bluuebunny/crossref_metadata_2025_split huggingface dataset:
Líl̓wat oral traditions of Qw̓elqw̓elústen (Mount Meager): Indigenous records of volcanic eruption, outburst flood, and landscape change in southwest British Columbia
Authors: Wilson Michael C. , Angelbeck Bill , Jones / Yaqalatqa7 Johnny 
Published: February 2024

Indigenous oral traditions of the Líl̓wat Nation recount observations of Qw̓elqw̓elústen (Mount Meager), a Garibaldi Volcanic Belt volcano in southwestern British Columbia, Canada; and associated eruptive activity, mass-wasting, and outburst flooding. We present Líl̓wat observations relating to Qw̓elqw̓elústen’s ∼2360 cal year B.P. eruption and its aftermath, a devastating outburst flood down the Lillooet valley. The Copper Canoe story correlates with the event sequence of pyroclastic damming of the Lillooet River and an outburst flood traveling far downstream, interrupting salmon runs and displacing people. Other stories suggest an eruptive plume and fumaroles. Recounted valley-floor changes, with proximal scouring and downstream filling of marshes allowing human resettlement, closely parallel and augment geological evidence, showing that oral traditions are equally important in holding landscape history. Oral traditions portray dramatic landscape changes, some by the Transformers, said to have traveled this land to make imperfect things right. Geologically documented debris-flow delta progradation and infill of the upper 50 km of Lillooet Lake since ∼12 000 cal B.P. underscore the land’s dynamism and the need for both sources to inform planning for future eruptive, mass-wasting, and flooding events. Traditional landscape knowledge, like Western science, is observational and evidence-based, though interpretations can differ given Indigenous belief in a sentient landscape, capable of acting with intention. Binding of stories to geographical locations has functioned as a powerful mnemonic device to preserve orally transmitted information across many generations.
Mesothelin Secretion by Pancreatic Cancer Cells Co-opts Macrophages and Promotes Metastasis
Authors: Luckett Teifion , Abudula Maidinaimu , Ireland Lucy , Glenn Mark , Bellomo Gaia , Stafferton Ruth , Halloran Chris , Ghaneh Paula , Jones Rob , Schmid Michael C. , Mielgo Ainhoa 
Published: February 2024

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease, yet effective treatments to inhibit PDAC metastasis are lacking. The rich PDAC tumor microenvironment plays a major role in disease progression. Macrophages are the most abundant immune cell population in PDAC tumors and can acquire a range of functions that either hinder or promote tumor growth and metastasis. Here, we identified that mesothelin secretion by pancreatic cancer cells co-opts macrophages to support tumor growth and metastasis of cancer cells to the lungs, liver, and lymph nodes. Mechanistically, secretion of high levels of mesothelin by metastatic cancer cells induced the expression of VEGF alpha (VEGFA) and S100A9 in macrophages. Macrophage-derived VEGFA fed back to cancer cells to support tumor growth, and S100A9 increased neutrophil lung infiltration and formation of neutrophil extracellular traps. These results reveal a role for mesothelin in regulating macrophage functions and interaction with neutrophils to support PDAC metastasis.

Significance:
Mesothelin secretion by cancer cells supports pancreatic cancer metastasis by inducing macrophage secretion of VEGFA and S100A9 to support cancer cell proliferation and survival, recruit neutrophils, and stimulate neutrophil extracellular trap formation.
See related commentary by Alewine, p. 513
Analysis of Tumor-Associated AXIN1 Missense Mutations Identifies Variants That Activate β-Catenin Signaling
Authors: Zhang Ruyi , Li Shanshan , Schippers Kelly , Li Yunlong , Eimers Boaz , Lavrijsen Marla , Wang Ling , Cui Guofei , Chen Xin , Peppelenbosch Maikel P. , Lebbink Joyce H.G. , Smits Ron 
Published: February 2024

Abstract

AXIN1 is a major component of the β-catenin destruction complex and is frequently mutated in various cancer types, particularly liver cancers. Truncating AXIN1 mutations are recognized to encode a defective protein that leads to β-catenin stabilization, but the functional consequences of missense mutations are not well characterized. Here, we first identified the GSK3β, β-catenin, and RGS/APC interaction domains of AXIN1 that are the most critical for proper β-catenin regulation. Analysis of 80 tumor-associated variants in these domains identified 18 that significantly affected β-catenin signaling. Coimmunoprecipitation experiments revealed that most of them lost binding to the binding partner corresponding to the mutated domain. A comprehensive protein structure analysis predicted the consequences of these mutations, which largely overlapped with the observed effects on β-catenin signaling in functional experiments. The structure analysis also predicted that loss-of-function mutations within the RGS/APC interaction domain either directly affected the interface for APC binding or were located within the hydrophobic core and destabilized the entire structure. In addition, truncated AXIN1 length inversely correlated with the β-catenin regulatory function, with longer proteins retaining more functionality. These analyses suggest that all AXIN1-truncating mutations at least partially affect β-catenin regulation, whereas this is only the case for a subset of missense mutations. Consistently, most colorectal and liver cancers carrying missense variants acquire mutations in other β-catenin regulatory genes such as APC and CTNNB1. These results will aid the functional annotation of AXIN1 mutations identified in large-scale sequencing efforts or in individual patients.

Significance:
Characterization of 80 tumor-associated missense variants of AXIN1 reveals a subset of 18 mutations that disrupt its β-catenin regulatory function, whereas the majority are passenger mutations.
Considering Functional Outcomes as Efficacy Endpoints in Pediatric Low-Grade Glioma Clinical Trials: An FDA Educational Symposium
Authors: Fangusaro Jason , Avery Robert A. , Fisher Michael J. , Packer Roger J. , Walsh Karin S. , Schouten-van Meeteren Antoinette , Karres Dominik , Bradford Diana , Bhatnagar Vishal , Singh Harpreet , Kluetz Paul G. , Donoghue Martha , Duke Elizabeth S. 
Published: February 2024

Abstract
In October 2022, the FDA Oncology Center of Excellence hosted an educational symposium entitled, “Considering Functional Outcomes as Efficacy Endpoints in Pediatric Low-Grade Glioma (pLGG) Clinical Trials.” The symposium brought together patient advocates, regulators from the FDA and the European Medicines Agency (EMA), and an international group of academic thought leaders in the field of pediatric neuro-oncology to discuss the potential role of functional outcomes, including visual acuity, motor function, and neurocognitive performance, as endpoints in clinical trials enrolling patients with pLGG. The panel discussed challenges and opportunities regarding the selection, implementation, and evaluation of clinical outcome assessments in these functional domains and outlined key considerations for their inclusion in future clinical trial design and role in new drug development.
Inhibition of Aurora Kinase Induces Endogenous Retroelements to Induce a Type I/III IFN Response via RIG-I
Authors: Choy Lisa , Norris Stephen , Wu Xiumin , Kolumam Ganesh , Firestone Ari , Settleman Jeffrey , Stokoe David 
Published: February 2024

Abstract

Type I IFN signaling is a crucial component of antiviral immunity that has been linked to promoting the efficacy of some chemotherapeutic drugs. We developed a reporter system in HCT116 cells that detects activation of the endogenous IFI27 locus, an IFN target gene. We screened a library of annotated compounds in these cells and discovered Aurora kinase inhibitors (AURKi) as strong hits. Type I IFN signaling was found to be the most enriched gene signature after AURKi treatment in HCT116, and this signature was also strongly enriched in other colorectal cancer cell lines. The ability of AURKi to activate IFN in HCT116 was dependent on MAVS and RIG-I, but independent of STING, whose signaling is deficient in these cells. MAVS dependence was recapitulated in other colorectal cancer lines with STING pathway deficiency, whereas in cells with intact STING signaling, the STING pathway was required for IFN induction by AURKi. AURKis were found to induce expression of endogenous retroviruses (ERV). These ERVs were distinct from those induced by the DNA methyltransferase inhibitors (DNMTi), which can induce IFN signaling via ERV induction, suggesting a novel mechanism of action. The antitumor effect of alisertib in mice was accompanied by an induction of IFN expression in HCT116 or CT26 tumors. CT26 tumor growth inhibition by alisertib was absent in NSG mice versus wildtype (WT) mice, and tumors from WT mice with alisertib treatment showed increased in CD8+ T-cell infiltration, suggesting that antitumor efficacy of AURKi depends, at least in part, on an intact immune response.

Significance:
Some cancers deactivate STING signaling to avoid consequences of DNA damage from aberrant cell division. The surprising activation of MAVS/RIG-I signaling by AURKi might represent a vulnerability in STING signaling deficient cancers.
Valvular Prostaglandins Are Elevated in Severe Human Aortic Valve Stenosis
Authors: Cayer Lucien G.J. , Surendran Arun , Karakach Tobias , Aukema Harold M. , Ravandi Amir 
Published: February 2024

BACKGROUND:
Aortic valve stenosis (AVS) is the most common valvular disease in the developed world. AVS involves the progressive fibrocalcific remodeling of the aortic valve (AV), which impairs function and can ultimately lead to heart failure. Due to gaps in our understanding of the underlying mechanisms of AVS, there are no pharmacological treatments or dietary interventions known to slow AVS progression. Recent studies have begun to suggest oxylipins—a class of bioactive lipids—may be dysregulated in the valves of patients with AVS.

METHODS:
We utilized high-performance liquid chromatography–tandem mass spectrometry to conduct a targeted oxylipin analysis on human AV tissue and plasma from a cohort of 110 patients undergoing AV surgery.

RESULTS:
We identified 36 oxylipins in human AV tissue with all showing significant increase in patients with severe AVS. A multivariate model including patient characteristics and valvular oxylipins identified the arachidonic acid-COX (cyclooxygenase) pathway–derived prostanoids to be the most associated with AVS severity. Plasma oxylipin levels were measured in a subset of AV surgery patients and compared with a control group of healthy participants, showing distinct oxylipin profiles between control and disease.

CONCLUSIONS:
Our comprehensive analysis of oxylipins in the human AV identified the inflammatory and osteogenic regulating prostanoids to be positively correlated with AVS severity. This elucidation of prostanoid dysregulation warrants further research into COX inhibition to mitigate AVS.
S-Nitrosylation of Septin2 Exacerbates Aortic Aneurysm and Dissection by Coupling the TIAM1-RAC1 Axis in Macrophages
Authors: Zhang Yan , Zhang Hao , Zhao Shuang , Qi Zhenhua , He Yiwei , Zhang Xuhong , Wu Wencheng , Yan Ke , Hu Lulu , Sun Shixiu , Tang Xinlong , Zhou Qing , Chen Feng , Gu Aihua , Wang Liansheng , Zhang Zhiren , Yu Bo , Wang Dongjin , Han Yi , Xie Liping , Ji Yong 
Published: February 2024

BACKGROUND:
S-Nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in cardiovascular disease. Aortic aneurysm and dissection are high-risk cardiovascular diseases without an effective cure. The aim of this study was to determine the role of SNO of Septin2 in macrophages in aortic aneurysm and dissection.

METHODS:

Biotin-switch assay combined with liquid chromatography–tandem mass spectrometry was performed to identify the S-nitrosylated proteins in aortic tissue from both patients undergoing surgery for aortic dissection and
Apoe

−/−

mice infused with angiotensin II. Angiotensin II–induced aortic aneurysm model and β-aminopropionitrile–induced aortic aneurysm and dissection model were used to determine the role of SNO of Septin2 (SNO-Septin2) in aortic aneurysm and dissection development. RNA-sequencing analysis was performed to recapitulate possible changes in the transcriptome profile of SNO-Septin2 in macrophages in aortic aneurysm and dissection. Liquid chromatography–tandem mass spectrometry and coimmunoprecipitation were used to uncover the TIAM1-RAC1 (Ras-related C3 botulinum toxin substrate 1) axis as the downstream target of SNO-Septin2. Both R-Ketorolac and NSC23766 treatments were used to inhibit the TIAM1-RAC1 axis.

RESULTS:

Septin2 was identified S-nitrosylated at cysteine 111 (Cys111) in both aortic tissue from patients undergoing surgery for aortic dissection and
Apoe

−/−

mice infused with Angiotensin II. SNO-Septin2 was demonstrated driving the development of aortic aneurysm and dissection. By RNA-sequencing, SNO-Septin2 in macrophages was demonstrated to exacerbate vascular inflammation and extracellular matrix degradation in aortic aneurysm. Next, TIAM1 (T lymphoma invasion and metastasis-inducing protein 1) was identified as a SNO-Septin2 target protein. Mechanistically, compared with unmodified Septin2, SNO-Septin2 reduced its interaction with TIAM1 and activated the TIAM1-RAC1 axis and consequent nuclear factor-κB signaling pathway, resulting in stronger inflammation and extracellular matrix degradation mediated by macrophages. Consistently, both R-Ketorolac and NSC23766 treatments protected against aortic aneurysm and dissection by inhibiting the TIAM1-RAC1 axis.

CONCLUSIONS:
SNO-Septin2 drives aortic aneurysm and dissection through coupling the TIAM1-RAC1 axis in macrophages and activating the nuclear factor-κB signaling pathway–dependent inflammation and extracellular matrix degradation. Pharmacological blockade of RAC1 by R-Ketorolac or NSC23766 may therefore represent a potential treatment against aortic aneurysm and dissection.
Machine Learning Estimation of Maximum Vertical Velocity from Radar
Authors: Chase Randy J. , McGovern Amy , Homeyer Cameron R. , Marinescu Peter J. , Potvin Corey K. 
Published: February 2024

Abstract
The quantification of storm updrafts remains unavailable for operational forecasting despite their inherent importance to convection and its associated severe weather hazards. Updraft proxies, like overshooting top area from satellite images, have been linked to severe weather hazards but only relate to a limited portion of the total storm updraft. This study investigates if a machine learning model, namely, U-Nets, can skillfully retrieve maximum vertical velocity and its areal extent from three-dimensional gridded radar reflectivity alone. The machine learning model is trained using simulated radar reflectivity and vertical velocity from the National Severe Storm Laboratory’s convection permitting Warn-on-Forecast System (WoFS). A parametric regression technique using the sinh–arcsinh–normal distribution is adapted to run with U-Nets, allowing for both deterministic and probabilistic predictions of maximum vertical velocity. The best models after hyperparameter search provided less than 50% root mean squared error, a coefficient of determination greater than 0.65, and an intersection over union (IoU) of more than 0.45 on the independent test set composed of WoFS data. Beyond the WoFS analysis, a case study was conducted using real radar data and corresponding dual-Doppler analyses of vertical velocity within a supercell. The U-Net consistently underestimates the dual-Doppler updraft speed estimates by 50%. Meanwhile, the area of the 5 and 10 m s−1 updraft cores shows an IoU of 0.25. While the above statistics are not exceptional, the machine learning model enables quick distillation of 3D radar data that is related to the maximum vertical velocity, which could be useful in assessing a storm’s severe potential.

Significance Statement
All convective storm hazards (tornadoes, hail, heavy rain, straight line winds) can be related to a storm’s updraft. Yet, there is no direct measurement of updraft speed or area available for forecasters to make their warning decisions from. This paper addresses the lack of observational data by providing a machine learning solution that skillfully estimates the maximum updraft speed within storms from only the radar reflectivity 3D structure. After further vetting the machine learning solutions on additional real-world examples, the estimated storm updrafts will hopefully provide forecasters with an added tool to help diagnose a storm’s hazard potential more accurately.
Suppression of Mesoscale Eddy Mixing by Topographic PV Gradients
Authors: Sterl Miriam F. , LaCasce Joseph H. , Groeskamp Sjoerd , Nummelin Aleksi , Isachsen Pål E. , Baatsen Michiel L. J. 
Published: February 2024

Abstract
Oceanic mesoscale eddy mixing plays a crucial role in Earth’s climate system by redistributing heat, salt, and carbon. For many ocean and climate models, mesoscale eddies still need to be parameterized. This is often done via an eddy diffusivity , which sets the strength of turbulent downgradient tracer fluxes. A well-known effect is the modulation of in the presence of background potential vorticity (PV) gradients, which suppresses mixing in the direction of the PV gradients. Topographic slopes can induce such suppression through topographic PV gradients. However, this effect has received little attention, and topographic effects are often not included in parameterizations for . In this study, we show that it is possible to describe the effect of topography on analytically in a barotropic framework, using a simple stochastic representation of eddy–eddy interactions. We obtain an analytical expression for the depth-averaged as a function of the bottom slope, which we validate against diagnosed eddy diffusivities from a numerical model. The obtained analytical expression can be generalized to any constant barotropic PV gradient. Moreover, the expression is consistent with empirical parameterizations for eddy diffusivity over topography from previous studies and provides a physical rationalization for these parameterizations. The new expression helps to understand how eddy diffusivities vary across the ocean, and thus how mesoscale eddies impact ocean mixing processes.

Significance Statement
Large oceanic “whirls,” called eddies, can mix and transport ocean properties such as heat, salt, carbon, and nutrients. Mixing plays an important role for oceanic ecosystems and the climate system. In numerical simulations of Earth’s climate, eddy mixing is typically represented using a simplified expression. However, an effect that is often not included is that eddy mixing is weaker over a sloping seafloor. In most areas of the ocean the bottom slope is steep enough for this effect to be significant. In this study we derive an expression for eddy mixing that accounts for oceanic bottom slopes. The present effort provides a physical basis for eddy mixing over oceanic bottom slopes, justifying their use in climate models.
Association Between Social Vulnerability and SARS-CoV-2 Seroprevalence in Specimens Collected From Commercial Laboratories, United States, September 2021–February 2022
Authors: Benoit Tina J. , Kim Yun , Deng Yangyang , Li Zheng , Harding Lee , Wiegand Ryan , Deng Xiaoyi , Jones Jefferson M. , Ronaldo Iachan , Clarke Kristie E.N. 
Published: February 2024

Objective: We conducted a national US study of SARS-CoV-2 seroprevalence by Social Vulnerability Index (SVI) that included pediatric data and compared the Delta and Omicron periods during the COVID-19 pandemic. The objective of the current study was to assess the association between SVI and seroprevalence of infection-induced SARS-CoV-2 antibodies by period (Delta vs Omicron) and age group. Methods: We used results of infection-induced SARS-CoV-2 antibody assays of clinical sera specimens (N = 406 469) from 50 US states from September 2021 through February 2022 to estimate seroprevalence overall and by county SVI tercile. Bivariate analyses and multilevel logistic regression models assessed the association of seropositivity with SVI and its themes by age group (0-17, ≥18 y) and period (Delta: September–November 2021; Omicron: December 2021–February 2022). Results: Aggregate infection-induced SARS-CoV-2 antibody seroprevalence increased at all 3 SVI levels; it ranged from 25.8% to 33.5% in September 2021 and from 53.1% to 63.5% in February 2022. Of the 4 SVI themes, socioeconomic status had the strongest association with seroprevalence. During the Delta period, we found significantly more infections per reported case among people living in a county with high SVI (odds ratio [OR] = 2.76; 95% CI, 2.31-3.21) than in a county with low SVI (OR = 1.65; 95% CI, 1.33-1.97); we found no significant difference during the Omicron period. Otherwise, findings were consistent across subanalyses by age group and period. Conclusions: Among both children and adults, and during both the Delta and Omicron periods, counties with high SVI had significantly higher SARS-CoV-2 antibody seroprevalence than counties with low SVI did. These disparities reinforce SVI’s value in identifying communities that need tailored prevention efforts during public health emergencies and resources to recover from their effects.
Medicaid Expansion and Health Care Use Among Adults With Asthma and Low Incomes: The Adult Asthma Call-Back Survey
Authors: Qin Xiaoting , Mirabelli Maria C. , Flanders W. Dana , Hsu Joy 
Published: February 2024

Objectives: Asthma disproportionately affects Black people and people with low incomes, but Medicaid expansion (hereinafter, expansion) data on these populations are limited. We investigated health care use among adults with asthma, before and after expansion, and examined whether asthma-related health care use after expansion varied by demographic characteristics. Methods: We analyzed data from the 2011-2013 and 2015-2019 Behavioral Risk Factor Surveillance System Adult Asthma Call-Back Survey on participants aged 18-64 years with current asthma and low incomes in 23 US states. We assessed 5 asthma-related outcomes, including medical visits (routine and emergency) and medication use, for expansion and nonexpansion groups. We used t tests to compare weighted percentages and 95% CIs, then performed adjusted difference-in-differences analyses. Secondary analyses stratified data by race, ethnicity, and sex. Results: Primary analyses (N = 10 796) found no significant associations between expansion and any outcome. Analyses stratified by race and ethnicity found no significant changes (eg, asthma controller medication use among non-Hispanic Black participants in the expansion group was 24.1% [95% CI, 14.4%-37.5%] in 2011-2013 and 35.5% [95% CI, 27.0%-45.1%] in 2015-2019; P = .13). Use of asthma controller medication increased significantly among non-Hispanic Other participants in the nonexpansion group (2011-2013: 16.0% [95% CI, 9.5%-25.5%]; 2015-2019: 40.2% [95% CI, 25.5%-56.8%]; P = .01). Asthma-related hospitalizations decreased significantly among women in the expansion group: 2011-2013 (7.8%; 95% CI, 5.3%-11.3%) and 2015-2019 (3.5%; 95% CI, 2.5%-4.9%) ( P = .009). Conclusions: Investigating factors other than health insurance (eg, social determinants of health) that influence the use of asthma-related health care could advance knowledge of potential strategies to advance health equity for adults with asthma and lower incomes.