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PubMed2002

Neurons expressing neuropeptide Y mRNA in the infundibular hypothalamus of Japanese quail are activated by fasting and co-express agouti-related protein mRNA.

The neural mechanisms involved in the compensatory hyperphagia exhibited by many vertebrate species after a fast are not fully understood but, in mammals, appear to involve nutritionally-sensitive neurons that co-express neuropeptide Y (NPY) and agouti-related protein (AGRP) in the infundibular hypothalamus. We investigated whether these neurons have been evolutionarily conserved in a non-mammalian vertebrate, the Japanese quail. Birds exhibited compensatory hyperphagia 1 h after return of food following a 24-h fast. We addressed a potential regulatory role for NPY, first, by using in situ hybridisation (ISH) to map NPY gene expression in the hypothalamus. This revealed a strong signal in the infundibular nucleus (IN). Secondly, we quantified NPY gene expression in 24-h fasted birds compared to ad libitum fed controls using two independent methods. In whole hypothalamus, measured by ribonuclease protection assay, NPY mRNA increased 1.5-fold in fasted birds. A similar, 1.7-fold, increase was observed specifically in the IN when analysed by ISH. No differences in NPY expression between fed and fasted birds were observed in other brain regions. To determine whether NPY neurons in the avian IN co-express AGRP, we cloned a fragment of the quail AGRP gene and used it to localise AGRP mRNA by ISH. The gene was expressed exclusively in the hypothalamus, specifically in the IN, where its distribution matched that of NPY. Double-label ISH revealed that the majority of NPY neurons in the IN co-express AGRP mRNA. Collectively, these data indicate that this cell type has been neuroanatomically and functionally conserved during vertebrate evolution.

Agouti-Related Protein↗

PubMed2004

Xenopus U3 snoRNA docks on pre-rRNA through a novel base-pairing interaction.

U3 small nucleolar RNA (snoRNA) is essential for rRNA processing to form 18S ribosomal RNA (rRNA). Previously, it has been shown that nucleolin is needed to load U3 snoRNA on pre-rRNA. However, as documented here, this is not sufficient. We present data that base-pairing between the U3 hinges and the external transcribed spacer (ETS) is critical for functional alignment of U3 on its pre-rRNA substrate. Additionally, the interaction between the U3 hinges and the ETS is proposed to serve as an anchor to hold U3 on the pre-rRNA substrate, while box A at the 5' end of U3 snoRNA swivels from ETS contacts to 18S rRNA contacts. Compensatory base changes revealed base-pairing between the 3' hinge of U3 snoRNA and region E1 of the ETS in Xenopus pre-rRNA; this novel interaction is required for 18S rRNA production. In contrast, base-pairing between the 5' hinge of U3 snoRNA and region E2 of the ETS is auxiliary, unlike the case in yeast where it is required. Thus, higher and lower eukaryotes use different interactions for functional association of U3 with pre-rRNA. The U3 hinge sequence varies between species, but covariation in the ETS retains complementarity. This species-specific U3-pre-rRNA interaction offers a potential target for a new class of antibiotics to prevent ribosome biogenesis in eukaryotic pathogens.

Animals↗

PubMed1992

Left ventricular hypertrophy as a risk factor in arterial hypertension.

Data on the evolution and prognostic implications of left ventricular hypertrophy (LVH) determined by ECG, chest X-ray and echocardiogram in the Framingham Study are reviewed. Echocardiographic examination provides the most sensitive and specific measure of left ventricular hypertrophy, providing a quantitative evaluation of the anatomical condition. Chest X-ray evaluation is also more sensitive than the ECG, but less specific than the echocardiogram. When ECG-LVH is present, X-ray and echocardiographic LVH are often found; but, when negative, the ECG clearly does not exclude anatomical LVH. The incidence of each variety of LVH increases with age, weight and blood pressure. Although it may also appear following coronary heart disease (CHD), valvular deformity and congenital cardiac defects, the former are the major determinants of LVH in the general population. Each contributes independently to the occurrence of LVH. LVH has emerged as a powerful non-invasive indicator of increased vulnerability to the occurrence of major cardiovascular disease outcomes in hypertension. It appears that X-ray and echocardiographic LVH measure anatomical hypertrophy, whereas the ECG variety is also indicative of ischaemic myocardial involvement when repolarization abnormality is present. Hypertension clearly predisposes to both anatomical and ECG-LVH which cannot be taken as an incidental compensatory feature since at any blood pressure those with ECG-LVH, X-ray or echo LVH are distinctly more prone to cardiovascular sequelae. ECG-LVH carries a greater risk than anatomical (X-ray) LVH. ECG-LVH with repolarization abnormality is more dangerous than that with voltage alone. The latter appears to reflect chiefly the severity and duration of accompanying hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Disease↗

PubMed1999

Patterns of sequence variation in two regions of the 16S rRNA multigene family of Escherichia coli.

Sequence heterogeneities of variable positions located at regions V1 and V6 of 56 cloned 16S rRNA genes were determined from six Escherichia coli strains. These nucleotides were involved in secondary structure base-pairing of stem-loops. Compensatory and single mutations have occurred but secondary structure was conserved. Eight different sequences were found in the stem at region V1 indicating that in these sites mutation rates are higher than those of homogenizatin processes. Region V6 showed two different structures (V6-I and V6-II) although heterogeneities were determined in nine sites. Strains ECOR52 and ECOR56 only showed the V6-I sequence, ECOR35 showed V6-II, whereas clones from ECOR42 and ECOR49 showed both types of V6 structures. Results were confirmed by PCR using V6 sequence-specific probes. Stem V6-II was also found in 16S rRNA sequences deposited in the RDP (Ribosomal Database Project) belonging to distantly related taxa; ancestral sequence V6-II seems to be homogenized in all rrn operons of the multigene family of strain ECOR35 producing effects of distortion in the molecular clock, similar to those that homoplasies could produce. V6 sequence-specific probes were applied to the 72 ECOR strains: half showed both V6-I and V6-II, and the rest had one or another. Only strain ECOR24 did not yield products in the PCR test and sequencing of 12 cloned 16S rRNA genes revealed a third form, V6-III, also found in the RDP. Concerted evolution by homogenization of the rRNA family may induce chronometric distortions responsible for a loss of ultrametricity in phylogenetic trees, particularly, of very closely related micro-organisms.

Base Sequence↗

PubMed1993

Recovery of functional status after stroke. A postrehabilitation follow-up study.

BACKGROUND AND PURPOSE: Information on predictors of long-term change in functional capacity after a rehabilitation program in stroke patients is scant. This study describes the long-term evolution of self-reported functional ability after discharge from rehabilitation and its relation with age, level of neural impairment at discharge, and changes in neural impairment during follow-up. METHODS: Fifty patients (31 men and 19 women; mean +/- SD age, 66.0 +/- 9.9 years; range, 47-86 years) with a first unilateral stroke and no severe cognitive impairment were consecutively enrolled. Self-reported disability in activities of daily living and neural impairment measured by the Fugl-Meyer Scale were evaluated after discharge from a rehabilitation program and 3 and 6 months later. RESULTS: Functional disability was significantly reduced after 3 and 6 months. Attenuation of disability occurred mainly among those patients with more severe baseline neural impairment. In this group, patients aged > or = 65 years were more disabled at baseline than younger individuals, but they had the same rate of improvement. In patients aged < 65 years, changes in disability over time could be attributed to changes in neural function, whereas older patients' functional recovery was greater than that expected from their improvement in neural impairment alone. CONCLUSIONS: These results suggest that in stroke patients with severe neural damage further functional improvement occurs even after completion of a rehabilitation program. There is evidence that older patients may be more likely to employ compensatory strategies to overcome some of the neural impairment that remains after stroke.

Activities of Daily Living↗

PubMed1998

Structural and kinetic characterization of an acyl transferase ribozyme.

We have previously isolated, by in vitro selection, an acyl-transferase ribozyme that is capable of transferring a biotinylated methionyl group from the 3' end of a hexanucleotide substrate to its own 5'-hydroxyl. Comparison of the sequences of a family of evolved derivatives of this ribozyme allowed us to generate a model of the secondary structure of the ribozyme. The predicted secondary structure was extensively tested and confirmed by single-mutant and compensatory double-mutant analyses. The role of the template domain in aligning the acyl-donor oligonucleotide and acyl-acceptor region of the ribozyme was confirmed in a similar manner. The significance of different domains of the ribozyme structure and the importance of two tandem G:U wobble base pairs in the template domain were studied by kinetic characterization of mutant ribozymes. The wobble base pairs contribute to the catalytic rate enhancement, but only in the context of the complete ribozyme; the ribozyme in turn alters the metal binding properties of this site. Competitive inhibition experiments with unacylated substrate oligonucleotide are consistent with the ribozyme acting to stabilize substrate binding to the template, while negative interactions with the aminoacyl portion of the substrate destabilize binding.

Acyltransferases↗

PubMed1984

Xenopus laevis 28S ribosomal RNA: a secondary structure model and its evolutionary and functional implications.

Based upon the three experimentally derived models of E. coli 23S rRNA (1-3) and the partial model for yeast 26S rRNA (4), which was deduced by homology to E. coli, we derived a secondary structure model for Xenopus laevis 28S rRNA. This is the first complete model presented for eukaryotic 28S rRNA. Compensatory base changes support the general validity of our model and offer help to resolve which of the three E. coli models is correct in regions where they are different from one another. Eukaryotic rDNA is longer than prokaryotic rDNA by virtue of introns, expansion segments and transcribed spacers, all of which are discussed relative to our secondary structure model. Comments are made on the evolutionary origins of these three categories and the processing fates of their transcripts. Functionally important sites on our 28S rRNA secondary structure model are suggested by analogy for ribosomal protein binding, the GTPase center, the peptidyl transferase center, and for rRNA interaction with tRNA and 5S RNA. We discuss how RNA-RNA interactions may play a vital role in translocation.

Animals↗

PubMed1989

Evolution of left ventricular function after intracoronary thrombolysis for acute myocardial infarction.

The temporal evolution of left ventricular (LV) function after intracoronary streptokinase therapy for acute myocardial infarction (AMI) was assessed from the data of 264 patients who had complete occlusion of either the left anterior descending or the right coronary artery before treatment. Angiography was performed immediately, and at 3 days and 6 months after AMI in 91%, 71% and 47% of the study group, respectively. Wall motion was measured by the centerline method. In patients with sustained reperfusion, the ejection fraction decreased at 3 days (delta = -2.0 +/- 9.9%, n = 134, p = 0.02) and recovered later (from 54 +/- 12% acutely to 57 +/- 12% at 6 months, n = 82, p less than 0.05). These changes in global function were associated with a marked regression in hyperkinesis in the noninfarcted wall by 3 days, and delayed recovery of wall motion in the infarct region (delta = 0.2 +/- 0.9 at 3 days, p = 0.055; 1.0 +/- 1.2 at 6 months, p less than 0.001). Patients without reperfusion or with reocclusion had a more severe decrease in ejection fraction at 3 days, and little or no subsequent functional recovery. The length of the hypokinetic segment increased significantly by 3 days but subsequently diminished to slightly less than the acute value. It is concluded that full recovery of ischemically impaired myocardium takes greater than 3 days, but compensatory hyperkinesis regresses earlier so that global LV function deteriorates by the third day. Variability or deterioration of LV function early after AMI need not be due to infarct extension; it can reflect regression of hyperkinesis in the noninfarcted region.

Angiography↗

PubMed2004

Estimating the frequency of events that cause multiple-nucleotide changes.

Existing mathematical models of DNA sequence evolution assume that all substitutions derive from point mutations. There is, however, increasing evidence that larger-scale events, involving two or more consecutive sites, may also be important. We describe a model, denoted SDT, that allows for single-nucleotide, doublet, and triplet mutations. Applied to protein-coding DNA, the SDT model allows doublet and triplet mutations to overlap codon boundaries but still permits data to be analyzed using the simplifying assumption of independence of sites. We have implemented the SDT model for maximum-likelihood phylogenetic inference and have applied it to an alignment of mammalian globin sequences and to 258 other protein-coding sequence alignments from the Pandit database. We find the SDT model's inclusion of doublet and triplet mutations to be overwhelmingly successful in giving statistically significant improvements in fit of model to data, indicating that larger-scale mutation events do occur. Distributions of inferred parameter values over all alignments analyzed suggest that these events are far more prevalent than previously thought. Detailed consideration of our results and the absence of any known mechanism causing three adjacent nucleotides to be substituted simultaneously, however, leads us to suggest that the actual evolutionary events occurring may include still-larger-scale events, such as gene conversion, inversion, or recombination, or a series of rapid compensatory changes.

Animals↗

PubMed1990

Phylogenetic and genetic evidence for base-triples in the catalytic domain of group I introns.

Understanding the mechanisms by which ribozymes catalyse chemical reactions requires a detailed knowledge of their structure. The secondary structure of the group I introns has been confirmed by comparison of over 70 published sequences, by chemical protection studies, and by genetic experiments involving compensatory mutations. Phylogenetic data can also be used to identify tertiary interactions in RNA molecules. This was first done by Levitt, who predicted tertiary interactions in transfer RNA, which were subsequently confirmed by X-ray crystallography. More recently, sequence comparison data have been used to predict tertiary interactions in ribosomal RNA. We have searched a complete alignment of the core regions of group I introns for evolutionary covariations that could not be ascribed to classical Watson-Crick or wobble base pairings. Here we describe two examples of phylogenetic covariation that are most simply explained by postulating hydrogen-bonded base-triples similar to those found in tRNA. Genetic experiments with the Tetrahymena and sunY introns confirm the importance of these interactions for the structure of the ribozyme.

Animals↗

PubMed2000

18S rRNA secondary structure and phylogenetic position of Peloridiidae (Insecta, hemiptera).

A secondary structure model for 18S rRNA of peloridiids, relict insects with a present-day circumantarctic distribution, is constructed using comparative sequence analysis, thermodynamic folding, a consensus method using 18S rRNA models of other taxa, and support of helices based on compensatory substitutions. Results show that probable in vivo configuration of 18S rRNA is not predictable using current free-energy models to fold the entire molecule concurrently. This suggests that refinements in free-energy minimization algorithms are needed. Molecular phylogenetic datasets were created using 18S rRNA nucleotide alignments produced by CLUSTAL and rigorous interpretation of homologous position based on certain secondary substructures. Phylogenetic analysis of a hemipteran data matrix of 18S rDNA sequences placed peloridiids sister to Heteroptera. Resolution of affiliations between the three main euhemipteran lineages was unresolved. The peloridiid 18S RNA model presented here provides the most accurate template to date for aligning homologous nucleotides of hemipteran taxa. Using folded 18S rRNA to infer homology of character as morpho-molecular structures or nucleotides and scoring particular sites or substructures is discussed.

Animals↗

PubMed2002

Secondary structure of mitochondrial 12S rRNA among fish and its phylogenetic applications.

The complete 12S ribosomal RNA(rRNA) sequences from 23 gobioid species and nine diverse assortments of other fish species were employed to establish a core secondary structure model for fish 12S rRNA. Of the 43 stems recognized, 41 were supported by at least some compensatory evidence among vertebrates. The rates of nucleotide substitution were lower in stems than in loops. This may produce less phylogenetic information in stems when recently diverged taxa are compared. An analysis of compensatory substitution shows that the percentage of covariation is 68%, and the weighting factor for phylogenetic analyses to account for the dependence of mutations should be 0.66. Different stem-loop weighting schemes applied to the analyses of phylogenetic relationships of the Gobioidei indicate that down-weighting paired regions because of nonindependence could not improve the present phylogenetic analysis. A biased nucleotide composition (adenine% [A%] > thymine% [T%], cytosine% [C%] > guanine% [G%]) in the loop regions was also observed in the mammalian counterpart. The excess of A and C in the loop regions may be because of the asymmetric mechanism of mtDNA replication, which leads to the spontaneous deamination of C and A. This process may also be responsible for a transition-transversion bias and the patterns of nucleotide substitutions in both stems and loops.

Animals↗

PubMed2005

A unified model of codon reassignment in alternative genetic codes.

Many modified genetic codes are found in specific genomes in which one or more codons have been reassigned to a different amino acid from that in the canonical code. We present a new framework for codon reassignment that incorporates two previously proposed mechanisms (codon disappearance and ambiguous intermediate) and introduces two further mechanisms (unassigned codon and compensatory change). Our theory is based on the observation that reassignment involves a gain and a loss. The loss could be the deletion or loss of function of a tRNA or release factor. The gain could be the gain of a new type of tRNA or the gain of function of an existing tRNA due to mutation or base modification. The four mechanisms are distinguished by whether the codon disappears from the genome during the reassignment and by the order of the gain and loss events. We present simulations of the gain-loss model showing that all four mechanisms can occur within the same framework as the parameters are varied. We investigate the way the frequencies of the mechanisms are influenced by selection strengths, the number of codons undergoing reassignment, directional mutation pressure, and selection for reduced genome size.

Anticodon↗

PubMed2000

Leukocyte activation and cytokine production during experimental human endotoxemia.

Background: At present, it is unclear whether in experimental endotoxemia, the pro-inflammatory response observed in healthy volunteers is followed by an anti-inflammatory response, as observed in patients with sepsis. We studied the evolution of a number of inflammatory parameters during a prolonged period (24 h) after infusion of endotoxin in healthy subjects. Methods: Six healthy male subjects received an infusion of endotoxin (4 ng/kg body weight). Blood was drawn before, and at various intervals up to and including 24 h after, endotoxin infusion. Circulating cytokine levels, leukocyte activation surface markers, plasma lactoferrin, and neopterin levels were measured, and clinical signs and symptoms were noted during a 24-h period. Monocyte and neutrophil activation after endotoxin infusion is investigated in relation to the inflammatory response. The extent of neutrophil and monocyte activation was correlated to clinical markers and blood levels of inflammatory mediators and cytokines. Results: Tumor necrosis factor-alpha appeared 30 min after infusion in the circulation, peaking (5665+/-1910 pg/ml) at 2 h. Interleukin-10 appeared 60 min after infusion, peaking (427+/-348 pg/ml) at 3 h. The expression of leukocyte activation markers increased significantly after infusion. Expression of HLA-DR on monocytes decreased significantly after 3 h (P=0.03). There was a correlation between the TNF-alpha:IL-10 ratio and the CD11b:HLA-DR ratio (P=0.03). Conclusions: During experimental human endotoxemia, an initial pro-inflammatory response is successfully compensated by an anti-inflammatory response, leading to homeostasis. This is in contrast to what happens in septic patients with compensatory anti-inflammatory response syndrome. The inflammatory balance, expressed as the cytokine pro:anti-inflammatory ratio, is reflected at a cellular level.

Journal Article↗

PubMed1995

Lilly Lecture 1994. The beta-cell in diabetes: from molecular genetics to clinical research.

Pancreatic insulin secretion rates can be accurately derived by mathematical deconvolution of peripheral C-peptide concentrations either by using individual C-peptide kinetic parameters obtained by analysis of the decay curve of biosynthetic human C-peptide or by using published group parameters with appropriate adjustments for age and degree of obesity. Since the cross-reactivity of proinsulin and related peptides is low (< 10%) in many C-peptide assays, this experimental approach avoids the spurious increase in insulin immunoreactivity resulting from cross-reactivity with proinsulin and related peptides in the insulin assay. Application of this technique has demonstrated that the phenotypic expression of beta-cell dysfunction differs in subjects with different genetic mechanisms of non-insulin-dependent diabetes mellitus (NIDDM). Subjects who have maturity-onset diabetes of the young (MODY) due to mutations in the glucokinase gene demonstrate different patterns of altered insulin secretion when compared with subjects who have mutations in the MODY1 gene on chromosome 20. Glucokinase mutations affect the ability of the beta-cell to detect and respond to small increases in glucose above the basal level. However, compensatory mechanisms operative in vivo, which include a priming effect of glucose on insulin secretion, limit the severity of the observed insulin secretory defect, resulting in a generally mild clinical course in these subjects. In contrast, mutations in the MODY1 gene are associated with an inability to increase insulin secretion as the plasma glucose concentration increases above 7-8 mmol/l and the normal priming effect of glucose on insulin secretion is lost. These characteristics of the dose-response relationships between glucose and insulin secretion result in a more severe degree of hyperglycemia than observed in subjects with glucokinase mutations, and these subjects more frequently need insulin treatment. These alterations are evident in prediabetic subjects with normal glucose levels who carry the MODY1 mutation, suggesting that defective beta-cell function is the primary pathogenetic defect in the diabetic syndrome in these subjects. Studies performed in the classic form of NIDDM demonstrate that subjects with mild glucose intolerance and normal fasting glucose concentrations and glycosylated hemoglobin levels consistently demonstrate defective beta-cell function. These results are consistent with studies in the Zucker diabetic fatty rat, an animal model of NIDDM in which prediabetic animals demonstrate extensive alterations in expression of multiple genes involved in the regulation of insulin secretion. It thus appears that abnormal beta-cell function is present at a relatively early stage in the evolution of NIDDM, even before the onset of overt hyperglycemia.

Adult↗

PubMed2003

Tooth wear and the "design" of the human dentition: a perspective from evolutionary medicine.

Worn, flat occlusal surfaces and anterior edge-to-edge occlusion are ubiquitous among the dentitions of prehistoric humans. The concept of attritional occlusion was proposed in the 1950s as a hypothesis to explain these characteristics. The main aspects of this hypothesis are: 1) the dentitions of ancient populations in heavy-wear environments were continuously and dynamically changing owing to life-long attritional tooth reduction and compensatory tooth migration, 2) all contemporary humans inherit these compensatory mechanisms, and recent reduction in wear severity has resulted in failure to develop attritional occlusion, and 3) this failure leads to an increased frequency of various dental problems in modern societies. Because of the potential significance of this concept, we review and synthesize relevant works and discuss attritional occlusion in the light of current knowledge. Available evidence, on balance, supports the first and second points of the hypothesis. As noted by many workers, the human dentition is basically "designed" on the premise that extensive wear will occur, a conclusion that seems reasonable when one realizes that humans evolved in heavy-wear environments until relatively recently. Some dental problems in contemporary societies appear to reflect the disparity between the original design of our dentition and our present environment, in which extensive wear no longer occurs, but this possibility still needs further investigation.

Adaptation, Physiological↗

PubMed2005

A secondary structural model of the 28S rRNA expansion segments D2 and D3 for Chalcidoid wasps (Hymenoptera: Chalcidoidea).

We analyze the secondary structure of two expansion segments (D2, D3) of the 28S ribosomal (rRNA)-encoding gene region from 527 chalcidoid wasp taxa (Hymenoptera: Chalcidoidea) representing 18 of the 19 extant families. The sequences are compared in a multiple sequence alignment, with secondary structure inferred primarily from the evidence of compensatory base changes in conserved helices of the rRNA molecules. This covariation analysis yielded 36 helices that are composed of base pairs exhibiting positional covariation. Several additional regions are also involved in hydrogen bonding, and they form highly variable base-pairing patterns across the alignment. These are identified as regions of expansion and contraction or regions of slipped-strand compensation. Additionally, 31 single-stranded locales are characterized as regions of ambiguous alignment based on the difficulty in assigning positional homology in the presence of multiple adjacent indels. Based on comparative analysis of these sequences, the largest genetic study on any hymenopteran group to date, we report an annotated secondary structural model for the D2, D3 expansion segments that will prove useful in assigning positional nucleotide homology for phylogeny reconstruction in these and closely related apocritan taxa.

Animals↗

PubMed2005

Using information theory to search for co-evolving residues in proteins.

MOTIVATION: Some functionally important protein residues are easily detected since they correspond to conserved columns in a multiple sequence alignment (MSA). However important residues may also mutate, with compensatory mutations occurring elsewhere in the protein, which serve to preserve or restore functionality. It is difficult to distinguish these co-evolving sites from other non-conserved sites. RESULTS: We used Mutual Information (MI) to identify co-evolving positions. Using in silico evolved MSAs, we examined the effects of the number of sequences, the size of amino acid alphabet and the mutation rate on two sources of background MI: finite sample size effects and phylogenetic influence. We then assessed the performance of various normalizations of MI in enhancing detection of co-evolving positions and found that normalization by the pair entropy was optimal. Real protein alignments were analyzed and co-evolving isolated pairs were often found to be in contact with each other. AVAILABILITY: All data and program files can be found at http://www.biochem.uwo.ca/cgi-bin/CDD/index.cgi

Amino Acid Sequence↗