bluuebunny/crossref_metadata_2025_split huggingface dataset:
ETS1, a Target Gene of the EWSR1::FLI1 Fusion Oncoprotein, Regulates the Expression of the Focal Adhesion Protein TENSIN3
Authors: Ebegboni Vernon Justice , Jones Tamara L. , Brownmiller Tayvia , Zhao Patrick X. , Pehrsson Erica C. , Sundara Rajan Soumya , Caplen Natasha J. 
Published: April 2024

Abstract
The mechanistic basis for the metastasis of Ewing sarcomas remains poorly understood, as these tumors harbor few mutations beyond the chromosomal translocation that initiates the disease. Instead, the epigenome of Ewing sarcoma cells reflects the regulatory state of genes associated with the DNA-binding activity of the fusion oncoproteins EWSR1::FLI1 or EWSR1::ERG. In this study, we examined the EWSR1::FLI1/ERG's repression of transcription factor genes, concentrating on those that exhibit a broader range of expression in tumors than in Ewing sarcoma cell lines. Focusing on one of these target genes, ETS1, we detected EWSR1::FLI1 binding and an H3K27me3-repressive mark at this locus. Depletion of EWSR1::FLI1 results in ETS1’s binding of promoter regions, substantially altering the transcriptome of Ewing sarcoma cells, including the upregulation of the gene encoding TENSIN3 (TNS3), a focal adhesion protein. Ewing sarcoma cell lines expressing ETS1 (CRISPRa) exhibited increased TNS3 expression and enhanced movement compared with control cells. Visualization of control Ewing sarcoma cells showed a distributed vinculin signal and a network-like organization of F-actin; in contrast, ETS1-activated Ewing sarcoma cells showed an accumulation of vinculin and F-actin toward the plasma membrane. Interestingly, the phenotype of ETS1-activated Ewing sarcoma cell lines depleted of TNS3 resembled the phenotype of the control cells. Critically, these findings have clinical relevance as TNS3 expression in Ewing sarcoma tumors positively correlates with that of ETS1.
Implications: ETS1’s transcriptional regulation of the gene encoding the focal adhesion protein TENSIN3 in Ewing sarcoma cells promotes cell movement, a critical step in the evolution of metastasis.
The Pan-RAF–MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS–MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers
Authors: Ryan Meagan B. , Quade Bradley , Schenk Natasha , Fang Zhong , Zingg Marshall , Cohen Steven E. , Swalm Brooke M. , Li Chun , Özen Ayşegül , Ye Chaoyang , Ritorto Maria Stella , Huang Xin , Dar Arvin C. , Han Yongxin , Hoeflich Klaus P. , Hale Michael , Hagel Margit 
Published: April 2024

Abstract
Alterations in the RAS–MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF–MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS–MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analyses of RAF–MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF–CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF–MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies, NST-628 is positioned to make an impact clinically in areas of unmet patient need.
Significance: This study introduces NST-628, a molecular glue having differentiated mechanism and drug-like properties. NST-628 treatment leads to broad efficacy with high tolerability and central nervous system activity across multiple RAS- and RAF-driven tumor models. NST-628 has the potential to provide transformative clinical benefits as both monotherapy and vertical combination anchor.
See first author Meagan B. Ryan discuss this research article, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932606757/4d0bd5aa98
Interplay Between Plasma Glycine and Branched-Chain Amino Acids Contributes to the Development of Hypertension and Coronary Heart Disease
Authors: Dziedzic Mateusz , Józefczuk Ewelina , Guzik Tomasz J. , Siedlinski Mateusz 
Published: April 2024

BACKGROUND:
Higher levels of plasma glycine are linked to a reduced risk, while increased levels of total branched-chain amino acids (tBCAAs) are associated with a higher risk of essential hypertension and coronary heart disease (CHD). As these metabolic components are interconnected, analyzing the tBCAAs/glycine ratio may help to understand their interplay in the pathogenesis of cardiovascular disease.

METHODS:

The Cox regression approach was combined with the development of novel genetic tools for assessments of associations between plasma metabolomic data (glycine, tBCAAs, and tBCAAs/glycine ratio) from the UK Biobank and the development of hypertension and CHD. Genome-wide association study was performed on 186 523 White UK Biobank participants to identify new independent genetic instruments for the 2-sample Mendelian randomization analyses.
P
-gain statistic >10 identified instruments associated with tBCAAs/glycine ratio significantly stronger compared with individual amino acids. Outcomes of genome-wide association study on hypertension and CHD were derived from the UK Biobank (nonoverlapping sample), FinnGen, and CARDIoGRAMplusC4D.

RESULTS:

The tBCAAs/glycine ratio was prospectively associated with a higher risk of developing hypertension and CHD (hazard ratio quintile Q5 versus Q1, 1.196 [95% CI, 1.109–1.289] and 1.226 [95% CI, 1.160–1.296], respectively). Mendelian randomization analysis demonstrated that tBCAAs/glycine ratio (
P
-gain >10) was a risk factor for hypertension (meta-analyzed inverse-variance weighted causal estimate 0.45 log odds ratio/SD (95% CI, 0.26–0.64) and CHD (0.48 [95% CI, 0.29–0.67]) with an absolute effect significantly larger compared with the effect of glycine (−0.06 [95% CI, −0.1 to −0.03] and −0.08 [95% CI, −0.11 to −0.05], respectively) or tBCAAs (0.22 [95% CI, 0.09–0.34] and 0.12 [95% CI, 0.01–0.24], respectively).

CONCLUSIONS:
The total BCAAs/glycine ratio is a key element of the metabolic signature contributing to hypertension and CHD, which may reflect biological pathways shared by glycine and tBCAAs.
Characteristics and Influencing Factors of Provincial Industrial Convergence Networks in China
Authors: Yuan Yuan , Han Guoying 
Published: April 2024

Abstract
The 20th National Congress of the Communist Party of China proposed accelerating the promotion of Chinese-style modernization, placing higher requirements on regional economic development. In this context, interregional industrial convergence has become a new driving force for achieving high-quality economic development and regional industrial transformation and upgrading. Using the 2017 interregional input-output table provided by Carbon Emission Accounts and Datasets (CEADs), this study constructs a directed weighted network from both the supply side and the demand side, with “province-industry” as the node and the real flow between industries as the edge weight. Network analysis is used to investigate the overall status of industrial convergence in China, as well as differences according to industry and region. Finally, an exponential random graph model (ERGM) is used to examine the influencing factors and effects of network formation. The results show the following: (1) the industrial convergence relationship between regions in China is transitive and reciprocal, and the overall tendency of the network is one in which output capacity is greater than absorption capacity. (2) The marginal flow of manufacturing and services occupies an absolute advantage in China’s industrial convergence network, in which mid-end manufacturing and producer services are the most prominent. (3) Industrial convergence between provinces has formed a hierarchical spatial layout of “output-conduction-absorption”. In the absorption layer, the breadth and depth of Beijing’s industrial integration are characterized by absorption-dominant development. In the output layer, Shanghai’s capital-intensive industries have a strong external radiation capacity and generally show open-led development. (4) Interregional industrial convergence tends to occur in areas with similar economic levels and output value levels, showing a coordinated development trend of high-level output and low-level absorption, which is also affected by location proximity relationships, regional technology gaps, and employment population gaps. This research shows that China’s inter-provincial industrial convergence network generally shows the characteristics of spatial hierarchy, significant industry differences and multi-factor drivers.
Efficiency or Fairness? Research on the Allocation of Energy Consumption and Carbon Emission Rights among Chinese Provinces
Authors: Lei Anqi , Zhang Te , Yang Li 
Published: April 2024

Abstract
Using a dynamic ZSG-SBM model under the common frontier, this paper allocates provincial energy consumption and carbon emission rights in China and conducts theoretical analysis and efficiency analysis from the perspective of balancing efficiency and fairness. The research results show that, under the allocation method that prioritizes efficiency, fossil energy consumption and carbon emission rights are significantly adjusted from the central and western regions to the economically developed eastern regions. Under the allocation model that considers fairness indicators, the net inflow of energy consumption and carbon emission rights from the eastern region is significantly reduced, with a greater focus on regional coordinated development, and a tendency to allocate more indicators to the relatively underdeveloped central and western regions in terms of energy consumption and carbon emissions. In addition, there is a significant regional difference in the initial technical efficiency gap between different regions, with the efficiency value in the eastern region significantly higher than that in the central and western regions. The allocation method that prioritizes efficiency can significantly improve energy consumption and carbon emission efficiency nationwide, but the allocation method that balances efficiency and fairness will cause some efficiency losses. Improving the national technical efficiency is the key to achieving the national “dual-carbon” and “dual-control” goals.
UFNet: Joint U-Net and Fully Connected Neural Network to Bias Correct Precipitation Predictions from Climate Models
Authors: Yu Shuang , Chakraborty Indrasis , Anderson Gemma J. , Lucas Donald D. , Lops Yannic , Galea Daniel 
Published: April 2024

Abstract
Precipitation values produced by climate models are biased due to the parameterization of physical processes and limited spatial resolution. Current bias-correction approaches usually focus on correcting lower-order statistics (mean and standard deviation), which make it difficult to capture precipitation extremes. However, accurate modeling of extremes is critical for policymaking to mitigate and adapt to the effects of climate change. We develop a deep learning framework, leveraging information from key dynamical variables impacting precipitation to also match higher-order statistics (skewness and kurtosis) for the entire precipitation distribution, including extremes. The deep learning framework consists of a two-part architecture: a U-Net convolutional network to capture the spatiotemporal distribution of precipitation and a fully connected network to capture the distribution of higher-order statistics. The joint network, termed UFNet, can simultaneously improve the spatial structure of the modeled precipitation and capture the distribution of extreme precipitation values. Using climate model simulation data and observations that are climatologically similar but not strictly paired, the UFNet identifies and corrects the climate model biases, significantly improving the estimation of daily precipitation as measured by a broad range of spatiotemporal statistics. In particular, UFNet significantly improves the underestimation of extreme precipitation values seen with current bias-correction methods. Our approach constitutes a generalized framework for correcting other climate model variables which improves the accuracy of the climate model predictions, while utilizing a simpler and more stable training process.
Simplified Approximations of Direct Cumulus Entrainment and Detrainment
Authors: Kirshbaum Daniel J. , Morrison Hugh , Peters John M. 
Published: April 2024

Abstract
In recent years, direct calculations of simulated cumulus entrainment and detrainment have facilitated new physical insights into these highly elusive but critically important processes. However, these calculations require substantial computational resources that may limit their widespread usage. To facilitate such calculations, two simplified approximations of direct cumulus entrainment and detrainment are examined herein. The first approximation, termed the “semidirect” method, follows a standard bulk approach but makes more realistic assumptions about the sources of entrained and detrained air near the cloud edges. In contrast, the second approximation (the “projection” method) uses the governing equations of motion to project whether grid points near the cloud edge will entrain or detrain as the mean cloud ascends by one grid point. Verification exercises using large-eddy simulations reveal that both methods generally agree better with corresponding direct entrainment/detrainment estimates than the traditional bulk formulation, with the projection method outperforming the semidirect method. The two methods can be used in a synergistic fashion, with the semidirect method helping to optimize the projection method, to suit a wide range of applications. Because the latter incorporates the essential dynamics of entrainment and detrainment at the local scale, it can be used to gain physical insight into the causal mechanisms regulating these complex processes.
Agroecology and Institutional Framework in Eastern Antioquia, Colombia: A Case Study
Authors: Mesa Valencia Andrés Felipe , Hendrickson Mary K. 
Published: April 2024

Agroecology promotes the formation of networks based on principles of closeness, trust, and collective action among participating actors and with external institutions and agencies. This institutionalized vertical power is based on hierarchical relationships, which impact access to resources, policy influence, and the ability to navigate bureaucratic systems. This qualitative case study aims to investigate the intersection between power relations and linking social capital to comprehend the challenges actors in agroecological supply chains face in accessing external resources and operating under the current legal framework governing food supply chains in Colombia. We present the case of agroecological networks in Eastern Antioquia to uncover the impact of their relationships on existing power dynamics within networks and associated institutions. Our findings suggest that social capital does not consistently facilitate the enhancement of associativity within agroecological chains. Moreover, it can function as a mechanism of oppression and promote the formation of exclusive and exclusionary groups. La agroecología promueve la formación de redes basadas en principios de cercanía, confianza y acción colectiva entre los actores participantes, así como con instituciones y agencias externas. Este poder vertical institucionalizado se basa en relaciones jerárquicas que afectan el acceso a los recursos al igual que la influencia que puedan tener las políticas y la capacidad de navegar por entramados burocráticos. Este estudio de caso de índole cualitativa tiene como propósito investigar la intersección entre las relaciones de poder y la vinculación del capital social para comprender los desafíos que enfrentan los actores de las cadenas de suministro agroecológicas que buscan acceder a recursos externos y operar bajo el marco legal que actualmente rige las cadenas de suministro alimentario en Colombia. Presentamos el caso de las redes agroecológicas en el Oriente antioqueño para estudiar el impacto de sus relaciones en las dinámicas de poder ya existentes dentro de las redes e instituciones asociadas. Nuestros hallazgos sugieren que el capital social no facilita la mejoría de la asociatividad dentro de las cadenas agroecológicas de manera consistente. Además, puede fungir como un mecanismo de opresión y promover la formación de grupos exclusivos y excluyentes.
Optokinetic stimulation in the rehabilitation of visually induced dizziness in people with vestibular disorders: A systematic review
Authors: Law Jessica HJ , Koh Hui Ying , Kua Agnes 
Published: April 2024

Objective This systematic review and meta-analysis investigates the effects optokinetic stimulation in people with vestibular disorders, with a specific focus on people with visually induced dizziness. Data sources A systematic review was conducted using three electronic databases, CINAHL, PubMed and Physiotherapy Evidence Database (PEDro), from 2000 up to February 2024. Review methods Randomised controlled trials were included, which compared: (a) adults above 18 years old with vestibular disorders, (b) the study evaluated interventions using optokinetic stimulation, (c) the intervention was compared with usual care; placebo or to no intervention, (d) the study included at least one outcome measure evaluating vestibular symptoms and (e) published in English. The methodological quality of the included studies was assessed using the PEDro scale and PROSPERO's registration number ID: CRD42021273382). Results Eleven randomised control trials, reported in 12 records, fulfilled the inclusion criteria. All of the studies were considered to have ‘good’ methodological quality according to the PEDro scale. All studies showed significant improvement in vestibular symptoms in both the intervention and control groups. A meta-analysis performed on six of the records found a preference towards the addition of OKS to conventional vestibular rehabilitation helped to further reduce dizziness symptoms for patients, but the results were not statistically significant. Conclusion No optimal duration or frequency for OKS has been determined. The addition of OKS to conventional vestibular rehabilitation may be beneficial in further improving vestibular symptoms in patients with dizziness. OKS could help to improve enjoyment and adherence to vestibular rehabilitation.
Can coracoacromial ligament degeneration be evaluated with preoperative MRI?
Authors: Özdemir Faruk , Ayanoğlu Tacettin , Dağıstan Emine , Kalaycıoğlu Oya , Çelik İlhan , Kalfaoğlu Melike Elif , Kanatlı Ulunay 
Published: April 2024

Background Subacromial impingement syndrome is one of the most common causes of painful shoulder in the middle-aged and elderly population. Coracoacromial ligament (CAL) degeneration is a well-known indicator for subacromial impingement. Purpose To examine the relationship between CAL thickness on preoperative magnetic resonance imaging (MRI), arthroscopic CAL degeneration and types of rotator cuff tears. Material and Methods Video records of patients who underwent arthroscopic shoulder surgery between 2015 and 2021 were retrospectively scanned through the hospital information record system. In total, 560 patients were included in this study. Video records of the surgery were used to evaluate the grade of coracoacromial ligament degeneration and the type of cuff tear. Preoperative MRI was used to measure CAL thickness, acromiohumeral distance, critical shoulder angle, acromial index, and acromion angulation. Results Significant differences were observed between grades of CAL degeneration in terms of CAL thickness ( P < 0.001). As CAL degeneration increases, the mean of CAL thickness decreases. According to the results of post-hoc analysis, the mean CAL thickness of normal patients was significantly higher than those of patients with full-thickness tears ( P = 0.024) and massive tears ( P <0.001). Patients with articular-side, bursal-side, and full-thickness tears had significantly higher CAL thickness averages than patients with massive tears. Conclusion This study showed that the CAL thickness decreases on MRI as arthroscopic CAL degeneration increases. High-grade CAL degeneration and therefore subacromial impingement syndrome can be predicted by looking at the CAL thickness in MRI, which is a non-invasive method.
End-of-life care at home: Dignity of family caregivers
Authors: Staats Katrine , Jeppestøl Kristin , Søvde Bente Egge , Brenne Bodil Aarmo , Tarberg Anett Skorpen 
Published: April 2024

Background Healthcare services are increasingly being shifted to home settings for patients nearing end-of-life. Consequently, the burden on family caregivers is significant. Their vulnerable situation remains poorly understood and there is little information available regarding their experiences of dignity. Aim This study seeks to understand the experiences of family caregivers related to dignity and loss of dignity, aiming to provide a deeper insight into their situation when caring for a home-dwelling family member nearing end-of-life. Research design and participants This exploratory study consists of a second analysis combining data from two primary studies, including 24 family caregivers of a family member nearing end-of-life, and is founded upon Gadamer’s philosophical hermeneutics. Ethical considerations Approval was obtained from the Norwegian Agency for Shared Services in Education and Research and was based on voluntary participation, informed consent, and confidentiality. Results The following three main themes were identified: Having a meaningful existence within the living environment, being seen and valued as a family caregiver in relation with others and suffering in a space of loneliness. These contextual, relational, and existential perspectives were found to be closely interrelated. Conclusion and final considerations The dignity of family caregivers was closely tied to being seen as unique individuals, not merely caregivers, thereby requiring healthcare professionals (HCPs) to understand their personal needs. This study highlights the emotional distress and loneliness family caregivers feel in their dual role within the healthcare system, thereby calling for HCPs to adopt an attitude of gentleness and recognition to impart dignity-preserving care in homecare practices.