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Abstract Hippo pathway is an evolutionarily conservative key pathway that regulates organ size and tissue regeneration by regulating cell proliferation, differentiation and apoptosis. Yes-associated protein 1 (YAP)/ WW domain-containing transcription regulator 1 (TAZ) serves as a pivotal transcription factor within the Hippo signaling pathway, which undergoes negative regulation by the Hippo pathway. The expression of YAP/TAZ affects various biological processes, including differentiation of osteoblasts (OB) and osteoclasts (OC), cartilage homeostasis, skeletal muscle development, regeneration and quality maintenance. At the same time, the dysregulation of the Hippo pathway can concurrently contribute to the development of various musculoskeletal disorders, including bone tumors, osteoporosis (OP), osteoarthritis (OA), intervertebral disc degeneration (IDD), muscular dystrophy, and rhabdomyosarcoma (RMS). Therefore, targeting the Hippo pathway has emerged as a promising therapeutic strategy for the treatment of musculoskeletal disorders. The focus of this review is to elucidate the mechanisms by which the Hippo pathway maintains homeostasis in bone, cartilage, and skeletal muscle, while also providing a comprehensive summary of the pivotal role played by core components of this pathway in musculoskeletal diseases. The efficacy and feasibility of Hippo pathway-related drugs for targeted therapy of musculoskeletal diseases are also discussed in our study. These endeavors offer novel insights into the application of Hippo signaling in musculoskeletal disorders, providing effective therapeutic targets and potential drug candidates for treating such conditions.

Abstract Disease modeling with isogenic Induced Pluripotent Stem Cell (iPSC)-differentiated organoids serves as a powerful technique for studying disease mechanisms. Multiplexed coculture is crucial to mitigate batch effects when studying the genetic effects of disease-causing variants in differentiated iPSCs or organoids, and demultiplexing at the single-cell level can be conveniently achieved by assessing natural genetic barcodes. Here, to enable cost-efficient time-series experimental designs via multiplexed bulk and single-cell RNA-seq of hybrids, we introduce a computational method in our Vireo Suite, Vireo-bulk, to effectively deconvolve pooled bulk RNA-seq data by genotype reference, and thereby quantify donor abundance over the course of differentiation and identify differentially expressed genes among donors. Furthermore, with multiplexed scRNA-seq and bulk RNA-seq, we demonstrate the usefulness and necessity of a pooled design to reveal donor iPSC line heterogeneity during macrophage cell differentiation and to model rare WT1 mutation-driven kidney disease with chimeric organoids. Our work provides an experimental and analytic pipeline for dissecting disease mechanisms with chimeric organoids.

Abstract Background Sequencing the mitochondrial genome has been increasingly important for the investigation of primary mitochondrial diseases (PMD) and mitochondrial genetics. To overcome the limitations originating from PCR-based mtDNA enrichment, we set out to develop and evaluate a PCR-independent approach in this study, named Pime-Seq (PCR-independent mtDNA enrichment and next generation Sequencing). Results By using the optimized mtDNA enrichment procedure, the mtDNA reads ratio reached 88.0 ± 7.9% in the sequencing library when applied on human PBMC samples. We found the variants called by Pime-Seq were highly consistent among technical repeats. To evaluate the accuracy and reliability of this method, we compared Pime-Seq with lrPCR based NGS by performing both methods simultaneously on 45 samples, yielding 1677 concordant variants, as well as 146 discordant variants with low-level heteroplasmic fraction, in which Pime-Seq showed higher reliability. Furthermore, we applied Pime-Seq on 4 samples of PMD patients retrospectively, and successfully detected all the pathogenic mtDNA variants. In addition, we performed a prospective study on 192 apparently healthy pregnant women during prenatal screening, in which Pime-Seq identified pathogenic mtDNA variants in 4 samples, providing extra information for better health monitoring in these cases. Conclusions Pime-Seq can obtain highly enriched mtDNA in a PCR-independent manner for high quality and reliable mtDNA deep-sequencing, which provides us an effective and promising tool for detecting mtDNA variants for both clinical and research purposes.

Abstract Simultaneous multi-target detection and multi-site gene editing are two key factors restricting the development of disease diagnostic and treatment technologies. Despite numerous explorations on the source, classification, functional features, crystal structure, applications and engineering of CRISPR-Cas13a, all reports use the contiguous target RNA activation paradigm that only enables single-target detection in vitro and one-site gene editing in vivo. Here we propose a noncontiguous target RNA activation paradigm of Cas13a and establish a CRISPR-Cas13a Gemini System composed of two Cas13a:crRNA binary complexes, which can provide rapid, simultaneous, highly specific and sensitive detection of two RNAs in a single readout, as well as parallel dual transgene knockdown. CRISPR-Cas13a Gemini System are demonstrated in the detection of two miRNAs (miR-155 and miR-375) for breast cancer diagnosis and two small RNAs (EBER-1 and EBER-2) for Epstein-Barr virus diagnosis using multiple diagnostic platforms, including fluorescence and colorimetric-based lateral flow systems. We also show that CRISPR-Cas13a Gemini System can knockdown two foreign genes (EGFP and mCherry transcripts) in mammalian cells simultaneously. These findings suggest the potential of highly effective and simultaneous detection of multiple biomarkers and gene editing of multiple sites.

To effectively grasp the interactive evolution mechanism of relevant entities in the process of competitive neutrality and reveal the impact of the implementation effect of the principle of competitive neutrality on the evolution path of the game system is the key to guiding the development of the government, industry associations and enterprises with reasonable policies. The equilibrium point of the game is analyzed by the four-party evolutionary game model, and the influence of the change of relevant parameters on the evolution result of the game system is further simulated by numerical simulation. The results show that the central government supervision plays an important role in guiding the strategy selection of different game players. By raising the penalty standards for non-neutral competitive behavior of market players and increasing the non-neutral penalty for local governments, the system can evolve faster to the ideal state of “loose supervision by the central government, neutral implementation by local governments, strong supervision by industry associations, and active cooperation by enterprises.” Therefore, to improve the execution effect of competitive neutrality, the central government shall formulate a reasonable regulatory system, and to maximize inspire the enthusiasm of local government, industry associations and enterprises, to promote stability in the sustainable development of the market.

Superhydrophobic coatings for umbrella canopies have the potential to solve the issue of rain residue. However, achieving both impalement resistance and mechanical robustness in these coatings poses a significant challenge and limits their practical applications. In this study, we propose a similar “pole erecting” method utilizing perfluorodecyl polysiloxane modified SiO2 nanoparticles (F-silica) as the pole and poly(dimethylsiloxane) (PDMS) as the screw to enhance impalement resistance and mechanical robustness, which is attributed to the three-tier hierarchical micro-/micro-/nanostructure bonded by PDMS, along with a reduction in aspect ratio. The obtained PDMS0.5-F-silica could withstand 150 min of water drop impacting (equivalent to approximately 19,000 water drops) and 60 s of 50 kPa water jetting, also showed exceptional endurance against various mechanical tests, including 200 cycles of reciprocating abrasion, 1000 cycles of Martindale abrasion and 200 cycles of tape peeling. Moreover, when applying the PDMS0.5-F-silica coating to umbrella canopies, we observed an absence of rain residue after subjecting the umbrella to 20 h rain. These findings are promising for the development and practical implementation of superhydrophobic coatings.

Unmanned Aerial Vehicle (UAV) can be used as wireless aerial mobile base station for collecting data from sensors in UAV-based Wireless Sensor Networks (WSNs), which is crucial for providing seamless services and improving the performance in the next generation wireless networks. However, since the UAV are powered by batteries with limited energy capacity, the UAV cannot complete data collection tasks of all sensors without energy replenishment when a large number of sensors are deployed over large monitoring areas. To overcome this problem, we study the Real-time Data Collection with Laser-charging UAV (RDCL) problem, where the UAV is utilized to collect data from a specified WSN and is recharged using Laser Beam Directors (LBDs). This problem aims to collect all sensory data from the WSN and transport it to the base station by optimizing the flight trajectory of UAV such that real-time data performance is ensured It has been proven that the RDCL problem is NP-hard. To address this, we initially focus on studying two sub-problems, the Trajectory Optimization of UAV for Data Collection (TODC) problem and the Charging Trajectory Optimization of UAV (CTO) problem, whose objectives are to find the optimal flight plans of UAV in the data collection areas and charging areas, respectively. Then we propose an approximation algorithm to solve each of them with the constant factor. Subsequently, we present an approximation algorithm that utilizes the solutions obtained from TODC and CTO problems to address the RDCL problem. Finally, the proposed algorithm is verified by extensive simulations.

Osteoporosis is the most common skeletal disease characterized by an imbalance between bone resorption and bone remodeling. Osteoporosis can lead to bone loss and bone microstructural deterioration. This increases the risk of bone fragility and fracture, severely reducing patients’ mobility and quality of life. However, the specific molecular mechanisms involved in the development of osteoporosis remain unclear. Increasing evidence suggests that multiple noncoding RNAs show differential expression in the osteoporosis state. Meanwhile, noncoding RNAs have been associated with an increased risk of osteoporosis and fracture. Noncoding RNAs are an important class of factors at the level of gene regulation and are mainly involved in cell proliferation, cell differentiation, and cell death. Programmed cell death is a genetically-regulated form of cell death involved in regulating the homeostasis of the internal environment. Noncoding RNA plays an important role in the programmed cell death process. The exploration of the noncoding RNA-programmed cell death axis has become an interesting area of research and has been shown to play a role in many diseases such as osteoporosis. In this review, we summarize the latest findings on the mechanism of noncoding RNA-mediated programmed cell death on bone homeostasis imbalance leading to osteoporosis. And we provide a deeper understanding of the role played by the noncoding RNA-programmed cell death axis at the gene regulatory level of osteoporosis. We hope to provide a unique opportunity to develop novel diagnostic and therapeutic approaches for osteoporosis.

Abstract Pathogenic mutations in mitochondrial DNA cause severe and often lethal multi-system symptoms in primary mitochondrial defects. However, effective therapies for these defects are still lacking. Strategies such as employing mitochondrially targeted restriction enzymes or programmable nucleases to shift the ratio of heteroplasmic mutations and allotopic expression of mitochondrial protein-coding genes have limitations in treating mitochondrial homoplasmic mutations, especially in non-coding genes. Here, we conduct a proof of concept study applying a screened DdCBE pair to correct the homoplasmic m.A4300G mutation in induced pluripotent stem cells derived from a patient with hypertrophic cardiomyopathy. We achieve efficient G4300A correction with limited off-target editing, and successfully restore mitochondrial function in corrected induced pluripotent stem cell clones. Our study demonstrates the feasibility of using DdCBE to treat primary mitochondrial defects caused by homoplasmic pathogenic mitochondrial DNA mutations.

Abstract The pro-inflammatory state of macrophages, underpinned by their metabolic condition, is essentially affecting their capacity of combating tumor cells. Here we find, via a pooled metabolic gene knockout CRISPR screen that KEAP1 and ACOD1 are strong regulators of the pro-inflammatory state in macrophages. We show that ACOD1 knockout macrophages, generated in our induced pluripotent stem cell-derived CAR-macrophage (CAR-iMAC) platform, are strongly and persistently polarized toward the pro-inflammatory state, which manifests in increased reactive oxygen species (ROS) production, more potent phagocytosis and enhanced cytotoxic functions against cancer cells in vitro. In ovarian or pancreatic cancer mouse models, ACOD1-depleted CAR-iMACs exhibit enhanced capacity in repressing tumors, leading to increased survival. In addition, combining ACOD1-depleted CAR-iMACs with immune checkpoint inhibitors (ICI), such as anti-CD47 or anti-PD1 antibodies, result in even stronger tumor suppressing effect. Mechanistically, the depletion of ACOD1 reduces levels of the immuno-metabolite itaconate, allowing KEAP1 to prevent NRF2 from entering the nucleus to activate an anti-inflammatory program. This study thus lays down the proof of principle for targeting ACOD1 in myeloid cells for cancer immunotherapy and introduces metabolically engineered human iPSC-derived CAR-iMACs cells with enhanced polarization and anti-tumor functions in adoptive cell transfer therapies.

This research paper gives an overview of students’ experience in a virtual learning context during the Covid-19 pandemic lockdown. By categorising students’ perceptions based on a geographic-based social context, the research analyses a general tendency of their learning experience at three different levels — family and community-based level (small-sized), region-based level (medium-sized), and international level (grand-sized). The investigation uses a hybrid research method including direct observation, interviews, and design thinking strategies — including empathising, redefining and prototyping. The author has also been referring to two directions that may enhance the future learning environment design for students’ better experience. 1. To leverage the power of existing memory. 2. To research people’s micro habits and the hidden psychological factor behind them.

Abstract The quantitative control of FLOWERING LOCUS T (FT) activation is important for the floral transition in flowering plants. However, the flowering regulation mechanisms in the day-neutral, summer-flowering chrysanthemum plant remain unclear. In this study, the chrysanthemum BBX7 homolog CmBBX7 was isolated and its flowering function was identified. The expression of CmBBX7 showed a diurnal rhythm and CmBBX7 exhibited higher expression levels than CmBBX8. Overexpression of CmBBX7 in transgenic chrysanthemum accelerated flowering, whereas lines transfected with a chimeric repressor (pSRDX-CmBBX7) exhibited delayed flowering. Yeast single hybridization, luciferase, electrophoretic mobility shift, and chromatin immunoprecipitation assays showed that CmBBX7 directly targets CmFTL1. In addition, we found that CmBBX7 and CmBBX8 interact to positively regulate the expression of CmFTL1 through binding to its promoter. Collectively, these results highlight CmBBX7 as a key cooperator in the BBX8–FT module to control chrysanthemum flowering. Graphical Abstract

The successful 2020 launch and 2021 landing of the National Aeronautics and Space Administration’s (NASA) Perseverance Mars rover initiated the first phase of the NASA and European Space Agency (ESA) Mars Sample Return (MSR) campaign. The goal of the MSR campaign is to collect scientifically interesting samples from the Martian surface and return them to Earth for further study in terrestrial laboratories. The MSR campaign consists of three major spacecraft components to accomplish this objective: the Perseverance Mars rover, the Sample Retrieval Lander (SRL) and the Earth Return Orbiter (ERO). Onboard the ERO spacecraft is the Capture, Containment and Return System (CCRS). CCRS will capture, process and return to Earth the samples that have been collected after they are launched into Mars orbit by the Mars Ascent Vehicle (MAV), which is delivered to Mars onboard the SRL. To facilitate the processing of the orbiting sample (OS) via the CCRS, we have designed and developed a vision system to determine the OS capture orientation. The vision system is composed of two cameras sensitive to the visible portion of the electromagnetic spectrum and two illumination modules constructed from broadband light emitting diodes (LED). Vision system laboratory tests and physics-based optical simulations predict CCRS ground processing will be able to correctly identify the OS post-capture orientation using only a single vision system image that is transmitted to Earth from Mars orbit.

Various polymers are the most widely used product to provide rheology for water-based fracturing fluid, however, they have weaknesses in terms of temperature resistance and salt resistance. The change from organic-based to inorganic thickeners may be a meaningful attempt. Inorganic silica gel is a potentially alternative viscosifier with high temperature resistance, excellent proppant carrying capacity, and can even be used to prepare fracturing fluids with high salinity of produced water. In this paper, the silica gel viscosifier was firstly prepared using sol–gel method. Then, the gelation time under different influencing factors and rheological properties of the silica gel viscosifier were studied in detail. Subsequently, the silica gel-based fracturing fluid was prepared by adding the desired amount of drag reducer to the silica sol solution, and the properties of novel fracturing fluid were systematically evaluated with regard to the temperature and shearing resistance, drag reduction, and static proppant suspension. The potential mechanism of gelation process by syneresis of silica gel was revealed at last. Results showed that the microstructure of silica gel is synthetic, amorphous and consists of a three-dimensional network of SiO2 particles. The effect of SiO2 concentration on the gelation time is more pronounced than other factors such as temperature and pH level. In addition, the silica gel viscosifier exhibits strong salt resistance, whether monovalent ions (Na+, K+) or divalent ions (Ca2+, Mg2+), and the gelation time decreased significantly with the increase of salt concentration. The shear viscosity of the silica gel viscosifier increased with an increase of SiO2 concentration, showing shear thinning behavior as well. Meanwhile, the silica gel-based fracturing fluid prepared by adding drag reducer into silica sol solution also presented excellent thermal stability and shear resistance, drag reduction and proppant suspension performances. The retained viscosity can be maintained above 50 mPa·s after shearing at 180 °C for 60 mins; the drag reduction rate shows a declining trend at high displacement due to the gelation process; the settling rate of 40/70 mesh sand proppant with 35 % sand ratio is less than 30 % after standing at 90 °C for 4 h. In addition, the gelation process is essentially the formation of Si-O-Si linkage by dehydration between SiO2 particles, which is gradually extended at both ends and sides of the chain, and eventually forms a rigid, highly porous, entangled network. Findings found in this study provide a research basis for the popularization and application of silica gel-based fracturing fluid.

To foster high-quality economic development, it is critical to not only enhance the “hard environment,” such as infrastructure, but also to make significant strides in the “soft environment,” such as the relationship between government and businesses. This study posits that the government, industry associations, and enterprises should collectively participate in fostering a “cordial and clean” government-business relationship. By resolving the equilibrium solution of the three-party game, it has been identified that achieving the goal of constructing a cordial and clean government-business relationship and aligning with the ambitions of enterprises necessitates policy guidance and a balance of interests among the government, industry associations, and enterprises. The research also contributes to the beneficial exploration of game theory, by constructing a network model from the perspective of public management and integrating it with the practice of local administrative reform. This integration is particularly relevant for industry associations, and their systematic analysis further enhances the practical applicability of the research.

This investigation delves into the dynamic optimization of the progression from outsider to insider status within the context of family businesses. Utilizing a dynamic game model that incorporates three agents—leaders, insiders, and outsiders—it conducts a rigorous examination of the optimal pathway for the status transition of outsider employees in family businesses. The paramount objective of this study is to generate theoretical insights that may inform the optimization of human resources management and thereby bolster the overall performance of family businesses. The key findings of the research are as follows: 1) Outsider employees necessitate support from both leaders and insiders for a successful elevation in ranks. A collaborative relationship with insiders significantly enhances their performance. 2) The harmonious functioning of the workplace demands concerted efforts from all parties—leaders, insiders, and outsiders. The upward mobility of outsiders is contingent upon synergistic cooperation amongst all stakeholders. 3) A myriad of factors such as potential costs, benefits, and favoritism heavily influence the degree to which leaders endorse the upward mobility of outsiders. 4) Encouraging outsiders to move up in the ranks can instigate a sense of urgency among insiders, serving as a deterrent against complacency. This urgency can act as a catalyst for insiders to enhance their performance and mitigate the perceived threat to their own status.

The increasing uncertainty in the socio-economic landscape has heightened management’s interest in and expectations for employees’ opinions and suggestions. Concurrently, employee silence behavior is pervasive in today’s corporate world, prompting widespread academic attention. This study employs the dynamic evolutionary game approach to further examine the impact of differential leadership on employee silence of both insiders and outsiders and underlying mechanisms, with a focus on the Chinese socio-economic context. The research findings reveal that both insiders and outsiders may exhibit non-silent behaviors to gain their leaders’ attention and favor, ultimately achieving and sustaining benefit-seeking. Psychological empowerment and out-group preference emerge as key drivers of non-silent behaviors for internal and external employees, respectively. Based on the theories of psychology and social network, this research enriches the theory system of differential leadership behavior evolution and makes up for the deficiency of management in depicting the dynamic process of differential leadership behavior evolution, it provides a theoretical basis for grasping the evolution of differential leadership behavior and its rules of action. The investigation not only supplements and broadens the scope of relevant empirical research but also offers a theoretical foundation for analyzing and comprehending the evolution of differential leadership behavior and its consequences.

Abstract Background The incidence rate of metabolic-associated fatty liver disease (MAFLD) is increasing annually; however, there are still no effective methods for establishing an early diagnosis and conducting real-time tracing. Vaspin can affect the metabolic processes in the body, and it is closely associated with many metabolic diseases. Many previous studies have speculated on the association between vaspin and MAFLD, but the results of these studies have not been conclusive. This meta-analysis examined the differences in circulating vaspin levels between patients with MAFLD and healthy individuals. Methods Six databases and other sources were searched with free terms and Medical Subject Headings terms, and a total of 13 articles were included (900 cases and 669 controls). RevMan 5.3 and Stata 16 were used for analysis. The standardised mean difference (SMD) and 95% confidence interval (CI) were used to assess the overall outcomes. Cohen’s kappa coefficient was applied to examine the differences between the two authors in the selection of studies and in the evaluation of the quality of evidence for the studies. Results The results demonstrated that there was no significant difference in the circulating vaspin levels between the MAFLD group and healthy group (SMD = 0.46, 95% CI: [− 0.12, 1.04]). The subgroup analysis suggested that area and body mass index (BMI) may be the sources of heterogeneity, and the results of univariate meta-regression analysis were consistent with those of the subgroup analysis (P = 0.005 and P

The 14-3-3 (GRF, general regulatory factor) regulatory proteins are highly conserved and are widely distributed throughout the eukaryotes. They are involved in the growth and development of organisms via target protein interactions. Although many plant 14-3-3 proteins were identified in response to stresses, little is known about their involvement in salt tolerance in apples. In our study, nineteen apple 14-3-3 proteins were cloned and identified. The transcript levels of Md14-3-3 genes were either up or down-regulated in response to salinity treatments. Specifically, the transcript level of MdGRF6 (a member of the Md14-3-3 genes family) decreased due to salt stress treatment. The phenotypes of transgenic tobacco lines and wild-type (WT) did not affect plant growth under normal conditions. However, the germination rate and salt tolerance of transgenic tobacco was lower compared to the WT. Transgenic tobacco demonstrated decreased salt tolerance. The transgenic apple calli overexpressing MdGRF6 exhibited greater sensitivity to salt stress compared to the WT plants, whereas the MdGRF6-RNAi transgenic apple calli improved salt stress tolerance. Moreover, the salt stress-related genes (MdSOS2, MdSOS3, MdNHX1, MdATK2/3, MdCBL-1, MdMYB46, MdWRKY30, and MdHB-7) were more strongly down-regulated in MdGRF6-OE transgenic apple calli lines than in the WT when subjected to salt stress treatment. Taken together, these results provide new insights into the roles of 14-3-3 protein MdGRF6 in modulating salt responses in plants.

Abstract The consideration of nonextensivity effects is crucial to the accurate diagnosis of plasma parameters; common plasma nonextensive parameters include electron nonextensive parameter and ion nonextensive parameter, and the former can be measured, while the ion nonextensive parameter cannot be measured yet. Here we show the measurement of ion nonextensive parameter of plasma based on the theory of nonextensive geodesic acoustic modes. We assume that the plasma to be measured can be described by nonextensive statistical mechanics, and on this basis, the nonextensive geodesic acoustic mode theory is established. Utilizing this theory, we have measured the ion nonextensive parameter $${{q}_{{{F}_{\mathrm {i}}}}}= 1.565$$ q F i = 1.565 which cannot be diagnosed even by a nonextensive single electric probe. Our research points out that the proposed measurement method of ion nonextensive parameter may play a role in plasma diagnosis and will help us to grasp the nonextensivity of plasma more precisely. We hope the proposed method of ion nonextensive parameter diagnosis based on the nonextensive geodesic acoustic mode theory can be the starting point of more complex ion nonextensive parameter diagnosis methods. In addition, the measurement of ion nonextensive parameter is closely related to the study of various plasma waves, instabilities, turbulence and abnormal transport, and a defined and quantitative test of nonextensive geodesic acoustic mode theory will bound up deeply with such developments.

Abstract The exploration of single‐cell 3D genome maps reveals that chromatin domains are indeed physical structures presenting in single cells, and domain boundaries vary from cell to cell. However, systematic analysis of the association between regulatory factor binding and elements and the formation of chromatin domains in single cells has not yet emerged. To this end, a hierarchical chromatin domain structure identification algorithm (named as HiCS) is first developed from individual single‐cell Hi‐C maps, with superior performance in both accuracy and efficiency. The results suggest that in addition to the known CTCF‐cohesin complex, Polycomb, TrxG, pluripotent protein families, and other multiple factors also contribute to shaping chromatin domain boundaries in single embryonic stem cells. Different cooperation patterns of these regulatory factors drive genomic position categories with differential preferences forming boundaries, and the most extensive six types of retrotransposons are differentially distributed in these genomic position categories with preferential localization. The above results suggest that these different retrotransposons within genomic regions interplay with regulatory factors navigating the preference of genomic positions forming boundaries, driving the formation of higher‐order chromatin structures, and thus regulating cell functions in single mouse embryonic stem cells.

The role of the nucleolus in cell fate is not well known. Here the authors show nucleolar integrity maintained by rRNA-mediated liquid-liquid phase separation and 3D chromatin structure of perinucleolar heterochromatin regulates the fate transition of mouse embryonic stem cells to 2 cell-stage embryo-like cells, and that rRNA biogenesis regulates the 2-cell-to-4-cell transition of development.

Given the complex business environment worldwide and rapid development of information technologies, employees’ deviant innovation behavior has attracted increasing attention. However, few scholars have explored the internal mechanism of the influence of differential leadership on the deviant innovation behavior of outsider subordinates from a positive perspective. Based on relative deprivation theory and attribution theory, we construct a theoretical model to study the influence of differential leadership in family businesses on the deviant innovation behavior of outsider subordinates, and hypothesis testing is conducted based on 243 questionnaire responses. The result shows that: differential leadership has a positive impact on the deviant innovation behavior of outsider subordinates; relative deprivation plays a mediating role; and internal control personality enhances the moderation effect between relative deprivation and outsider subordinates’ deviant innovation behavior. This study provides a reference point for the promotion of the innovation performance both of employees and organizations.

Pseudobulbus Cremastrae seu Pleiones (PCsP) is a traditional Chinese herbal medicine known as “Shancigu” in China. It has the property of relieving fever, counteracting toxicity, dissipating phlegm and resolving masses. Officially recognized species of PCsP include Pleione bulbocodioides (Franch.) Rolfe (PB), Cremastra appendiculata (D. Don) Makino (CA), and Pleione yunnanensis (Rolfe) Rolfe (PY). Approximately, 234 compounds have been isolated and identified from PCsP. The most thoroughly investigated constituents are stilbenes (bibenzyls and phenanthrenes) and glucosyloxybenzyl succinate derivatives. Other compounds include lignans, flavonoids, and simple phenolics. The extracts and purified compounds of PCsP have exhibited anti-cancer, hepatoprotective, anti-inflammatory, neuroprotective and antioxidant potentials. Furthermore, pharmacological investigations support its traditional use for treating cancer. However, there is not enough data on the toxicity and quality control of this important herb. Moreover, the mechanism of action of active compounds and extracts need to be studied, with special attention to the effectiveness of PCsP against cancer. This review article aims to provide a critical overview of the botanical description, traditional uses, chemical constituents, pharmacological effects and clinical studies to provide a solid base for further research and development.

Food grade hydrogel has become an ideal delivery system for bioactive substances and attracted wide attention. Hybrids of whey protein isolate amyloid fibrils (WPF) and gliadin nanoparticles (GNP) were able to assemble into WPF-GNP hydrogel at a low protein concentration of 2 wt%, among which WPF and GNP were fabricated from the hydrolysis of whey protein isolate under 85°C water bath (pH 2.0) and antisolvent precipitation, respectively. Atomic force microscope (AFM) images indicated that the ordered nanofibrillar network of WPF was formed at pH 2.0 with a thickness of about 10 nm. Cryo-SEM suggested that WPF-GNP hydrogel could arrest GNP within the fibrous reticular structure of the partially deformed WPF, while the hybrids of native whey protein isolate (WPI) and GNP (WPI-GNP hybrids) only led to protein aggregates. WPF-GNP hydrogel formed at pH 4.0 (85°C, 3 h, WPF:GNP = 4:1) possessed the largest elastic modulus (G’ = 419 Pa), which far exceeded the elastic modulus of the WPI-GNP hybrids (G’ = 16.3 Pa). The presence of NaCl could enhance the strength of WPF-GNP hydrogel and the largest value was achieved at 100 mM NaCl (∼105 mPa) in the range of 0∼500 mM due to electrostatic screening. Moreover, WPF-GNP hydrogel showed a high encapsulation efficiency for curcumin, 89.76, 89.26, 89.02, 85.87, and 79.24% for pH 2.0, 3.0, 4.0, 5.0, and 6.0, respectively, which suggested that the formed hydrogel possess good potential as a delivery system. WPF-GNP hydrogel also exhibited a good protection effect on the photodegradation stability of the loaded curcumin with the retention of up to 75.18% after hydrogel was exposed to ultraviolet radiation for 7 days. These results suggested that the viscoelasticity of WPF-GNP hydrogel was tunable via pH-, ion-, or composition-adjustment and the hydrogel showed excellent protection on the thermal and photodegradation stability of curcumin.

Abstract The Chimera antigen receptor (CAR)-T cell therapy has gained great success in the clinic. However, there are still major challenges for its wider applications in a variety of cancer types including lack of effectiveness due to the highly complex tumor microenvironment, and the forbiddingly high cost due to the personalized manufacturing procedures. In order to overcome these hurdles, numerous efforts have been spent focusing on optimizing Chimera antigen receptors, engineering and improving T cell capacity, exploiting features of subsets of T cell or NK cells, or making off-the-shelf universal cells. Here, we developed induced pluripotent stem cells (iPSCs)-derived, CAR-expressing macrophage cells (CAR-iMac). CAR expression confers antigen-dependent macrophage functions such as expression and secretion of cytokines, polarization toward the pro-inflammatory/anti-tumor state, enhanced phagocytosis of tumor cells, and in vivo anticancer cell activity. This technology platform for the first time provides an unlimited source of iPSC-derived engineered CAR-macrophage cells which could be utilized to eliminate cancer cells.

Abstract Background Short or long sleep duration is proposed as a potential risk factor for all-cause mortality in the older people, yet the results of published studies are not often reproducible. Methods Literature retrieval, study selection and data extraction were completed independently and in duplicate. Only prospective cohort studies were included. Effect-size estimates are expressed as hazard ratio (HR) and 95% confidence interval (CI). Results Summary data from 28 articles, involving a total of 95,259 older people, were meta-analyzed. Overall analyses revealed a remarkably significant association between long sleep duration and all-cause mortality (adjusted HR = 1.24, 95% CI: 1.16–1.33, P

Abstract We present scMAGeCK, a computational framework to identify genomic elements associated with multiple expression-based phenotypes in CRISPR/Cas9 functional screening that uses single-cell RNA-seq as readout. scMAGeCK outperforms existing methods, identifies genes and enhancers with known and novel functions in cell proliferation, and enables an unbiased construction of genotype-phenotype network. Single-cell CRISPR screening on mouse embryonic stem cells identifies key genes associated with different pluripotency states. Applying scMAGeCK on multiple datasets, we identify key factors that improve the power of single-cell CRISPR screening. Collectively, scMAGeCK is a novel tool to study genotype-phenotype relationships at a single-cell level.

Alport syndrome is an inherited chronic kidney disease with genetic heterogeneity. There are three modes of inheritance: X-linked dominant inheritance, autosomal recessive inheritance, and autosomal dominant inheritance. Autosomal recessive inheritance accounts for about 14%–15% of all cases of Alport syndrome and is caused by the COL4A3 or COL4A4 gene mutation. In this study, the peripheral blood mononuclear cells (PBMCs) of a patient with a novel COL4A4 homozygous mutation were reprogrammed into an induced pluripotent stem cell (iPSC) line. The iPSC line can provide a cell model for studying the pathogenesis of the disease and drug screening.

Alport syndrome is the second most common genetic renal disease which caused by mutations in COL4A3/COL4A4/COL4A5, according to different modes of inheritance. Recently, we identified a novel homozygous mutation in COL4A3 gene in a patient with Alport syndrome. The Peripheral Blood Mononuclear Cells (PBMCs) of the patient were obtained and a line of induced pluripotent stem cells (iPSCs) was successfully generated. The iPSC line will be useful for further study of the pathogenesis and drug screening for Alport syndrome.

In the field of plasma diagnosis, the measurement of the distribution function is significant because the distribution function is the basis for the use of plasma kinetic theory and it is the prerequisite for analyzing many physical phenomena, such as Landau damping (wave-particle resonance phenomenon) and ion sheath. Theoretical analysis and a large number of experiments have proved that plasma components do not obey Boltzmann–Gibbs statistics and can be well described by nonextensive statistical mechanics. The field of nonextensive electric probe has also made great progress, and the invention of the nonextensive single electric probes has developed and strengthened the power of plasma diagnostics. The nonextensive electric probe can not only measure the electron nonextensive parameter of plasma that cannot be measured by traditional probes but can also measure more accurate plasma parameters that can also be measured by traditional probes, such as Te, Φp, ne, Φf, and αqFe. However, diagnosing the plasma distribution function by the nonextensive electric probe has not been thoroughly and systematically analyzed and discussed. Here, we show the measurement of the plasma distribution function with a nonextensive single electric probe. This work expands the diagnostic capabilities of the nonextensive single electric probe. We utilize the nonextensive single electric probe theory to analyze the experimental data points of the I–V curve, measure the plasma electron distribution function fvx, and display the distribution curve (figure f-vx), and we also measure the plasma parameters of qFe, Te, Φp, ne, Φf, αqFe, etc. The proposed method provides a new approach to the diagnosis of the plasma distribution function and contributes to a more accurate and comprehensive grasp of plasma, which creates better conditions for us to take advantage of plasma. These initial results illustrate the potential of the nonextensive electric probe in the field of plasma diagnosis and, more generally, in accelerating the progress of fusion-energy science and helping to understand complex physical systems.

PBMCs were collected from a patient with a novel GLA gene mutation (c.140G > A) which contributed to Fabry disease. Subsequently, an induced pluripotent stem cell (iPSC) line was derived using an episomal reprogramming method that transfer the reprogramming plasmids expressing OCT3/4, SOX2, KLF4, LIN28 and L-MYC into the PBMCs. The expected mutation in the iPSC line was confirmed by Sanger sequencing, while the pluripotency status was validated by immunofluorescence assay and flow cytometry for pluripotency markers, as well as teratoma formation.

Focal Segmental Glomerular Sclerosis (FSGS) is a glomerular disease which can be classified into primary, secondary, genetic, and unknown forms. WT1 mutation has been shown to be associated with this disorder. Recently, we identified a mutation in the Zinc finger C2H2 domain of WT1 gene in a patient with FSGS who also carried a family history of end-stage renal disease (ESRD). The Peripheral Blood Mononuclear Cells (PBMCs) of the patient were obtained and a line of induced pluripotent stem cells (iPSCs) was successfully generated. The iPSC line will be useful for further study of the pathogenesis and drug screening for FSGS.

The clinical manifestations of Alport syndrome may vary depending on the involved organs such as the kidneys, cochlea and eyes. The pathogenic genes involved are those encoding different chains of type IV collagen. We collected PBMCs of a patient with a novel COL4A5 gene mutation(c.2687G > C). Subsequently, we used the electroporation system to transfer the reprogramming plasmids expressing OCT3/4, SOX2, KLF4, LIN28 and L-MYC into the PBMCs. We simultaneously carried out the tests on the iPSCs including Sanger sequencing for confirming the mutation site, immunofluorescence assay and flow cytometry for pluripotency markers as well as teratoma experiment for validating the pluripotency.

A basic-yet nontrivial-function which neocortical circuitry must satisfy is the ability to maintain stable spiking activity over time. Stable neocortical activity is asynchronous, critical, and low rate, and these features of spiking dynamics contribute to efficient computation and optimal information propagation. However, it remains unclear how neocortex maintains this asynchronous spiking regime. Here we algorithmically construct spiking neural network models, each composed of 5000 neurons. Network construction synthesized topological statistics from neocortex with a set of objective functions identifying naturalistic low-rate, asynchronous, and critical activity. We find that simulations run on the same topology exhibit sustained asynchronous activity under certain sets of initial membrane voltages but truncated activity under others. Synchrony, rate, and criticality do not provide a full explanation of this dichotomy. Consequently, in order to achieve mechanistic understanding of sustained asynchronous activity, we summarized activity as functional graphs where edges between units are defined by pairwise spike dependencies. We then analyzed the intersection between functional edges and synaptic connectivity- i.e. recruitment networks. Higher-order patterns, such as triplet or triangle motifs, have been tied to cooperativity and integration. We find, over time in each sustained simulation, low-variance periodic transitions between isomorphic triangle motifs in the recruitment networks. We quantify the phenomenon as a Markov process and discover that if the network fails to engage this stereotyped regime of motif dominance "cycling", spiking activity truncates early. Cycling of motif dominance generalized across manipulations of synaptic weights and topologies, demonstrating the robustness of this regime for maintenance of network activity. Our results point to the crucial role of excitatory higher-order patterns in sustaining asynchronous activity in sparse recurrent networks. They also provide a possible explanation why such connectivity and activity patterns have been prominently reported in neocortex.

Theoretical analysis and a large number of experiments have proved that plasma components do not satisfy Boltzmann–Gibbs statistics and can be well described by nonextensive statistical mechanics, while sheath potential coefficients in plasma with nonextensive distribution are not investigated deeply and comprehensively. Here, we investigate the ion sheath formed around a nonextensive single electric probe in plasma described by nonextensive statistical mechanics, and find that the sheath potential coefficient is related to the electron nonextensive parameter, besides the extensive limit the results return to the case of the Boltzmann–Gibbs statistical framework. The sheath potential coefficient presents different dependences on the electron nonextensive parameters in different regions. We also have calculated the corresponding method error and evaluated with a set of real experiment data, and found that the error is as high as 83.91% indicating that the effect of nonextensive parameters should be considered in the actual measurement.

A magnetic dispersive solid phase extraction method coupled with high-performance liquid chromatography was proposed for the simultaneous separation and determination of paraquat (PQ) and diquat (DQ) in human plasma and urine samples. Based on the reduction of PQ and DQ to a blue radical and yellow-green radical by sodium dithionite in an alkaline medium, a fast colorimetric method was also developed for the fast detection of PQ or DQ. In this paper, CoFe2O4@SiO2 magnetic nanoparticles were used as the adsorbent for the magnetic dispersive solid phase extraction of paraquat and diquat, and these two analytes were found to be eluted directly from the adsorbent by NaOH solution. The main factors affecting the extraction efficiency including amount of extractant, extraction time, sample volume, sample solution pH, and elution volume were optimized. Under the optimized experimental conditions, the calibration curve was linear at a concentration range of 28.5–570.2 μg/L, and the correlation coefficient of paraquat and diquat was 0.9986 and 0.9980, respectively. The limits of detection of paraquat and diquat were 4.5 μg/L and 4.3 μg/L. The proposed MSPE-HPLC method was successfully applied to the detection of the paraquat and diquat in human plasma and urine with satisfied recoveries of PQ and DQ in the range of 87.5%–98.7%.

Chlorophyll is vital for photosynthesis to produce sugars and other useful biochemical products in green plants. However, the molecular effects of chlorophyll deficiency in Chrysanthemum are largely unknown. In this study, we identified a bud sport mutant chrysanthemum belonging to the variety ‘Nannong Binyun’, which has yellow branches. Plant physiological studies have shown that the yellow color is revealed due to chlorophyll loss. RNA extracts of yellow and green tissues were analyzed using high-throughput RNA-sequencing, and a total of 11,649 tissue enriched unigenes that respond to chlorophyll deficiency were identified, including 4803 unigenes upregulated in yellow tissues and 6846 unigenes in green tissues. GO analysis revealed that these tissue-enriched genes may involve in the physiological processes of chlorophyll accumulation and photosynthesis. In addition, many DEGs from the families of AP2-EREBP, bHLH, MYB, and FAR1 that are associated with plant development and stress response were detected. Our study found that most of the genes from the GRAS family were downregulated in yellow leaves, indicating their putative roles in stem cell maintenance and possible contribution to leaf size determination.

Abstract Chronic lymphocytic thyroiditis (CLT) is a common autoimmune disorder. The possible pathogenic role and mechanism of dibutyl phthalate (DBP) in CLT is still controversial. Experiments were conducted after 35-days of oral exposure to the three concentrations of DBP or saline, and three immunizations with thyroglobulin (TG). Healthy female Wistar rats were randomly divided into ten exposure groups (n = 8 each): (A) saline control, (B) 0.5 mg/kg/d DBP, (C) 5 mg/kg/d DBP, (D) 50 mg/kg/d DBP, (E) TG-immunized group, (F) TG- combined with 0.5 mg/kg/d DBP, (G) TG- combined with 5 mg/kg/d DBP, (H) TG- combined with 50 mg/kg/d DBP, (I) TG- combined with 50 mg/kg/d DBP plus 100 mg/kg/d vitamin C; (J) 100 mg/kg/d vitamin C. We showed that oral exposure DBP can aggravate CLT in rats. This deterioration was concomitant with increased thyroid auto antibodies, Th1/Th2 imbalance and Th17 immune response, activated pro-inflammatory and apoptosis pathways, and increased thyroid dysfunction in rats. Our results also suggested that DBP could promote oxidative damage. The study also found that vitamin C reduced the levels of oxidative stress and alleviated CLT. In short, the study showed that DBP exacerbated CLT through oxidative stress.

Baicalin, a flavonoid isolated from Scutellaria baicalensis Georgi, has shown a wide range of anti-inflammatory, antioxidative, antiviral, and antitumor properties. However, the molecular mechanism of how baicalin exerts its effects, especially on inflammation regulation, has not been fully investigated. In this article, we report the effects of baicalin on the mouse macrophage cell line RAW264.7. Our results demonstrate that baicalin inhibits the production of inflammatory factors interleukin-6 and tumor necrosis factor-alpha upon lipopolysaccharide stimulation of macrophages. We observed that baicalin inhibits STAT3 activation through retarding its expression and phosphorylation. Interestingly, baicalin treatment promotes the elevation of miR-124 in lipopolysaccharide-treated macrophages. Overexpression of the miR-124 mimic in RAW264.7 reduced STAT3 expression and phosphorylation. Furthermore, inhibition of miR-124 attenuated the dysregulation of STAT3 and reduction of inflammatory factors upon baicalin treatment. Our results revealed the molecular mechanism that baicalin attenuates pro-inflammatory cytokine production through miR-124-STAT3 signaling pathway, suggesting that miR-124 is an important modulator in regulating anti-inflammation by baicalin in macrophages.

Variation in the quality and quantity of nutrition is a major contributor to phenotypic variation in animal populations. Although we know much of how dietary restriction impacts phenotype, and of the molecular-genetic and physiological mechanisms that underlie this response, we know much less of the effects of dietary imbalance. Specifically, although dietary imbalance and restriction both reduce overall body size, it is unclear whether both have the same effect on the size of individual traits. Here, we use the fruit fly Drosophila melanogaster to explore the effect of dietary food versus protein-to-carbohydrate ratio on body proportion and trait size. Our results indicate that body proportion and trait size respond differently to changes in diet quantity (food concentration) versus diet quality (protein-to-carbohydrate ratio), and that these effects are sex specific. While these differences suggest that Drosophila use at least partially distinct developmental mechanisms to respond to diet quality versus quantity, further analysis indicates that the responses can be largely explained by the independent and contrasting effects of protein and carbohydrate concentration on trait size. Our data highlight the importance of considering macronutrient composition when elucidating the effect of nutrition on trait size, at the levels of both morphology and developmental physiology.

A tram with on-board hybrid energy storage systems based on batteries and supercapacitors is a new option for the urban traffic system. This configuration enables the tram to operate in both catenary zones and catenary-free zones, and the storage of regenerative braking energy for later usage. This paper presents a multiple phases integrated optimization (MPIO) method for the coordination of speed profiles and power split considering the signal control strategy. The objective is to minimize the equivalent total energy consumption of all the power sources, which includes both the energy from the traction substation and energy storage systems. The constraints contain running time, variable gradients and curves, speed limits, power balance and signal time at some intersections. The integrated optimization problem is formulated as a multiple phases model based on the characters of the signalized route. An integrated calculation framework, using hp-adaptive pseudospectral method, is proposed for the integrated optimization problem. The effectiveness of the method is verified under fixed time signal (FTS) control strategy and tram priority signal (TPS) control strategy. Illustrative results show that this method can be successfully applied for trams with hybrid energy storage systems to improve their energy efficiency.

In this paper an adaptive non-singular fast terminal sliding mode (NFTSM) control scheme is proposed to control the electro-mechanical actuator (EMA) in an electric braking system which is a complex electro-mechanical system. In order to realize high-performance brake pressure servo control, a radial basis function (RBF) neural network method is adopted to deal with the difficulty of estimating the upper bound of the compound disturbance in the system, to reduce the conservatism of the design of sliding mode switching gain, and effectively eliminate sliding mode chattering. The simulation results show that, compared with a linear controller, the proposed control strategy is able to improve the servo performance and control precision. In addition the response speed of the braking actuator is enhanced significantly, without changing the traditional double-loop control structure.