
insertion/deletion events in the genealogy of the myosin alkali light chain
(Mlc1) gene is consistent with neutrality, and if not, to determine the
underlying forces of evolutionary change. Mlc1 pre-mRNA is alternatively
spliced, and one constraint is that signals necessary for
tissue-specificity of directed splicing must be conserved. If the total
length of an intron is functionally constrained, then the distribution of
indels on branches of the gene genealogy should reflect a departure from
randomness. Here we perform a phylogenetic analysis, inferring ancestral
states wherever possible on a phylogeny of 29 alleles of Mlc1 from six
species of Drosophila. Observed patterns of indels on the genealogy were
compared to those from simulated data, with the result that we cannot
reject the null hypothesis of neutrality. A clear departure from a neutral
prediction was seen in the excess folding free energy predicted for the
introns flanking the alternatively spliced exon. Relative rate tests also
suggest a retardation in the rate of Mlc1 sequence evolution in the
simulans clade.
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59.
60.
A likelihood approach for comparing synonymous and nonsynonymous nucleotide substitution rates, with application to the chloroplast genome 总被引:29,自引:24,他引:5
A model of DNA sequence evolution applicable to coding regions is
presented. This represents the first evolutionary model that accounts for
dependencies among nucleotides within a codon. The model uses the codon, as
opposed to the nucleotide, as the unit of evolution, and is parameterized
in terms of synonymous and nonsynonymous nucleotide substitution rates. One
of the model's advantages over those used in methods for estimating
synonymous and nonsynonymous substitution rates is that it completely
corrects for multiple hits at a codon, rather than taking a parsimony
approach and considering only pathways of minimum change between homologous
codons. Likelihood-ratio versions of the relative-rate test are constructed
and applied to data from the complete chloroplast DNA sequences of Oryza
sativa, Nicotiana tabacum, and Marchantia polymorpha. Results of these
tests confirm previous findings that substitution rates in the chloroplast
genome are subject to both lineage-specific and locus-specific effects.
Additionally, the new tests suggest tha the rate heterogeneity is due
primarily to differences in nonsynonymous substitution rates. Simulations
help confirm previous suggestions that silent sites are saturated, leaving
no evidence of heterogeneity in synonymous substitution rates.
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