Differential Retention of Pfam Domains Contributes to Long-term Evolutionary Trends.

Protein domains that emerged more recently in evolution have a higher structural disorder and greater clustering of hydrophobic residues along the primary sequence. It is hard to explain how selection acting via descent with modification could act so slowly as not to saturate over the extraordinarily long timescales over which these trends persist. Here, we hypothesize that the trends were created by a higher level of selection that differentially affects the retention probabilities of protein domains with different properties. This hypothesis predicts that loss rates should depend on disorder and clustering trait values. To test this, we inferred loss rates via maximum likelihood for animal Pfam domains, after first performing a set of stringent quality control methods to reduce annotation errors. Intermediate trait values, matching those of ancient domains, are associated with the lowest loss rates, making our results difficult to explain with reference to previously described homology detection biases. Simulations confirm that effect sizes are of the right magnitude to produce the observed long-term trends. Our results support the hypothesis that differential domain loss slowly weeds out those protein domains that have nonoptimal levels of disorder and clustering. The same preferences also shape the differential diversification of Pfam domains, thereby further impacting proteome composition.

Race-Ethnicity, Rurality, and Age in Prospective Preferences and Concerns Regarding Closed-Loop Implanted Neural Devices.

OBJECTIVE: Responsive and human-centered neurotechnology development requires attention to public perceptions, particularly among groups underserved by existing treatments. METHODS: The authors conducted a preregistered nationally representative survey (https://osf.io/ej9h2) using the NORC at the University of Chicago AmeriSpeak panel. One vignette compared an implanted neural device with surgical resection in a scenario involving epilepsy, and another compared an implanted neural device with medications in a scenario involving mood disorders. The survey also contained questions about respondents' confidence that a device would be available if needed and confidence that enough research has been conducted among people like themselves. Responses were entered into nested survey-weighted logistic regression models, including a base demographic model (to test the overall effect of demographic factors) and an adjusted model that also included socioeconomic, religious and political, and health care access predictors. RESULTS: A total of 1,047 adults responded to the survey, which oversampled Black non-Hispanic (N=214), Hispanic (N=210), and rural (N=219) Americans. In the base demographic model, older Americans were more likely to prefer an implanted device in the two scenarios, and non-Hispanic Black Americans were less likely than non-Hispanic White Americans to prefer a device; rural Americans were less confident than urban or suburban Americans in having access, and non-Hispanic Black and rural Americans were less confident that enough research has been conducted among people like themselves. In adjusted models, income was a key mediator, partially explaining the effect of age and the contrast between Black and White non-Hispanic respondents on preferences for a device in the epilepsy scenario and fully explaining the effect of rurality on confidence in access. CONCLUSIONS: Demographic differences in prospective preferences and concerns highlight the importance of including members of underserved communities in neurotechnology development.

Racial Equity, Diversity and Inclusion in Bioethics: Recommendations from the Association of Bioethics Program Directors Presidential Task Force.

Recent calls to address racism in bioethics reflect a sense of urgency to mitigate the lethal effects of a lack of action. While the field was catalyzed largely in response to pivotal events deeply rooted in racism and other structures of oppression embedded in research and health care, it has failed to center racial justice in its scholarship, pedagogy, advocacy, and practice, and neglected to integrate anti-racism as a central consideration. Academic bioethics programs play a key role in determining the field's norms and practices, including methodologies, funding priorities, and professional networks that bear on equity, inclusion, and epistemic justice. This article describes recommendations from the Racial Equity, Diversity, and Inclusion (REDI) Task Force commissioned by the Association of Bioethics Program Directors to prioritize and strengthen anti-racist practices in bioethics programmatic endeavors and to evaluate and develop specific goals to advance REDI.

Selective sweeps on novel and introgressed variation shape mimicry loci in a butterfly adaptive radiation.

Natural selection leaves distinct signatures in the genome that can reveal the targets and history of adaptive evolution. By analysing high-coverage genome sequence data from 4 major colour pattern loci sampled from nearly 600 individuals in 53 populations, we show pervasive selection on wing patterns in the Heliconius adaptive radiation. The strongest signatures correspond to loci with the greatest phenotypic effects, consistent with visual selection by predators, and are found in colour patterns with geographically restricted distributions. These recent sweeps are similar between co-mimics and indicate colour pattern turn-over events despite strong stabilising selection. Using simulations, we compare sweep signatures expected under classic hard sweeps with those resulting from adaptive introgression, an important aspect of mimicry evolution in Heliconius butterflies. Simulated recipient populations show a distinct 'volcano' pattern with peaks of increased genetic diversity around the selected target, characteristic of sweeps of introgressed variation and consistent with diversity patterns found in some populations. Our genomic data reveal a surprisingly dynamic history of colour pattern selection and co-evolution in this adaptive radiation.

Inferring Genome-Wide Correlations of Mutation Fitness Effects between Populations.

The effect of a mutation on fitness may differ between populations depending on environmental and genetic context, but little is known about the factors that underlie such differences. To quantify genome-wide correlations in mutation fitness effects, we developed a novel concept called a joint distribution of fitness effects (DFE) between populations. We then proposed a new statistic w to measure the DFE correlation between populations. Using simulation, we showed that inferring the DFE correlation from the joint allele frequency spectrum is statistically precise and robust. Using population genomic data, we inferred DFE correlations of populations in humans, Drosophila melanogaster, and wild tomatoes. In these species, we found that the overall correlation of the joint DFE was inversely related to genetic differentiation. In humans and D. melanogaster, deleterious mutations had a lower DFE correlation than tolerated mutations, indicating a complex joint DFE. Altogether, the DFE correlation can be reliably inferred, and it offers extensive insight into the genetics of population divergence.

The rate of adaptive evolution in animal mitochondria.

We have investigated whether there is adaptive evolution in mitochondrial DNA, using an extensive data set containing over 500 animal species from a wide range of taxonomic groups. We apply a variety of McDonald-Kreitman style methods to the data. We find that the evolution of mitochondrial DNA is dominated by slightly deleterious mutations, a finding which is supported by a number of previous studies. However, when we control for the presence of deleterious mutations using a new method, we find that mitochondria undergo a significant amount of adaptive evolution, with an estimated 26% (95% confidence intervals: 5.7-45%) of nonsynonymous substitutions fixed by adaptive evolution. We further find some weak evidence that the rate of adaptive evolution is correlated to synonymous diversity. We interpret this as evidence that at least some adaptive evolution is limited by the supply of mutations.

The protein domains of vertebrate species in which selection is more effective have greater intrinsic structural disorder.

The nearly neutral theory of molecular evolution posits variation among species in the effectiveness of selection. In an idealized model, the census population size determines both this minimum magnitude of the selection coefficient required for deleterious variants to be reliably purged, and the amount of neutral diversity. Empirically, an 'effective population size' is often estimated from the amount of putatively neutral genetic diversity and is assumed to also capture a species' effectiveness of selection. A potentially more direct measure of the effectiveness of selection is the degree to which selection maintains preferred codons. However, past metrics that compare codon bias across species are confounded by among-species variation in %GC content and/or amino acid composition. Here, we propose a new Codon Adaptation Index of Species (CAIS), based on Kullback-Leibler divergence, that corrects for both confounders. We demonstrate the use of CAIS correlations, as well as the Effective Number of Codons, to show that the protein domains of more highly adapted vertebrate species evolve higher intrinsic structural disorder.

Evolution is the process through which populations change over time, starting with mutations in the genetic sequence of an organism. Many of these mutations harm the survival and reproduction of an organism, but only by a very small amount. Some species, especially those with large populations, can purge these slightly harmful mutations more effectively than other species. This fact has been used by the 'drift barrier theory' to explain various profound differences amongst species, including differences in biological complexity. In this theory, the effectiveness of eliminating slightly harmful mutations is specified by an 'effective' population size, which depends on factors beyond just the number of individuals in the population. Effective population size is normally calculated from the amount of time a 'neutral' mutation (one with no effect at all) stays in the population before becoming lost or taking over. Estimating this time requires both representative data for genetic diversity and knowledge of the mutation rate. A major limitation is that these data are unavailable for most species. A second limitation is that a brief, temporary reduction in the number of individuals has an oversized impact on the metric, relative to its impact on the number of slighly harmful mutations accumulated. Weibel, Wheeler et al. developed a new metric to more directly determine how effectively a species purges slightly harmful mutations. Their approach is based on the fact that the genetic code has 'synonymous' sequences. These sequences code for the same amino acid building block, with one of these sequences being only slightly preferred over others. The metric by Weibel, Wheeler et al. quantifies the proportion of the genome from which less preferred synonymous sequences have been effectively purged. It judges a population to have a higher effective population size when the usage of synonymous sequences departs further from the usage predicted from mutational processes. The researchers expected that natural selection would favour 'ordered' proteins with robust three-dimensional structures, i.e., that species with a higher effective population size would tend to have more ordered versions of a protein. Instead, they found the opposite: species with a higher effective population size tend to have more disordered versions of the same protein. This changes our view of how natural selection acts on proteins. Why species are so different remains a fundamental question in biology. Weibel, Wheeler et al. provide a useful tool for future applications of drift barrier theory to a broad range of ways that species differ.

The effectiveness of selection in a species affects the direction of amino acid frequency evolution.

Nearly neutral theory predicts that species with higher effective population size (N e ) are better able to purge slightly deleterious mutations. We compare evolution in high-N e vs. low-N e vertebrates to reveal which amino acid frequencies are subject to subtle selective preferences. We take three complementary approaches, two measuring flux and one measuring outcomes. First, we fit non-stationary substitution models of amino acid flux using maximum likelihood, comparing the high-N e clade of rodents and lagomorphs to its low-N e sister clade of primates and colugos. Second, we compare evolutionary outcomes across a wider range of vertebrates, via correlations between amino acid frequencies and N e . Third, we dissect the details of flux in human, chimpanzee, mouse, and rat, as scored by parsimony - this also enables comparison to a historical paper. All three methods agree on which amino acids are preferred under more effective selection. Preferred amino acids tend to be smaller, less costly to synthesize, and to promote intrinsic structural disorder. Parsimony-induced bias in the historical study produces an apparent reduction in structural disorder, perhaps driven by slightly deleterious substitutions. Within highly exchangeable pairs of amino acids, arginine is strongly preferred over lysine, and valine over isoleucine, consistent with more effective selection preferring a marginally larger free energy of folding. These two preferences match differences between thermophiles and mesophilic relatives. These results reveal the biophysical consequences of mutation-selection-drift balance, and demonstrate the utility of nearly neutral theory for understanding protein evolution.

The protein domains of vertebrate species in which selection is more effective have greater intrinsic structural disorder.

The nearly neutral theory of molecular evolution posits variation among species in the effectiveness of selection. In an idealized model, the census population size determines both this minimum magnitude of the selection coefficient required for deleterious variants to be reliably purged, and the amount of neutral diversity. Empirically, an "effective population size" is often estimated from the amount of putatively neutral genetic diversity and is assumed to also capture a species' effectiveness of selection. A potentially more direct measure of the effectiveness of selection is the degree to which selection maintains preferred codons. However, past metrics that compare codon bias across species are confounded by among-species variation in %GC content and/or amino acid composition. Here we propose a new Codon Adaptation Index of Species (CAIS), based on Kullback-Leibler divergence, that corrects for both confounders. We demonstrate the use of CAIS correlations, as well as the Effective Number of Codons, to show that the protein domains of more highly adapted vertebrate species evolve higher intrinsic structural disorder.

"Good luck, social distance": rapid decarceration and community care for serious mental illness and substance use disorder during the COVID-19 pandemic.

The COVID-19 pandemic inspired calls for rapid decarceration of prisons and jails to slow the spread of disease in a high-risk congregate setting. Due to the rarity of intentionally-decarcerative policies, little is known about the effects of rapid decarceration on individuals with serious mental illness (SMI) substance use disorder (SUD), a population who receive many services via the criminal legal system (CLS). We conducted interviews with 13 key informants involved in CLS in San Francisco, CA to better understand the implication of the decarcerative policies put into practice in early 2020. Participants described a tension between the desire to have fewer people incarcerated and the challenges of accessing services and support - especially during the lockdown period of the pandemic - outside of the CLS given the number of services that are only accessible to those who have been arrested, incarcerated, or sentenced. These findings emphasize the need for investing in community social services rather than further expanding the CLS to achieve the goal of supporting individuals with SMI and SUD shrinking the US system of mass incarceration.

A qualitative study of primary care clinician's approach to ending cervical cancer screening in older women in the United States.

The United States Preventive Services Task Force (USPSTF) recommends that cervical cancer screening end in average-risk patients with a cervix at 65 years of age if adequate screening measures have been met, defined as having 1) at least three normal consecutive cytology (Pap) tests, or 2) two normal cytology tests and/or two negative high-risk human papillomavirus tests between ages 55-65; the last test should be performed within the prior 5 years. Up to 60 % of all women aged 65 years and older who are ending screening do not meet the criteria for adequate screening. The objective of this study was to understand the process and approach that healthcare clinicians use to determine eligibility to end cervical cancer screening. In 2021 we conducted semi-structured interviews in San Francisco, CA with twelve healthcare clinicians: two family medicine physicians, three general internal medicine physicians, two obstetrician/gynecologists and five nurse practitioners. Thematic analysis, using inductive and deductive coding, was utilized. Three major themes emerged: following guidelines, relying on self-reported data regarding prior screening, and considering sexual activity as a factor in the decision to end screening. All interviewees endorsed following the USPSTF guidelines and they utilized self-report to determine eligibility to end screening. Clinicians' approach was dependent in part on their judgement about the reliability of the patient to convey their screening history. Sexual activity of the patient was considered when making clinical recommendations. Shared decision-making was often utilized. Clinicians voiced a strong reliance on self-reported screening history to end cervical cancer screening.

Hospice Quality, Race, and Disenrollment in Hospice Enrollees With Dementia.

Background: Racial and ethnic minoritized people with dementia (PWD) are at high risk of disenrollment from hospice, yet little is known about the relationship between hospice quality and racial disparities in disenrollment among PWD. Objective: To assess the association between race and disenrollment between and within hospice quality categories in PWD. Design/Setting/Subjects: Retrospective cohort study of 100% Medicare beneficiaries 65+ enrolled in hospice with a principal diagnosis of dementia, July 2012-December 2017. Race and ethnicity (White/Black/Hispanic/Asian and Pacific Islander [AAPI]) was assessed with the Research Triangle Institute (RTI) algorithm. Hospice quality was assessed with the publicly-available Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey item on overall hospice rating, including a category for hospices exempt from public reporting (unrated). Results: The sample included 673,102 PWD (mean age 86, 66% female, 85% White, 7.3% Black, 6.3% Hispanic, 1.6% AAPI) enrolled in 4371 hospices nationwide. Likelihood of disenrollment was higher in hospices in the lowest quartile of quality ratings (vs. highest quartile) for both White (adjusted odds ratio [AOR] 1.12 [95% confidence interval 1.06-1.19]) and minoritized PWD (AOR range 1.2-1.3) and was substantially higher in unrated hospices (AOR range 1.8-2.0). Within both low- and high-quality hospices, minoritized PWD were more likely to be disenrolled compared with White PWD (AOR range 1.18-1.45). Conclusions: Hospice quality predicts disenrollment, but does not fully explain disparities in disenrollment for minoritized PWD. Efforts to improve racial equity in hospice should focus both on increasing equity in access to high-quality hospices and improving care for racial minoritized PWD in all hospices.

"Prison life is very hard and it's made harder if you're isolated": COVID-19 risk mitigation strategies and the mental health of incarcerated women in California.

PURPOSE: This study aims to describe the COVID-19 risk mitigation strategies implemented in California prisons and the impact of these policies on the mental health of incarcerated women. DESIGN/METHODOLOGY/APPROACH: The authors conducted semi-structured qualitative interviews with ten women who were over the age of 50 and/or had a chronic illness and had been incarcerated in California prisons during the COVID-19 pandemic. The authors also interviewed ten health-care providers working in California jails or prisons during the pandemic. Interviews were analyzed using a grounded theory coding framework and triangulated with fieldnotes from ethnographic observations of medical and legal advocacy efforts during the pandemic. FINDINGS: Participants described being locked in their cells for 23 hours per day or more, often for days, weeks or even months at a time in an effort to reduce the spread of COVID-19. For many participants, these lockdowns and the resulting isolation from loved ones both inside and outside of the prison were detrimental to both their physical and mental health. Participants reported that access to mental health care for those in the general population was limited prior to the pandemic, and that COVID-19 risk mitigation strategies, including the cessation of group programs and shift to cell-front mental health services, created further barriers. ORIGINALITY/VALUE: There has been little qualitative research on the mental health effects of the COVID-19 pandemic on incarcerated populations. This paper provides insight into the mental health effects of both the COVID-19 pandemic and COVID-19 risk mitigation strategies for the structurally vulnerable older women incarcerated in California prisons.

COVID-19 and the reimaging of compassionate release.

PURPOSE: The purpose of this paper is to provide a historical overview of compassionate release policies in the USA and describe how these policies have been used during the COVID-19 pandemic. The authors then describe how these programs have been shaped by COVID-19 and could be reimagined to address the structural conditions that make prisons potentially life limiting for older adults and those with chronic illness. DESIGN/METHODOLOGY/APPROACH: This paper is primarily descriptive, offering an overview of the history of compassionate release policies before and during the COVID-19 pandemic. The authors augmented this description by surveying state Departments of Corrections about their utilization of compassionate release during 2019 and 2020. The findings from this survey were combined with data collected via Freedom of Information Act Requests sent to state Departments of Corrections about the same topic. FINDINGS: The findings demonstrate that while the US federal prison system saw a multifold increase in the number of individuals released under compassionate release policies in 2020 compared to 2019, most US states had modest change, with many states maintaining the same number, or even fewer, releases in 2020 compared with 2019. ORIGINALITY/VALUE: This paper provides both new data and new insight into compassionate release utilization during the COVID-19 pandemic and offers new possibilities for how compassionate release might be considered in the future.

Universal and taxon-specific trends in protein sequences as a function of age.

Extant protein-coding sequences span a huge range of ages, from those that emerged only recently to those present in the last universal common ancestor. Because evolution has had less time to act on young sequences, there might be 'phylostratigraphy' trends in any properties that evolve slowly with age. A long-term reduction in hydrophobicity and hydrophobic clustering was found in previous, taxonomically restricted studies. Here we perform integrated phylostratigraphy across 435 fully sequenced species, using sensitive HMM methods to detect protein domain homology. We find that the reduction in hydrophobic clustering is universal across lineages. However, only young animal domains have a tendency to have higher structural disorder. Among ancient domains, trends in amino acid composition reflect the order of recruitment into the genetic code, suggesting that the composition of the contemporary descendants of ancient sequences reflects amino acid availability during the earliest stages of life, when these sequences first emerged.

Corrigendum: Creativity, Resilience and Resistance: Black Birthworkers' Responses to the COVID-19 Pandemic.

[This corrects the article DOI: 10.3389/fsoc.2021.636029.].