bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutant KRAS Downregulates the Receptor for Leukemia Inhibitory Factor (LIF) to Enhance a Signature of Glycolysis in Pancreatic Cancer and Lung Cancer
Authors: Liu Suhu , Gandler Helen I. , Tošić Isidora , Ye Darwin Q. , Giaccone Zachary T. , Frank David A. 
Published: April 2021

Abstract

Pancreatic cancer is characterized by aberrant activity of oncogenic KRAS, which is mutated in 90% of pancreatic adenocarcinomas. Because KRAS itself is a challenging therapeutic target, we focused on understanding key signaling pathways driven by KRAS as a way to reveal dependencies that are amenable to therapeutic intervention. Analyses in primary human pancreatic cancers and model systems revealed that the receptor for the cytokine leukemia inhibitory factor (LIF) is downregulated by mutant KRAS. Furthermore, downregulation of the LIF receptor (LIFR) is necessary for KRAS-mediated neoplastic transformation. We found LIFR exerts inhibitory effects on KRAS-mediated transformation by inhibiting expression of the glucose transporter GLUT1, a key mediator of the enhanced glycolysis found in KRAS-driven malignancies. Decreased LIFR expression leads to increased GLUT1 as well as increases in glycolysis and mitochondrial respiration. The repression of GLUT1 by LIFR is mediated by the transcription factor STAT3, indicating a tumor-suppressive role for STAT3 within cancer cells with mutated KRAS. Finally, reflecting a clinically important tumor-suppressive role of LIFR, decreased LIFR expression correlates with shorter survival in pancreatic cancer patients with mutated KRAS. Similar findings were found in non–small cell lung cancers driven by mutated KRAS, suggesting that silencing LIFR is a generalized mechanism of KRAS-mediated cellular transformation. These results indicate that the LIFR/STAT3 pathway may mediate either tumor-promoting or tumor-suppressive signaling pathways depending on the genetic background of tumor cells, and may play diverse roles within other cells in the tumor microenvironment.

Implications:
Mutant KRAS drives downregulation of the receptor for LIF, thereby allowing an increase in expression of the glucose transporter GLUT1 and increases in glycolysis and mitochondrial respiration.
Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy
Authors: Feyen Dries A.M. , Perea-Gil Isaac , Maas Renee G.C. , Harakalova Magdalena , Gavidia Alexandra A. , Arthur Ataam Jennifer , Wu Ting-Hsuan , Vink Aryan , Pei Jiayi , Vadgama Nirmal , Suurmeijer Albert J. , te Rijdt Wouter P. , Vu Michelle , Amatya Prashila L. , Prado Maricela , Zhang Yuan , Dunkenberger Logan , Sluijter Joost P.G. , Sallam Karim , Asselbergs Folkert W. , Mercola Mark , Karakikes Ioannis 
Published: April 2021

Background:
Phospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in PLN (R14del) is associated with dilated cardiomyopathy with a high prevalence of ventricular arrhythmias. How the R14 deletion causes dilated cardiomyopathy is poorly understood, and there are no disease-specific therapies.

Methods:
We used single-cell RNA sequencing to uncover PLN R14del disease mechanisms in human induced pluripotent stem cells (hiPSC-CMs). We used both 2-dimensional and 3-dimensional functional contractility assays to evaluate the impact of modulating disease-relevant pathways in PLN R14del hiPSC-CMs.

Results:
Modeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs recapitulated the contractile deficit associated with the disease in vitro. Single-cell RNA sequencing revealed the induction of the unfolded protein response (UPR) pathway in PLN R14del compared with isogenic control hiPSC-CMs. The activation of UPR was also evident in the hearts from PLN R14del patients. Silencing of each of the 3 main UPR signaling branches (IRE1, ATF6, or PERK) by siRNA exacerbated the contractile dysfunction of PLN R14del hiPSC-CMs. We explored the therapeutic potential of activating the UPR with a small molecule activator, BiP (binding immunoglobulin protein) inducer X. PLN R14del hiPSC-CMs treated with BiP protein inducer X showed a dose-dependent amelioration of the contractility deficit in both 2-dimensional cultures and 3-dimensional engineered heart tissues without affecting calcium homeostasis.

Conclusions:
Together, these findings suggest that the UPR exerts a protective effect in the setting of PLN R14del cardiomyopathy and that modulation of the UPR might be exploited therapeutically.
IL33 (Interleukin 33)/ST2 (Interleukin 1 Receptor-Like 1) Axis Drives Protective Microglial Responses and Promotes White Matter Integrity After Stroke
Authors: Xie Di , Liu Huan , Xu Fei , Su Wei , Ye Qing , Yu Fang , Austin Taylor J. , Chen Jun , Hu Xiaoming 
Published: April 2021

Background and Purpose:
Emerging evidence highlights the importance of IL33 (interleukin 33) and its receptor (ST2 [interleukin 1 receptor-like 1]) in normal brains and neurological disorders. This study explores the function of the IL33/ST2 signaling axis and a transcription factor STAT6 (signal transducer and activator of transcription 6) in white matter integrity and long-term recovery after stroke.

Methods:

Transient middle cerebral artery occlusion was induced in wild type, ST2 knockout, STAT6 knockout, and microglia/macrophage-depleted (by PLX5622 diet) mice. Sensorimotor and cognitive functions were evaluated. White matter integrity was measured by immunofluorescent staining, diffusion tensor imaging, electron microscopy, and electrophysiology. The death of oligodendrocytes and its precursor cells (OPC) and the microglia/macrophage responses were evaluated 3 days after stroke. Primary microglia-oligodendrocyte/OPC cocultures were used for mechanistic studies. Parametric tests (Student
t
test or ANOVA) or nonparametric Mann-Whitney
U
test were used for statistical analysis based on the numbers of groups, types of variables, and the structure of each data set.

Results:
ST2 deficiency exacerbates sensorimotor and cognitive deficits for 28 days after middle cerebral artery occlusion compared with wild-type mice, which was accompanied by deteriorated structural damages and impaired conduction of compound action potentials in white matter. ST2 knockout mice displayed increased death of oligodendrocytes and OPCs, and a concomitant exacerbation in neuroinflammation 3 days after stroke. Using microglia/macrophage-depleted mice and microglia-oligodendrocyte/OPC cocultures, we showed that IL33 protected oligodendrocytes and OPCs against ischemic injury in a microglia/macrophage dependent manner. Further mechanistic studies identified STAT6 as a molecule that mediates the protective effects of IL33/ST2 on oligodendrocytes in the ischemic brain. IL33 treatment failed to rescue oligodendrocytes and OPCs after stroke in STAT6 knockout mice.

Conclusions:
These results shed light on the IL33/ST2/STAT6 signaling as a potential immune regulatory mechanism to modulate microglia/macrophage activity, improve white matter integrity, and restore long-term neurological functions after stroke.
Changes in the Subantarctic Mode Water Properties and Spiciness in the Southern Indian Ocean based on Argo Observations
Authors: ZHANG Ying , DU Yan , QU Tangdong , HONG Yu , DOMINGUES Catia M. , FENG Ming 
Published: April 2021

AbstractThe Subantarctic Mode Water (SAMW) plays an essential role in the global heat, freshwater, carbon, and nutrient budgets. In this study, decadal changes in the SAMW properties in the Southern Indian Ocean (SIO) and associated thermodynamic and dynamic processes are investigated during the Argo era. Both temperature and salinity of the SAMW in the SIO show increasing trends during 2004-2018. A two-layer structure of the SAMW trend, with more warm and salty light SAMW but less cool and fresh dense SAMW, is identified. The heaving and spiciness processes are important but have opposite contributions to the temperature and salinity trends of the SAMW. A significant deepening of isopycnals (heaving), peaking atσθ=26.7-26.8 kg m−3in the middle layer of the SAMW, expands the warm and salty light SAMW and compresses the cool and fresh dense SAMW corresponding to the change in subduction rate during 2004-2018. The change in the SAMW subduction rate is dominated by the change in the mixed layer depth, controlled by the changes in wind stress curl and surface buoyancy loss. An increase in the mixed-layer temperature due to weakening northward Ekman transport of cool water leads to a lighter surface density in the SAMW formation region. Consequently, density outcropping lines in the SAMW formation region shift southward and favor the intrusion and entrainment of the cooler and fresher Antarctic surface water from the south, contributing to the cooling/freshening trend of isopycnals (spiciness). Subsequently, the cooler and fresher SAMW spiciness anomalies spread in the SIO via the subtropical gyre.
On the Performance of Airborne Meteorological Observations Against Other In-situ Measurements
Authors: Wagner Timothy J. , Petersen Ralph A. 
Published: April 2021

AbstractRoutine in situ observations of the atmosphere taken in flight by commercial aircraft provide atmospheric profiles with greater temporal density and, in many parts of the country, at more locations than the operational radiosonde network. Thousands of daily temperature and wind observations are provided by largely complementary systems, the Airborne Meteorological Data Relay (AMDAR) and the Tropospheric Airborne Meteorological Data Reporting (TAMDAR). All TAMDAR aircraft also measure relative humidity while a subset of AMDAR aircraft are equipped with the Water Vapor Sensing System (WVSS) measure specific humidity.One year of AMDAR/WVSS and TAMDAR observations are evaluated against operational National Weather Service (NWS) radiosondes to characterize the performance of these systems in similar environments. For all observed variables, AMDAR reports showed both smaller average differences and less random differences with respect to radiosondes than the corresponding TAMDAR observations. Observed differences were not necessarily consistent with known radiosonde biases. Since the systems measure different humidity variables, moisture is evaluated in both specific and relative humidity using both aircraft and radiosonde temperatures to derive corresponding moisture variables. Derived moisture performance is improved when aircraft-based temperatures are corrected prior to conversion. AMDAR observations also show greater consistency between different aircraft than TAMDAR observations do. The small variability in coincident WVSS humidity observations indicates that they may prove more reliable than humidity observations from NWS radiosondes.
Suicide crisis calls to emergency services: Cohort profile and findings from a data linkage study in Queensland, Australia
Authors: Meurk Carla , Wittenhagen Lisa , Bosley Emma , Steele Megan L , Bunting Denise , Waterson Elissa , Edwards Bronwen , Martain Ben , Heffernan Ed 
Published: April 2021

Background and Aims: Police and paramedics play a crucial role in responding to suicide crises in the community. However, little is known about the nature, extent, precipitating factors, pathways and outcomes of a suicide-related call to emergency services and what responses will most effectively and compassionately meet the needs of those in crisis. Partners in Prevention: Understanding and Enhancing First Responses to Suicide Crisis Situations (PiP) was established to address these knowledge gaps. Methods: This article describes (1) the methodology used to construct the PiP dataset, a population-wide linked dataset that investigates the characteristics and health pathways of individuals in Queensland who were the subject of a suicide-related call to police or paramedics; and (2) preliminary findings on service demand, demographics and health services utilisation. Results: We identified 219,164 suicide-related calls to Queensland Police Service or Queensland Ambulance Service that were made over the 3-year period 1 February 2014 to 31 January 2017. A total of 70,893 individuals were identifiable via records linkage. The cohort linked to more than 7,000,000 health records. We estimated that police or paramedics in Queensland received on average 209 calls per day, with increases year on year over the study period. Analysis of demographic data highlighted the heterogeneous nature of this cohort and important demographic variations between individuals in contact with police versus ambulance services. Discussion: The PiP dataset provides a strong foundation for a multi-modal dataset that can be built on over time, both cross-sectionally and longitudinally. Further linkages to Medicare Benefits Schedule, Pharmaceutical Benefits Scheme and social care datasets are planned. Conclusion: Detailed population-level analysis that data linkage can provide is critical to improving understanding and responses to suicide crisis situations. The PiP study is a world first and provides a unique opportunity to improve responses to this public health problem.
3D Modeling of Blood Flow in Simulated Abdominal Aortic Aneurysm
Authors: Gonzalez-Urquijo Mauricio , de Zamacona Raul Garza , Mendoza Ana Karen Martinez , Iribarren Miranda Zamora , Ibarra Erika Garza , Bencomo Marcos David Moya , Fabiani Mario Alejandro 
Published: April 2021

Background: Besides biological factors, abdominal aortic aneurysm rupture is also caused by mechanical parameters, which are constantly affecting the wall’s tissue due to their abnormal values. The ability to evaluate these parameters could vastly improve the clinical treatment of patients with abdominal aortic aneurysms. The objective of this study was to develop and demonstrate a methodology to analyze the fluid dynamics that cause the wall stress distribution in abdominal aortic aneurysms, using accurate 3D geometry and a realistic, nonlinear, elastic biomechanical model using a computer-aided software. Methods: The geometry of the abdominal aortic aneurysm; was constructed on a 3D scale using computer-aided software SolidWorks (Dassault Systems SolidWorksCorp., Waltham MA). Due to the complex nature of the abdominal aortic aneurysm geometry, the physiological forces and constraints acting on the abdominal aortic aneurysm wall were measured by using a simulation setup using boundary conditions and initial conditions for different studies such as finite element analysis or computational fluid dynamics. Results: The flow pattern showed an increase velocity at the angular neck, followed by a stagnated flow inside the aneurysm sack. Furthermore, the wall shear stress analysis showed to focalized points of higher stress, the top and bottom of the aneurysm sack, where the flow collides against the wall. An increase of the viscosity showed no significant velocity changed but results in a slight increase in overall pressure and wall shear stress. Conclusions: Conducting computational fluid dynamics modeling of the abdominal aortic aneurysm using computer-aided software SolidWorks (Dassault Systems SolidWorksCorp., Waltham MA) proves to be an insightful approach for the clinical setting. The careful consideration of the biomechanics of the abdominal aortic aneurysm may lead to an improved, case-specific prediction of the abdominal aortic aneurysm rupture potential, which could significantly improve the clinical management of these patients.
Serum-derived exosomes containing NEAT1 promote the occurrence of rheumatoid arthritis through regulation of miR-144-3p/ROCK2 axis
Authors: Liu Rui , Jiang Chunbo , Li Jingjing , Li Xiaoru , Zhao Lin , Yun Haifeng , Xu Weiwei , Fan Weijian , Liu Qiuhong , Dong Hongli 
Published: April 2021

Background: Evidence has demonstrated that non-coding RNAs (ncRNAs) could be delivered efficiently to recipient cells using exosomes as a carrier. Additionally, long ncRNA nuclear enriched abundant transcript 1 (NEAT1) is emerging as a vital regulatory molecule in the progression of rheumatoid arthritis (RA). The aim of this study was to identify the NEAT1/miR-144-3p/Rho-associated protein kinase 2 (ROCK2) functional network regulating the WNT signaling pathway in RA. Methods: In vivo, a collagen-induced arthritis (CIA) model was established to analyze the effects of blood exosomes on the incidence, clinical score, and bone degradation of RA. In vitro, the CD4+T cells were characterized by flow cytometry and the cell activities were analyzed in the presence of exosome treatment alone or in combination with altered expression of NEAT1, miR-144-3p or Rho-associated protein kinase 2 (ROCK2). The expression of NEAT1, miR-144-3p, ROCK2, and corresponding proteins in the WNT signaling pathway was detected by RT-qPCR and western blot techniques. The binding profile of NEAT1 to miR-144-3p was evaluated via a combination approach of luciferase activity assay, RNA immunoprecipitation, and RNA pull-down experiments. Results: Blood exosomes extracted from RA patients increased the incidence of RA and bone destruction significantly. Overexpression of NEAT1 or ROCK2 promoted immune cell (CD4+T cells) proliferation, Th17 cell differentiation, and cell migration in response to stimulus, whereas knockout of the NEAT1 gene induced the expression of miR-144-3p in CD4+T cells. ROCK2 exogenous expression inhibited the expression of miR-144-3p, inducing activation of the WNT signaling pathway. Conclusion: A novel regulatory pathway NEAT1/miR-144-3p/ROCK2/WNT in RA was investigated as a potential target for RA therapy.
Effects of an eHealth Intervention on Patient-Provider Interaction and Functional Health Literacy in Adults With Hypertension
Authors: Hickman Ronald L. , Clochesy John M. , Alaamri Marym 
Published: April 2021

Introduction Hypertension is a life-limiting, chronic condition affecting millions of Americans. Modifiable factors, quality of the patient-provider interaction and functional health literacy, have been linked to effective hypertension self-management. However, there has been limited interventional research targeting these modifiable factors. Electronic hypertension self-management interventions, in particular those incorporating virtual simulation, may positively influence the quality of the patient-provider interaction and functional health literacy status of adults with hypertension. Yet there is a dearth of evidence examining the efficacy of eHealth interventions targeting these modifiable factors of hypertension self-management. Objective Evaluate the effects of two electronic hypertension self-management interventions on the quality of the patient-provider interaction and functional health literacy in adults with hypertension. Methods A convenience sample of community-dwelling adults (>18 years) with hypertension were recruited and randomized to an avatar-based simulation (eSMART-HTN) or a video presentation on hypertension self-management (attention control). Participants were administered questionnaires to capture demographic characteristics, the quality of the patient-provider interaction, and functional health literacy. Questionnaire data were collected at baseline, and then monthly across three months. Two separate repeated measures analysis of covariance models were conducted to assess the effects of the interventions across the time points. Results The sample included 109 participants who were predominately middle-aged and older, nonwhite, and female. Scores for the quality of the patient-provider interaction demonstrated significant within-group changes across time. However, there were no significant differences in the quality of the patient-provider interaction or functional health literacy scores between experimental conditions while adjusting for covariates. Conclusion An avatar-based simulation (eSMART-HTN) intervention proved to have a positive effect on patient-provider interaction compared to an attention control condition. Although the results are promising, future research is needed to optimize the effectiveness of eSMART-HTN and enhance its efficacy and scalability in a larger cohort of adults with hypertension.
Reopening Oral Health Services during the COVID-19 Pandemic through a Knowledge Exchange Coalition
Authors: McNally M. , Rock L. , Gillis M. , Bryan S. , Boyd C. , Kraglund F. , Cleghorn B. 
Published: April 2021

Background: The COVID-19 novel coronavirus closed oral health care in Nova Scotia (NS) Canada in March 2020. Preparing for a phased reopening, a knowledge exchange coalition (representing government, academia, hospitals, oral health professions, and regulators) developed return-to-work (RTW) guidelines detailing the augmentation of standard practices to ensure safety for patients, oral health care providers (OHPs), and the community. Using online surveys, this study explored the influence of the RTW guidelines and related education on registered NS OHPs during a phased return to work. Methods: Dissemination of R2W guidelines included website or email communiques and interdisciplinary education webinars that coincided with 2 RTW phases approved by the government. Aligned with each phase, all registered dentists, dental hygienists, and dental assistants were invited to complete an online survey to gauge the influence of the coalition-sponsored education and RTW guidelines, confidence, preparedness, and personal protective equipment use before and after the pandemic. Results: Three coalition-sponsored multidisciplinary webinars hosted 3541 attendees prior to RTW. The response to survey 1 was 41% (881/2156) and to survey 2 was 26% (571/2177) of registrants. Survey 1 (82%) and survey 2 (89%) respondents “agreed/strongly agreed” that R2W guidelines were a primary source for guiding return to practice, and most were confident with education received and had the skills needed to effectively treat patients during the COVID-19 pandemic. Confidence and preparedness improved in survey 2. Gowns/lab coat use for aerosol-generating procedures increased from 26% to 93%, and the use of full face shields rose from 6% to 93% during the pandemic. Conclusions: A multistakeholder coalition was effective in establishing and communicating comprehensive guidelines and web-based education to ensure unified reintegration of oral health services in NS during a pandemic. This multiorganizational cooperation lay the foundation for responses to subsequent waves of COVID-19 and may serve as an example for collaboratively responding to future public health threats in other settings. Knowledge Transfer Statement: The return-to-work strategy that was developed, disseminated, and assessed through this COVID-19 knowledge exchange coalition will benefit oral health practitioners, professional regulators, government policy makers, and researchers in future pandemic planning.