bluuebunny/crossref_metadata_2025_split huggingface dataset:
From Fluid Flow to Coupled Processes in Fractured Rock: Recent Advances and New Frontiers
Authors: Viswanathan H. S. , Ajo‐Franklin J. , Birkholzer J. T. , Carey J. W. , Guglielmi Y. , Hyman J. D. , Karra S. , Pyrak‐Nolte L. J. , Rajaram H. , Srinivasan G. , Tartakovsky D. M. 
Published: February 2022

AbstractQuantitative predictions of natural and induced phenomena in fractured rock is one of the great challenges in the Earth and Energy Sciences with far‐reaching economic and environmental impacts. Fractures occupy a very small volume of a subsurface formation but often dominate fluid flow, solute transport and mechanical deformation behavior. They play a central role in CO2 sequestration, nuclear waste disposal, hydrogen storage, geothermal energy production, nuclear nonproliferation, and hydrocarbon extraction. These applications require predictions of fracture‐dependent quantities of interest such as CO2 leakage rate, hydrocarbon production, radionuclide plume migration, and seismicity; to be useful, these predictions must account for uncertainty inherent in subsurface systems. Here, we review recent advances in fractured rock research covering field‐ and laboratory‐scale experimentation, numerical simulations, and uncertainty quantification. We discuss how these have greatly improved the fundamental understanding of fractures and one's ability to predict flow and transport in fractured systems. Dedicated field sites provide quantitative measurements of fracture flow that can be used to identify dominant coupled processes and to validate models. Laboratory‐scale experiments fill critical knowledge gaps by providing direct observations and measurements of fracture geometry and flow under controlled conditions that cannot be obtained in the field. Physics‐based simulation of flow and transport provide a bridge in understanding between controlled simple laboratory experiments and the massively complex field‐scale fracture systems. Finally, we review the use of machine learning‐based emulators to rapidly investigate different fracture property scenarios and accelerate physics‐based models by orders of magnitude to enable uncertainty quantification and near real‐time analysis.
Packing Fraction, Tortuosity, and Permeability of Granular‐Porous Media With Densely Packed Spheroidal Particles: Monodisperse and Polydisperse Systems
Authors: Xu Wenxiang , Zhang Kaixing , Zhang Yufeng , Jiang Jinyang 
Published: February 2022

AbstractThe geometrical and topological configurations of particles have great influences on their surrounding pore tortuosity and the permeability of granular‐porous media. In this work, we develop a relaxation iteration scheme to create random dense packings of different anisotropic‐shaped spheroidal particles with monodispersity and polydispersity in sizes, which manifest the effects of particle shape, fineness, and size distribution on the random packing fraction of particles. Subsequently, we propose a direction‐guided rapidly exploring random tree (DGRRT) algorithm to probe the geometrical tortuosity of complex pore space interstitial to spheroidal particles. A non‐linear pore tortuosity prediction model that relies on the specific surface area and packing fraction of particles, is developed to suit for polydisperse and monodisperse spheroidal particle systems. We further investigate the permeability of granular‐porous media through the lattice Boltzmann method (LBM) of fluid flow. These proposed methods can accurately predict the tortuosity and permeability by comparing against available experimental, theoretical, and numerical results reported in literature. Moreover, the effects of particle packing fraction (i.e., porosity), shape, fineness, and size distribution on the pore tortuosity and permeability of granular‐porous media are evaluated. The results reveal that these microstructural configurations have important influences on the permeability and tortuosity. Our results give an intrinsic interplay between the geometrical tortuosity and permeability of monodisperse and polydisperse particle systems, which have implications for a broad range of scientific disciplines, including the properties of rocks, sandstones and soils, and the design of ultra‐high performance concrete.
Absence of a sexual dimorphism in postprandial glucose metabolism after administration of a balanced mixed meal in healthy young volunteers
Authors: Leone Alessandro , De Amicis Ramona , Bertoli Simona , Spadafranca Angela , De Carlo Giulia , Battezzati Alberto 
Published: February 2022

Abstract
Background/Objectives
A different ability to regulate glucose homeostasis between men and women may contribute to their difference in diabetes prevalence and in its predisposing conditions. Data on this issue are controversial because of heterogeneous protocols and insufficient control of confounders affecting glucose metabolism like age, body composition, and physical activity level. To clarify this issue, we compared among sexes the postprandial glucose metabolism after the administration of a balanced mixed meal normalized to daily energy expenditure.

Subjects/Methods
Thirty-six healthy young volunteers (18 men and 18 women; age, 23.9 ± 2.8 years; BMI, 21.9 ± 1.7 kg/m2) were recruited for the experiment. After overnight fast, subjects consumed a mixed meal providing 40% of daily energy expenditure (60% carbohydrates, 25% lipids, 15% proteins) estimated multiplying resting energy expenditure, obtained by Harris & Benedict equation, for the corresponding physical activity level. Blood was sampled at 0, 10, 20, 30, 45, 60, 90, 120, and 180 min and serum concentrations of glucose, insulin, and C-peptide were measured.

Results
Fasting serum glucose concentrations were lower in women than in men, while fasting insulin and C-peptide concentrations did not differ between sexes. Linear mixed models did not show any significant effect of sex and sex # time interaction on postprandial serum glucose, insulin, and C-peptide concentrations. The comparison of areas under the curve between the sexes revealed similar glycemic, insulinemic, and C-peptide postprandial responses between men and women.

Conclusions
Our results do not support the hypothesis of a sexual dimorphism in the regulation of carbohydrate metabolism in young when a mixed meal normalized on individual daily energy expenditure is ingested.
EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastoma
Authors: Gai Qu-Jing , Fu Zhen , He Jiang , Mao Min , Yao Xiao-Xue , Qin Yan , Lan Xi , Zhang Lin , Miao Jing-Ya , Wang Yan-Xia , Zhu Jiang , Yang Fei-Cheng , Lu Hui-Min , Yan Ze-Xuan , Chen Fang-Lin , Shi Yu , Ping Yi-Fang , Cui You-Hong , Zhang Xia , Liu Xindong , Yao Xiao-Hong , Lv Sheng-Qing , Bian Xiu-Wu , Wang Yan 
Published: February 2022

AbstractPlatelet-derived growth subunit A (PDGFA) plays critical roles in development of glioblastoma (GBM) with substantial evidence from TCGA database analyses and in vivo mouse models. So far, only platelet-derived growth receptor α (PDGFRA) has been identified as receptor for PDGFA. However, PDGFA and PDGFRA are categorized into different molecular subtypes of GBM in TCGA_GBM database. Our data herein further showed that activity or expression deficiency of PDGFRA did not effectively block PDGFA activity. Therefore, PDGFRA might be not necessary for PDGFA function.To profile proteins involved in PDGFA function, we performed co-immunoprecipitation (Co-IP) and Mass Spectrum (MS) and delineated the network of PDGFA-associated proteins for the first time. Unexpectedly, the data showed that EPHA2 could be temporally activated by PDGFA even without activation of PDGFRA and AKT. Furthermore, MS, Co-IP, in vitro binding thermodynamics, and proximity ligation assay consistently proved the interaction of EPHA2 and PDGFA. In addition, we observed that high expression of EPHA2 leaded to upregulation of PDGF signaling targets in TCGA_GBM database and clinical GBM samples. Co-upregulation of PDGFRA and EPHA2 leaded to worse patient prognosis and poorer therapeutic effects than other contexts, which might arise from expression elevation of genes related with malignant molecular subtypes and invasive growth. Due to PDGFA-induced EPHA2 activation, blocking PDGFRA by inhibitor could not effectively suppress proliferation of GBM cells, but simultaneous inhibition of both EPHA2 and PDGFRA showed synergetic inhibitory effects on GBM cells in vitro and in vivo. Taken together, our study provided new insights on PDGFA function and revealed EPHA2 as a potential receptor of PDGFA. EPHA2 might contribute to PDGFA signaling transduction in combination with PDGFRA and mediate the resistance of GBM cells to PDGFRA inhibitor. Therefore, combination of inhibitors targeting PDGFRA and EHA2 represented a promising therapeutic strategy for GBM treatment.
Cultivation and biogeochemical analyses reveal insights into methanogenesis in deep subseafloor sediment at a biogenic gas hydrate site
Authors: Katayama Taiki , Yoshioka Hideyoshi , Kaneko Masanori , Amo Miki , Fujii Tetsuya , Takahashi Hiroshi A , Yoshida Satoshi , Sakata Susumu 
Published: February 2022

Abstract
Gas hydrates deposited in subseafloor sediments are considered to primarily consist of biogenic methane. However, little evidence for the occurrence of living methanogens in subseafloor sediments has been provided. This study investigated viable methanogen diversity, population, physiology and potential activity in hydrate-bearing sediments (1–307 m below the seafloor) from the eastern Nankai Trough. Radiotracer experiments, the quantification of coenzyme F430 and molecular sequencing analysis indicated the occurrence of potential methanogenic activity and living methanogens in the sediments and the predominance of hydrogenotrophic methanogens followed by methylotrophic methanogens. Ten isolates and nine representative culture clones of hydrogenotrophic, methylotrophic and acetoclastic methanogens were obtained from the batch incubation of sediments and accounted for 0.5–76% of the total methanogenic sequences directly recovered from each sediment. The hydrogenotrophic methanogen isolates of Methanocalculus and Methanoculleus that dominated the sediment methanogen communities produced methane at temperatures from 4 to 55 °C, with an abrupt decline in the methane production rate at temperatures above 40 °C, which is consistent with the depth profiles of potential methanogenic activity in the Nankai Trough sediments in this and previous studies. Our results reveal the previously overlooked phylogenetic and metabolic diversity of living methanogens, including methylotrophic methanogenesis.
Hypoxia-induced lncRNA RBM5-AS1 promotes tumorigenesis via activating Wnt/β-catenin signaling in breast cancer
Authors: Li Xinping , Yang Jingyan , Ni Ruiqi , Chen Jintian , Zhou Yanhao , Song Hao , Jin Liang , Pan Yi 
Published: February 2022

AbstractBreast cancer is the most common malignancy among women across the globe. Recent studies have revealed that many long non-coding RNAs (lncRNAs) regulate the Wnt/β-catenin signaling pathway in several types of cancer. Hyperactivation of the Wnt/β-catenin pathway has been extensively presented in breast cancer and is involved in breast cancer progression. However, the underlying molecular mechanism remains elusive. In the current study, we found lncRNA RBM5-AS1 was remarkably upregulated in breast cancer cells and tissues. Overexpression of RBM5-AS1 facilitated proliferation, migration, invasion, EMT, and stemness maintenance of breast cancer cells in vitro and in vivo. Mechanism studies suggested that RBM5-AS1 could be transcriptionally activated by hypoxia-induced RUNX2. Upregulated RBM5-AS1 further activated the Wnt/β-catenin signaling by preventing β-catenin degradation and by helping organize β-catenin-TCF4 transcriptional complex. These findings suggested that RBM5-AS1, a regulator of Wnt/β-catenin signaling, plays a vital role in breast cancer initiation and progression, implicating its potential as a new target for breast cancer treatment.
Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury
Authors: He Ruyuan , Liu Bohao , Xiong Rui , Geng Boxin , Meng Heng , Lin Weichen , Hao Bo , Zhang Lin , Wang Wei , Jiang Wenyang , Li Ning , Geng Qing 
Published: February 2022

AbstractItaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As a form of iron and lipid hydroperoxide-dependent regulated cell death, ferroptosis plays a critical role in sepsis-induced acute lung injury (ALI). However, the relationship between itaconate and ferroptosis remains unclear. This study aims to explore the regulatory role of itaconate on ferroptosis in sepsis-induced ALI. In in vivo experiments, mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis models. Differential gene expression analysis indicated that genes associated with ferroptosis existed significant differences after itaconate pretreatment. 4-octyl itaconate (4-OI), a cell-permeable derivative of endogenous itaconate, can significantly alleviate lung injury, increase LPS-induced levels of glutathione peroxidase 4 (GPX4) and reduce prostaglandin-endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), and lipid ROS. In vitro experiments showed that both 4-OI and ferrostatin-1 inhibited LPS-induced lipid peroxidation and injury of THP-1 macrophage. Mechanistically, we identified that 4-OI inhibited the GPX4-dependent lipid peroxidation through increased accumulation and activation of Nrf2. The silence of Nrf2 abolished the inhibition of ferroptosis from 4-OI in THP-1 cells. Additionally, the protection of 4-OI for ALI was abolished in Nrf2-knockout mice. We concluded that ferroptosis was one of the critical mechanisms contributing to sepsis-induced ALI. Itaconate is promising as a therapeutic candidate against ALI through inhibiting ferroptosis.
OTUB2 regulates KRT80 stability via deubiquitination and promotes tumour proliferation in gastric cancer
Authors: Ouyang Siwen , Zeng Ziyang , Liu Zhen , Zhang Zimu , Sun Juan , Wang Xianze , Ma Mingwei , Ye Xin , Yu Jianchun , Kang Weiming 
Published: February 2022

AbstractOTUB2 is a deubiquitinating enzyme that contributes to tumor progression. However, the expression of OTUB2 and its prognostic importance in gastric cancer remain unclear. The expression of OTUB2 and KRT80 in GC tissues was investigated using western blotting, qRT-PCR, multiple immunofluorescence staining, and immunohistochemistry. For survival studies, Kaplan–Meier analysis with the log-rank test was used. The role of OTUB2 during GC proliferation was investigated using in vivo and in vitro assays. OTUB2 was found to be overexpressed in GC tissues and to act as an oncogene, which was linked to patients’ poor prognosis. Knockdown of OTUB2 inhibited the proliferative capacity of GC cells in vitro and in vivo, although the proliferative capacity was restored upon re-supplementation with KRT80. OTUB2 mechanically stabilized KRT80 by deubiquitinating and shielding it from proteasome-mediated degradation through Lys-48 and Lys-63. Furthermore, by activating the Akt signaling pathway, OTUB2 and KRT80 facilitated GC proliferation. In summary, OTUB2 regulates KRT80 stability via deubiquitination promoting proliferation in GC via activation of the Akt signaling pathway, implying that OTUB2 could be a novel prognostic marker.
Salmonella pSLT-encoded effector SpvB promotes RIPK3-dependent necroptosis in intestinal epithelial cells
Authors: Dong Kedi , Zhu Yuan , Deng Qifeng , Sun Lanqing , Yang Sidi , Huang Kai , Cao Yu , Li Yuanyuan , Wu Shuyan , Huang Rui 
Published: February 2022

AbstractSalmonella is one of the most important worldwide zoonotic pathogens. After invading a host orally, the bacteria break through the intestinal epithelial barrier for further invasion. Intestinal epithelial cells (IECs) play a crucial role in maintaining the integrity of the intestinal epithelial barrier. Necroptosis is considered one of the virulence strategies utilized by invasive Salmonella. Our previous work has shown that SpvB, an effector encoded by S. Typhimurium virulence plasmid (pSLT), promotes bacterial translocation via the paracellular route. However, it is still unknown whether SpvB could promote bacterial invasion through disrupting the integrity of IECs. Here, we demonstrated that SpvB promoted necroptosis of IECs and contributed to the destruction of the intestinal barrier during Salmonella infection. We found that SpvB enhanced the protein level of receptor-interacting protein kinase 3 (RIPK3) through inhibiting K48-linked poly-ubiquitylation of RIPK3 and the degradation of the protein in an autophagy-dependent manner. The abundant accumulation of RIPK3 upregulated the phosphorylation of MLKL, which contributed to necroptosis. The damage to IECs ultimately led to the disruption of the intestinal barrier and aggravated infection. In vivo, SpvB promoted the pathogenesis of Salmonella, favoring intestinal injury and colonic necroptosis. Our findings reveal a novel function of Salmonella effector SpvB, which could facilitate salmonellosis by promoting necroptosis, and broaden our understanding of the molecular mechanisms of bacterial invasion.
BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids
Authors: Luo Juan , Zou Hailin , Guo Yibo , Huang Ke , Ngan Elly Sau-Wai , Li Peng 
Published: February 2022

Abstractβ-site APP-cleaving enzyme 2 (BACE2) is a homolog of BACE1, which is considered as the most promising therapeutic target for Alzheimer’s disease (AD). However, the expression and functional role of BACE2 in central nervous system (CNS) remain obscured. Previously, we identified several BACE2 rare variants in Hirschsprung disease (HSCR) patients and proved that BACE2-mediated APP cleavage might represent a novel HSCR pathogenesis mechanism in enteric nervous system. Here, we validated that these HSCR-associated BACE2 variants were loss-of-function mutations. Using the human pluripotent stem cell (hPSC)-derived brain organoids (BOs), we further demonstrated that BACE2 was mainly expressed in the ventricular zone and cortical plate of BOs, and its expression level was gradually increased along with the BO maturation. Functionally, we found that the BOs carrying the BACE2 loss-of-function mutation (BACE2G446R) showed greater apoptosis and increased levels of Aβ oligomers compared to the control BOs, resembling with the AD-associated phenotypes. All these phenotypes could be rescued via the removal of APP protein in BACE2G446R BOs. Furthermore, rather than BACE2G446R, BACE2WT overexpression in BOs carrying the APP Swedish/Indiana mutations attenuated the AD-associated phenotypes, including Aβ accumulation and neuronal cell death. Taken together, our results unravel that BACE2 can protect the neuronal cell from apoptosis caused by Aβ accumulation, and the deficiency of BACE2-mediated APP cleavage may represent a common pathological mechanism for both HSCR and AD.
Engineered bacterial voltage-gated sodium channel platform for cardiac gene therapy
Authors: Nguyen Hung X. , Wu Tianyu , Needs Daniel , Zhang Hengtao , Perelli Robin M. , DeLuca Sophia , Yang Rachel , Pan Michael , Landstrom Andrew P. , Henriquez Craig , Bursac Nenad 
Published: February 2022

AbstractTherapies for cardiac arrhythmias could greatly benefit from approaches to enhance electrical excitability and action potential conduction in the heart by stably overexpressing mammalian voltage-gated sodium channels. However, the large size of these channels precludes their incorporation into therapeutic viral vectors. Here, we report a platform utilizing small-size, codon-optimized engineered prokaryotic sodium channels (BacNav) driven by muscle-specific promoters that significantly enhance excitability and conduction in rat and human cardiomyocytes in vitro and adult cardiac tissues from multiple species in silico. We also show that the expression of BacNav significantly reduces occurrence of conduction block and reentrant arrhythmias in fibrotic cardiac cultures. Moreover, functional BacNav channels are stably expressed in healthy mouse hearts six weeks following intravenous injection of self-complementary adeno-associated virus (scAAV) without causing any adverse effects on cardiac electrophysiology. The large diversity of prokaryotic sodium channels and experimental-computational platform reported in this study should facilitate the development and evaluation of BacNav-based gene therapies for cardiac conduction disorders.
Fast plasmoid-mediated reconnection in a solar flare
Authors: Yan Xiaoli , Xue Zhike , Jiang Chaowei , Priest E. R. , Kliem Bernhard , Yang Liheng , Wang Jincheng , Kong Defang , Song Yongliang , Feng Xueshang , Liu Zhong 
Published: February 2022

AbstractMagnetic reconnection is a multi-faceted process of energy conversion in astrophysical, space and laboratory plasmas that operates at microscopic scales but has macroscopic drivers and consequences. Solar flares present a key laboratory for its study, leaving imprints of the microscopic physics in radiation spectra and allowing the macroscopic evolution to be imaged, yet a full observational characterization remains elusive. Here we combine high resolution imaging and spectral observations of a confined solar flare at multiple wavelengths with data-constrained magnetohydrodynamic modeling to study the dynamics of the flare plasma from the current sheet to the plasmoid scale. The analysis suggests that the flare resulted from the interaction of a twisted magnetic flux rope surrounding a filament with nearby magnetic loops whose feet are anchored in chromospheric fibrils. Bright cusp-shaped structures represent the region around a reconnecting separator or quasi-separator (hyperbolic flux tube). The fast reconnection, which is relevant for other astrophysical environments, revealed plasmoids in the current sheet and separatrices and associated unresolved turbulent motions.
Phase classification of multi-principal element alloys via interpretable machine learning
Authors: Lee Kyungtae , Ayyasamy Mukil V. , Delsa Paige , Hartnett Timothy Q. , Balachandran Prasanna V. 
Published: February 2022

AbstractThere is intense interest in uncovering design rules that govern the formation of various structural phases as a function of chemical composition in multi-principal element alloys (MPEAs). In this paper, we develop a machine learning (ML) approach built on the foundations of ensemble learning, post hoc model interpretability of black-box models, and clustering analysis to establish a quantitative relationship between the chemical composition and experimentally observed phases of MPEAs. The originality of our work stems from performing instance-level (or local) variable attribution analysis of ML predictions based on the breakdown method, and then identifying similar instances based on k-means clustering analysis of the breakdown results. We also complement the breakdown analysis with Ceteris Paribus profiles that showcase how the model response changes as a function of a single variable, when the values of all other variables are fixed. Results from local model interpretability analysis uncover key insights into variables that govern the formation of each phase. Our developed approach is generic, model-agnostic, and valuable to explain the insights learned by the black-box models. An interactive web application is developed to facilitate model sharing and accelerate the design of MPEAs with targeted properties.