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61.
Background
Many homeobox genes show remarkable conservation between divergent animal phyla. In contrast, the ARGFX (Arginine-fifty homeobox) homeobox locus was identified in the human genome but is not present in mouse or invertebrates. Here we ask when and how this locus originated and examine its pattern of molecular evolution. 相似文献62.
A mouse genomic clone containing a lactate dehydrogenase-A (LDH-A)
processed pseudogene and a B1 repetitive element was isolated, and a
nucleotide sequence of approximately 3 kb was determined. The pseudogene
and B1 element are flanked by perfect 13-bp repeats, and the B1 sequence
starts at 14 nucleotides 3' to the presumptive polyadenylation signal of
the pseudogene. The nucleotide sequences of the LDH-A genes and processed
pseudogenes from mouse, rat, and human were compared, and a phylogenetic
tree was constructed. The rate and pattern of nucleotide substitutions in
the LDH-A pseudogenes are similar to previously reported results (Li et al.
1984). The average rate of nucleotide substitutions in the LDH-A
pseudogenes is 4.3 X 10(- 9)/site/year. The substitutions of C----T and
G----A are most frequent, and A----G substitutions are relatively high. The
rate of synonymous substitutions in the LDH-A genes is 5.3 X 10(-9), which
is not significantly higher than the average rate of 4.7 X 10(-9) for 35
mammalian genes. The rate of nonsynonymous substitutions in the LDH-A genes
is 0.20 X 10(-9), which is considerably lower than the average rate of 0.88
X 10(-9) for 35 mammalian genes. Thus, the mammalian LDH-A gene appears to
be highly conserved in evolution.
相似文献
63.
Scott C. Borinstein David Agamasu Jonathan S. Schildcrout Lisa Bastarache Minoo Bagheri Lea K. Davis Dan M. Roden C. Michael Stein Sara L. Van Driest Jonathan D. Mosley 《Journal of cellular and molecular medicine》2022,26(13):3628
Healthy individuals in the United States identified as having Black race have lower neutrophil counts, on average, than individuals identified as having White race, which could result in more negative diagnostic evaluations for neutropenia. To test this hypothesis, the proportion of evaluations where the final diagnosis was clinically insignificant neutropenia for Black and White individuals who underwent an evaluation by a haematologist that included a bone marrow (BM) biopsy to investigate neutropenia was assessed. 172 individuals without prior haematological diagnoses who underwent a haematological evaluation to investigate neutropenia. Individuals diagnosed with clinically insignificant neutropenia between Black and White individuals were compared using a propensity‐score‐adjusted logistic regression. Of 172 individuals, 42 (24%) were classified as Black race, 86 (50%) were males, and the 79 (46%) were over 18 years old. A BM biopsy did not identify pathology in 95% (40 of 42) of Black individuals and 68% (89 of 130) of White Individuals. Black individuals (25 of 42 [60%]) received a final diagnosis of clinically insignificant neutropenia, compared to White individuals (12 of 130 [9%]) (adjusted odds ratio =7.9, 95% CI: 3.1 – 21.1). We conclude that black individuals were more likely to receive a diagnosis of clinically insignificant neutropenia after haematological assessment. 相似文献
64.
Roden M 《Cell metabolism》2007,6(2):89-91
Elevated circulating fatty acids are associated with impaired insulin action and inflammation. During intracellular transit, fatty acids use fatty acid-binding proteins (FABPs) as shuttles. A recent study (Furuhashi et al., 2007) explores inhibiting FABP4/aP2 as a strategy for treating atherosclerosis and type 2 diabetes. 相似文献
65.
Marc Ingenwerth Anna Lena Reinbeck Anna Stahr Hans-Joachim Partke Michael Roden Volker Burkart 《Chronobiology international》2016,33(10):1369-1375
Circadian disruption is associated with the development of diabetes. Non-obese diabetic (NOD) mice show abnormal diurnal profiles in energy balance and locomotor activity suggesting circadian misalignment. Therefore, we analyzed cFos and mPER1 as markers for rhythmic neuronal activity within the suprachiasmatic nucleus (SCN) of wildtype (WT) and non-diabetic (nNOD) as well as acutely diabetic NOD (dNOD) mice. cFos levels show a day/night difference in both WT and nNOD but not in dNOD. mPER1 levels did not show a day/night difference in both nNOD and dNOD. This suggests that disruption of SCN rhythmicity in NOD mice precedes the actual onset of diabetes. 相似文献
66.
The genomes of homeothermic (warm-blooded) vertebrates are mosaic
interspersions of homogeneously GC-rich and GC-poor regions (isochores).
Evolution of genome compartmentalization and GC-rich isochores is
hypothesized to reflect either selective advantages of an elevated GC
content or chromosome location and mutational pressure associated with the
timing of DNA replication in germ cells. To address the present controversy
regarding the origins and maintenance of isochores in homeothermic
vertebrates, newly obtained as well as published nucleotide sequences of
the insulin and insulin-like growth factor (IGF) genes, members of a
well-characterized gene family believed to have evolved by repeated
duplication and divergence, were utilized to examine the evolution of base
composition in nonconstrained (flanking) and weakly constrained (introns
and fourfold degenerate sites) regions. A phylogeny derived from amino acid
sequences supports a common evolutionary history for the insulin/IGF family
genes. In cold- blooded vertebrates, insulin and the IGFs were similar in
base composition. In contrast, insulin and IGF-II demonstrate dramatic
increases in GC richness in mammals, but no such trend occurred in IGF- I.
Base composition of the coding portions of the insulin and IGF genes across
vertebrates correlated (r = 0.90) with that of the introns and flanking
regions. The GC content of homologous introns differed dramatically between
insulin/IGF-II and IGF-I genes in mammals but was similar to the GC level
of noncoding regions in neighboring genes. Our findings suggest that the
base composition of introns and flanking regions is determined by
chromosomal location and the mutational pressure of the isochore in which
the sequences are embedded. An elevated GC content at codon third positions
in the insulin and the IGF genes may reflect selective constraints on the
usage of synonymous codons.
相似文献
67.
Julia Szendroedi Elisabeth Zwettler Albrecht Ingo Schmid Marek Chmelik Giovanni Pacini Gertrud Kacerovsky Gerhard Smekal Peter Nowotny Oswald Wagner Christoph Schnack Guntram Schernthaner Klaus Klaushofer Michael Roden 《PloS one》2008,3(12)
Background
Impaired mitochondrial function and ectopic lipid deposition in skeletal muscle and liver have been linked to decreased insulin sensitivity. As growth hormone (GH) excess can reduce insulin sensitivity, we examined the impact of previous acromegaly (AM) on glucose metabolism, lipid storage and muscular ATP turnover.Participants and Methods
Seven AM (4f/3 m, age: 46±4 years, BMI: 28±1 kg/m2) and healthy volunteers (CON: 3f/4 m, 43±4 years, 26±2 kg/m2) matched for age and body mass underwent oral glucose testing for assessment of insulin sensitivity (OGIS) and ß-cell function (adaptation index, ADAP). Whole body oxidative capacity was measured with indirect calorimetry and spiroergometry. Unidirectional ATP synthetic flux (fATP) was assessed from 31P magnetic resonance spectroscopy (MRS) of calf muscle. Lipid contents of tibialis anterior (IMCLt) and soleus muscles (IMCLs) and liver (HCL) were measured with 1H MRS.Results
Despite comparable GH, insulin-like growth factor-1 (IGF-I) and insulin sensitivity, AM had ∼85% lower ADAP (p<0.01) and ∼21% reduced VO2max (p<0.05). fATP was similarly ∼25% lower in AM (p<0.05) and related positively to ADAP (r = 0.744, p<0.01), but negatively to BMI (r = −0.582, p<0.05). AM had ∼3fold higher HCL (p<0.05) while IMCLt and IMCLs did not differ between the groups.Conclusions
Humans with a history of acromegaly exhibit reduced insulin secretion, muscular ATP synthesis and oxidative capacity but elevated liver fat content. This suggests that alterations in ß-cell function and myocellular ATP production may persist despite normalization of GH secretion after successful treatment of acromegaly. 相似文献68.
Anchoori RK Khan SR Sueblinvong T Felthauser A Iizuka Y Gavioli R Destro F Isaksson Vogel R Peng S Roden RB Bazzaro M 《PloS one》2011,6(8):e23888
Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate, and for specific signaling pathways, notably HPV E6-targeted degradation of p53 and PDZ proteins. Natural compounds with antioxidant properties including flavonoids and triterpenoids hold promise as anticancer agents by interfering with ubiquitin-dependent protein degradation. An increasing body of evidence indicates that their α-β unsaturated carbonyl system is the molecular determinant for inhibition of ubiquitin-mediated protein degradation up-stream of the catalytic sites of the 20S proteasome. Herein we report the identification and characterization of a new class of chalcone-based, potent and cell permeable chemical inhibitors of ubiquitin-dependent protein degradation, and a lead compound RAMB1. RAMB1 inhibits ubiquitin-dependent protein degradation without compromising the catalytic activities of the 20S proteasome, a mechanism distinct from that of Bortezomib. Treatment of cervical cancer cells with RAMB1 triggers unfolded protein responses, including aggresome formation and Hsp90 stabilization, and increases p53 steady state levels. RAMB1 treatment results in activation of lysosomal-dependent degradation pathways as a mechanism to compensate for increasing levels of poly-ubiquitin enriched toxic aggregates. Importantly, RAMB1 synergistically triggers cell death of cervical cancer cells when combined with the lysosome inhibitor Chloroquine. 相似文献
69.
70.
Kanki H Kupershmidt S Yang T Wells S Roden DM 《The Journal of biological chemistry》2004,279(32):33976-33983
Normal membrane protein function requires trafficking from the endoplasmic reticulum. Here, we studied processing of the KCNQ1 channel mutated in LQT1, the commonest form of the long QT syndrome. Serial C terminus truncations identified a small region (amino acids (aa) 610-620) required for normal cell surface expression. Non-trafficked truncations assembled as tetramers but were nevertheless retained in the endoplasmic reticulum. Further mutagenesis did not identify specific residues mediating channel processing; cell surface expression was preserved with the mutation of known trafficking motifs in the channel and with alanine scanning across aa 610-620. Structural prediction algorithms place aa 610-620 at the C-terminal end of an alpha-helix (aa 586-618) that includes a leucine zipper and is part of a coiled coil. Mutants disrupting the leucine zipper but preserving the predicted coiled coil reached the cell surface, whereas those disrupting the coil did not. These data suggest that specific protein-protein interactions are required for normal channel processing. Further biochemical studies ruled out three candidate proteins, namely KCNE1, yotiao, and KCNQ1 itself, as effectors of this coiled coil-mediated trafficking. Four LQT1 mutations within this helix generated little or no current and were not expressed on the cell surface, whereas LQT1 mutations in adjacent residues, which produce a milder clinical phenotype, generate only slightly reduced current and are expressed on the cell surface. These data suggest that mutations within this domain cause human disease by interfering with normal channel processing. More generally, we have identified a domain whose structural integrity is required for normal surface expression of the KCNQ1 channel. 相似文献