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Abstract Most cancers and neoplastic progenitor cells have elevated telomerase activity and preservation of telomeres that promote cellular immortality, making telomerase a rational target for the treatment of cancer. Imetelstat is a first‐in‐class, 13‐mer oligonucleotide that binds with high affinity to the template region of the RNA component of human telomerase and acts as a competitive inhibitor of human telomerase enzymatic activity. Pharmacokinetics, pharmacodynamics, exposure‐response analyses, efficacy, and safety of imetelstat have been evaluated in vitro, in vivo, and clinically in solid tumor and hematologic malignancies, including lower‐risk myelodysplastic syndromes (LR‐MDS) and myeloproliferative neoplasms. Imetelstat was approved in the United States in June 2024 for the treatment of adult patients with LR‐MDS with transfusion‐dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis‐stimulating agents, with a recommended dosing regimen of 7.1 mg/kg administered via 2‐h intravenous infusion every 4 weeks. In the pivotal trial, significantly more patients treated with imetelstat versus placebo achieved ≥8‐week and ≥24‐week red blood cell‐transfusion independence, and imetelstat was associated with a manageable safety profile characterized primarily by short‐lived and manageable neutropenia and thrombocytopenia. This mini‐review summarizes the mechanism of action, pharmacokinetic and pharmacodynamic characteristics, clinical development, and clinical efficacy and safety data of imetelstat.

Abstract Imetelstat is a novel, first‐in‐class, oligonucleotide telomerase inhibitor in development for the treatment of hematologic malignancies including lower‐risk myelodysplastic syndromes and myelofibrosis. A nonlinear mixed‐effects model was developed to characterize the population pharmacokinetics of imetelstat and identify and quantify covariates that contribute to its pharmacokinetic variability. The model was developed using plasma concentrations from 7 clinical studies including 424 patients with solid tumors or hematologic malignancies who received single‐agent imetelstat via intravenous infusion at various dose levels (0.4–11.7 mg/kg) and schedules (every week to every 4 weeks). Covariate analysis included factors related to demographics, disease, laboratory results, renal and hepatic function, and antidrug antibodies. Imetelstat was described by a two‐compartment, nonlinear disposition model with saturable binding/distribution and dose‐ and time‐dependent elimination from the central compartment. Theory‐based allometric scaling for body weight was included in disposition parameters. The final covariates included sex, time, malignancy, and dose on clearance; malignancy and sex on volume of the central compartment; and malignancy and spleen volume on concentration of target. Clearance in females was modestly lower, resulting in nonclinically relevant increases in predicted exposure relative to males. No effects on imetelstat pharmacokinetics were identified for mild‐to‐moderate hepatic or renal impairment, age, race, and antidrug antibody status. All model parameters were estimated with adequate precision (relative standard error

Abstract The electrochemical conversion of nitrate to ammonia is a way to eliminate nitrate pollutant in water. Cu-Co synergistic effect was found to produce excellent performance in ammonia generation. However, few studies have focused on this effect in high-entropy oxides. Here, we report the spin-related Cu-Co synergistic effect on electrochemical nitrate-to-ammonia conversion using high-entropy oxide Mg0.2Co0.2Ni0.2Cu0.2Zn0.2O. In contrast, the Li-incorporated MgCoNiCuZnO exhibits inferior performance. By correlating the electronic structure, we found that the Co spin states are crucial for the Cu-Co synergistic effect for ammonia generation. The Cu-Co pair with a high spin Co in Mg0.2Co0.2Ni0.2Cu0.2Zn0.2O can facilitate ammonia generation, while a low spin Co in Li-incorporated MgCoNiCuZnO decreases the Cu-Co synergistic effect on ammonia generation. These findings offer important insights in employing the synergistic effect and spin states inside for selective catalysis. It also indicates the generality of the magnetic effect in ammonia synthesis between electrocatalysis and thermal catalysis.

Abstract Dermal fibroblasts and cutaneous nerves are important players in skin diseases, while their reciprocal roles during skin inflammation have not been characterized. Here we identify an inflammation-induced subset of papillary fibroblasts that promotes aberrant neurite outgrowth and psoriasiform skin inflammation by secreting the extracellular matrix protein tenascin-C (TNC). Single-cell analysis of fibroblast lineages reveals a Tnc + papillary fibroblast subset with pro-axonogenesis and neuro-regulation transcriptomic hallmarks. TNC overexpression in fibroblasts boosts neurite outgrowth in co-cultured neurons, while fibroblast-specific TNC ablation suppresses hyperinnervation and alleviates skin inflammation in male mice modeling psoriasis. Dermal γδT cells, the main producers of type 17 pathogenic cytokines, frequently contact nerve fibers in mouse psoriasiform lesions and are likely modulated by postsynaptic signals. Overall, our results highlight the role of an inflammation-responsive fibroblast subset in facilitating neuro-immune synapse formation and suggest potential avenues for future therapeutic research.

In order to ensure the security of computer systems and networks, it is very important to design and implement intrusion detection systems that can detect and mitigate network attacks and threats. Deep learning has great advantages in processing complex, high-dimensional and large-scale traffic data. Therefore, intrusion detection system based on deep learning method has better detection effect. Through the analysis of the research status, this paper finds that there are some problems in the existing intrusion detection system. To solve the problems of low detection accuracy, structure to be optimized and high false positive rate, this paper presents a hierarchical intrusion detection model which combines multiple deep learning models with attention mechanism. The advantages of this hierarchical model include: Firstly, the SCDAE model is used to extract the features of traffic data and reduce noise; Secondly, CNN is used to extract spatial features of network traffic data from the spatial dimension; Thirdly, BiLSTM is able to fully consider the relationship between the front and back features, so that the temporal features of network traffic data can be mined; Fourthly, a Self-Attention mechanism is added to weight the output of each time step to sum up and retain the important information in it. Thus, a CNN-BiLSTM-Attention model is constructed; Finally, the Softmax classifier is used to obtain the classification results. To verify the effectiveness of the proposed model, four time-sensitive and representative datasets are selected for experiments and five classical detection models are compared in this paper. The experimental results show that the classification accuracy of the proposed model reaches 93.26 % and the false positive rate reaches 7.53%.

Psoriasis is an inflammatory disease which has proven difficult to cure. Prof. Honglin Wang’s team describes L-menthol for treating models of psoriasis and uncovers the dysfunctional HES1- IGBP1-PP6 axis in psoriasis pathology by using L-menthol as a probe.

Mobile Edge Computing (MEC) is a well-known network architecture that extends cloud computing to the network edge. Compared with cloud computing, Network Function Virtualization (NFV) can provide flexible services in MEC for mobile users. Virtual Network Functions (VNFs) have emerged as software-based hardware middleboxes by NFV technology to host real-time applications. Basically, the combination of multiple VNF instances is defined as a Service Function Chain (SFC), which can provide dynamic service requirements in the MEC. Despite the rapid growth of MEC and the widespread support of service providers for SFC, many issues are still challenging and need to be addressed. In MEC scenarios with limited resources, the effective placement of SFCs with the aim of resource efficiency remains a challenging problem. Motivated by the scalability shortcomings of existing schemes to solve dynamic placement of SFCs, we propose Deep Reinforcement Learning (DRL)-based approaches to solve this problem, i.e., Asynchronous Advantage Actor-Critic (A3C). The proposed scheme is based on the reuse of initialized VNFs to improve the Quality of Service (QoS), which is developed with the aim of maximizing the long-term cumulative reward. In addition, a parallel processing approach of SFCs is included in the proposed scheme, which can split the traffic in each flow into sub-flows. This shares the processing load by instantiating duplicate instances of each VNF type in the SFC. The simulation results guarantee the efficiency of the proposed scheme and improves the average performance between 6% and 24% compared to the state-of-the-art clustering methods.

Abstract A disubstituted quaterpyridine based cobalt complex non‐covalently tethered to multiwalled carbon nanotube (MWCNT) substrate, forming a hybrid catalyst, Co‐qpyCOOH/CNT, catalyzed the conversion of CO2 to CO under aqueous conditions. At an optimal and uniform loading, it exhibited remarkable catalytic activity, near‐exclusive selectivity, and high stability towards the formation of CO. At a mere cathodic potential of −0.65 V versus RHE (η = 0.54 V), it achieved a high partial current density of −6.7 mA/cm2 and a F.E.CO = 100%. In addition, with 20 h of stable operation, hydrogen evolution remained practically undetected. Its hybrid structure due to noncovalent immobilization on MWCNT imparted the intrinsic activity and much‐needed stability in performance whereas ‒COOH groups may stabilize the intermediates by acting as H‐bond donors, promoting catalytic activity. Tethering to a conductive solid substrate and tuning of the second sphere of coordination played an important role in its performance to achieve desired reduction product with high selectivity and activity.

Regulatory T (Treg) cells constitute a dynamic population that is critical in autoimmunity. Treg cell therapies for autoimmune diseases are mainly focused on enhancing their suppressive activities. However, recent studies demonstrated that certain inflammatory conditions induce Treg cell instability with diminished FoxP3 expression and convert them into pathogenic effector cells. Therefore, the identification of novel targets crucial to both Treg cell function and plasticity is of vital importance to the development of therapeutic approaches in autoimmunity. In this study, we found that conditional Pp6 knockout (cKO) in Treg cells led to spontaneous autoinflammation, immune cell activation, and diminished levels of FoxP3 in CD4+ T cells in mice. Loss of Pp6 in Treg cells exacerbated two classical mouse models of Treg-related autoinflammation. Mechanistically, Pp6 deficiency increased CpG motif methylation of the FoxP3 locus by dephosphorylating Dnmt1 and enhancing Akt phosphorylation at Ser473/Thr308, leading to impaired FoxP3 expression in Treg cells. In summary, our study proposes Pp6 as a critical positive regulator of FoxP3 that acts by decreasing DNA methylation of the FoxP3 gene enhancer and inhibiting Akt signaling, thus maintaining Treg cell stability and preventing autoimmune diseases.

MicroRNAs (miRNAs) and their target genes are aberrantly expressed in many cancers and are linked to carcinogenesis and metastasis, especially among hepatocellular carcinoma (HCC) patients. This study sought to identify new biomarkers related to HCC prognosis using small RNA sequencing from the tumor and matched normal adjacent tissue of 32 patients with HCC. Eight miRNAs were downregulated and 61 were upregulated more than twofold. Of these, five miRNAs, hsa-miR-3180, hsa-miR-5589-5p, hsa-miR-490-5p, hsa-miR-137, and hsa-miR-378i, were significantly associated with 5-year overall survival (OS) rates. Differential upregulation of hsa-miR-3180 and downregulation of hsa-miR-378i in tumor samples supported the finding that low and high concentrations of hsa-miR-3180 (p = 0.029) and hsa-miR-378i (p = 0.047), respectively, were associated with higher 5-year OS. Cox regression analyses indicated that hsa-miR-3180 (HR = 0.08; p = 0.013) and hsa-miR-378i (HR = 18.34; p = 0.045) were independent prognostic factors of poor survival. However, high hsa-miR-3180 expression obtained larger AUCs for OS and progression-free survival (PFS) and had better nomogram prediction than hsa-miR-378i. These findings indicate that hsa-miR-3180 may be associated with HCC progression and could serve as a potential biomarker for this disease.

IntroductionAlthough we had identified that the methylation of AHNAK was a good diagnostic marker for hepatopathy, here we speculate that there was also another marker, STAP1, whose methylation also involved in the detection of hepatopathy.MethodsWe investigated the methylation levels of the AHNAK and STAP1 in peripheral blood mononuclear cells of chronic hepatitis B (CHB) patients, compensatory liver cirrhosis (CLC) patients, decompensated liver cirrhosis (DCLC) patients, hepatocellular carcinoma (HCC) patients and healthy controls by methylation-specific PCR. We also evaluated the differences and changes of methylation and expression of AHNAK and STAP1 at different stages of liver disease using the TCGA and GEO public datasets.ResultsMethylation level of STAP1 in PBMC was positively correlated with the course of liver cancer. The combination of AHNAK and STAP1 methylation was able to predict differrent HBV related hepatopathy. The GEO datasets also supported that the methylation of AHNAK and STAP1 was associated with different types of hepatopathy. The TCGA data showed that the levels of methylation and expression of STAP1 were down-regulated in HCC. We also found the STAP1 methylation level in PBMC and T cells was associated with age, gender, alcohol drinking and anti-HBe. Hyper-methylation of STAP1 was correlated with the poor prognosis of patients but its expression had no association.ConclusionWe concluded that combination of AHNAK and STAP1 methylation in peripheral blood immune cells can be used as a diagnostic marker for HBV related hepatopathy and STAP1 methylation may be a potential prognostic marker for HBV related HCC. Our clinical study registration number was ChiCTR2000039860.

Background. Lung cancer is considered to be the second most aggressive and rapidly fatal cancer after breast cancer. Necroptosis, a novel discovered pattern of cell death, is mediated by Receptor-interacting serine/threonine-protein kinase 1 (RIPK1), Receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and Mixed Lineage Kinase Domain Like Pseudokinase (MLKL). Methods. For the purpose of developing a prognostic model, Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was conducted. Using Pearson’s correlation analysis, we evaluated the correlation between necroptosis-related markers and tumor immune infiltration. A bioinformatics analysis was conducted to construct a necroptosis-related regulatory axis. Results. There was a downregulation of most of necroptosis-related genes in lung adenocarcinoma (LUAD) versus lung tissues but an increase in PGAM5, HMGB1, TRAF2, EZH2 levels. We also summarized the Single Nucleotide Variant (SNV) and copy number variation (CNV) of necroptosis-related genes in LUAD. Consensus clustering identified two clusters in LUAD with distinct immune cell infiltration and ESTIMATEScore. Genes related to necroptosis were associated with necroptosis, Tumor necrosis factor (TNF) signaling pathway, and apoptosis according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Four prognostic genes (ALDH2, HMGB1, NDRG2, TLR2) were combined to develop a prognostic gene signature for LUAD patients, which was highly accurate in predicting prognosis. Univariate and multivariate analysis identified HMGB1, pT stage, and pN stage as independent factors impacting on LUAD patients’ prognosis. A significant correlation was found between the level of TLR2 and NDRG2 and clinical stage, immunity infiltration, and drug resistance. Additionally, the progression of LUAD might be regulated by lncRNA C5orf64/miR-582-5p/NDRG2/TLR2. Conclusion. The current bioinformatics analysis identified a necroptosis-related prognostic signature for LUAD and their relation to immunity infiltration. This result requires further investigation.

Abstract Background Long non-coding RNAs (lncRNAs) have been considered as one type of gene expression regulator for cancer development, but it is not clear how these are regulated. This study aimed to identify a specific lncRNA that promotes glioma progression. Methods RNA sequencing (RNA-seq) and quantitative real-time PCR were performed to screen differentially expressed genes. CCK-8, transwell migration, invasion assays, and a mouse xenograft model were performed to determine the functions of TMEM44-AS1. Co-IP, ChIP, Dual-luciferase reporter assays, RNA pulldown, and RNA immunoprecipitation assays were performed to study the molecular mechanism of TMEM44-AS1 and the downstream target. Results We identified a novel lncRNA TMEM44-AS1, which was aberrantly expressed in glioma tissues, and that increased TMEM44-AS1 expression was correlated with malignant progression and poor survival for patients with glioma. Expression of TMEM44-AS1 increased the proliferation, colony formation, migration, and invasion of glioma cells. Knockdown of TMEM44-AS1 in glioma cells reduced cell proliferation, colony formation, migration and invasion, and tumor growth in a nude mouse xenograft model. Mechanistically, TMEM44-AS1 is directly bound to the SerpinB3, and sequentially activated Myc and EGR1/IL-6 signaling; Myc transcriptionally induced TMEM44-AS1 and directly bound to the promoter and super-enhancer of TMEM44-AS1, thus forming a positive feedback loop with TMEM44-AS. Further studies demonstrated that Myc interacts with MED1 regulates the super-enhancer of TMEM44-AS1. More importantly, a novel small-molecule Myc inhibitor, Myci975, alleviated TMEM44-AS1-promoted the growth of glioma cells. Conclusions Our study implicates a crucial role of the TMEM44-AS1-Myc axis in glioma progression and provides a possible anti-glioma therapeutic agent.

Background: Three-dimensional (3D) printed tissue engineered bone was used to repair the bone tissue defects in the oral and maxillofacial (OMF) region of experimental dogs. Material and methods: Canine bone marrow stromal cells (BMSCs) were obtained from 9 male Beagle dogs and in vitro cultured for osteogenic differentiation. The OMF region was scanned for 3D printed surgical guide plate and mold by ProJet1200 high-precision printer using implant materials followed sintering at 1250 °C. The tissue engineered bones was co-cultured with BASCs for 2 or 8 d. The cell scaffold composite was placed in the defects and fixed in 9 dogs in 3 groups. Postoperative CT and/or micro-CT scans were performed to observe the osteogenesis and material degradation. Results: BMSCs were cultured with osteogenic differentiation in the second generation (P2). The nanoporous hydroxyapatite implant was made using the 3D printing mold with the white porous structure and the hard texture. BMSCs with osteogenic induction were densely covered with the surface of the material after co-culture and ECM was secreted to form calcium-like crystal nodules. The effect of the tissue engineered bone on the in vivo osteogenesis ability was no significant difference between 2 d and 8 d of the compositing time. Conclusions: The tissue-engineered bone was constructed by 3D printing mold and high-temperature sintering to produce nanoporous hydroxyapatite scaffolds, which repair in situ bone defects in experimental dogs. The time of compositing for tissue engineered bone was reduced from 8 d to 2 d without the in vivo effect. Keywords: Mandibular defect, Tissue engineering bone, 3D printing, CAD/CAM, BMSCs

Soil moisture is connected to atmospheric moisture through direct evaporation and vegetation transpiration. This is a complex process that is in focus of numerous hydrological studies. We used the long-term measurements from a typical farming-pastoral ecotone in northern Hebei Province of China to study the relationship between the daytime and nighttime fluctuations of grassland surface soil moisture and evapotranspiration. The results show that the surface soil of grassland above 60 cm is the main water consumption area, while below 60 cm is the main water storage area. The 80–100 cm layer responds to precipitation 263 h later than that of the 0–20 cm layer. In the 0–20 cm and 20–40 cm layers where the moisture fluctuation is more obvious, the moisture movement in the lower layer occurs on average 7.85 h after the upper layer. The fluctuations were digitalized, and they were significantly correlated with potential evapotranspiration and actual evapotranspiration. This research suggests that soil moisture is affected by evapotranspiration and thus it always moves upward in the surface soil. When the evapotranspiration is large, the amount of water transport increases and it suggests that the use soil moisture fluctuation signals can be used to reflect evapotranspiration. This research hopes to provide a reference for a precise analysis of soil and atmospheric water resources and their interactions.

Neuroblast differentiation-associated protein AHNAK, a large structural scaffold protein, remains mysterious in biological processes. AHNAK plays a suppressive or progressive role in different types of cancers. To investigate the role of the AHNAK in hepatocellular carcinoma (HCC), cell viability assays were performed to determine the cell proliferation of the stable AHNAK-knockdown HepG2 cell line; co-immunoprecipitation (Co-IP) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were performed on HCC and matched paracancerous (MPC) tissues. The Metascape platform was used for enrichment analyses; the “ComplexHeatmap” package was applied for cluster analyses and visualization. Co-IP, Western botting and immunofluorescence double staining were performed to assess the interactions between AHNAK and insulin-like growth factor 1 receptor (IGF-1R). AHNAK silencing reduced the viability of HepG2 cells; the interactome in HCC and MPC tissues enriched 204 pathways and processes, which partially reflected the signature of HCC field cancerization. AHNAK could co-localize and interact with IGF-1R. These results suggested that the AHNAK complex contributes to HCC growth, potentially by interacting with IGF-1R.

Background: Child unintentional injuries have become a hot topic worldwide, and substantial regional disparities existed in causes and characteristics. To date, limited data are available to investigate the causes and characteristics of child unintentional injuries from hospitals for children in China.Methods: A cross-sectional study was conducted between January 2017 and December 2018 in Shanghai, China. Patients aged

Abstract Tuning and optimization of electronic structures and related reaction energetics are critical toward the rational design of efficient electrocatalysts. Herein, experimental and theoretical calculation demonstrate the originally inert N site within polyaniline (PANI) can be activated for hydrogen evolution by proper d‐π interfacial electronic coupling with metal oxide. As a result, the as‐synthesized WO3 assemblies@PANI via a facile redox‐induced assembly and in situ polymerization, exhibits the electrocatalytic production of hydrogen better than other control samples including W18O49@PANI and most of the reported nobel‐metal‐free electrocatalysts, with low overpotential of 74 mV at 10 mA·cm−2 and small Tafel slope of 46 mV·dec−1 in 0.5M H2SO4 (comparable to commercial Pt/C). The general efficacy of this methodology is also validated by extension to other metal oxides such as MoO3 with similar improvements.

Abstract Background Swainsonine is a natural indolizidine alkaloid, its anti-tumor activity has been widely reported in varied cancers. This study aimed to investigate whether Swainsonine exerted anti-tumor impact on glioma cells, likewise uncovered the relative molecular mechanisms. Methods After administration with diverse concentrations of Swainsonine, cell growth, migration and invasion in U251 and LN444 cells were appraised by the common-used CCK-8, BrdU, flow cytometry and Transwell assays. MiR-92a mimic, inhibitor and the correlative NC were transfected into U251 and LN444 cells, and assessment of miR-92a expression was by utilizing qRT-PCR. Functions of miR-92a in above-mentioned cell biological processes were analyzed again in Swainsonine-treated cells. The momentous proteins of cell cycle, apoptosis and PI3K/AKT/mTOR pathway were ultimately examined by western blot. Results Swainsonine significantly hindered cell proliferation through decreasing cell viability, declining the percentage of BrdU cells, down-regulating CyclinD1 and up-regulating p16 expression. Enhancement of percentage of apoptotic cells was presented in Swainsonine-treated cells via activating cleaved-Caspase-3 and cleaved-Caspase-9. Additionally, Swainsonine impeded the abilities of migration and invasion by decreasing MMP-2, MMP-9, Vimentin and E-cadherin. Repression of miR-92a was observed in Swainsonine-treated cells, and miR-92a overexpression overturned the anti-tumor activity of Swainsonine in glioma cells. Finally, western blot assay displayed that Swainsonine hindered PI3K/AKT/mTOR pathway via regulating miR-92a. Conclusions These discoveries corroborated that Swainsonine exerted anti-tumor impacts on glioma cells via repression of miR-92a, and inactivation of PI3K/AKT/mTOR signaling pathway.

Glioma is one of the most common malignant tumors of the central nervous system, and its prognosis is extremely poor. Aberrant methylation of lncRNA promoter region is significantly associated with the prognosis of glioma patients. In this study, we investigated the potential impact of methylation of lncRNA promoter region in glioma patients to establish a signature of nine lncRNA methylated genes for determining glioma patient prognosis. Methylation data and clinical follow-up data were obtained from The Cancer Genome Atlas (TCGA). The multistep screening strategy identified nine lncRNA methylated genes that were significantly associated with the overall survival (OS) of glioma patients. Subsequently, we constructed a risk signature that containing nine lncRNA methylated genes. The risk signature successfully divided the glioma patients into high-risk and low-risk groups. Compared with the low-risk group, the high-risk group had a worse prognosis, higher glioma grade, and older age. Furthermore, we identified two lncRNAs termed PCBP1-AS1 and LINC02875 that may be involved in the malignant progression of glioma cells by using the TCGA database. Loss-of-function assays confirmed that knockdown of PCBP1-AS1 and LINC02875 inhibited the proliferation, migration, and invasion of glioma cells. Therefore, the nine lncRNA methylated genes signature may provide a novel predictor and therapeutic target for glioma patients.

Abstract The construction of isolated metal sites represents a promising approach for electrocatalyst design toward the efficient electrochemical conversion of carbon dioxide (CO2). Herein, Fe‐doped graphitic carbon nitride is rationally prepared by a simple adsorption method and is used as template to construct isolated FeN4 sites through a confined pyrolysis strategy, which avoids the agglomeration of metal atoms to particles during the synthesis process and thus provides abundant active sites for the CO2 reduction reaction. The isolated FeN4 sites lower the energy barrier for the key intermediate in the CO2 reduction process, leading to the enhanced selectivity for CO production with a faradaic efficiency of up to 93%.

This paper presents an approach for solving the crowd navigation problem in an unknown and dynamic environment based on deep reinforcement learning. In our approach, we first make four leader agents learn how to reach their goals and avoid collisions with static and dynamic obstacles in an unknown environment by use of proximal policy optimization combined with Long short-term memory and a collision prediction algorithm. In the second stage, we make each leader agent arrive at a specific goal several times and record its trajectory as the guiding path so that the members in its group know how to reach their goals. We adopt the Reciprocal Velocity Obstacle algorithm to make agents not collide with others. Finally, we simulate the scenario of four groups moving towards their goals simultaneously using the Unity 3D engine. The experimental results demonstrate self-learning ability of a crowd who can reach their goals successfully in an unknown and dynamic environment.

There have been some biomechanics-based control systems that have achieved better realistic virtual human motion. Yet their abilities to adapt the changing environments are weaker than the traditional control systems with characters driven by proportional derivative actuators directly. In our method, we build a hierarchical neuromuscular virtual human (NMVH) motion control system that consists of a low-level spine reflex layer and a high-level policy control layer. The spine reflex layer uses a feedback net to map sensory information to excitations, which stimulate muscles to generate joint torques. The policy control layer includes a deep neural network, which provides a learned action policy to spine reflex layer for achieving terrain-adaptive motion skills. The particle swarm optimization algorithm is used to optimize the gain factors of the feedback net for finding out a basic policy to make the virtual human walk on the flat terrain autonomously. The proximal policy optimization algorithm is employed to train the deep neural network in policy control layer for learning how to modulate the actions to adapt to the changing terrain. The simulation results in Matlab show that virtual human can walk smoothly and better adapt to the given terrain changes. It demonstrates that our control system improves the terrain-adaptive walking skill of the neuromuscular virtual human.

Ultraconserved RNAs are a class of long non-coding RNAs whose functions are yet to be identified. Here Guo and colleagues show that an ultraconserved RNA uc.372 promotes lipogenesis and lipid accumulation within the hepatocytes by suppressing the maturation of miR-195/miR-4668 that inhibits lipogenic gene expression.

Herein, a non-stacked γ-Fe2O3/C@TiO2 double-layer hollow nano photocatalyst has been developed with ultrathin nanosheets-assembled double shells for photodegradation phenol. High catalytic performance was found that the phenol could be completely degraded in 135 min under visible light, due to the moderate band edge position (VB at 0.59 eV and CB at −0.66 eV) of the non-stacked γ-Fe2O3/C@TiO2, which can expand the excitation wavelength range into the visible light region and produce a high concentration of free radicals (such as ·OH, ·O2−, holes). Furthermore, the interior of the hollow composite γ-Fe2O3 is responsible for charge generation, and the carbon matrix facilitates charge transfer to the external TiO2 shell. This overlap improved the selection/utilization efficiency, while the unique non-stacked double-layered structure inhibited initial charge recombination over the photocatalysts. This work provides new approaches for photocatalytic applications with γ-Fe2O3/C-based materials.

Objective: Insulin resistance is a critical factor contributing to the pathogenesis of type 2 diabetes and other metabolic diseases. Recent studies have indicated that miR-338-3p plays an important role in cancer. Here, we investigated whether miR-338-3p mediates tumour necrosis factor-α (TNF-α)-induced hepatic insulin resistance. Methods: The activation of the insulin signalling pathway and the level of glycogenesis were examined in the livers of the db/db and high fat diet (HFD)-fed mice and in HEP1-6 cells transfected with miR-338-3p mimic or inhibitor. Computational prediction of microRNA target, luciferase assay and Western blot were used to assess the miR-338-3p target. Chromatin immunoprecipitation (ChIP) assay was used to determine the transcriptional regulator of miR-338-3p. Results: miR-338-3p was down-regulated in the livers of the db/db, HFD-fed and TNF-α-treated C57BL/6J mice, as well as in mouse HEP1-6 hepatocytes treated with TNF-α. Importantly the down-regulation of miR-338-3p induced insulin resistance, as indicated by impaired glucose tolerance and insulin tolerance. Further research showed that the down-regulated miR-338-3p resulted in the impaired AKT/ glycogen synthase kinase 3 beta (GSl·Gβ) signalling pathway and glycogen synthesis. In contrast, hepatic over-expression of miR-338-3p rescued the TNF-α-induced insulin resistance. Moreover, protein phosphatase 4 regulator subunit 1 (PP4R1) was identified as a direct target of miR-338-3p that mediated hepatic insulin signalling by regulating protein phosphatase 4 (PP4). Finally we identified hepatic nuclear factor 4 alpha (HNF-4α) as the transcriptional regulator of miRNA-338-3p. Conclusions: Our studies provide novel insight into the critical role and molecular mechanism by which miR-338-3p is involved in TNF-α-induced hepatic insulin resistance. miR-338-3p might mediate TNF-α-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression.

Persistent hypoglossal artery (PHA), a rare embryological carotid–basilar anastomosis, is usually accompanied by hypoplastic vertebral and posterior communicating arteries, and thereby such vascular anomaly serves as the main feeder supplying the vertebrobasilar territory. Although rarely reported, simultaneous anterior and posterior territory infarcts related to PHA and carotid atherosclerosis can occur. To date, as far as we know, only 4 such cases have been previously reported in the literature. Here, we present the case of a 65-year-old female with a PHA and carotid atherosclerotic plaques, who developed acute multiterritorial infarcts involving the left carotid and vertebrobasilar territories. This case highlights that such a persistent anastomosis should be considered when multiple infarcts involving the anterior and posterior territories are encountered, and should be kept in mind when dealing with carotid atherosclerotic lesion.

Statistical analysis of accidents in recent years shows that crowd crushes have become significant non-combat, non-environmental public disasters. Unlike common accidents such as fires, crowd crushes may occur without obvious external causes, and may arise quickly and unexpectedly in otherwise normal surroundings. We use physics-based simulations to understand the processes and consequences of compressive forces on high density static crowds consisting of up to 400 agents in a restricted space characterized by barriers to free movement. According to empirical observation and experimentation by others, we know that local high packing density is an important factor leading to crowd crushes and consequent injuries. We computationally verify our hypothesis that compressive forces create high local crowd densities which exceed human tolerance. Affected agents may thus be unable to move or escape and will present additional movement obstacles to others. Any high density crowd simulation should therefore take into account these possible negative effects on crowd mobility and behavior. Such physics-based simulations may therefore assist in the design of crowded spaces that could reduce the possibility of crushes and their consequences.

A pot experiment was performed to study the effectiveness of remediation using different plant species and the enzyme response involved in remediating PAH-contaminated soil. The study indicated that species Echinacea purpurea, Festuca arundinacea Schred, Fire Phoenix (a combined F. arundinacea), and Medicago sativa L. possess the potential for remediation in PAH-contaminated soils. The study also determined that enzymatic reactions of polyphenol oxidase (except Fire Phoenix), dehydrogenase (except Fire Phoenix), and urease (except Medicago sativa L.) were more prominent over cultivation periods of 60d and 120d than 150d. Urease activity of the tested species exhibited prominently linear negative correlations with alkali-hydrolyzable nitrogen content after the tested plants were cultivated for 150d (R2 = 0.9592). The experiment also indicated that alkaline phosphatase activity in four of the five tested species (Echinacea purpurea, Callistephus chinensis, Festuca arundinacea Schred and Fire Phoenix) was inhibited during the cultivation process (at 60d and 120d). At the same time, the study determined that the linear relationship between alkaline phosphatase activity and effective phosphorus content in plant rhizosphere soil exhibited a negative correlation after a growing period of 120d (R2 = 0.665). Phytoremediation of organic contaminants in the soil was closely related to specific characteristics of particular plant species, and the catalyzed reactions were the result of the action of multiple enzymes in the plant rhizosphere soil.

BACKGROUND: Nitric oxide (NO) plays an important role in mobilization of endothelial progenitor cells (EPCs). We hypothesized that inhaled NO (iNO) would induce EPC mobilization and therefore promote lung repair in acute respiratory distress syndrome (ARDS). METHODOLOGY/PRINCIPAL FINDINGS: Healthy piglets were randomized into four groups (n = 6): Control (Con; mechanical ventilation only); ARDS (established by oleic acid infusion and mechanical ventilation); ARDS plus granulocyte-colony stimulating factor (G-CSF; 10 µg/kg/d subcutaneously); ARDS plus NO inhalation (iNO; 10 ppm). EPCs and mobilizing cytokines were assayed at different time points (baseline, 0, 24, 72 and 168 h) and injury reparation was assessed at 168 h. Compared to the Con group, the levels of EPCs were increased in bone marrow but not in blood in the ARDS group at 24 h. Compared to the ARDS group, inhaled NO induced a rapid elevation in the number of CD34(+)KDR(+), KDR(+)CD133(+) and CD34(+)KDR(+)CD133(+) EPCs in blood (2163±454 vs. 1094±416, 1302±413 vs. 429±244, 1140±494 vs. 453±273 cells/ml, respectively, P

Artemisinins, derived from the wormwood herb Artemisia annua, are the most potent antimalarial drugs currently available. Despite extensive research, the exact mode of action of artemisinins has not been established. Here we use yeast, Saccharamyces cerevisiae, to probe the core working mechanism of this class of antimalarial agents. We demonstrate that artemisinin's inhibitory effect is mediated by disrupting the normal function of mitochondria through depolarizing their membrane potential. Moreover, in a genetic study, we identify the electron transport chain as an important player in artemisinin's action: Deletion of NDE1 or NDI1, which encode mitochondrial NADH dehydrogenases, confers resistance to artemisinin, whereas overexpression of NDE1 or NDI1 dramatically increases sensitivity to artemisinin. Mutations or environmental conditions that affect electron transport also alter host's sensitivity to artemisinin. Sensitivity is partially restored when the Plasmodium falciparum NDI1 ortholog is expressed in yeast ndi1 strain. Finally, we showed that artemisinin's inhibitory effect is mediated by reactive oxygen species. Our results demonstrate that artemisinin's effect is primarily mediated through disruption of membrane potential by its interaction with the electron transport chain, resulting in dysfunctional mitochondria. We propose a dual role of mitochondria played during the action of artemisinin: the electron transport chain stimulates artemisinin's effect, most likely by activating it, and the mitochondria are subsequently damaged by the locally generated free radicals.