On the rate of molecular evolution

Summary There are at least two outstanding features that characterize the rate of evolution at the molecular level as compared with that at the phenotypic level. They are; (1) remarkable uniformity for each molecule, and (2) very high overall rate when extrapolated to the whole DNA content.The population dynamics for the rate of mutant substitution was developed, and it was shown that if mutant substitutions in the population are carried out mainly by natural selection, the rate of substitution is given byk = 4 N _e s ₁ v, whereN _e is the effective population number,s ₁ is the selective advantage of the mutants, andv is the mutation rate per gamete for such advantageous mutants (assuming that 4N _e s ₁ 1). On the other hand, if the substitutions are mainly carried out by random fixation of selectively neutral or nearly neutral mutants, we havek = v, wherev is the mutation rate per gamete for such mutants.Reasons were presented for the view that evolutionary change of amino acids in proteins has been mainly caused by random fixation of neutral mutants rather than by natural selection.It was concluded that if this view is correct, we should expect that genes of living fossils have undergone almost as many DNA base replacements as the corresponding genes of more rapidly evolving species.Contribution No. 789 from the National Institute of Genetics, Mishima, Shizuokaken 411 Japan. Aided in part by a grant-in-aid from the Ministry of Education, Japan.     

Population size and rate of evolution

Summary It is suggested that in evolution there is much substitution of nearly neutral mutations, for which the selection intensity varies from time to time or from region to region. Since the variance among the selection coefficients of new mutants decreases when the environment becomes uniform, the probability of a mutant being advantageous to the species as a whole increases in more uniform environment (Fig. 1).Therefore the rate of gene substitution increases in smaller populations, as smaller populations are likely to be distributed over less varied environments.The adequacy of the model was discussed in relation with the following facts or plausible postulates. 1. A large number of amino acid substitutions during a period corresponding to the formation of new species. 2. Rapid evolution at the phenotypic level of populations having a small size. 3. Many extinctions and expansions of the species in the past.Contribution No. 871 from the National Institute of Genetics, Mishima, Shizuokaken 411 Japan.     

Algal polymorphism in high rate wastewater treatment ponds

In the past as well as today there have been two conflicting opinions as to whether changes in the algal species in water bodies indicate polymorphism or the development of separate species. Similar changes were also found in High Rade Algae Pond (HRAP) used for wastewater treatment, effluent reclamation and protein production. To critically examine both opinions, samples of HRAP effluent were taken and the algal species identified and measured continuously, using conventional methods.Two main algal species were identified. These remained stable during all four monitoring sessions over a three-year period. The external changes observed in the algae were a reflection of controlled periods of organic loading and the conditions under which the pond was operated, such as retention time (a dependant of radiation), ambient temperature, effluent depth and aeration methods.Current address: Institute for Desert Research, Ben-Gurion University of the Negev, Sde-Boker, Israel 84990     

Simplified approach for developing the rate expressions for enzyme-catalyzed reactions

A Simplified version of rate equations for enzyme-catalyzed reactions has been developed in which the rate equation is analyzed with two different mechanisms: ordered bi–ter and Ping-Pong bi–bi mechanisms. This procedure is able to develop the rate expressions accurately. Random sequential order mechanism can be effectively explained by this approach.     

Phylogenetic analysis, genome evolution and the rate of gene gain in the Herpesviridae

We used complete sequence data from 30 complete Herpesviridae genomes to investigate phylogenetic relationships and patterns of genome evolution. The approach was to identify orthologous gene clusters among taxa and to generate a genomic matrix of gene content. We identified 17 genes with homologs in all 30 taxa and concatenated a subset of 10 of these genes for phylogenetic inference. We also constructed phylogenetic trees on the basis of gene content data. The amino acid and gene content phylogenies were largely concordant, but the amino acid data had much higher internal support. We mapped gene gain events onto the phylogenetic tree by assuming that genes were gained only once during the evolution of herpesviruses. Thirty genes were inferred to be present in the ancestor of all herpesvirus, a number smaller than previously hypothesized. Few genes of recent origin within herpesviruses could be identified as originating from transfer between virus and vertebrate hosts. Inferred rates of gene gain were heterogeneous, with both taxonomic and temporal biases. Nonetheless, the average rate of gene gain was approximately 3.5 x 10(-7) genes gained per year, which is an order of magnitude higher than the nucleotide mutation rate for these large DNA viruses.     

The influence of rate of temperature change and peak stimulus duration on pain intensity and quality

An important aspect of experimental pain research is that the assessment methods can investigate the different aspects of pain perception. The aim of the present study was to investigate the influence of rate of temperature change and peak stimulus duration on heat evoked pain intensity and quality. All stimuli were applied within the medial aspect of the anterior forearm. The rate of temperature change was varied from 1 to 16 C/s without any effect on the pain threshold. The pain threshold decreased with an increasing peak stimulus duration from 0.1 to 2 s, but not from 2 to 3 s. The pain intensity for suprathreshold stimuli (46 C, 48 C, 50 C) increased for decreasing rates and increasing duration. The pain intensity was highly correlated with the energy of the stimulus. When the rates of temperature change (1-16 C/s) are varied, no differences between pricking and burning pain were present at either low stimulus intensity (46 C) or high stimulus intensity (50 C). At low stimulus intensity (46 C), the pricking pain was not influenced by the duration (0.1-3 s), but the burning pain was intensified when the duration was increased from 1.5 to 3 s. At high intensity stimuli (50 C), the pricking pain intensified with an increased duration, whereas burning pain did not. The heat pain threshold is influenced by the peak stimulus duration, and not by the rate of temperature change. If suprathreshold stimuli are used, both the rate of temperature change and the peak stimulus duration can strongly affect the pain intensity and the pain quality. Therefore, the same stimulus modality can be used to assess the modulation of different pain intensities and of the pricking and burning pain qualities simply by varying the stimulus configuration.     

On the constancy of the evolutionary rate of cistrons

Summary The variations of evolutionary rates in hemoglobins and cytochrome c among various lines of vertebrates are analysed by estimating the variance. The observed variances appear to be larger than expected purely by chance.If the amino acid substitutions in evolution are the result of random fixation of selectively neutral or nearly neutral mutations, the evolutionary rate of cistrons can be represented by the integral of the product of mutation rate and fixation probability in terms of selective values around the neutral point. This integral is called the effective neutral mutation rate.The influence of effective population number and generation time on the effective neutral mutation rate is discussed. It is concluded that the uniformity of the rate of amino acid substitutions over diverse lines is compatible with random fixation of neutral or very slightly deleterious mutations which have some chance of being selected against during the course of substitution. On the other hand, definitely advantageous mutations will introduce significant variation in the substitution rate among lines. Approximately 10% of the amino acid substitutions of average cistrons might be adaptive and create slight but significant variations in evolutionary rate among vertebrate lines, although the uniformity of evolutionary rate is still valid as a first approximation.Contribution No. 813 from the National Institute of Genetics, Mishima, Shizuokaken 411 Japan. Aided in part by a grant-in-aid from the Ministry of Education, Japan.     

Influence of signal filtering and sample rate on isometric torque – time parameters using a traditional isokinetic dynamometer

Isometric force- or torque-time parameters are commonly reported in the research literature. The processing methods of the electronic dynamometer-derived signal may influence the outcome measures. This study determined the influence of filtering and sample rate (SR) on isometric torque-time parameters and provides specific signal processing recommendations for future studies. Twenty-three subjects performed 49 isometric maximum voluntary contractions (MVCs) of the knee extensors on an isokinetic dynamometer. Outcome measures included peak torque (PT), and rate of torque development at peak (RTDPEAK), 50 (RTD50) and 200 (RTD200) ms for seven filter conditions including low-pass filter cutoffs at 5, 10, 20, 50, 100 and 150 Hz and a notch filter at 100 and 200 Hz. Comparisons were also made across four SR conditions at 100, 500, 1000 and 2000 Hz. The RTDPEAK variable was markedly changed (−5.4 to −37.9%) for all filter frequencies compared to the 150 Hz condition and the RTD50 variable was altered for all frequencies between 50 and 5 Hz. No differences were found for RTD200. For SR, compared to the 2000 Hz condition, differences were revealed for the 100 Hz condition for the RTDPEAK and RTD50 variables. The filtering or SR did not alter PT across any of the conditions. The filter and SR applied to the signal was capable of distorting the MVC signal and skewing the torque–time parameters, specifically for the early and maximum RTD variables of the MVC curve (RTD50 and RTDPEAK). For traditional isokinetic dynamometers, a low-pass filter cutoff of 150 Hz and a SR of at least 1000 Hz is recommended when assessing early isometric force- or torque-time MVC parameters.     

Determination of relative rate constants for in vitro RNA processing reactions by internal competition

Studies of RNA recognition and catalysis typically involve measurement of rate constants for reactions of individual RNA sequence variants by fitting changes in substrate or product concentration to exponential or linear functions. A complementary approach is determination of relative rate constants by internal competition, which involves quantifying the time-dependent changes in substrate or product ratios in reactions containing multiple substrates. Here, we review approaches for determining relative rate constants by analysis of both substrate and product ratios and illustrate their application using the in vitro processing of precursor transfer RNA (tRNA) by ribonuclease P as a model system. The presence of inactive substrate populations is a common complicating factor in analysis of reactions involving RNA substrates, and approaches for quantitative correction of observed rate constants for these effects are illustrated. These results, together with recent applications in the literature, indicate that internal competition offers an alternate method for analyzing RNA processing kinetics using standard molecular biology methods that directly quantifies substrate specificity and may be extended to a range of applications.     

Effects of altitude on exercise level and heart rate in patients with coronary artery disease and healthy controls

Background. To evaluate the safety and effects of high altitude on exercise level and heart rate in patients with coronary artery disease compared with healthy controls. Methods. Eight patients with a history of an acute myocardial infarction (ejection fraction >5%) with a low-risk score were compared with seven healthy subjects during the Dutch Heart Expedition at the Aconcagua in Argentina in March 2007. All subjects underwent a maximum exercise test with a cycle ergometer at sea level and base camp, after ten days of acclimatisation, at an altitude of 4200 m. Exercise capacity and maximum heart rate were compared between groups and within subjects. Results. There was a significant decrease in maximum heart rate at high altitude compared with sea level in both the patient and the control group (166 vs. 139 beats/min, p<0.001 and 181 vs. 150 beats/min, p<0.001). There was no significant difference in the decrease of the exercise level and maximum heart rate between patients and healthy controls (-31 vs. -30%, p=0.673). Conclusion. Both patients and healthy controls showed a similar decrease in exercise capacity and maximum heart rate at 4200 m compared with sea level, suggesting that patients with a history of coronary artery disease may tolerate stay and exercise at high altitude similarly to healthy controls. (Neth Heart J 2010;18:118-21.)     

老年患者脓毒性休克液体复苏速度与预后的关系

目的探讨老年患者脓毒性休克液体复苏过程中输液速度与预后的相关性。方法回顾性分析92例严重感染病人液体复苏效果。按液体复苏期间的输液速度分为慢速组（〈500ml/h）和快速组（≥500ml/h）,并对两组患者的心率、有创及无创血压、血氧饱和度、呼吸、中心静脉压（CVP）、每小时尿量、尿比重、血乳酸、ScVO2及有无发生肺水肿、急性心功能不全、急性肾功能不全、MODS和7天死亡率、28天死亡率及入住ICU时间、住院时间等指标进行分析比较。结果两组患者在液体复苏过程中CVP和MAP两项指标比较无统计学意义。慢速组的尿量达标时间耗时较长（P〈0.05）;ScVO2及乳酸清除率比较无明显差异。快速组对液体的需求量多,而应用血管活性药物的病例数则少于慢速组;发生肺水肿、急性心功能不全的比例高于慢速组（P〈0.05）。两组急性肾功能不全的发生率相近,但慢速组出现MODS的例数少（P〈0.05）。7天死亡率和28天死亡率比较,慢速组低于快速组,但无统计学意义。两组患者住院时间无显著统计学意义,入住ICU时间慢速组明显短于快速组（P〈0.05）。结论在脓毒性休克复苏过程中不可一味靠加快输液速度来保证组织灌注,尤其对于老年患者,更应控制单位时间内的输液量,避免给储备能力较差的心功能造成更大的负担。在保证主要脏器灌注的情况下可以适当应用血管活性药物。     

Effect of aggregation on the reproductive rate of populations

The effect of spatial distribution on the reproductive rate of a population was examined by applying an approximate equation to several data based on the entomological literature. This study suggests that aggregation generally reduces the equilibrium level of the population density if the population density is not very high.     

Enhanced motor unit rate coding with improvements in a force-matching task

These data describe improved modulation of discharge rates (rate coding) of first dorsal interosseous motor units throughout the acquisition of a complex force-matching skill involving isometric index finger abduction. In each of 15 consecutive trials, subjects attempted to match their force to a trajectory consisting of the sum of two sine waves (0.15 and 0.5 Hz) and random oscillations (overall mean force level ˜20% MVC). Reductions in root-mean-square (RMS) error of each subject’s force relative to the trajectory indicated substantial improvements in force-matching ability (F=33.8, p<0.001). With the acquisition of this new skill, there was increased amplitude modulation of muscular force near both dominant frequencies of the force-matching trajectory (F=10.6, p=0.008). The standard deviation and coefficient of variation of motor unit inter-spike intervals both decreased with improved performance indicating a general reduction in the amplitude of firing rate modulations (SD: F=18.69, p=0.001; CV: F=43.6, p<0.001). After skill acquisition, there was decreased firing rate modulation outside of the two dominant frequencies and increased amplitude of firing rate modulation at the higher of the two dominant frequencies (0.5 Hz, F=8.23, p=0.015). These findings indicate that improved precision of rate coding was a contributor to the acquisition of the new force-matching task. That the change in rate coding was frequency dependent suggests that factors other than frequency coding may contribute to the improved force matching at 0.15 Hz.     

Nucleic acid composition,codon usage,and the rate of synonymous substitution in protein-coding genes

Summary Based on the rates of synonymous substitution in 42 protein-codin gene pairs from rat and human, a correlation is shown to exist between the frequency of the nucleotides in all positions of the codon and the synonymous substitution rate. The correlation coefficients were positive for A and T and negative for C and G. This means that AT-rich genes accumulate more synonymous substitutions than GC-rich genes. Biased patterns of mutation could not account for this phenomenon. Thus, the variation in synonymous substitution rates and the resulting unequal codon usage must be the consequence of selection against A and T in synonymous positions. Most of the varition in rates of synonymous substitution can be explained by the nucleotide composition in synonymous positions. Codon-anticodon interactions, dinucleotide frequencies, and contextual factors influence neither the rates of synonymous substitution nor codon usage. Interestingly, the nucleotide in the second position of codons (always a nonsynonymous position) was found to affect the rate of synonymous substitution. This finding links the rate of nonsynonymous substitution with the synonymous rate. Consequently, highly conservative proteins are expected to be encoded by genes that evolve slowly in terms of synonymous substitutions, and are consequently highly biased in their codon usage.     

C- and Aδ-fibre mediated thermal perception: response to rate of temperature change using method of limits

Studies investigating the effect of rate of temperature change on thermal thresholds have used a variety of different methods and threshold combinations, and many display incomplete reporting of statistical analyses. It has been suggested that C- and A &#105 -fibre mediated thresholds differ in their reaction to different rates of temperature change. Ten healthy female volunteers (aged 18-26 years; mean 21 &#45 S.D. 2.53) undertook cold sensation (CS), warm sensation (WS), cold pain (CP) and heat pain (HP) threshold determinations on the thenar eminence of the dominant hand. Rates of temperature change of 0.5, 1, 2.5 and 4°C/s were used, with a modified method of limits. Adaptation temperature was 32°C and thermode size 3cm &#50 3cm. Results showed a significant increase in WS, HP and CP thresholds with increased rates of temperature change (all p < 0.001), but no significant change for CS ( p = 0.653). These results suggest that thresholds with a C-fibre component (WS, HP and CP) and those that are A &#105 -fibre mediated (CS) behave differently. A traditional explanation of measurement artefact alone is insufficient in rationalizing these results, with additional factors potentially involved. Slow rates of temperature change were shown to reduce mean intra-individual differences in recorded threshold values, and also to abolish ceiling effects with HP threshold determinations. Clinically, therefore, using slow rates of temperature change with method of limits has a range of benefits over and above simply minimizing measurement artefact.     

The relationship between size,budding rate,and growth efficiency in three species of hydra

Three species of the fresh water carnivore hydra, H. littoralis, H. pseudoligactis, and C. viridissima present a graduation in size with the first species the largest and albino Chlorohydra the smallest. When presented with a daily overabundance of food (artemia), considerable variation in food intake and gross efficiency of growth (proportion of food energy consumed that is turned into new protoplasm or buds) existed among the species. The degree of association between size of species and food intake was highly significant. However, budding efficiency among the species was found to be independent of food intake (when the effects of species size were eliminated) and of species size (when the effects of food intake were removed). However, species with high (low) efficiencies have significantly higher (lower) reproductive rates. A lowering of the temperature from 25° to 15° C. increased the size of the species, increased food intake, but decreased reproductive rate. In all species except H. pseudoligactis a corresponding increase in the production of bud energy with no change in efficiency also occurred. On the other hand, lowering of the temperature for H. pseudoligactis significantly lowered reproductive efficiency but had no effect on the total calorific output of buds. This species, in constrast to the others, appears to have a compensatory ability to adjust its efficiency to maintain a high calorific output when temperature increases. It was also found that albino Chlorohydra have budding efficiencies of around 35 percent which are not influenced by changes in food intake or light. Normal green hydras, however, have efficiencies which range from 40 to 62 percent above their albino counterparts when fed once a day and once every two days in light respectively. It it concluded first, that the symbiotic algae in the gastrodermals cells of green hydra contribute quantitatively in the order of the above amounts to the growth process in this species, and second, that green hydras have the ablity to increase their growth efficiency when food intake is reduced thus reducing the drop in calorific but output that normally occurs in the albino (control) form.     

Enhancement of the rate of pyrophosphate hydrolysis by nonenzymatic catalysts and by inorganic pyrophosphatase

To estimate the proficiency of inorganic pyrophosphatase as a catalyst, ³¹P NMR was used to determine rate constants and thermodynamics of activation for the spontaneous hydrolysis of inorganic pyrophosphate (PP_i) in the presence and absence of Mg²⁺ at elevated temperatures. These values were compared with rate constants and activation parameters determined for the reaction catalyzed by Escherichia coli inorganic pyrophosphatase using isothermal titration calorimetry. At 25 °C and pH 8.5, the hydrolysis of MgPP_i²⁻ proceeds with a rate constant of 2.8 × 10⁻¹⁰ s⁻¹, whereas E. coli pyrophosphatase was found to have a turnover number of 570 s⁻¹ under the same conditions. The resulting rate enhancement (2 × 10¹²-fold) is achieved entirely by reducing the enthalpy of activation (ΔΔH^‡ = −16.6 kcal/mol). The presence of Mg²⁺ ions or the transfer of the substrate from bulk water to dimethyl sulfoxide was found to increase the rate of pyrophosphate hydrolysis by as much as ∼10⁶-fold. Transfer to dimethyl sulfoxide accelerated PP_i hydrolysis by reducing the enthalpy of activation. Mg²⁺ increased the rate of PP_i hydrolysis by both increasing the entropy of activation and reducing the enthalpy of activation.     

A rate distortion approach to protein symmetry

A spontaneous symmetry breaking argument is applied to the problem of protein folding, via a rate distortion analysis of the relation between genome coding and the final condensation of the protein molten globule that is, in spirit, analogous to Tlusty’s (2007) exploration of the evolution of the genetic code. In the ‘energy’ picture, the average distortion between codon message and final protein structure, under constraints driven by evolutionary selection, serves as a temperature analog, so that low values limit the possible distribution of protein forms, producing the canonical folding funnel. A dual ‘developmental’ perspective sees the rate distortion function itself as the temperature analog, and permits incorporation of chaperons or toxic exposures as catalysts, driving the system to different possible outcomes or affecting the rate of convergence. The rate distortion function appears constrained by the availability of metabolic free energy, with implications for prebiotic evolution, and a nonequilibrium empirical Onsager treatment provides an adaptable statistical model that can be fitted to data, in the same manner as a regression equation. In sum, mechanistic models of protein folding fail to account for the observed spectrum of protein folding and aggregation disorders, suggesting that a biologically based cognitive paradigm describing folding will be needed for understanding the etiology, prevention, and treatment of these diseases. The developmental formalism introduced here may contribute substantially to such a paradigm.     

Kinetic evaluation of multiple initial rate data by simultaneous analysis with two equations

During the acetylcholinesterase catalytic process, the acetylcholine substrate attaches to the peripheral anionic site and then slides to the catalytic site situated in the center of the enzyme, at the bottom of a deep and narrow active gorge. Before the first catalytic cycle is complete, a second substrate molecule approaches and modulates the reaction. An inhibitor interferes with all steps and further complicates the situation. The reaction can be studied separately in the presence of two substrates, one good and one poor, and it can also be conducted simultaneously using a poor substrate as an inhibitor of the hydrolysis of a good substrate. Here, we have performed such an analysis, reducing the number of unknowns to those for the two substrates, while gaining additional information from the inhibition measurements without introducing new unknowns. To lower the number of realistic global minima in the analysis, we coupled the specific rate equation of the model to the rational polynomial of the corresponding degree. In contrast to the good substrate, the acetylation step by the poor substrate is found to be enhanced by the binding of the second substrate molecule to the peripheral anionic site. We attribute this to the different rate-limiting steps during the acetylation process: enhanced accommodation of the substrate paranitrophenylacetate is still slower than the hindered exit of the product paranitrophenol.