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Molecular evolution of the mitochondrial 12S rRNA in Ungulata (mammalia).

The complete 12S rRNA gene has been sequenced in 4 Ungulata (hoofed eutherians) and 1 marsupial and compared to 38 available mammalian sequences in order to investigate the molecular evolution of the mitochondrial small-subunit ribosomal RNA molecule. Ungulata were represented by one artiodactyl (the collared peccary, Tayassu tajacu, suborder Suiformes), two perissodactyls (the Grevy's zebra, Equus grevyi, suborder Hippomorpha; the white rhinoceros, Ceratotherium simum, suborder Ceratomorpha), and one hyracoid (the tree hyrax, Dendrohyrax dorsalis). The fifth species was a marsupial, the eastern gray kangaroo (Macropus giganteus). Several transition/transversion biases characterized the pattern of changes between mammalian 12S rRNA molecules. A bias toward transitions was found among 12S rRNA sequences of Ungulata, illustrating the general bias exhibited by ribosomal and protein-encoding genes of the mitochondrial genome. The derivation of a mammalian 12S rRNA secondary structure model from the comparison of 43 eutherian and marsupial sequences evidenced a pronounced bias against transversions in stems. Moreover, transversional compensatory changes were rare events within double-stranded regions of the ribosomal RNA. Evolutionary characteristics of the 12S rRNA were compared with those of the nuclear 18S and 28S rRNAs. From a phylogenetic point of view, transitions, transversions and indels in stems as well as transversional and indels events in loops gave congruent results for comparisons within orders. Some compensatory changes in double-stranded regions and some indels in single-stranded regions also constituted diagnostic events. The 12S rRNA molecule confirmed the monophyly of infraorder Pecora and order Cetacea and demonstrated the monophyly of the suborder Ruminantia was not supported and the branching pattern between Cetacea and the artiodacytyl suborders Ruminantia and Suiformes was not established. The monophyly of the order Perissodactyla was evidenced, but the relationships between Artiodactyla, Cetacea, and Perissodactyla remained unresolved. Nevertheless, we found no support for a Perissodactyla + Hyracoidea clade, neither with distance approach, nor with parsimony reconstruction. The 12S rRNA was useful to solve intraordinal relationships among Ungulata, but it seemed to harbor too few informative positions to decipher the bushlike radiation of some Ungulata orders, an event which has most probably occurred in a short span of time between 55 and 70 MYA.

Animals

Reconstruction and analysis of human Alu genes.

The existing classification of human Alu sequences is revised and expanded using a novel methodology and a larger set of sequence data. Our study confirms that there are two major Alu subfamilies, Alu-J and Alu-S. The Alu-S subfamily consists of at least five distinct subfamilies referred to as Alu-Sx, Alu-Sq, Alu-Sp, Alu-Sc, and Alu-Sb. The Alu-Sp and Alu-Sq subfamilies have been revealed by this study. Alu subfamilies differ from one another in a number of positions called diagnostic. In this paper the diagnostic positions are defined in quantitative terms and are used to evaluate statistical significance of the observed subfamilies. Each Alu subfamily most likely represents pseudogenes retroposed from evolving functional source Alu genes. Evidence presented in this paper indicates that Alu-Sp and Alu-Sc pseudogenes were retroposed from different source genes, during overlapping periods of time, and at different rates. Our analysis also indicates that the previously identified Alu-type transcript BC200 comes from an active Alu gene that might have existed even before the origin of dimeric Alu sequences. The source genes for Alu pseudogene families are reconstructed. It is assumed that diagnostic differences between reconstructed source genes reflect mutations that have occurred in true source Alu genes under natural selection. Some of these mutations are compensatory and are used to reconstruct a common secondary structure of Alu RNAs transcribed from the source genes. The biological function of Alu RNA is discussed in the context of its homology to the elongation-arresting domain of 7SL RNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

[Morphofunctional specialization of tissue components of the mammalian placenta and adaptational value in changes in the rate of their differentiation (evolutionary and clinical aspects)].

It has been shown that in the ontogenesis of human placenta there occur regular changes in the percentage of the villi of various calibre having different interrelationships between the trophoblast, the connective tissue stroma and the fetal vessel. The changes of the number of chorial villi affected by fibrinoid and containing blood vessels under the trophoblast in late toxicoses of women and the anemic syndrom are analyzed (treated and not treated groups of women suffering from different forms of toxicosis were compared). An increased amount of chorial villi having blood vessels under the trophoblast is noted which is a morphofunctional feature of compensatory-adaptational alterations. Possible ecologo-evolutionary approaches to clearing the biological significance of adaptational changes of morphogenesis of the human placenta in pathological pregnancy are shown by the example of the analysis of morphological peculiarities of the placenta of the dolphin.

Adaptation, Physiological

Neurotransmitters and stress.

In this article definitions of stress and distress are proposed and the relationships between stress and activities of neurohormonal systems explored. The idea is developed that stress is a condition where expectations--whether genetically programmed, established by prior learning, or deduced from circumstances--do not match the current or anticipated perceptions of the internal or external environment, and this discrepancy between what is observed or sensed and what is expected or programmed elicits patterned, compensatory responses. Distress is viewed here as a form of stress characterized by specific behavioral and autonomic communicated signs, pituitary-adrenocortical and sympathoadrenomedullary activation, and a negative experience that motivates escape or avoidance. During stress, many body systems--including the sympathoadrenal, parasympathetic, and hormonal homeostatic systems--are activated or inhibited in primitively specific patterns regulated by physiological, biochemical, and psychological homeostats. Many of these patterns, which are at least partly inherited, can be understood teleologically on the basis of preservation of the internal environmental and natural selection in evolution.

Animals

[Human hemoglobin: polymorphism, neutrality of variants, evolutionary aspect].

Integrated analysis of the polymorphism of human hemoglobin has been made using populational genetics, hematological, physiological, protein chemistry and molecular biology data. The known variants of human hemoglobin are conventionally classified as "widely common", "less common" and "rare", depending on their contribution to polymorphism. The importance of homeostasis and compensatory reactions for maintaining the resistance of the human body against mutant hemoglobins is emphasized. Hb D Punjab and Hb O Arab being relatively neutral, the genetic structure of populations may restrict their distribution. A hypothesis is put forward concerning the possible role of an increased local conformational mobility of protein in creating neutral protein variants. It is proposed to discriminate between truly neutral and pseudoneutral protein variants. In case of possible changes in the genetic and environmental factors, the former are not subject to selection, while the latter may be. Contribution to neutral evolution can be made only by truly neutral variants. In a compensated heterozygotic state the truly neutral and pseudoneutral variants may give rise to new functions and adaptively valuable properties in protein. The evolution of proteins is believed to proceed from a stage which is consistent with M. Kimura's concept of neutrality of protein polymorphism toward a stage which is consistent with the concept of selectionism. It is concluded, that the currently observed degree of polymorphism of human hemoglobin corresponds to the present stage of molecular evolution of the protein.

Biological Evolution

Enhanced RNA replication and pathogenesis in recent SARS-CoV-2 variants harboring the L260F mutation in NSP6.

The COVID-19 pandemic has been driven by SARS-CoV-2 variants with enhanced transmission and immune escape. Apart from extensive evolution in the Spike protein, non-Spike mutations are accumulating across the entire viral genome and their functional impact is not well understood. To address the contribution of these mutations, we reconstructed genomes of recent Omicron variants with disabled Spike expression (replicons) to systematically compare their RNA replication capabilities independently from Spike. We also used a single reference replicon and complemented it with various Omicron variant Spike proteins to quantify viral entry capabilities in single-round infection assays. Viral entry and RNA replication were negatively correlated, suggesting that as variants evolve reduced entry functions under growing immune pressure on Spike, RNA replication increases as a compensatory mechanism. We identified multiple mutations across the viral genome that enhanced viral RNA replication. NSP6 emerged as a hotspot with a distinct L260F mutation independently arising in the BQ.1.1 and XBB.1.16 variants. Using mutant and revertant NSP6 viral clones, the L260F mutation was validated to enhance viral replication in cells and increase pathogenesis in mice. Notably, this mutation reduced host lipid droplet content by NSP6. Collectively, a systematic analysis of RNA replication of recent Omicron variants defined NSP6's key role in viral RNA replication that provides insight into evolutionary trajectories of recent variants with possible therapeutic implications.

SARS-CoV-2

Plasticity of the central nervous system--a neurosurgeon's experience of cerebral compensation and decompensation.

Cerebral plasticity constitutes one of the most decisive factors in recovery and readaptation after cerebral lesions. In contrast to the considerable progress in current studies on normal neuronal plasticity including the idea of "l'homme neuronal", the concept of plasticity postulated by Albrecht Bethe in 1929 received little attention. The author, as a neurosurgeon, has tried to describe cranial morphological plasticity, morphological and functional plasticity in infantile encephalopathies and especially in hemiatrophic lesions. It is supposed that a true morphological substrate exists due to compensatory hyperplasia of the uninvolved hemisphere. Modern neurosurgical techniques have demonstrated that the functional plastic capacity is much larger than has been supposed, even in the elderly. Some aspects of the mechanisms of compensation and decompensation of cortical and subcortical structures as well as of the central regulation systems are discussed. The full extent of the amazing recovery and functional reorganization is reached by plastic capacity, personal motivation, adequate training and sufficient time. The contribution ends with an exposition of a personal philosophy concerning psycho-somatic dualism, the body-mind problem, the future of the human brain and the ethical outlook, based on the progressive biological evolution of the basal neocortex and the immanent functional development (H. Spatz).

Adaptation, Physiological

Gene expression is stable despite widespread cis and trans regulatory divergence in Saccharomyces yeasts.

Regulatory evolution can alter phenotypes, but cis- and trans-regulatory mechanisms may also diverge extensively while total transcript abundance remains stable. Comparisons of parental expression with allele-specific expression in F1 hybrids provide a framework for separating cis- and trans-regulatory effects because both parental alleles are measured in a shared trans-regulatory environment. Here, we analyzed RNA sequencing data from Saccharomyces cerevisiae, Saccharomyces paradoxus, and their F1 hybrid. Regulatory divergence was widespread, with 61.3% of tested orthologs showing significant divergence in at least one cis or trans component. However, hybrid expression remained largely conserved, with 81.6% of genes not significantly different from either parent. Compensatory cis-trans divergence predominated over reinforcing divergence, consistent with widespread buffering of transcript abundance. To connect genome-wide patterns to mechanism, we analyzed the strongly cis-diverged locus LYS2 and found species differences in promoter architecture, including an S. cerevisiae-specific AT-rich insertion, altered spacing among candidate regulatory features, and a promoter-proximal TATA-like element unique to S. cerevisiae. Sequence-based nucleosome prediction suggests that these differences create a broader promoter-proximal nucleosome-depleted region in S. cerevisiae than in S. paradoxus. We also quantified allele-resolved intron retention and found that splicing was broadly conserved, with only rare locus-specific hybrid-associated shifts. Together, these results show that regulatory divergence is widespread but often buffered in the hybrid, whereas post-transcriptional divergence is comparatively limited.

Gene expression

Sequences similar to genes for two mitochondrial proteins and portions of ribosomal RNA in tandemly arrayed 6-kilobase-pair DNA of a malarial parasite.

Erythrocytic stages of mammalian malarial parasites contain acristate mitochondria whose functions are not well understood. Moreover, little is known about the genome of these organelles. We have previously reported that all species of malarial parasites examined contain highly conserved, tandemly arrayed DNA with a unit length of about 6.0 kb that is transcribed into discrete RNA molecules in erythrocytic stages. We now report the complete DNA sequence of the 5984-bp repeating unit of Plasmodium yoelii, a rodent parasite. Two slightly overlapping regions transcribed into large RNA molecules were found to have significant DNA and protein sequence similarity with mitochondrion-coded proteins, cytochrome c oxidase subunit I and cytochrome b. Significant sequence similarity with other mitochondrial protein genes could not be detected. Ribosomal RNA (rRNA)-like genes were not detected in this sequence either. However, two regions, 82 and 50 nucleotides long, specified by different strands, were found to have extensive similarity with the highly conserved central loop of the peptidyl transferase domain of the large rRNA of Escherichia coli, mitochondria, and chloroplasts. Compensatory nucleotide substitutions were present in these regions, so that the predicted secondary structure was not affected. Functional utilization of these regions, if it exists, could argue for a trans-associative origin of rRNA. In organization, size and sequence, the tandem arrays of 6.0 kb malarial DNA appear to be a very unusual form of mitochondrial DNA.

Acyltransferases

[The clinical picture of spinal cord tumors with different histostructures in children].

An analysis into the results of treatment accorded to 101 sick children wiht tumours of the spinal cord evidences that the clinical picture of this pathology is distinguished by a number of features that depend on the histological structure, high compensatory potentialities and extraordinary plasticity of the child's spinal cord and vertebral column. In this connection of prime importance becomes the significance of assessing the data derived from a comprehensive examination, due consideration being given to the age-specific features of the patients. As concerns their incidence in children first and foremost are tumours of the glial series, distinguished by a comparatively mild course of the disease, paucity of focal and conduction symptomatology that is incongrous with the extent of the lesion involving the spinal cord both along its vertical and transverse section. The tumours of the meningovasal series are of rare occurrence, their salient feature being malignant evolution of the affection with extradural localization. Notwithstanding their intensive growth the heterotopic tumours cause in a number of cases some difficulty in the topicodiagnostic respect, this being due to a well-pronounced memingeal syndrome with an extremely poor focal symptomatology. An early surgical and radiation treatment of tumours in the glial series renders a realively good curative effect with partial restoration of disturbed functions in the early and late post-treatment periods.

Adolescent

Gene expression is stable despite widespread cis and trans regulatory divergence in Saccharomyces yeasts.

Regulatory evolution can alter phenotypes, but cis- and trans-regulatory mechanisms may also diverge extensively while total transcript abundance remains stable. Comparisons of parental expression with allele-specific expression in F1 hybrids provide a framework for separating cis- and trans-regulatory effects because both parental alleles are measured in a shared trans-regulatory environment. Here, we analyzed RNA sequencing data from Saccharomyces cerevisiae, Saccharomyces paradoxus, and their F1 hybrid. Among the 4,164 genes with sufficient allele-specific support for strict classification, 2,134 (51.2%) showed detectable cis and/or trans regulatory divergence. However, hybrid expression remained largely conserved, with 81.5% of genes not significantly different from either parent. Compensatory cis-trans divergence predominated over reinforcing divergence; cross-replicate estimation reduced the apparent magnitude of this excess, but opposite-sign effects remained predominant in all 20 non-overlapping replicate comparisons. To connect gene expression to genome sequence, we analyzed the strongly cis-diverged locus LYS2 and found species differences in promoter architecture, including an S. cerevisiae-specific AT-rich insertion, altered spacing among candidate regulatory features, and a promoter-proximal TATA-like element unique to S. cerevisiae. Sequence-based nucleosome prediction suggests that these differences create a broader promoter-proximal nucleosome-depleted region in S. cerevisiae than in S. paradoxus. We also quantified allele-resolved intron retention and found that allele-resolved intron retention was broadly conserved, with only rare locus-specific hybrid-associated shifts. Together, these results show that regulatory divergence is widespread but often buffered in the hybrid, whereas intron-retention divergence is comparatively limited.

Saccharomyces

Temporal evolution of altered islet neurotransmitter sensitivity after VMH lesion.

It has been suggested that increased insulin secretion after ventromedial hypothalamic (VMH) obesity is mediated by decreased sympathetic and increased parasympathetic neural input. The evolution of pancreatic islet adaptation was studied from 1 to 130 days after VMH lesion in rats by assessing the sensitivity of insulin secretion from incubated isolated islets to 10 mM glucose and selected acetylcholine and norepinephrine concentrations. Insulin secretion in response to glucose increased by 1 day, reaching a twofold plateau from 7 to 130 days. Sensitivity to norepinephrine increased by 1 day, whereas sensitivity to acetylcholine decreased by 2 days, and both remained altered up to 130 days. These data suggest that elevated plasma insulin concentrations characteristic of VMH obesity were associated with increased insulin secretion in response to glucose before decreased sensitivity to acetylcholine and concurrent with increased sensitivity to norepinephrine. We conclude that these compensatory responses, which shift the islet to a new operating point secondary to altered neural input, are essential to pancreatic adaptation in VMH obesity.

Acetylcholine

The Convergence of Antimicrobial Resistance and Virulence in Streptococcus pneumoniae: A Molecular and Clinical Perspective.

Antimicrobial resistance (AMR) and virulence have traditionally been viewed as competing traits in bacterial evolution due to fitness costs. However, Streptococcus pneumoniae has emerged as a paradigm of successful coevolution, with multidrug-resistant clones simultaneously maintaining or enhancing pathogenic potential. This review examines the molecular mechanisms, epidemiological patterns, and clinical consequences of the convergence between AMR and virulence in Streptococcus pneumoniae. Resistance to β-lactams is driven by mosaic penicillin-binding protein genes (pbp1a, pbp2b, pbp2x), while macrolide resistance is mediated primarily by the erm(B) gene (MLS phenotype) and mef(A/E)-msr(D) genes encoding an efflux system. These determinants are frequently co-localized on integrative and conjugative elements, ICEs, (e.g., Tn916 family) within successful clonal complexes such as CC271/320 and lineages including ST320 and GPSC10. Contrary to the classical fitness cost hypothesis, compensatory epistasis, capsular recombination, metabolic adaptations, and intra-serotype phenotypic variation enable certain clones to combine high-level resistance to β-lactams, macrolides, and tetracyclines with enhanced colonization, biofilm formation, immune evasion, and invasive capacity. Post-pneumococcal conjugate vaccine (PCV) surveillance reveals the persistence and expansion of these high-risk lineages, contributing to treatment-refractory invasive pneumococcal disease (IPD), increased morbidity, and mortality. Although PCVs have reduced vaccine-type resistant strains in some settings, serotype replacement and emerging metabolic genotypes continue to drive adaptation. This review highlights the need for integrated genomic surveillance, novel therapeutics (e.g., omadacycline, lefamulin, endolysins), monoclonal antibodies, and next-generation vaccines targeting both resistance and conserved virulence determinants. A multifaceted strategy combining antimicrobial stewardship, strengthened surveillance, and innovative interventions is essential to curb the evolving threat of resistant and virulent S. pneumoniae.

Streptococcus pneumoniae

Chromosomal resistance mutations facilitate acquisition of multidrug-resistant plasmids in Escherichia coli.

Bacteria can gain multiple resistance mechanisms in a single step by the acquisition of multidrug-resistant (MDR) plasmids, but it is unclear how antibiotic selection during the acquisition of MDR plasmids affects the evolution of additional resistance mechanisms. Through conjugating separate extended-spectrum β-lactamase (ESBL)- and carbapenemase-producing MDR plasmids into plasmid-naive Escherichia coli hosts, we examine the effects of acquisition of a single plasmid or co-acquisition of multiple plasmids upon fitness costs, resistance and subsequent genomic adaptation. We show that acquisition of pOXA-48, encoding OXA-48 carbapenemase, is associated with highly variable fitness costs and levels of resistance to ertapenem in transconjugants independent of the presence of pLL35. This phenomenon was not observed during the acquisition of ESBL CTX-M-15-encoding pLL35 alone. Within a single growth cycle, transconjugants receiving pOXA-48 rapidly gained parallel mutations affecting the membrane porin OmpF, or its regulators OmpR or EnvZ. These chromosomal mutations were not compensatory for the fitness costs imposed by the plasmid, nor did they provide significant increases in resistance to carbapenems in the absence of the pOXA-48. Rather, they acted synergistically with the plasmid-encoded carbapenemase, which alone only provided marginal resistance, together providing high-level resistance to ertapenem. Such rapid evolutionary processes may play an important role in plasmid dynamics within environments with strong antibiotic selection for plasmid-encoded antimicrobial resistance genes (ARGs), particularly when these ARGs provide only marginal resistance.

Escherichia coli

[The osmoregulatory and natriuretic functions of the kidneys in the early stages of the evolution of hypertension].

Overall 78 men were examined. Of these, 30 presented with borderline arterial hypertension (BAH), 30 with stage I essential hypertension (EH), and 18 healthy subjects served as control. To assess osmoregulating and natriuretic renal functions, water and water plus salt were administered (at a rate of 22 ml water or isotonic sodium chloride per kg bw). Use was made of classic approaches in this case, with the determination of K+, Na+ excretion, blood plasma and urine osmolarity, calculation of the concentration index, clearance of osmotic-active substances and free water, total reabsorption of Na in the distal parts of nephron and intensity of that process. Besides, flame photometry was employed to measure blood K+, Na+ concentration and RIA to examine plasma renin activity. The data obtained indicate the heterogeneity of the patients with BAH and stage I EN according to the response to water and water and salt administration. Approximately 1/3 of the patients showed a tendency towards water retention in the body as well, which is common to patients with the volume-dependent form of arterial hypertension. In that case the compensatory potentialities of modulating renin-angiotensin system activity were preserved.

Adult

Protein restriction and progression of chronic renal failure.

The effect of protein restriction upon the rate of renal functional decline was studied in 7 patients with moderate chronic renal failure (CRF). The rate of progression of CRF was evaluated by the reciprocal of plasma creatinine concentration (1/Cr) in time method, every 1-3 months, during 12 months while on ad-libitum diet and 23-40 months thereafter while on protein restriction. While on ad-libitum diet, 4/7 patients showed a progressive disease and the other 3 showed a relatively stable evolution. Six months after protein restriction, patients with a previous progressive disease showed an amelioration in the decline in renal function, and those with stable CRF showed a worsening of the disease in two cases and an improvement in the other one. During the first six months on low protein diet, a transitory increase in plasma creatinine concentration was observed, being maximum at 2.7 months. Plasma urea concentration fell, after protein restriction, to values close to that predicted at the time of the prescription of the diet. Mean systolic and diastolic arterial blood pressure remained stable throughout the study and it was not necessary to change the pharmacological treatment. Our data show that protein restriction decreases the rate of progression of CRF in patients with previous progressive disease. This benefit may result from the suppression of compensatory hyperfiltration induced by low protein diet, as suggested by the increase in plasma creatinine concentration.

Adult

Base pairing between Escherichia coli RNase P RNA and its substrate.

Base pairing between the substrate and the ribozyme has previously been shown to be essential for catalytic activity of most ribozymes, but not for RNase P RNA. By using compensatory mutations we have demonstrated the importance of Watson-Crick complementarity between two well-conserved residues in Escherichia coli RNase P RNA (M1 RNA), G292 and G293, and two residues in the substrate, +74C and +75C (the first and second C residues in CCA). We suggest that these nucleotides base pair (G292/+75C and G293/+74C) in the ribozyme-substrate complex and as a consequence the amino acid acceptor stem of the precursor is partly unfolded. Thus, a function of M1 RNA is to anchor the substrate through this base pairing, thereby exposing the cleavage site such that cleavage is accomplished at the correct position. Our data also suggest possible base pairing between U294 in M1 RNA and the discriminator base at position +73 of the precursor. Our findings are also discussed in terms of evolution.

Base Composition

Nucleolin gene organization in rodents: highly conserved sequences within three of the 13 introns.

The complete nucleotide (nt) sequence of the rat nuc gene encoding nucleolin, the major nucleolar-specific protein in eukaryotic exponentially growing cells, is compared with the corresponding locus recently characterized in mouse. [Bourbon et al., J. Mol. Biol. 200 (1988) 627-638]. In both murine species the genomic organization has been strikingly conserved during evolution, i.e., the coding region extends over 9 kb and is split into 14 exons, encoding a 712-amino acid protein. Moreover, all the exon-intron junction positions were strictly maintained during evolution. More unexpectedly, this analysis revealed that several introns contain highly conserved sequence elements of about 120 nt. The nt sequence of the homologous locus isolated from a Chinese hamster genomic clone established that these regions were under unusually high selective constraints (84-96% identity between the hamster and murine nuc genes) and, although they do not contain open reading frames, they surprisingly appear to be more conserved than most of the exons, suggesting that they play an important role. Such an element of 130 nt presents features of known genes transcribed by RNA polymerase III. Furthermore, in the rat nuc pre-mRNA the 5'- and 3'-end regions of the last intron are fully complementary over 16 nt, and so are predicted to be included in a prominent stem structure. Moreover, an homologous RNA stem structure can be derived from the mouse sequence, including two compensatory nt changes. As the secondary structure would occlude the canonical sequences required for the proper excision of this intron in both murine species, this remarkable finding could be relevant to the regulation of the nuc gene expression at the RNA processing level.

Amino Acid Sequence