FEP Augmentation as a Means to Solve Data Paucity Problems for Machine Learning in Chemical Biology.

In the realm of medicinal chemistry, the primary objective is to swiftly optimize a multitude of chemical properties of a set of compounds to yield a clinical candidate poised for clinical trials. In recent years, two computational techniques, machine learning (ML) and physics-based methods, have evolved substantially and are now frequently incorporated into the medicinal chemist's toolbox to enhance the efficiency of both hit optimization and candidate design. Both computational methods come with their own set of limitations, and they are often used independently of each other. ML's capability to screen extensive compound libraries expediently is tempered by its reliance on quality data, which can be scarce especially during early-stage optimization. Contrarily, physics-based approaches like free energy perturbation (FEP) are frequently constrained by low throughput and high cost by comparison; however, physics-based methods are capable of making highly accurate binding affinity predictions. In this study, we harnessed the strength of FEP to overcome data paucity in ML by generating virtual activity data sets which then inform the training of algorithms. Here, we show that ML algorithms trained with an FEP-augmented data set could achieve comparable predictive accuracy to data sets trained on experimental data from biological assays. Throughout the paper, we emphasize key mechanistic considerations that must be taken into account when aiming to augment data sets and lay the groundwork for successful implementation. Ultimately, the study advocates for the synergy of physics-based methods and ML to expedite the lead optimization process. We believe that the physics-based augmentation of ML will significantly benefit drug discovery, as these techniques continue to evolve.

"One Stone Two Birds" Strategy of Synthesizing the Battery Material Lithium Sulfide: Aluminothermal Reduction of Lithium Sulfate.

Lithium sulfide (Li2S) is a critical material for clean energy technologies, i.e., the cathode material in lithium-sulfur batteries and the raw material for making sulfide solid electrolytes in all-solid-state batteries. However, its practical application at a large scale is hindered by its industrial production method of reducing lithium sulfate with carbon materials at high temperatures, which emits carbon dioxide and is time-consuming. We hereby report a method of synthesizing Li2S by thermally reducing lithium sulfate with aluminum. Compared with the carbothermal method, this aluminothermal approach has several advantages, such as operation at lower temperatures, completion in minutes, no emission of greenhouse gases, and valuable byproducts of aluminum oxide (Al2O3). The home-made Li2S demonstrates competitive performance in battery tests versus the commercial counterpart. Moreover, using the byproduct Al2O3 to coat the cathode side of the separator can enhance the battery's capacity without influencing its rate capability. Thus, this "one stone two birds" method has great potential for practical applications of developing Li-S batteries.

Identification of Neofusicoccum parvum as the causative agent of leaf spot disease on Bletilla striata in China.

Bletilla striata (Thunb.) Rchb. f. (Orchidaceae) is an essential traditional Chinese medicinal plant used to treat hemorrhage, swelling, inflammation, ulcers, and pulmonary diseases (Xu et al. 2019). In April of 2020, an unknown leaf spot disease was observed on B. striata in a plantation (~ 0.2 ha) in Nanning, Guangxi province, China. Disease incidence was estimated at approximately 25% (n = 150 plants). The initial symptoms were small brown circular spots, which then expanded into reddish to brown, circular to irregular lesions 5-10 mm in diameter. As the disease developed, the whole leaf became densely covered with lesions. Finally, the lesions coalesced, killing the leaf and resulting in defoliation. To isolate the causal agent, six symptomatic leaves were collected from individual plants. Small pieces (~ 5 mm2) were cut from the margin of the necrotic lesions (n = 18), disinfected in 1% NaOCl for 2 min before rinsing three times in sterile water, and placed on potato dextrose agar (PDA) at 26°C for 3 days. Hyphal tips from the resulting cultures were transferred to PDA to obtain pure cultures. Fifteen isolates were obtained, of which twelve isolates exhibited similar morphology. Colonies on PDA were initially white, then turned dark gray after 7 days. Pycnidia were produced on the surface of PDA after 50 days. Conidia were hyaline, aseptate, ellipsoidal to fusiform, externally smooth, thin-walled, and measuring 11.5 to 15.2 × 4.9 to 6.1 µm (mean ± SD: 13.4 ± 1.0 × 5.4 ± 0.3 µm, n = 60). Morphological features were similar to N. parvum (Phillips et al. 2013). For further molecular identification, the internal transcribed spacer (ITS) region, partial translational elongation factor subunit 1-α (EF-1α), ß-tubulin (TUB2) genes were amplified and sequenced using the primer pairs ITS1/ITS4 (White et al. 1990), EF1-728F (Carbone and Kohn 1999)/EF-2 (O'Donnell et al. 1998), and Bt2a/Bt2b (Glass and Donaldson 1995), respectively. Sequences of the two isolates BJ-111.1 and BJ-111.4 were deposited in NCBI GenBank under the following accession numbers: OM348509-10, OM397537-40. The obtained ITS, EF1-α, and TUB2 sequences showed 99% (514/516, and 513/516 bp), 99% (275/276, and 274/275 bp), and 99% (429/431, and 429/430 bp) homology with several GenBank sequences of the ex-type strain N. parvum CMW 9081 (AY236943, AY236888, and AY236917, respectively) (Zhang et al. 2017). In addition, a phylogenetic analysis confirmed the isolates as N. parvum. Therefore, the isolates were identified as N. parvum based on morphological and molecular evidence. Furthermore, pathogenicity tests were carried out on 1.5-year-old B. striata plants. Healthy leaves on six plants (1 leaf per plant) were inoculated with a 10-µl droplet of conidial suspensions (106 conidia/mL). Three plants treated with sterile water served as the control. All plants were covered with transparent plastic bags and incubated in a greenhouse at 26°C with a 12 h photoperiod. Six days post-inoculation, the inoculated leaves showed leaf spot symptoms, while the control plants remained healthy. The experiments repeated three times showed similar results. Finally, N. parvum was consistently re-isolated from the infected leaves and confirmed by morphology and sequencing, fulfilling Koch's postulates. No fungus was isolated from the controls. To our knowledge, this is the first report of N. parvum causing leaf spot of B. striata worldwide. This result will help develop disease management strategies against this pathogen.

Exploring lipid biomarkers of coronary heart disease for elucidating the biological effects of gelanxinning capsule by lipidomics method based on LC-MS.

High-throughput lipidomics technology was used to explore the potential therapeutic targets and mechanism of action of gelanxinning capsule on rat model with coronary heart disease (CHD). This study attempts to provide a novel method to interpret the molecular mechanism of traditional medicine. The lipid markers of CHD were determined by full-scan analysis based on ultra-performance liquid chromatography-high-definition mass spectrometry. Then, the metabolic changes associated with gelanxinning capsule treatment via the modulation of lipid biomarkers and pathway in rats were characterized. After gelanxinning treatment, the metabolic profile tended to recover compared with the model group. A total of 26 potential biomarkers were identified to represent the disorders of lipid metabolism in CHD animal model, of which 19 were regulated by gelanxinning capsule administration, and four metabolic pathways such as glycerophospholipid metabolism, sphingolipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, and glycerolipid metabolism were involved. From the pathway analysis, it was found that glycerophospholipid metabolism and sphingolipid metabolism with significant differences have the potential to be regarded as new targets for the treatment of CHD. Gelanxinning capsule with its good therapeutic effect protects against CHD by regulating lipid biomarkers and pathway from lipidomics-guided biochemical analysis.

Mechanism of µ-Opioid Receptor-Magnesium Interaction and Positive Allosteric Modulation.

In the era of opioid abuse epidemics, there is an increased demand for understanding how opioid receptors can be allosterically modulated to guide the development of more effective and safer opioid therapies. Among the modulators of the µ-opioid (MOP) receptor, which is the pharmacological target for the majority of clinically used opioid drugs, are monovalent and divalent cations. Specifically, the monovalent sodium cation (Na+) has been known for decades to affect MOP receptor signaling by reducing agonist binding, whereas the divalent magnesium cation (Mg2+) has been shown to have the opposite effect, notwithstanding the presence of sodium chloride. Although ultra-high-resolution opioid receptor crystal structures have revealed a specific Na+ binding site and molecular dynamics (MD) simulation studies have supported the idea that this monovalent ion reduces agonist binding by stabilizing the receptor inactive state, the putative binding site of Mg2+ on the MOP receptor, as well as the molecular determinants responsible for its positive allosteric modulation of the receptor, are unknown. In this work, we carried out tens of microseconds of all-atom MD simulations to investigate the simultaneous binding of Mg2+ and Na+ cations to inactive and active crystal structures of the MOP receptor embedded in an explicit lipid-water environment and confirmed adequate sampling of Mg2+ ion binding with a grand canonical Monte Carlo MD method. Analyses of these simulations shed light on 1) the preferred binding sites of Mg2+ on the MOP receptor, 2) details of the competition between Mg2+ and Na+ cations for specific sites, 3) estimates of binding affinities, and 4) testable hypotheses of the molecular mechanism underlying the positive allosteric modulation of the MOP receptor by the Mg2+ cation.

Kinetic and thermodynamic insights into sodium ion translocation through the µ-opioid receptor from molecular dynamics and machine learning analysis.

The differential modulation of agonist and antagonist binding to opioid receptors (ORs) by sodium (Na+) has been known for decades. To shed light on the molecular determinants, thermodynamics, and kinetics of Na+ translocation through the µ-OR (MOR), we used a multi-ensemble Markov model framework combining equilibrium and non-equilibrium atomistic molecular dynamics simulations of Na+ binding to MOR active or inactive crystal structures embedded in an explicit lipid bilayer. We identify an energetically favorable, continuous ion pathway through the MOR active conformation only, and provide, for the first time: i) estimates of the energy differences and required timescales of Na+ translocation in inactive and active MORs, ii) estimates of Na+-induced changes to agonist binding validated by radioligand measurements, and iii) testable hypotheses of molecular determinants and correlated motions involved in this translocation, which are likely to play a key role in MOR signaling.

Characterization of chemical constituents and absorbed components, screening the active components of gelanxinning capsule and an evaluation of therapeutic effects by ultra-high performance liquid chromatography with quadrupole time of flight mass spectrometry.

We revealed the potential biomarker and pathway of gelanxinning capsule on rat model with coronary heart disease, which aims to clarify holistic therapeutic effect and predict quality-markers of gelanxinning capsule. Ultra-high performance liquid chromatography coupled with mass spectrometry based on metabolomics technique was used to find the biomarkers and related metabolic pathways of coronary heart disease model, which evaluates the intervention effect of gelanxinning capsule. Using serum pharmacochemistry of traditional Chinese medicine and Pearson correlation analysis, effective ingredients in serum is analyzed to characterize the activity of gelanxinning capsule on coronary heart disease under valid state. A total of 20 biomarkers from coronary heart disease were identified and 12 of them were regulated by gelanxinning capsule treatment, which is mainly involved in sphingolipid metabolism and glycerophospholipid metabolism. With the high sensitivity liquid chromatography coupled with mass spectrometry technology, a total of 46 compounds from gelanxinning capsule were identified in vitro and 25 of them were absorbed in blood. The correlation analysis of serum biomarkers and absorbed components was used to find 11 compounds as quality-markers to be responsible for the efficacy of gelanxinning capsule. This strategy was successfully applied to screening of potential mechanism and quality-markers from herbal medicine.

Quasielastic neutron scattering in biology: Theory and applications.

Neutrons scatter quasielastically from stochastic, diffusive processes, such as overdamped vibrations, localized diffusion and transitions between energy minima. In biological systems, such as proteins and membranes, these relaxation processes are of considerable physical interest. We review here recent methodological advances and applications of quasielastic neutron scattering (QENS) in biology, concentrating on the role of molecular dynamics simulation in generating data with which neutron profiles can be unambiguously interpreted. We examine the use of massively-parallel computers in calculating scattering functions, and the application of Markov state modeling. The decomposition of MD-derived neutron dynamic susceptibilities is described, and the use of this in combination with NMR spectroscopy. We discuss dynamics at very long times, including approximations to the infinite time mean-square displacement and nonequilibrium aspects of single-protein dynamics. Finally, we examine how neutron scattering and MD can be combined to provide information on lipid nanodomains. This article is part of a Special Issue entitled "Science for Life" Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazù and Dr. Federica Migliardo.

Microbially derived surfactants: an ecofriendly, innovative, and effective approach for managing environmental contaminants.

The natural environment is often contaminated with hydrophobic pollutants such as long-chain hydrocarbons, petrochemicals, oil spills, pesticides, and heavy metals. Hydrophobic pollutants with a toxic nature, slow degradation rates, and low solubility pose serious threats to the environment and human health. Decontamination based on conventional chemical surfactants has been found to be toxic, thereby limiting its application in pharmaceutical and cosmetic industries. In contrast, biosurfactants synthesized by various microbial species have been considered superior to chemical counterparts due to their non-toxic and economical nature. Some biosurfactants can withstand a wide range of fluctuations in temperature and pH. Recently, biosurfactants have emerged as innovative biomolecules not only for solubilization but also for the biodegradation of environmental pollutants such as heavy metals, pesticides, petroleum hydrocarbons, and oil spills. Biosurfactants have been well documented to function as emulsifiers, dispersion stabilizers, and wetting agents. The amphiphilic nature of biosurfactants has the potential to enhance the solubility of hydrophobic pollutants such as petroleum hydrocarbons and oil spills by reducing interfacial surface tension after distribution in two immiscible surfaces. However, the remediation of contaminants using biosurfactants is affected considerably by temperature, pH, media composition, stirring rate, and microorganisms selected for biosurfactant production. The present review has briefly discussed the current advancements in microbially synthesized biosurfactants, factors affecting production, and their application in the remediation of environmental contaminants of a hydrophobic nature. In addition, the latest aspect of the circular bioeconomy is discussed in terms of generating biosurfactants from waste and the global economic aspects of biosurfactant production.

Precision nutrition-based strategy for management of human diseases and healthy aging: current progress and challenges forward.

Currently, the treatment of various human ailments is based on different therapeutic approaches including traditional and modern medicine systems. Precision nutrition has come into existence as an emerging approach considering the diverse aspects such as age, sex, genetic and epigenetic makeup, apart from the pathophysiological conditions. The continuously and gradually evolving disciplines of genomics about nutrition have elucidated the importance of genetic variations, epigenetic information, and expression of myriads of genes in disease progression apart from the involvement in modulating therapeutic responses. Further, the investigations have presented the considerable role of gut microbiota comprising of commensal and symbionts performing innumerable activities such as release of bioactive molecules, defense against pathogenic microbes, and regulation of immunity. Noteworthy, the characteristics of the microbiome change depending on host attributes, environmental factors, and habitat, in addition to diet, and therefore can be employed as a biomarker to unravel the response to given food. The specific diet and the components thereof can be suggested for supporting the enrichment of the desired microbial community to some extent as an important part of precision nutrition to achieve not only the goal of human health but also of healthy aging.

A Synthetic Microbial Community of Plant Core Microbiome Can Be a Potential Biocontrol Tool.

Microbes are accepted as the foremost drivers of the rhizosphere ecology that influences plant health in direct or indirect ways. In recent years, the rapid development of gene sequencing technology has greatly facilitated the study of plant microbiome structure and function, and various plant-associated microbiomes have been categorized. Additionally, there is growing research interest in plant-disease-related microbes, and some specific microflora beneficial to plant health have been identified. This Review discusses the plant-associated microbiome's biological control pathways and functions to modulate plant defense against pathogens. How do plant microbiomes enhance plant resistance? How does the plant core microbiome-associated synthetic microbial community (SynCom) improve plant health? This Review further points out the primary need to develop smart agriculture practices using SynComs against plant diseases. Finally, this Review provides ideas for future opportunities in plant disease control and mining new microbial resources.

The complete chloroplast genome of Striga asiatica (L.) Kuntze 1891 (Orobanchaceae), a hemiparasitic weed from Guangxi China.

Striga asiatica (L.) Kuntze 1891 is a hemiparasitic plant native to Asia and Africa. It is invasive and causes yield losses in crops such as corn, rice and sorghum. Lack of chloroplast genomic data has limited research into its obligate parasitic lifestyle. In this study, the complete chloroplast genome of Striga asiatica was sequenced and characterized. It is a quadripartite structure with a total length of 191,085 bp and a GC content of 37.86%. It has a large single copy region (LSC) of 51,406 bp, a small single copy region (SSC) of 273 bp, and two copies of the reverse repeat sequence (IRA and IRB) of 69,703 bp. A total of 122 protein-coding genes, 8 rRNA genes, and 44 tRNA genes were annotated in the chloroplast genome. There were a lot of ndh gene deletions and pseudogenizations in this chloroplast genome. For example, ndhA, D, E, H, I, and K were all pseudogenes because they were missing the 5' end start codon. ndhB, C, and J had shorter gene lengths than their homologs, and ndhF and ndhG were missing genes. The phylogenetic tree reveals that all Striga species form a clade, and a bootstrap value of 100 indicates that S. asiatica is closely related to Striga hermonthica and Striga sepera. The comprehensive chloroplast genomic resource of S. asiatica would assist researchers in comprehending hemiparasitic mechanisms, molecular markers, and evolutionary patterns of the genus Striga.

Synthesis of Deliquescent Lithium Sulfide in Air.

In the field of lithium-sulfur batteries (LSBs) and all-solid-state batteries, lithium sulfide (Li2S) is a critical raw material. However, its practical application is greatly hindered by its high price due to its deliquescent property and production at high temperatures (above 700 °C) with carbon emission. Hereby, we report a new method of preparing Li2S, in air and at low temperatures (∼200 °C), which presents enriched and surprising chemistry. The synthesis relies on the solid-state reaction between inexpensive and air-stable raw materials of lithium hydroxide (LiOH) and sulfur (S), where lithium sulfite (Li2SO3), lithium thiosulfate (Li2S2O3), and water are three major byproducts. About 57% of lithium from LiOH is converted into Li2S, corresponding to a material cost of ∼$64.9/kg_Li2S, less than 10% of the commercial price. The success of conducting this water-producing reaction in air lies in three-fold: (1) Li2S is stable with oxygen below 220 °C; (2) the use of excess S can prevent Li2S from water attack, by forming lithium polysulfides (Li2Sn); and (3) the byproduct water can be expelled out of the reaction system by the carrier gas and also absorbed by LiOH to form LiOH·H2O. Two interesting and beneficial phenomena, i.e., the anti-hydrolysis of Li2Sn and the decomposition of Li2S2O3 to recover Li2S, are explained with density functional theory computations. Furthermore, our homemade Li2S (h-Li2S) is at least comparable with the commercial Li2S (c-Li2S), when being tested as cathode materials for LSBs.

Triggering endogenous Z-RNA sensing for anti-tumor therapy through ZBP1-dependent necroptosis.

ZBP1 senses viral Z-RNAs to induce necroptotic cell death to restrain viral infection. ZBP1 is also thought to recognize host cell-derived Z-RNAs to regulate organ development and tissue inflammation in mice. However, it remains unknown how the host-derived Z-RNAs are formed and how these endogenous Z-RNAs are sensed by ZBP1. Here, we report that oxidative stress strongly induces host cell endogenous Z-RNAs, and the Z-RNAs then localize to stress granules for direct sensing by ZBP1 to trigger necroptosis. Oxidative stress triggers dramatically increase Z-RNA levels in tumor cells, and the Z-RNAs then directly trigger tumor cell necroptosis through ZBP1. Localization of the induced Z-RNAs to stress granules is essential for ZBP1 sensing. Oxidative stress-induced Z-RNAs significantly promote tumor chemotherapy via ZBP1-driven necroptosis. Thus, our study identifies oxidative stress as a critical trigger for Z-RNA formation and demonstrates how Z-RNAs are directly sensed by ZBP1 to trigger anti-tumor necroptotic cell death.

A Low-Cost Liquid-Phase Method of Synthesizing High-Performance Li6PS5Cl Solid-Electrolyte.

Li6PS5Cl is an extensively studied sulfide-solid-electrolyte for developing all-solid-state lithium batteries. However, its practical application is hindered by the high cost of its raw material lithium sulfide (Li2S), the difficulty in its massive production, and its substandard performance. Herein we report an economically viable and scalable method, denoted as "de novo liquid phase method", which enables in synthesizing high-performance Li6PS5Cl without using commercial Li2S but instead in situ making Li2S from cheap materials of lithium chloride (LiCl) and sodium sulfide. LiCl, a raw material needed for making both Li2S and Li6PS5Cl, can be added at a full-scale in the beginning and unrequired to separate when making the intermediate Li3PS4. Such a consecutive feature makes this method time-efficient; and the excess amount of LiCl in the step of making Li2S also facilitates removing the byproduct of sodium chloride via the common ion effect. The materials cost of this method for Li6PS5Cl is ∼ $55/kg, comparable with the practical need of $50/kg. Moreover, the obtained Li6PS5Cl shows high ionic conductivity and outstanding cyclability in full battery tests, that is, ∼2 mS/cm and >99.8% retention for 400+ cycles at 1 C, respectively. Thus, this innovative method is expected to pave the way to develop practical sulfide-solid-electrolytes for all-solid-state lithium batteries.

Green synthesis of the battery material lithium sulfide via metathetic reactions.

We report a synthesis of lithium sulfide, the cost-determining material for making sulphide solid electrolytes (SSEs), via spontaneous metathesis reactions between lithium salts (halides and nitrate) and sodium sulfide. This innovative method is economical, scalable and green. It will pave the way to developing practical SSE-based solid-state lithium batteries.

Coenzyme A binding to the aminoglycoside acetyltransferase (3)-IIIb increases conformational sampling of antibiotic binding site.

NMR spectroscopy experiments and molecular dynamics simulations were performed to describe the dynamic properties of the aminoglycoside acetyltransferase (3)-IIIb (AAC) in its apo and coenzyme A (CoASH) bound forms. The (15)N-(1)H HSQC spectra indicate a partial structural change and coupling of the CoASH binding site with another region in the protein upon the CoASH titration into the apo enzyme. Molecular dynamics simulations indicate a significant structural and dynamic variation of the long loop in the antibiotic binding domain in the form of a relatively slow (250 ns), concerted opening motion in the CoASH-enzyme complex and that binding of the CoASH increases the structural flexibility of the loop, leading to an interchange between several similar equally populated conformations.

Response of water to electric fields at temperatures below the glass transition: a molecular dynamics analysis.

The electric field dependence of the structure and dynamics of water at 77 K, i.e., below the glass transition temperature (136 K), is investigated using molecular dynamics simulations. Transitions are found at two critical field strengths, denoted E(1) and E(2). The transition around E(1)≈3.5 V/nm is characterized by the onset of significant structural disorder, a rapid increase in the orientational polarization, and a maximum in the dynamical fluctuations. At E(2)≈40 V/nm, the system crystallizes in discrete steps into a body-centered-cubic unit cell that minimizes the potential energy by simultaneous superpolarization of the water molecular dipoles and maximization of the intermolecular hydrogen bonds. The stepwise and discontinuous increase of the orientational polarization with the increasing electric field indicates that the dipole relaxation in the electric field is highly cooperative.

Genetic, transcriptional, and regulatory landscape of monolignol biosynthesis pathway in Miscanthus × giganteus.

BACKGROUND: Miscanthus × giganteus is widely recognized as a promising lignocellulosic biomass crop due to its advantages of high biomass production, low environmental impacts, and the potential to be cultivated on marginal land. However, the high costs of bioethanol production still limit the current commercialization of lignocellulosic bioethanol. The lignin in the cell wall and its by-products released in the pretreatment step is the main component inhibiting the enzymatic reactions in the saccharification and fermentation processes. Hence, genetic modification of the genes involved in lignin biosynthesis could be a feasible strategy to overcome this barrier by manipulating the lignin content and composition of M. × giganteus. For this purpose, the essential knowledge of these genes and understanding the underlying regulatory mechanisms in M. × giganteus is required. RESULTS: In this study, MgPAL1, MgPAL5, Mg4CL1, Mg4CL3, MgHCT1, MgHCT2, MgC3'H1, MgCCoAOMT1, MgCCoAOMT3, MgCCR1, MgCCR2, MgF5H, MgCOMT, and MgCAD were identified as the major monolignol biosynthetic genes in M. × giganteus based on genetic and transcriptional evidence. Among them, 12 genes were cloned and sequenced. By combining transcription factor binding site prediction and expression correlation analysis, MYB46, MYB61, MYB63, WRKY24, WRKY35, WRKY12, ERF021, ERF058, and ERF017 were inferred to regulate the expression of these genes directly. On the basis of these results, an integrated model was summarized to depict the monolignol biosynthesis pathway and the underlying regulatory mechanism in M. × giganteus. CONCLUSIONS: This study provides a list of potential gene targets for genetic improvement of lignocellulosic biomass quality of M. × giganteus, and reveals the genetic, transcriptional, and regulatory landscape of the monolignol biosynthesis pathway in M. × giganteus.

Fracture Characterization Using Flowback Water Transients from Hydraulically Fractured Shale Gas Wells.

Fracture characterization is necessary to evaluate fracturing operations and forecast well performance. However, it is challenging to quantitatively characterize the complex fracture network in shale gas reservoirs because of the unknown density and reactivation of natural fractures. The flowback water transients can provide useful information about the complexity of the fracture network after the fracturing operations. In this paper, a mathematical model for modeling fracturing fluid flowback of hydraulically fractured shale gas wells is established. This proposed model characterizes the flow of water and gas in a hydraulic fracture-induced natural fracture-shale matrix system. Hydraulic, capillary, and osmotic convections; gas adsorption; and natural fracture closure are considered in this model. Flowback simulation of a hydraulically fractured shale gas well is conducted using the developed numerical simulator, and the water/gas transients between hydraulic fractures, natural fractures, and matrix are obtained. Finally, two field cases from the Longmaxi Formation, Southern Sichuan Basin, China, are used for comparison of the flowback data with the model results. The good match of the two water transients provides a group of fracture network parameters, that is, the effective length and conductivity of main hydraulic fractures and the density of induced natural fractures. The proposed model for describing the flowback process and its meaningful relationship with the fracture-network complexity provides an alternative approach for post-stimulation evaluation.