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The prevalence of environmental problems and the increasing risk of human exposure to environmental pollutants have become a global concern. The increasing environmental pollution is one of the main reasons for the rising incidence of most neurological-related diseases in recent years. However, the ethical constraints of direct human research and the racial limitations of animal models have slowed the progress of research in this area. The purpose of this study is to review the neurotoxicity of different environmental pollutants on the brain using brain organoids as a new model and to conclude that brain organoids may play a key role in assessing the mechanisms by which environmental pollutants affect neurogenesis and cause neurological pathogenesis. To accurately determine the negative effects of environmental pollutants on the nervous system, self-organizing brain organoids that are highly similar to the developing brain have become a new model system for studying the effects of environmental pollutants on human brain development and disease. This study uses brain organoids as a model to summarize the neurotoxicity of different environmental pollutants on the nervous system, including structural changes in brain organoids, inhibition of neuronal differentiation and migration, impairment of mitochondrial function, damage to cellular cilia, and influence on signaling pathways. In conclusion, exposure to environmental pollutants may cause different neurotoxicity to the nervous system. Therefore, it is crucial to understand how to use brain organoids to ameliorate neurological disorders caused by environmental pollution.

Particulate matter (PM) has always received widespread attention, PM2.5 pollution is associated with many adverse effects, including cardiovascular, respiratory and metabolic diseases and mood disorders. However, the underlying mechanisms are not yet clear. In this study, the small animal whole body inhalation exposure system collected real-time PM2.5 in the real environment, which can truly reflect the presence status of PM2.5 in the atmospheric environment. This study investigated the depressive like behavior of mice exposed to PM2.5 for a long time and proved its molecular mechanism through RNA-seq. C57BL/6 male mice were exposed to ambient air together with control mice, who breathed air filtered through high-efficiency air particulate filters. Depression like behavior was observed in mice exposed to PM for 4, 6, and 8 weeks through behavioral experiments, EEG signals, and pathological sections. RNA-seq results indicated that the depressive like behavior of mice exposed to PM2.5 might be related to pro-inflammatory and anti-inflammatory cytokines, as well as the BDNF pathways in the hippocampus and olfactory bulb. This study suggests that PM2.5 may induce depression in mice through the MAPK/CREB/BDNF pathway. Environmental Implication: Atmospheric particulate matter has been classified as Class 1 pollutant by the International Agency for Research on Cancer. Current research mainly believed that PM2.5 seriously affected lung health, but there was little research on the effects of PM2.5 on other organs. With the improvement of quality of life, people were paying more attention to mental health, while there is little research on the effects of PM2.5 on brain. This study simulated a real PM2.5 exposure environment and explored the effects of PM2.5 on the brain of mice, provided a solid scientific basis for inducing depression after PM2.5 exposure.

Cancer therapies based on energy conversion, such as photothermal therapy (PTT, light-to-thermal energy conversion) and photodynamic therapy (PDT, light-to-chemical energy conversion) have attracted extensive attention in preclinical research. However, the PTT-related hyperthermia damage to surrounding tissues and shallow penetration of PDT-applied light prevent further advanced clinical practices. Here, we developed a thermoelectric therapy (TET) based on thermoelectric materials constructed p-n heterojunction (SrTiO3/Cu2Se nanoplates) on the principle of light-thermal-electricity-chemical energy conversion. Upon irradiation and natural cooling-induced the temperature gradient (35–45 oC), a self-build-in electric field was constructed and thereby facilitated charges separation in bulk SrTiO3 and Cu2Se. Importantly, the contact between SrTiO3 (n type) and Cu2Se (p type) constructed another interfacial electric field, further guiding the separated charges to re-locate onto the surfaces of SrTiO3 and Cu2Se. The formation of two electric fields minimized probability of charges recombination. Of note, high-performance superoxide radicals and hydroxyl radicals’ generation from O2 and H2O under catalyzation by separated electrons and holes, led to intracellular ROS burst and cancer cells apoptosis without apparent damage to surrounding tissues. Construction of bulk and interfacial electric fields in heterojunction for improving charges separation and transfer is also expected to provide a robust strategy for diverse applications.

BackgroundSarcopenia is a complication of asthma, and asthmatics with sarcopenia are at an increased risk of poor prognosis. Anti-inflammatory intervention promising as an effective measure to prevent sarcopenia among patients with asthma. Diet is an important way to regulate inflammation throughout the body. The dietary inflammatory index (DII) is an index that assesses an individual’s overall dietary inflammatory potential. The relationship between DII and sarcopenia among patients with asthma is not clear.ObjectiveTo examine the correlation between DII and the sarcopenia among individuals with asthma.MethodsThe National Health and Nutrition Examination Survey (NHANES) was the data source utilized in this study, spanning two time periods from 1999 to 2006 and 2011 to 2018. The study encompassed 3,389 participants in total. DII was calculated using the results of the participants’ 24-h dietary recall interviews. Patients were categorized into three groups based on the DII tertile: T1 group (n = 1,130), T2 group (n = 1,129), and T3 group (n = 1,130). Logistic regression analysis, taking into account the NHANES recommended weights, was performed to assess the relationship between DII and sarcopenia.ResultsAfter full adjustment, there was a significant positive correlation between DII levels and the risk of sarcopenia in asthmatic patients (OR: 1.27, 95% CI: 1.13–1.42, p

Metastasis is one of the leading causes of cancer-related deaths. A comprehensive comparison of the differences between primary and metastatic cancers within the same organ can aid in understanding the growth mechanisms of cancer cells at metastatic sites, thereby helping to develop more effective targeted treatment strategies. Primary liver cancer is one of the most common types of cancer, and the liver is also one of the main metastatic sites. In this paper, we utilize single-cell RNA-Seq data to compare primary liver cancer and colorectal liver metastases from multiple perspectives, including cell types and proportions, activity of various cell types, cell–cell communication, mRNA expression differences within the same types of cells, key factors associated with cell proliferation, etc. Our analysis results show the following: (i) Compared to primary tissue, metastatic tissue contains more cytotoxic T cells and exhausted T cells, and it retains some specific characteristics of the primary site. (ii) Cells of the same type exhibit functional differences between primary and metastatic cancers, with metastatic cancer cells showing lower metabolism levels and immune cells exhibiting stronger immune activity. (iii) Interactions between monocytes and hepato-associated cells are strong in primary cancer, while depleted T cells frequently communicate with hepatocytes in metastatic cancer. (iv) Proliferation-related genes in primary and metastatic cancers are mainly involved in cell energy supply and basic metabolism activity, respectively.

Because of its non-contact measurement characteristics, trackside acoustic technology is now utilized for train bearing fault diagnosis. However, the collected acoustic signal produces Doppler distortions that can impact the accuracy of bearing fault diagnosis. Additionally, when a fault occurs in the train bearing, it is analyzed using cyclostationary methods. In this study, we combine bearing fault characteristics with Doppler distortion correction and cyclostationary analysis methods. The trackside acoustic test platform is employed to collect and test the fault signals from bearings. These signals are processed and analyzed using Doppler distortion correction algorithms and cyclostationary techniques. A comparison between time domain maps and power spectrum maps before and after correction reveals an increase in SNR (signal to noise ratio) and a more concentrated energy distribution within the fault signals—at least a 50% improvement is observed. To further validate our method’s effectiveness, we select existing TADS equipment from a depot to collect bearing signals for analysis and processing using our proposed bearing fault diagnosis method. Comparison of time domain maps and power spectrum maps before and after correction shows clearer overall images and amplitude increase of nearly 125%. Therefore, we have successfully developed a stepwise method for bearing fault diagnosis based on cyclostationary Doppler distortion correction.

Hydrogels have blossomed as superstars in various fields, owing to their prospective applications in tissue engineering, soft electronics and sensors, flexible energy storage, and biomedicines. Two-dimensional (2D) nanomaterials, especially 2D mono-elemental nanosheets (Xenes) exhibit high aspect ratio morphology, good biocompatibility, metallic conductivity, and tunable electrochemical properties. These fascinating characteristics endow numerous tunable application-specific properties for the construction of Xene-based hydrogels. Hierarchical multifunctional hydrogels can be prepared according to the application requirements and can be effectively tuned by different stimulation to complete specific tasks in a spatiotemporal sequence. In this review, the synthesis mechanism, properties, and emerging applications of Xene hydrogels are summarized, followed by a discussion on expanding the performance and application range of both hydrogels and Xenes. Public summary: • Two-dimensional mono-elemental nanosheets (Xenes) endow tunable application • Synthesis mechanism, properties, and applications of Xene hydrogels are summarized • Expanding performance and applications of both hydrogels and Xenes are presented

Spontaneous bursts in neuronal networks with propagation involving a large number of synchronously firing neurons are considered to be a crucial feature of these networks both in vivo and in vitro. Recently, learning has been shown to improve the association and synchronization of spontaneous events in neuronal networks by promoting the firing of spontaneous bursts. However, little is known about the relationship between the learning phase and spontaneous bursts. By combining high-resolution measurement with a 4,096-channel complementary metal-oxide-semiconductor (CMOS) microelectrode array (MEA) and graph theory, we studied how the learning phase influenced the initiation of spontaneous bursts in cultured networks of rat cortical neurons in vitro. We found that a small number of selected populations carried most of the stimulus information and contributed to learning. Moreover, several new burst propagation patterns appeared in spontaneous firing after learning. Importantly, these “learning populations” had more hubs in the functional network that governed the initiation of spontaneous burst activity. These results suggest that changes in the functional structure of learning populations may be the key mechanism underlying increased bursts after learning. Our findings could increase understanding of the important role that synaptic plasticity plays in the regulation of spontaneous activity.

With the rapid development of nanotechnology and nanoscience, nanosafety assessment has raised public concern. Although many studies have illustrated that nanomaterials could lead to genotoxicity, the early alterations of DNA methylation with nanomaterials under low-dose exposure have not been completely clear. In this study, we investigated the potential effect and molecular mechanism of AgNPs on the alternation of DNA methylation fingerprints in HEK293T cells under sublethal exposure. Intriguingly, silver nanoparticle treatment increased 5-mC level and changed methylation-related enzyme contents. Mechanistically, we scrutinized the changes in the molecular signaling and biological functions by means of MeDIP-Seq and RNA-seq. Our results revealed that AgNPs might undermine a number of vital regulatory networks including the metabolic processes, biological regulation and other cellular processes. More specifically at the DNA methylation fingerprints, there were 12 up-regulated and simultaneous hypomethylated genes, and 22 down-regulated and concomitant hypermethylated genes in HEK293T cells responding to AgNPs. Notably, these genes were primarily involved in lipid metabolism and ion metabolism. Together, these responsive genes might be used as early sensitive indicators for the variations of early epigenetic integrity through changing the DNA methylation fingerprints, as reflective of biological risk and toxicity of silver nanoparticles under realistic exposure scenarios.

The reduction in driving range and the degradation of vehicle performance in cold weather has become one of the challenges in vehicle electrification in recent years. The root cause of this phenomenon is the property of lithium-ion batteries with capacity and power capability reduction at low temperatures. In this study, an external battery heating system was developed by employing an electrothermal film affixed to the surface of each cell, and the heating process was performed during driving. An equivalent circuit model combined with a thermal model was established for the simulation and control design. A fuzzy logic control strategy was developed to optimize the external heating power provided by the battery pack, and to achieve the maximum range by the end of discharge. A global optimal control strategy obtained by dynamic programming and a constant maximum power heating strategy were used for comparison. Simulation and experimental validations show that the proposed fuzzy logic control algorithm can achieve a 3.6% to 5.3% improvement in driving range than the maximum power heating method, and has close performance to the global optimal solution. Furthermore, the vehicle equipped with the proposed heating system can have up to 150.4% of the range recovery under different driving conditions.

As the market size of the cosmetics industry increases, the safety and effectiveness of new products face higher requirements. The marine environment selects for species of micro-organisms with metabolic pathways and adaptation mechanisms different from those of terrestrial organisms, resulting in their natural products exhibiting unique structures, high diversity, and significant biological activities. Natural products are usually safe and non-polluting. Therefore, considerable effort has been devoted to searching for cosmetic ingredients that are effective, safe, and natural for marine micro-organisms. However, marine micro-organisms can be difficult, or impossible, to culture because of their special environmental requirements. Metagenomics technology can help to solve this problem. Moreover, using marine species to produce more green and environmentally friendly products through biotransformation has become a new choice for cosmetic manufacturers. In this study, the natural products of marine micro-organisms are reviewed and evaluated with respect to various cosmetic applications.

Abstract The Nuclear receptor 4A (NR4A) subfamily, which belongs to the nuclear receptor (NR) superfamily, has three members: NR4A1 (Nur77), NR4A2 (Nurr1) and NR4A3 (Nor1). They are gene regulators with broad involvement in various signaling pathways and human disease responses, including autophagy. Here, we provide a concise overview of the current understanding of the role of the NR4A subfamily members in human diseases and review the research into their regulation of cell autophagy. A deeper understanding of these mechanisms has potential to improve drug development processes and disease therapy.

Objective. To explore the differential efficacy of chemoradiotherapy combined with adoptive immunotherapy and radiochemotherapy alone in patients with non-small-cell lung cancer (NSCLC). Methods. Qualified randomized controlled trial (randomized controlled trial, RCT), or nonrandomized concurrent controlled trial (NRCCT), published in various databases, including PubMed, EMBASE, Chinese journal full-text database, Medline, Cochrane database, and VIP Chinese database, and the Revman5. 0 software performed the data analysis. Results. We found the significantly different curative effect between the experimental and control groups (OR=1.94, 95% CI (1.46, 2.58), P

Debris-covered glaciers are an important glacier type and have attracted more and more attention. This study presents the results of ablation patterns of debris-covered tongue of the Halong Glacier in the northeastern Tibetan Plateau, by using two repeated unmanned aerial vehicle (UAV) surveys performed on August 11 and September 15, 2019. The results show that the tongue of Halong Glacier has experienced strong ablation during the surveyed period, with an overall ice loss amount to 4.17 × 105 metric tons. Among all the briefly classified surface types, supraglacial debris has the largest area (80.9%) and also mass losses (58.6%) comparing to others. However, ice cliffs show the strongest and the most significant ablation rates (averagely 1.36 and 1.22 m w.e. for supraglacial and lateral ice cliffs, respectively), followed by clean ice regions (1.01 m w.e.). The backwastes of ice cliffs also resulted in up to 7.8 m horizontal back-off at different parts of Halong Glacier, lead to fast terminal retreat and narrowing down of the glacier tongue, and may result in the break off of Halong Glacier tongue into separated parts in the future. The surface ablation rates show a clear negative exponential relationship with the measured debris thicknesses, well in accordance with previous studies. Regions in cutting and flushing by supraglacial and lateral rivers have the largest surface elevation decreases but are not significant due to their limited area and the relatively lower quality of UAV digital surface models (DSMs) in those covered regions.

A multiplex PCR assay was developed to simultaneously differentiate four antelope species and identify adulteration in Cornu Saigae Tataricae. Four novel primer sets were designed with high inter-species specificity and intra-species stability. Limit of detection was estimated to be 10 ng of genomes. When a mixture of antelope hornand fake species was assayed, it exhibited powerful differentiation capability. 5 out of 12 batches of commercialproducts were identified to be counterfeited or adulterated with Ovis aries Linnaeus and/or Capra hircus Linnaeus. It is readily applicable in routine analysis for identification of sham or adulterants of Cornu Saigae Tataricae.

Abstract Paclitaxel is a well-known anticancer agent with a unique mechanism of action. It is considered to be one of the most successful natural anticancer drugs available. This study summarizes the recent advances in our understanding of the sources, the anticancer mechanism, and the biosynthetic pathway of paclitaxel. With the advancement of biotechnology, improvements in endophytic fungal strains, and the use of recombination techniques and microbial fermentation engineering, the yield of extracted paclitaxel has increased significantly. Recently, paclitaxel has been found to play a large role in tumor immunity, and it has a great potential for use in many cancer treatments.

Abstract A change in the metabolic flux of glucose from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regarded as one hallmark of cancer. However, the mechanisms underlying the metabolic switch between aerobic glycolysis and OXPHOS are unclear. Here we show that the M2 isoform of pyruvate kinase (PKM2), one of the rate-limiting enzymes in glycolysis, interacts with mitofusin 2 (MFN2), a key regulator of mitochondrial fusion, to promote mitochondrial fusion and OXPHOS, and attenuate glycolysis. mTOR increases the PKM2:MFN2 interaction by phosphorylating MFN2 and thereby modulates the effect of PKM2:MFN2 on glycolysis, mitochondrial fusion and OXPHOS. Thus, an mTOR-MFN2-PKM2 signaling axis couples glycolysis and OXPHOS to modulate cancer cell growth.

To solve the problem of large-sized blocks in single-process broccoli cutting, this paper proposes the design of broccoli secondary cutting equipment, in which the screening device with differential round belts, spiral attitude-adjusting mechanism, double-baffle conveyor belt, block-centering chute and disc-type cutter are analyzed and designed. According to the simulation of the motion of the blocks on the differential belts, the speeds of the two belts were 300 mm/s and 600 mm/s, respectively. The kinematic analysis of the spiral attitude-adjusting mechanism was performed, and the speed of the spiral rod was calculated to be greater than 64.5 rpm. The speed of the double-baffle conveyor belt was greater than 10.61 rpm to not obstruct the blocks and achieve diversion. A force analysis of the inclined centering chute was performed to reduce the damage during block conveying, and the inclination angle of the inclined centering chute was calculated to be greater than 27.02°. The parameters of the blade and its driving motor were calculated. Effective secondary cutting equipment for broccoli was thus developed. After secondary cutting, the size difference of two small florets obtained was between 0–8 mm, the success rate of cutting was 94.8%, and the efficiency was 47 pieces/min, which verified the reasonableness and feasibility of the second cutting equipment scheme.

Objective. To develop a method for the rapid isolation of rat RPE cells with high yield and maintain its epithelial state in modified culture system. Methods. The eyeballs were incubated with dispase. The retina was isolated with RPE attached and cut into several pieces. Following a brief incubation in growth medium, large RPE sheets can be harvested rapidly. RPE cells were divided into four groups and cultured for several weeks, that is, (1) in cell culture dishes with 10% FBS containing medium (CC dish-FBS), (2) in petri dishes with 10% FBS containing medium (Petri dish-FBS), (3) in cell culture dishes with N2 and B27 containing medium (CC dish-N2B27), and (4) in petri dishes with N2 and B27 containing medium (Petri dish-N2B27). Morphological and biological characteristics were investigated using light microscopy, Q-PCR, and western blot. Results. The retina would curl inwardly during the growth medium incubation period, releasing RPE sheets in the medium. Compared with low density group (5,000 cells/cm2), RPE cells plated at high density (15,000 cells/cm2) can maintain RPE morphology for a more extended period. Meanwhile, plating RPE cells at low density significantly reduced the expression of RPE cell type-specific genes (RPE65, CRALBP, and bestrophin) and increased the expression of EMT-related genes (N-cadherin, fibronectin, and α-SMA), in comparison with the samples from the high density group. The petri dish culture condition reduced cell adhesion and thus inhibited RPE cell proliferation. As compared with other culture conditions, RPE cells in the petri dish-N2B27 condition could maintain RPE phenotype with increased expression of RPE-specific genes and decreased expression of EMT-related genes. The AKT/mTOR pathway was also decreased in petri dish-N2B27 condition. Conclusion. The current study provided an alternative method for easy isolation of RPE cells with high yield and maintenance of its epithelial morphology in the petri dish-N2B27 condition.

Restriction of pollen germination before the pollen grain is pollinated to stigma is essential for successful fertilization in angiosperms. However, the mechanisms underlying the process remain poorly understood. Here, we report functional characterization of the MAPKKK kinases, MAP3Kε1 and MAP3Kε2, involve in control of pollen germination in Arabidopsis. The two genes were expressed in different tissues with higher expression levels in the tricellular pollen grains. The map3kε1 map3kε2 double mutation caused abnormal callose accumulation, increasing level of JA and precocious pollen germination, resulting in significantly reduced seed set. Furthermore, the map3kε1 map3kε2 double mutations obviously upregulated the expression levels of genes in JA biosynthesis and signaling. The MAP3Kε1/2 interacted with MOB1A/1B which shared homology with the core components of Hippo singling pathway in yeast. The Arabidopsis mob1a mob1b mutant also exhibited a similar phenotype of precocious pollen germination to that in map3kε1 map3kε2 mutants. Taken together, these results suggested that the MAP3Kεs interacted with MOB1s and played important role in restriction of the precocious pollen germination, possibly through crosstalk with JA signaling and influencing callose accumulation in Arabidopsis.

Abstract The nuclear receptor RXRα (retinoid X receptor-α) is a transcription factor that regulates the expression of multiple genes. Its non-genomic function is largely related to its structure, polymeric forms and modification. Previous research revealed that some non-genomic activity of RXRα occurs via formation of heterodimers with Nur77. RXRα–Nur77 heterodimers translocate from the nucleus to the mitochondria in response to certain apoptotic stimuli and this activity correlates with cell apoptosis. More recent studies revealed a significant role for truncated RXRα (tRXRα), which interacts with the p85α subunit of the PI3K/AKT signaling pathway, leading to enhanced activation of AKT and promoting cell growth in vitro and in animals. We recently reported on a series of NSAID sulindac analogs that can bind to tRXRα through a unique binding mechanism. We also identified one analog, K-80003, which can inhibit cancer cell growth by inducing tRXRα to form a tetramer, thus disrupting p85α–tRXRα interaction. This review analyzes the non-genomic effects of RXRα in normal and tumor cells, and discusses the functional differences based on RXRα protein structure (structure source: the RCSB Protein Data Bank).

Glomerular podocytes are highly specialized epithelial cells and play an essential role in establishing the selective permeability of the glomerular filtration barrier of kidney. Maintaining the viability and structural integrity of podocytes is critical to the clinical management of glomerular diseases, which requires a thorough understanding of podocyte cell biology. As mature podocytes lose proliferative capacity, a conditionally SV40 mutant tsA58-immortalized mouse podocyte line (designated as tsPC) was established from the Immortomouse over 20 years ago. However, the utility of the tsPC cells is hampered by the practical inconvenience of culturing these cells. In this study, we establish a user-friendly and reversibly-immortalized mouse podocyte line (designated as imPOD), on the basis of the tsPC cells by stably expressing the wildtype SV40 T-antigen, which is flanked with FRT sites. We show the imPOD cells exhibit long-term high proliferative activity, which can be effectively reversed by FLP recombinase. The imPOD cells express most podocyte-related markers, including WT-1, Nephrin, Tubulin and Vinculin, but not differentiation marker Synaptopodin. The imPOD cells do not form tumor-like masses in vivo. We further demonstrate that TGFβ1 induces a podocyte injury-like response in the FLP-reverted imPOD cells by suppressing the expression of slit diaphragm-associated proteins P-Cadherin and ZO-1 and upregulating the expression of mesenchymal markers, α-SMA, Vimentin and Nestin, as well as fibrogenic factors CTGF and Col1a1. Collectively, our results strongly demonstrate that the newly engineered imPOD cells should be a valuable tool to study podocyte biology both under normal and under pathological conditions. Keywords: Chronic kidney disease, FLP recombinase, Glomerular disease, Glomerulus, Immortalization, Nephropathy, Podocyte, SV40 T antigen

Background/Aims: As the most lethal urological cancers, renal cell carcinoma (RCC) comprises a heterogeneous group of cancer with diverse genetic and molecular alterations. There is an unmet clinical need to develop efficacious therapeutics for advanced, metastatic and/or relapsed RCC. Here, we investigate whether anthelmintic drug Niclosamide exhibits anticancer activity and synergizes with targeted therapy Sorafenib in suppressing RCC cell proliferation. Methods: Cell proliferation and migration were assessed by Crystal violet staining, WST-1 assay, cell wounding and cell cycle analysis. Gene expression was assessed by qPCR. In vivo anticancer activity was assessed in xenograft tumor model. Results: We find that Niclosamide effectively inhibits cell proliferation, cell migration and cell cycle progression, and induces apoptosis in human renal cancer cells. Mechanistically, Niclosamide inhibits the expression of C-MYC and E2F1 while inducing the expression of PTEN in RCC cells. Niclosamide is further shown to synergize with Sorafenib in suppressing RCC cell proliferation and survival. In the xenograft tumor model, Niclosamide is shown to effectively inhibit tumor growth and suppress RCC cell proliferation. Conclusions: Niclosamide may be repurposed as a potent anticancer agent, which can potentiate the anticancer activity of the other agents targeting different signaling pathways in the treatment of human RCC.

The notion of decryption rights delegation was initially introduced by Blaze et al. in EUROCRYPT 1998. It, defined as proxy re-encryption, allows a semi-trusted proxy to convert a ciphertext intended for a party to another ciphertext of the same plaintext, without knowledge of the underlying plaintext and decryption key. It has been explored to many real-world applications, e.g., encrypted email forwarding. However, the intrinsic all-or-nothing share feature of proxy re-encryption yields a limitation that the share cannot be revoked. This may hinder the scalability of its applications in practice. In this paper, for the first time, we define the concept of revocability in terms of decryption rights delegation. The novel concept enables data owner to revoke the shared decryption rights when needed. Inspired by the seminal lattice-based proxy re-encryption proposed in PKC 2014, we design a concrete lattice-based construction which satisfies the notion. In our construction, we make use of binary-tree structure to implement the revocation of decryption rights, so that the update of re-encryption key is reduced to O(logN) (instead of O(N)), where N is the maximum number of delegatee. Furthermore, the security of our scheme is based on the standard learning with errors problem (LWE problem), which could be reduced to the worst-case hard problems (such as GapSVP and SIVP) in the context of lattices. The scheme is chosen ciphertext secure in the standard model. As of independent interest, our scheme achieves both backward and forward security, which means that once a user is revoked after a time period t, it cannot gain access to all encrypted files before and after t.

Since the first fully homomorphic encryption scheme was published in 2009, many papers have been published on fully homomorphic encryption and its applications. Machine learning is one of the most interesting applications and has drawn a lot of attention from researchers. To better represent and understand the field of Homomorphic Encryption in Machine Learning (HEML), this paper utilizes automated citation and topic analysis to characterize the HEML research literature over the years and provide the bibliometrics assessments for this burgeoning field. This is conducted by using a bibliometric statistical analysis approach. We make use of web-based literature databases and automated tools to present the development of HEML. This allows us to target several popular topics for in-depth discussion. To achieve these goals, we have chosen the well-established Scopus literature database and analyzed them through keyword counts and Scopus relevance searches. The results show a relative increase in the number of papers published each year that involve both homomorphic cryptography and machine learning. Using text mining of articles titles, we have found that cloud computing is a popular topic in this field, which also includes neural networks, big data, and the Internet of Things. The analysis results show that China, the US, and India have generated almost half of all the research contributions in HEML. The citation statistics, keyword statistics, and topic analyses give us a quick overview of the development of the field, which can be of great help to new researchers. It is also possible to apply our methodology to other research areas, and we see great value in this approach.

Abstract Meiotic recombination is initiated from the formation of DNA double-strand breaks (DSBs). In Arabidopsis, several proteins, such as AtPRD1, AtPRD2, AtPRD3, AtDFO and topoisomerase (Topo) VI-like complex, have been identified as playing important roles in DSB formation. Topo VI-like complex in Arabidopsis may consist of subunit A (Topo VIA: AtSPO11-1 and AtSPO11-2) and subunit B (Topo VIB: MTOPVIB). Little is known about their roles in Arabidopsis DSB formation. Here, we report on the characterization of the MTOPVIB gene using the Arabidopsis mutant alleles mtopVIB-2 and mtopVIB-3, which were defective in DSB formation. mtopVIB-3 exhibited abortion in embryo sac and pollen development, leading to a significant reduction in fertility. The mtopVIB mutations affected the homologous chromosome synapsis and recombination. MTOPVIB could interact with Topo VIA proteins AtSPO11-1 and AtSPO11-2. AtPRD1 interacted directly with Topo VI–like proteins. AtPRD1 also could interact with AtPRD3 and AtDFO. The results indicated that AtPRD1 may act as a bridge protein to interact with AtPRD3 and AtDFO, and interact directly with the Topo VI-like proteins MTOPVIB, AtSPO11-1 and AtSPO11-2 to take part in DSB formation in Arabidopsis.

The transcription factor retinoid X receptor-alpha (RXRα) can also form homotetramers. Here the authors show that the anti-cancer agent K-80003 selectively inhibits the nongenomic action of N-terminally-cleaved RXRα in tumour cells by stabilizing its tetramerization but not that of full-length RXRα.

Background/Aims: While recombinant adenoviruses are among the most widely-used gene delivery vectors and usually propagated in HEK-293 cells, generating recombinant adenoviruses remains time-consuming and labor-intense. We sought to develop a rapid adenovirus production and amplification (RAPA) line by assessing human Ad5 genes (E1A, E1B19K/55K, pTP, DBP, and DNA Pol) and OCT1 for their contributions to adenovirus production. Methods: Stable transgene expression in 293T cells was accomplished by using piggyBac system. Transgene expression was determined by qPCR. Adenoviral production was assessed with titering, fluorescent markers and/or luciferase activity. Osteogenic activity was assessed by measuring alkaline phosphatase activity. Results: Overexpression of both E1A and pTP led to a significant increase in adenovirus amplification, whereas other transgene combinations did not significantly affect adenovirus amplification. When E1A and pTP were stably expressed in 293T cells, the resultant RAPA line showed high efficiency in adenovirus amplification and production. The produced AdBMP9 infected mesenchymal stem cells with highest efficiency and induced most effective osteogenic differentiation. Furthermore, adenovirus production efficiency in RAPA cells was dependent on the amount of transfected DNA. Under optimal transfection conditions high-titer adenoviruses were obtained within 5 days of transfection. Conclusion: The RAPA cells are highly efficient for adenovirus production and amplification.

Background/Aims: Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into several lineages including bone. Successful bone formation requires osteogenesis and angiogenesis coupling of MSCs. Here, we investigate if simultaneous activation of BMP9 and Notch signaling yields effective osteogenesis-angiogenesis coupling in MSCs. Methods: Recently-characterized immortalized mouse adipose-derived progenitors (iMADs) were used as MSC source. Transgenes BMP9, NICD and dnNotch1 were expressed by adenoviral vectors. Gene expression was determined by qPCR and immunohistochem¡stry. Osteogenic activity was assessed by in vitro assays and in vivo ectopic bone formation model. Results: BMP9 upregulated expression of Notch receptors and ligands in iMADs. Constitutively-active form of Notch1 NICD1 enhanced BMP9-induced osteogenic differentiation both in vitro and in vivo, which was effectively inhibited by dominant-negative form of Notch1 dnNotch1. BMP9- and NICD1-transduced MSCs implanted with a biocompatible scaffold yielded highly mature bone with extensive vascularization. NICD1 enhanced BMP9-induced expression of key angiogenic regulators in iMADs and Vegfa in ectopic bone, which was blunted by dnNotch1. Conclusion: Notch signaling may play an important role in BMP9-induced osteogenesis and angiogenesis. It’s conceivable that simultaneous activation of the BMP9 and Notch pathways should efficiently couple osteogenesis and angiogenesis of MSCs for successful bone tissue engineering.

Abstract We recently demonstrated that retinoic acid receptor-γ (RARγ) is overexpressed and acts as a tumor promoter in hepatocellular carcinoma (HCC). The oncogenic activity of RARγ is mainly attributed to its physiological interaction with p85α regulatory subunit of PI3K leading to constitutive activation of AKT. Here we report RARγ as a negative regulator of p53 signaling and thus extend the oncogenic potential of RARγ to a new role in controlling the balance between AKT and p53. A natural flavonoid acacetin is then identified to be capable of modulating RARγ-dependent AKT-p53 network. It specifically binds to RARγ and inhibits all-trans retinoic acid (atRA) stimulation of RARγ transactivation. However, the anticancer action of acacetin is independent on its modulation of RARγ-driven transcriptional activity. Acacetin induces cancer cell apoptosis through antagonizing the non-genomic effect of RARγ on AKT and p53. When bound to RARγ, acacetin prevents RARγ from its activation of AKT followed by recovery of the normal p53 signaling. Given the implication of AKT-p53 dysregulation in most HCC, targeting the non-genomic signaling of RARγ that switches AKT-p53 from a pro-survival to a pro-apoptotic program in cancer cells should be a promising strategy for developing novel anti-HCC drugs.

Background: BMP9 induces both osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs). Nell1 is a secretory glycoprotein with osteoinductive and anti-adipogenic activities. We investigated the role of Nell1 in BMP9-induced osteogenesis and adipogenesis in MSCs. Methods: Previously characterized MSCs iMEFs were used. Overexpression of BMP9 and NELL1 or silencing of mouse Nell1 was mediated by adenoviral vectors. Early and late osteogenic and adipogenic markers were assessed by staining techniques and qPCR analysis. In vivo activity was assessed in an ectopic bone formation model of athymic mice. Results: We demonstrate that Nell1 expression was up-regulated by BMP9. Exogenous Nell1 potentiated BMP9-induced late stage osteogenic differentiation while inhibiting the early osteogenic marker. Forced Nell1 expression enhanced BMP9-induced osteogenic regulators/markers and inhibited BMP9-upregulated expression of adipogenic regulators/markers in MSCs. In vivo ectopic bone formation assay showed that exogenous Nell1 expression enhanced mineralization and maturity of BMP9-induced bone formation, while inhibiting BMP9-induced adipogenesis. Conversely, silencing Nell1 expression in BMP9-stimulated MSCs led to forming immature chondroid-like matrix. Conclusion: Our findings indicate that Nell1 can be up-regulated by BMP9, which in turn accelerates and augments BMP9-induced osteogenesis. Exogenous Nell1 may be exploited to enhance BMP9-induced bone formation while overcoming BMP9-induced adipogenesis in regenerative medicine.

Tooth is a complex hard tissue organ and consists of multiple cell types that are regulated by important signaling pathways such as Wnt and BMP signaling. Serious injuries and/or loss of tooth or periodontal tissues may significantly impact aesthetic appearance, essential oral functions and the quality of life. Regenerative dentistry holds great promise in treating oral/dental disorders. The past decade has witnessed a rapid expansion of our understanding of the biological features of dental stem cells, along with the signaling mechanisms governing stem cell self-renewal and differentiation. In this review, we first summarize the biological characteristics of seven types of dental stem cells, including dental pulp stem cells, stem cells from apical papilla, stem cells from human exfoliated deciduous teeth, dental follicle precursor cells, periodontal ligament stem cells, alveolar bone-derived mesenchymal stem cells (MSCs), and MSCs from gingiva. We then focus on how these stem cells are regulated by bone morphogenetic protein (BMP) and/or Wnt signaling by examining the interplays between these pathways. Lastly, we analyze the current status of dental tissue engineering strategies that utilize oral/dental stem cells by harnessing the interplays between BMP and Wnt pathways. We also highlight the challenges that must be addressed before the dental stem cells may reach any clinical applications. Thus, we can expect to witness significant progresses to be made in regenerative dentistry in the coming decade.

Accumulating evidence has shown that preeclampsia (PE) was associated with an aberrant maternal-fetal inflammatory response. In the present study, we first found that in human PE placentas levels of toll-like receptor 4 (TLR4), phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and inflammatory cytokines IL-6 and MCP-1 were significantly upregulated. Next, we demonstrated a notable increase in systolic blood pressure (SBP) and proteinuria in lipopolysaccharide (LPS)-treated pregnant rats and concomitant high levels of TLR4 and p-p38 in these PE-like rat placentas, which led to aberrant overexpression of both IL-6 and MCP-1, as well as deficient trophoblast invasion and spiral artery (SA) remodeling, and these abnormalities were ameliorated by SB203580, a reported inhibitor of p38. In vitro we further confirmed that LPS triggered the activation of TLR4/p38 signaling pathway, which promoted trophoblast apoptosis and damaged trophoblastic invasion via downstream effectors IL-6 and MCP-1; these mutations were rectified by silencing this signaling pathway. These findings elaborated potential mechanisms that aberrant TLR4/p38 signaling might contribute to PE and LPS-induced PE-like symptom by damaging trophoblast invasion and SA remodeling via activating inflammatory cytokines including IL-6 and MCP-1.

Background/Aims: Ovarian cancer is the most lethal gynecologic malignancy, and there is an unmet clinical need to develop new therapies. Although showing promising anticancer activity, Niclosamide may not be used as a monotherapy. We seek to investigate whether inhibiting IGF signaling potentiates Niclosamide's anticancer efficacy in human ovarian cancer cells. Methods: Cell proliferation and migration are assessed. Cell cycle progression and apoptosis are analyzed by flow cytometry. Inhibition of IGF signaling is accomplished by adenovirus-mediated expression of siRNAs targeting IGF-1R. Cancer-associated pathways are assessed using pathway-specific reporters. Subcutaneous xenograft model is used to determine anticancer activity. Results: We find that Niclosamide is highly effective on inhibiting cell proliferation, cell migration, and cell cycle progression, and inducing apoptosis in human ovarian cancer cells, possibly by targeting multiple signaling pathways involved in ELK1/SRF, AP-1, MYC/MAX and NFkB. Silencing IGF-1R exert a similar but weaker effect than that of Niclosamide's. However, silencing IGF-1R significantly sensitizes ovarian cancer cells to Niclosamide-induced anti-proliferative and anticancer activities both in vitro and in vivo. Conclusion: Niclosamide as a repurposed anticancer agent may be more efficacious when combined with agents that target other signaling pathways such as IGF signaling in the treatment of human cancers including ovarian cancer.

A novel non-sequencing approach was developed to detect short DNA fragments (ca 100 bp) for rapid authentication of two natural products, namely Testudinis Carapax et Plastrum and Trionycis Carapax, based on the difference in mitochondrial genome. Five specifically designed primer reactions were established to target species for reliable identification of their commercial products. They were confirmed to have a high level of inter-species-specificity and good intra-species stability. The limit of detection was estimated to be 1 ng of genomes for all of five assays. Also, the validation results demonstrated that the raw materials and processed products in addition to some of the highly processed products can be conveniently authenticated with good sensitivity and precision by this newly proposed approach. Especially, when reference sample mixtures were assayed, these primer sets have still performed well but not the prevailing COI barcoding technology. These could assist in the discrimination and identification of other animal-derived medicines for their form of raw material, the pulverized and the complex.

Fyn, a member of the Src family of tyrosine kinases, is a key regulator in cytoskeletal remodeling in a variety of cell types. Recent studies have demonstrated that Fyn is responsible for nephrin tyrosine phosphorylation, which will result in polymerization of actin filaments and podocyte damage. Thus detailed involvement of Fyn in podocytes is to be elucidated. In this study, we investigated the potential role of Fyn/ROCK signaling and its interactions with paxillin. Our results presented that high glucose led to filamentous actin (F-actin) rearrangement in podocytes, accompanied by paxillin phosphorylation and increased cell motility, during which Fyn and ROCK were markedly activated. Gene knockdown of Fyn by siRNA showed a reversal effect on high glucose-induced podocyte damage and ROCK activation; however, inhibition of ROCK had no significant effects on Fyn phosphorylation. These observations demonstrate that in vitro Fyn mediates high glucose-induced actin cytoskeleton remodeling of podocytes via promoting ROCK activation and paxillin phosphorylation.

The internet-of-things (also known as IoT) connects a large number of information-sensing devices to the Internet to collect all kinds of information needed in real time. The reliability of the source of a large number of accessed information tests the processing speed of signatures. Batch signature allows a signer to sign a group of messages at one time, and signatures’ verification can be completed individually and independently. Therefore, batch signature is suitable for data integration authentication in IoT. An outstanding advantage of batch signature is that a signer is able to sign as many messages as possible at one time without worrying about the size of signed messages. To reduce complexity yielded by multiple message signing, a binary tree is usually leveraged in the construction of batch signature. However, this structure requires a batch residue, making the size of a batch signature (for a group of messages) even longer than the sum of single signatures. In this paper, we make use of the intersection method from lattice to propose a novel generic method for batch signature. We further combine our method with hash-and-sign paradigm and Fiat–Shamir transformation to propose new batch signature schemes. In our constructions, a batch signature does not need a batch residue, so that the size of the signature is relatively smaller. Our schemes are securely proved to be existential unforgeability against adaptive chosen message attacks under the small integer solution problem, which shows great potential resisting quantum computer attacks.

Axially moving stepped beam (AMSB) with different length and tip mass is represented by adopting Euler-Bernoulli beam theory, and its characteristics and displacements of transverse free vibration are calculated by using semianalytical method. Firstly, the governing equation of the transverse free vibration is established based on Hamilton’s principle. The equation is cast into eigenvalue equation through the complex modal analysis. Then, a scheme is proposed to derive the continuous condition accordingly as the displacement, rotation, bending moment, and shear force are all equal at the connections of any two segments. Another scheme is to derive frequency equation from the given boundary conditions which contain a tip mass in the last segment. Finally, the natural frequency and modal function are calculated by using numerical method according to the eigenvalue equation and frequency equation. Due to the introduction of modal truncation, displacement and, the free vibration solution can be obtained by adopting modal superposition after Hilbert transform. The numerical examples illustrate that length, velocity, mass, and geometry affect characteristics and displacements significantly; the series of methods are effective and accurate to investigate the vibration of the AMSB with different length and tip mass after comparing several results.

A critical challenge in a fully homomorphic encryption (FHE) scheme is to manage noise. Modulus switching technique is currently the most efficient noise management technique. When using the modulus switching technique to design and implement a FHE scheme, how to choose concrete parameters is an important step, but to our best knowledge, this step has drawn very little attention to the existing FHE researches in the literature. The contributions of this paper are twofold. On one hand, we propose a function of the lower bound of dimension value in the switching techniques depending on the LWE specific security levels. On the other hand, as a case study, we modify the Brakerski FHE scheme (in Crypto 2012) by using the modulus switching technique. We recommend concrete parameter values of our proposed scheme and provide security analysis. Our result shows that the modified FHE scheme is more efficient than the original Brakerski scheme in the same security level.

The current study used the improved fuzzy analytic hierarchy process to construct a sustainable deforestation development evaluation system and evaluation model, which has refined a diversified system to evaluate the theory of sustainable deforestation development. Leveraging the visual image of the system dynamics causal and power flow diagram, we illustrated here that sustainable forestry development is a complex system that encompasses the interaction and dynamic development of ecology, economy, and society and has reflected the time dynamic effect of sustainable forestry development from the three combined effects. We compared experimental programs to prove the direct and indirect impacts of the ecological, economic, and social effects of the corresponding deforest techniques and fully reflected the importance of developing scientific and rational ecological harvesting and transportation technologies. Experimental and theoretical results illustrated that light cableway skidding is an ecoskidding method that is beneficial for the sustainable development of resources, the environment, the economy, and society and forecasted the broad potential applications of light cableway skidding in timber production technology. Furthermore, we discussed the sustainable development countermeasures of forest ecosystems from the aspects of causality, interaction, and harmony.

Mixture toxicity is an important issue for the risk assessment of environmental pollutants, for which an extensive amount of data are necessary in evaluating their potential adverse health effects. However, it is very hard to decipher the interaction between compounds due to limited techniques. Contamination of heavy metals and organophosphoric insecticides under the environmental and biological settings poses substantial health risk to humans. Although previous studies demonstrated the co-occurrence of cadmium (Cd) and chlorpyrifos (CPF) in environmental medium and food chains, their interaction and potentially synergistic toxicity remain elusive thus far. Here we integrated the approaches of thin-layer chromatography and (1)H NMR to study the interaction between Cd(2+) and CPF in inducing hepatoxicity. A novel interaction was identified between Cd(2+) and CPF, which might be the bonding between Cd(2+) and nitrogen atom in the pyridine ring of CPF, or the chelation formation between one Cd(2+) and two CPF molecules. The Cd-CPF complex was conferred with distinct biological fate and toxicological performances from its parental components. We further demonstrated that the joint hepatoxicity of Cd ion and CPF was chiefly due to the Cd-CPF complex-facilitated intracellular transport associated with oxidative stress.

BACKGROUND: Retinoid X receptor-alpha (RXRα) is a key member of the nuclear receptor superfamily. We recently demonstrated that proteolytic cleavage of RXRα resulted in production of a truncated product, tRXRα, which promotes cancer cell survival by activating phosphatidylinositol-3-OH kinase (PI3K)/AKT pathway. However, how the tRXRα-mediated signaling pathway in cancer cells is regulated remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: We screened a natural product library for tRXRα targeting leads and identified that triptolide, an active component isolated from traditional Chinese herb Trypterygium wilfordii Hook F, could modulate tRXRα-mediated cancer cell survival pathway in vitro and in animals. Our results reveal that triptolide strongly induces cancer cell apoptosis dependent on intracellular tRXRα expression levels, demonstrating that tRXRα serves as an important intracellular target of triptolide. We show that triptolide selectively induces tRXRα degradation and inhibits tRXRα-dependent AKT activity without affecting the full-length RXRα. Interestingly, such effects of triptolide are due to its activation of p38. Although triptolide also activates Erk1/2 and MAPK pathways, the effects of triptolide on tRXRα degradation and AKT activity are only reversed by p38 siRNA and p38 inhibitor. In addition, the p38 inhibitor potently inhibits tRXRα interaction with p85α leading to AKT inactivation. Our results demonstrate an interesting novel signaling interplay between p38 and AKT through tRXRα mediation. We finally show that targeting tRXRα by triptolide strongly activates TNFα death signaling and enhances the anticancer activity of other chemotherapies. CONCLUSIONS/SIGNIFICANCE: Our results identify triptolide as a new xenobiotic regulator of the tRXRα-dependent survival pathway and provide new insight into the mechanism by which triptolide acts to induce apoptosis of cancer cells. Triptolide represents one of the most promising therapeutic leads of natural products of traditional Chinese medicine with unfortunate side-effects. Our findings will offer new strategies to develop improved triptolide analogs for cancer therapy.