Robust genetic codes enhance protein evolvability.

The standard genetic code defines the rules of translation for nearly every life form on Earth. It also determines the amino acid changes accessible via single-nucleotide mutations, thus influencing protein evolvability-the ability of mutation to bring forth adaptive variation in protein function. One of the most striking features of the standard genetic code is its robustness to mutation, yet it remains an open question whether such robustness facilitates or frustrates protein evolvability. To answer this question, we use data from massively parallel sequence-to-function assays to construct and analyze 6 empirical adaptive landscapes under hundreds of thousands of rewired genetic codes, including those of codon compression schemes relevant to protein engineering and synthetic biology. We find that robust genetic codes tend to enhance protein evolvability by rendering smooth adaptive landscapes with few peaks, which are readily accessible from throughout sequence space. However, the standard genetic code is rarely exceptional in this regard, because many alternative codes render smoother landscapes than the standard code. By constructing low-dimensional visualizations of these landscapes, which each comprise more than 16 million mRNA sequences, we show that such alternative codes radically alter the topological features of the network of high-fitness genotypes. Whereas the genetic codes that optimize evolvability depend to some extent on the detailed relationship between amino acid sequence and protein function, we also uncover general design principles for engineering nonstandard genetic codes for enhanced and diminished evolvability, which may facilitate directed protein evolution experiments and the bio-containment of synthetic organisms, respectively.

SUBTLEX-CY: A new word frequency database for Welsh.

We present SUBTLEX-CY, a new word frequency database created from a 32-million-word corpus of Welsh television subtitles. An experiment comprising a lexical decision task examined SUBTLEX-CY frequency estimates against words with inconsistent frequencies in a much smaller Welsh corpus that is often used by researchers, the Cronfa Electroneg o'r Gymraeg (CEG), and three other Welsh word frequency databases. Words were selected that were classified as low frequency (LF) in SUBTLEX-CY and high frequency (HF) in CEG and compared with words that were classified as medium frequency (MF) in both SUBTLEX-CY and CEG. Reaction time analyses showed that HF words in CEG were responded to more slowly compared to MF words, suggesting that SUBTLEX-CY corpus provides a more reliable estimate of Welsh word frequencies. The new Welsh word frequency database that also includes part-of-speech, contextual diversity, and other lexical information is freely available for research purposes on the Open Science Framework repository at https://osf.io/9gkqm/.

A novel automated peak frequency annotation algorithm for identifying deceleration zones and ventricular tachycardia ablation sites.

BACKGROUND: Current annotation of local fractionated signals during ventricular electroanatomic mapping (EAM) requires manual input subject to variability and error. OBJECTIVES: The purpose of this study was to evaluate a novel peak frequency (PF) annotation software for its ability to automatically detect late potentials (LPs) and local abnormal ventricular activity (LAVA), determine an optimal range for display, and assess its impact on isochronal late activation mapping (ILAM). METHODS: EAM data from 25 patients who underwent ventricular tachycardia (VT) ablation were retrospectively analyzed. Samplings of electrogram PFs from areas of normal bipolar voltage, areas of low voltage, and areas of low voltage with fractioned signals were performed. An optimal range of frequency display was identified from these patients and applied to a validation cohort of 10 prospective patients to assess high PF within scar as a predictor of VT ablation target sites, in particular deceleration zones (DZs) identified by ILAM, LP, and LAVA. RESULTS: Voltage and PF ranges of normal endocardial tissue varied widely. Using 220 Hz as a frequency cutoff value in areas of low bipolar voltage, areas of high fractionation were identified with sensitivity of 91% and specificity of 85% There was no significant reduction in targeted DZ surface areas, and colocalization with DZs was observed in all cases. Applied to the prospective cohort, PF predicted fractionated areas and DZ in 9 of 10 patients. CONCLUSION: A PF annotation algorithm with a cutoff of 220 Hz accurately identifies areas of fractioned signals and accurately predicts DZs during ILAM.

Mutation and Selection Induce Correlations between Selection Coefficients and Mutation Rates.

AbstractThe joint distribution of selection coefficients and mutation rates is a key determinant of the genetic architecture of molecular adaptation. Three different distributions are of immediate interest: (1) the "nominal" distribution of possible changes, prior to mutation or selection; (2) the "de novo" distribution of realized mutations; and (3) the "fixed" distribution of selectively established mutations. Here, we formally characterize the relationships between these joint distributions under the strong-selection/weak-mutation (SSWM) regime. The de novo distribution is enriched relative to the nominal distribution for the highest rate mutations, and the fixed distribution is further enriched for the most highly beneficial mutations. Whereas mutation rates and selection coefficients are often assumed to be uncorrelated, we show that even with no correlation in the nominal distribution, the resulting de novo and fixed distributions can have correlations with any combination of signs. Nonetheless, we suggest that natural systems with a finite number of beneficial mutations will frequently have the kind of nominal distribution that induces negative correlations in the fixed distribution. We apply our mathematical framework, along with population simulations, to explore joint distributions of selection coefficients and mutation rates from deep mutational scanning and cancer informatics. Finally, we consider the evolutionary implications of these joint distributions together with two additional joint distributions relevant to parallelism and the rate of adaptation.

Developmental Selection and the Perception of Mutation Bias.

The notion that mutations are random relative to their fitness effects is central to the Neo-Darwinian view of evolution. However, a recent interpretation of the patterns of mutation accumulation in the genome of Arabidopsis thaliana has challenged this notion, arguing for the presence of a targeted DNA repair mechanism that causes a nonrandom association of mutation rates and fitness effects. Specifically, this mechanism was suggested to cause a reduction in the rates of mutations on essential genes, thus lowering the rates of deleterious mutations. Central to this argument were attempts to rule out selection at the population level. Here, we offer an alternative and parsimonious interpretation of the patterns of mutation accumulation previously attributed to mutation bias, showing how they can instead or additionally be caused by developmental selection, that is selection occurring at the cellular level during the development of a multicellular organism. Thus, the depletion of deleterious mutations in A. thaliana may indeed be the result of a selective process, rather than a bias in mutation. More broadly, our work highlights the importance of considering development in the interpretation of population-genetic analyses of multicellular organisms, and it emphasizes that efforts to identify mechanisms involved in mutational biases should explicitly account for developmental selection.

Substrate Imaging Before Catheter Ablation of Ventricular Tachycardia: Risk Prediction for Acute Hemodynamic Decompensation.

BACKGROUND: The PAINESD (Pulmonary disease, Age, Ischemic cardiomyopathy, NYHA functional class, Ejection fraction, Storm, Diabetes mellitus) risk score has been validated as a predictor of periprocedural acute hemodynamic decompensation (AHD) in patients undergoing ventricular tachycardia (VT) ablation. Whether the addition of total scar volume (TSV) determined by preprocedure computed tomography imaging provides additional risk stratification has not been previously investigated. OBJECTIVES: The purpose of this study was to evaluate the impact of TSV on the risk of AHD and its adjunctive benefit to the PAINESD score newly modified as Pulmonary disease, Age, Ischemic cardiomyopathy, NYHA class, Ejection fraction, Storm, Scar volume, Diabetes mellitus (PAINES2D) based on the addition of scar volumes. METHODS: This was a retrospective analysis of all index VT ablations at a quaternary care center from 2017 to 2022. Associations between TSV and AHD were evaluated among patients with structural heart disease. RESULTS: Among 61 patients with TSV data, 13 (21%) had periprocedural AHD. TSV and PAINESD were independently associated with AHD risk. Both TSV and PAINESD were associated with AHD (P = 0.016 vs P = 0.053, respectively). The highest TSV tertile (≥37.30 mL) showed significant association with AHD (P = 0.018; OR: 4.80) compared to the other tertiles. The PAINESD and PAINES2D scores had significant impact on AHD (P = 0.046 and P = 0.010, respectively). The PAINES2D score had a greater impact on AHD compared to PAINESD (area under the curve: 0.73; P = 0.011; 95% CI: 0.56-0.91 and area under the curve: 0.67; P = 0.058; 95% CI: 0.49-0.85, respectively). CONCLUSIONS: Addition of TSV to a modified PAINESD score, PAINES2D, enhances risk prediction of AHD. Further prospective study is needed to assess benefit in various cardiomyopathy populations undergoing VT ablation.

Environment-dependent epistasis increases phenotypic diversity in gene regulatory networks.

Mutations to gene regulatory networks can be maladaptive or a source of evolutionary novelty. Epistasis confounds our understanding of how mutations affect the expression patterns of gene regulatory networks, a challenge exacerbated by the dependence of epistasis on the environment. We used the toolkit of synthetic biology to systematically assay the effects of pairwise and triplet combinations of mutant genotypes on the expression pattern of a gene regulatory network expressed in Escherichia coli that interprets an inducer gradient across a spatial domain. We uncovered a preponderance of epistasis that can switch in magnitude and sign across the inducer gradient to produce a greater diversity of expression pattern phenotypes than would be possible in the absence of such environment-dependent epistasis. We discuss our findings in the context of the evolution of hybrid incompatibilities and evolutionary novelties.

Mutation bias and the predictability of evolution.

Predicting evolutionary outcomes is an important research goal in a diversity of contexts. The focus of evolutionary forecasting is usually on adaptive processes, and efforts to improve prediction typically focus on selection. However, adaptive processes often rely on new mutations, which can be strongly influenced by predictable biases in mutation. Here, we provide an overview of existing theory and evidence for such mutation-biased adaptation and consider the implications of these results for the problem of prediction, in regard to topics such as the evolution of infectious diseases, resistance to biochemical agents, as well as cancer and other kinds of somatic evolution. We argue that empirical knowledge of mutational biases is likely to improve in the near future, and that this knowledge is readily applicable to the challenges of short-term prediction. This article is part of the theme issue 'Interdisciplinary approaches to predicting evolutionary biology'.

The impact of phonological relatedness on semantic congruency judgements in readers with dyslexia: Evidence from behavioural judgements, event related potentials and pupillometry.

Readers with developmental dyslexia are known to be impaired in representing and accessing phonology, but their ability to process meaning is generally considered to be intact. However, neurocognitive studies show evidence of a subtle semantic processing deficit in dyslexic readers, relative to their typically-developing peers. Here, we compared dyslexic and typical adult readers on their ability to judge semantic congruency (congruent vs. inconcongruent) in short, two-word phrases, which were further manipulated for phonological relatedness (alliterating vs. non-alliterating); "dazzling-diamond"; "sparkling-diamond"; "dangerous-diamond"; and "creepy-diamond". At the level of behavioural judgement, all readers were less accurate when evaluating incongruent alliterating items compared with incongruent non-aliterating, suggesting that phonological patterning creates the illusion of semantic congruency (as per Egan et al., 2020). Dyslexic readers showed a similar propensity for this form-meaning relationship despite a phonological processing impairment as evidenced in the cognitive and literacy indicative assessments. Dyslexic readers also showed an overall reduction in the ability to accurately judge semantic congruency, suggestive of a subtle semantic impairment. Whilst no group differences emerged in the electrophysiological measures, our pupil dilation measurements revealed a global tendency for dyslexic readers to manifest a reduced attentional response to these word stimuli, compared with typical readers. Our results show a broad manifestation of neurocognitive differences in adult dyslexic and typical readers' processing of print, at the level of autonomic arousal as well as in higher level semantic judgements.

Epicardial mapping and ablation of ventricular tachycardia from the coronary venous system in post-coronary bypass patients.

BACKGROUND: Ventricular tachycardia (VT) ablation of mid- or epicardial substrate is difficult and requires a creative approach in patients with a history of coronary bypass that precludes percutaneous epicardial catheter manipulation. The coronary venous system (CVS) provides limited access to the epicardial surface of the heart. The objective of this study is to assess the feasibility, safety, and efficacy of epicardial mapping and ablation of VT substrates from the CVS in patients with history of coronary bypass. METHODS: Patients undergoing VT ablation at our institution were retrospectively reviewed. Those who had basal to mid ventricular substrate based on computed tomography imaging and history of coronary bypass were included. Endocardial and CVS mapping and ablation was performed in standard fashion using 3D electroanatomic mapping. The primary endpoint was defined as VT circuit elimination, termination, non-inducibility, or perturbation of the circuit. RESULTS: Of 192 consecutive VT ablations from 2017 to 2020, 35 (18%) had a history of coronary bypass and basal to the mid-ventricular substrate by imaging. There were no significant characteristic differences between the endocardial only (n = 19) vs endocardial + CVS (n = 16) groups. In 14 (88%) of patients undergoing CVS mapping, the VT circuit was identified to be within access from the epicardial surface. Ablation was attempted in 8 (57%) of these patients, and the primary endpoint was reached in 88% of those undergoing CVS ablation. There were no complications related to CVS ablation. CONCLUSION: Mapping and ablation of mid- or epicardial VT circuits from the CVS branches are feasible and safe and may be helpful in the treatment of VT in patients who are otherwise not candidates for percutaneous epicardial ablation.

The Adaptive Potential of Nonheritable Somatic Mutations.

AbstractThe adaptive potential of nonheritable somatic mutations has received limited attention in traditional evolutionary theory because heritability is a fundamental pillar of Darwinian evolution. We hypothesized that the ability of a germline genotype to express a novel phenotype via nonheritable somatic mutations can be selectively advantageous and that this advantage will channel evolving populations toward germline genotypes that constitutively express the phenotype. We tested this hypothesis by simulating evolving populations of developing organisms with an impermeable germline-soma separation navigating a minimal fitness landscape. The simulations revealed the conditions under which nonheritable somatic mutations promote adaptation. Specifically, this can occur when the somatic mutation supply is high, when few cells with the advantageous somatic mutation are required to increase organismal fitness, and when the somatic mutation also confers a selective advantage at the cellular level. We therefore provide proof of principle that nonheritable somatic mutations can promote adaptive evolution via a process we call "somatic genotypic exploration." We discuss the biological plausibility of this phenomenon as well as its evolutionary implications.

Cardiogenic Shock Due to Atrial Myxoma With Mitral Valve Involvement.

Despite being the most common primary cardiac neoplasm, the incidence of cardiac myxomas remains low. The majority of myxomas usually have a nonspecific presentation often leading to symptoms such as cough, dyspnea, and weakness. Larger tumors may cause arrhythmia, syncope, or cerebrovascular events due to embolization. Rarely, patients with myxomas may present with signs and symptoms of cardiogenic shock. A 50-year-old female presented to our Emergency Department with an altered mental status and hypotension. Initial imaging of the patient's head showed an embolic infarction. Subsequent investigations revealed a large atrial mass protruding through the mitral valve. The patient was initially resuscitated and then taken to the operating room emergently where the mass was removed. Postoperatively, she was observed in the intensive care unit and eventually transferred to a step-down unit. Her pathology report confirmed that the mass was a cardiac myxoma. Here, we report the case of a patient with an atrial myxoma protruding through the mitral valve who presented in cardiogenic shock. The etiologies of cardiogenic shock and atrial myxomas are explored. The medical and surgical management of a patient with an atrial myxoma presenting in cardiogenic shock is reviewed. We reflect on our diagnostic evaluation, determining that patients who present in undifferentiated cardiogenic shock should be approached with a broad differential diagnosis.

On the incongruence of genotype-phenotype and fitness landscapes.

The mapping from genotype to phenotype to fitness typically involves multiple nonlinearities that can transform the effects of mutations. For example, mutations may contribute additively to a phenotype, but their effects on fitness may combine non-additively because selection favors a low or intermediate value of that phenotype. This can cause incongruence between the topographical properties of a fitness landscape and its underlying genotype-phenotype landscape. Yet, genotype-phenotype landscapes are often used as a proxy for fitness landscapes to study the dynamics and predictability of evolution. Here, we use theoretical models and empirical data on transcription factor-DNA interactions to systematically study the incongruence of genotype-phenotype and fitness landscapes when selection favors a low or intermediate phenotypic value. Using the theoretical models, we prove a number of fundamental results. For example, selection for low or intermediate phenotypic values does not change simple sign epistasis into reciprocal sign epistasis, implying that genotype-phenotype landscapes with only simple sign epistasis motifs will always give rise to single-peaked fitness landscapes under such selection. More broadly, we show that such selection tends to create fitness landscapes that are more rugged than the underlying genotype-phenotype landscape, but this increased ruggedness typically does not frustrate adaptive evolution because the local adaptive peaks in the fitness landscape tend to be nearly as tall as the global peak. Many of these results carry forward to the empirical genotype-phenotype landscapes, which may help to explain why low- and intermediate-affinity transcription factor-DNA interactions are so prevalent in eukaryotic gene regulation.

Asynchronous Online Instruction Leads to Learning Gaps When Compared to a Flipped Classroom.

With the gradual shift to online education models that has taken place in recent decades, research has sought to understand the nuances of student performance in an online model in comparison to more traditional in-person modalities. However, the effects of instructional modality have been difficult to determine given the many variables that exist in course design between these methods. In this study, we attempt to determine the efficacy of asynchronous online instruction by comparing two nearly equivalent courses. The first course was a flipped classroom, a recent and well-studied hybrid model of instruction. The second was an asynchronous fully online course that contained all the same instructional elements as the in-person course but lacked any student or instructor interaction. Student performance was tracked at both a highly-selective private institution and an open-enrollment public institution. Results show that students' performance drops in an asynchronous online course compared to an equivalent in-person experience. Several potential hypotheses are put forth to explain a change in performance that can potentially shape the design of online instruction.

Mutation bias shapes the spectrum of adaptive substitutions.

Evolutionary adaptation often occurs by the fixation of beneficial mutations. This mode of adaptation can be characterized quantitatively by a spectrum of adaptive substitutions, i.e., a distribution for types of changes fixed in adaptation. Recent work establishes that the changes involved in adaptation reflect common types of mutations, raising the question of how strongly the mutation spectrum shapes the spectrum of adaptive substitutions. We address this question with a codon-based model for the spectrum of adaptive amino acid substitutions, applied to three large datasets covering thousands of amino acid changes identified in natural and experimental adaptation in Saccharomyces cerevisiae, Escherichia coli, and Mycobacterium tuberculosis Using species-specific mutation spectra based on prior knowledge, we find that the mutation spectrum has a proportional influence on the spectrum of adaptive substitutions in all three species. Indeed, we find that by inferring the mutation rates that best explain the spectrum of adaptive substitutions, we can accurately recover the species-specific mutation spectra. However, we also find that the predictive power of the model differs substantially between the three species. To better understand these differences, we use population simulations to explore the factors that influence how closely the spectrum of adaptive substitutions mirrors the mutation spectrum. The results show that the influence of the mutation spectrum decreases with increasing mutational supply ([Formula: see text]) and that predictive power is strongly affected by the number and diversity of beneficial mutations.