Mutation protocols share with sexual reproduction the physiological role of producing genetic variation within 'constraints that deconstrain'.

Because the universe of possible DNA sequences is inconceivably vast, organisms have evolved mechanisms for exploring DNA sequence space while substantially reducing the hazard that would otherwise accrue to any process of random, accidental mutation. One such mechanism is meiotic recombination. Although sexual reproduction imposes a seemingly paradoxical 50% cost to fitness, sex evidently prevails because this cost is outweighed by the advantage of equipping offspring with genetic variation to accommodate environmental vicissitudes. The potential adaptive utility of additional mechanisms for producing genetic variation has long been obscured by a presumption that the vast majority of mutations are deleterious. Perhaps surprisingly, the probability for adaptive variation can be increased by several mechanisms that generate mutations abundantly. Such mechanisms, here called 'mutation protocols', implement implicit 'constraints that deconstrain'. Like meiotic recombination, they produce genetic variation in forms that minimize potential for harm while providing a reasonably high probability for benefit. One example is replication slippage of simple sequence repeats (SSRs); this process yields abundant, reversible mutations, typically with small quantitative effect on phenotype. This enables SSRs to function as adjustable 'tuning knobs'. There exists a clear pathway for SSRs to be shaped through indirect selection favouring their implicit tuning-knob protocol. Several other molecular mechanisms comprise probable components of additional mutation protocols. Biologists might plausibly regard such mechanisms of mutation not primarily as sources of deleterious genetic mistakes but also as potentially adaptive processes for 'exploring' DNA sequence space.

A Double-Blind, Randomized, Placebo-Controlled Pilot Study examining an Oxygen Nanobubble Beverage for 16.1-km Time Trial and Repeated Sprint Cycling Performance.

There is growing interest of ergogenic aids that deliver supplemental oxygen during exercise and recovery, however, breathing supplemental oxygen via specialist facemasks is often not feasible. Therefore, this study investigated the effect of an oxygen-nanobubble beverage during submaximal and repeated sprint cycling. In a double-blind, randomized, placebo-controlled study, 10 male cyclists (peak aerobic capacity, 56.9 ± 6.1 mL·kg-1·min-1; maximal aerobic power, 385 ± 25 W) completed submaximal or maximal exercise after consuming an oxygen-nanobubble (O2) or placebo (PLA) beverage. Submaximal trials comprised 30-min of steady-state cycling at 60% peak aerobic capacity and 16.1-km time-trial (TT). Maximal trials involved 4 × 30 s Wingate tests interspersed by 4-min recovery. Time-to-completion during the 16.1-km TT was 2.4% faster after O2 compared with PLA (95% CI = 0.7-4.0%, p = 0.010, d = 0.41). Average power for the 16.1-km TT was 4.1% higher for O2 vs. PLA (95% CI = 2.1-7.3%, p = 0.006, d = 0.28). Average peak power during the repeated Wingate tests increased by 7.1% for O2 compared with PLA (p = 0.002, d = 0.58). An oxygen-nanobubble beverage improves performance during submaximal and repeated sprint cycling, therefore may provide a practical and effective ergogenic aid for competitive cyclists.

Sodium Bicarbonate and Time-to-Exhaustion Cycling Performance: A Retrospective Analysis Exploring the Mediating Role of Expectation.

BACKGROUND: Research has shown that ingesting 0.3 g·kg-1 body mass sodium bicarbonate (NaHCO3) can improve time-to-exhaustion (TTE) cycling performance, but the influence of psychophysiological mechanisms on ergogenic effects is not yet understood. OBJECTIVE: This study retrospectively examined whether changes in TTE cycling performance are mediated by positive expectations of receiving NaHCO3 and/or the decline in blood bicarbonate during exercise. METHODS: In a randomised, crossover, counterbalanced, double-blind, placebo-controlled design, 12 recreationally trained cyclists (maximal oxygen consumption, 54.4 ± 5.7 mL·kg·min-1) performed four TTE cycling tests 90 min after consuming: (1) 0.3 g·kg-1 body mass NaHCO3 in 5 mL·kg-1 body mass solution, (2) 0.03 g·kg-1 body mass sodium chloride in solution (placebo), (3) 0.3 g·kg-1 body mass NaHCO3 in capsules and (4) cornflour in capsules (placebo). Prior to exercise, participants rated on 1-5 Likert type scales how much they expected the treatment they believe had been given would improve performance. Capillary blood samples were measured for acid-base balance at baseline, pre-exercise and post-exercise. RESULTS: Administering NaHCO3 in solution and capsules improved TTE compared with their respective placebos (solution: 27.0 ± 21.9 s, p = 0.001; capsules: 23.0 ± 28.1 s, p = 0.016). Compared to capsules, NaHCO3 administered via solution resulted in a higher expectancy about the benefits on TTE cycling performance (Median: 3.5 vs. 2.5, Z = 2.135, p = 0.033). Decline in blood bicarbonate during exercise was higher for NaHCO3 given in solution compared to capsules (2.7 ± 2.1 mmol·L-1, p = 0.001). Mediation analyses showed that improvements in TTE cycling were indirectly related to expectancy and decline in blood bicarbonate when NaHCO3 was administered in solution but not capsules. CONCLUSIONS: Participants' higher expectations when NaHCO3 is administered in solution could result in them exerting themselves harder during TTE cycling, which subsequently leads to a greater decline in blood bicarbonate and larger improvements in performance. KEY POINTS: Ingesting 0.3 g·kg-1 body mass sodium bicarbonate in solution and capsules improved time-to-exhaustion cycling performance Positive expectancy about the benefits of sodium bicarbonate and decline in blood bicarbonate were higher when sodium bicarbonate was administered in solution compared with capsules Improvements in time-to-exhaustion cycling performance for sodium bicarbonate administered in solution were related to expectancy and the enhanced extracellular buffering response.

Consumption of New Zealand Blackcurrant Extract Improves Recovery from Exercise-Induced Muscle Damage in Non-Resistance Trained Men and Women: A Double-Blind Randomised Trial.

BACKGROUND: Blackcurrant is rich in anthocyanins that may protect against exercise-induced muscle damage (EIMD) and facilitate a faster recovery of muscle function. We examined the effects of New Zealand blackcurrant (NZBC) extract on indices of muscle damage and recovery following a bout of strenuous isokinetic resistance exercise. METHODS: Using a double-blind, randomised, placebo controlled, parallel design, twenty-seven healthy participants received either a 3 g·day-1 NZBC extract (n = 14) or the placebo (PLA) (n = 13) for 8 days prior to and 4 days following 60 strenuous concentric and eccentric contractions of the biceps brachii muscle on an isokinetic dynamometer. Muscle soreness (using a visual analogue scale), maximal voluntary contraction (MVC), range of motion (ROM) and blood creatine kinase (CK) were assessed before (0 h) and after (24, 48, 72 and 96 h) exercise. RESULTS: Consumption of NZBC extract resulted in faster recovery of baseline MVC (p = 0.04), attenuated muscle soreness at 24 h (NZBC: 21 ± 10 mm vs. PLA: 40 ± 23 mm, p = 0.02) and 48 h (NZBC: 22 ± 17 vs. PLA: 44 ± 26 mm, p = 0.03) and serum CK concentration at 96 h (NZBC: 635 ± 921 UL vs. PLA: 4021 ± 4319 UL, p = 0.04) following EIMD. CONCLUSIONS: Consumption of NZBC extract prior to and following a bout of eccentric exercise attenuates muscle damage and improves functional recovery. These findings are of practical importance in recreationally active and potentially athletic populations, who may benefit from accelerated recovery following EIMD.

Effects of post-exercise sodium bicarbonate ingestion on acid-base balance recovery and time-to-exhaustion running performance: a randomised crossover trial in recreational athletes.

This study investigated the effect of post-exercise sodium bicarbonate (NaHCO3) ingestion on acid-base balance recovery and time-to-exhaustion (TTE) running performance. Eleven male runners (stature, 1.80 ± 0.05 m; body mass, 74.4 ± 6.5 kg; maximal oxygen consumption, 51.7 ± 5.4 mL·kg-1·min-1) participated in this randomised, single-blind, counterbalanced and crossover design study. Maximal running velocity (v-V̇O2max) was identified from a graded exercise test. During experimental trials, participants repeated 100% v-V̇O2max TTE protocols (TTE1, TTE2) separated by 40 min following the ingestion of either 0.3 g·kg-1 body mass NaHCO3 (SB) or 0.03 g·kg-1 body mass sodium chloride (PLA) at the start of TTE1 recovery. Acid-base balance (blood pH and bicarbonate, HCO3-) data were studied at baseline, post-TTE1, after 35 min recovery and post-TTE2. Blood pH and HCO3- concentration were unchanged at 35 min recovery (p > 0.05), but HCO3- concentration was elevated post-TTE2 for SB vs. PLA (+2.6 mmol·L-1; p = 0.005; g = 0.99). No significant differences were observed for TTE2 performance (p > 0.05), although a moderate effect size was present for SB vs. PLA (+14.3 s; g = 0.56). Post-exercise NaHCO3 ingestion is not an effective strategy for accelerating the restoration of acid-base balance or improving subsequent TTE performance when limited recovery is available. Novelty: Post-exercise sodium bicarbonate ingestion did not accelerate the restoration of blood pH or bicarbonate after 35 min. Performance enhancing effects of sodium bicarbonate ingestion may display a high degree of inter-individual variation. Small-to-moderate changes in performance were likely due to greater up-regulation of glycolytic activation during exercise.

A small dose of whey protein co-ingested with mixed-macronutrient breakfast and lunch meals improves postprandial glycemia and suppresses appetite in men with type 2 diabetes: a randomized controlled trial.

Background: Large doses of whey protein consumed as a preload before single high-glycemic load meals has been shown to improve postprandial glycemia in type 2 diabetes. It is unclear if this effect remains with smaller doses of whey co-ingested at consecutive mixed-macronutrient meals. Moreover, whether hydrolyzed whey offers further benefit under these conditions is unclear. Objective: The aim of this study was to investigate postprandial glycemic and appetite responses after small doses of intact and hydrolyzed whey protein co-ingested with mixed-nutrient breakfast and lunch meals in men with type 2 diabetes. Design: In a randomized, single-blind crossover design, 11 men with type 2 diabetes [mean ± SD age: 54.9 ± 2.3 y; glycated hemoglobin: 6.8% ± 0.3% (51.3 ± 3.4 mmol/mol)] attended the laboratory on 3 mornings and consumed 1) intact whey protein (15 g), 2) hydrolyzed whey protein (15 g), or 3) placebo (control) immediately before mixed-macronutrient breakfast and lunch meals, separated by 3 h. Blood samples were collected periodically and were processed for insulin, intact glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), leptin, peptide tyrosine tyrosine (PYY3-36), and amino acid concentrations. Interstitial glucose was measured during and for 24 h after each trial. Subjective appetite was assessed with the use of visual analog scales. Results: Total postprandial glycemia area under the curve was reduced by 13% ± 3% after breakfast following the intact whey protein when compared with control (P < 0.05). Hydrolyzed whey attenuated early glucose after breakfast when compared with control (P < 0.05). Glycemia was improved postlunch after the intact whey protein only when compared with control (P < 0.05). Greater satiety was observed after the intact whey protein only after both meals when compared with control (P < 0.05). Insulin concentrations increased after both the intact and hydrolyzed whey protein, showing strong positive correlations with increases in valine and isoleucine (P < 0.05). Incretin and appetite regulatory hormone responses were similar across trials (P > 0.05). Conclusions: The consumption of a small 15-g dose of intact whey protein immediately before consecutive mixed-macronutrient meals improves postprandial glycemia, stimulates insulin release, and increases satiety in men with type 2 diabetes. This trial was registered at www.clinicialtrials.gov as NCT02903199.

Indirect selection of implicit mutation protocols.

A hypothesis that mutability evolves to facilitate evolutionary adaptation is dismissed by many biologists. Their skepticism is based on a theoretical expectation that natural selection must minimize mutation rates. That view, in turn, is historically grounded in an intuitive presumption that "the vast majority of mutations are harmful." But such skepticism is surely misplaced. Several highly mutagenic genomic patterns, including simple sequence repeats, and transposable elements, are integrated into an unexpectedly large proportion of functional genetic loci. Because alleles arising within such patterns can retain an intrinsic propensity toward a particular style of mutation, natural selection that favors any such allele can indirectly favor the site's mutability as well. By exploiting patterns that have produced beneficial alleles in the past, indirect selection can encourage mutation within constraints that reduce the probability of deleterious effect, thereby shaping implicit "mutation protocols" that effectively promote evolvability.

Evolution of simple sequence repeats as mutable sites.

Because natural selection is commonly presumed to minimize mutation rates, the discovery of mutationally unstable simple sequence repeats (SSRs) in many functional genomic locations came as a surprise to many biologists. Whether such SSRs persist in spite of or because of their intrinsic mutability-whether they constitute a genetic burden or an evolutionary boon--remains uncertain. Two contrasting evolutionary explanations can be offered for SSR abundance. First, suppressing the inherent mutability of repetitive sequences might simply lie beyond the reach of natural selection. Alternatively, natural selection might indirectly favor SSRs at sites where particular repeat-number variants have provided positive contributions to fitness. Indirect selection could thereby shape SSRs into "tuning knobs" that facilitate evolutionary adaptation by implementing an implicit protocol of incremental adjustability. The latter possibility is consistent with deep evolutionary conservation of some SSRs, including several in genes with neurological and neurodevelopmental function.

Simple sequence repeats: genetic modulators of brain function and behavior.

Simple sequence repeats (SSRs), sometimes described as genetic 'stutters,' are DNA tracts in which a short base-pair motif is repeated several to many times in tandem (e.g. CAGCAGCAG). These sequences experience frequent mutations that alter the number of repeats. Because SSRs are commonly located in promoters, untranslated regions and even coding sequences, such mutations can directly influence almost any aspect of gene function. Mutational expansion of certain triplet repeats is responsible for several hereditary neurodegenerative disorders, but SSR alleles can also contribute to normal variation in brain and behavioral traits. Here we review studies implicating SSRs not just in disease but also in circadian rhythmicity, sociosexual interaction, aggression, cognition and personality. SSRs can affect neuronal differentiation, brain development and even behavioral evolution.

Simple sequence repeats as advantageous mutators in evolution.

Simple sequence repeats (SSRs) often serve to modify genes with which they are associated. The influence of SSRs on gene regulation, transcription and protein function typically depends on the number of repeats, while mutations that add or subtract repeat units are both frequent and reversible. SSRs thus provide a prolific source of quantitative and qualitative variation. Over the past decade, researchers have found that this spontaneous variation has been tapped by natural and artificial selection to adjust almost every aspect of gene function. These studies support the hypothesis that SSRs, by virtue of their special mutational and functional qualities, have a major role in generating the genetic variation underlying adaptive evolution.

Electron beam computed tomographic scanning in preventive medicine.

Undetected coronary atherosclerosis is present in the majority of patients suffering myocardial infarction or sudden death. Electron beam computed tomography affords noninvasive scanning of the heart to detect and measure coronary calcification. These data permit dramatically improved assessment of both short-term and future risk for cardiac and other events. Knowledge of this risk gives the physician an opportunity for timely and cost-effective interventions.

THE ORIGIN OF AN ORGAN: PHYLOGENETIC ANALYSIS OF EVOLUTIONARY INNOVATION IN THE DIGESTIVE TRACT OF FLIES (INSECTA: DIPTERA).

The cardia, a prominent digestive tract organ consisting of several specialized cell types, occurs throughout the "higher" or muscoid flies, division Schizophora of order Diptera. Phylogenetic analysis of cellular organization in 65 insect species from 36 families indicates that this organ originated within the order Diptera from ancestrally undifferentiated tissues. "Lower" flies, suborder "Nematocera," display little or no epithelial cell specialization at the corresponding site. Scorpionflies of the outgroup order Mecoptera are similarly unspecialized. Intermediate levels of cellular specialization occur in Tabanomorpha, Asilomorpha and Aschiza, dipteran taxa that diverge between "Nematocera" and Schizophora. The distribution of epithelial characteristics suggests that the cardia evolved through a sequence of simple tissue transformations, combining changes in epithelial configuration with local differentiation of cell structure and function. The evolution of locally specialized cell types implies the emergence of structural genes and regulatory mechanisms through the modification of an ancestral genome that had not supported such extensive differentiation. Comparison of localized gene expression in Drosophila melanogaster with that in other fly species having greater or lesser degrees of cell specialization may provide a practical model system for studying specific patterns of mutation associated with such evolutionary innovation.

Evolutionary loss of a neural pathway from the nervous system of a fly (Glossina morsitans/Diptera).

Three pairs of specialized axons found in other muscoid flies are absent in the tsetse, Glossina morsitans, which also lacks the tergotrochanteral muscle. Neither light nor electron microscopy could demonstrate any evidence for the cervical giant fiber axon, the peripherally synapsing axon, or the tergotrochanteral motor axon. The specialized characteristics of these axons must have been altered during the evolution of Glossina. This divergence of individual neurons from the more typical muscoid pattern not only demonstrates the evolutionary modification of specific identified cells; it may also provide an opportunity to study the ontogenetic determination of unique neuronal features.