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PubMed2025

Enrichment of G-to-U Substitution in SARS-CoV-2 Functional Regions and Its Compensation via Concurrent Mutations.

We surveyed single nucleotide variant (SNV) patterns from 5 903 647 complete SARS-CoV-2 genomes. Among 10 012 SNVs, APOBEC-mediated C-to-U (C > U) deamination was the most prevalent, followed by G > U and other RNA editing-related substitutions including (A > G, U > C, G > A). However, C > U mutations were less frequent in functional regions, for example, S protein, intrinsic disordered regions, and nonsynonymous mutations, where G > U were over-represented. Notably, G-loss substitutions rarely appeared together. Instead, G-gain mutations tended to more frequently co-occur with others, with a marked preference in the S protein, suggesting a compensatory mechanism for G loss in G > U mutations. The temporal patterns revealed C > U frequency declined until late 2021 then resurged in early 2022. Conversely, G > U steadily decreased, with a pronounced drop in January 2022, coinciding with reduced COVID-19 severity. Vaccinated individuals exhibited a slightly but significantly higher C > U frequency and a notably lower G > U frequency compared to the unvaccinated group. Additionally, cancer patients had higher G > U frequency than general patients during the same period. Interestingly, none of the C > U SNVs were uniquely identified in 2724 environmental samples. These findings suggest novel functional roles of G > U in COVID-19 symptoms, potentially linked to oxidative stress and reactive oxygen species, while C > U remains the dominant substitution, likely driven by host immune-mediated RNA editing.

SARS-CoV-2↗
PubMed1995

The transverse plane evolution of the most common adolescent idiopathic scoliosis deformities. A cross-sectional study of 181 patients.

STUDY DESIGN: The transverse plane evolution of the most common idiopathic deformities was studied using a cross-sectional database of 181 patients whose deformities were visualized by precise three-dimensional techniques. OBJECTIVE: The objective was to test the hypothesis that for all common idiopathic scoliosis deformities evolution occurs as a torsion, the apex vertebra translating away from the upper end vertebra and at the same time angulating in a clockwise arc for right apex deformities and a counterclockwise arc for left apex deformities. SUMMARY OF BACKGROUND DATA: Perdriolle and Vidal proposed this hypothesis in 1987, which explained observations we had made in 1983 and which was partially supported in thoracic curves in our 1992 study. METHODS: Deformities were characterized as single thoracic major, thoracic major and thoracolumbar or lumbar minor, double thoracic and thoracolumbar or lumbar major, and single thoracolumbar or lumbar major curves. The dependent variable studied was the coronal plane regional angular (Cobb) deformity. The independent variables studied were the lateral and anteroposterior translation of the apex vertebra in relation to the upper end vertebra, and the transverse plane translation and angulation of the apex vertebra in relation to the upper end vertebra. For the model or hypothesis to be true, the apex vertebra to upper end vertebra transverse plane translational distance and angular relationship should increase as the Cobb angle increases. RESULTS: In relation to the upper end vertebra, the apex vertebra always translated laterally, almost always was accompanied by transverse plane translation increase, and usually was accompanied by transverse plane angulation increase. Anteroposterior translation was minimal, but for thoracolumbar and lumbar curves it tended to be posterior. CONCLUSION: The theory that these deformities evolve as torsions, with the apex vertebra translating away from the upper end vertebra and at the same time following a clockwise angular pathway to the upper end vertebra of right apex curves and a counterclockwise angular pathway for left apex curves is supported. Compensatory thoracolumbar and lumbar curves evolve in the same manner as major curves.

Adolescent↗
PubMed1996

Patterns of nucleotide change in mitochondrial ribosomal RNA genes and the phylogeny of piranhas.

The patterns and rates of nucleotide substitution in mitochondrial ribosomal RNA genes are described and applied in a phylogenetic analysis of fishes of the subfamily Serrasalminae (Teleostei, Characiformes, Characidae). Fragments of 345 bp of the 12S and 535 bp of the 16S genes were sequenced for 37 taxa representing all but three genera in the subfamily. Secondary-structure models based on comparative sequence analysis were derived to characterize the pattern of change among paired and unpaired nucleotides, forming stem and loop regions, respectively. Base compositional biases were in the direction of A-rich loops and G-rich stems. Ninety-five percent of substitutions in stem regions were compensatory mutations, suggesting that selection for maintenance of base pairing is strong and that independence among characters cannot be assumed in phylogenetic analyses of stem characters. The relative rate of nucleotide substitution was similar in both fragments sequenced but higher in loop than in stem regions. In both genes, C-T transitions were the most common type of change, and overall transitions outnumbered transversions by a factor of two in 16S and four in 12S. Phylogenetic analysis of the mitochondrial DNA sequences suggests that a clade formed by the genera Piaractus, Colossoma, and Mylossoma is the sister group to all other serrasalmins and that the genera Myleus, Serrasalmus, and Pristobrycon are paraphyletic. A previous hypothesis concerning relationships for the serrasalmins, based on morphological evidence, is not supported by the molecular data. However, phylogenetic analysis of host-specific helminth parasites and cytogenetic data support the phylogeny of the Serrasalminae obtained in this study and provide evidence for coevolution between helminth parasites and their fish hosts.

Animals↗
PubMed2002

Tracking the evolutionary loss of hemoglobin expression by the white-blooded Antarctic icefishes.

The blood of Antarctic icefishes (family Channichthyidae, suborder Notothenioidei) is completely devoid of hemoglobin. Icefishes have developed compensatory adaptations that reduce oxygen demand and enhance oxygen transport. Oxygen delivery to tissues occurs by carrying the gas physically dissolved in the plasma. To evaluate the evolutionary pathway leading to the icefish hemoglobinless phenotype, the adult and embryonic/juvenile gene complexes from a closely related, red-blooded notothenioid species were isolated and characterized. The hybridization pattern of notothenioid adult globin cDNAs showed that the genomes of three icefish species retain transcriptionally inactive alpha1-globin-related DNA sequences, which are identical truncated variants of the alpha1-globin gene of the red-blooded fish, containing part of intron 2, all of exon 3, and the 3'-untranslated region. The icefish genomes have no beta-globin genes. Furthermore, Southern blots of genomic DNA from red- and white-blooded (two species) notothenioids, probed with fragments of the genes flanking the ends of the embryonic/juvenile complex, indicated that icefishes have also lost embryonic/juvenile globin genes. It is proposed that inability to express hemoglobin arose from a single, large-scale deletional event, which removed all icefish globin genes with the exception of the 3' end of alpha1.

Animals↗
PubMed2004

Resistance and replicative capacity of HIV-1 strains selected in vivo by long-term enfuvirtide treatment.

Enfuvirtide is the prototype member of a new class of anti HIV-1 agents, the fusion inhibitors (FI). In recent clinical trials, the compound has shown its efficacy in combination with other antiretroviral agents in vivo. However mutant strains resistant to the action of the drug arise quite rapidly in vitro and in vivo. To analyze the process of selection and evolution of HIV-1 strains resistant to enfuvirtide in vivo and to evaluate the impact of resistance on viral fitness, 12 HIV-1 infected subjects treated with T20 (enfuvirtide) for at least one year were included in the study. Gp41-coding sequences were amplified from plasma samples of these subjects at baseline and at different time points during treatment. Seven of the 12 subjects showed selection of gp41 mutations under the selective pressure of enfuvirtide. In particular, these mutations clustered in two distinct regions: (i) a mutational hot-spot localized, as previously described, in the first residues of the N-HR domain, with position number 38 as the most heavily mutated, but including also a G36V, a N42D/T, a N43D, a L44M and a L45M; (ii) other mutations were localized further downstream, within N-HR/C-HR junction and in the C-HR. A recombinant assay specifically designed for the determination of HIV-1 phenotype to FI was developed and validated. Using this assay, we observed that all of the 7 mutated clones displayed substantially reduced susceptibility to T20, IC50 ranging from 0.6 to12.8 microg/ml (>100 fold change). The residues whose mutation was associated with a potent reduction in susceptibility were V38, N42, and N43, other positions such as G36, N44 and L45 playing a minor role. None of the mutant HIV isolates showed cross-resistance to T-1249. By the same method, the HIV-1 replicative capacity of the recombinant clones was tested in the absence of drugs, and for each subject, pre-therapy clones were compared to post-therapy ones. In 3/7 subjects a significant decrease in replicative capacity of the recombinant clones was observed. The phenotypic data from this study suggest that the secondary additional mutations, could be associated with improved resistance or recovery of replicative capacity (compensatory mutations).

Amino Acid Sequence↗
PubMed1993

Reptilian and avian ovarian cycles and the evolutionary origin of volant birds.

The first birds probably evolved from a line of theropod dinosaurs in the late Jurassic or early Cretaceous. The "trees down" theory proposes that avian ancestors were arboreal, whereas the "ground-up" (cursorial) theory suggests that they were terrestrial, and ran and jumped for prey. We present suggestive evidence from reptilian and avian female reproductive biology that supports the arboreal theory, although neontological evidence can never authenticate a paleontological event. The "law of follicular constancy" is an empirical observation that the number of ovulations per female per ovulatory cycle (instantaneous fecundity, or IF) is the same regardless of the amount of ovarian tissue present. In vertebrates with an IF of two or more, surgical removal of one of the paired ovaries (unilateral ovariectomy, or ULO) leads to a doubling of ovulations from the remaining ovary (compensatory ovarian hypertrophy, or COH), this ovary cycling at the same frequency as it did before surgery. In vertebrates that produce one egg alternately from each ovary (an IF of one), however, ULO leads to a form of COH in which the remaining ovary still ovulates one egg at a time but twice as frequently. In most birds, only the left ovary is present; it ovulates a single egg every 1-2 days until the species-specific clutch size is reached. Inasmuch as this avian ovulatory pattern is similar to an accelerated version of that occurring after ULO in a species that alternates ovulation, we propose that birds evolved from dinosaurs with such a pattern. A great majority of extant reptiles with an IF of one are either anoline or gekkonid lizards, and many of these ovulate several times a year. Furthermore, most species in these tropical groups are arboreal. Even considering phylogenetic constraints within anoline and gekkonid lizards, we propose that correlations of arboreality and an IF of one in these groups are implied as adaptive relationships and represent ecological parallelisms. Therefore, we propose that the ancestors of birds were arboreal. Furthermore, they probably were of small size, as are all lizards with an IF of one.

Animals↗
PubMed2003

Variability at human immunodeficiency virus type 1 subtype C protease cleavage sites: an indication of viral fitness?

Naturally occurring polymorphisms in the protease of human immunodeficiency virus type 1 (HIV-1) subtype C would be expected to lead to adaptive (compensatory) changes in protease cleavage sites. To test this hypothesis, we examined the prevalences and patterns of cleavage site polymorphisms in the Gag, Gag-Pol, and Nef cleavage sites of C compared to those in non-C subtypes. Codon-based maximum-likelihood methods were used to assess the natural selection and evolutionary history of individual cleavage sites. Seven cleavage sites (p17/p24, p24/p2, NC/p1, NC/TFP, PR/RT, RT/p66, and p66/IN) were well conserved over time and in all HIV-1 subtypes. One site (p1/p6(gag)) exhibited moderate variation, and four sites (p2/NC, TFP/p6(pol), p6(pol)/PR, and Nef) were highly variable, both within and between subtypes. Three of the variable sites are known to be major determinants of polyprotein processing and virion production. P2/NC controls the rate and order of cleavage, p6(gag) is an important phosphoprotein required for virion release, and TFP/p6(pol), a novel cleavage site in the transframe domain, influences the specificity of Gag-Pol processing and the activation of protease. Overall, 58.3% of the 12 HIV-1 cleavage sites were significantly more diverse in C than in B viruses. When analyzed as a single concatenated fragment of 360 bp, 96.0% of group M cleavage site sequences fell into subtype-specific phylogenetic clusters, suggesting that they coevolved with the virus. Natural variation at C cleavage sites may play an important role, not only in regulation of the viral cycle but also in disease progression and response to therapy.

Amino Acid Sequence↗
PubMedDate not supplied

Transient hepatic attenuation differences (THAD) not connected to focal lesions.

PURPOSE: To report our experience with helical CT evaluation of transient hepatic attenuation differences (THAD), and in particular of those not associated with focal lesions, in an attempt to provide an aetiopathogenetic picture that accounts for the morphology, evolution and density of THAD. MATERIALS AND METHODS: Between January 1998 and January 2001 we observed THAD in 130/988 biphasic helical CT liver examinations performed in the arterial and portal dominant phase. THAD were associated to focal hepatic lesions in 87 patients; in 43 patients there was no such association. This second group of patients, composed of 23 males and 20 females ranging in age from 17 to 80 years (average = 58.8), was enrolled in the study. THAD were associated to: Budd-Chiari syndrome (9), portal venous thrombosis (10), liver cirrhosis (7), acute inflammation of an adjacent organ (4), dilatation of the entire biliary tree (3), hepatic stasis caused by heart failure (2) and constrictive pericarditis (1), fine-needle percutaneous biopsy (2), arterioportal shunting (2), parenchymal compression by fractured ribs (2) and by a strengthened phrenic pillar (1). THAD were evaluated according to extension, morphology and density. For each case at least 10 density measurements were performed by sampling regions of interest on the parenchyma with THAD and on the contralateral parenchyma. The results (mean and standard deviation) were compared to those relative to 30 healthy patients. 22/43 patients were followed up for 6#150;24 months by at least one US and helical CT examination. During CT, the direct appreciation of vascular thrombus during the portal dominant phase was also considered. RESULTS: We detected 18 localised and 25 diffuse THAD. The localised sectoral THAD (11), wedge-shaped with clear border sign, were associated to thrombosis of a portal branch (6), fine-needle percutaneous biopsy (2), arterioportal shunting (2) and partial Budd-Chiari syndrome (1). The localised non-sectoral THAD (7), with variable morphology and without the clear border sign, were associated to acute inflammation of an adjacent organ (4) and to parenchymal compression by the ribs or diaphragm (3). Diffuse THAD associated to Budd-Chiari syndrome (8) and to heart failure (3) showed mosaic enhancement of hepatic parenchyma (patchy pattern); those linked to portal trunk thrombosis (4) and cirrhosis (7) revealed predominant enhancement of external hepatic parenchyma (central-peripheral phenomenon); finally, those concurrent with dilatation of the entire biliary tree showed parenchymal enhancement close to the dilated bile ducts (peribiliary pattern). Follow-up (22/43) demonstrated complete THAD regression after removal (5/22) and less conspicuity of THAD after partial overcome of the stoppage (1/22). In 2/22 cases of arterioportal shunting no substantial changes were seen. The remaining 14/22 cases showed a gradual, slow tendency towards THAD regression with hypotrophy of the involved parenchyma and compensatory contralateral hypertrophy even in the case of endurance of the causative agents. CONCLUSIONS: Based on our experience and the literature we suggest a classification for THAD unrelated to focal hepatic lesions. We recognise 4 causes: portal vein stoppage-obstruction, portal in-flow diversion, trauma and inflammation. When THAD is related to the first three causes pathogenesis is portal hypoperfusion. In the fourth group the mediators of the arterial phenomena are those of inflammation even though portal hypoperfusion might be involved as well. THAD identification makes the detection of vascular thrombi easier by comparison with their direct finding during the portal dominant phase. Finally, THAD are to be investigated for their potential utility in the detection and characterisation of several hepatic diseases. As a consequence, hepatic CT studies cannot ignore arterial dominant phase evaluation, even if no focal hepatic lesions are expected.

Adolescent↗
PubMed2003

Flowering phenology and compensation for herbivory in Ipomopsis aggregata.

The mechanisms and circumstances that affect a plant's ability to tolerate herbivory are subjects of ongoing interest and investigation. Phenological differences, and the timing of flowering with respect to pollinators and pre-dispersal seed predators, may provide one mechanism underlying variable responses of plants to herbivore damage. The subalpine wildflower, Ipomopsis aggregata, grows across a wide range of elevations and, because phenology varies with elevation, phenological delays associated with elevation may affect the ability of I. aggregata to compensate for or tolerate browsing. Thus, we examined the response of I. aggregata to herbivory across an elevation gradient and addressed the interactions among phenological delays imposed by damage, elevation, pre-dispersal seed predation and pollination, on I. aggregata's compensatory response. Among high and low elevation populations in areas near the Rocky Mountain Biological Laboratory (RMBL) in Gothic, Colorado, we compared the responses of naturally browsed, artificially browsed (clipped), and unbrowsed (control) plants of I. aggregata. We compared responses in the date of initiation of flowering, timing of peak bloom, floral display, nectar production and sugar concentration, oviposition and fruit destruction by the pre-dispersal seed predator Hylemya sp. (Anthomyiidae), fruit production, and aboveground biomass production. Clipping had the greatest effect on reproductive success and clipped plants at high elevation exhibited the lowest tolerance for herbivory. The effects of browsing appear to be mediated by flowering phenology, and both browsing and elevation delayed flowering phenology. Time needed for regrowth delays flowering, and thus affects the overlap with seed predators and pollinators. As a result of delayed flowering, naturally browsed and clipped plants incurred lower rates of seed predation. In the absence of seed predation, plants would exhibit a lower tolerance to herbivory since naturally and artificially browsed plants had fewer fruits destroyed by Hylemya larvae. We provide additional evidence that, for populations near the RMBL, clipping and natural browsing do not have the same effect on I. aggregata plants. This may be due to the selection of larger plants by herbivores. Although under some conditions plants may tolerate browsing, in areas where the growing season is short a phenological delay imposed by damage is likely to significantly reduce plant fitness. Identifying the mechanisms that allow plants to tolerate herbivore damage will help to develop a general framework for understanding the role of tolerance in plant population and community dynamics, as well as plant-herbivore interactions.

Adaptation, Physiological↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗