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Background: Metabolic disorder increases the risk of abdominal aortic aneurysm (AAA). NRs (nuclear receptors) have been increasingly recognized as important regulators of cell metabolism. However, the role of NRs in AAA development remains largely unknown. Methods: We analyzed the expression profile of the NR superfamily in AAA tissues and identified NR1D1 (NR subfamily 1 group D member 1) as the most highly upregulated NR in AAA tissues. To examine the role of NR1D1 in AAA formation, we used vascular smooth muscle cell (VSMC)–specific, endothelial cell–specific, and myeloid cell–specific conditional Nr1d1 knockout mice in both AngII (angiotensin II)– and CaPO 4 -induced AAA models. Results: Nr1d1 gene expression exhibited the highest fold change among all 49 NRs in AAA tissues, and NR1D1 protein was upregulated in both human and murine VSMCs from AAA tissues. The knockout of Nr1d1 in VSMCs but not endothelial cells and myeloid cells inhibited AAA formation in both AngII- and CaPO 4 -induced AAA models. Mechanistic studies identified ACO2 (aconitase-2), a key enzyme of the mitochondrial tricarboxylic acid cycle, as a direct target trans-repressed by NR1D1 that mediated the regulatory effects of NR1D1 on mitochondrial metabolism. NR1D1 deficiency restored the ACO2 dysregulation and mitochondrial dysfunction at the early stage of AngII infusion before AAA formation. Supplementation with αKG (α-ketoglutarate, a downstream metabolite of ACO2) was beneficial in preventing and treating AAA in mice in a manner that required NR1D1 in VSMCs. Conclusions: Our data define a previously unrecognized role of nuclear receptor NR1D1 in AAA pathogenesis and an undescribed NR1D1-ACO2 axis involved in regulating mitochondrial metabolism in VSMCs. It is important that our findings suggest αKG supplementation as an effective therapeutic approach for AAA treatment.

Compared with traditional computed tomography (CT), dual-layer spectral detector CT (SDCT) shows significant improvement in imaging soft tissues of the digestive tract. This work aimed to explore the application of SDCT to evaluate the expression of the molecular marker Ki-67 in colorectal cancer.We retrospectively analyzed the imaging data of the SDCT (IQon Spectral CT; Philips Healthcare) of 45 patients with colorectal cancer in our centre. We used Spearman's test for the imaging parameters (reconstruction of 40, 70, and 100 keV virtual monoenergetic images [VMIs] and the slope of the Hounsfield unit attenuation plot [VMI Slope] based on venous phase CT images, the arterial phase iodine concentration [AP-IC] and venous phase iodine concentration [VP-IC], and the effective atomic number [Z effect]) and correlation analysis for the Ki-67 index. Multivariate logistic regression was used to eliminate confounding factors. We evaluated the expression level of Ki-67 and drew the receiver operating characteristic curve.The 40-keV VMI, VMI Slope, and AP-IC were found to better reflect the Ki-67 index in patients with colorectal cancer with statistical significance. The 40-keV VMI (r = -0.612, p0.001) and VMI Slope (r = -0.523, p0.001) were negatively correlated with the Ki-67 index, and AP-IC (r = 0.378, p = 0.010) was positively correlated with the Ki-67 index. The other indexes (p0.05) were not statistically significant. The SDCT parameters demonstrated good performance, with area under curves of 0.785 for 40-keV VMI and 0.752 for AP-IC.The SDCT parameters 40-keV VMI and AP-IC can be used for preliminary evaluation of the Ki-67 index in colorectal cancer.

To evaluate the efficacy and safety of marking ground glass nodules (GGNs) with pulmonary nodules localization needle (PNLN) prior to video-assisted thoracoscopic surgery (VATS).From June 2020 to February 2021, all patients with GGNs who received CT-guided localization using PNLN before VATS were enrolled. Clinical and imaging data were retrospectively analyzed.A total of 352 consecutive patients with 395 GGNs were included in the study. The mean diameter of GGNs was 0.95 ± 0.48 cm, and the shortest distance from nodules to the pleura was 1.73 ± 0.96 cm. All 395 GGNs were marked using PNLNs. The time required for marking was 7.8 ± 2.2 min. The marking success rate was 99.0% (391/395). The marking failure of four nodules was all due to the unsatisfactory position of PNLNs. No marker dislocation occurred. Marking-related complications included pneumothorax in 63 cases (17.9%), hemorrhage in 34 cases (9.7%), and hemoptysis in 6 cases (1.7%). All the complications were minor and did not need special treatment. Localization and VATS were performed on the same day in 95 cases and on different days in 257 cases. All GGNs were successfully removed by VATS. No patient converted to thoracotomy. Histopathological examination revealed 74 (18.7%) benign nodules and 321 (81.3%) malignant nodules.It is safe and reliable to perform preoperative localization of GGNs using PNLNs, which can effectively guide VATS to remove GGNs.• Preoperative localization of GGNs could effectively guide VATS to remove GGNs. • PNLN was based on the marking principle of hook-wire, through the improvement of its material, specially designed to mark pulmonary nodules. • The application of PNLN to mark GGNs had high success rate, good patient tolerance, and no dislocation. Meanwhile, VATS could be performed 2 to 3 days after marking GGNs with PNLN.

Immune checkpoints are the crucial regulators of immune system and play essential roles in maintaining self-tolerance, preventing autoimmune responses, and minimizing tissue damage by regulating the duration and intensity of the immune response. Furthermore, immune checkpoints are usually overexpressed in cancer cells or noninvasive cells in tumor tissues and are capable of suppressing the antitumor response. Based on substantial physiological analyses as well as preclinical and clinical studies, checkpoint molecules have been evaluated as potential therapeutic targets for the treatment of multiple types of cancers. In the last few years, extensive evidence has supported the immunoregulatory effects of traditional Chinese medicines (TCMs). The main advantage of TCMs and natural medicine is that they usually contain multiple active components, which can act on multiple targets at the same time, resulting in additive or synergistic effects. The strong immune regulation function of traditional Chinese medicine on immune checkpoints has also been of great interest. For example, Astragalus membranaceus polysaccharides can induce anti-PD-1 antibody responses in animals, and these antibodies can overcome the exhaustion of immune cells under tumor immune evasion. Furthermore, many other TCM molecules could also be novel and effective drug candidates for the treatment of cancers. Therefore, it is essential to assess the application of immune checkpoints in the development of new drugs and TCMs. In this review, we focus on research progress in the field of immune checkpoints based on three topics: (1) immune checkpoint targets and pathways, (2) development of novel immune checkpoint-based drugs, and (3) application of immune checkpoints in the development of TCMs., Graphical abstract In this review, we provide a discussion of the applications of immune checkpoints in the development of novel drugs and TCMs.Image 1

This study aims to explore the effectiveness of exchange programs between Taiwan and mainland China in terms of shaping participants’ support for Taiwan, given that the cross-strait relationship has reached a deadlock. Academic and social involvement, social contact, social identity, patriotism, animosity, and political familiarity were integrated into a theoretical framework. The participants, who have joined an exchange program commissioned by the Mainland Affairs Council in Taiwan, were invited. The results showed that the level of involvement can either positively influence patriotism and support for Taiwan, or negatively influence animosity, whereas patriotism can positively influence animosity. This seemingly contradicting result indicates that exchange students who went back to mainland China have developed a coping mechanism in which patriotism does not dominate their support for Taiwan. Hence, the exchange programs, to some extent, were effective in promoting support for Taiwan.

This study aimed to add two functional components—antibacterial 45S5BGs particles and AIE nanoparticles (TPE-NIM+) with bioprobe characteristics—to the guided tissue regeneration (GTR) membrane, to optimize the performance. The PLGA/BG/TPE-NIM+ membrane was synthesized. The static water contact angle, morphologies, and surface element analysis of the membrane were then characterized. In vitro biocompatibility was tested with MC3T3-E1 cells using CCK-8 assay, and antibacterial property was evaluated with Streptococcus mutans and Porphyromonas gingivalis by the LIVE/DEAD bacterial staining and dilution plating procedure. The fluorescence staining of bacteria was observed by Laser Scanning Confocal Microscope. The results showed that the average water contact angle was 46°. In the cytotoxicity test, except for the positive control group, there was no significant difference among the groups (p > 0.05). The antibacterial effect in the PLGA/BG/TPE-NIM+ group was significantly (p < 0.01), while the sterilization rate was 99.99%, better than that in the PLGA/BG group (98.62%) (p < 0.01). Confocal images showed that the membrane efficiently distinguished G+ bacteria from G− bacteria. This study demonstrated that the PLGA/BG/TPE-NIM+ membrane showed good biocompatibility, efficient sterilization performance, and surface mineralization ability and could be used to detect pathogens in a simple, fast, and wash-free protocol.

Recent investigations of gut microbiota have contributed to understanding of the critical role of microbial community in pathophysiology. Dysbiosis not only causes disturbance directly to the gastrointestinal tract but also affects the liver through gut-liver axis. Various types of dysbiosis have been documented in alcoholic liver disease (ALD), nonalcoholic fatty liver disease, autoimmune hepatitis (AIH), primary sclerosing cholangitis, and may be crucial for the initiation, progression, or deterioration to end-stage liver disease. A few microbial species have been identified as the causal factors leading to these chronic illnesses that either do not have clear etiologies or lack effective treatment. Notably, cytolysin-producing Enterococcus faecalis, Klebsiella pneumoniae and Enterococcus gallinarum were defined for ALD, NASH, and AIH, respectively. These groundbreaking discoveries drive a rapid development in innovative therapeutics, such as fecal microbial transplantation and implementation of specific bacteriophages in addition to prebiotics, probiotics, or synbiotics for intervention of dysbiosis. Although most emerging interventions are in preclinical development or early clinical trials, a better delineation of specific dysbiosis in these disorders at metabolic, immunogenic, or molecular levels in establishing particular causal effects aids in modulating or correcting the microbial community which is the part of daily life for human being.

Many types of adherent cells are known to reorient upon uniaxial cyclic stretching perpendicularly to the direction of stretching to facilitate such important events as wound healing, angiogenesis, and morphogenesis. While this phenomenon has been documented for decades, the underlying mechanism remains poorly understood. Using an on-stage stretching device that allowed programmable stretching with synchronized imaging, we found that the reorientation of NRK epithelial cells took place primarily during the relaxation phase when cells underwent rapid global retraction followed by extension transverse to the direction of stretching. Inhibition of myosin II caused cells to orient along the direction of stretching, whereas disassembly of microtubules enhanced transverse reorientation. Our results indicate distinct roles of stretching and relaxation in cell reorientation and implicate a role of myosin II-dependent contraction via a microtubule-modulated mechanism. The importance of relaxation phase also explains the difference between the responses to cyclic and static stretching.

The main problem in investigating the band gap energy of the dilute oxygen CdxZn1-xOyTe1-y is how to set up a model to predict its band gap energy in a wide composition range. In this work, a model predicting the band gap energy of the dilute oxygen CdxZn1-xOyTe1-y is established. The result shows that the model can offer an excellent estimation. Three findings are as follows. (1) Incorporating Cd fraction in the dilute oxygen ZnOyTe1-y alloy can lower the Г CBM of CdxZn1-xOyTe1-y, resulting in a complex alteration of the coupling interaction between the oxygen level and the Г CBM of CdxZn1-xTe. (2) The variations of the cation and anion fractions influence the different parts of the parameter which describes the coupling interaction. (3) The localized oxygen level can not only be lined up in the common-cation systems, but also be lined up in common-anion systems if the small location differences in the different host materials are ignored.

Network pharmacology is a powerful tool to reflect the pharmacologically active effects, mechanism of action and toxic activity of traditional Chinese medicines (TCMs). The ingredients of TCMs, associated with quality control of TCM products, are those fundamental chemicals that exhibit biological activities. A great amount of effort has been made by scientists in that field in order to improve the quality of TCMs, though the approaches to determine their quality and the TCM theory and compatibility rules remain ambiguous. Now some methods and technologies must be applied to predict and explore the quality marker (Q-marker) for quality control, as well as to clarify the factors affecting the quality of TCM, which may give new insight into rational ground of establishment of appropriate quality control and assessment system. In this review paper, authors focus on the prediction of quality markers of TCMs by network pharmacology based on three aspects: (1) from network medicine to network pharmacology, (2) complex network system of traditional Chinese medicine, and (3) predicting TCM quality markers based on network pharmacology. Authors proposed the research pattern on network pharmacology based on biological and medical networks, and further TCM network pharmacology based on substantial basis of TCM formulae, and the idea of “effect-ingredient-target-fingerprint” to predict and recognize the TCM Q-marker was the ultimate goal. In addition, authors yet noted how to make full use of the advantages of network toxicology to provide new ideas for the toxicity study of complex TCM systems and the prediction of TCM toxicity markers.

Knowledge of the geologic structure at a field site is a useful piece of information for hydrologic modeling since it can serve as more site-specific prior information about the hydraulic parameter patterns at the site than generic spatial statistics. Widely accepted electrical resistivity tomography (ERT) survey for mapping subsurface anomalies could be a viable tool for acquiring this information. However, their ability to delineate geologic structures has not been thoroughly investigated. In this study, two-dimensional ERT numerical experiments were first conducted to study the effects of boundary conditions on the dipole-dipole and pole-pole array configurations. An ERT setup subsequently was implemented in a sandbox consisting of complex layers of different sands. A continuous copper wire was installed along the sides of the sandbox to impose potential boundaries. Using data collected with the pole-pole array in the sandbox under different degrees of drainage and the Successive Linear Estimator (SLE) algorithm, we show that ERT yields electrical conductivity estimates of complex layer structures with small uncertainties. In addition, using SLE with physically meaningful correlation scales as prior information can lead to an electrical conductivity field that is consistent with visually observed layer structures. The correlation scale concept also was demonstrated to provide guidance to the design of the electrode spacing in the surveys. Moreover, the estimated field was validated by predicting electrical potential fields from two independent ERT surveys using electrodes at different locations. Results of this study suggest that the combination of ERT and SLE is a viable geophysical survey tool for mapping geologic layer structures. Research Significance This study develops a method to implement prescribed potential boundaries for enhancing the pole-pole ERT survey, illustrates the importance of correlation scales and develops an approach for validating ERT results.

U.S. Civilian Research and Development Foundation (CRDF Global) [DAA2-15-61224-1]; Global Expert award through Tianjin Normal University from the Thousand Talents Plan of Tianjin City

Esophageal cancer (EC) is one of the most deadly malignant diseases. Several studies revealed that variations of the phospholipase C epsilon 1 (PLCE1) gene were associated with EC susceptibility. PLCE1 is located downstream of the epidermal growth factor receptor (EGFR) pathway. Presently, the single nucleotide polymorphisms (SNPs) of EGFR/PLCE1 genes and their associations with EC survival remain unclear. In this study, the associations between genetic variants in the EGFR/PLCE1 pathway and prognosis in 124 esophageal squamous cell carcinoma (ESCC) patients with radical resection were explored. The results showed that CC genotype of both PLCE1 rs17109671 and EGFR rs2072454 was associated with ESCC prognosis. Multivariate analysis revealed that patients with the two unfavorable genotypes had the worst overall survival (OS) or disease-free survival (DFS) (HR=6.099, 95%CI=1.903-19.552; HR=3.994, 95%CI=1.49-10.702, respectively). Additionally, combination of SNPs and tumor stage could better predict OS (for AUC, 0.774 vs. 0.709) and PFS (for AUC, 0.773 vs. 0.704) than tumor stage alone. In conclusion, genetic variants of the EGFR/PLCE1 may be predictors of the prognosis of ESCC after surgery. The individuals with the CC genotype of PLCE1 rs17109671 and EGFR rs2072454 should receive more aggressive treatments.

Pump-and-treat (P&T) is a widely adopted technology for groundwater containment/remediation. Over the past decades, we have recognized that mapping aquifer heterogeneity, especially the low hydraulic conductivity (K) zones, has become an urgent need in remediation efforts. Meanwhile, many studies have proved that hydraulic tomography (HT) utilizing groundwater responses from a series of cross-hole pumping tests is a viable technology for detailing hydraulic heterogeneity (high and low K zones) of aquifers. At a P&T field site, operation of pumping and injection wells often vary, creating changes in flow fields analogous to those in HT surveys. Therefore, collecting groundwater monitoring data and analyzing them is tantamount to a cost-effective large-scale HT survey during P&T operations. To demonstrate this idea, water level data was collected at 41 wells for one year at the U.S. Air Force Plant 44 (AFP44) P&T site in Tucson, Arizona, where the pumping and injection rates of the P&T system were changed many times during the year. This dataset was analyzed with a geostatistical inverse model to estimate the hydraulic property distribution, which can reasonably predict the pressure responses of the site under different conditions. Moreover, we showed that large-scale geological information, built based on 245 borehole logs at the site, could improve the model calibration performance through a two-step calibration procedure. Additionally, we used synthetic experiments to verify that the use of a larger variety of P&T configurations can yield non-redundant HT information, and enhance site characterization. Overall, we demonstrated that the proper scheduling of pumping and injection operations at a P&T site and collecting corresponding groundwater responses are equivalent to conducting a large-scale HT survey, with minimal additional costs.

Hydraulic tomography (HT) has emerged as a potentially viable method for mapping fractures in geologic media as demonstrated by recent studies. However, most of the studies adopted equivalent porous media (EPM) models to generate and invert hydraulic interference test data for HT. While these models assign significant different hydraulic properties to fractures and matrix, they may not fully capture the discrete nature of the fractures in the rocks. As a result, HT performance may have been overrated. To explore this issue, this study employed a discrete fracture network (DFN) model to simulate hydraulic interference tests. HT with the EPM model was then applied to estimate the distributions of hydraulic conductivity (K) and specific storage (S-s) of the DFN. Afterward, the estimated fields were used to predict the observed heads from DFN models, not used in the HT analysis (i.e., validation). Additionally, this study defined the spatial representative elementary volume (REV) of the fracture connectivity probability for the entire DFN dominant. The study showed that if this spatial REV exists, the DFN is deemed equivalent to EPM and vice versa. The hydraulic properties estimated by HT with an EPM model can then predict head fields satisfactorily over the entire DFN domain with limited monitoring wells. For a sparse DFN without this spatial REV, a dense observation network is needed. Nevertheless, HT is able to capture the dominant fractures.

Over the past decades, a new aquifer test technology (sequential pumping tests or hydraulic tomography, HT) has been developed and successfully applied to many field sites to delineate the spatial distributions of hydraulic properties (e.g., transmissivity (T) and storage coefficient (S)). Yet, the reproducibility of its estimated T and S fields and the predictive capabilities of the estimates for different flow scenarios at different time periods remain unexplored. That is to say, if the estimated fields based on sequential pumping tests conducted during different years are the same since the geologic formation and processes may have undergone changes. In order to answer this important question, this study first compares the drawdown-time behaviors from the sequential pumping tests (SPTs) conducted in 2010 with those conducted in 2012 at a field site and then finds they are similar but different in detail. It then uses these data to estimate the T and S fields and checks the reproducibility of the estimates. The estimated heterogeneity patterns are found to be generally reproducible in spite of uncertainties. In addition, the estimates from each year are capable of predicting the observed drawdowns, induced by independent pumping tests during the corresponding year (i.e., self-validation). Moreover, the estimated fields are cross-validated. That is, this study uses the estimates obtained from the 2010 pumping tests to predict the observed drawdowns of the independent pumping tests conducted in 2012. Likewise, it uses the estimates from 2012 pumping tests to forecast the drawdowns of the independent pumping tests of 2010. The results of both self-validation and cross-validation indicate that the estimated T and S fields based on the test in one year can be used to predict bulk flow behavior in the other year. Differences in detailed behaviors may be attributed to changes in the processes, omitted in the depth-averaged flow model.

We developed a novel preparative method for nanoparticle albumin-bound (nab) paclitaxel with high drug loading, which was based on improved paclitaxel solubility in polyethylene glycol (PEG) and self-assembly of paclitaxel in PEG with albumin powders into nanoparticles. That is, paclitaxel and PEG were firstly dissolved in ethanol, which was subsequently evaporated under vacuum. The obtained liquid was then mixed with human serum albumin powders. Thereafter, the mixtures were added into phosphate-buffered saline and nab paclitaxel suspensions emerged after ultrasound. Nab paclitaxel was finally acquired after dialysis and freeze drying. The drug loading of about 15% (W/V) were realized in self-made nab paclitaxel, which was increased by approximately 50% compared to 10% (W/V) in Abraxane. Now this new preparative method has been authorized to obtain patent from China and Japan. The similar characteristics of self-made nab paclitaxel compared to Abraxane were observed in morphology, encapsulation efficiency, in vitro release, X-ray diffraction analysis, differential scanning calorimetry analysis, and circular dichroism spectra analysis. Consistent concentration-time curves in rats, biodistributions in mice, anti-tumor activities in mice, and histological transmutation in mice were also found between Abraxane and self-made nanoparticles. In a word, our novel preparative method for nab paclitaxel can significantly improve drug loading, obviously decrease product cost, and is considered to have potent practical value.

Many types of adherent cells are known to reorient upon uniaxial cyclic stretching perpendicularly to the direction of stretching to facilitate such important events as wound healing, angiogenesis, and morphogenesis. While this phenomenon has been documented for decades, the underlying mechanism remains poorly understood. Using an on-stage stretching device that allowed programmable stretching with synchronized imaging, we found that the reorientation of NRK epithelial cells took place primarily during the relaxation phase when cells underwent rapid global retraction followed by extension transverse to the direction of stretching. Inhibition of myosin II caused cells to orient along the direction of stretching, whereas disassembly of microtubules enhanced transverse reorientation. Our results indicate distinct roles of stretching and relaxation in cell reorientation and implicate a role of myosin II-dependent contraction via a microtubule-modulated mechanism. The importance of relaxation phase also explains the difference between the responses to cyclic and static stretching.

Adherent cells cultured on flat, homogeneous surfaces typically maintain an intact cell body with a polygonal or fan shape, despite active migration and strong mechanical interactions with the substratum. We hypothesized that, in addition to the constraint of the surface membrane, an active mechanism may be involved in maintaining the shape and integrity of the cell body particularly where cells encounter complex topographic patterns of guidance cues. To detect if there is a mechanism that constrains cell shape, we plated NIH 3T3 fibroblasts on ring-patterned substrata 8–17.5 microns in width and 53–133 microns in outer diameter. Untreated cells have a limited angular span, encompassing an average of 108 degrees around the ring, even though these cells were able to cover a much larger surface when plated on flat surfaces of the same material. Treatment of 3T3 cells with a myosin II inhibitor, blebbistatin, induced a striking increase in the bending ability, causing cells to cover more than 60% of the ring. Inhibition of the Rho-dependent kinase with Y-27632 caused a similar but smaller increase in the angular span. Our results suggest that cell shape is controlled not only by the passive constraint of the surface membrane but also by an active mechanism driven by myosin II-mediated contractility under the regulation of Rho-dependent kinase. The inward surface tension-like forces allow the cell to maintain its integrity while navigating through complex physiological environments.

Due to its favorable physical and chemical properties, including chemical inertness, low fouling by biological molecules, high porosity and permeability, optical transparency, and adjustable elasticity, polyacrylamide has found a wide range of biomedical and non-biomedical applications. To further increase its versatility, this communication describes a simple method, using readily available reagents and equipment, for 3D printing polyacrylamide hydrogels at a resolution of 100–150 microns to create complex structures. As a demonstration of the application, the method is used for creating a lab-on-a-chip cell culture surface with micropatterned stiffness, which then led to the discovery of stiffness-guided collective cell segregation distinct from durotaxis. The present technology is expected to unleash new applications such as the construction of biocompatible elastic medical devices and artificial organs.

The COVID-19 epidemic, which is caused by the novel coronavirus SARS-CoV-2, has spread rapidly to become a world-wide pandemic. Chest radiography and chest CT are frequently used to support the diagnosis of COVID-19 infection. However, multiple cases of COVID-19 transmission in radiology department have been reported. Here we summarize the lessons we learned and provide suggestions to improve the infection control and prevention practices of healthcare workers in departments of radiology.

The outbreak of 2019 novel coronavirus (2019-nCoV) pneumonia was reported in Wuhan, Hubei Province, China in December 2019 and has spread internationally. This article discusses how radiology departments can most effectively respond to this public health emergency.

The COVID-19 epidemic has swept across China and spread to other countries. The rapid spreading of COVID-19 and panic combined with the lack of a hierarchical medical system in China have resulted in a huge number of hospital visiting which are overwhelming local medical system and increasing the incidence of cross infection. To meliorate this situation, we adopted the management concept of the system of Tiered Diagnosis and Treatment and developed an online tool for self-triage based on the mostly used multi-purpose smartphone app Wechat in China. This online tool helps people perform self-triage so that they can decide whether to quarantine at home or visit hospital. This tool further provides instructions for home quarantine and help patients make an appointment online if hospital visiting suggested. This smartphone application can reduce the burden on hospitals without losing the truly COVID-19 patients and protect people from the danger of cross infection.

To properly account the subsurface heterogeneity, geostatistical inverse models usually permit enormous amount of spatial correlated parameters to interpret the collected states. Several reduced-order techniques for the brick domain are investigated to leverage the memory burden of parameter covariance. Their capability to irregular domain is limited. Furthermore, due to the over fitting of states, the estimated parameters usually diverge to unreasonable values. Although some propriate tolerances can be used to eliminate this problem, they are presumed and heavily rely on the personal judgement. To address these two issues, we present a model reduction technique to the irregular domain by singular value decomposition (SVD). Afterward, the state errors and parameters are sequentially updated to leverage the over fitting. The computational advantages of the proposed reduced-order dual state-parameter inverse algorithm are demonstrated through two numerical experiments and one case study in a catchment scale field site. The investigations suggest that the stability of convergence dramatically improves. The estimated parameter values stabilize to reasonable order of magnitude. In addition, the memory requirement significantly reduces while the resolution of estimate preserves. The proposed method benefits multi-discipline scientific problems, especially useful and convenient for assimilating different types of measurements.

The design of artificial tissues and implantable devices must incorporate the knowledge of how cells and tissues respond to changes in mechanical forces or properties introduced into the body. Mechanobiology is a field that investigates these fundamentals, including not only the biological responses to mechanical signals but also how cells convert external mechanical stimuli into internal chemical signals, and how they communicate mechanically with their environment and with each other. Mechanobiology is thus crucial to the understanding of many clinically relevant biological phenomena, such as morphogenesis, tissue regeneration, and cancer metastasis, and to the development of medical applications such as implants, wound healing, and tissue engineering.

Contact inhibition of locomotion (CIL), the repulsive response of cells upon cell–cell contact, has been the predominant paradigm for contact-mediated responses. However, it is difficult for CIL alone to account for the complex behavior of cells within a multicellular environment, where cells often migrate in cohorts such as sheets, clusters, and streams. Although cell–cell adhesion and mechanical interactions play a role, how individual cells coordinate their migration within a multicellular environment remains unclear. Using micropatterned substrates to guide cell migration and manipulate cell–cell contact, we show that contacts between different regions of cells elicit different responses. Repulsive responses were limited to interaction with the head of a migrating cell, while contact with the tail of a neighboring cell promoted migration toward the tail. The latter behavior, termed contact following of locomotion (CFL), required the Wnt signaling pathway. Inhibition of the Wnt pathway disrupted not only CFL but also collective migration of epithelial cells, without affecting the migration of individual cells. In contrast, inhibition of myosin II with blebbistatin disrupted the migration of both individual epithelial cells and collectives. We propose that CFL, in conjunction with CIL, plays a major role in guiding and coordinating cell migration within a multicellular environment.

The objectives of this paper are (1) to introduce a numerical first order method to calculate the gas containment reliability within a heterogeneous, two-dimensional, unlined rock caverns (URCs), and (2) to suggest a strategy for improving the gas containment reliability. In order to achieve these goals, we first analyzed the spatial variability of saturated hydraulic conductivity (Ks) at a field site. We then conducted deterministic simulations to demonstrate the importance of heterogeneity of Ks in the analysis of gas tightness performance of URCs. Considering the uncertainty of the heterogeneity in the real world situations, we subsequently developed a numerical first order method (NFOM) to determine the gas tightness reliability at crucial locations of URCs. Using the NFOM, the effect of spatial variability of Ks on gas tightness reliability was investigated. Results show that as variance or spatial structure anisotropy of Ks increases, most of the gas tightness reliability at crucial locations reduces. Meanwhile, we compare the results of NFOM with those of Monte Carlo simulation, and we find the accuracy of NFOM is mainly affected by the magnitude of the variance of Ks. At last, for improving gas containment reliability at crucial locations at this study site, we suggest that vertical water-curtain holes should be installed in the pillar rather than increasing density of horizontal water-curtain boreholes.

This paper develops a sequential displacement data collection and back analysis approach for mapping spatially distributed Young’s modulus (E) in a rock mass during the excavation of an unlined rock cavern (URC). Results show that this approach provides an unbiased estimate of the E field and its uncertainty. It also reveals a more detailed E distribution than kriging approach, which is based on samples of E values from boreholes before excavations. Further, predicted shear strain distribution and displacement of cavern periphery based on the estimates from this approach are more accurate than those based on the kriging estimate.

This paper develops a finite analytic method (FAM) for solving the two-dimensional Richards' equation. The FAM incorporates the analytic solution in local elements to formulate the algebraic representation of the partial differential equation of unsaturated flow so as to effectively control both numerical oscillation and dispersion. The FAM model is then verified using four examples, in which the numerical solutions are compared with analytical solutions, solutions from VSAFT2, and observational data from a field experiment. These numerical experiments show that the method is not only accurate but also efficient, when compared with other numerical methods.

Objectives: To compare the efficacy and safety of pre-operative localization of ground glass nodule (GGN) using embolization microcoils and the locating needles designed for pulmonary nodules. Methods: From June 2019 to December 2020, 429 patients who received CT-guided localization of single GGN before video-assisted thoracoscopic surgery (VATS) were enrolled. The diameter and depth of GGNs were 0.84 ± 0.39 cm and 1.66 ± 1.37 cm. Among 429 cases, the first 221 GGNs were marked with microcoils (the microcoil group), and the remaining 208 GGNs were marked with the locating needles designed for pulmonary nodules (the locating needle group). SPSS 17.0 statistical software was used to compare the marking success rate, marking time, marking-related complications between two groups. p values < 0.05 were considered statistically significant. Results: The marking time in the microcoil group was longer than that in the locating needle group (11.1 ± 3.9 vs 8.2 ± 2.0 min, t = −7.87, p = 0.000). The marking success rate in the microcoil group was lower than that in the locating needle group (91.4% vs 98.6%, χ2 = 11.27, p = 0.001). In the microcoil group, marking failures included 16 cases of microcoil dislocation and 3 cases of unsatisfactory microcoil position, while all 3 cases of marking failure in the locating needle group were due to unsatisfactory anchor position. No significant differences in the incidence of total complications (23.1% vs 22.1%), pneumothorax (18.1% vs 19.2%), hemorrhage (9.5% vs 9.1%), and hemoptysis (1.8% vs 1.4%) were observed between the two groups. All the complications were minor and did not need special treatment. Except for one case in the microcoil group, which was converted to thoracotomy, the remaining 428 GGNs were successfully resected by VATS. Conclusions: It is safe and effective to perform pre-operative localization of GGN using either embolization microcoil or the locating needle designed for pulmonary nodules. The locating needle is superior to microcoil for marking GGN in terms of procedure time and the success rate. The complication rate of both methods is similar. Advances in knowledge: The locating needle designed for pulmonary nodules has recently been used to mark pulmonary nodule. Its structure can effectively avoid dislocation after localization, and the marking process is simple and quick. Compared with localization using microcoil, it takes less time and has higher success rate to mark GGNs using the locating needle. The complication rate of both methods is similar.

Taking advantage of the strong polarity of cells migrating along micropatterned lines, combined with computational modeling and microsurgery, we found that the centrosome must be localized toward the rear of a cell, likely for controlling the distribution of tail formation signals. This discovery clarifies a long-standing controversy in cell biology., The importance of centrosome in directional cell migration has long been recognized. However, the conventional view that centrosome determines cell’s front, based on its often-observed position in front of the nucleus, has been challenged by contradictory observations. Here we show that centrosome defines the rear instead of the front, using cells plated on micropatterned adhesive strips to facilitate directional migration. We found that centrosome is always located proximal to the future rear before polarity is established through symmetry breaking or reversed as the cell reaches a dead end. In addition, using microsurgery to alter the distance of centrosomes from cells’ ends, we show that centrosomal proximity is predictive of the placement of the rear. Removal of centrosome impairs directional cell migration, whereas the removal of nucleus alone makes no difference in most cells. Computer modeling under the framework of a local-enhancement/global-inhibition mechanism further demonstrates that positioning of rear retraction, mediated by signals concentrated near the centrosome, recapitulates all the experimental observations. Our results resolve a long-standing controversy and explain how cells use centrosome and microtubules to maintain directional migration.

Ministry of Science and Technology, Taiwan [MOST 104-2917-I-564-085, 105-2221-E-009-054-MY3, 105-2811-E-009-018]; Strategic Environmental Research and Development Program (SERDP) [ER-1365]; Environmental Security Technology Certification Program (ESTCP) [ER201212]; US National Science Foundation-Division of Earth Sciences [1014594]; Outstanding Oversea Professorship award through Jilin University from Department of Education, China; Global Expert award through Tianjin Normal University from the Thousand Talents Plan of Tianjin City

We compared physiochemical changes in wheat cultivars of different hardnesses during long-term storage. Respiration, ATP content, germination ability, expansin gene expression, and the activities of dehydrogenase, catalase, and peroxidase were studied in soft wheat (‘Zhengmai 004’), medium hard wheat (‘Aikang 58’), and hard wheat (‘Zhengmai 9023’). Wheat cultivars were stored under natural conditions for one year or harvested fresh and then stored for eight weeks either naturally or with artificial aging. Enzymatic activities decreased about 10% during one year of natural storage. Physiochemical properties of fresh and naturally aged wheats did not change significantly in eight weeks of further storage at 12% moisture content (MC) and 30 °C, which suggests that wheat stores well. However, physiochemical quality deteriorated rapidly in artificially aged wheat stored at 12% MC and 30 °C. Changes were relatively small in the soft wheat cultivar, with low basal metabolism and slow reduction of physiological enzymes indicating that soft wheat may have better storage tolerance than harder cultivars. This study provides important data for determining storage tolerances of different wheat cultivars.

Strategic Environmental Research and Development Program (SERDP) [ER-1365]; Environmental Security, and Technology Certification Program (ESTCP) [ER201212]; NSF EAR from the United State [1014594]; Jilin University from Department of Education, China; Global Expert award through Tianjin Normal University from the Thousand Talents Plan of Tianjin City from China; Taiwan Typhoon and Flood Research Institute, National Applied Research Laboratories; Natural Science Foundation of China [51409029]

Natural Science Foundation of China [51409029, 51479014]; China Postdoctoral Science Foundation [2014M562288]; Strategic Environmental Research and Development Program (SERDP) [ER-1365]; Environmental Security, and Technology Certification Program (ESTCP) [ER201212]; NSF EAR [1014594]; Jilin University from Department of Education, China; Global Expert award through Tianjin Normal University from the Thousand Talents Plan of Tianjin City

Recent studies indicate that adherent cells are keenly sensitive to external physical environment, such as substrate rigidity and topography, and internal physical states, such as cell shape and spreading area. Many of these responses are believed to involve coupled output and input of mechanical forces, which may constitute the key sensing mechanism to generate downstream regulatory signals for cell growth and differentiation. Here, we show that the state of cell migration also plays a regulatory role. Compared with migrating cells, stationary cells generate stronger, less dynamic, and more peripherally localized traction forces. These changes are coupled to reduced focal adhesion turnover and enhanced paxillin phosphorylation. Further, using cells migrating along checkerboard micropatterns, we show that the appearance of new focal adhesions directly in front of existing focal adhesions is associated with the down-regulation of existing focal adhesions and associated traction forces. Together, our results imply a mechanism where cell migration regulates traction forces by promoting dynamic turnover of focal adhesions, which may then regulate processes such as wound healing and embryogenesis where cell differentiation must coordinate with migration state and proper localization.

Background Lung adenocarcinoma (LUAD) is widely known as the leading cause of death in patients with lung cancer. Extensive evidence has determined that microRNAs (miRNAs) exert critical effects on various biological processes in tumorigenesis. microRNA-147b (miR-147b) has been reported to serve as an oncogenic molecule in colorectal cancer and hepatocellular carcinoma, however, its prognostic value and biological effect in LUAD remain rare. Materials and methods miR-147b and microfibril-associated glycoprotein 4 (MFAP4) data were collected from The Cancer Genome Atlas (TCGA) database to determine their expression levels in LUAD tissues. Kaplan-Meier method was used to plot the overall survival curves for the prognostic power of miR-147b and MFAP4 identification. Chi-square test was utilized to demonstrate the association between clinical characteristics and miR-147b or MFAP4 in LUAD. Luciferse reporter assay was implemented to identify the correlation between miR-147b and MFAP4. The mRNA and protein levels were detected by qRT-PCR and western blotting, respectively. To explore the effects of miR-147b and its potential mechanism in LUAD, cell counting kit 8 (CCK-8), colony formation and transwell assays were performed in LUAD cells with abnormal expression of miR-147b or/and MFAP4. Results Our results showed that miR-147b was up-regulated in LUAD tissues and cell lines, which induced poor outcome. Conversely, MFAP4, the putative target gene of miR-147b, was down-regulated in LUAD. The expression of MFAP4 in LUAD cells was negatively regulated by miR-147b. Results of experiments in vitro revealed that miR-147b could promote cell proliferation, colony formation, invasion and migration, while up-regulation of MFAP4 suppressed the impacts of miR-147b on cell malignant aggressiveness in A549 and Calu-3 cells. Conclusion In conclusion, these findings determined that miR-147b contributed to the progression of LUAD via targeting MFAP4. Thus, understanding the potential mechanism of miR-147b/MFAP4 may improve the treatment of cancers, especially LUAD.

Xiao-Yang Chu,1–3,* Wei Huang,2,* Yu-Li Wang,1 Ling-Wei Meng,2 Li-Qing Chen,2 Ming-Ji Jin,2 Lu Chen,1 Chun-Hong Gao,1 Cheng Ge,3 Zhong-Gao Gao,2 Chun-Sheng Gao11State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, P.R. China; 2State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China; 3Department of Stomatology, The 5th Medical Center of Chinese PLA General Hospital, Beijing 100071, P.R. China *These authors contributed equally to this workBackground: Intratumoral injection is a palliative treatment that aims at further improvement in the survival and quality of life of patients with advanced or recurrent carcinomas, or cancer patients with severe comorbidities or those with a poor performance status.Methods: In this study, a solvent-injection method was used to prepare paclitaxel–cholesterol complex-loaded lecithin–chitosan nanoparticles (PTX-CH-loaded LCS_NPs) for intratumoral injection therapy, and the physicochemical properties of NPs were well characterized.Results: The particle size and zeta potential of PTX-CH-loaded LCS_NPs were 142.83±0.25 nm and 13.50±0.20 mV, respectively. Release behavior of PTX from PTX-CH-loaded LCS_NPs showed a pH-sensitive pattern. The result of cell uptake assay showed that PTX-CH-loaded LCS_NPs could effectively enter cells via the energy-dependent caveolae-mediated endocytosis and macropinocytosis in company with the Golgi apparatus. Meanwhile, PTX-CH-loaded LCS_NPs had a better ability to induce cell apoptosis than PTX solution. The in vivo antitumor results suggested that PTX-CH-loaded LCS_NPs effectively inhibited mouse mammary cancer growth and metastasis to distant organs and significantly improved the survival rate of tumor-bearing mice by intratumoral administration.Conclusion: In general, our study demonstrated that PTX-CH-loaded LCS_NPs used for palliative treatment by intratumoral injection showed improved safety and antitumor efficacy, which provided an alternative approach in the field of palliative chemotherapy. Keywords: lecithin, chitosan, paclitaxel, nanoparticles, pH responsive, palliative chemotherapy, intratumoral injection