Convergent evolution as a mechanism for pathogenic adaptation

The survival of human pathogens depends on their ability to modulate defence pathways in human host cells. This was thought to be attained mainly by pathogen specific "virulence factors". However, pathogens are increasingly being discovered that use distant homologs of the human regulatory proteins as virulence factors. We analyzed several cases of this approach, with a particular focus on virulence proteases. The analysis reveals clear cases of bacterial proteases mimicking the specificity of their human counterparts, such as strong similarities in their active and/or binding sites. With more sensitive tools for distant homology recognition, we could expect to discover many more such cases.     

Aging mechanism as the "down side" of adaptation: a network approach

Many diverse hypotheses on aging are in play. All from "aging genes" over decreasing telomere length to increased level of gene mutations has been suggested to determine an organism's lifespan, but no unifying theory exists. As part of a growing interest toward more integrative approaches in the field we propose a simplistic model based on the "use-it-or-lose-it" concept: we hypothesize that biological aging is a systemic property and the down side of adaptation in complex biological networks at various levels of organization: from brain over the immune system to specialized tissues or organs. The simple dynamical model undergoes three phases during its lifetime: (1) general plasticity (childhood), (2) optimization/adaptation to given conditions (youth and adolescence) and (3) steady state associated with high rigidity (aging). Furthermore, our model mimics recent data on the dynamics of the immune system during aging and, although simplistic, thus captures essential characteristics of the aging process. Finally, we discuss the abstract model in relation to current knowledge on aging and propose experimental setups for testing some of the theoretical predictions.     

Par force evolution as a mechanism for rapid adaptation

An important task is to reduce the cost of natural selection. The stress provides a short-term non-specific resistance to a number of factors (cross resistance); however, in the long term, it is harmful (distress). In a small population, it is more expedient to change the stress flow (prolonging the phase of cross resistance, neutralizing distress) by natural selection within a small group of stress genes than to test all mutations of genome in a search for preadaptations. This process can provoke allo- or aromorphosis.     

Dopaminergic system as the mechanism underlying personality in a beetle

Individuals in many animal species exhibit 'personality,' consistent differences in behaviour across time, situations and/or contexts. Previous work has revealed a negative genetic correlation between intensity of tonic immobility and walking activity levels in the confused flour beetle, Tribolium confusum, thus suggesting these beetles exhibit personality in activity-related traits. The present study investigated the mechanism underlying this correlation. We used individuals derived from two strains established via artificial divergent selection for duration of tonic immobility. "Long" (L) strains exhibited higher frequencies and longer durations of tonic immobility, and lower activity levels, while "Short" (S) strains exhibited lower frequencies and shorter durations of tonic immobility and higher activity levels. We found that the duration of tonic immobility, and activity level, could be altered by caffeine administration; L strains fed with caffeine exhibited decreased durations of tonic immobility and increased activity levels. We also found that brain dopamine levels were lower in L strains than in S strains. Consequently, this study demonstrates that the dopaminergic system plays an important part in controlling the genetic correlation between tonic immobility and activity levels in this species.     

EEG pattern as an instrument for evaluation of neurophysiological mechanisms underlying adaptation disorders

The method of statistical evaluation of probable interaction between the main constituents of bioelectrical activity of the brain (BEA) enables to reveal the character of intercentral relations both under normal conditions and at adaptation disorders of different severance. Several types of statistic interactions have been revealed between EEG components (SSIC) correlating with normal interrelations between cortex and subcortex, level of preferential involvement of non-specific brain formations (cortex, thalamic, hypothalamic and brain-stem) into the process, and the degree of instability of neuro-dynamic processes. The findings obtained have shown the degree of expression of adaptation disorders to be connected with gradual destruction of "functional nuclear" within alpha-range, amplification of statistical interrelations with beta-EEG and teta-EEG components and formation of pathological nuclear structures within the ranges aforesaid.     

Phosphorylation of rhodopsin as a possible mechanism of adaptation.

Light-induced phosphorylation of rhodopsin has been extensively studied by a number of investigators from a biochemical point of view. However, little is known about the physiological function of this reaction. The slow rates measured for phosphorylation and dephosphorylation suggest that it may be involved in visual adaptation rather than in excitation. This paper presents biochemical data obtained from phosphorylation experiments in isolated photoreceptor membranes as well as in the physiological system of whole retinas and living animals. An attempt is made to compare the phosphorylation reaction with visual adaptation hypotheses taken from the electrophysiological literature. Finally, effects of cyclic nucleotide metabolism on the sensitivity of photoreceptors are presented and discussed.     

Gene duplication as a mechanism of genomic adaptation to a changing environment

A subject of extensive study in evolutionary theory has been the issue of how neutral, redundant copies can be maintained in the genome for long periods of time. Concurrently, examples of adaptive gene duplications to various environmental conditions in different species have been described. At this point, it is too early to tell whether or not a substantial fraction of gene copies have initially achieved fixation by positive selection for increased dosage. Nevertheless, enough examples have accumulated in the literature that such a possibility should be considered. Here, I review the recent examples of adaptive gene duplications and make an attempt to draw generalizations on what types of genes may be particularly prone to be selected for under certain environmental conditions. The identification of copy-number variation in ecological field studies of species adapting to stressful or novel environmental conditions may improve our understanding of gene duplications as a mechanism of adaptation and its relevance to the long-term persistence of gene duplications.     

Integrin shedding as a mechanism of cellular adaptation during cardiac growth

Integrin-mediated cell-extracellular matrix (ECM) interactions are essential for multiple cellular processes; however, little is known regarding integrin turnover during these events. Recent studies have demonstrated shedding of cell surface molecules and suggested this as a potential mechanism for integrin turnover. Confocal microscopy of mouse hearts under different physiological conditions demonstrated the presence of beta(1)-integrin-immunoreactive material in the interstitium. Culture media from neonatal rat cardiac myocytes and fibroblasts contained a 55-kDa fragment of beta(1)-integrin. Attachment to ECM components, response to phorbol 12-myristate 13-acetate stimulation, and matrix metalloproteinase inhibition assays demonstrated that fibroblasts responded differently to the fragment compared with myocytes. The beta(1)-integrin fragment stimulated myocyte attachment to collagen and the fragment itself bound a variety of ECM proteins. These studies indicate that as myocytes and fibroblasts change size and shape, cellular contacts with the ECM are altered, resulting in the liberation of a beta(1)-integrin fragment from the cell surface. Integrin shedding may represent a novel mechanism of rapidly modifying cell-ECM contacts during various cellular processes.     

Transcription: a mechanism for short-term memory

Yeast growing for a considerable time in glucose 'remember' a previous exposure to galactose, the inducer of its galactose-utilization (GAL) genes. This memory is conveyed by a cytoplasmically transmitted galactokinase working as a signal transducer.     

The role of calmodulin as a signal integrator for synaptic plasticity

Excitatory synapses in the brain show several forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), which are initiated by increases in intracellular Ca(2+) that are generated through NMDA (N-methyl-D-aspartate) receptors or voltage-sensitive Ca(2+) channels. LTP depends on the coordinated regulation of an ensemble of enzymes, including Ca(2+)/calmodulin-dependent protein kinase II, adenylyl cyclase 1 and 8, and calcineurin, all of which are stimulated by calmodulin, a Ca(2+)-binding protein. In this review, we discuss the hypothesis that calmodulin is a central integrator of synaptic plasticity and that its unique regulatory properties allow the integration of several forms of signal transduction that are required for LTP and LTD.     

Nijmegen breakage syndrome 1 protein hyperacetylation as a molecular mechanism underlying metabolic syndrome

Metabolic Syndrome (MetS) is characterized by visceral obesity, insulin resistance, hypertension, atherogenic dyslipidemia, and increased atherosclerotic plaque development and cardiovascular disease. It arises from a high-calorie “Western diet” and physical inactivity. MetS confers an elevated risk for type II diabetes, cancer, and cardiovascular disease, significantly shortening the affected individual's life. While many gene products affect the course of MetS, SirT1 and ataxia–telangiectasia mutated (ATM) protein activities ameliorate the pathophysiological effects of MetS in rodent models. SirT1 activity protects mice from the deleterious effects of a high-fat diet, promoting insulin sensitivity, fat mobilization, lowered blood pressure, and cell survival and genomic stability. ATM activation attenuates hypertension, diet-induced atherosclerotic plaque development, and glucose resistance in mice. ATM activity partially depends on Nijmegen breakage syndrome 1 protein (NBS1) activity. NBS1 can be acetylated, which inhibits its interactions with ATM, attenuating ATM function. Restoration of ATM activity requires NBS1 deacetylation by Sirt1. Interestingly, ATM activation increases SirT1 expression. Several studies show that a high-fat–sugar/high-calorie diet suppresses SirT1 expression in many tissues. Here we hypothesize that SirT1 suppression increases NBS1 acetylation, suppressing ATM activity, and finally attenuating ATM-mediated SirT1 expression. The resulting viscous cycle would promote MetS.     

Loss of adaptation to oxidative stress as a mechanism for aortic damage in aging rats

Cells are armed with a vast repertoire of antioxidant defence mechanisms to prevent the accumulation of oxidative damage. The cellular adaptive response is an important antioxidant mechanism against physiological and pathophysiological oxidative alterations in a cell's microenvironment. The aim of this paper was to study, in the rat aorta, whether this adaptive response and the inflammation associated with oxidative stress were expressed throughout the aging process. We examined the rat aorta, as it is a very sensitive tissue to oxidative stress. Male Wistar rats of 1.5, 3, 12, 18 and 24 months of age were used. Superoxide anion (O2(-)) generation; levels of two antioxidant enzymes, superoxide dismutase (SOD) and catalase; and the levels of prostaglandin E2 (PGE2), an inflammatory marker, were measured. The results for rats at different ages were compared with those for 3 months of age. A balance between production of O2(-) and SOD activity was found in the aorta of rats from 1.5 to 12 months old. Oxidative stress was present in the aorta of old animals (18-24 months), due to a failure in the mechanisms of adaptation to oxidative stress. The observed increase in PGE2 levels in these rats reflected an inflammatory response. All together suggest that vascular oxidative stress and the inflammatory process observed in the old groups of rats could be closely related to vascular aging. Our results also remark the importance of the adaptative response to oxidative stress.     

Interpreting voltage-sensitivity of gap junctions as a mechanism of cardiac memory

Memory in the nervous system is essentially a network effect, resulting from activity-dependent synaptic modification in a network of neurons. Like the nervous system, the heart is a network of cardiac cells electrically coupled by gap junctions. The heart too has memory, termed cardiac memory, whereby the effect of an external electrical activation persists long after the presentation of stimulus is terminated. We have earlier proposed that adaptation of gap junctions, as a function of membrane voltages of the cells that are coupled by the gap junctions, is related to cardiac memory [V.S. Chakravarthy, J. Ghosh, On Hebbian-like adaption in heart muscle: a proposal for "Cardiac Memory", Biol. Cybern. 76 (1997) 207, J. Krishnan, V.S. Chakravarthy, S. Radhakrishnan, On the role of gap junctions on cardiac memory effect, Comput. Cardiol. 32 (2005) 13]. Using the proposed mechanism, we demonstrate memory effect using computational models of interacting cell pairs. In this paper, we address the biological validity of the proposed mechanism of gap junctional adaptation. It is known from electrophysiology of gap junctions that the conductance of these channels adapts as a function of junctional voltage. At a first sight, this form of voltage dependence seems to be at variance with the form required by our mechanism. But we show, with the help of a theoretical model, that the proposed mechanism of voltage-dependent adaptation of gap junctions, is compatible with the known voltage-sensitivity of gap junctions observed in electrophysiological studies. Our analysis suggests a new significance of the voltage-sensitivity of gap junctions and its possible link to the phenomenon of cardiac memory.     

Insulin signaling as a mechanism underlying developmental plasticity: the role of FOXO in a nutritional polyphenism

We investigated whether insulin signaling, known to mediate physiological plasticity in response to changes in nutrition, also facilitates discrete phenotypic responses such as polyphenisms. We test the hypothesis that the gene FOXO--which regulates growth arrest under nutrient stress--mediates a nutritional polyphenism in the horned beetle, Onthophagus nigriventris. Male beetles in the genus Onthophagus vary their mating strategy with body size: large males express horns and fight for access to females while small males invest heavily in genitalia and sneak copulations with females. Given that body size and larval nutrition are linked, we predicted that 1) FOXO expression would differentially scale with body size (nutritional status) between males and females, and 2) manipulation of FOXO expression would affect the nutritional polyphenism in horns and genitalia. First, we found that FOXO expression varied with body size in a tissue- and sex-specific manner, being more highly expressed in the abdominal tissue of large (horned) males, in particular in regions associated with genitalia development. Second, we found that knockdown of FOXO through RNA-interference resulted in the growth of relatively larger copulatory organs compared to control-injected individuals and significant, albeit modest, increases in relative horn length. Our results support the hypothesis that FOXO expression in the abdominal tissue limits genitalia growth, and provides limited support for the hypothesis that FOXO regulates relative horn length through direct suppression of horn growth. Both results support the idea that tissue-specific FOXO expression may play a general role in regulating scaling relationships in nutritional polyphenisms by signaling traits to be relatively smaller.