Glycyrrhizin alleviates BoAHV-1-induced lung injury in guinea pigs by inhibiting the NF-κB/NLRP3 Signaling pathway and activating the Nrf2/HO-1 Signaling pathway.

Varicellovirus bovinealpha 1 (BoAHV-1) is a significant pathogen responsible for respiratory disease in cattle, capable of inducing lung damage independently or co-infection with bacteria. The widespread spread of BoAHV-1 in cattle herds has caused substantial economic losses to the cattle industry. The pathogenic mechanisms of BoAHV-1 are often relevant to robust inflammatory responses, increased oxidative burden, and the initiation of apoptosis. Glycyrrhizin (GLY) is a small-molecule triterpenoid saponin compound obtained from the herb liquorice, which has a broad spectrum of pharmacological properties such as antiviral, anti-inflammatory, and antioxidant effects. Furthermore, GLY regulates lung physiology by modulating oxidative stress, inflammatory response, and cell apoptosis through interference with the NF-κB/NLRP3 and Nrf2/HO-1 Signaling pathways. However, the potential of GLY to mitigate lung injury induced by BoAHV-1 and its underlying mechanism remains unclear. Therefore, in this study, we investigated the protective effect of GLY against pulmonary injury induced by BoAHV-1 in a guinea pig model by reducing viral load and suppressing the inflammatory response, oxidative stress, and apoptosis. The results of this study demonstrated that GLY exerted a protective effect against BoAHV-1-induced lung injury in guinea pigs. Specifically, GLY reduced the levels of pro-inflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and interleukin (IL)-8 in guinea pig tissues while suppressing the expression of Caspase-1. Additionally, GLY reduced BoAHV-1 load and the number of TUNEL-positive lung cells in guinea pig lungs while inhibiting Caspase 3 protein expression. Furthermore, GLY significantly enhanced lung antioxidant capacity by increasing superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity while simultaneously reducing malondialdehyde (MDA) levels. Lung histological observation and score further validated the protective effect of GLY on BoAHV-1-induced lung injury. Furthermore, we observed that the expression of phosphorylated NF-κB p65 (p-NF-κB p65) and NLRP3 proteins in the lung tissue of BoAHV-1-infected guinea pigs decreased after GLY treatment while the expression of Nrf2 and HO-1 proteins increased. These results indicated that GLY inhibited the NF-κB/NLRP3 Signaling pathway and activated the Nrf2/HO-1 Signaling pathway during BoAHV-1 infection. Ultimately, our findings demonstrated that GLY alleviates BoAHV-1-induced inflammation response, oxidative stress, and cell apoptosis by inhibiting the NF-κB/NLRP3 Signaling pathway and activating the Nrf2/HO-1 Signaling pathway to protect guinea pigs from lung injury caused by BoAHV-1. Ultimately, our findings demonstrated that GLY alleviates BoAHV-1-induced inflammation response, oxidative stress, and cell apoptosis by inhibiting the NF-κB/NLRP3 Signaling pathway and activating the Nrf2/HO-1 Signaling pathway to protect guinea pigs from lung injury caused by BoAHV-1. Importantly, this study provides a compelling argument for the GLY in combating respiratory disease in cattle caused by BoAHV-1.

A Pump-Free Strategy for the Controllable Generation of Alginate Microgels as Cellular Microcarriers.

Microgels are advanced scaffolds for tissue engineering due to their proper biodegradability, good biocompatibility, and high specific surface area for effective oxygen and nutrient transfer. However, most of the current monodispersed microgel fabrication systems rely heavily on various precision pumps, which highly increase the cost and complexity of their downstream application. In this work, we developed a simple and facile system for the controllable generation of uniform alginate microgels by integrating a gas-shearing strategy into a glass microfluidic device. Importantly, the cell-laden microgels can be rapidly prepared in a pump-free manner under an all-aqueous environment. The three-dimensional cultured green fluorescent protein-human A549 cells in alginate microgels exhibited enhanced stemness and drug resistance compared to those under two-dimensional conditions. The pancreatic cancer organoids in alginate microgels exhibited some of the key features of pancreatic cancer. The proposed microgels showed decent monodispersity, biocompatibility, and versatility, providing great opportunities in various biomedical applications such as microcarrier fabricating, organoid engineering, and high-throughput drug screening.

Identification and biochemical characterization of a carboxylesterase gene associated with ß-cypermethrin resistance in Dermanyssus gallinae.

Dermanyssus gallinae is a major hematophagous ectoparasite in layer hens. Although the acaricide ß-cypermethrin has been used to control mites worldwide, D. gallinae has developed resistance to this compound. Carboxylesterases (CarEs) are important detoxification enzymes that confer resistance to ß-cypermethrin in arthropods. However, CarEs associated with ß-cypermethrin resistance in D. gallinae have not yet been functionally characterized. Here, we isolated a CarE gene (Deg-CarE) from D. gallinae and assayed its activity. The results revealed significantly higher expression of Deg-CarE in the ß-cypermethrin-resistant strain (RS) than in the susceptible strain (SS) toward α-naphthyl acetate (α-NA) and ß-naphthyl acetate (ß-NA). These findings suggest that enhanced esterase activities might have contributed to ß-cypermethrin resistance in D. gallinae. Quantitative real-time PCR analysis revealed that Deg-CarE expression levels were significantly higher in adults than in other life stages. Although Deg-CarE was upregulated in the RS, significant differences in gene copy numbers were not observed. Additionally, Deg-CarE expression was significantly induced by ß-cypermethrin in both the SS and RS. Moreover, silencing Deg-CarE via RNA interference decreased the enzyme activity and increased the susceptibility of the RS to ß-cypermethrin, confirming that Deg-CarE is crucial for ß-cypermethrin detoxification. Finally, recombinant Deg-CarE (rDeg-CarE) expressed in Escherichia coli displayed high enzymatic activity toward α/ß-NA. However, metabolic analysis indicated that rDeg-CarE did not directly metabolize ß-cypermethrin. The collective findings indicate that D. gallinae resistance to ß-cypermethrin is associated with elevated CarEs protein activity and increased Deg-CarE expression levels. These findings provide insights into the metabolic resistance of D. gallinae and offer scientific guidance for the management and control of D. gallinae.

A generic pump-free organ-on-a-chip platform for assessment of intestinal drug absorption.

Organ-on-a-chip technology has shown great potential in disease modeling and drug evaluation. However, traditional organ-on-a-chip devices are mostly pump-dependent with low throughput, which makes it difficult to leverage their advantages. In this study, we have developed a generic, pump-free organ-on-a-chip platform consisting of a 32-unit chip and an adjustable rocker, facilitating high-throughput dynamic cell culture with straightforward operation. By utilizing the rocker to induce periodic fluid forces, we can achieve fluidic conditions similar to those obtained with traditional pump-based systems. Through constructing a gut-on-a-chip model, we observed remarkable enhancements in the expression of barrier-associated proteins and the spatial distribution of differentiated intestinal cells compared to static culture. Furthermore, RNA sequencing analysis unveiled enriched pathways associated with cell proliferation, lipid transport, and drug metabolism, indicating the ability of the platform to mimic critical physiological processes. Additionally, we tested seven drugs that represent a range of high, medium, and low in vivo permeability using this model and found a strong correlation between their Papp values and human Fa, demonstrating the capability of this model for drug absorption evaluation. Our findings highlight the potential of this pump-free organ-on-a-chip platform as a valuable tool for advancing drug development and enabling personalized medicine.

Glycyrrhizin alleviates varicellovirus bovinealpha 1-induced oxidative stress, inflammation, and apoptosis in MDBK cells by inhibiting NF-κB/NLRP3 axis through the Nrf2 signalling pathway.

Varicellovirus bovinealpha 1 (BoAHV-1) is one of the crucial pathogens of bovine respiratory diseases, and its pathogenic mechanism involves oxidative stress, inflammation response, and apoptosis. Glycyrrhizin (GLY) possesses powerful antiviral, antioxidant, anti-inflammatory, and anti-apoptotic bioactivities. However, the anti-BoAHV-1 activity of GLY and its role in BoAHV-1-induced oxidative stress, inflammation, and apoptosis remain unclear. Therefore, the current study investigated the anti-BoAHV-1 effect of GLY and its ability to alleviate BoAHV-1-induced oxidative stress, inflammation, and apoptosis using an in vitro model (MDBK cells). Our results showed that BoAHV-1 titers significantly increased in MDBK cells after infection, and GLY reduced the BoAHV-1 titers in MDBK cells exposed to it. Furthermore, Interleukin (IL)-1ß, IL-8, tumor necrosis factor (TNF)-α, phosphorylated NF-κB p65 (p-NF-κB p65), the NLR pyrin domain containing 3 (NLRP3), Caspase-1, and Cleaved Caspase-3 levels were significantly upregulated when MDBK cells were challenged with BoAHV-1. In BAY 11-7085 (a specific NF-κB inhibitor) treated MDBK cells, IL-1ß, IL-8, TNF-α, p-NF-κB p65, NLRP3, Caspase-1, and Cleaved Caspase-3 levels were downregulated. Notably, GLY treatment had the same trend as the BAY 11-7085 treatment. Thus, these results suggested that GLY exerted anti-inflammatory and anti-apoptotic activities by blocking NF-κB/NLRP3 axis. In addition, after BoAHV-1 infection, the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and p-NF-κB p65 and apoptosis rate were increased, and catalase (CAT) and glutathione peroxidase (GSH-Px) enzyme activities, as well as NF-E2-related nuclear factor erythroid-2 (Nrf2) protein expression were repressed. Compared with BoAHV-1-infected MDBK cells, GLY treatment significantly downregulated intracellular ROS, MDA, and p-NF-κB p65 levels and apoptotic rates and significantly increased intracellular CAT and GSH-Px enzyme activities and Nrf2 expression. Additionally, ML385 (a specific Nrf2 inhibitor) abolished the enhancing effect of GLY on Nrf2 and the attenuating effect on ROS, p-NF-κB p65, and apoptosis. These results suggested that GLY had an anti-BoAHV-1 effect and could mitigate BoAHV-1-induced oxidative stress, inflammation, and apoptosis by activating the Nrf2 signalling and restraining NF-κB/NLRP3 axis.

Models for evaluating glioblastoma invasion along white matter tracts.

White matter tracts (WMs) are one of the main invasion paths of glioblastoma multiforme (GBM). The lack of ideal research models hinders our understanding of the details and mechanisms of GBM invasion along WMs. To date, many potential in vitro models have been reported; nerve fiber culture models and nanomaterial models are biocompatible, and the former have electrically active neurons. Brain slice culture models, organoid models, and microfluidic chip models can simulate the real brain and tumor microenvironment (TME), which contains a variety of cell types. These models are closer to the real in vivo environment and are helpful for further studying not only invasion along WMs by GBM, but also perineural invasion and brain metastasis by solid tumors.

Anisotropic evolutions of the magnetohydrodynamic Richtmyer-Meshkov instability induced by a converging shock.

The investigation of the converging shock-induced Richtmyer-Meshkov instability, which arises from the interaction of converging shocks with the interface between materials of differing densities in cylindrical capsules, is of significant importance in the field of inertial confinement fusion (ICF). The use of converging shocks, which exhibit higher efficiency than planar shocks in the development of the RMI due to the Bell-Plesset effects, is particularly relevant to energy production in the ICF. Moreover, external magnetic fields are often utilized to mitigate the development of the RMI. This paper presents a systematic investigation of the anisotropic nature of the Richtmyer-Meshkov instability in magnetohydrodynamic induced by the interaction between converging shocks and perturbed semicylindrical density interfaces (DI) based on numerical simulations using Athena++. The results reveal that magnetic fields with ß=1000, 100, and 10 (ß is defined as the ratio of the plasma pressure to the magnetic pressure) lead to an anisotropic intensification of magnetic fields, anisotropic accelerations of various shock waves [including the converging incident shock (CIS), transmitted shock (TS), and reflected shock (RS)], and anisotropic growth of the DI with subsequent anisotropic vorticity distribution. Upon closer inspection, it becomes evident that these phenomena are strongly interconnected. In particular, the region where the wave front of the CIS impacts the middle point of semicylindrical DI, where the magnetic field is more perpendicular to the fluid motion, experiences a more significant amplification of the magnetic fields. This generates higher-pressure jumps, which in turn accelerates the shock wave near this region. Furthermore, the anisotropic amplification of the magnetic fields reduces the movement of the RMI near the middle point of semicylindrical DI and leads to the anisotropic formation of RMI-induced bubbles and spikes, as well as vortices. By examining vorticity distributions, the results underscore the crucial role of magnetic tension forces in inhibiting fluid rotation.

Advances in Microfluidic Technologies in Organoid Research.

Organoids have emerged as major technological breakthroughs and novel organ models that have revolutionized biomedical research by recapitulating the key structural and functional complexities of their in vivo counterparts. The combination of organoid systems and microfluidic technologies has opened new frontiers in organoid engineering and offers great opportunities to address the current challenges of existing organoid systems and broaden their biomedical applications. In this review, the key features of the existing organoids, including their origins, development, design principles, and limitations, are described. Then the recent progress in integrating organoids into microfluidic systems is highlighted, involving microarrays for high-throughput organoid manipulation, microreactors for organoid hydrogel scaffold fabrication, and microfluidic chips for functional organoid culture. The opportunities in the nascent combination of organoids and microfluidics that lie ahead to accelerate research in organ development, disease studies, drug screening, and regenerative medicine are also discussed. Finally, the challenges and future perspectives in the development of advanced microfluidic platforms and modified technologies for building organoids with higher fidelity and standardization are envisioned.

Prognostic factors for sublingual gland carcinoma: a population-based Surveillance, Epidemiology and End Results database study.

OBJECTIVE: To identify the clinical features and prognostic factors for sublingual gland carcinoma. METHODS: This was a case-control study. Patients with surgically treated sublingual gland carcinoma were retrospectively included in the Surveillance, Epidemiology and End Results database and divided into adenoid cystic carcinoma (ACC) and non-ACC groups. Primary outcome variables were disease-specific survival (DSS) and overall survival (OS). Prognostic factors for each group were analyzed using Cox models. RESULTS: We included 251 patients (115 men and 136 women). Compared with the non-ACC group, the ACC group had a larger average tumor size and received more adjuvant radiotherapy. In patients with ACC, the pathologic grade had an independent impact on DSS and OS, and patients who were undergoing adjuvant chemotherapy had worse DSS than those who were not receiving chemotherapy. In the non-ACC group, pathologic grade IV, lymph node metastasis, and adjuvant chemotherapy were associated with poor DSS and OS, and tumor extension predicted worsening DSS. CONCLUSIONS: In sublingual gland carcinoma, the pathologic grade and adjuvant chemotherapy were the most important prognostic factors, whereas lymph node metastasis had a negative impact in non-ACC patients but not in ACC patients.

Creating mini-pregnancy models in vitro with clinical perspectives.

During the last decade, organs-on-chips or organoids microphysiological analysis platforms (MAP) have garnered attention in the practical applications of disease models, drug discovery, and developmental biology. Research on pregnant women has firm limitations due to ethical issues; thus, remodelling human pregnancy in vitro is highly beneficial for treatment modality development via disease remodelling or drug monitoring. This review highlights current efforts in bioengineering devices to reproduce human pregnancy and emphasises the significant convergence of biology, engineering, and maternal-foetal medicine. First, we review recent achievements in culturing cells from tissues involved in pregnancy; specifically, trophoblasts from the placenta. Second, we highlight developments in the reconstitution of pregnancy-related female reproductive organs across several structural and functional interpretations. Last, we examine research on the fundamental comprehension of pregnancy-associated diseases to find bioengineering solutions. Recreating human pregnancy through an engineered model is naturally complex; nevertheless, challenges are inevitable to progress precision medicine.

[One-step generation of droplet-filled hydrogel microfibers for 3D cell culture using an all-aqueous microfluidic system].

Hydrogel microfibers, which are characterized by flexible mechanical properties, a uniform spatial distribution, large surface areas, and excellent biocompatibility, hold great potential for various biomedical applications. However, the fabrication of heterogeneous hydrogel microfibers with high cell-loading capacity and the ability to carry multiple components via an environmentally friendly method remains challenging. In this study, we developed a novel pneumatic pump-assisted all-aqueous microfluidic system that enables the one-step fabrication of all-aqueous droplet-filled hydrogel microfibers with unique morphologies and adjustable configurations. By designing a pump-valve cycling system and selecting two immiscible fluids with stable water interfaces (dextran and polyethylene glycol), we successfully fabricated alginate microfibers with equidistantly arranged droplets through the ionotropic gelation reaction between sodium alginate and calcium chloride. The droplet size, interdroplet spacing, and microfiber dimensions could be flexibly controlled by adjusting the flow rates of the inner-phase, middle-phase, and outer-phase inlets. The results showed that the system enabled the high-throughput in situ formation of functional three-dimensional cell spheroids. The generated cell spheroids exhibited excellent cell viability and drug-testing functionality, indicating their potential applications in cell cultures. The developed technique offers strong support for future biomedical research and applications, and provides a new approach for the preparation of multifunctional hydrogel microfibers for materials science, tissue engineering, and drug testing.

Novel mesothelin-targeted chimeric antigen receptor-modified UNKT cells are highly effective in inhibiting tumor progression.

The design of chimeric antigen receptors (CAR) significantly enhances the antitumor efficacy of T cells. Although some CAR-T products have been approved by FDA in treating hematological tumors, adoptive immune therapy still faces many difficulties and challenges in the treatment of solid tumors. In this study, we reported a new strategy to treat solid tumors using a natural killer-like T (NKT) cell line which showed strong cytotoxicity to lyse 15 cancer cell lines, safe to normal cells and had low or no Graft-versus-host activity. We thus named it as universal NKT (UNKT). In both direct and indirect 3D tumor-like organ model, UNKT showed efficient tumor-killing properties, indicating that it could penetrate the microenvironment of solid tumors. In mesothelin (MSLN)-positive tumor cells (SKOV-3 and MCF-7), MSLN targeting CAR modified-UNKT cells had enhanced killing potential against MSLN positive ovarian cancer compared with the wild type UNKT, as well as MSLN-CAR-T cells. Compared with CAR-T, Single-cell microarray 32-plex proteomics revealed CAR-UNKT cells express more effector cytokines, such as perforin and granzyme B, and less interleukin-6 after activation. Moreover, our CAR-UNKT cells featured in more multifunctionality than CAR-T cells. CAR-UNKT cells also demonstrated strong antitumor activity in mouse models of ovarian cancer, with the ability to migrate and infiltrate the tumor without inducing immune memory. The fast-in and -out, enhanced and prolonged tumor killing properties of CAR-UNKT suggested a novel cure option of cellular immunotherapy in the treatment of MSLN-positive solid tumors.

Back acupoint location method based on prior information and deep learning.

Acupuncture points have a positive effect on the auxiliary prevention and treatment of diseases, so medical devices such as acupuncture robots often need to combine acupuncture points to improve the treatment effect when working, however, intelligent acupoint selection technology is not yet mature, the automatic rapid and accurate positioning of acupoints is still challenging. Therefore, this paper proposes a method of back acupoint location and an evaluation index of acupoint location. First, we propose an improved Keypoint RCNN network for the preliminary location of back acupoints and introduce a channel and spatial attention mechanism module (CBAM) to improve the performance of the model. Then, we set up a posterior median line positioning method to improve the accuracy of acupoint positioning. Finally, expand and locate other acupoints according to the prior information of acupoints. According to the experimental results, the accuracy of acupoint positioning was 87.32%. After the correction of acupoint positioning, the accuracy was increased by 2.8%, which was 90.12%. In this paper, the application of depth learning in automatic location of back acupoints is realized for the first time. Only one image can be used to locate the back acupoints, with an accuracy of 90.12%.

RNA helicase DExD/H-box 5 modulates intestinal microbiota in mice.

The RNA helicase DExD/H-box (DDX) family of proteins plays a central role in host cellular RNA metabolism, including mRNA regulation, microRNA biogenesis, and ribosomal processing. DDX5, also known as p68, promotes viral replication and tumorigenesis. However, there have been no studies on the regulation of the intestinal microbiota by DDX family proteins. We constructed DDX5 knockout mice (Ddx5+/-) using CRISPR/CAS9 technology. Subsequently, DDX5 knockout mice were analyzed for PCR products, mRNA levels, protein expression, immunohistochemistry, and histopathological lesions. Fecal (n = 12) and ileum (n = 12) samples were collected from the Ddx5+/- and wild-type (Ddx5+/+) mice. The diversity, richness, and structural separation of the intestinal microbiota of the Ddx5+/- and Ddx5+/+ mice were determined by 16S rRNA sequencing and analysis. Ddx5+/- mice were successfully established, and the ileum had normal morphology, a clear layer of tissue structures, and neatly arranged cupped cells. DDX5 knockout mice did not exhibit adverse effects on the ileal tissue. Microbial diversity and abundance were not significantly different, but the microbial structure of the intestinal microbiota was clustered separately between Ddx5+/+ and Ddx5+/- mice. Furthermore, we found that the relative abundance of Akkermansia and Clostridium_sensu_stricto_1 in the Ddx5+/- mice was significantly lower than in the Ddx5+/+ mice. These analyses indicated specific interactions between the intestinal microbiota and DDX5 protein. Our results indicate that DDX5 has a significant effect on the composition of the intestinal microbiota in mice, suggesting its potential as a promising novel target for the treatment of inflammation and tumorigenesis in the intestine.

Recent advances in defined hydrogels in organoid research.

Organoids are in vitro model systems that mimic the complexity of organs with multicellular structures and functions, which provide great potential for biomedical and tissue engineering. However, their current formation heavily relies on using complex animal-derived extracellular matrices (ECM), such as Matrigel. These matrices are often poorly defined in chemical components and exhibit limited tunability and reproducibility. Recently, the biochemical and biophysical properties of defined hydrogels can be precisely tuned, offering broader opportunities to support the development and maturation of organoids. In this review, the fundamental properties of ECM in vivo and critical strategies to design matrices for organoid culture are summarized. Two typically defined hydrogels derived from natural and synthetic polymers for their applicability to improve organoids formation are presented. The representative applications of incorporating organoids into defined hydrogels are highlighted. Finally, some challenges and future perspectives are also discussed in developing defined hydrogels and advanced technologies toward supporting organoid research.

Blood-brain barrier injury and neuroinflammation induced by SARS-CoV-2 in a lung-brain microphysiological system.

In some patients, COVID-19 can trigger neurological symptoms with unclear pathogenesis. Here we describe a microphysiological system integrating alveolus and blood-brain barrier (BBB) tissue chips that recapitulates neuropathogenesis associated with infection by SARS-CoV-2. Direct exposure of the BBB chip to SARS-CoV-2 caused mild changes to the BBB, and infusion of medium from the infected alveolus chip led to more severe injuries on the BBB chip, including endothelial dysfunction, pericyte detachment and neuroinflammation. Transcriptomic analyses indicated downregulated expression of the actin cytoskeleton in brain endothelium and upregulated expression of inflammatory genes in glial cells. We also observed early cerebral microvascular damage following lung infection with a low viral load in the brains of transgenic mice expressing human angiotensin-converting enzyme 2. Our findings suggest that systemic inflammation is probably contributing to neuropathogenesis following SARS-CoV-2 infection, and that direct viral neural invasion might not be a prerequisite for this neuropathogenesis. Lung-brain microphysiological systems should aid the further understanding of the systemic effects and neurological complications of viral infection.

Study on the Difference in CO2 and Air Injection in the Fracture/Matrix Dual Medium of Continental Shale Reservoirs.

To clarify the impact of different displacement media on the enhanced oil recovery of continental shale and realize the efficient and reasonable development of shale reservoirs, this paper takes the continental shale of the Lucaogou Formation in the Jimusar Sag in the Junggar Basin (China, Xinjiang) as the research object and uses real cores to build the fracture/matrix dual-medium model. Computerized tomography (CT) scanning is used to visually compare and analyze the influence of fracture/matrix dual-medium and single-matrix medium seepage systems on oil production characteristics and clarify the difference between air and CO2 in enhancing the oil recovery of continental shale reservoirs. Through a comprehensive analysis of the production parameters, the whole oil displacement process can be divided into three stages: the oil-rich and gas-poor stage, oil and gas coproduction stage, and gas-rich and oil-poor stage. Shale oil production follows the rule of fractures first and matrix second. However, for CO2 injection, after the crude oil in the fractures is recovered, the oil in the matrix migrates to the fractures under the action of CO2 dissolution and extraction. Overall, the oil displacement effect of CO2 is better than that of air, resulting in a 5.42% higher final recovery factor. Additionally, fractures can increase the permeability of the reservoir, which can greatly enhance oil recovery in the early oil displacement process. However, as the amount of injected gas increases, its impact gradually decreases, and ultimately, it is consistent with the recovery of nonfractured shale, which can achieve nearly the same development effect.

Multi-organ microphysiological system: A new paradigm for COVID-19 research.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, is a systemic disease with a broad spectrum of manifestations in multiple organs. Till now, it remains unclear whether these multi-organ dysfunctions arise from direct viral infection, or indirect injuries. There is an urgent need to evaluate the impacts of SARS-CoV-2 infection on human bodies and explore the pathogenesis of extrapulmonary organ injuries at a systemic level. Multi-organ microphysiological systems, which can model whole-body physiology with engineered tissues and physiological communications between different organs, serve as powerful platforms to model COVID-19 in a multi-organ manner. In this perspective, we summarize the recent advancement in multi-organ microphysiological system-based researches, discuss the remaining challenges, and proposed some prospects in the application of multi-organ model system for COVID-19 research.

Self-assembled human placental model from trophoblast stem cells in a dynamic organ-on-a-chip system.

The placental barrier plays a key role in protecting the developing fetus from xenobiotics and exchanging substances between the fetus and mother. However, the trophoblast cell lines and animal models are often inadequate to recapitulate the key architecture and functional characteristics of human placental barrier. Here, we described a biomimetic placental barrier model from human trophoblast stem cells (hTSCs) in a perfused organ chip system. The placental barrier was constructed by co-culture of hTSCs and endothelial cells on the opposite sides of a collagen-coated membrane on chip. hTSCs can differentiate into cytotrophoblasts (CT) and syncytiotrophoblast (ST), which self-assembled into bilayered trophoblastic epithelium with placental microvilli-like structure under dynamic cultures. The formed placental barrier displayed dense microvilli, higher level secretion of human chorionic gonadotropin (hCG), enhanced glucose transport activity. Moreover, RNA-seq analysis revealed upregulated ST expression and activation of trophoblast differentiation-related signalling pathways. These results indicated the key role of fluid flow in promoting trophoblast syncytialization and placental early development. After exposure to mono-2-ethylhexyl phthalate, one of the endocrine disrupting chemicals, the model showed inhibited hCG production and disturbed ST formation in trophoblastic epithelium, suggesting impaired placental structure and function elicited by environmental toxicants. Collectively, the hTSCs-derived placental model can recapitulate placenta physiology and pathological response to external stimuli in a biomimetic manner, which is useful for the study of placental biology and associated diseases.