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.

Complex Polyploids: Origins, Genomic Composition, and Role of Introgressed Alleles.

Introgression allows polyploid species to acquire new genomic content from diploid progenitors or from other unrelated diploid or polyploid lineages, contributing to genetic diversity and facilitating adaptive allele discovery. In some cases, high levels of introgression elicit the replacement of large numbers of alleles inherited from the polyploid's ancestral species, profoundly reshaping the polyploid's genomic composition. In such complex polyploids it is often difficult to determine which taxa were the progenitor species and which taxa provided additional introgressive blocks through subsequent hybridization. Here, we use population-level genomic data to reconstruct the phylogenetic history of Betula pubescens (downy birch), a tetraploid species often assumed to be of allopolyploid origin and which is known to hybridize with at least four other birch species. This was achieved by modeling of polyploidization and introgression events under the multispecies coalescent and then using an approximate Bayesian computation (ABC) rejection algorithm to evaluate and compare competing polyploidization models. We provide evidence that B. pubescens is the outcome of an autoploid genome doubling event in the common ancestor of B. pendula and its extant sister species, B. platyphylla, that took place approximately 178,000-188,000 generations ago. Extensive hybridization with B. pendula, B. nana, and B. humilis followed in the aftermath of autopolyploidization, with the relative contribution of each of these species to the B. pubescens genome varying markedly across the species' range. Functional analysis of B. pubescens loci containing alleles introgressed from B. nana identified multiple genes involved in climate adaptation, while loci containing alleles derived from B. humilis revealed several genes involved in the regulation of meiotic stability and pollen viability in plant species.

Diagnosis and the practices of patienthood: How diagnostic journeys shape illness experiences.

Sociologists have a rich history of studying the process of diagnosis and how people experience illness. Yet, the sociology of diagnosis and illness experience literatures have seldom been fully integrated. Instead, these literatures highlight one element of the illness journey, wherein scholars either primarily study diagnostic processes and categories or people's illness experiences. Drawing on empirical studies that examine diagnosis and experiences of illness in varied settings (diagnosis during breast cancer surveillance, diagnosis and experience of autoimmune illness and incarcerated women's experiences of diagnoses and illness), in this article we build on our concept of regimes of patienthood to explain how diagnostic journeys, and the relations and power dynamics that manifest during this time, shape the illness experience and practices of patienthood. We construct a classification of diagnostic processes grounded in our empirical research that span (1) sudden diagnoses, (2) long, changing diagnostic journeys and (3) diagnostic journeys marked by disbelief and denial of care. Our findings demonstrate how diagnostic journeys and illness experiences are intertwined, with different diagnostic pathways impacting how illness is experienced. Analysing these categories collectively demonstrates that diagnostic journeys, while heterogenous, shape the practices that patients develop to manage health conditions and navigate unequal health-care encounters.

"We're Not Patients. We're Inmates": Older Black Women's Experience of Aging, Health, and Illness During and After Incarceration.

BACKGROUND AND OBJECTIVES: The incarcerated population is growing older and by the year 2030, more than one third of people incarcerated in the United States will be over the age of 55. This population shift will have a profound impact on correctional health care systems as older incarcerated people often have multiple chronic illnesses and correctional institutions were not designed with aging and disability in mind. Black women experience greater burdens of comorbid conditions and are disproportionately represented among incarcerated women. RESEARCH DESIGN AND METHODS: We utilized Black Feminist Epistemological Methodology to explore the intersection of aging, chronic illness, and mass incarceration via in-depth interviews with 13 formerly incarcerated older Black women. RESULTS: First, participants described needing to prove themselves to be trustworthy prior to becoming ill in order to be believed and granted access to care when they report symptoms. Next, participants report being treated, not as patients, but as "inmates." The punitive nature of prison health care disrupted the patient-provider relationship and complicated the ability of patients to maintain autonomy in health care interactions. Finally, I describe how carceral health extends beyond the walls of both the clinic and the institution. DISCUSSION AND IMPLICATIONS: For older Black women, medical care and decision making inside prisons occur within a punitive context, which presents unique barriers when seeking care. Their experiences of health and illness while incarcerated may continue to influence if and how they seek care as they age in the community and thus must be interrogated when discussing aging in the Black community.

A horizon scan of global biological conservation issues for 2024.

We present the results of our 15th horizon scan of novel issues that could influence biological conservation in the future. From an initial list of 96 issues, our international panel of scientists and practitioners identified 15 that we consider important for societies worldwide to track and potentially respond to. Issues are novel within conservation or represent a substantial positive or negative step-change with global or regional extents. For example, new sources of hydrogen fuel and changes in deep-sea currents may have profound impacts on marine and terrestrial ecosystems. Technological advances that may be positive include benchtop DNA printers and the industrialisation of approaches that can create high-protein food from air, potentially reducing the pressure on land for food production.

The Problem Is Not (Merely) Mass Incarceration: Incarceration as a Bioethical Crisis and Abolition as a Moral Obligation.

Mass incarceration is an ethical crisis. Yet it is not only the magnitude of the system that is troubling. Mass incarceration has been created and sustained by racism, classism, and ableism, and the problems of the criminal legal system will not be solved without meaningfully intervening upon these forms of oppression. Beyond that, incarceration itself-whether of one person or 2 million-represents a moral failing. To punish and control, rather than invest in community and healing, is antithetical to the values of the field of bioethics. This commentary, which responds to the article "Fifty Years of U.S. Mass Incarceration and What It Means for Bioethics," by Sean Valles, considers abolition as a crucial form of justice that must be centered in the work of bioethics. Abolition is both an antiracist intervention and a means of considering the ways health care broadly and bioethics specifically have allowed for the perpetuation of carcerality in the United States.

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.

Between but Not Within-Species Variation in the Distribution of Fitness Effects.

New mutations provide the raw material for evolution and adaptation. The distribution of fitness effects (DFE) describes the spectrum of effects of new mutations that can occur along a genome, and is, therefore, of vital interest in evolutionary biology. Recent work has uncovered striking similarities in the DFE between closely related species, prompting us to ask whether there is variation in the DFE among populations of the same species, or among species with different degrees of divergence, that is whether there is variation in the DFE at different levels of evolution. Using exome capture data from six tree species sampled across Europe we characterized the DFE for multiple species, and for each species, multiple populations, and investigated the factors potentially influencing the DFE, such as demography, population divergence, and genetic background. We find statistical support for the presence of variation in the DFE at the species level, even among relatively closely related species. However, we find very little difference at the population level, suggesting that differences in the DFE are primarily driven by deep features of species biology, and those evolutionarily recent events, such as demographic changes and local adaptation, have little impact.

"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.

The role of polygenic risk scores in breast cancer risk perception and decision-making.

Polygenic risk scores (PRS) have the potential to improve the accuracy of clinical risk assessments, yet questions about their clinical validity and readiness for clinical implementation persist. Understanding how individuals integrate and act on the information provided by PRS is critical for their effective integration into routine clinical care, yet few studies have examined how individuals respond to the receipt of polygenic risk information. We conducted an embedded Ethical, Legal, and Social Implications (ELSI) study to examine if and how unaffected participants in a US population breast cancer screening trial understood and utilized PRS, as part of a multifactorial risk score combining traditional risk factors with a genetic risk assessment, to make screening and risk-reduction decisions. Semi-structured qualitative interviews were conducted with 24 trial participants who were designated at elevated risk for breast cancer due to their combined risk score. Interviews were analyzed using a grounded theory approach. Participants understood PRS conceptually and accepted it as one of many risk factors to consider, yet the value and meaning they ascribed to this risk estimate varied. Most participants reported financial and insurance barriers to enhanced screening with MRI and were not interested in taking risk-reducing medications. These findings contribute to our understanding of how PRS may be best translated from research to clinical care. Furthermore, they illuminate ethical concerns about identifying risk and making recommendations based on polygenic risk in a population screening context where many may have trouble accessing appropriate care.

Echinomycin as a promising therapeutic agent against KSHV-related malignancies.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), which preferentially arise in immunocompromised patients while lack of effective therapeutic options. Oncoproteins Myc and hypoxia-inducible factor-1α (HIF1α) have been found closely related to KSHV infection, replication and oncogenesis. However, the strategies of dual targeting these two oncoproteins have never been developed and tested for treatments of KSHV-related malignancies. In the current study, we report that treatment of echinomycin dramatically regresses cell growth both in vitro-cultured KSHV + tumor cells and in vivo KS or PEL xenograft mice models, through simultaneously inhibiting Myc and HIF1α expression. Echinomycin treatment also induces viral lytic gene expression whereas not increasing infectious virions production from KSHV + tumor cells. Our comparative transcriptomic analysis has identified a bunch of new Echinomycin-regulated, Myc- and HIF1α-related genes contributed to KSHV pathogenesis, including KDM4B and Tau, which are required for the survival of KSHV + tumor cells with functional validation. These data together reveal that dual targeting Myc and HIF1α such as using Echinomycin may represent a new and promising option for treatments of these virus-associated malignancies.

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.

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.

Activation of IL1 signaling molecules by Kaposi's sarcoma-associated herpesvirus.

Objective: Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi's sarcoma (KS) and Primary effusion lymphoma (PEL), which are usually seen in immunocompromised patients while lack of effective therapeutic options. Interleukin1 (IL1) family is a major mediator for inflammation response and has functional role in both innate and adaptive immunity. In contrast to the well-studied IL1 molecules, the activation and functional role of IL1 receptor/co-receptor and other related ligands, such as the IL1 receptor accessory protein (IL1RAP), in KSHV pathogenesis and tumorigenesis remain almost unknown. Methods: In the current study, a series of KSHV negative and positive primary or tumor cells, as well as AIDS-KS tumor samples from cohort HIV+ patients were used to compare and determine the activation status of IL1 signaling molecules, and their functional roles in KSHV pathogenesis. Results: We reported the high activation of multiple IL1 signaling molecules, including IL1, IL36, IL1R1, IL1RAP and IRAKs, during KSHV latent and lytic stages, as well as in clinical samples from patients with KSHV-related malignancies. Directly targeting these molecules especially IL1R1 and IL1RAP significantly impaired the survival and growth of KSHV+ tumor cells, as well as their colony formation on 3-D culture. Conclusion: Our data indicate the importance of IL1 signaling molecules in KSHV pathogenesis and tumorigenesis, which may represent attractive therapeutic targets against these virus-associated diseases.

"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.

Underwater hearing in sea ducks with applications for reducing gillnet bycatch through acoustic deterrence.

As diving foragers, sea ducks are vulnerable to underwater anthropogenic activity, including ships, underwater construction, seismic surveys and gillnet fisheries. Bycatch in gillnets is a contributing source of mortality for sea ducks, killing hundreds of thousands of individuals annually. We researched underwater hearing in sea duck species to increase knowledge of underwater avian acoustic sensitivity and to assist with possible development of gillnet bycatch mitigation strategies that include auditory deterrent devices. We used both psychoacoustic and electrophysiological techniques to investigate underwater duck hearing in several species including the long-tailed duck (Clangula hyemalis), surf scoter (Melanitta perspicillata) and common eider (Somateria mollissima). Psychoacoustic results demonstrated that all species tested share a common range of maximum auditory sensitivity of 1.0-3.0 kHz, with the long-tailed ducks and common eiders at the high end of that range (2.96 kHz), and surf scoters at the low end (1.0 kHz). In addition, our electrophysiological results from 4 surf scoters and 2 long-tailed ducks, while only tested at 0.5, 1 and 2 kHz, generally agree with the audiogram shape from our psychoacoustic testing. The results from this study are applicable to the development of effective acoustic deterrent devices or pingers in the 2-3 kHz range to deter sea ducks from anthropogenic threats.

Decreasing Intubation for Ineffective Ventilation after Birth for Very Low Birth Weight Neonates.

Despite recommendations promoting noninvasive delivery room (DR) ventilation, local historical preterm DR noninvasive ventilation rates were low (50%-64%). Project aims were to improve DR noninvasive ventilation rate in very low birth weight (VLBW) neonates (<1500 g) with a focus on decreasing DR intubations for ineffective positive pressure ventilation (PPV). Methods: We addressed drivers for improving noninvasive ventilation and decreasing intubations for ineffective PPV through plan-do-study-act cycles. Outcome measures were intubation for ineffective PPV (defined as intubation for heart rate <100 despite ongoing PPV) and final respiratory support in the DR. Our process measure was adherence to division-wide DR-intubation guidelines. Balancing measures were maximum FiO2 and hypothermia. We analyzed data using statistical process control charts and special cause variation rules. Results: There were 139 DR intubations among 521 VLBW neonates between January 2015 and February 2020. The noninvasive ventilation rate upon intensive care nursery admission was higher than historically reported at 73% and sustained throughout the project. The intubation rate for ineffective PPV was 10% and did not change. The number of VLBW neonates between intubations for ineffective PPV increased from 6.1 to 8.0. Ten intubations did not comply with guidelines. Balancing measures were unaffected. Conclusions: Noninvasive ventilation rates were higher than historically reported and remained high. After plan-do-study-act cycles, the number of VLBW neonates between intubations for ineffective PPV increased without impacting balancing measures. Our data demonstrate that effective ventilation (heart rate > 100) using noninvasive support is possible in up to 90% of VLBW infants but requires ongoing PPV training.