Mapping of specialized metabolite terms onto a plant phylogeny using text mining and large language models.

Plants produce a staggering array of chemicals that are the basis for organismal function and important human nutrients and medicines. However, it is poorly defined how these compounds evolved and are distributed across the plant kingdom, hindering a systematic view and understanding of plant chemical diversity. Recent advances in plant genome/transcriptome sequencing have provided a well-defined molecular phylogeny of plants, on which the presence of diverse natural products can be mapped to systematically determine their phylogenetic distribution. Here, we built a proof-of-concept workflow where previously reported diverse tyrosine-derived plant natural products were mapped onto the plant tree of life. Plant chemical-species associations were mined from literature, filtered, evaluated through manual inspection of over 2500 scientific articles, and mapped onto the plant phylogeny. The resulting "phylochemical" map confirmed several highly lineage-specific compound class distributions, such as betalain pigments and Amaryllidaceae alkaloids. The map also highlighted several lineages enriched in dopamine-derived compounds, including the orders Caryophyllales, Liliales, and Fabales. Additionally, the application of large language models, using our manually curated data as a ground truth set, showed that post-mining processing can largely be automated with a low false-positive rate, critical for generating a reliable phylochemical map. Although a high false-negative rate remains a challenge, our study demonstrates that combining text mining with language model-based processing can generate broader phylochemical maps, which will serve as a valuable community resource to uncover key evolutionary events that underlie plant chemical diversity and enable system-level views of nature's millions of years of chemical experimentation.

Health Insurance For People Younger Than Age 65: Expiration Of Temporary Policies Projected To Reshuffle Coverage, 2023-33.

The Congressional Budget Office estimates that in 2023, 248 million people in the US who are younger than age sixty-five have health insurance coverage (mostly through employment-based plans), and twenty-three million people, or 8.3 percent of that age group, are uninsured-with significant variations in coverage by income and, to a lesser extent, by race and ethnicity. The unprecedented low uninsurance rate is largely attributable to temporary policies that kept beneficiaries enrolled in Medicaid and enhanced the subsidies available through the health insurance Marketplaces during the COVID-19 pandemic. As the continuous eligibility provisions unwind in 2023 and 2024, an estimated 9.3 million people in that age group will transition to other forms of coverage, and 6.2 million will become uninsured. If the enhanced subsidies expire after 2025, 4.9 million fewer people are estimated to enroll in Marketplace coverage, instead enrolling in unsubsidized nongroup or employment-based coverage or becoming uninsured. By 2033 the uninsurance rate is projected to be 10.1 percent, which is still below the 2019 rate of about 12 percent.

Association Between Treatment by Fraud and Abuse Perpetrators and Health Outcomes Among Medicare Beneficiaries.

Importance: Fraud and abuse contribute to unnecessary spending in the Medicare program, and federal agencies have prioritized fund recovery and the exclusion of health care practitioners who violate policy. However, the human costs of fraud and abuse in terms of patient health are unknown. Objective: To assess whether Medicare beneficiaries' receipt of health care services from fraud and abuse perpetrators (FAPs) is associated with worse health outcomes. Design, Setting, and Participants: Retrospective cross-sectional study comparing mortality and emergency hospitalization rates of 8204 patients treated by an FAP with those among patients treated by a randomly selected non-FAP in 2013. Known FAPs were identified from the December 2018 List of Excluded Individuals/Entities (LEIE) published by the Office of the Inspector General in the Department of Health and Human Services. Patients were identified in a 5% sample of Medicare claims data and were enrolled in the Fee-for-Service program. Exposures: Treatment by a health care professional subsequently excluded from Medicare for fraud, patient harm, or a revoked license. Main Outcomes and Measures: All-cause mortality between 2013 and 2015 and 2013 emergency hospitalizations. Results: A total of 8204 Medicare beneficiaries in the study sample (mean [SD] age, 69.2 [14.2] years; 58.2% female, and 23.0% nonwhite) saw an FAP for the first time in 2013. Of these, 5054 (61.6%) were treated by fraud perpetrators, 1157 (14.1%) by patient harm perpetrators, and 1193 (24.3%) by revoked license perpetrators. Compared with 296 298 beneficiaries treated by non-FAPs (mean [SD] age, 71.1 [12.4] years; 58.6% female, and 16.5% nonwhite), beneficiaries exposed to an FAP were more likely to be eligible for both Medicare and Medicaid (34.7% [2845 of 8204] vs 21.9% [64 989 of 296 298]; P < .001) and more likely to be disabled at an age younger than 65 years (27.2% [2231 of 8204] vs 18.6% [55 168 of 296 298]; P < .001). All FAP exposures were associated with higher mortality and emergency hospitalization rates after risk adjustment and propensity score weighting: for mortality, exposures to fraud FAPs were associated with an increase of 4.58 percentage points (95% CI, 2.02-7.13; P < .001); to patient harm FAPs, with an increase of 3.34 percentage points (95% CI, 1.40-5.27; P = .001); and to revoked license FAPs, with an increase of 3.33 percentage points (95% CI, 1.58-5.09; P < .001). Increases were similar for emergency hospitalization rates: for fraud FAP exposures, 3.24 percentage points (95% CI, 0.01-6.46; P = .049); for patient harm FAP exposures, 9.34 percentage points (95% CI, 6.02-12.65; P < .001); and for revoked license FAP exposures, 9.28 percentage points (95% CI, 6.43-12.13; P < .001). Conclusions and Relevance: This study's findings suggest that receiving medical care from FAPs may be associated with significantly higher rates of all-cause mortality and emergency hospitalization after risk adjustment. Identifying and permanently removing FAPs from the Medicare program may be associated with improved beneficiary health in addition to financial savings.

Medicare Beneficiaries' Exposure To Fraud And Abuse Perpetrators.

In the period 2012-15, 1,364 fraud and abuse perpetrators (FAPs) treated over 1.2 million Medicare beneficiaries and received more than $630 million in Medicare payments. Compared to beneficiaries treated by non-FAPs, beneficiaries exposed to FAPs were more likely to be nonwhite, dually enrolled in Medicaid, and disabled and younger than age sixty-five.

Do health insurance and hospital market concentration influence hospital patients' experience of care?

OBJECTIVE: To examine the effects of insurance and hospital market concentration on hospital patients' experience of care, as hospitals may compete on quality for favorable insurance contracts. DATA SOURCES/STUDY SETTING: Secondary data for 2008-2015 on patient experience from Hospital Compare's patient survey data, hospital characteristics from the American Hospital Association (AHA) Annual Survey, and insurance market characteristics from HealthLeaders-InterStudy. STUDY DESIGN: Hospital/year-level regressions predict each hospital's patient experience measure as a function of insurance and hospital market concentration and hospital fixed effects. The model is identified by longitudinal variation in insurance and hospital concentration. DATA COLLECTION/EXTRACTION METHODS: Hospital/year-level data from Hospital Compare and the AHA merged by market/year to insurance and hospital concentration measures. PRINCIPAL FINDINGS: Changes in patient satisfaction are positively associated with increases in insurance concentration and negatively associated with increases in hospital concentration. Moving from a market with 20th percentile insurance concentration and 80th percentile hospital concentration to a market with 80th percentile insurance concentration and 20th percentile hospital concentration increases the share of patients that rated the hospital highly from 66.9 percent (95% CI: 66.5-67.2 percent) to 67.9 percent (95% CI: 67.5-68.3 percent) and the share of patients that definitely recommend the hospital from 69.7 percent (95% CI: 69.4-70.0 percent) to 70.8 percent (95% CI: 70.5-71.2 percent). The relationship for insurance concentration is stronger in more concentrated hospital markets, while the relationship for hospital concentration is stronger in less concentrated hospital markets. CONCLUSIONS: These findings add to the evidence on the harms of hospital consolidation but suggest that insurer consolidation may improve patient experience.

Caveolin-1 is an aggresome-inducing protein.

Caveolin-1 (Cav1) drives the formation of flask-shaped membrane invaginations known as caveolae that participate in signaling, clathrin-independent endocytosis and mechanotransduction. Overexpression or mutations of Cav1 can lead to its mistrafficking, including its accumulation in a perinuclear compartment previously identified as the Golgi complex. Here, we show that in the case of overexpressed Cav1-GFP, this perinuclear compartment consists of cytoplasmic inclusion bodies generated in response to the accumulation of aggregates of misfolded proteins, known as aggresomes. Aggresomes containing Cav1-GFP are encased within vimentin cages, form in a microtubule-dependent manner, and are enriched in a number of key regulators of protein turnover, including ubiquitin, VCP/p97 and proteasomes. Interestingly, aggresome induction was cell-type dependent and was observed for many but not all Cav1 constructs tested. Furthermore, endogenous Cav1 accumulated in aggresomes formed in response to proteosomal inhibition. Our finding that Cav1 is both an aggresome-inducing and aggresome-localized protein provides new insights into how cells handle and respond to misfolded Cav1. They also raise the possibility that aggresome formation may contribute to some of reported phenotypes associated with overexpressed and/or mutant forms of Cav1.

Developing a Patient-Centered Benefit-Risk Survey: A Community-Engaged Process.

OBJECTIVES: To provide a community-engaged process to inform the design of a stated-preferences experiment. The process involved integrating patients and caregivers of people with Duchenne/Becker muscular dystrophy, advocates, clinicians, and the sponsor in conceptualizing and developing a benefit-risk survey on the basis of phase III trial results. METHODS: Our community-engagement process for the development of a stated-preference survey included a set of five guiding principles with a foundation in the principles of community-engaged research. Engagement efforts were carried out through an informal network of three committees. Members of the leadership, stakeholder, and review committees comprised patients, caregivers, clinicians, advocacy leadership, and industry representatives. RESULTS: Committee members participated in 15 hours of formal engagement including interviews and conference calls that ranged from 45 to 90 minutes, plus additional less-formal ad hoc communication. Committees comprised 20 individuals across three committees including adults with DMD (n = 6), parents of children with DMD (n = 6), clinicians (n = 3), members of research and advocacy organizations (n = 4), and an industry representative (n = 1). Community engagement informed attribute selection, survey length, word choice, and eligibility criteria. Challenges in the process included managing diverse stakeholder perspectives, time requirements, and the inherent tension between outcomes used in clinical trials versus attributes that correspond to patient- and family-relevant outcomes. CONCLUSIONS: We demonstrated how community engagement can successfully influence study design to support the design of a relevant survey instrument that is ethical, acceptable, meaningful to the community, and enhances patient-centered benefit-risk assessment for regulatory decision making.

Overexpression of caveolin-1 is sufficient to phenocopy the behavior of a disease-associated mutant.

Mutations and alterations in caveolin-1 expression levels have been linked to a number of human diseases. How misregulation of caveolin-1 contributes to disease is not fully understood, but has been proposed to involve the intracellular accumulation of mutant forms of the protein. To better understand the molecular basis for trafficking defects that trap caveolin-1 intracellularly, we compared the properties of a GFP-tagged version of caveolin-1 P132L, a mutant form of caveolin-1 previously linked to breast cancer, with wild-type caveolin-1. Unexpectedly, wild-type caveolin-1-GFP also accumulated intracellularly, leading us to examine the mechanisms underlying the abnormal localization of the wild type and mutant protein in more detail. We show that both the nature of the tag and cellular context impact the subcellular distribution of caveolin-1, demonstrate that even the wild-type form of caveolin-1 can function as a dominant negative under some conditions, and identify specific conformation changes associated with incorrectly targeted forms of the protein. In addition, we find intracellular caveolin-1 is phosphorylated on Tyr14, but phosphorylation is not required for mistrafficking of the protein. These findings identify novel properties of mistargeted forms of caveolin-1 and raise the possibility that common trafficking defects underlie diseases associated with overexpression and mutations in caveolin-1.

Cellular stress triggers TEL nuclear export via two genetically separable pathways.

TEL (translocation ets leukemia, also known as ETV6) is a repressor of transcription that is disrupted by the t(12;21), which is the most frequent chromosomal translocation in pediatric acute lymphocytic leukemia. TEL is modified by SUMOylation, and the lysine (Lys 99) that is conjugated to SUMO is required for TEL nuclear export. In addition, TEL is phosphorylated by p38 kinase, which is activated by cellular stress. Induction of cellular stress reduced the ability of TEL to repress transcription in vitro, but the mechanistic basis of this phenomenon was unclear. In this study, we show that osmotic stress causes re-localization of TEL to the cytoplasm and that p38-mediated phosphorylation of TEL is sufficient for this re-localization. However, impairment of both SUMOylation of Lys 99 and p38-dependent phosphorylation of Ser 257 of TEL were required to impair the re-localization of TEL in response to cellular stress induced by high salt, identifying two separate nuclear export pathways. Thus, alteration of the cellular localization of TEL may be a part of the cellular stress response and re-localization of TEL to the cytoplasm is an important step in the regulation of TEL.

Non-traditional roles for the Adenomatous Polyposis Coli (APC) tumor suppressor protein.

The Adenomatous Polyposis Coli (APC) tumor suppressor is a multifunctional protein that is mutated in a majority of colon cancers. The role of APC as an antagonist of the Wnt signaling pathway is well known and it is widely accepted that inappropriate activation of this pathway through loss of APC function contributes to the progression of colon cancers. However, a body of evidence is growing to support the idea that APC plays non-traditional functions outside of the Wnt pathway with roles in cell migration, adhesion, chromosome segregation, spindle assembly, apoptosis, and neuronal differentiation. This review highlights the research into alternate functions for APC beyond its role in Wnt signaling and discusses the possible contributions for these non-traditional functions of APC in tumor formation.