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Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a chronic disease with an increasing incidence, which can further develop into liver fibrosis and hepatocellular carcinoma at the end stage. Alantolactone (Ala), a sesquiterpene lactone isolated from Asteraceae, has shown anti-inflammatory effects in different models. However, the therapeutic effect of Ala on NAFLD is not clear. Methods C57BL/6 mice were fed a high-fat diet (HFD) to induce NAFLD. After 16 weeks, Ala was administered by gavage to observe its effect on NAFLD. RNA sequencing of liver tissues was performed to investigate the mechanism. In vitro, mouse cell line AML-12 was pretreated with Ala to resist palmitic acid (PA)-induced inflammation, oxidative stress and fibrosis. Results Ala significantly inhibited inflammation, fibrosis and oxidative stress in HFD-induced mice, as well as PA-induced AML-12 cells. Mechanistic studies showed that the effect of Ala was related to the induction of Nrf2 and the inhibition of NF-κB. Taken together, these findings suggested that Ala exerted a liver protective effect on NAFLD by blocking inflammation and oxidative stress. Conclusions The study found that Ala exerted a liver protective effect on NAFLD by blocking inflammation and oxidative stress, suggesting that Ala is an effective therapy for NAFLD.

The calculation of nuclear electromagnetic sum rules by directly solving for numerous eigenstates in a large basis is numerically challenging and has not been performed for A>2 nuclei. With the significant progress of high performance computing, we show that calculating sum rules using numerous discretized continuum states obtained with the ab initio no-core shell model in the harmonic oscillator basis is achievable numerically. Specifically, we calculate the 4He electric dipole (E1) polarizability, that is an inverse energy weighted sum rule, employing the Daejeon16 NN interaction. We demonstrate that the calculations are numerically tractable as the dimension of the basis increases and are convergent. Our results for the 4He electric dipole polarizability are consistent with the most recent experimental data and are compared with those of other theoretical studies employing different techniques and various interactions.

Groundwater serves as an important water source for residents in and around mining areas. To achieve scientific planning and efficient utilization of water resources in mining areas, it is essential to figure out the chemical formation process and the ground water sulfur cycle that transpire after the coal mining activities. Based on studies of hydrochemistry and D,18O-H2O,34S-SO4 isotopes, this study applied principal component analysis, ion ratio and other methods in its attempts to reveal the hydrogeochemical action and sulfur cycle in the subsidence area of Pingyu mining area. The study discovered that, in the studied area, precipitation provides the major supply of groundwater and the main water chemistry effects are dominated by oxidation dissolution of sulfide minerals as well as the dissolution of carbonate and silicate rocks. The sulfate in groundwater primarily originates from oxidation and dissolution of sulfide minerals in coal-bearing strata and human activities. The mixed sulfate formed by the oxidation of sulfide minerals and by human activities continuously recharges the groundwater, promoting the dissolution of carbonate rock and silicate rock in the process.

Abstract. Background:. The KangDuo-Surgical Robot-01 (KD-SR-01) system is a new surgical robot recently developed in China. The aim of this study was to present our single-center experience and mid-term outcomes of urological procedures using the KD-SR-01 system. Methods:. From August 2020 to April 2023, consecutive urologic procedures were performed at Peking University First Hospital using the KD-SR-01 system. The clinical features, perioperative data, and follow-up outcomes were prospectively collected and analyzed. Results:. A total of 110 consecutive patients were recruited. Among these patients, 28 underwent partial nephrectomy (PN), 41 underwent urinary tract reconstruction (26 underwent pyeloplasty, 3 underwent ureteral reconstruction and 12 underwent ureterovesical reimplantation [UR]), and 41 underwent radical prostatectomy (RP). The median operative time for PN was 112.5 min, 157.0 min for pyeloplasty, 151.0 min for ureteral reconstruction, 142.5 min for UR, and 138.0 min for RP. The median intraoperative blood loss was 10 mL for PN, 10 mL for pyeloplasty, 30 mL for ureteral reconstruction, 20 mL for UR, and 50 mL for RP. All procedures were successfully completed without conversion, and there were no major complications in any patient. The median warm ischemia time of PN was 17.3 min, and positive surgical margin was not noted in any patient. The overall positive surgical margin rate of RP was 39% (16/41), and no biochemical recurrence was observed in any RP patient during the median follow-up of 11.0 months. The surgical success rates of pyeloplasty and UR were 96% (25/26) and 92% (11/12) during the median follow-up of 29.5 months and 11.5 months, respectively. Conclusion:. The KD-SR-01 system appears feasible, safe, and effective for most urological procedures, based on our single-center experience.

Abstract Background Compassionate use is a system that provides patients with expedited access to drugs which has not yet been approved, but currently in clinical trials. The investigational drugs have been authorized for compassionate use in cases involving patients suffered from life-threatening diseases and with no alternative treatments. For instance, patients afflicted with highly heterogeneous rare diseases are eligible for treatment assistance through the compassionate use program. This study aims to investigate the characteristics of compassionate use in the context of rare diseases, evaluate the efficacy and safety of compassionate use for rare diseases, and analyze the marketing approval of investigational drugs. Methods The case reports/case series of compassionate use were collected by conducting searches on Embase, PubMed, Web of Science, CNKI and SinoMed, spanning from January 1991 to December 2022. Subsequently, two independent reviewers evaluated these reports. Case reports/case series that met the inclusion criteria and exclusion criteria were enrolled. Information extracted from these reports and series included patients' basic information, the investigational drug's name, its indication, adverse events, treatment outcomes, and other relevant data. Results A total of forty-six studies were included, encompassing 2079 patients with an average age of 38.1 years. Thirty-nine different drugs were involved in 46 studies. Furthermore, neoplasms emerged as the most common therapeutic area for compassionate use in rare disease management (23/46, 50.0%). Regarding the treatment efficacy, four studies reported successful disease resolution, while 35 studies observed symptom improvement among patients. Conversely, four studies documented no significant effects on patients' diseases. Moreover, one study reported worsened results following compassionate use, while the efficacy was not described in 2 studies. Adverse events were reported in 31 studies (67.4%) because of the compassionate use, while no adverse events occurred in 13 studies (28.3%). In other 2 studies, there was no description about whether treatment-emergent adverse events (TEAEs) were happened. 136 patients (6.5%) had Grade 5 adverse events (death), of which 19 deaths (0.9%) were considered to be related to compassionate use. Furthermore, the investigational drugs in 33 studies (33/46, 71.7%) received new drug approval at the end of January 31, 2023.The time lag from the start of the compassionate use to the formal approval of the investigational drug was 790.5 (IQR 359–2199.3) days. We found that in 11 studies, encompassing 9 different drugs, some compassionate use indications had not received regulatory authorities at the end of January 31, 2023. Conclusion The current status of compassionate use for rare diseases was clarified systematically in this study. Compassionate use of investigational drug is a significant treatment option for rare disease. In general, compassionate use appears to demonstrate favorable efficacy in the context of rare diseases, with a significant proportion of compassionate use drugs subsequently receiving marketing approval. However, the safety of drugs for compassionate use cannot be fully evaluated due to the safety data were not covered in some enrolled studies. Therefore, the establishment of an adverse event reporting system specific to compassionate use is warranted.

Sewage sludge has long been perceived as the bottleneck of wastewater treatment plants in China, restraining the healthy development of sewage treatment for decades. In recent years, pyrolysis as a promising multifunctional platform has attracted increasing interest for converting sludge into valuable resources. However, the generation and presence of pyrolysis tar, one of the key by-products during sludge pyrolysis, limit the wide application of pyrolysis product resources. The efficient and selective conversion of tar is complicated by the inherent complexity of sludge and various pollutants (e.g., N-, S-, and Cl-containing organic pollutants, heavy metals) in pyrolysis products, which may either migrate into tar or be released into the environment, complicating the in-depth treatment of tar and posing environmental risks. This review systematically examines the transformation and migration of tar and related secondary pollutants during sludge pyrolysis in order to optimize the pyrolysis process for resource recovery. We provide an overview of the research progress on tar generation, transformation, and secondary pollutants during pyrolysis; discuss potential control strategies for pollution abatement; and highlight the importance of understanding tar transformation during pyrolysis. Additionally, we offer insights into future development trends and research hotpots in this field. This review aims to deliver valuable information on the mechanism of tar formation, the conversion pathways of secondary pollutants, and corresponding control strategies, thus guiding the design and optimization of sludge pyrolysis processes to achieve higher efficiency and selectivity, with minimal environmental pollution.

Abstract Oxygen evolution reaction (OER) is a critical anodic reaction of electrochemical water splitting, developing a high‐efficiency electrocatalyst is essential. Transition metal‐based catalysts are much more cost‐effective if comparable activities can be achieved. Among them, fluorides are rarely reported due to their low aqueous stability of coordination and low electric conductivity. Herein, a NiCo bimetallic fluoride with good crystallinity is designed and constructed, and significantly enhanced catalytic activity and conductivity are observed. The inevitable oxidation of transition metal ions at high potential and the dissociation of F− are attributed to the low aqueous stability of coordination. The theoretical researches predicte that transition metal fluorides should have a strong tendency to electrochemical reconstruction. Therefore, based on the observations on their electrochemical behavior, high‐resolution transmission electron microscopy, X‐ray photoelectron spectroscopy, and bode plots, it is further demonstrated that surface reconstruction occurred during the electrochemical process, meanwhile a significant increase of electrochemically active area, which is created by F migration, are also directly observed. Additionally, DFT calculation results show that the electronic structure of the catalysts is modulated by the bimetallic centers, and this reconstruction helps optimizing the adsorption energy of oxygen‐containing species and improves OER activity.

Groundwater in mining areas play an important supporting role in the surrounding residents' living and the construction of coal industries. Mine drainage during coal mining will change the original groundwater circulation process in mining areas, leading to changes in the groundwater environment. Therefore, clarifying the mutual transformation relationship between the “three waters” is the key to the scientific utilization of water resources in mining areas. Chemical components and hydrogen and oxygen isotopes of the groundwater in the Pingyu mining area are combined to determine the characteristics of groundwater circulation after large-scale drainage of the mine, identify the origin and controlling factors of the major components in the groundwater. Hydrohemical analyses show that most of the groundwater are of HCO3—Ca·Mg type, The hydrochemical components are controlled by the weathering and dissolution of silicate, and the ions in the groundwater mainly come from water-rock interactions and the waste generated by human activities, with concentration of \begin{document}${\rm{NO}}_3^- $\end{document} exceeding the standard. The hydrogen and oxygen isotopic data demonstrates that the groundwater in the study area receives recharge from modern precipitation, and there is a close hydraulic relationship between the groundwater in the unconsolidated aquifers and the groundwater in the karst aquifer. After the mine drainage, the groundwater circulation process in the mining area changes, the karst groundwater changes from supporting the upper pore groundwater to accepting the leakage recharge of the upper pore groundwater, and then discharges to the surface water by the mine drainage. The mine drainage becomes the main groundwater drainage way in the mine area. The research results can provide scientific and effective basis for groundwater development management and land subsidence prevention in mining areas.

In the world’s first pig-to-human cardiac cytomegalovirus (PCMV), xenotransplant and elevated levels of porcine key factors contributing to patient mortality were considered. This has renewed attention on PCMV, a virus widely prevalent in pigs. Currently, there are no effective drugs or vaccines targeting PCMV, and its high detection difficulty poses challenges for prevention and control research. In this study, antiviral small hairpin RNA (shRNA) was selected and inserted into the Rosa26 and miR-17-92 loci of pigs via a CRISPR/Cas9-mediated knock-in strategy. Further in vitro viral challenge experiments demonstrated that these genetically edited pig cells could effectively limit PCMV replication. Through this process, we constructed a PCMV-infected cell model, validated partial viral interference sites, enhanced gene knock-in efficiency, performed gene editing at two different gene loci, and ultimately demonstrated that RNA interference (RNAi) technology combined with CRISPR/Cas9 has the potential to generate pig cells with enhanced antiviral infection capabilities. This opens up possibilities for the future production of pig populations with antiviral functionalities.

Abstract Background Retinoblastoma (RB) is frequently occurring malignant tumors that originate in the retina, and their exact cause and development mechanisms are yet to be fully comprehended. In this study, we identified possible biomarkers for RB and delved into the molecular mechanics linked with such markers. Methods In this study GSE110811 and GSE24673 were analyzed. Weighted gene co-expression network analysis (WGCNA) was applied to screen modules and genes associated with RB. By overlapping RB-related module genes with differentially expressed genes (DEGs) between RB and control samples, differentially expressed retinoblastoma genes (DERBGs) were acquired. A gene ontology (GO) enrichment analysis and a kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were conducted to explore the functions of these DERBGs. To study the protein interactions of DERBGs, a protein–protein interaction (PPI) network was constructed. Hub DERBGs were screened using the least absolute shrinkage and selection operator (LASSO) regression analysis, as well as the random forest (RF) algorithm. Additionally, the diagnostic performance of RF and LASSO methods was evaluated using receiver operating characteristic (ROC) curves and single-gene gene set enrichment analysis (GSEA) was conducted to explore the potential molecular mechanisms involved with these Hub DERBGs. In addition, the competing endogenous RNA (ceRNA) regulatory network of Hub DERBGs was constructed. Result About 133 DERBGs were found to be associated with RB. GO and KEGG enrichment analyses revealed that the important pathways of these DERBGs. Furthermore, the PPI network revealed 82 DERBGs interacting with each other. By RF and LASSO methods, PDE8B, ESRRB, and SPRY2 were identified as Hub DERBGs in patients with RB. From the expression assessment of Hub DERBGs, it was found that the levels of expression of PDE8B, ESRRB, and SPRY2 were significantly decreased in the tissues of RB tumors. Secondly, single-gene GSEA revealed a connection between these 3 Hub DERBGs and oocyte meiosis, cell cycle, and spliceosome. Finally, the ceRNA regulatory network revealed that hsa-miR-342-3p, hsa-miR-146b-5p, hsa-miR-665, and hsa-miR-188-5p may play a central role in the disease. Conclusion Hub DERBGs may provide new insight into RB diagnosis and treatment based on the understanding of disease pathogenesis.

Cholangiocarcinoma (CCA) is an aggressive biliary epithelial tumor with limited therapeutic options and poor prognosis. Curcumin is a promising active natural compound with several anti-cancer properties, though its clinical uses remain hindered due to its poor bioavailability. We recently synthesized curcumin analogs with multifunctional pharmacological and bioactivities with enhanced bioavailability. Among these novel curcumin analogs, WZ26 is a representative molecule. However, the anti-tumor effect of WZ26 against CCA is unclear. In this study, we evaluated the anti-tumor effect of WZ26 in both CCA cells and CCA xenograft mouse model. The underlying molecular anti-cancer mechanism of WZ26 was also studied. Our results show that WZ26 significantly inhibited cell growth and induced mitochondrial apoptosis in CCA cell lines, leading to significant inhibition of tumor growth in xenograft tumor mouse model. Treatment of WZ26 increased reactive oxygen species (ROS) generation, subsequently decreased mitochondrial membrane potential and inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby inducing G2/M cell cycle arrest and cell apoptosis. Pretreatment of N-acetyl cysteine (NAC), an antioxidant agent, could fully reverse the WZ26-induced ROS-mediated changes in CCA cells. Our findings provide experimental evidence that curcumin analog WZ26 could be a potential candidate against CCA via enhancing ROS induction and inhibition of STAT3 activation.

Introduction: Mantle cell lymphoma (MCL) can be stratified into blastoid and classical subtypes based on morphological features, with the former subtype having a poorer prognosis. Despite recent advances in targeted approaches, including multiple bruton tyrosine kinase inhibitors which yield impressive clinical responses and improve prognoses, MCL remains an incurable disease with frequent relapses. Additional therapeutic interventions are therefore unmet medical needs for the management of patients with MCL. Methods: Cell viability and apoptosis assays were employed to analyze the therapeutic interaction of venetoclax combined with selinexor in MCL cells. Western blot was used to investigate the potential mechanism of action for the synergy of venetoclax in combination with selinexor in MCL cells. Results: In this study, we revealed that both blastoid and classical MCL cells were vulnerable to the cytotoxic effects of selinexor, a well-established XPO1 inhibitor, manifested by loss of cell viability and induction of cell apoptosis. Moreover, our data indicated that the addition of venetoclax to selinexor showed synergistically decreased cell viabilities and increased cell deaths in blastoid and classical MCL cells compared to each single drug treatment. Either selinexor or venetoclax treatment alone decreased MCL1 expressions and increased BAX levels in MCL cells, and these effects were further enhanced by their combined regimen. Mechanistically, our findings demonstrated that induction of DNA damage and inactivation of DNA damage response were involved in the synergistic interaction of the drug combination regimen. Conclusion: Collectively, this study might provide a potential attractive therapy option for the treatment of MCL. However, the conclusion needs additional experimental validation in in vivo models and clinical evaluations are mandatory.

Abstract Background Histone deacetylases (HDAC) contribute to oncogenic program, pointing to their inhibitors as a potential strategy against cancers. We, thus, studied the mechanism of HDAC inhibitor ITF2357 in resistance of mutant (mut)-KRAS non-small cell lung cancer (NSCLC) to pemetrexed (Pem). Methods We first determined the expression of NSCLC tumorigenesis-related HDAC2 and Rad51 in NSCLC tissues and cells. Next, we illustrated the effect of ITF2357 on the Pem resistance in wild type-KARS NSCLC cell line H1299, mut-KARS NSCLC cell line A549 and Pem-resistant mut-KARS cell line A549R in vitro and in xenografts of nude mice in vivo. Results Expression of HDAC2 and Rad51 was upregulated in NSCLC tissues and cells. Accordingly, it was revealed that ITF2357 downregulated HDAC2 expression to diminish the resistance of H1299, A549 and A549R cells to Pem. HDAC2 bound to miR-130a-3p to upregulate its target gene Rad51. The in vitro findings were reproduced in vivo, where ITF2357 inhibited the HDAC2/miR-130a-3p/Rad51 axis to reduce the resistance of mut-KRAS NSCLC to Pem. Conclusion Taken together, HDAC inhibitor ITF2357 restores miR-130a-3p expression by inhibiting HDAC2, thereby repressing Rad51 and ultimately diminishing resistance of mut-KRAS NSCLC to Pem. Our findings suggested HDAC inhibitor ITF2357 as a promising adjuvant strategy to enhance the sensitivity of mut-KRAS NSCLC to Pem.

Salmonella Typhimurium (S. Typhimurium) is a zoonotic pathogen posing a threat to animal husbandry and public health. Due to the emergence of antibiotic-resistant strains, alternative prevention and control strategies are needed. Live attenuated vaccines are an ideal option that provide protection against an S. Typhimurium pandemic. To develop a safe and effective vaccine, double-gene mutations are recommended to attenuate virulence. In this study, we chose aroA and luxS genes, whose deletion significantly attenuates S. Typhimurium’s virulence and enhances immunogenicity, to construct the double-gene mutant vaccine strain SAT52ΔaroAΔluxS. The results show that the mutant strain’s growth rate, adherence and invasion of susceptible cells are comparable to a wild-type strain, but the intracellular survival, virulence and host persistence are significantly attenuated. Immunization assay showed that 106 colony-forming units (CFUs) of SAT52ΔaroAΔluxS conferred 100% protection against wild-type challenges; the bacteria persistence in liver and spleen were significantly reduced, and no obvious pathological lesions were observed. Therefore, the double-gene mutant strain SAT52ΔaroAΔluxS exhibits potential as a live attenuated vaccine candidate against S. Typhimurium infection.

With the continual expansion of urban road networks and global commitments to net zero, electric vehicles (EVs) have been considered to be the most viable solution to decarbonize the transportation sector. In recent years, the electric road system (ERS) has been introduced and piloted in a few countries and regions to decarbonize heavy-duty vehicles. However, little research has been carried out on its reliability. This paper fills the gap and investigates the reliability of electric truck power supply systems for electric road (ETPSS–ER), which considers both the power system and truck traffic networks. First, a brief introduction of electric roads illustrates the working principle of EV charging on roads. Then, an optimized electric truck (ET) travel pattern model is built, based on which the corresponding ET charging load demand, including both static charging and dynamic charging, is conducted. Then, based on the new ET travel pattern model, a daily travel-pattern-driven Monte Carlo simulation-based reliability assessment method for ETPSS–ER system is presented. Case studies based on the IEEE RBTS system shows that ETs driving on ERS systems can meet the daily travel demands. The case studies also examine the impacts of increasing number of ETs, extra wind power, and battery energy storage systems (BESS) on the reliability of ERS power systems.

Abstract Trait evolution in invasive plant species is important because it can impact demographic parameters key to invasion success. Invasive plant species often show phenotypic clines along geographic and climatic gradients. However, the relative contributions of natural selection and neutral evolutionary processes to phenotypic trait variation among populations of invasive plants remain unclear. A common method to assess whether a trait has been shaped by natural selection or neutral evolutionary processes is to compare the geographical pattern for the trait of interest to the divergence in neutral genetic loci (i.e., QST–FST comparisons). Subsequently, a redundancy analysis (RDA) can facilitate identification of putative agents of natural selection on the trait. Here, we employed both a QST–FST comparisons approach and RDA to infer whether natural selection shaped traits of invasive populations of Solidago canadensis in China and identify the potential environmental drivers of natural selection. We addressed two questions: (1) Did natural selection drive phenotypic trait variation among S. canadensis populations? (2) Did climatic, latitudinal, longitudinal, and altitudinal gradients drive patterns of genetic variation among S. canadensis populations? We found significant directional selection for several morphological and reproductive traits (i.e., QST > FST) and stabilizing selection for physiological traits (i.e., QST

Introduction: The aim of the present study was to establish a simple method for the determination of riluzole in human plasma by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and apply it for the determination of riluzole in amyotrophic lateral sclerosis (ALS) patients.Methods: Samples were prepared by protein precipitation and were then gradient-eluted on a column of ACQUITY UPLC® HSS T3 by using 0.1% formic acid acetonitrile and 0.1% formic acid water as the mobile phase. Detection was performed on a Xevo TQ-S tandem mass spectrometer in the multiple-reaction monitoring mode using positive electrospray ionization. Validation was performed in the range of 5–800 ng/mL.Results and discussion: Three batches of precision accuracy, selectivity, matrix effects, extraction recovery, and stability were also verified and met the requirements. The results showed that the method was reliable and successfully applied to the pharmacokinetics study of riluzole in Chinese amyotrophic lateral sclerosis patients. Meanwhile, in comparison with other prior published methods, our method has the advantages of simple sample preparation, relatively short running time, and small plasma sample consumption, which represented a high-throughput sample determination potential.

Abstract Background Early identification of axillary lymph node metastasis (ALNM) in breast cancer (BC) is still a clinical difficulty. There is still no good method to replace sentinel lymph node biopsy (SLNB). The purpose of our study was to develop and validate a nomogram to predict the probability of ALNM preoperatively based on ultrasonography (US) and clinicopathological features of primary tumors. Methods From September 2019 to April 2022, the preoperative US) and clinicopathological data of 1076 T1-T2 BC patients underwent surgical treatment were collected. Patients were divided into a training set (875 patients from September 2019 to October 2021) and a validation set (201 patients from November 2021 to April 2022). Patients were divided into positive and negative axillary lymph node (ALN) group according pathology of axillary surgery. Compared the US and clinicopathological features between the two groups. The risk factors for ALNM were determined using multivariate logistic regression analysis, and a nomogram was constructed. AUC and calibration were used to assess its performance. Results By univariate and multivariate logistic regression analysis, age (p = 0.009), histologic grades (p = 0.000), molecular subtypes (p = 0.000), tumor location (p = 0.000), maximum diameter (p = 0.000), spiculated margin (p = 0.000) and distance from the skin (p = 0.000) were independent risk factors of ALNM. Then a nomogram was developed. The model was good discriminating with an AUC of 0.705 and 0.745 for the training and validation set, respectively. And the calibration curves demonstrated high agreement. However, in further predicting a heavy nodal disease burden (> 2 nodes), none of the variables were significant. Conclusion This nomogram based on the US and clinicopathological data can predict the presence of ALNM good in T1-T2 BC patients. But it cannot effectively predict a heavy nodal disease burden (> 2 nodes).

Abstract This paper proposes an inertia‐emulation‐based cooperative control strategy for the multi‐parallel energy storage system (ESS) to meet the requirements of state‐of‐charge (SoC) balance, inertia enhancement and zero‐steady‐state voltage deviation. The inertia emulation loop (IEL) is constructed by analogy with DC motors to dampen voltage oscillation, while the secondary voltage recovery loop is derived from the circuit equivalence of an inductor to indicate the system stiffness. Moreover, to equalize SoCs of energy storage units (ESUs) dynamically, a SoC self‐balance algorithm is developed. The redefined SoC mismatch degree and balance speed adjustment factor k are introduced into the droop resistance, adjusting the SoC self‐balance rate and eliminating the SoC deviation among ESUs. The dynamic performance of the SoC self‐balance algorithm is analyzed and the small signal model of the DC microgrid (DC‐MG) with proposed strategy is established. Based on eigenvalue analysis and step response, the system stability is assessed, and the influence of control parameters on transient characteristics and stability margin is investigated. Considering power constraint, voltage deviation constraint and dynamic stability constraint, the optimal design method of k is given. Finally, simulation and experiment verify that the proposed control, without modifying hardware, performs better dynamic and static characteristics and can equalize SoC among ESUs in charge and discharge mode.

Abstract Background There are about 7000 rare diseases worldwide, of which only 5% of the diseases can be treated with medicines, showing that it’s important to improve patient access to orphan drugs. Recently, China has actively worked to set up a national system for rare diseases to improve the diagnosis and treatment capabilities and ensure the accessibility of drugs. However, the benefits of the system have yet not to be measured. This study aimed to provide an overview of orphan drug access based on the Compendium of China’s First List of Rare Diseases and National Network to Collaborate on Diagnosis and Treatment of Rare Diseases, expecting to map a blueprint for orphan drug access in China. Methods Framework of China’s national system for rare diseases was summarized. We surveyed the availability and affordability of 79 approved orphan drugs based on the Compendium of China’s First List of Rare Diseases in 30 leading provincial institutions from 2017 to 2020. The availability was measured annually at 3 levels (market, hospital and drug), and affordability was reflected by comparing costs of daily defined dose with per capita income of urban and rural residents, with the National Basic Medical Insurance considered. Results The market availability of orphan drugs in China showed an upward trend. As of 2020, the median hospital-level availability was 41.1% (increased by 1.5 times), highly available drugs increased by 16.5%. There were 64/74 orphan drugs that were affordable to rural/urban residents with the National Basic Medical Insurance considered (an increase of 14.1%), and the urban–rural gap of affordability ratio was narrowed (down by 6.0%). Comprehensive analysis showed the proportions of drugs with better availability and affordability in urban and rural areas by 2020 were 39.4% and 32.3%, respectively, which had increased but were still at a low level. Conclusions China’s national system for rare diseases has made great progress in orphan drug access, indicating that it’s been functioning under the joint reformation of medical treatment, medical insurance and medicines supply. The list of rare diseases will be updated and collaboration in networks will be enhanced to further improve the system.

Abstract Background CPT-11 (irinotecan) is one of the most efficient agents used for colorectal cancer chemotherapy. However, as for many other chemotherapeutic drugs, how to minimize the side effects of CPT-11 still needs to be thoroughly described. Objectives This study aimed to develop the CPT-11-loaded DSPE-PEG 2000 targeting EGFR liposomal delivery system and characterize its targeting specificity and therapeutic effect on colorectal cancer (CRC) cells in vitro and in vivo. Results The synthesized liposome exhibited spherical shapes (84.6 ± 1.2 nm to 150.4 nm ± 0.8 nm of estimated average sizes), good stability, sustained release, and enough drug loading (55.19%). For in vitro experiments, SW620 cells treated with CPT-11-loaded DSPE-PEG2000 targeting EGFR liposome showed lower survival extended level of intracellular ROS production. In addition, it generated an enhanced apoptotic cell rate by upregulating the protein expression of both cleaved-caspase-3 and cleaved-caspase-9 compared with those of SW620 cells treated with free CPT-11. Importantly, the xenograft model showed that both the non-target and EGFR-targeted liposomes significantly inhibited tumor growth compared to free CPT-11. Conclusions Compared with the non-target CPT-11-loaded DSPE-PEG2000 liposome, CPT-11-loaded DSPE-PEG2000 targeting EGFR liposome treatment showed much better antitumor activity in vitro in vivo. Thus, our findings provide new assets and expectations for CRC targeting therapy.

Background and objective Lung adenocarcinoma (LUAD) is the most common clinical histological subtype of lung cancer and microRNAs (miRNAs) are a type of small non-coding RNAs which play a central role in cells. miR-30b-3p plays a key effect in many types of carcinoma, but there is still very little research on how it works in lung adenocarcinoma. The role and mechanism of miR-30b-3p in the proliferation and invasion of LUAD were explored in this study, to provide new targets for inhibiting the proliferation and invasion of LUAD. Methods NCBI database was used to screen out miRNA with obvious differential expression, and the differential expression and survival curve were searched by StarBase database. Real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to detect the relative expression of miR-30b-3p in each lung adenocarcinoma cell line. 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay and Transwell invasion assay were used to detect the proliferation and invasion of A549 cells in each group. The target genes of miR-30b-3p were determined by the target gene prediction websites. Western blot assay was used to detect the expression of COX6B1 in each group of A549 cells. Double luciferase assay was used to verify the targeted binding relationship between miR-30b-3p and COX6B1. Results The expression of miR-30b-3p in lung adenocarcinoma tissues and lung adenocarcinoma cells was downregulated (P

Abstract Background Generic medicines substitution is an important means to control rapid growth of pharmaceutical expenditures for the healthcare system in China. Acceptance and utilization of generic medicines is highly influenced by healthcare providers’ perceptions. This study aimed to compare the knowledge, awareness and perceptions of generic medicines between physicians and pharmacists in China. Methods We used an online, cross-sectional survey across China. The questionnaire explored four sections: demographic characteristics, assessment of the participants’ knowledge and awareness of generic medicines, perceptions of generic medicines and generic substitution practices. Chi-square or Mann–Whitney-U tests were applied to compare differences between physicians and pharmacists. P-values

Abstract Objective Our study aimed to identify predictors as well as develop machine learning (ML) models to predict the risk of 30-day mortality in patients with sepsis-associated encephalopathy (SAE). Materials and methods ML models were developed and validated based on a public database named Medical Information Mart for Intensive Care (MIMIC)-IV. Models were compared by the area under the curve (AUC), accuracy, sensitivity, specificity, positive and negative predictive values, and Hosmer–Lemeshow good of fit test. Results Of 6994 patients in MIMIC-IV included in the final cohort, a total of 1232 (17.62%) patients died following SAE. Recursive feature elimination (RFE) selected 15 variables, including acute physiology score III (APSIII), Glasgow coma score (GCS), sepsis related organ failure assessment (SOFA), Charlson comorbidity index (CCI), red blood cell volume distribution width (RDW), blood urea nitrogen (BUN), age, respiratory rate, PaO2, temperature, lactate, creatinine (CRE), malignant cancer, metastatic solid tumor, and platelet (PLT). The validation cohort demonstrated all ML approaches had higher discriminative ability compared with the bagged trees (BT) model, although the difference was not statistically significant. Furthermore, in terms of the calibration performance, the artificial neural network (NNET), logistic regression (LR), and adapting boosting (Ada) models had a good calibration—namely, a high accuracy of prediction, with P-values of 0.831, 0.119, and 0.129, respectively. Conclusions The ML models, as demonstrated by our study, can be used to evaluate the prognosis of SAE patients in the intensive care unit (ICU). Online calculator could facilitate the sharing of predictive models.

Avian reovirus (ARV) causing viral arthritis/tenosynovitis and viral enteritis in domestic fowl has significantly threatened on the poultry industry worldwide. ARV is a non-enveloped fusogenic virus that belongs to the Reoviridae family. Previous research revealed that cellular cholesterol in lipid rafts is essential for ARV replication. It has been reported that cholesterol 25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25HC) have antiviral activities against enveloped viruses. However, few studies characterized the association of non-enveloped viruses with CH25H and the role of CH25H in the regulation of ARV replication. In this study, the expression of chicken CH25H (chCH25H) was found to be upregulated in ARV-infected cells at the early stage of infection. The results of overexpression and knockdown assays revealed that chCH25H has a significant antiviral effect against ARV infection. Furthermore, a 25HC treatment significantly inhibited ARV replication in a dose-dependent manner at both the entry and post-entry stages, and a chCH25H mutant lacking hydroxylase activity failed to inhibit ARV infection. These results indicate that CH25H, depending on its enzyme activity, exerts the antiviral effect against ARV via the synthesis of 25HC. In addition, we revealed that 25HC produced by CH25H inhibits viral entry by delaying the kinetics of ARV uncoating, and CH25H blocks cell–cell membrane fusion induced by the p10 protein of ARV. Altogether, our findings showed that CH25H, as a natural host restriction factor, possessed antiviral activity against ARV targeting viral entry and syncytium formation, through an enzyme activity-dependent way. This study may provide new insights into the development of broad-spectrum antiviral therapies.

Background Chronic intermittent hypoxia (CIH) has been regarded as an important cause of atherosclerotic disease. In our study, we set out to investigate whether CIH regulated the high mobility group box 1/receptor for advanced glycation endproducts/NOD‐like receptor family pyrin domain‐containing 3 (HMGB1/RAGE/NLRP3) axis to affect the progression of atherosclerosis. Methods and Results Initially, peripheral blood samples were collected from patients with single obstructive sleep apnea, atherosclerosis complicated with obstructive sleep apnea, and healthy volunteers. In vitro cell experiments were conducted using human monocyte cell line THP‐1 and human umbilical vein endothelial cells to explore the role of HMGB1 in cell migration, apoptosis, adhesion, and transendothelial migration. In addition, a CIH‐induced atherosclerosis mouse model was established for further identifying the critical role of the HMGB1/RAGE/NLRP3 axis in atherosclerosis. Upregulated HMGB1 and RAGE were found in patients with atherosclerosis complicated with obstructive sleep apnea. CIH induction increased HMGB1 expression by inhibiting HMGB1 methylation, activating the RAGE/NLRP3 axis. After inhibition of the HMGB1/RAGE/NLRP3 axis, monocyte chemotaxis and adhesion were repressed, and macrophage‐derived foam cell formation was inhibited, accompanied by suppression of endothelial and foam cell apoptosis and inflammatory factor secretion. In vivo animal experiments also noted that the progression of atherosclerosis was prevented by inhibition of the HMGB1/RAGE/NLRP3 axis in CIH‐induced ApoE−/− mice. Conclusions Taken together, CIH induction can upregulate HMGB1 through inhibition of HMGB1 methylation, which activates the RAGE/NLRP3 axis to promote inflammatory factor secretion, thereby promoting the progression of atherosclerosis.

BackgroundArtificial intelligence-assisted colonoscopy (AIAC) has been proposed and validated in recent years, but the effectiveness of clinic application remains unclear since it was only validated in some clinical trials rather than normal conditions. In addition, previous clinical trials were mostly concerned with colorectal polyp identification, while fewer studies are focusing on adenoma identification and polyps size measurement. In this study, we validated the effectiveness of AIAC in the clinical environment and further investigated its capacity for adenoma identification and polyps size measurement.MethodsThe information of 174 continued patients who went for coloscopy in Chongqing Rongchang District People’s hospital with detected colon polyps was retrospectively collected, and their coloscopy images were divided into three validation datasets, polyps dataset, polyps/adenomas dataset (all containing narrow band image, NBI images), and polyp size measurement dataset (images with biopsy forceps and polyps) to assess the competence of the artificial intelligence system, and compare its diagnostic ability with endoscopists with different experiences.ResultsA total of 174 patients were included, and the sensitivity of the colorectal polyp recognition model was 99.40%, the accuracy of the colorectal adenoma diagnostic model was 93.06%, which was higher than that of endoscopists, and the mean absolute error of the polyp size measurement model was 0.62 mm and the mean relative error was 10.89%, which was lower than that of endoscopists.ConclusionArtificial intelligence-assisted model demonstrated higher competence compared with endoscopists and stable diagnosis ability in clinical use.

Laboratory analysis of returned Chang’E-5 samples from the lunar surface show their hydroxyl contents to be on the weak end of lunar hydration features.

Abstract Helicobacter pylori (H. pylori) infection is a well-recognized contributing factor to gastritis, but the underlying mechanisms remain to be established. It is interesting to note that AQP5 was predicted to be highly expressed in intestinal metaplasia (IM) based on H. pylori infection-related microarray data, and the transcription factor ASCL1 was bioinformatically predicted to associate with AQP5. Therefore, the purpose of this study is to evaluate the mechanistic significance of ASCL1 and AQP5 in H. pylori infection of gastritis. Gastritis mouse models were established by H. pylori infection, followed by determination of AQP5 and ASCL1 in gastric mucosa. Besides, the effects of AQP5 on H. pylori-induced gastritis were explored using AQP5−/− mice. It was observed that H. pylori infection elevated expression of AQP5 and ASCL1 in gastric mucosa and gastric epithelial cells (GECs). H. pylori induced AQP5 expression by regulating ASCL1 and activated WNT/β-catenin signaling pathway in GECs. It was also found that AQP5 knockdown suppressed inflammatory response and apoptosis in H. pylori-infected mice. Moreover, H. pylori infection-elevated ASCL1 and AQP5 expression promoted apoptosis and inflammation in GECs. Taken together, the key findings of the present study demonstrate that H. pylori infection activated WNT/β-catenin signaling pathway by upregulating ASCL1/AQP5 to induce gastritis.

Background: Individualized pharmaceutical care, which consists of therapeutic drug monitoring (TDM), pharmacogenetic (PGx) testing and pharmacist-managed clinic (PMC), is one of the most important trends in clinical pharmacy development in the future. While relevant studies in China were primarily single-center or regional. This study aims to explore the current status of individualized pharmaceutical care in China, find out the existing problems and provide references for its further development.Methods: An electronic questionnaire was used and national hospitals’ pharmaceutical administration data from January to December 2019 were collected. The data were sorted into Excel for further statistical analysis. All analyses were descriptive.Results: The proportions of hospitals that performed TDM and PGx testing were 12.83% and 9.48%, respectively. The major responsible departments were the clinical laboratory and pharmacy department. External quality control was carried out in around 70% of hospitals for both TDM and PGx testing. More than half of hospitals provided TDM services for valproate sodium, digoxin, carbamazepine, vancomycin and cyclosporine. And an average of 6.84 drugs were performed TDM in 540 hospitals. Clopidogrel and warfarin were the top two drugs that performed PGx testing. As for the PMC, 10.03% of hospitals opened PMC, of which 60.00% had independent PMC. Approximately 80% of PMC services were free of charge.Conclusion: The development of individualized pharmaceutical care in China is still in the early stage. Different sectors have to coalesce to promote its implementation, including the appropriate education, coverage, reimbursement policies, high-quality evidence, data systems, health system processes and health policies, etc.

BackgroundsDespite the genomic landscape of urothelial carcinomas (UC) patients, especially those with UC of bladder (UCB), has been comprehensively delineated and associated with pathogenetic mechanisms and treatment preferences, the genomic characterization of upper tract UC (UTUC) has yet to be fully elucidated.Materials and methodsA total of 131 Chinese UTUC (74 renal pelvis & 57 ureter) and 118 UCB patients were enrolled in the present study, and targeted next-generation sequencing (NGS) of 618 cancer-associated genes were conducted to exhibit the profile of somatic and germline alterations. The COSMIC database, including 30 mutational signatures, were utilized to evaluate the mutational spectrums. Moreover, TCGA-UCB, MSKCC-UCB, and MSKCC-UTUC datasets were retrieved for preforming genomic alterations (GAs) comparison analysis between Western and Chinese UC patients.ResultsIn our cohort, 93.98% and 56.63% of UC patients were identified with oncogenic and actionable somatic alterations, respectively. Meanwhile, 11.24% of Chinese UC patients (of 14.50% and 7.63% of UTUC and UCB cases, respectively) were identified to harbor a total of 32 pathogenic/likely-pathogenic germline variants in 22 genes, with DNA damage repair (DDR)-associated BRCA1 (1.20%) and CHEK2 (1.20%) being the most prevalent. Chinese UTUC and UCB patients possessed distinct somatic genomic characteristics, especially with significantly different prevalence in KMT2D/C/A, GNAQ, ERCC2, RB1, and PPM1D. In addition, we also found notable differences in the prevalence of ELF3, TP53, PMS2, and FAT4 between renal pelvis and ureter carcinomas. Moreover, 22.90% and 33.90% of UTUC and UCB patients, respectively, had at least one deleterious/likely deleterious alteration in DDR related genes/pathways. Subsequently, mutational signature analysis revealed that UC patients with mutational signature 22, irrespective of UTUC or UCB, consistently had the markedly higher level of tumor mutational burden (TMB), which was proved to be positively correlated with the objective complete/partial response rate in the IMvigor210 cohort. By comparison, Chinese and Western UTUC patients also differed regrading GAs in oncogenic-related genes/pathways, especially in TP53, RTK/RAS, and PI3K pathways; besides, more alterations in WNT pathway but less TP53, RTK/RAS, HIPPO, and PI3K pathways were identified in Chinese UCB.DiscussionsThe in-depth analysis of genomic mutational landscapes revealed distinct pathogenetic mechanisms between Chinese UTUC and UCB, and specific genomic characterizations could identify high risk population of UTUC/UCB and provided information regarding the selection of alternative therapeutic regimens.

Abstract Background Resistance of colorectal cancer (CRC) cells to radiotherapy considerably contributes to poor clinical outcomes of CRC patients. Microarray profiling in this study revealed the differentially expressed forkhead box Q1 (FOXQ1) in CRC, and thus we aimed to illustrate the role of FOXQ1 in CRC by modulating stemness and radio-resistance of CRC cells. Methods CRC and adjacent normal tissues were collected from CRC patients, and the correlation between FOXQ1 expression and CRC prognosis was analyzed. Subsequently, we determined the expression of FOXQ1, sirtuin 1 (SIRT1) and β-catenin in CRC tissues and cell lines. The binding affinity between FOXQ1 and SIRT1 and that between SIRT1 and β-catenin were validated with luciferase reporter gene, Co-IP and ChIP assays. Following a metagenomics analysis of CRC intestinal microbiota, the effects of the FOXQ1/SIRT1/β-catenin axis on CRC stem cell phenotypes and radio-resistance was evaluated in vitro and in vivo through manipulation of gene expression. Besides, mouse feces were collected to examine changes in intestinal microbiota. Results FOXQ1 was highly expressed in CRC tissues and cells and positively correlated with poor prognosis of CRC patients. FOXQ1 overexpression contributed to resistance of CRC cells to radiation. Knockdown of FOXQ1 inhibited the stemness of CRC cells and reversed their radio-resistance. FOXQ1 enhanced the transcriptional expression of SIRT1, and SIRT1 enhanced the expression and nuclear translocation of β-catenin. Knockdown of FOXQ1 repressed SIRT1 expression, thus reducing the stemness and radio-resistance of CRC cells. Moreover, FOXQ1 knockdown suppressed CRC xenograft formation in xenograft-bearing nude mice through inhibiting SIRT1 and β-catenin to reduce the content of pathological bacteria that were up-regulated in CRC. Conclusion FOXQ1-mediated SIRT1 upregulation augments expression and nuclear translocation of β-catenin and benefits CRC-related intestinal pathological bacterial, thereby enhancing the stemness and radio-resistance of CRC cells.

Abstract Information about the dynamic change and post-injury regeneration of cervical epithelium is relatively rare, even though it is tightly related to gynecologic malignancy. Here, using a feeder cell-based culturing system, we stably cloned mouse and human P63 and KRT5 expressing cells from the adult cervix as putative cervical stem/progenitor cells (CVSCs). When subjected to differentiation, the cultured cells gave rise to mature cervical epithelium by differentiating into squamous or glandular cells. The ability of endogenous mouse CVSCs to reconstitute cervical epithelium after injury was also evident from the genetic lineage tracing experiments. Single-cell transcriptomic analysis further classified the CVSCs into three subtypes and delineated their bi-lineage differentiation roadmap by pseudo-time analysis. We also tracked the real-time differentiation routes of two representing single CVSC lines in vitro and found that they recapitulated the predicted roadmap in pseudo-time analysis. Signaling pathways including Wnt, TGF-beta, Notch and EGFR were found to regulate the cervical epithelial hierarchy and implicated the different roles of distinct types of cells in tissue homeostasis and tumorigenesis. Collectively, the above data provide a cloning system to achieve stable in vitro culture of a bi-lineage stem/progenitor cell population in the cervix, which has profound implications for our understanding of the cervix stem/progenitor cell function in homeostasis, regeneration, and disease and could be helpful for developing stem cell-based therapies in future.

The Gamow shell model (GSM) is a powerful method for the description of the exotic properties of drip line nuclei. Internucleon correlations are included via a configuration interaction framework. Continuum coupling is directly included at basis level by using the Berggren basis, in which, bound, resonance, and continuum single-particle states are treated on an equal footing in the complex momentum plane. Two different types of Gamow shell models have been developed: its first embodiment is that of the GSM defined with phenomenological nuclear interactions, whereas the GSM using realistic nuclear interactions, called the realistic Gamow shell model, was introduced later. The present review focuses on the recent applications of the GSM to drip line nuclei.

Objectives(1) To clarify the dynamic relationship between the expression of myeloperoxidase (MPO) and microglial activation of intracerebral hemorrhage (ICH), (2) to explore the effect of inhibition of MPO on microglial activation, and (3) to observe the improvement in the neurobehavior of mice with inhibition of MPO.MethodsC57 BL/6 mice and CX3CR1 + /GFP mice were used to establish a phosphate-buffered saline (PBS) group, an ICH group, and a 4-aminobenzoic acid hydrazide (ABAH) group. Longa score, open field locomotion, hind-limb clasping test, immunohistochemistry, immunofluorescence, blood routine detection, and flow cytometry were used.ResultsThe neurobehavior of the mice was significantly impaired following ICH (P < 0.01); the expression of MPO was significantly increased following ICH, and reached a peak value at 6 h post-injury (P < 0.001). Moreover, the microglial activation increased significantly following ICH, and reached a peak level at 24 h post-injury (P < 0.01). Following inhibition of MPO, the activation of microglia in the ICH group decreased significantly (P < 0.001). Moreover, the neurobehavior of the ICH group was significantly improved with MPO inhibition (P < 0.05).ConclusionMPO may be an upstream molecule activated by microglia and following inhibition of MPO can improve secondary injury resulting from ICH.

Abstract We propose a classification method using the radiomics features of CT chest images to identify patients with coronavirus disease 2019 (COVID-19) and other pneumonias. The chest CT images of two groups of participants (90 COVID-19 patients who were confirmed as positive by nucleic acid test of RT-PCR and 90 other pneumonias patients) were collected, and the two groups of data were manually drawn to outline the region of interest (ROI) of pneumonias. The radiomics method was used to extract textural features and histogram features of the ROI and obtain a radiomics features vector from each sample. Then, we divided the data into two independent radiomic cohorts for training (70 COVID-19 patients and 70 other pneumonias patients), and validation (20 COVID-19 patients and 20 other pneumonias patients) by using support vector machine (SVM). This model used 20 rounds of tenfold cross-validation for training. Finally, single-shot testing of the final model was performed on the independent validation cohort. In the COVID-19 patients, correlation analysis (multiple comparison correction—Bonferroni correction, P

Abstract The poor damping of bidirectional dc (bi‐dc) converter caused by constant power load makes power system prone to oscillation, and non‐minimum phase characteristic also jeopardises voltage stability. To solve these challenges, the interconnection and damping assignment passivity‐based control (IDA‐PBC) is utilised to improve transient response. The influences of the right‐half‐plane (RHP) zero on the stability margin and controller design are illustrated by zero dynamics analysis. Then the port‐controlled Hamiltonian modelling is used to obtain the IDA‐PBC control law, which is suitable to the bi‐dc converter and independent of the operation mode. The system dissipation property is modified, and thus the desired damping is injected to smooth the transient voltage. To remove the voltage error caused by RHP zero and adjust the damping ratio, an energy controller with an adjustment factor is introduced. Besides, a virtual circuit is established to explain the physical meaning of the control parameter, and the parameter design method is given. Passivity analysis assesses the controller performance. Simulation results are analysed and compared with other control strategies to test the proposed IDA‐PBC strategy.

BackgroundLong-term alcohol exposure is associated with oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation, which may impair cognitive function. Probiotics supplements can significantly improve cognitive function in neurodegenerative diseases such as Alzheimer’s disease. Nevertheless, the effect of Lactobacillus plantarum ST-III culture supernatant (LP-cs) on alcohol-induced cognitive dysfunction remains unclear.MethodsA mouse model of cognitive dysfunction was established by intraperitoneal injection of alcohol (2 g/kg body weight) for 28 days. Mice were pre-treated with LP-cs, and cognitive function was evaluated using the Morris water maze test. Hippocampal tissues were collected for biochemical and molecular analysis.ResultsLP-cs significantly ameliorated alcohol-induced decline in learning and memory function and hippocampal morphology changes, neuronal apoptosis, and synaptic dysfunction. A mechanistic study showed that alcohol activated protein kinase R-like endoplasmic reticulum kinase (PERK) signaling and suppressed brain derived neurotrophic factor (BDNF) levels via ER stress in the hippocampus, which LP-cs reversed. Alcohol activated oxidative stress and inflammation responses in the hippocampus, which LP-cs reversed.ConclusionLP-cs significantly ameliorated alcohol-induced cognitive dysfunction and cellular stress. LP-cs might serve as an effective treatment for alcohol-induced cognitive dysfunction.

BackgroundLong non-coding RNAs (LncRNAs) has been confirmed to play a crucial role in the development and progression of various cancer types. Here we evaluated the expression profiles of LncRNAs in Lung adenocarcinoma (LUAD) tissues and identified a novel LncRNA, termed LncRNA-AC009948.5. However, the role and potential molecular mechanisms of this novel LncRNA in LUAD carcinogenesis is unknown.MethodsRegarding the public databases and based on integrating bioinformatics analyses, we determined whether LncRNA-AC009948.5 exerts its oncogenic functions via sponging miR-186-5p in LUAD. Furthermore, we determined whether NCAPG2 was a downstream target of miR-186-5p. Moreover, the expression level and biological function of LncRNA-AC009948.5 in LUAD were determined by qRT-PCR, cell apoptosis, Edu, transwell, wound healing and western blot assays. Besides, xenograft mice were established for validation. We explored the expression of LncRNA-AC009948.5 and its roles in the prognosis of LUAD.ResultsLncRNA expression microarray data indicate that LncRNA-AC009948.5 is upregulated in LUAD samples. The present study confirmed the upregulation of LncRNA-AC009948.5 in LUAD tissues and cells. Encreased expression of LncRNA-AC009948.5 was correlated with tumor size, lymph nodes, distant metastasis and histological grade, and poor prognosis.LncRNA-AC009948.5 knockdown significantly inhibited cell proliferation, migration, and invasion in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, LncRNA-AC009948.5 upregulated had opposite effects. Mechanistically, we elucidated that LncRNA-AC009948.5 could directly bind to miR-186-5p and subsequently suppress expression of the target gene of NCAPG2.ConclusionsLncRNA-AC009948.5 promotes lung adenocarcinoma cells metastasis via the miR-186-5p/NCAPG2 axis and activation of the EMT process. Which may serve as potential targets for the treatment of LUAD in the future.

Unmanned aerial vehicle swarms (UAVSs) can carry out numerous tasks such as detection and mapping when outfitted with machine learning (ML) models. However, due to the flying height and mobility of UAVs, it is very difficult to ensure a continuous and stable connection between ground base stations and UAVs, as a result of which distributed machine learning approaches, such as federated learning (FL), perform better than centralized machine learning approaches in some circumstances when utilized by UAVs. However, in practice, functions that UAVs must perform often, such as emergency obstacle avoidance, require a high sensitivity to latency. This work attempts to provide a comprehensive analysis of energy consumption and latency sensitivity of FL in UAVs and present a set of solutions based on an efficient asynchronous federated learning mechanism for edge network computing (EAFLM) combined with ant colony optimization (ACO) for the cases where UAVs execute such latency-sensitive jobs. Specifically, UAVs participating in each round of communication are screened, and only the UAVs that meet the conditions will participate in the regular round of communication so as to compress the communication times. At the same time, the transmit power and CPU frequency of the UAV are adjusted to obtain the shortest time of an individual iteration round. This method is verified using the MNIST dataset and numerical results are provided to support the usefulness of our proposed method. It greatly reduces the communication times between UAVs with a relatively low influence on accuracy and optimizes the allocation of UAVs’ communication resources.

Taking the Chang’e-5 (CE-5) sampling area as an example, this study carried out an investigation on improving the crater size-frequency distribution (CSFD) dating accuracy of lunar surface geologic units based on the crater degradation model. We constructed a three-parted crater degradation model, which consists of the diffusion equation describing crater degradation and equations describing the original crater profile for small craters (D < 1 km) and larger craters (D ≥ 1 km). A method that can improve the accuracy of CSFD dating was also proposed in this study, which utilizes the newly constructed degradation model to simulate the degradation process of the craters to help determine the crater degradation process and screen out the craters suitable for CSFD analysis. This method shows a good performance in regional dating. The age determined for the CE-5 sampling area is 2.0 ± 0.2 Ga, very close to the 2.03 ± 0.004 Ga of isotopic dating result of the returned sample. We found that the degradation state of the craters simulated by our constructed degradation model is highly consistent with the real existing state of the craters in terms of their topographic, geomorphological, and compositional (e.g., FeO) features. It fully demonstrates that the degradation model proposed in this study is effective and reliable for describing and distinguishing the degradation state of craters over time due to the cumulative effects of small craters. The proposed method can effectively distinguish between diffusively degraded (which conform to the degradation model) and non-diffusively degraded (which do not conform to the degradation model) craters and improve the CSFD accuracy through the selection of the craters. This not only provides an effective solution to the problem of obtaining a more “exact” frequency distribution of craters, which has long plagued the practical application of the CSFD method in dating the lunar surface but also advances our understanding of the evolutionary history of the geologic units of the study area. The results of this work are important for the in-depth study of the formation and evolution of the moon, especially for lunar chronology.

PurposeThe aim of this study was to investigate whether 11q loss of heterozygosity (LOH) aberration would impact the response of the primary tumor to neoadjuvant chemotherapy or to the degree of surgical resection in neuroblastoma (NB) patients with MYCN amplification.MethodsThe clinical data of 42 NB patients with MYCN amplification who were newly diagnosed and received treatments at our hospital from 2011 to 2020 were retrospectively analyzed. According to the results of the segmental chromosome aberration analysis, the patients enrolled were assigned to an 11qLOH positive group and an 11qLOH negative group.ResultsThere was no significant difference in the mean number of chemotherapy courses completed before surgery between the 11qLOH positive and 11qLOH negative groups (p = 0.242). Each of the 42 patients had metaiodobenzylguanidine (MIBG) scans both before and after neoadjuvant chemotherapy. The percentage of patients who had a clinical MIBG change in the 11qLOH positive group was lower than the percentage in the 11qLOH negative group (27.27 vs. 66.67%, p = 0.030). The 11qLOH negative group seemed to have a higher rate of surgical resection (≥90%); however, the difference between the two groups was not statistically significant (p = 0.088). Furthermore, the 11qLOH negative group did not show significantly superior event-free survival and overall survival rates compared with the 11qLOH positive group.ConclusionsThis study showed that patients with NB and MYCN amplification in combination with 11qLOH might be less likely to respond to neoadjuvant chemotherapy when compared with patients with NB and MYCN amplification without 11qLOH.

ObjectiveAlthough alcohol abuse has been indicated to cause cerebral aneurysm development and rupture, there is limited data on the impact of alcohol abuse on outcomes after an aneurysmal subarachnoid hemorrhage (aSAH). This study aims to investigate whether alcohol abuse increases the risk of angiographic vasospasm and delayed cerebral ischemia (DCI) in critically ill patients with aSAH.MethodsWe conducted a secondary analysis based on a retrospective study in a French university hospital intensive care unit (ICU). Patients with aSAH requiring mechanical ventilation hospitalized between 2010 and 2015 were included. Patients were segregated according to alcohol abuse (yes or no). Multivariable logistic regression analysis was used to identify the independent risk factors associated with angiographic vasospasm and DCI.ResultsThe patient proportion of alcohol abuse was dramatically greater in males than that in females (p < 0.001). The Simplified Acute Physiology Score II (SAPSII) score on admission did not show a statistical difference. Neither did the World Federation of Neurosurgical Societies (WFNS) and Fisher scores. Patients with alcohol abuse were more likely to develop angiographic vasospasm (OR 3.65, 95% CI 1.17–11.39; p = 0.0260) and DCI (OR 3.53, 95% CI 1.13–10.97; p = 0.0294) as evidenced by multivariable logistic regression analysis.ConclusionsIn this study, patients with alcohol abuse are at higher odds of angiographic vasospasm and DCI, which are related to poor prognosis following aSAH. These findings are important for the prevention and clinical management of aSAH.

NKG2C+ natural killer (NK) cell plays a vital role in CMV infection control after hematopoietic stem cell transplantation (HSCT). However, the modulation on NKG2C+ NK cell reconstitution is still unclear. NK cell education is affected by the interactions of HLA-I/killer immunoglobulin receptor (KIR). Our aim is to figure out which HLA-I/KIR interaction plays a dominant role in NKG2C+ NK education. Based on allogeneic haploidentical HSCT, we investigated the expansion and function of single KIR positive NKG2C+ NK cells via the interaction of KIR with both donor HLA and recipient HLA at days 30, 90, and 180 after HSCT. KIR2DL2/L3 single-positive/NKG2C+ cells were significantly expanded compared with KIR2DL1 or KIR3DL1 single-positive/NKG2C+ cells when donors and recipients were both HLA-C1/C1 or HLA-C1C1BW4 (p < 0.05), with higher NKp30 expression (p < 0.05). Moreover, the proportion of single KIR positive NK cells increased in both NKG2C+/NKG2A- NK cells and conventional NKG2C-/NKG2A- NK cells over time. We also observed that increased proportion of KIR2DL2/L3 single-positive/NKG2C+ NK cells correlated with higher incidence of acute graft-versus-host disease (aGVHD). Our study allows a better understanding of HLA-I/KIR interaction in the NKG2C+ NK cell education after HSCT.

Abstract Background Non‐alcoholic fatty liver disease (NAFLD) is the most predominant form of liver diseases worldwide. Recent evidence shows that myeloid differentiation factor 2 (MD2), a protein in innate immunity and inflammation, regulates liver injury in models of NAFLD. Here, we investigated a new mechanism by which MD2 participates in the pathogenesis of experimental NAFLD. Methods Wild‐type, Md2−/− and bone marrow reconstitution mice fed with high‐fat diet (HFD) were used to identify the role of hepatocyte MD2 in NAFLD. Transcriptomic RNA‐seq and pathway enrich analysis were performed to explore the potential mechanisms of MD2. In vitro, primary hepatocytes and macrophages were cultured for mechanistic studies. Results Transcriptome analysis and bone marrow reconstitution studies showed that hepatocyte MD2 may participate in regulating lipid metabolism in models with NAFLD. We then discovered that Md2 deficiency in mice prevents HFD‐mediated suppression of AMP‐activated protein kinase (AMPK). This preservation of AMPK in Md2‐deficient mice was associated with normalized sterol regulatory element binding protein 1 (SREBP1) transcriptional program and a lack of lipid accumulation in both hepatocytes and liver. We then showed that hepatocyte MD2 links HFD to AMPK/SREBP1 through TANK binding kinase 1 (TBK1). In addition, MD2‐increased inflammatory factor from macrophages induces hepatic TBK1 activation and AMPK suppression. Conclusion Hepatocyte MD2 plays a pathogenic role in NAFLD through TBK1‐AMPK/SREBP1 and lipid metabolism pathway. These studies provide new insight into a non‐inflammatory function of MD2 and evidence for the important role of MD2 in NALFD.

Objective Nontraumatic osteonecrosis of the femoral head (ONFH) is one of the most common diseases in orthopaedics. The damage to vascular endothelial (VE) cells caused by glucocorticoids (GC) has been reported as a possible mechanism of pathogenesis for ONFH. Junction‐mediating and regulatory protein (JMY), originally identified as a p53 coactivator, plays prominent roles in the DNA damage response and in cell motility. This study aimed to discover the role of JMY in the pathogenesis of GC‐induced endothelial cell lesions. Methods High‐throughput RNA sequencing was performed to identify the differentially expressed genes between GC‐treated human umbilical vein endothelial cells (HUVEC) and control cells. JMY knockdown and overexpressing HUVEC lines were treated with GC. Cell proliferation was examined with a survival cell count assay (Cell Counting Kit‐8, CCK‐8); cell apoptosis was measured by flow cytometry; a scarification assay was used to detect the capability of cell migration; a Transwell chamber assay was done to detect the cell motility . Differential expression of cell protein was detected by western blot. Results A total of 1561 differential genes were obtained through transcription sequencing, of which 789 mRNA were upregulated and 772 mRNA were downregulated in the GC‐treated HUVEC compared with the control cells. CCK‐8 assay results showed that: without GC treatment, overexpression or knockdown of JMY did not affect the proliferation activity of HUVEC. In the presence of GC treatment, the proliferation activity of HUVEC in the JMY knockdown group was significantly higher than that in the control group (P

Anomaly detection has been widely researched in financial, biomedical and other areas. However, most existing algorithms have high time complexity. Another important problem is how to efficiently detect anomalies while protecting data privacy. In this paper, we propose a fast anomaly detection algorithm based on local density estimation (LDEM). The key insight of LDEM is a fast local density estimator, which estimates the local density of instances by the average density of all features. The local density of each feature can be estimated by the defined mapping function. Furthermore, we propose an efficient scheme named PPLDEM based on the proposed scheme and homomorphic encryption to detect anomaly instances in the case of multi-party participation. Compared with existing schemes with privacy preserving, our scheme needs less communication cost and less calculation cost. From security analysis, our scheme will not leak privacy information of participants. And experiments results show that our proposed scheme PPLDEM can detect anomaly instances effectively and efficiently, for example, the recognition of activities in clinical environments for healthy older people aged 66 to 86 years old using the wearable sensors.

Background and objective Cancer pain affect the physical activity, psychological state and quality of life seriously, and even shortened the survival time of patients. Rational and standard application of opioids could control cancer pain effectively. Since the high incidence of cancer pain in lung cancer patients, the status of opioids application should be analyzed to evaluate the rationality of analgesic application in lung cancer patients. Methods The clinical data of 305 patients with lung cancer who were hospitalized in Department of Respiratory and Critical Care Medicine of Peking Union Medical College Hospital from June 2018 to June 2019 were analyzed retrospectively. Results In the analysis of factors affecting the use of opioids in lung cancer patients, age and drug kinds were the main influencing factors. The proportion of male patients was higher than female. Moreover, male patients used more kinds of opioids and were mostly between 60 and 69 years old. The variety and structure of opioids used in lung cancer patients in our hospital met the requirements. Oxycodone hydrochloride prolonged-release tablet has the highest frequency of application, and defined daily cost (DDC) ranked the first with a serial number ratio of 1, which showed good synchronization. The quantity of morphine tablet and morphine injection were low, and the overall breakthrough cancer pain (BTcP) in lung cancer patients was well controlled. The overall application of opioids were reasonable (93.4%), and the unreasonable items mainly included the disposal of BTcP and the unreasonable frequency of opioids, as well as overdose. Conclusion The majority of patients with lung cancer who take opioids are male, and the cancer pain in elderly men are more difficult to control, which needs to pay more attention. The overall application of opioids in the patients with lung cancer pain in our hospital are reasonable, but there are still some problems to focus, such as the disposal of BTcP, the dosage of opioids and the medication of special groups.

Abstract Background Glucocorticoid-induced osteonecrosis of the femoral head (ONFH) is closely associated with the dysfunction of the bone microvascular endothelial cells (BMECs). The present study investigated the angiogenic and apoptotic activity of the BMECs in glucocorticoid-induced ONFH. Methods This study enrolled a total of 12 patients, six of whom were assigned to the ONFH group whereas the other six served as the control group. The ONFH group was composed of patients with glucocorticoid-induced ONFH while the control group had femoral neck fractures. BMECs were isolated from the subchondral region of the femoral head. Cell proliferation, cell viability, tube formation assay, Transwell assay, TUNEL assay, and Western blot analysis were performed. Results BMECs of the two groups were successfully isolated and identified. No significant differences were noticed in BMECs proliferation between the two groups. However, compared to the control, cell viability, tube formation, and migration of BMECs were significantly decreased and the number of TUNEL positive cells was markedly increased in the ONFH group. In the ONFH group, it was also noted that the amount of Bax and cleaved-caspase3 was elevated while that of Bcl-2 was reduced. Conclusion The findings of our study revealed that BMECs obtained from the glucocorticoid-induced ONFH patients had decreased angiogenic and increased apoptotic activities, which could explain the pathogenesis and progression of glucocorticoid-induced ONFH.

Objective Porous tantalum implantation (PTI) and bone impaction grafting (BIG) through a window at the femoral head neck junction are known as two types of joint‐preserving procedures. They provide an alternative option in the treatment of osteonecrosis of the femoral head by providing strong structural support to the subchondral plate. However, when earlier joint‐preserving treatments fail, conversion to a total hip arthroplasty seems to be the final treatment of choice. This emphasizes the importance of joint‐preserving procedures that do not hinder the clinical results of a subsequent total hip arthroplasty. The results of conversion total hip arthroplasty after failed PTI and BIG are still controversial. The purpose of this study was to compare the clinical and radiological outcomes of total hip arthroplasty after failed PTI or BIG surgery with primary total hip arthroplasty. Methods Patients at our institution between 2010 and 2014 who underwent total hip arthroplasty after failed PTI or BIG surgery compared to primary total hip arthroplasty were retrospectively reviewed. A total of 27 patients (30 hips) who underwent total hip arthroplasty after failed PTI surgery (group I) were matched according to age, gender and BMI index with 28 patients (30 hips) who underwent total hip arthroplasty after failed BIG surgery (group II) and 30 patients (30 hips) who underwent primary total hip arthroplasty (group III). The clinical results included preoperative and postoperative Harris Hip score, surgery duration, blood loss volume and clinical complications. Radiological follow‐up results included abduction angle and anteversion angle of the acetabular cup, periprosthetic osteolysis, and prosthesis subsidence. Results There was no significant difference in the preoperative and postoperative Harris Hip score among the three groups at the latest follow‐up (P = 0.247). The surgery duration was longer and intra‐operative blood loss volume was higher in group I than in group II and group III (P 0.05). There was no significant difference in radiological follow‐up results among the three groups (P > 0.05). Varying degrees of residual tantalum debris were seen on postoperative radiographs of all group I patients. There was no difference in the incidence of complications among the three groups (P > 0.05). Conclusions PTI group had higher blood loss volume and surgery duration than BIG group and primary total hip arthroplasty group. BIG group had no significant differences with primary total hip arthroplasty group in clinical and radiological follow‐up results. There were no significant differences between the three groups in the Harris Hip score and radiological follow‐up results.