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Matter entanglement is a common chaotic structure found in both quantum and classical systems. For classical turbulence, viscous vortices are like sinews in fluid flows, storing and dissipating energy and accommodating strain and stress throughout a complex vortex network. However, to explain how the statistical properties of turbulence arise from elemental vortical structures remains challenging. Here, we use the quantum vortex tangle as a skeleton to generate an instantaneous classical turbulent field with intertwined vortex tubes. Combining the quantum skeleton and tunable vortex thickness makes the synthetic turbulence satisfy key statistical laws, offering valuable insights for elucidating energy cascade and extreme events. By manipulating the elemental structures, we customize turbulence with desired statistical features. This bottom-up approach of designing turbulence provides a testbed for analyzing and modeling turbulence.
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The development of omics technologies has driven a profound expansion in the scale of biological data and the increased complexity in internal dimensions, prompting the utilization of machine learning (ML) as a powerful toolkit for extracting knowledge and understanding underlying biological patterns. Kidney disease represents one of the major growing global health threats with intricate pathogenic mechanisms and a lack of precise molecular pathology-based therapeutic modalities. Accordingly, there is a need for advanced high-throughput approaches to capture implicit molecular features and complement current experiments and statistics. This review aims to delineate strategies for integrating multi-omics data with appropriate ML methods, highlighting key clinical translational scenarios, including predicting disease progression risks to improve medical decision-making, comprehensively understanding disease molecular mechanisms, and practical applications of image recognition in renal digital pathology. Examining the benefits and challenges of current integration efforts is expected to shed light on the complexity of kidney disease and advance clinical practice.
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Enfermedades Renales , Aprendizaje Automático , Humanos , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Genómica/métodos , Biología Computacional/métodos , Proteómica/métodos , MultiómicaRESUMEN
The process of induced pluripotent stem cells (iPSCs) reprogramming involves several crucial events, including the mesenchymal-epithelial transition (MET), activation of pluripotent genes, metabolic reprogramming, and epigenetic rewiring. Although these events intricately interact and influence each other, the specific element that regulates the reprogramming network remains unclear. Dux, a factor known to promote totipotency during the transition from embryonic stem cells (ESC) to 2C-like ESC (2CLC), has not been extensively studied in the context of iPSC reprogramming. In this study, we demonstrate that the modification of H3K18la induced by Dux overexpression controls the metabolism-H3K18la-MET network, enhancing the efficiency of iPSC reprogramming through a metabolic switch and the recruitment of p300 via its C-terminal domain. Furthermore, our proteomic analysis of H3K18la immunoprecipitation experiment uncovers the specific recruitment of Brg1 during reprogramming, with both H3K18la and Brg1 being enriched on the promoters of genes associated with pluripotency and epithelial junction. In summary, our study has demonstrated the significant role of Dux-induced H3K18la in the early reprogramming process, highlighting its function as a potent trigger. Additionally, our research has revealed, for the first time, the binding of Brg1 to H3K18la, indicating its role as a reader of histone lactylation.
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Reprogramación Celular , Transición Epitelial-Mesenquimal , Histonas , Proteínas de Homeodominio , Células Madre Pluripotentes Inducidas , Factores de Transcripción , Animales , Humanos , Ratones , Reprogramación Celular/genética , ADN Helicasas/metabolismo , ADN Helicasas/genética , Transición Epitelial-Mesenquimal/genética , Histonas/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/citología , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genéticaRESUMEN
Individual oncogenic KRAS mutants confer distinct differences in biochemical properties and signaling for reasons that are not well understood. KRAS activity is closely coupled to protein dynamics and is regulated through two interconverting conformations: state 1 (inactive, effector binding deficient) and state 2 (active, effector binding enabled). Here, we use 31P NMR to delineate the differences in state 1 and state 2 populations present in WT and common KRAS oncogenic mutants (G12C, G12D, G12V, G13D, and Q61L) bound to its natural substrate GTP or a commonly used nonhydrolyzable analog GppNHp (guanosine-5'-[(ß,γ)-imido] triphosphate). Our results show that GppNHp-bound proteins exhibit significant state 1 population, whereas GTP-bound KRAS is primarily (90% or more) in state 2 conformation. This observation suggests that the predominance of state 1 shown here and in other studies is related to GppNHp and is most likely nonexistent in cells. We characterize the impact of this differential conformational equilibrium of oncogenic KRAS on RAF1 kinase effector RAS-binding domain and intrinsic hydrolysis. Through a KRAS G12C drug discovery, we have identified a novel small-molecule inhibitor, BBO-8956, which is effective against both GDP- and GTP-bound KRAS G12C. We show that binding of this inhibitor significantly perturbs state 1-state 2 equilibrium and induces an inactive state 1 conformation in GTP-bound KRAS G12C. In the presence of BBO-8956, RAF1-RAS-binding domain is unable to induce a signaling competent state 2 conformation within the ternary complex, demonstrating the mechanism of action for this novel and active-conformation inhibitor.
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Proteínas Proto-Oncogénicas p21(ras) , Proteínas ras , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas ras/metabolismo , Guanosina Trifosfato/metabolismo , Espectroscopía de Resonancia Magnética , Transducción de Señal , MutaciónRESUMEN
Apple rust is a serious fungal disease affecting Malus plants worldwide. Infection with the rust pathogen Gymnosporangium yamadae induces the accumulation of anthocyanins in Malus to resist rust disease. However, the mechanism of anthocyanin biosynthesis regulation in Malus against apple rust is still unclear. Here, we show that MpERF105 and MpNAC72 are key regulators of anthocyanin biosynthesis via the ethylene-dependent pathway in M. 'Profusion' leaves under rust disease stress. Exogenous ethephon treatment promoted high expression of MpERF105 and MpNAC72 and anthocyanin accumulation in G. yamadae-infected M. 'Profusion' leaves. Overexpression of MpERF105 increased the total anthocyanin content of Malus plant material and acted by positively regulating its target gene, MpMYB10b. MpNAC72 physically interacted with MpERF105 in vitro and in planta, and the two form a protein complex. Coexpression of the two leads to higher transcript levels of MpMYB10b and higher anthocyanin accumulation. In addition, overexpression of MpERF105 or MpNAC72 enhanced the resistance of M. 'Profusion' leaves to apple rust. In conclusion, our results elucidate the mechanism by which MpERF105 and MpNAC72 are induced by ethylene in G. yamadae-infected M. 'Profusion' leaves and promote anthocyanin accumulation by mediating the positive regulation of MpMYB10b expression.
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Antocianinas , Basidiomycota , Regulación de la Expresión Génica de las Plantas , Malus , Enfermedades de las Plantas , Hojas de la Planta , Proteínas de Plantas , Antocianinas/metabolismo , Antocianinas/biosíntesis , Hojas de la Planta/metabolismo , Hojas de la Planta/microbiología , Hojas de la Planta/genética , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Malus/microbiología , Malus/genética , Malus/metabolismo , Basidiomycota/fisiología , Etilenos/metabolismoRESUMEN
Ferroptosis inhibits tumor progression in pancreatic cancer cells, while PITX2 is known to function as a pro-oncogenic factor in various tumor types, protecting them from ferroptosis and thereby promoting tumor progression. In this study, we sought to investigate the regulatory role of PITX2 in tumor cell ferroptosis within the context of pancreatic cancer. We conducted PITX2 knockdown experiments using lentiviral infection in two pancreatic cancer cell lines, namely PANC-1 and BxPC-3. We assessed protein expression through immunoblotting and mRNA expression through RT-PCR. To confirm PITX2 as a transcription factor for GPX4, we employed Chromatin Immunoprecipitation (ChIP) and Dual-luciferase assays. Furthermore, we used flow cytometry to measure reactive oxygen species (ROS), lipid peroxidation, and apoptosis and employed confocal microscopy to assess mitochondrial membrane potential. Additionally, electron microscopy was used to observe mitochondrial structural changes and evaluate PITX2's regulation of ferroptosis in pancreatic cancer cells. Our findings demonstrated that PITX2, functioning as a transcription factor for GPX4, promoted GPX4 expression, thereby exerting an inhibitory effect on ferroptosis in pancreatic cancer cells and consequently promoting tumor progression. Moreover, PITX2 enhanced the invasive and migratory capabilities of pancreatic cancer cells by activating the WNT signaling pathway. Knockdown of PITX2 increased ferroptosis and inhibited the proliferation of PANC-1 and BxPC-3 cells. Notably, the inhibitory effect on ferroptosis resulting from PITX2 overexpression in these cells could be countered using RSL3, an inhibitor of GPX4. Overall, our study established PITX2 as a transcriptional regulator of GPX4 that could promote tumor progression in pancreatic cancer by reducing ferroptosis. These findings suggest that PITX2 may serve as a potential therapeutic target for combating ferroptosis in pancreatic cancer.
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Ferroptosis , Regulación Neoplásica de la Expresión Génica , Proteína del Homeodomínio PITX2 , Proteínas de Homeodominio , Neoplasias Pancreáticas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Especies Reactivas de Oxígeno , Factores de Transcripción , Animales , Humanos , Ratones , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Ferroptosis/genética , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Peroxidación de Lípido , Potencial de la Membrana Mitocondrial/genética , Ratones Desnudos , Mitocondrias/metabolismo , Mitocondrias/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Especies Reactivas de Oxígeno/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Vía de Señalización Wnt/genéticaRESUMEN
As one of the most common cancers, accurate, rapid, and simple histopathological diagnosis is very important for breast cancer. Raman imaging is a powerful technique for label-free analysis of tissue composition and histopathology, but it suffers from slow speed when applied to large-area tissue sections. In this study, we propose a dual-modal Raman imaging method that combines Raman mapping data with microscopy bright-field images to achieve virtual staining of breast cancer tissue sections. We validate our method on various breast tissue sections with different morphologies and biomarker expressions and compare it with the golden standard of histopathological methods. The results demonstrate that our method can effectively distinguish various types and components of tissues, and provide staining images comparable to stained tissue sections. Moreover, our method can improve imaging speed by up to 65 times compared to general spontaneous Raman imaging methods. It is simple, fast, and suitable for clinical applications.
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Neoplasias de la Mama , Espectrometría Raman , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Humanos , Espectrometría Raman/métodos , Femenino , Coloración y EtiquetadoRESUMEN
Captured by high theoretical capacity and low-cost, Sodium-Sulfur (Na-S) batteries have been deemed as promising energy-storage systems. However, their electrochemical properties, containing both cycling and rate properties, still suffer from the notorious "shuttle effect" of polysulfide. Herein, through the effective regulation of pore sizes, a series of S@SiO2 cathode materials are obtained. Benefitting from the abundant pore channels of SiO2 particles, the sulfur loading is as high as 76.3%. Importantly, a suitable pore size can lead to adequate reaction and rapid diffusion behaviors, resulting in excellent electrochemical performances. Specifically, at 2.0 A g-1, the initial capacity of the as-optimized sample can be up to 1370.6 mAh g-1. Surprisingly, even after 1050 cycles, it could achieve a high reversible capacity of 1280.8 mAh g-1 with an attenuation rate of 0.089%. At 5.0 A g-1, after 500 cycles, the capacity can still remain ≈ 1132.6 mAh g-1 (capacity retention rate, 97.5%). Given this, the work is anticipated to offer an effective strategy for advanced electrodes for Na-S batteries.
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Shaping covalent organic frameworks (COFs) into macroscopic objects with robust mechanical properties and hierarchically porous structure is of great significance for practical applications but remains formidable and challenging. Herein, a general and scalable protocol is reported to prepare ultralight and robust pure COF fiber aerogels (FAGs), based on the epitaxial growth synergistic assembly (EGSA) strategy. Specifically, intertwined COF nanofibers (100-200 nm) are grown in situ on electrospinning polyacrylonitrile (PAN) microfibers (≈1.7 µm) containing urea-based linkers, followed by PAN removal via solvent extraction to obtain the hollow COF microfibers. The resultant COF FAGs possess ultralow density (14.1-15.5 mg cm-3) and hierarchical porosity that features both micro-, meso-, and macropores. Significantly, the unique interconnected structure composed of nanofibers and hollow microfibers endows the COF FAGs with unprecedented mechanical properties, which can fully recover at 50% strain and be compressed for 20 cycles with less than 5% stress degradation. Moreover, the aerogels exhibit excellent capacity for organic solvent absorption (e.g., chloroform uptake of >90 g g-1). This study opens new avenues for the design and fabrication of macroscopic COFs with excellent properties.
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Hydrogen (H2) has emerged as a highly promising energy carrier owing to its remarkable energy density and carbon emission-free properties. However, the widespread application of H2 fuel has been limited by the difficulty of storage. In this work, spontaneous electrochemical hydrogen production is demonstrated using hydrazine (N2H4) as a liquid hydrogen storage medium and enabled by a highly active Co catalyst for hydrazine electrooxidation reaction (HzOR). The HzOR electrocatalyst is developed by a self-limited growth of Co nanoparticles from a Co-based zeolitic imidazolate framework (ZIF), exhibiting abundant defective surface atoms as active sites for HzOR. Notably, these self-limited Co nanoparticles exhibit remarkable HzOR activity with a negative working potential of -0.1 V (at 10 mA cm-2) in 0.1 m N2H4/1 m KOH electrolyte. Density functional theory (DFT) calculations are employed to validate the superior performance of low-coordinated Co active sites in facilitating HzOR. By taking advantage of the potential difference between HzOR and the hydrogen evolution reaction (HER), a novel HzOR||HER electrochemical system is developed to spontaneously produce H2 without external energy input. Overall, the work offers valuable guidance for developing active HzOR catalyst. The novel HzOR||HER electrochemical system represents a promising and innovative solution for energy-efficient hydrogen production.
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MAIN CONCLUSION: WOX family gene WOX2 is highly expressed during seed development, which functions redundantly with WOX1 and WOX4 to positively regulate seed germination. WOX (WUSCHEL-related homeobox) is a family of transcription factors in plants. They play essential roles in the regulation of plant growth and development, but their function in seed germination is not well understood. In this report, we show that WOX1, WOX2, and WOX4 are close homologues in Arabidopsis. WOX2 has a redundant function with WOX1 and WOX4, respectively, in seed germination. WOX2 is highly expressed during seed development, from the globular embryonic stage to mature dry seeds, and its expression is decreased after germination. Loss of function single mutant wox2, and double mutants wox1 wox2 and wox2 wox4-1 show decreased germination speed. WOX2 and WOX4 are essential for hypocotyl-radicle zone elongation during germination, potentially by promoting the expression of cell wall-related genes. We also found that WOX2 and WOX4 regulate germination through the gibberellin (GA) pathway. These results suggest that WOX2 and WOX4 integrate the GA pathway and downstream cell wall-related genes during germination.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Pared Celular , Germinación/genética , Giberelinas , Proteínas de Homeodominio/genética , Semillas/genéticaRESUMEN
We demonstrated a narrow linewidth semiconductor laser based on a deep-etched sidewall grating active distributed Bragg reflector (SG-ADBR). The coupling coefficients and reflectance were numerically simulated for deep-etched fifth-order SG-ADBR, and a reflectance of 0.86 with a bandwidth of 1.04â nm was obtained by the finite element method for a 500-period SG-ADBR. Then the fifth-order SG-ADBR lasers were fabricated using projection i-line lithography processes. Single-mode lasing at 1537.9â nm was obtained with a high side-mode suppression ratio (SMSR) of 65â dB, and a continuous tuning range of 10.3â nm was verified with SMSRs greater than 53â dB. Furthermore, the frequency noise power spectral density was characterized, from which a Lorentzian linewidth of 288 kHz was obtained.
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The X-ray sources for Compton radiography of ICF experiments are generated by using intense picosecond lasers to irradiate wire targets. The wire diameter must be designed thin enough, for example â¼ 10â µm in many published works, to comply a high spatial resolution. This results in a low laser-target interception, which limits the photon yield. We investigated a technique of coded-source radiography based on laser-driven annular sources via Monte Carlo and PIC simulations. The annular X-ray source is formed by laser irradiating tube target in which the effect of electron recirculation plays an important role. We proved that this technique has an increased spatial resolution and contrast than that using the Gaussian source produced by wire targets. Therefore, the diameter of the backlighter target can be significantly increased to uplift laser-target interception without compromising on spatial resolution. This contributes towards a reconciliation between the spatial resolution and photon yield for Compton radiography. The results predict the possibility of improving source photon yield by several times in future experiments.
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We propose and demonstrate a high-speed directly modulated laser based on a hybrid deformed-square-FP coupled cavity (DFC), aiming for a compact-size low-cost light source in next-generation optical communication systems. The deformed square microcavity is directly connected to the FP cavity and utilized as a wavelength-sensitive reflector with a comb-like and narrow-peak reflection spectrum for selecting the lasing mode, which can greatly improve the single-mode yield of the laser and the quality (Q) factor of the coupled mode. By optimizing the device design and operating condition, the modulation bandwidth of the DFC laser can be enhanced due to the intracavity-mode photon-photon resonance effect. Our experimental results show an enhancement of 3-dB modulation bandwidth from 19.3â GHz to 30â GHz and a clear eye diagram at a modulation rate of 25 Gbps.
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Insensitivity to external optical feedback is experimentally demonstrated in a self-chaotic deformed square microcavity laser for the first time, to the best of our knowledge. Both the optical and radio frequency (RF) spectra of the microlaser remain unaffected for external optical feedback with feedback strength as high as 9.9â dB. In addition, the autocorrelation function curve exhibits no time-delayed peaks. The insensitivity makes the self-chaotic microcavity laser promising for applications in feedback-insensitive optical sources.
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In this Letter, we theoretically explore the physical properties of a new type of three-dimensional graphite moiré superlattice, the bulk alternating twisted graphite (ATG) system with homogeneous twist angle, which is grown by in situ chemical vapor decomposition method. Compared to twisted bilayer graphene (TBG), the bulk ATG system is bestowed with an additional wave vector degree of freedom due to the extra dimensionality. As a result, when the twist angle of bulk ATG is smaller than twice of the magic angle of TBG, there always exist "magic momenta" which host topological flat bands with vanishing in-plane Fermi velocities. Most saliently, when the twist angle is relatively large, a dispersionless three-dimensional zeroth Landau level would emerge in the bulk ATG, which may give rise to robust three-dimensional quantum Hall effects and unusual quantum-Hall physics over a large range of twist angles.
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Low temperature has been a major challenge for lithium-ion batteries (LIBs) to maintain satisfied electrochemical performance, and the main reason is the deactivation of electrolyte with the decreasing temperature. To address this point, in present work, we develop a low-temperature resistant electrolyte which includes ethyl acetate (EA) and fluoroethylene carbonate (FEC) as solvent and lithium difluoro(oxalato)borate (LiDFOB) as the primary lithium salt. Due to the preferential decomposition of LiDFOB and FEC, a solid electrolyte interface rich in LiF is formed on the lithium metal anodes (LMAs) and lithium cobalt oxide (LCO) cathodes, contributing to higher stability and rapid desolvation of Li+ ions. The batteries with the optimized electrolyte can undergo cycling tests at -40 °C, with a capacity retention of 83.9 % after 200 cycles. Furthermore, the optimized electrolyte exhibits excellent compatibility with both LCO cathodes and graphite (Gr) anodes, enabling a Gr/LCO battery to maintain a capacity retention of 90.3 % after multiple cycles at -25 °C. This work proposes a cost-effective electrolyte that can activate potential LIBs in practical scenarios, especially in low-temperature environments.
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Long-term excessive exposure to manganese can impair neuronal function in the brain, but the underlying pathological mechanism remains unclear. Oxidative stress plays a central role in manganese-induced neurotoxicity. Numerous studies have established a strong link between abnormal histone acetylation levels and the onset of various diseases. Histone deacetylase inhibitors and activators, such as TSA and ITSA-1, are often used to investigate the intricate mechanisms of histone acetylation in disease. In addition, recent experiments have provided substantial evidence demonstrating that curcumin (Cur) can act as an epigenetic regulator. Given these findings, this study aims to investigate the mechanisms underlying oxidative damage in SH-SY5Y cells exposed to MnCl2·4H2O, with a particular focus on histone acetylation, and to assess the potential therapeutic efficacy of Cur. In this study, SH-SY5Y cells were exposed to manganese for 24 h, were treated with TSA or ITSA-1, and were treated with or without Cur. The results suggested that manganese exposure, which leads to increased expression of HDAC3, induced H3K27 hypoacetylation, inhibited the transcription of antioxidant genes, decreased antioxidant enzyme activities, and induced oxidative damage in cells. Pretreatment with an HDAC3 inhibitor (TSA) increased the acetylation of H3K27 and the transcription of antioxidant genes and thus slowed manganese exposure-induced cellular oxidative damage. In contrast, an HDAC3 activator (ITSA-1) partially increased manganese-induced cellular oxidative damage, while Cur prevented manganese-induced oxidative damage. In summary, these findings suggest that inhibiting H3K27ac is a possible mechanism for ameliorating manganese-induced damage to dopaminergic neurons and that Cur exerts a certain protective effect against manganese-induced damage to dopaminergic neurons.
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Curcumina , Neuroblastoma , Humanos , Curcumina/farmacología , Histonas/metabolismo , Antioxidantes/farmacología , Manganeso/toxicidad , Manganeso/metabolismo , Estrés Oxidativo , Línea Celular TumoralRESUMEN
In a recent paper (ChemPhysChem, 2023, 24, e202200947), based on the results computed using DFT method, the perfect core-shell octahedral configuration Be@B38 and Zn@B38 was reported to be the global minima of the MB38(M=Be and Zn) clusters. However, this paper presents the lower energy structures of MB38(M=Be and Zn) clusters as a quasi-planar configuration, the Be atom is found to reside on the convex surface of the quasi-planar B38 isomer, while the Zn atom tends to be attached to the top three B atoms of the quasi-planar B38 isomer. Our results show that quasi-planar MB38(M=Be and Zn) at DFT method have lower energy than core-shell octahedral configuration M@B38(M=Be and Zn). Natural atomic charges, valence electron density, electron localization function (ELF) analyses identify the MB38(M=Be and Zn) to be charge transfer complexes (Be2+B382-and Be1+B381-) and suggest primarily the electrostatic interactions between doped atom and B38 fragment. The photoelectron spectra of the corresponding anionic structures were simulated, providing theoretical basis for future structural identification.
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In this study, we innovatively combined the Fe-Ti-N potential function file to construct simulation models of different crystal facets of TiN/Fe ((001), (110), and (111)), which had not been previously explored. Employing molecular dynamics (MD) simulations, the research investigates the microscale differences in erosion resistance and surface properties of various TiN crystal planes under continuous impacts at varying velocities and angles. The results indicate that both surface wear and internal defects of the model increase with the impact velocity. Both TiN(110) and TiN(111) exhibit damage on their surfaces and interiors, with a larger wear range. In contrast, TiN(001), due to its superior elastic recovery capability, maintains a better surface condition, showing significantly less wear compared to TiN(110) and TiN(111). This disparity in performance among different crystal planes is attributed to variations in molecular gaps between planes, bonding points within the lattice, types of forces, and modes of action. Further research revealed that the wear volume increased with the rise in impact angle, reaching its peak at 90°. Regardless of the impact angle, TiN(001) consistently outperformed TiN(110) and TiN(111). The aim of the research is to compare the surface and internal defects of different crystal facets at the microscopic level, thereby selecting superior crystal facets and providing theoretical reference for the application of TiN materials in practical fracturing environments.