Genomic data reveal local endemism in Southern California Rubber Boas (Serpentes: Boidae, Charina) and the critical need for enhanced conservation actions.

The mountains of southern California represent unique, isolated ecosystems that support distinct high-elevation habitats found nowhere else in the area. Analyses of several moisture-dependent species across these sky-islands indicate they exist as locally endemic lineages that occur across these fragmented mountains ranges. The Rubber Boa is a semi-fossorial snake species that is widely distributed in the cooler and more moist ecoregions regions of western North America, including isolated populations across southern California mountain ranges. We developed a genomic and ecological dataset to examine genetic diversity within Rubber Boas and to determine if the endemic Southern Rubber Boa represents a distinct lineage. We quantified current and future habitat suitability under a range of climate change scenarios, and discuss the possible environmental threats facing these unique montane isolates. Our results support four major lineages within Rubber Boas, with genetic breaks that are consistent with biogeographic boundaries observed in other co-distributed, cool-temperature, moisture adapted species. Our data support previous studies that the Southern Rubber Boa is an independent evolutionary unit and now includes multiple locally endemic sky-island populations, restricted to isolated mountain tops and ranges across southern California. Analyses of future habitat suitability indicate that many of these sky-island populations will lose most of their suitable habitat over the next 70 years given predicted increases in drought, rising temperatures, and wildfires. Collectively these data emphasize the critical conservation needs of these montane ecosystems in southern California under current and projected climate change conditions.

Toll-like Receptor 8 Stability Is Regulated by Ring Finger 216 in Response to Circulating MicroRNAs.

TLR8 (Toll-like receptor 8) is an intracellular pattern recognition receptor that senses RNA in endosomes to initiate innate immune signaling through NF-κB, and mechanisms regulating TLR8 protein abundance are not completely understood. Protein degradation is a cellular process controlling protein concentrations, accomplished largely through ubiquitin transfer directed by E3 ligase proteins to substrates. In the present study, we show that TLR8 has a short half-life in THP-1 monocytes (∼1 h) and that TLR8 is ubiquitinated and degraded in the proteasome. Treatment with the TLR8 agonist R848 causes rapid depletion of TLR8 concentrations at early time points, an effect blocked by proteasomal inhibition. We show a novel role for RNF216 (ring finger protein 216), an E3 ligase that targets TLR8 for ubiquitination and degradation. RNF216 overexpression reduces TLR8 concentrations, whereas RNF216 knockdown stabilizes TLR8. We describe a potential role for TLR8 activation by circulating RNA ligands in humans with acute respiratory distress syndrome (ARDS): Plasma and extracted RNA fractions from subjects with ARDS activated TLR8 in vitro. MicroRNA (miRNA) expression profiling revealed several circulating miRNAs from subjects with ARDS. miRNA mimics promoted TLR8 proteasomal degradation in THP-1 cells. These data show that TLR8 proteasomal disposal through RNF216 in response to RNA ligands regulates TLR8 cellular concentrations and may have implications for innate immune signaling. In addition, TLR8 activation by circulating RNA ligands may be a previously underrecognized stimulus contributing to excessive innate immune signaling characteristic of ARDS.

Male Scientists' Competing Devotions to Work and Family: Changing Norms in a Male-Dominated Profession.

Using in-depth interviews with 74 men across different ranks in biology and physics at prestigious US universities, we ask to what extent changing norms of fatherhood and a flexible workplace affect men working in a highly male-dominated profession and what variation exists in family forms. We conceptualize four typologies of men: those forgoing children, egalitarian partners, neo-traditional dual-earners, and traditional breadwinners. Findings suggest male scientists hold strong work devotions yet a growing number seek egalitarian relationships, which they frame as reducing their devotion to work. The majority of men find the all-consuming nature of academic science conflicts with changing fatherhood norms.

Nonadherence to treatment protocol for severe hypertension in pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy are one of the leading causes of maternal mortality and severe morbidity. The American College of Obstetricians and Gynecologists recommends treatment of persistent severe hypertension because this has been shown to improve overall outcomes. Treatment remains inconsistent and may be influenced by patient-level sociodemographic and clinical characteristics. OBJECTIVE: This study aimed to identify which factors are associated with nonadherence to an institutional protocol for the treatment of severe hypertension in pregnancy. STUDY DESIGN: Retrospective cohort study of patients who had persistent severe hypertension (≥2 systolic blood pressures ≥160 mm Hg and/or diastolic blood pressures >110 mm Hg between 15 and 60 minutes apart) during their delivery hospitalization in 3 hospitals within an integrated health system from February 1, 2018 to March 1, 2020. Adherence to an institutional protocol was defined as receiving antihypertensive medication within 1 hour of a second severe blood pressure measurement. Demographic information, medical comorbidities, and delivery hospitalization characteristics were compared between women who received treatment based on institutional protocol and those who did not. Patient zone improvement plan codes were linked to neighborhood-level data from the US Census Bureau's American Community Survey to extract socioeconomic characteristics. A multivariable logistic regression was performed to evaluate factors associated with delayed treatment while adjusting for potential confounders. RESULTS: Of the 996 patients included, 449 (45%) received treatment within 60 minutes and 547 (55%) did not. Having an elevated, nonsevere range blood pressure (adjusted odds ratio, 0.55; 95% confidence interval, 0.38-0.79) or a severe range blood pressure (adjusted odds ratio, 0.25; 95% confidence interval, 0.16-0.38) on admission, persistent severe hypertension ≥1 hour before or after delivery (adjusted odds ratio, 0.27; 95% confidence interval, 0.27-0.45), and chronic hypertension (adjusted odds ratio, 0.58; 95% confidence interval, 0.37-0.93) were associated with timely treatment. Hospital site (adjusted odds ratio, 1.97; 95% confidence interval, 1.18-3.28) and increasing gestational age (adjusted odds ratio, 1.14; 95% confidence interval, 1.07-1.21) were associated with nonadherence to treatment protocol. A subanalysis evaluating treatment in 344 (35%) patients who had a nonelevated blood pressure on admission showed that White race, persistent severe hypertension within 1 hour of delivery, increasing gestational age, body mass index, twin gestation, preferred language other than English or Spanish, and a higher neighborhood unemployment rate were associated with nonadherence to treatment protocol. CONCLUSION: Several factors were associated with nonadherence to an institutional protocol for treatment of persistent severe hypertension. Provider bias may impact whether treatment is executed or not. Awareness of these risk factors may improve timely administration of antihypertensive medication in pregnant and postpartum patients.

A Repurposed Drug Screen for Compounds Regulating Aquaporin 5 Stability in Lung Epithelial Cells.

Aquaporin 5 (AQP5) is expressed in several cell types in the lung and regulates water transport, which contributes to barrier function during injury and the composition of glandular secretions. Reduced AQP5 expression is associated with barrier dysfunction during acute lung injury, and strategies to enhance its expression are associated with favorable phenotypes. Thus, pharmacologically enhancing AQP5 expression could be beneficial. Here, we optimized a high-throughput assay designed to detect AQP5 abundance using a cell line stably expressing bioluminescent-tagged AQP5. We then screened a library of 1153 compounds composed of FDA-approved drugs for their effects on AQP5 abundance. We show compounds Niclosamide, Panobinostat, and Candesartan Celexitil increased AQP5 abundance, and show that Niclosamide has favorable cellular toxicity profiles. We determine that AQP5 levels are regulated in part by ubiquitination and proteasomal degradation in lung epithelial cells, and mechanistically Niclosamide increases AQP5 levels by reducing AQP5 ubiquitination and proteasomal degradation. Functionally, Niclosamide stabilized AQP5 levels in response to hypotonic stress, a stimulus known to reduce AQP5 levels. In complementary assays, Niclosamide increased endogenous AQP5 in both A549 cells and in primary, polarized human bronchial epithelial cells compared to control-treated cells. Further, we measured rapid cell volume changes in A549 cells in response to osmotic stress, an effect controlled by aquaporin channels. Niclosamide-treated A549 cell volume changes occurred more rapidly compared to control-treated cells, suggesting that increased Niclosamide-mediated increases in AQP5 expression affects functional water transport. Taken together, we describe a strategy to identify repurposed compounds for their effect on AQP5 protein abundance. We validated the effects of Niclosamide on endogenous AQP5 levels and in regulating cell-volume changes in response to tonicity changes. Our findings highlight a unique approach to screen for drug effects on protein abundance, and our workflow can be applied broadly to study compound effects on protein abundance in lung epithelial cells.

Personal reflections on the life and legacy of Alexander Hollaender.

Mary Esther Gaulden presents a personal summary of the activities of Alexander Hollaender, from his days at the National Institutes of Health to his becoming Director of the Biology Division of the Oak Ridge National Laboratory in 1947. This appealing story deals with many of her reactions to his personality and organizational style. It reflects the atmosphere of science in those days, and her enthusiasm in this vibrant milieu. Next is a brief account by John Jagger of his first meeting with Dr. Hollaender, arrival in Oak Ridge in April 1956, and wedding to Mary Esther six months later at the house of the Hollaenders in Oak Ridge. The third section is an account by Virginia P. White of how she came to Oak Ridge in 1955 and became Dr. Hollaender's Laboratory Administrator. She gives a personal account of the many facets of his managerial style, as well as of the personality of his wife, Henrietta. She also describes one of Hollaender's many avocations, the collection of fossils on Sunday morning hikes in the Cumberland Mountains, accompanied by lab and visiting personnel, and finally comments on the annual research conferences in Gatlinburg TN, for which Hollaender and the lab became very well known, with some closing vignettes on his leadership style.

A review of influenza viruses in seals and the implications for public health.

With the public health community and general population more concerned with influenza than ever before, it is important to explore all potential vectors for the next pandemic. Potential sources include pinnipeds (seals and sea lions). Between subsistence hunting, managed animals, and shared shoreline habitat, humans are more likely to interact with pinnipeds than any other marine mammal. This paper summarizes documented influenza events and research on Phocidae and Otariidae and discusses the potential challenges they present to public health.