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PubMed2005

Anxiety and depression, attention, and executive functions in hypothyroidism.

BACKGROUND: Divergences in cognitive disturbances in hypothyroidism reported in the literature are a result of a methodological bias. METHODS: By using a precise methodology, we examined attention and executive functions in hypothyroidism, verified the presence of anxiety and depressive symptoms in hypothyroidism, and examined the possible link between these symptoms and the cognitive disturbances (searching for attentional bias for words with a negative emotional valence). We administered a battery of cognitive tests to 23 participants who had undergone thyroidectomy for thyroid carcinoma: for the first time in an euthyroid state, then 3 weeks later (still in the euthyroid state) to assess the test/retest effect, and finally 4 weeks later in an hypothyroid state. We compared their performance with that of a group of 26 control participants who were also administered the same cognitive tests, also 3 times. RESULTS: In hypothyroidism, the thyroid participants were more anxious and depressed than the controls and presented attentional and executive disturbances that reflected general slowing and difficulties in using their capacities of inhibition. However, they did not exhibit an attentional bias for words with a negative emotional valence. CONCLUSIONS: Contrary to what was expected, symptoms of anxiety and not symptoms of depression interfered with the cognitive performance of participants in hypothyroidism.

Adult↗

PubMed2006

The CRM domain: an RNA binding module derived from an ancient ribosome-associated protein.

The CRS1-YhbY domain (also called the CRM domain) is represented as a stand-alone protein in Archaea and Bacteria, and in a family of single- and multidomain proteins in plants. The function of this domain is unknown, but structural data and the presence of the domain in several proteins known to interact with RNA have led to the proposal that it binds RNA. Here we describe a phylogenetic analysis of the domain, its incorporation into diverse proteins in plants, and biochemical properties of a prokaryotic and eukaryotic representative of the domain family. We show that a bacterial member of the family, Escherichia coli YhbY, is associated with pre-50S ribosomal subunits, suggesting that YhbY functions in ribosome assembly. GFP fused to a single-domain CRM protein from maize localizes to the nucleolus, suggesting that an analogous activity may have been retained in plants. We show further that an isolated maize CRM domain has RNA binding activity in vitro, and that a small motif shared with KH RNA binding domains, a conserved "GxxG" loop, contributes to its RNA binding activity. These and other results suggest that the CRM domain evolved in the context of ribosome function prior to the divergence of Archaea and Bacteria, that this function has been maintained in extant prokaryotes, and that the domain was recruited to serve as an RNA binding module during the evolution of plant genomes.

Amino Acid Motifs↗

PubMed2001

BHRF1 is highly conserved in primate virus analogues of Epstein-Barr virus.

The Epstein-Barr virus (EBV) protein BHRF1 (BamHI rightward reading frame 1) was the first viral member of the Bcl-2 family of apoptosis-regulating proteins described. In vitro studies imply that BHRF1 is dispensable for virus-induced cellular transformation and virus replication. However, in contrast to several essential viral genes that show divergence outwith their functional domains, sequence data from a wide range of EBV isolates show there is striking conservation of the BHRF1 gene. Contrary to the in vitro studies, the high degree of conservation hints at a more important role for BHRF1. Analogous viruses are endemic in each of the higher primate species. Whilst their genome organisation is colinear, limited sequence analysis indicates that the viruses have diverged significantly and that only important functional domains of proteins are likely to be conserved. We have isolated the BHRF1 equivalents from the viruses which infect chimpanzees (Herpesvirus pan) and baboons (Herpesvirus papio) and find that they are highly homologous in both species, strengthening the hypothesis that BHRF1 plays a significant, evolutionarily conserved function in vivo and that changes to the protein are not well tolerated.

Amino Acid Sequence↗

PubMed2004

The interplay between help-seeking and alcohol-related outcomes: divergent processes for professional treatment and self-help groups.

This study examined the influence of self-selection, as reflected in alcohol-related functioning, on the duration of professional treatment and Alcoholics Anonymous (AA), and the influence of social causation, as reflected in the duration of treatment and AA, on alcohol-related outcomes. A sample of alcoholic individuals was surveyed at baseline and 1, 3, and 8 years later. At each point, participants completed an inventory that assessed participation in treatment and AA since the last assessment and alcohol-related functioning. There were divergent processes of self-selection and social causation with respect to the duration of participation in professional treatment and AA. Individuals with more severe alcohol-related problems obtained longer episodes of professional treatment, but this self-selection process was much less evident for AA. Longer participation in professional treatment in the first year predicted better alcohol-related outcomes; however, the duration of subsequent treatment was not associated with better subsequent outcomes. In contrast, longer participation in AA consistently predicted better subsequent alcohol-related outcomes. These findings are consistent with a need-based model of professional treatment, in which more treatment is selected by and allocated to individuals with more severe problems, and an egalitarian model of self-help, in which need factors play little or no role in continued participation.

Adult↗

PubMed1997

Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo.

Mouse delta-like 3 (Dll3), a novel vertebrate homologue of the Drosophila gene Delta was isolated by a subtracted library screen. In Drosphila, the Delta/Notch signalling pathway functions in many situations in both embryonic and adult life where cell fate specification occurs. In addition, a patterning role has been described in the establishment of the dorsoventral compartment boundary in the wing imaginal disc. Dll3 is the most divergent Delta homologue identified to date. We confirm that Dll3 can inhibit primary neurogenesis when ectopically expressed in Xenopus, suggesting that it can activate the Notch receptor and therefore is a functional Delta homologue. An extensive expression study during gastrulation and early organogenesis in the mouse reveals a diverse and dynamic pattern of expression. The three major sites of expression implicate Dll3 in somitogenesis and neurogenesis and in the production of tissue from the primitive streak and tailbud. A careful comparison of Dll3 and Dll1 expression by double RNA in situ hybridisation demonstrates that these genes have distinct patterns of expression, but implies that together they operate in many of the same processes. We postulate that during somitogenesis Dll3 and Dll1 coordinate in establishing the intersomitic boundaries. We confirm that, during neurogenesis in the spinal cord, Dll1 and Dll3 are expressed by postmitotic cells and suggest that expression is sequential such that cells express Dll1 first followed by Dll3. We hypothesise that Dll1 is involved in the release of cells from the precursor population and that Dll3 is required later to divert neurons along a specific differentiation pathway.

Amino Acid Sequence↗

PubMed2003

Parallel functional changes in the digestive RNases of ruminants and colobines by divergent amino acid substitutions.

A morphological or physiological trait may appear multiple times in evolution. At the molecular level, similar protein functions may emerge independently in different lineages. Whether these parallel functional changes are due to parallel amino acid substitutions has been a subject of debate. Here, I address this question using digestive ribonucleases (RNases) of two groups of foregut-fermenting mammals: ruminant artiodactyls and colobine monkeys. The RNase1 gene was duplicated twice in ancestral ruminants at least 40 MYA, and it was also duplicated in the douc langur, an Asian colobine, approximately 4 MYA. After duplication, similar functional changes occurred in the ruminant and monkey enzymes. Interestingly, five amino acid substitutions in ruminant RNases that are known to affect its catalytic activity against double-stranded (ds) RNA did not occur in the monkey enzyme. Rather, a similar functional change in the monkey was caused by a different set of nine substitutions. Site-directed mutagenesis was used to make three of the five ruminant-specific substitutions in the monkey enzyme. Functional assays of these mutants showed that one of the three substitutions has a similar effect in monkeys, the second has a stronger effect, and the third has an opposite effect. These results suggest that (1) an evolutionary problem can have multiple solutions, (2) the same amino acid substitution may have opposite functional effects in homologous proteins, (3) the stochastic processes of mutation and drift play an important role even at functionally important sites, and (4) protein sequences may diverge even when their functions converge.

Amino Acid Sequence↗

PubMed1991

Demonstration of a divergent transcript from the bidirectional heavy chain immunoglobulin promoter VH441 in B-cells.

The mouse heavy chain immunoglobulin promoter VH441 can lead in vitro to bidirectional transcription, due to a symmetrical organization of immunoglobulin heavy chain promoters with two TATA-like sequences bracketing the upstream promoter element ATGCAAAT (the so called octamer). We demonstrate here that divergent transcription also occurs in vivo in mature B cells from a myeloma which expresses the VH441 gene and even from the spleen of BALB/c mice. The level of VH441 divergent transcript increases in the spleen of BALB/c mice after immunisation by beta-(1,6)-galactan, showing that it is expressed in B cells which actively transcribe the VH441 gene. The divergent transcript has been characterized: its major transcription start site was mapped within 33 base pairs from the divergent TATA-like region, it is unspliced and not polyadenylated. In the light of these results, the functions of the divergent transcript and the bidirectional promoter are discussed.

Animals↗

PubMed2004

Empirical analysis of protein insertions and deletions determining parameters for the correct placement of gaps in protein sequence alignments.

To understand how protein segments are inserted and deleted during divergent evolution, a set of pairwise alignments contained exactly one gap, and therefore arising from the first insertion-deletion (indel) event in the time separating the homologs, was examined. The alignments showed that "structure breaking" amino acids (PGDNS) were preferred within and flanking gapped regions, as are two residues with hydrophilic side-chains (QE) that frequently occur at the surface of protein folds. Conversely, hydrophobic residues (FMILYVW) occur infrequently within and flanking the gapped region. These preferences are modestly different in protein pairs separated by an episode of adaptive evolution, than in pairs diverging under strong functional constraints. Surprisingly, regions near an indel have not evolved more rapidly than the sequence pair overall, showing no evidence that an indel event must be compensated by local amino acid replacement. The gap-lengths are best approximated by a Zipfian distribution, with the probability of a gap of length L decreasing as a function of L(-1.8). These features are largely independent of the length of the gap and the extent of divergence (measured by both silent and non-silent sequence changes) separating the two proteins. Surprisingly, amino acid repeats were discovered in more than a third of the polypeptide segments in and around the gap. These correspond to repeats in the DNA sequence. This suggests that a signature of the mechanism by which indels occur in the DNA sequence remains in the encoded protein sequences. These data suggest specific tools to score gap placement in an alignment. They also suggest tools that distinguish true indels from gaps created by mistaken gene finding, including under-predicted and over-predicted introns. By providing mechanisms to identify errors, the tools will enhance the value of genome sequence databases in support of integrated paleogenomics strategies used to extract functional information in a post-genomic environment.

Amino Acid Sequence↗

PubMed1986

Conservation and divergence in multigene families: alternatives to selection and drift.

It is generally assumed that conservation and divergence of DNA signify function (selection) and no function (drift), respectively. This assumption is based on the view that a mutation is a unique event on a single chromosome, the fate of which depends on selection or drift. Knowledge of the rates, units and biases of widespread mechanisms of non-reciprocal DNA exchange, in particular within multigene families, provides alternative explanations for conservation and divergence, notwithstanding biological function. Such mechanisms of DNA turnover cause continual fluctuations in the copy-number of variant genes in an individual and, hence, promote the gradual and cohesive spread of a variant gene throughout a family (homogenization) and throughout a population (fixation). The dual processes (molecular drive) of homogenization and fixation are inextricably linked. Data are presented of the expected stages of transition in the spread of variant repeats by molecular drive in some non-genic families of DNA, seemingly not under the influence of selection. When a molecularly driven change in a given gene family is accompanied by the coevolution (mediated by selection) of other DNA, RNA or protein molecules that interact with the gene family then biological function is observed to be maintained despite sequence divergence. Conversely, the mechanics of DNA turnover and a turnover bias in favour of ancestral sequences can dramatically retard the rate of sequence change, in the absence of function. Examples of the maintenance of function by molecular coevolution and conservation of sequences in the absence of function, are drawn mainly from the rDNA multigene family.

Animals↗

PubMed1998

Conservation and divergence of NF-Y transcriptional activation function.

The CCAAT-binding protein NF-Y is involved in the regulation of a variety of eukaryotic genes and is formed in higher eukaryotes by three subunits NF-YA/B/C. We have characterized NF-Y of the trematode parasite Schistosoma mansoni and studied the structure and the function of the SMNF-YA subunit. In this work, we present the cloning and sequence analysis of the B subunit of the parasite factor. SMNF-YB contains the conserved HAP-3 homology domain but the remaining part of the protein was found to be highly divergent from all other species. We demonstrated by transfections of GAL4 fusion constructs, that mouse NF-YB does not contain activation domains while the C-terminal part of SMNF-YB has transcriptional activation potential. On the other hand, the N-terminal parts of SMNF-YA and mouse NF-YA were shown to mediate transactivation; the integrity of a large 160 amino acid glutamine-rich domain of NF-YA was required for this function and an adjacent serine- and threonine-rich domain was necessary for full activity in HepG2, but redundant in other cell types. Transactivation domains identified in SMNF-YB are also rich in serine and threonine residues. Our results indicate that serine/threonine-richsequences from helminth parasites potentiate trans-cription and that such structures have diverged during evolution within the same transcription factor.

3T3 Cells↗

PubMedDate not supplied

Prevalence of monochloroacetate degrading genotypes among soil isolates of Pseudomonas sp.

This study reports the isolation of Pseudomonas sp. strains with monochloroacetate (MCA) degradation function, from uncontaminated soil, and the use of Southern blot hybridization technique to detect MCA degrading catabolic genes and their divergence. Based on their capacity to remove Cl- from MCA in a minimal medium containing 185 ppm Cl-, the strains were classified into three groups: poor degraders (Cl- release between 0-15 ppm), medium degraders (Cl- release between 16-30 ppm), and high degraders (Cl- release between 31-45 ppm). We have applied a gene probe assay for determining the diversity of MCA degradative genotypes of 61 strains. Two different gene probes, dehCI and dehCII were used in Southern blot hybridization assays. Majority of the DNA samples that produced signals on the membrane blots (18 out of 24) hybridized with only dehCI DNA probe, while 6 strains hybridized with only dehCII probe. On the other hand, 37 isolates did not hybridize to either of the gene probes used. The results indicated the high specificity of the DNA hybridization method and the divergence of metabolic functions and/or genotypes among the native MCA-degrading Pseudomonas sp. populations in the soil.

Acetates↗

PubMed1999

Toward an evolutionary taxonomy of treatable conditions.

The definition of disorder as a harmful dysfunction (J. C. Wakefield, 1999) is a useful concept, anchored in the recognition that the evolved human architecture consists of a collection of functional mechanisms that may potentially be impaired and whose impairment may be harmful. Because natural selection organized each mechanism to solve a distinct adaptive problem under ancestral conditions, the criteria for whether a mechanism is dysfunctional are supplied by whether the mechanism has become impaired in performing its ancestral function. Because evolutionary function and dysfunction diverge markedly from normal human standards of value, many dysfunctions are beneficial, whereas various mechanisms that are performing their evolved function may cause disturbing outcomes. For this reason, many conditions in addition to disorders may require treatment, and the authors attempt to sketch an evolutionary taxonomy of treatable conditions.

Biological Evolution↗

PubMed1999

The role of the mismatch repair machinery in regulating mitotic and meiotic recombination between diverged sequences in yeast.

Nonidentical recombination substrates recombine less efficiently than do identical substrates in yeast, and much of this inhibition can be attributed to action of the mismatch repair (MMR) machinery. In this study an intron-based inverted repeat assay system has been used to directly compare the rates of mitotic and meiotic recombination between pairs of 350-bp substrates varying from 82% to 100% in sequence identity. The recombination rate data indicate that sequence divergence impacts mitotic and meiotic recombination similarly, although subtle differences are evident. In addition to assessing recombination rates as a function of sequence divergence, the endpoints of mitotic and meiotic recombination events involving 94%-identical substrates were determined by DNA sequencing. The endpoint analysis indicates that the extent of meiotic heteroduplex DNA formed in a MMR-defective strain is 65% longer than that formed in a wild-type strain. These data are consistent with a model in which the MMR machinery interferes with the formation and/or extension of heteroduplex intermediates during recombination.

Base Sequence↗

PubMed1998

Adrenal function in patients with chronic renal failure.

Previous studies have reported divergent findings on the function of the hypothalamic-pituitary-adrenal axis in patients with chronic renal failure (CRF). The low-dose adrenocorticotropin (ACTH) test offers the possibility of unmasking adrenal dysfunction, which might remain undiscovered using the ACTH test with the standard 250-microg dose. Furthermore, the choice of renal replacement therapy (either hemodialysis or continuous ambulatory peritoneal dialysis [CAPD]) might have an impact on adrenal function. To investigate these possibilities, ACTH tests were performed with three different doses (ie, 1, 5, and 250 microg) in 14 CRF patients and in seven healthy controls. Seven of the CRF patients were receiving chronic hemodialysis and seven were receiving CAPD. Basal plasma concentrations of cortisol were comparable in the three groups tested (5.3+/-0.4 microg/dL in the controls, 6.6+/-0.7 microg/dL in the hemodialysis patients, and 7.9+/-1.0 microg/dL in the CAPD patients), whereas basal ACTH concentrations were significantly elevated in the CRF patients (28.5+/-3.8 pg/mL in the hemodialysis patients and 33.0+/-6.0 pg/mL in the CAPD patients) when compared with normal controls (17.0+/-1.4 pg/mL; P < 0.05). All three doses of ACTH resulted in a rapid increase of plasma cortisol concentrations that was comparable in all three groups. In the hemodialysis patients, a trend toward a diminished response to the lowest dose of 1 microg was noticed. We conclude, therefore, that adrenal response to ACTH in various doses is unaffected in CRF independent of whether hemodialysis or CAPD is chosen for renal replacement therapy.

Adrenal Glands↗

PubMed2005

Neurocognitive consequences of sleep deprivation.

Deficits in daytime performance due to sleep loss are experienced universally and associated with a significant social, financial, and human cost. Microsleeps, sleep attacks, and lapses in cognition increase with sleep loss as a function of state instability. Sleep deprivation studies repeatedly show a variable (negative) impact on mood, cognitive performance, and motor function due to an increasing sleep propensity and destabilization of the wake state. Specific neurocognitive domains including executive attention, working memory, and divergent higher cognitive functions are particularly vulnerable to sleep loss. In humans, functional metabolic and neurophysiological studies demonstrate that neural systems involved in executive function (i.e., prefrontal cortex) are more susceptible to sleep deprivation in some individuals than others. Recent chronic partial sleep deprivation experiments, which more closely replicate sleep loss in society, demonstrate that profound neurocognitive deficits accumulate over time in the face of subjective adaptation to the sensation of sleepiness. Sleep deprivation associated with disease-related sleep fragmentation (i.e., sleep apnea and restless legs syndrome) also results in neurocognitive performance decrements similar to those seen in sleep restriction studies. Performance deficits associated with sleep disorders are often viewed as a simple function of disease severity; however, recent experiments suggest that individual vulnerability to sleep loss may play a more critical role than previously thought.

Cognition Disorders↗

PubMed2002

Selection in the evolution of gene duplications.

BACKGROUND: Gene duplications have a major role in the evolution of new biological functions. Theoretical studies often assume that a duplication per se is selectively neutral and that, following a duplication, one of the gene copies is freed from purifying (stabilizing) selection, which creates the potential for evolution of a new function. RESULTS: In search of systematic evidence of accelerated evolution after duplication, we used data from 26 bacterial, six archaeal, and seven eukaryotic genomes to compare the mode and strength of selection acting on recently duplicated genes (paralogs) and on similarly diverged, unduplicated orthologous genes in different species. We find that the ratio of nonsynonymous to synonymous substitutions (Kn/Ks) in most paralogous pairs is <<1 and that paralogs typically evolve at similar rates, without significant asymmetry, indicating that both paralogs produced by a duplication are subject to purifying selection. This selection is, however, substantially weaker than the purifying selection affecting unduplicated orthologs that have diverged to the same extent as the analyzed paralogs. Most of the recently duplicated genes appear to be involved in various forms of environmental response; in particular, many of them encode membrane and secreted proteins. CONCLUSIONS: The results of this analysis indicate that recently duplicated paralogs evolve faster than orthologs with the same level of divergence and similar functions, but apparently do not experience a phase of neutral evolution. We hypothesize that gene duplications that persist in an evolving lineage are beneficial from the time of their origin, due primarily to a protein dosage effect in response to variable environmental conditions; duplications are likely to give rise to new functions at a later phase of their evolution once a higher level of divergence is reached.

Animals↗

PubMed2026

Species-specific structuring of gut bacterial and fungal communities in honey bees Apis cerana and Apis mellifera.

Honey bee gut microbiome studies have primarily emphasized bacteria, leaving fungal communities comparatively overlooked despite their ecological and functional importance. Whole-genome shotgun metagenomics of Apis cerana and Apis mellifera revealed fungal assemblages dominated by Ascomycota, with Basidiomycota and Microsporidia in minor proportions, alongside gut bacterial communities composed mainly of Pseudomonadota, Bacillota, and Actinomycetota. The bacterial diversity was markedly higher in A. mellifera (Shannon = 5.90; Simpson = 0.98) than in A. cerana (Shannon = 4.01; Simpson = 0.94; p > 0.05), while fungal diversity remained comparable between species (p > 0.05). Beta-diversity analyses revealed strong host-specific clustering for both bacterial (PERMANOVA R2 = 0.7989, p > 0.05) and fungal communities (R2 = 0.7218, p > 0.05), indicating distinct microbial organization driven by host species. Bacterial-fungal co-occurrence patterns exhibited host-specific structuring, suggesting differential inter-kingdom community organization between A. cerana and A. mellifera. Linear Discriminant Analysis Effect Size (LEfSe) identified 93 discriminatory fungal taxa (45 enriched in A. cerana, 48 in A. mellifera), highlighting yeast-dominated signatures in A. mellifera and Basidiomycota-affiliated enrichments in A. cerana. KEGG and CAZy profiling revealed host- and kingdom-specific functional differences, with bacterial communities of A. mellifera showing distinct representation of carbohydrate metabolism and nutrient-cycling functions, while fungal communities exhibited a comparatively narrower functional repertoire. Together, these findings provide a high-resolution view of honey bee bacterial and fungal microbiomes, highlighting strong host-driven divergence in taxonomy, function, and cross-kingdom interactions.

Animals↗

PubMed2004

Recent changes among human influenza viruses.

Recurrent epidemics of influenza are due to the frequent emergence of antigenic variants. With co-circulation of two influenza A subtypes and two antigenically distinct lineages of B viruses, genetic reassortment also has an important role in antigenic drift, as illustrated by recent changes in both A and B viruses. The H1N2 subtype viruses, which emerged during 2001, possessed a H1 HA similar to those of contemporary A/New Caledonia/20/99 (H1N1)-like viruses and seven genes closely related to those of recent H3N2 viruses, and did not represent a significant increase in the antigenic diversity of circulating viruses. The re-emergence of B/Victoria/2/87-lineage viruses, previously prevalent during the 1980s, in 2000 has been followed by the predominant circulation of reassortant B viruses possessing a B/Victoria-lineage HA and a B/Yamagata-lineage NA similar in sequence to those of recent B/Sichuan/379/99-like viruses. These events emphasize not only the lack of divergence in the complementary functional characteristics of the HA and NA of divergent influenza B lineages, but also the apparent convergence in compatibility between the H1 and N2 components of the two influenza A subtypes.

Antigenic Variation↗