bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Ovarian Cancer Stem Cells by Dual Inhibition of the Long Noncoding RNA HOTAIR and Lysine Methyltransferase EZH2
Authors: Wang Weini , Zhou Yanchi , Wang Ji , Zhang Shu , Ozes Ali , Gao Hongyu , Fang Fang , Wang Yue , Chu Xiaona , Liu Yunlong , Wan Jun , Mitra Anirban K. , O’Hagan Heather M. , Nephew Kenneth P. 
Published: July 2024

Abstract
The persistence of cancer stem cells (CSC) is believed to contribute to resistance to platinum-based chemotherapy and disease relapse in ovarian cancer, the fifth leading cause of cancer-related death among US women. HOXC transcript antisense RNA (HOTAIR) is a long, noncoding RNA (lncRNA) overexpressed in high-grade serous ovarian cancer and linked to chemoresistance. However, HOTAIR impacts chromatin dynamics in ovarian CSCs. Oncogenic lncRNA’s contributions to drug-resistant disease are incompletely understood. Here, we generated HOTAIR knockout (KO) high-grade serous ovarian cancer cell lines using paired CRISPR guide RNA design to investigate the function of HOTAIR. We show the loss of HOTAIR function resensitized ovarian cancer cells to platinum treatment and decreased the population of ovarian CSCs. Furthermore, HOTAIR KO inhibited the development of stemness-related phenotypes, including spheroid formation ability and expression of key stemness-associated genes ALDH1A1, NOTCH3, SOX9, and PROM1. HOTAIR KO altered the cellular transcriptome and chromatin accessibility landscape of multiple oncogenic-associated genes and pathways, including the NF-kB pathway. HOTAIR functions as an oncogene by recruiting enhancer of zeste homolog 2 (EZH2) to catalyze H3K27 trimethylation to suppress downstream tumor suppressor genes, and it was of interest to inhibit both HOTAIR and EZH2. In vivo, combining a HOTAIR inhibitor with an EZH2 inhibitor and platinum chemotherapy decreased tumor formation and increased survival. These results suggest a key role for HOTAIR in ovarian CSCs and malignant potential. Targeting HOTAIR in combination with epigenetic therapies may represent a therapeutic strategy to ameliorate ovarian cancer progression and resistance to platinum-based chemotherapy.
Effects and Thresholds of Young to Midlife Vascular Risks on Brain Health
Authors: Maas Matthew B. , Mahinrad Simin , Sedaghat Sanaz , Yaffe Kristine , Launer Lenore J. , Bryan R. Nick , Sidney Stephen , Gorelick Philip B. , Lloyd-Jones Donald M. , Sorond Farzaneh A. 
Published: July 2024

BACKGROUND:
Vascular risk factors, particularly hypertension, are important contributors to accelerated brain aging. We sought to quantify vascular risk factor risks over adulthood and assess the empirical evidence for risk thresholds.

METHODS:
We used SBP (systolic blood pressure) and diastolic blood pressure, total cholesterol, fasting blood glucose, and body mass index measurements collected from participants in the CARDIA study (Coronary Artery Risk Development in Young Adults) at 2- to 5-year intervals through year 30. The Montreal Cognitive Assessment and domain-specific cognitive tests were performed at year 30. White matter hyperintensity volume was measured by magnetic resonance imaging. We used a 2-step method to fit longitudinal vascular risk factor exposures to optimized spline functions with mixed-effects models, then used the participant-specific random effects that characterized individual exposures over time in cross-sectional models adjusted for sex, race, age, and education to study effects on midlife brain health.

RESULTS:

Change in SBP up to 33 years of age was negatively associated with Montreal Cognitive Assessment scores (−0.29 Montreal Cognitive Assessment
Z
score per mm Hg/y change [95% CI, −0.49 to −0.09];
P
=0.005), with similar effects for SBP changes from 33 to 49 years of age (−0.08 [95% CI, −0.16 to 0.01];
P
=0.08). We observed comparable, significant associations between SBP exposure during those ages, midlife performance on specific cognitive domains, and volume of white matter hyperintensity (all
P
<0.05). SBP ≤111 mm Hg was the estimated threshold below which no harmful association with midlife cognitive performance was identified.

CONCLUSIONS:
SBP in early adulthood is the vascular risk factor most strongly associated with midlife cognitive performance and white matter hyperintensity burden, with SBP 111 mm Hg suggested as a harm threshold.
Coronary and Systemic Vasodilator Responsiveness of Patients Receiving Conventional Intermittent or Nocturnal Hemodialysis
Authors: Overgaard Christopher B. , Chan William , Chowdhary Saqib , Zur Rebecca L. , Wainstein Rodrigo , Džavík Vladimír , Chan Christopher T. , Floras John S. 
Published: July 2024

BACKGROUND:
Nocturnal hemodialysis (nHD) restores the attenuated brachial artery vasodilator responsiveness of patients receiving conventional intermittent hemodialysis (iHD). Its impact on coronary vasodilatation is unknown.

METHODS:
We evaluated 25 patients on hemodialysis who fulfilled transplant criteria: 15 on iHD (4-hour sessions, 3 d/wk) and 10 on nHD (≈40 h/wk over 8–10-hour sessions) plus 6 control participants. Following diagnostic angiography, left anterior descending (LAD) coronary flow reserve and mean luminal diameter were quantified at baseline and during sequential intracoronary administration of adenosine (infusion and bolus), nitroglycerin (bolus), acetylcholine (infusion), acetylcholine coinfused with vitamin C, and, finally, sublingual nitroglycerin.

RESULTS:

Coronary flow reserve in those receiving nHD was augmented relative to iHD (3.28±0.26 versus 2.17±0.12 [mean±SEM];
P
<0.03) but attenuated, relative to controls (4.80±0.63;
P
=0.011). Luminal dilatations induced by intracoronary adenosine and nitroglycerin were similar in nHD and controls but blunted in the iHD cohort (
P
<0.05 versus both). ACh elicited vasodilatation in controls but constriction in both dialysis groups (both
P
<0.05, versus control); vitamin C coinfusion had no effect. Sublingual nitroglycerin increased mid-left anterior descending diameter and reduced mean arterial pressure in controls (+15.2±2.68%; −16.00±1.60%) and in nHD recipients (+14.78±5.46%; −15.82±1.32%); iHD responses were markedly attenuated (+1.9±0.86%; −5.89±1.41%;
P
<0.05, all comparisons).

CONCLUSIONS:
Coronary and systemic vasodilator responsiveness to both adenosine and nitroglycerin is augmented in patients receiving nHD relative to those receiving iHD, whereas vasoconstrictor responsiveness to acetylcholine does not differ. By improving coronary conduit and microvascular function, nHD may reduce the cardiovascular risk of patients on dialysis.
Novel Role of 5-Methyl-(6S)-Tetrahydrofolate in Mediating Endothelial Cell Tetrahydrobiopterin in Pregnancy and Implications for Gestational Hypertension
Authors: Dickinson Yasmin , Boehni Ruth , Obeid Rima , Knapp Jean-Pierre , Moser Rudolf , Lewandowski Adam J. , Douglas Gillian , Leeson Paul , Channon Keith M. , Chuaiphichai Surawee 
Published: July 2024

BACKGROUND:
Folate intake during pregnancy is essential for fetal development and maternal health. However, the specific effects of folic acid (FA) and 5-methyl-(6S)-tetrahydrofolate (5-MTHF) on the prevention and treatment of hypertensive disorders of pregnancy remain unclear. We investigated whether FA and 5-MTHF have different effects on endothelial cell tetrahydrobiopterin (BH4) metabolism in pregnancy and the possible consequences for endothelial NO generation, maternal blood pressure, and fetal growth.

METHODS:

We analyzed the maternal blood pressure in pregnant wild-type (

Gch1
fl/fl

) and

Gch1
fl/fl

Tie2cre mice treated with either FA or 5-MTHF starting before pregnancy, mid-pregnancy or late pregnancy. BH4, superoxide, and NO bioavailability were determined in mouse and human models of endothelial cell BH4 deficiency by high-performance liquid chromatography.

RESULTS:
In vitro studies in mouse and human endothelial cells showed that treatment with 5-MTHF, but not FA, elevated BH4 levels, reduced superoxide production, and increased NO synthase activity. In primary endothelial cells isolated from women with hypertensive pregnancies, exposure to 5-MTHF, but not FA, restored the reduction in BH4 levels and NO synthase activity. In vivo studies in mice revealed that oral treatment with 5-MTHF, but not FA, prevented and treated hypertension in pregnancy when administered either before or during pregnancy, respectively, and normalized placental and fetal growth restriction if administered from mid-gestation onward.

CONCLUSIONS:
Collectively, these studies identify a critical role for 5-MTHF in endothelial cell function in pregnancy, related to endothelial cell BH4 availability and NO synthase activity. Thus, 5-MTHF represents a novel therapeutic agent that may potentially improve endothelial function in hypertensive disorders of pregnancy by targeting endothelial cell BH4.
Impact of Systolic Blood Viscosity on Deep White Matter Hyperintensities in Patients With Acute Ischemic Stroke
Authors: Lee Minwoo , Park Soo‐Hyun , Kim Yeo Jin , Bae Jong Seok , Lee Ju‐Hun , Lee Sang‐Hwa , Kim Chulho , Lee Kijeong , Kim Yerim 
Published: July 2024

Background
Elevated blood viscosity (BV), a critical determinant in blood rheology, is a contributing factor in cerebrovascular diseases. The specific influence of BV on small vessel disease burden remains unexplored. This study aims to examine the relationship between BV and regional white matter hyperintensity (WMH) volume in patients with acute ischemic stroke.

Methods and Results
We enrolled a cohort of 302 patients with acute ischemic stroke or transient ischemic attack who were admitted to a hospital within 7 days of symptom onset in this study. We measured whole BV using a scanning capillary‐tube viscometer and categorized systolic blood viscosity into 3 groups based on established references. We quantified and normalized WMH volumes using automated localization and segmentation software by NEUROPHET Inc. We performed multivariable logistic regression analysis to assess the correlation between systolic BV and WMH. The mean subject age was 66.7±13.4 years, and 38.7% (n=117) of the participants were female. Among a total of 302 patients, patients with higher deep WMH volume (T3) were typically older and had an atrial fibrillation, strokes of cardioembolic or undetermined cause, elevated levels of C‐reactive protein, diastolic blood viscosity and systolic BV. A multivariable adjustment revealed a significant association between high systolic BV and increased deep‐WMH volume (odds ratio [OR], 2.636 [95% CI, 1.225–5.673]).

Conclusions
Elevated systolic BV is more likely to be associated with deep WMH volume in patients with acute ischemic stroke or transient ischemic attack. These findings reveal novel therapeutic strategies focusing on blood rheology to enhance cerebral microcirculation in stroke management.
Cell–Cell Interactions: How Coupled Boolean Networks Tend to Criticality
Authors: Braccini Michele , Baldini Paolo , Roli Andrea 
Published: July 2024

Abstract
Biological cells are usually operating in conditions characterized by intercellular signaling and interaction, which are supposed to strongly influence individual cell dynamics. In this work, we study the dynamics of interacting random Boolean networks, focusing on attractor properties and response to perturbations. We observe that the properties of isolated critical Boolean networks are substantially maintained also in interaction settings, while interactions bias the dynamics of chaotic and ordered networks toward that of critical cells. The increase in attractors observed in multicellular scenarios, compared to single cells, allows us to hypothesize that biological processes, such as ontogeny and cell differentiation, leverage interactions to modulate individual and collective cell responses.
Peering into Cloud Physics Using Ultra-Fine-Resolution Radar and Lidar Systems
Authors: Zhu Zeen , Yang Fan , Kollias Pavlos , Lamer Katia , Luke Edward , Mead James B. , Sua Yong Meng , Vogelmann Andrew M. , McComiskey Allison 
Published: July 2024

Abstract
Cloud microphysical processes, such as droplet activation, condensational growth, and collisional growth, play a central role in the evolution of clouds and precipitation. Accurate representations of these processes in numerical models are challenging partially due to incomplete understanding of them at the process level arising from limited systematic observations. Most surface-based active remote sensors, including today’s operational cloud radars and lidars, have a resolution on the order of tens of meters. This resolution is insufficient to resolve cloud microphysical processes that manifest at finer (meter and submeter) scales. A new set of ultra-high-resolution ground-based radar and lidar systems have been developed to address this observational gap. The newly developed 94-GHz cloud radar has a range resolution down to 2.8 m, or a factor of 10 finer than typical radars, using a large bandwidth and quadratic phase coding techniques. The lidar has a range resolution down to 10 cm, or a factor of 100 finer than typical lidars, using a time-gated time-correlated single-photon-counting technique. Such high-resolution observations were previously only achievable through in situ aircraft measurements. Even then, aircraft measurements do not permit continuous long-term cloud observation as is possible with ground-based remote sensing instruments. In this study, the first-light cloud observations from the new radar and lidar systems are shown to reveal detailed cloud structures that conventional sensors could only perceive in a bulk sense, thus providing new avenues to investigate cloud microphysical processes and their impact on weather and climate.
Quasi-Linear Convective Systems and Derechos across Europe: Climatology, Accompanying Hazards, and Societal Impacts
Authors: Surowiecki Artur , Pilguj Natalia , Taszarek Mateusz , Piasecki Krzysztof , Púčik Tomáš , Brooks Harold E. 
Published: July 2024

Abstract
In this work, we use 8 years (2014–21) of Operational Programme for the Exchange of Weather Radar Information (OPERA) radar data, ESWD severe weather reports, and arrival time difference (ATD) lightning detection network (ATDnet) data to create a climatology of quasi-linear convective systems (QLCSs) across Europe. In the first step, 15-min radar scans were used to identify 1475 QLCS polygons. Severe weather reports, lightning data, and morphological properties were used to classify QLCSs according to their intensity into 1151 marginal (78.0%), 272 moderate (18.5%), and 52 derecho (3.5%) events. The manual evaluation led to the recognition of QLCS morphological and precipitation archetypes, areal extent, duration, speed, forward motion, width, length, accompanying hazards, injuries, and fatalities. Results indicate that QLCSs are the most frequent during summer in central Europe, while in southern Europe, their occurrence is extended to late autumn. A bow echo feature occurred in around 29% of QLCS cases, while a mesoscale convective vortex occurred in almost 9%. Among precipitation modes, trailing and embedded stratiform types accounted for around 50% of QLCSs. The most frequent hazard accompanying QLCSs was lightning (taking up on average 94.4% of the area impacted by QLCS), followed by severe wind gusts (7.9%), excessive precipitation (6.1%), large hail (2.9%), and tornadoes (0.5%). Derechos had the largest coverage of severe wind reports (49.8%), while back-building QLCSs were the most prone to excessive precipitation events (13.5%). QLCSs caused 104 fatalities and 886 injuries. Severe wind gusts were responsible for 87.6% of fatalities and 73.6% of injuries. Nearly half of all fatalities and injuries were associated with only the 10 most impactful QLCS events, mostly warm-season derechos.
Southern Hemisphere Winter Storm Tracks Respond Differently to Low and High CO2 Forcings
Authors: Mitevski Ivan , Chemke Rei , Orbe Clara , Polvani Lorenzo M. 
Published: July 2024

Abstract
In the Southern Hemisphere, Earth system models project an intensification of winter storm tracks by the end of the twenty-first century. Previous studies using idealized models showed that storm track intensity saturates with increasing temperatures, suggesting that the intensification of the winter storm tracks might not continue further with increasing greenhouse gases. Here, we examine the response of midlatitude winter storm tracks in the Southern Hemisphere to increasing CO2 from two to eight times preindustrial concentrations in more realistic Earth system models. We find that at high CO2 levels (beyond 4×CO2), winter storm tracks no longer exhibit an intensification across the extratropics. Instead, they shift poleward, weakening the storm tracks at lower midlatitudes and strengthening at higher midlatitudes. By analyzing the eddy kinetic energy (EKE) budget, the nonlinear storm-track response to an increase in CO2 levels in the lower midlatitudes is found to stem from a scale-dependent conversion of eddy available potential energy to EKE. Specifically, in the lower midlatitudes, this energy conversion acts to oppositely change the EKE of long and short scales at low CO2 levels, but at high CO2 levels, it mostly reduces the EKE of shorter scales, resulting in a poleward shift of the storms. Furthermore, we identify a “tug of war” between the upper and lower temperature changes as the primary driver of the nonlinear-scale-dependent EKE response in the lower midlatitudes. Our results suggest that in the highest emission scenarios beyond the twenty-first century, the storm tracks’ response may differ in magnitude and latitudinal distribution from projected changes by 2100.

Significance Statement
The Southern Hemisphere winter storm track is projected to intensify by the end of the century, with the most significant intensification occurring in the higher midlatitudes. However, we show that the intensification is not a linear function of the radiative forcing associated with increasing CO2 levels. In fact, our study shows a poleward shift at very high CO2 levels, with the storm track moving southward. This suggests that the Southern Hemisphere winter storm track may require time-sensitive adaptation strategies, as the impacts of global warming on the storm track may not be a linear function of CO2 concentration in the atmosphere.
Multidecadal Variability from Ocean to Atmosphere in the North Atlantic: Perturbation Potential Energy as the Bridge
Authors: Zhao Hongyuan , Li Jianping , Liu Yuan , Delarme Emerson , Wang Ning 
Published: July 2024

Abstract
The North Atlantic Ocean forcings are considered an important origin of the North Atlantic atmospheric multidecadal variability. Here, we reveal the energetics mechanisms of the phenomenon using the perturbation potential energy (PPE) theory. Supporting the previous model studies, a cyclic pattern involving the Atlantic multidecadal oscillation (AMO) and the North Atlantic tripole (NAT) is observed: positive AMO phase (AMO+) → NAT− → AMO− → NAT+, with a phase lag of approximately 15–20 years. An atmospheric mode characterized by basinscale sea level pressure anomaly in the North Atlantic is associated with the AMO, which is termed the North Atlantic uniformity (NAU). The AMO+ induces positive uniform PPE anomalies over the ocean through precipitation heating, leading to decreased energy conversion to perturbation kinetic energy (PKE) and a large-scale anomalous cyclone. For the NAT+, tripolar precipitation anomalies result in tripolar PPE anomalies. Anomalous energy conversions occur where the PPE anomaly gradient is large, explained by an energy balance derived from thermal wind relationship. The PKE around 15° and 50°N (25° and 75°N) increases (decreases), forming the anomalous anticyclone and cyclone at subtropical and subpolar regions, respectively, known as the North Atlantic Oscillation (NAO). The reverse holds for the NAT− and AMO−. As the phases of the ocean modes alternate, the energetics induce the NAU−, NAO−, NAU+, and NAO+ sequentially. In the multidecadal cycle, the accumulated energetics process is related to delayed effect, and the difference in variance explanation between the NAU and NAO is attributed to the feedback mechanisms.

Significance Statement
The North Atlantic Ocean’s multidecadal changes affect the atmosphere above it. Our study explores the energy processes behind this phenomenon. The North Atlantic Ocean’s temperature distribution goes through a shift every 15–20 years, persistently affecting the air’s potential energy through the heat release related to vapor condensation. The changed potential energy converts into kinetic energy, causing the atmospheric circulation to alternate between different states. Our study provides a comprehensive explanation of how the ocean affects the region’s climate. This insight may contribute to making more accurate models and predictions of climate changes in the North Atlantic.
An Implementation of the Particle Flow Filter in an Atmospheric Model
Authors: Hu Chih-Chi , van Leeuwen Peter Jan , Anderson Jeffrey L. 
Published: July 2024

Abstract
The particle flow filter (PFF) shows promise for fully nonlinear data assimilation (DA) in high-dimensional systems. However, its application in atmospheric models has been relatively unexplored. In this study, we develop a new algorithm, PFF-DART, in order to conduct DA for high-dimensional atmospheric models. PFF-DART combines the PFF and the two-step ensemble filtering algorithm in the Data Assimilation Research Testbed (DART), exploiting the highly parallel structure of DART. To evaluate the performance of PFF-DART, we conduct an observing system simulation experiment (OSSE) in a simplified atmospheric general circulation model and compare the performance of PFF-DART with an existing linear and Gaussian DA method. Using the PFF-DART algorithm, we demonstrate, for the first time, the capability of the PFF to yield stable results in a yearlong cycling DA OSSE. Moreover, PFF-DART retains the important ability of the PFF to improve the assimilation of nonlinear and non-Gaussian observations. Finally, we emphasize that PFF-DART is a versatile algorithm that can be integrated with numerous other non-Gaussian DA techniques. This quality makes it a promising method for further investigation within a more sophisticated numerical weather prediction model in the future.

Significance Statement
Data assimilation is an important tool in weather forecasting. However, fundamental issues arising from linear and Gaussian approximations still exist, which can limit our utilization of observations. The particle flow filter is a promising method that avoids these approximations, but efficient algorithms for this method have yet to be developed. In this study, we develop an algorithm for the particle flow filter that can be implemented in high-dimensional geophysical models. We have demonstrated, for the first time, that the particle flow filter runs efficiently for a yearlong experiment in an atmospheric model. The new algorithm also improves the results over a commonly used data assimilation method. The results in this work demonstrate the potential usage of the particle flow filter in the weather forecasting and other high-dimensional forecasting problems.