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It is necessary to achieve current matching for GaN-based CMOS-like inverters. However, due to the low hole mobility of GaN p-FET devices, the weak output capacity of GaN p-FET devices makes it difficult to obtain current matching with n-FET devices in the off-state, which hinders the development of GaN-based CMOS-like inverters. In this study, a GaN-based CMOS-like device with an AlGaN back barrier layer is designed and its off-state leakage current is compared with that without an AlGaN back-barrier layer. The results show that the 2DEG confinement in the GaN-based n-FET device with an AlGaN back barrier layer can be enhanced and the leakage current is reduced from 10–3A to 10–6A in the off-state. This is accomplished without influencing the current of the GaN-based p-FET device in the off-state, resulting in a good current consistency between the n-FET device and the p-FET device in the off-state. The static power consumption is 4.5 µW for GaN-based CMOS-like inverters with an AlGaN back barrier structure when it is operated at Vdd= 5 V. The rise time (tr) and fall time (tf) of the GaN-based CMOS-like inverters are 4 μs and 0.12 μs, respectively. The low noise margin (NML) is 1.90 V and the high noise margin (NMH) is 2.55 V. This work lays a foundation for the development of the future of GaN-based integrated ICs.

We describe aggregative microconchid tubes from Middle-Late Triassic lacustrine strata of the Tanzhuang Formation in the Jiyuan-Yima Basin, North China. These microconchid tubes are attached to plant fragments and are preserved with bivalves, ostracodes, phyllostachys, gastropods, and coleoptera fragments. The findings confirm that the extinct lophophorate group inhabited non-marine continental basins. Microconchids dispersed extensively in continental basins and became common in lacustrine strata during Middle-Late Triassic. Its expansion may have been promoted by the recovery of the land ecosystem in the aftermath of the end-Permian crisis.

Despite the extensive use of next-generation sequencing (NGS) of RNA, simultaneous direct sequencing and quantitative mapping of multiple RNA nucleotide modifications remains challenging. Mass spectrometry (MS)-based sequencing can directly sequence all RNA modifications without being limited to specific ones, but it requires a perfect MS ladder that few tRNAs can provide. Here, we describe an MS ladder complementation sequencing approach (MLC-Seq) that circumvents the perfect ladder requirement, allowing de novo MS sequencing of full-length heterogeneous cellular tRNAs with multiple nucleotide modifications at single-nucleotide precision. Unlike NGS-based methods, which lose RNA modification information, MLC-Seq preserves RNA sequence diversity and modification information, revealing new detailed stoichiometric tRNA modification profiles and their changes upon treatment with the dealkylating enzyme AlkB. It can also be combined with reference sequences to provide quantitative analysis of diverse tRNAs and modifications in total tRNA samples. MLC-Seq enables systematic, quantitative, and site-specific mapping of RNA modifications, revealing the truly complete informational content of tRNA.

•Th-B-H ternary compounds reveal promising low-pressure superconductivity.•Metastable ThBH5and ThBH7show Tc of 46.9 K at 20 GPa and 40.0 K and 50 GPa, respectively.•Th2BH10and ThBH display metallic nature but with low Tc values at 50 GPa.•No stable Th-B hydrides at ambient pressure; insights for low-pressure design.

ABSTRACTVibrating consolidation process is widely applied to field construction of cement concrete. Improper vibration can easily lead to the instability of fresh concrete and then induce performance degradation of hardened [...]

This study focuses on the investigation of stratification phenomena during the transportation and storage of hydrogen-enriched natural gas (HENG) in enclosed spaces. Two mathematical models, namely, the species transport model and the multiphase mixture model, are commonly used to describe the stratification phenomena of HENG. To evaluate the suitability of both models in simulating the stratification phenomena of HENG, the model accuracy was initially validated by comparing with published experimental data. Subsequently, the spontaneous concentration distribution trend in a binary gas mixture (hydrogen + methane) system within an enclosed space is analyzed based on the principles of minimum energy. The findings indicate that the species transport model is more suitable for describing the distribution of HENG in enclosed spaces; the HENG mixture gradually attains uniform concentration distribution when it remains static and eventually reaches equilibrium without any obvious concentration stratification. This study aims at offering valuable insights for ensuring safe transportation and storage of HENG.

Under the influence of anthropogenic and climate change, the problems caused by urban heat island (UHI) has become increasingly prominent. In order to promote urban sustainable development and improve the quality of human settlements, it is significant for exploring the evolution characteristics of urban thermal environment and analyzing its driving forces. Taking the Landsat series images as the basic data sources, the winter land surface temperature (LST) of the rapid urbanization area of Fuzhou City in China was quantitatively retrieved from 2001 to 2021. Combing comprehensively the standard deviation ellipse model, profile analysis and GeoDetector model, the spatio-temporal evolution characteristics and influencing factors of the winter urban thermal environment were systematically analyzed. The results showed that the winter LST presented an increasing trend in the study area during 2001–2021, and the winter LST of the central urban regions was significantly higher than the suburbs. There was a strong UHI effect from 2001 to 2021 with an expansion trend from the central urban regions to the suburbs and coastal areas in space scale. The LST of green lands and wetlands are significantly lower than croplands, artificial surface and unvegetated lands. Vegetation and water bodies had a significant mitigation effect on UHI, especially in the micro-scale. The winter UHI had been jointly driven by the underlying surface and socio-economic factors in a nonlinear or two-factor interactive enhancement mode, and socio-economic factors had played a leading role. This research could provide data support and decision-making references for rationally planning urban layout and promoting sustainable urban development.

A multilayer perceptron neural network (MLP-NN) inverse model based on the time-domain scattering (TDS) parameters (TDS-MLP-NN) is proposed for antenna design. Inputting desired antenna electromagnetic responses, the MLP-NN inverse model can directly output the antenna geometric parameters. Integration of TDS into MLP-NN allows for reducing the complexity of the neural network topology and the dimension of the input data, thus contributing to an improved generalization ability of the MLP-NN. The feasibility and effectiveness of the TDS-MLP-NN model are investigated using a resonant and traveling-wave hybrid antenna of Fabry–Perot unidirectional dielectric radiator (UDR) antenna, and it is found that the proposed model can output desired geometric parameters even when antenna performances as input to the neural network are better than those in the training dataset. The proposed model yields a better antenna performance than the UDR antenna, with an impedance bandwidth of 30.07% and a maximum gain of 9.59 dBi. Moreover, the TDS-MLP-NN is shown to be able to significantly improve the generalization ability of the MLP-NN inverse model and the design efficiency of antennas.

In the present study, a series of in situ TiB/Ti6Al4V composites were fabricated using selective laser melting. The formability, microstructure evolution and mechanical properties of the as-built samples added with different contents of TiB2were studied. It is found that the densification level is related to both the content of TiB2and laser energy density. The added TiB2reinforcement particle can spontaneously react with titanium and then form the TiB phase. The needle-like TiB phase tends to transform into dot-like particles with the decrease in energy density. Additionally, with the increase in TiB2content, the TiB phase is coarsened due to the increased nucleation rate and more reactions. The grain morphology is found to largely depend on the translational speed of solid–fluid interface determined by the temperature gradient and cooling rate. Also, the microhardness of the as-built TiB/Ti6Al4V composites is obviously improved. More interestingly, as the energy density increases, the microhardness of the as-built TiB/Ti6Al4V composites firstly increases and then decreases due to the synergy of grain size and different morphologies and distribution of TiB phases. The wear resistance of TiB/Ti6Al4V composites is far superior to that of Ti6Al4V alloy owing to the increased microhardness resulted from the uniform distribution of the hard TiB phase in the matrix.

Previous study has highlighted an association between cannabis use (CU) and an increased risk of erectile dysfunction (ED), potentially due to indirect effects on sex hormonal balance. However, the evidence remains controversial, and the causal relationship is unclear. This study utilized genome-wide association study (GWAS) data to investigate the causal relationships between cannabis use disorder (CUD), lifetime cannabis use (LCU), and ED, as well as levels of sex hormones including estradiol (E2), bioavailable testosterone (BT), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) through Mendelian randomization (MR) analysis. The primary method of analysis was the inverse variance weighted (IVW) method. Data from the FinnGen and UK Biobank were used for replication and meta-analysis. The results indicated no causal relationship between genetically predicted CUD (OR = 0.97, 95% CI 0.87–1.10, P= 0.66) and LCU (OR = 1.13, 95% CI 0.84–1.50, P= 0.42) with the risk of ED. The meta-analysis provided consistent evidence (P> 0.05). No causal relationships were found between CUD and LCU with E2(CUD: β = 0.00, 95% CI 0.00–0.01, P= 0.37; LCU: β = 0.00, 95% CI −0.02–0.01, P= 0.62), BT (CUD: β = 0.00, 95% CI −0.03–0.02, P= 0.90; LCU: β = 0.02, 95% CI −0.04–0.09, P= 0.46), FSH (CUD: β = 0.01, 95% CI −0.18–0.20, P= 0.92; LCU: β = 0.01, 95% CI −0.44–0.47, P= 0.95), and LH (CUD: β = 0.01, 95% CI −0.18–0.21, P= 0.90; LCU: β = 0.13, 95% CI −0.22–0.49, P= 0.46). Sensitivity analyses detected no evidence of horizontal pleiotropy or heterogeneity, ensuring the robustness of the results. In conclusion, this MR analysis did not provide evidence supporting a causal relationship between CU and ED or sex hormone levels.

The hydrogenation of CO2enables the production of high-value fuels and chemicals, contributing to a sustainable and environment-friendly energy transition. Currently, for the CO2hydrogenation to methanol reaction, either increasing the CO2conversion or improving the methanol selectivity while maintaining high CO2conversion is challenging. Herein, a new catalyst loaded with Cu nanoparticles (NPs) dispersed on amorphous MoOxwith Li2CO3as a promoter (denoted as Li–Cu/MoOx) was constructed viaan in situdispersion and alkali metal-promotion stepwise regulation strategy. At 260 °C and 5 MPa, the as-designed catalyst exhibited a satisfactory catalytic performance with a CO2conversion of 13.4% and a methanol selectivity of 88.8%. The methanol selectivity of the Li–Cu/MoOxcatalyst is higher than that of all the Cu-based catalysts reported in the literature to date under the conditions of CO2conversion >10% and reaction pressure <8 MPa in a fixed-bed reactor. Furthermore, the Li–Cu/MoOxcatalyst showed an excellent thermal stability. It was found that the in situdispersion step enabled a high dispersion of Cu NPs and the production of the amorphous MoOxsupport, resulting in the formation of more Cu–support interfaces, which increased the number of active sites in the catalyst. The high methanol selectivity was attributed to an alkali metal-promotion step, which increased the Mo4+content in MoOx, leading to a change in the types of active sites. In addition, the strong metal–support interaction (SMSI) in the catalyst was responsible for the high thermal stability. This strategy also has potential for designing other highly efficient catalysts.

IntroductionNovel therapeutic strategies are urgently needed for Mycobacterium aviumcomplex pulmonary disease (MAC-PD). Human mesenchymal stromal cells (MSCs) can directly inhibit MAC growth, but their effect on intracellular bacilli is unknown. We investigated the ability of human MSCs to reduce bacterial replication and inflammation in MAC-infected macrophages and in a murine model of MAC-PD.MethodsHuman monocyte-derived macrophages (MDMs) were infected with M. aviumChester strain and treated with human bone marrow-derived MSCs. Intracellular and extracellular colony-forming units (CFUs) were counted at 72 hours. Six-week-old female balb/c mice were infected by nebulisation of M. aviumChester. Mice were treated with 1×106intravenous human MSCs or saline control at 21 and 28 days post-infection. Lungs, liver and spleen were harvested 42 days post-infection for bacterial counts. Cytokines were quantified by ELISA.ResultsMSCs reduced intracellular bacteria in MDMs over 72 hours (median 35% reduction, p=0.027). MSC treatment increased extracellular concentrations of prostaglandin E2 (PGE2) (median 10.1-fold rise, p=0.002) and reduced tumour necrosis factor-α (median 28% reduction, p=0.025). Blocking MSC PGE2 production by cyclo-oxygenase-2 (COX-2) inhibition with celecoxib abrogated the antimicrobial effect, while this was restored by adding exogenous PGE2. MSC-treated mice had lower pulmonary CFUs (median 18% reduction, p=0.012), but no significant change in spleen or liver CFUs compared with controls.ConclusionMSCs can modulate inflammation and reduce intracellular M. aviumgrowth in human macrophages via COX-2/PGE2 signalling and inhibit pulmonary bacterial replication in a murine model of chronic MAC-PD.

ABSTRACTA protein called cleavage-stimulating factor subunit 2 (CSTF2, additionally called CSTF-64) binds RNA and is needed for the cleavage and polyadenylation of mRNA. CSTF2 is an important component subunit of the cleavage stimulating factor (CSTF), which is located on the X chromosome and encodes 557 amino acids. There is compelling evidence linking elevated CSTF2 expression to the pathological advancement of cancer and on its impact on the clinical aspects of the disease. The progression of cancers, including hepatocellular carcinoma, melanoma, prostate cancer, breast cancer, and pancreatic cancer, is correlated with the upregulation of CSTF2 expression. This review provides a fresh perspective on the investigation of the associations between CSTF2 and various malignancies and highlights current studies on the regulation of CSTF2. In particular, the mechanism of action and potential clinical applications of CSTF2 in cancer suggest that CSTF2 can serve as a new biomarker and individualized treatment target for a variety of cancer types.

ABSTRACTObjectivesTo compare the pharmacokinetic and safety of the test group capecitabine tablets (0.5 g) and the reference group capecitabine tablets (0.5 g).MethodsThis study was registered at www.chinadrugtrials.org.cnunder the registration number CTR20220138. 48 subjects with solid tumor were recruited and randomized to receive either the test group or the reference group at a dose of 2 g per cycle for three cycles of the entire trial.ResultsThe point estimate of the geometric mean ratio of Cmaxfor the subject and reference groups was 1.0670, which was in the range of 80.00%-125.00%. And the upper limit of 95% confidence interval was −0.0450 < 0. The statistics of geometric mean ratio of AUC0-tand AUC0-∞(test group/reference group) and their 90% confidence intervals were in the range of 80.00%-125.00%, thus the test group was bioequivalent to the reference group under the conditions of this postprandial test. There were no major or serious adverse events. Conclusion: The pharmacokinetic profiles of capecitabine under postprandial conditions were consistent between the two groups. The two groups were bioequivalent and had a similar favorable safety profile in Chinese patients with solid tumor.

We used mortality, rehospitalization rates, quality of life, the New York Heart Association (NYHA), and 6-min walk test (6 MWT) to assess the impact of weight loss (WL) on the prognosis of overweight and obese heart failure (HF) patients.Key findings: WL is associated with improvements in long-term rehospitalization rates, quality of life, cardiac function, and exercise capacity.Bariatric surgery (BS) may reduce mortality in overweight and obese HF patients. Unintentional WL of more than 5% may mean a bad condition and could increase mortality.

Tantalum-based oxide electrodes have recently drawn much attention as promising anode materials owing to their hybrid Li+storage mechanism. However, the utilization of LiTaO3electrode materials that can deliver a high theoretical capacity of 568 mAh g–1has been neglected. Herein, we prepare a layered LiTaO3electrode formed artificially by restacking LiTaO3nanosheets using a facile synthesis method and investigate the Li+storage performance of this electrode compared with its bulk counterpart. The designed artificially layered anode reaches specific capacities of 474, 290, and 201 mAh g–1, respectively, at 56 (>500 cycles), 280 (>1000 cycles), and 1120 mAg–1(>2000 cycles) current densities. We also determine that the Li+storage capacity of the layered LiTaO3demonstrates a cycling-induced capacity increase after a certain number of cycles. Adopting various characterization techniques on LiTaO3electrodes before and after electrochemical cycling, we attribute the origin of the cycling-induced improvement of the Li+storage capacity in these electrodes to the amorphization of the electrode after cycling, formation of metallic tantalum during the partially irreversible conversion mechanism, lower activation overpotential of electrodes due to the formation of Li-rich species by the lithium insertion mechanism, and finally the intrinsic piezoelectric behavior of LiTaO3that can regulate Li+diffusion kinetics.

Increasing tobacco control and public health awareness have increased smokers’ attempts to quit smoking. However, some smokers also seek alternative products claimed to pose less risks. The use of smokeless tobacco (ST) products may thus increase in some countries which are not traditionally ST markets. To provide a cross-sectional picture on ST usage in China, a survey was conducted from December 2019 to March 2020 in representative metropolitan cities (divided into three tiers by their populations and gross domestic product (GDP) sizes), from which 3,000 tobacco users and 801 ST users were randomly recruited to provide a snapshot of ST usage behaviour and other pertinent factors for Chinese tobacco users. The study included questionnaires designed to probe potential reasons behind ST use, usage habits, and nicotine dependence attributes. These questions were devised to cover the type of tobacco products used, users’ age, gender, city of residence, residence time, household monthly income, etc., and was supported by some verification questions. Mann-Whitney-analysis was used for significance analysis between different groups. The results showed that ST prevalence for Chinese tobacco users was around 2.1%. The proportion of exclusively ST use was about 8.99%, and the mean conversion time to habitual ST use was about three months. Demographic information such as the city tiers where ST users lived, their age, gender, educational and income levels appeared to correlate with ST use habits although more studies are needed to verify the observations. The fact that a small but measurable population of Chinese ST users exists has important implications for tobacco control. This study provides the first large-scale, single-time-point survey on Chinese ST user profiles, which may help the future research on tobacco control policy regarding ST products in China.

To achieve efficient gene delivery in vitroor in vivo, nonviral vectors should have excellent biostability across cellular and tissue barriers and also smart stimuli responsiveness toward controlled release of therapeutic genes into the cell nucleus. However, it remains a key challenge to effectively combine the biostability of covalent polymers with the stimuli responsiveness of noncovalent polymers into one nonviral vehicle. In this work, we report the construction of a kind of cationic supramolecular block copolymers (SBCs) through noncovalent polymerization of β-cyclodextrin/azobenzene-terminated pentaethylenehexamine (DMA-Azo-PEHA-β-CD) in aqueous media using β-CD-monosubstituted poly(ethylene glycol) (PEG-β-CD) as a supramolecular initiator. The resultant SBC exhibits superior biostability, biocompatibility, and light/pH dual-responsive characteristics, and it also demonstrates efficient plasmid DNA condensation capacity and the ability to rapidly release plasmid DNA into cells driven by visible light (450 nm). Eventually, this SBC-based delivery system demonstrates visible light-induced enhancement of gene delivery in both COS-7 and HeLa cells. We anticipate that this work provides a facile and robust strategy to enhance gene delivery in vitroor in vivoviavisible light-guided manipulation of genes, further achieving safe, highly efficient, targeting gene therapy for cancer.

Modified kaolinites possess excellent adsorption properties and, therefore, are regarded widely as potential catalytic components. The use of modified kaolinites as a catalytic component for Fischer–Tropsch synthesis (FTS) has remained unexplored, however. In the current study, delaminated and pit-rich nano-kaolinite was prepared via acid treatment of N-methylformamide (NMF)-intercalated kaolinite (intercalation-etching strategy), and was used as a support to prepare a cobalt-based FTS catalyst (denoted as 15%-Co-HNKln). Compared with other FTS catalysts, the supports for which were raw kaolinite or directly acid-treated kaolinite, the 15%-Co-HNKln showed several advantages such as large specific surface area, dispersed Co particles with small particle size, more new active sites, and significant surface acidity. Given the aforementioned advantages, the 15%-Co-HNKln catalyst demonstrated very good FTS performance. Compared with that of the raw kaolinite-supported FTS catalyst, the CO conversion rate and C5–C12hydrocarbon selectivity of 15%-Co-HNKln increased by 20% and 15%, respectively.

Reachability is the basis for studying other dynamic properties of Petri nets (PNs). When a state equation is used to determine the reachability of a marking, we need to judge whether there is a corresponding legal firing sequence (LFS) for a non-negative integer solution (NIS), i.e., a firing count vector, of the state equation. The search for an LFS is an NP-hard problem, and previous work cannot always find an LFS for any NISs. This article proposes that transition-dependent circuits or firing-dependent circuits are the root cause that a state equation has an NIS but the marking is nonreachable, i.e., there is no LFS corresponding to an NIS in PNs. Based on this, we propose a state-equation-based backward algorithm (SBA) to determine whether there is an LFS corresponding to an NIS of the state equation in a PN. The correctness and effectiveness of SBA are verified by a case study on a PN-based flexible manufacturing system and through simulation on an S 4PR net. The experimental results show that the time required for SBA to determine the existence of an LFS increases linearly with the transition firing count in NISs. When the number of NISs of a state equation is finite, we can efficiently determine the reachability of a marking. This represents an important result in theory and applications of PNs.

It is crucial to investigate the urban agglomerations spatio-temporal evolution patterns and driving factors for analyzing the urban spatial structure-functional division and promoting the coordinated development of urban agglomerations. In this study, a novel vegetation-building-nighttime light-adjusted index (VBNAI) was established for rapid and effective mapping of urban construction land (UCL) in Central Plains Urban Agglomeration (CPUA), China during 2000–2020 based on Google Earth Engine (GEE) platform. Compared with traditional indices, VBNAI can significantly decrease the blooming effect, Normalized Difference Vegetation Index (NDVI) saturation, and soil background of nighttime light data. In addition, the urban expansion indices and standard deviation ellipse model were synthetically adopted to analyze the spatio-temporal evolution pattern of urban expansion. The gravity model and the geographically weighted regression model were employed to determine the spatial interaction forces and drivers of urban expansion, respectively. The results showed that the VBNAI index has obvious advantages in efficiency and accuracy to extract UCL with the overall accuracy of more than 91%. The UCL of CPUA had increased by 4489.84 km2during 2000–2020 with the gravity center moving towards southeast continuously. From 2000 to 2010, the urban expansion was in a ‘center-hinterland’ pattern which had benefit from the favorable effect of the traffic shaft belt. During 2010–2020, the urban network structure had basically established. Urban expansion had been influenced by a variety of socio-economic and demographic factors, and the impact degree varied from region to region. This study could provide scientific references for facilitating the intensive utilization of urban resources and optimizing the spatial development pattern of urban agglomeration.

The combination of chemotherapy and photodynamic therapy (PDT) based on nanoparticles (NPs) has been extensively developed to improve the therapeutic effect and decrease the systemic toxicity of current treatments. However, overexpressed glutathione (GSH) in tumor cells efficiently scavenges singlet oxygens (1O2) generated from photosensitizers and results in the unsatisfactory efficacy of PDT. To address this obstacle, here we design H2O2-responsive polymer prodrug NPs with GSH-scavenger (Ce6@P(EG-a-CPBE) NPs) for chemo-photodynamic synergistic cancer therapy. They are constructed by the co-self-assembly of photosensitizer chlorin e6 (Ce6) and amphiphilic polymer prodrug P(EG-a-CPBE), which is synthesized from a hydrophilic alternating copolymer P(EG-a-PD) by conjugating hydrophobic anticancer drug chlorambucil (CB) via an H2O2-cleavable linker 4-(hydroxymethyl)phenylboronic acid (PBA). Ce6@P(EG-a-CPBE) NPs can efficiently prevent premature drug leakage in blood circulation because of the high stability of the PBA linker under the physiological environment and facilitate the delivery of Ce6 and CB to the tumor site after intravenous injection. Upon internalization of Ce6@P(EG-a-CPBE) NPs by tumor cells, PBA is cleaved rapidly triggered by endogenous H2O2to release CB and Ce6. Ce6 can effectively generate abundant 1O2under 660 nm light irradiation to synergistically kill cancer cells with CB. Concurrently, PBA can be transformed into a GSH-scavenger (quinine methide, QM) under intracellular H2O2and prevent the depletion of 1O2, which induces the cooperatively strong oxidative stress and enhanced cancer cell apoptosis. Collectively, such H2O2-responsive polymer prodrug NPs loaded with photosensitizer provide a feasible approach to enhance chemo-photodynamic synergistic cancer treatment.

Activation of stimulator of interferon genes (STING) can reprogram the immunosuppressive tumor microenvironment (TME) by initiating innate and adaptive immunity. As natural STING agonists, clinical translation of cyclic dinucleotides (CDNs) has been challenged by their short half-life in circulation, poor stability, and low membrane permeability. Herein, we use the natural endogenous small molecules oleic acid and deoxycytidine to construct a ligand for the STING agonist c-di-GMP (CDG), a hydrophobic nucleotide lipid (3′,5′-diOA-dC), which can assemble with CDG into stable cyclic dinucleotide nanoparticles (CDG-NPs) through various supramolecular forces driven by molecular recognition. CDG-NPs are homogeneous and stable spherical nanoparticles with an average diameter of 59.0 ± 13.0 nm. Compared with free CDG, CDG-NPs promote the retention and intracellular delivery of CDG in the tumor site, boost STING activation and TME immunogenicity, and potentiate STING-mediated anti-tumor immunity when administered by either intratumoral or systemic routes in melanoma-bearing mice. We propose a flexible supramolecular nanodelivery system for CDG by using endogenous small molecules, which provides a CDN delivery platform for STING-mediated cancer immunotherapy.

Ibuprofen is a nonsteroidal anti‐inflammatory agent. In this study, we compared the pharmacokinetic properties, bioequivalence, and safety of a newly developed generic formulation (test) and a branded formulation (reference) of 0.2 g ibuprofen granules in healthy Chinese participants in fasting and fed arms. The randomized, single‐dose, open‐label, two‐preparation, two‐sequence, two‐period crossover study had a washout period of 7 days between each period. It was conducted in 72 participants, 24 in the fasting arm and 48 in the fed arm. The concentration of ibuprofen in the plasma was determined using high‐performance liquid chromatography‐tandem mass spectroscopy. The primary pharmacokinetic parameters were calculated using a noncompartmental model. Safety assessments were performed throughout the study. The mean values of Cmax, AUC0‐t, and AUC0‐∞for the test and reference preparations of ibuprofen were 19 295 and 21 101 ng/mL, 70 795 and 70 558 ng * h/mL, and 72 023 and 71 647 ng * h/mL, respectively, in the fasting arm and 11 299 and 11 605 ng/mL, 70 983 and 69 157 ng * h/mL, and 73 279 and 71 267 ng * h/mL, respectively, in the fed arm. For all parameters, bioequivalence was within acceptable limits. No serious adverse reactions were reported in this study. This study demonstrated that the 2 formulations of ibuprofen granules were bioequivalent in healthy Chinese volunteers under fasting and fed conditions.

Ni-rich layered oxide cathode materials LiNixCoyMnzO2 (x>0.6) have been widely used in high specific energy Li-ion batteries. Compared with polycrystalline LiNixCoyMnzO2, single crystal Ni-rich cathode materials have attracted much attention for their unique advantages. However, they also suffer from some drawbacks, such rapid capacity decay and intragranular crack during cycling. In order to enhance the structure and electrochemical performance of single crystal LiNi0.8Co0.1Mn0.1O2 (SC811), different amount of aluminium (1 mol%, 2 mol% and 3 mol%) is utilized to substitute the materials. Physical characterizations of SC811 show the successful synthesis and Al doping of the single-crystal materials as well as lower Li/Ni intermixing after Al doping. Electrochemical tests illustrate that the single-crystal materials doped with 2mol% Al (2Al-SC811) shows superior electrochemical performance, and maintains 83.5 % of the initial discharge capacity after 100 cycles at 1 C in comparison with 68.9 % of the pristine SC811. It is hoped this work should shed light on the development of advanced cathode materials for Li-ion batteries.

Specific cancer diagnosis at an early stage plays a significant role in preventing cancer metastasis and reducing cancer mortality. Thus, exploring specific and sensitive fluorescent probes to realize early cancer diagnosis is an urgent need in clinic. Aminopeptidase N (APN/CD13), overexpressed in numerous malignant tumors, is an important tumor biomarker associated with cancer progression, invasion, and metastasis. In this study, a novel fluorescent molecule APN–SUB, capable of monitoring APN in real time, is encapsulated in a pH-responsive block copolymer (termed APN–SUB nanoprobe) for cancer diagnosis. APN–SUB contains a fluorophore center and a trigger moiety (leucine group), which is covalently conjugated on the fluorophore with an amide bond. The hydrolysis of the amide bond in APN–SUB activated by APN leads to a red shift of maximum fluorescence emission wavelength from 495 nm to 600 nm, realizing dual-color transformation from green to red. Moreover, the APN–SUB nanoprobe with pH-responsiveness is prepared to improve the accumulation and the release rate in the tumor region. It is worth noting that the APN–SUB nanoprobe exhibits good performance for APN imaging, namely, superior limit of detection (0.14 nU mL−1), excellent selectivity and strong photostability. More importantly, the APN–SUB nanoprobe can be successfully employed as a color-convertible fluorescent probe for cancer diagnosis by tracking the activity of APN with high specificity and sensitivity in vivo, demonstrating its potential value for cancer diagnosis.

RationaleA better understanding of the mechanism of action of mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) is needed to support their use as novel therapies for acute respiratory distress syndrome (ARDS). Macrophages are important mediators of ARDS inflammatory response. Suppressor of cytokine signalling (SOCS) proteins are key regulators of the macrophage phenotype switch. We therefore investigated whether SOCS proteins are involved in mediation of the MSC effect on human macrophage reprogramming.MethodsHuman monocyte-derived macrophages (MDMs) were stimulated with lipopolysaccharide (LPS) or plasma samples from patients with ARDS (these samples were previously classified into hypo-inflammatory and hyper-inflammatory phenotype) and treated with MSC conditioned medium (CM) or EVs. Protein expression was measured by Western blot. EV micro RNA (miRNA) content was determined by miRNA sequencing. In vivo: LPS-injured C57BL/6 mice were given EVs isolated from MSCs in which miR-181a had been silenced by miRNA inhibitor or overexpressed using miRNA mimic.ResultsEVs were the key component of MSC CM responsible for anti-inflammatory modulation of human macrophages. EVs significantly reduced secretion of tumour necrosis factor-α and interleukin-8 by LPS-stimulated or ARDS plasma-stimulated MDMs and this was dependent on SOCS1. Transfer of miR-181a in EVs downregulated phosphatase and tensin homolog (PTEN) and subsequently activated phosphorylated signal transducer and activator of transcription 5 (pSTAT5) leading to upregulation of SOCS1 in macrophages. In vivo, EVs alleviated lung injury and upregulated pSTAT5 and SOCS1 expression in alveolar macrophages in a miR181-dependent manner. Overexpression of miR-181a in MSCs significantly enhanced therapeutic efficacy of EVs in this model.ConclusionmiR-181a-PTEN-pSTAT5-SOCS1 axis is a novel pathway responsible for immunomodulatory effect of MSC EVs in ARDS.

Photothermal catalytic Fischer–Tropsch synthesis (FTS) enhances the catalytic efficiency of thermal-driven FTS reaction using a mild strategy, which is in line with the future trends in the chemical industry. However, constructing catalytic systems with high C5+product selectivity is a challenge for photothermal FTS, since the hydrocracking reaction involving photogenerated electrons would decrease the long carbon chain product selectivity. In this work, the C5+product selectivity of FTS was significantly improved from 65% to 93% under photothermal conditions by using heteropoly acid (H3PW12O40) as a catalyst promotor. Further characterization revealed that the enhancement mechanism of the C5+product selectivity was that the as-designed Co/T-PW catalyst inhibited the hydrocracking reaction involving photoelectrons, promoted carbon chain growth, and directly participated in the cracking of C20+products. This work provided a simple and efficient strategy to improve the C5+product selectivity of photothermal FTS, making the photothermal FTS reaction more attractive.

Objective: This study assessed the necessity of surgical re-staging in women with borderline ovarian tumors (BOTs) and evaluated the impact of complete surgical staging, lymphadenectomy, and omentectomy on disease recurrence and survival. Methods: We retrospectively reviewed the medical records of patients with BOTs. A total of 901 patients were eligible for inclusion in the study, and we evaluated some of the variables and clinical/surgical characteristics of the cases. The effects of the type of surgical procedure, surgical staging, and complete or incomplete staging on recurrence were calculated. The rates of disease-free survival, overall survival, and recurrence were compared according to complete surgical staging. A Cox regression analysis was performed to identify potential prognostic factors, and survival curves were constructed using the Kaplan-Meier method. Results: The overall recurrence rate was 13.9%, and recurrence was comparable between the complete surgical staging group and the incomplete groups (P>0.05). The performance of complete surgical staging did not show an effect on long-term survival, and complete surgical staging, omentectomy, and lymphadenectomy had no effect on recurrence. In multivariate analyses, only radical surgery and adjuvant chemotherapy were risk factors for the recurrence of BOTs. Furthermore, we found that omentectomy led to a relatively low recurrence rate in patients with International Federation of Gynecology and Obstetrics (FIGO) stage > I (P=0.022). Conclusion: Our results suggest that complete surgical staging should be considered a standard treatment for patients with advanced stage BOTs but not for those at FIGO stage I. It might be safe to reduce the scope of surgical procedures in patients with early-stage BOTs. However, it is not necessary to perform re-staging operations for BOTs with a macroscopically normal extra-ovarian appearance.

Telitacicept, an injectable recombinant human B‐lymphocyte stimulating factor receptor‐antibody fusion protein, is a new dual B lymphocyte stimulator (BLyS)/APRIL (a proliferation‐inducing ligand) inhibitor that effectively blocks proliferation of B lymphocytes. This study evaluates the pharmacokinetic characteristics, tolerability, and safety of a single subcutaneous injection of various doses (80, 160, and 240 mg) of telitacicept in healthy Chinese subjects. This trial is a single‐center, randomized, open‐label phase I clinical study that includes three dose groups (80, 160, and 240 mg) with 12 subjects in each dose group. The subjects were randomly assigned to different dose groups in a 1:1:1 ratio for a single subcutaneous administration trial. After a single dose, the maximum serum concentration (Cmax) of total and free telitacicept was reached within 0.5‐1 days. The elimination half‐lives of total and free telitacicept at doses of 80–240 mg were 10.9–11.9 days and 11–12.5 days, respectively. The formation and elimination of the BLyS‐telitacicept complex were much slower; the median time to Cmaxwas 15–57 days and was significantly prolonged with increasing dose. Only two of the 36 healthy subjects had positive antidrug antibodies with antibody titers of 1:15. The severity of adverse events was mild or moderate, and no higher treatment‐emergent adverse events were reported. In conclusion, total telitacicept within a dose range of 80–240 mg and free telitacicept within a dose range of 160–240 mg had linear pharmacokinetic characteristics.

Nanocrystalline and monomodal pore size mesoporous transition metal oxides have attracted considerable attention because of their interconnected networks and high surface areas. These materials have demonstrated improved characteristics such as electron transport, dye loading, electrolyte permeation, and oxidative capabilities when compared to those of typical nanostructured catalysts when used for different catalytic applications. Of particular interest are ferrites that have demonstrated roles in biomedical and magnetic devices, rechargeable batteries, sensors, catalysis, and water treatment. In addition, microwave hydrothermal synthesis is an attractive method due to its simplicity, rapid synthesis rate, and ease of operation. This paper details the synthesis of mesoporous first-row transition metal ferrites. M2+(Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+) ferrite synthesis was systematically studied using a Biotage Initiator microwave apparatus, and the effects of reaction time and initial M2+concentration on the crystal structure, morphology, composition, and magnetic and catalytic activities were evaluated. Various characterization techniques were utilized to study the synthesis mechanism and characteristics of the materials. These materials were then applied to the electrochemical oxygen evolution reaction, where NiFe2O4showed high activity vs other ferrites with a low overpotential of 278 mV at 10 mA/cm2.

Transportation is a necessary aspect of the aquaculture industry that might induce inevitable stress and compromise product quality. In the present study, the transcriptomic profiles in the brain and liver of Chinese sea bass (Lateolabrax maculatus) were characterized after transportation stress at two different densities (low-density: 20 kg/m3and high-density: 40 kg/m3). Transcriptome analysis revealed that 485 and 627 differentially expressed genes (DEGs) were determined in the brain and liver from sea bass after transportation stress, respectively. KEGG enrichment analysis demonstrated that the DEGs were significantly enriched in focal adhesion, PI3K-Akt, MAPK signaling pathway, apoptosis, and circadian rhythm under transportation stress. Protein-Protein Interaction (PPI) networks showed that COL1A1, COL1A2, COL5A2, COL10A1, and COL16A1 associated with protein digestion and absorption, together with LUM, SERPINH1, and ADAMTS2 were recognized as hub genes in the brain, while JUN, NFKB1, MAPK14, MAP3K7, HSPA1, HSP90AA1, PIK3CA and PIK3R1 tightly related to MAPK and PI3K-Akt signaling pathway and SMAD3 and PPARGC1A were considered as hub genes in the liver. These results indicated that the alterations in transcripts of sea bass are primarily involved in cell adhesion, signal transduction, immune response, and metabolic regulation in response to transportation stress. Our study provides new perspectives into the molecular mechanism underlying responses to transportation and theoretical support for optimizing transportation in the Chinese sea bass.

Background: Sarcopenia (SP) is an aging-related loss of muscle mass and function, affecting the respiratory system. However, the causality of the association between sarcopenia on lung diseases remains elusive. Methods: The bidirectional univariate Mendelian randomization (UVMR), multivariate MR (MVMR) analysis, and mediation MR were utilized to systematically investigate the genetic causal relationship of SP and 11 respiratory diseases. Independent genomic variants related to sarcopenia or respiratory diseases were identified as instrumental variables (IVs), and the summary level data of genome-wide associated studies (GWAS) were obtained from the UK biobank and FinnGen. MVMR analysis was conducted to explore the mediation effects of body mass index (BMI), Alcohol Use Disorders Identification Test (AUDIT), smoking, education attainment (EA), physical activity, and Type 2 Diabetes Mellitus (T2DM). Results: Forward UVMR analysis based on the primary method revealed that pneumoconiosis was associated with a higher risk of appendicular lean mass (ALM) (OR = 1.01, p= 0.03), and BMI (10.65%), smoking (10.65%), and physical activity (17.70%) had a mediating role in the effect of pneumoconiosis on ALM. In reverse MR analysis, we found that genetically predicted ALM was significantly associated with an increased risk of pulmonary embolism (PE) (OR = 1.24, p= 7.21E-05). Chronic obstructive pulmonary disease (COPD) (OR = 0.98, p= 0.002) and sarcoidosis (OR = 1.01, p= 0.004) were identified to increase the loss of left-hand grip strength (HGS). Conversely, the increase in left- HGS presented a protective effect on chronic bronchitis (CB) (OR = 0.35, p= 0.03), (OR = 0.80, p= 0.02), and asthma (OR = 0.78, p= 0.04). Similarly, the loss of the right-HGS elevated the risk of low respiratory tract infection (LRTI) (OR = 0.97, p= 0.02) and bronchiectasis (OR = 1.01, p= 0.03), which is also an independent protective factor for LRTI and asthma. In the aspects of low HGS, the risk of LRTI was increased after MVMR analysis, and the risk of sarcoidosis and pneumoconiosis was elevated in the reverse analysis. Lastly, asthma was found to be related to the loss of the usual walking pace, and the reverse MR analysis suggested a causal relationship between the usual walking pace and LRTI (OR = 0.32, p= 2.79 × 10−5), asthma (OR = 0.24, p= 2.09 × 10−6), COPD (OR = 0.22, p= 6.64 × 10−4), and PE(OR = 0.35, p= 0.03). Conclusions: This data-driven MR analysis revealed SP was bidirectional causally associated with lung diseases, providing genetic evidence for further mechanistic and clinical studies to understand the crosstalk between SP and lung diseases.

Light‐assisted thermocatalytic Fischer–Tropsch synthesis (FTS) provides a more efficient and sustainable approach to synthesizing high‐value chemicals compared to the thermal‐driven FTS. However, producing liquid fuel via cobalt‐based light‐assisted thermocatalytic FTS catalyst poses a challenge since photogenerated electrons increase CO conversion simultaneously with a significant reduction in the selectivity of C5+product. Herein, a cobalt‐based light‐assisted thermocatalytic FTS catalyst containing ZSM‐5 molecular sieve promoter is prepared by a unique wet chemical reduction method, and the constructed 15%Co/Ta3N5‐ZSM‐5 catalyst exhibits nearly 90% C5+product selectivity and 63% CO conversion under photothermal condition. Further characterization indicates that the simultaneous increase in the number of active sites and the density of acidic sites in the catalyst is crucial to achieve a simultaneous increase in CO conversion and C5+product selectivity, which enables the catalyst to produce liquid fuel via light‐assisted thermocatalytic FTS reaction. This work provides an approach to introduce solar energy into the process of liquid fuel production, which can improve the sustainability of the liquid fuel production process. The 15%Co/Ta3N5‐ZSM‐5 catalyst can significantly enhance the C5+product selectivity while simultaneously increasing the CO conversion by simultaneously increasing the number of active sites and the density of acidic sites in the catalyst. This allows Co‐based light‐assisted thermocatalytic Fischer–Tropsch synthesis catalyst to have more practical potential in liquid fuel production.

Argillaceous dolomite and mudstone are two terrestrial source rocks that commonly occur together, and the difference in hydrocarbon generation characteristics determines the oil accumulation mode. The fourth member of the Shahejie Formation (Es4) in the Leijia area was used as an example to study the hydrocarbon generation characteristics and the overpressure difference caused by oil generation between argillaceous dolomite and mudstone, using hydrocarbon generation kinetics. Furthermore, the source of oil in the argillaceous dolomite reservoir was analyzed by combining the biomarker characteristics. The results indicated that the hydrocarbon generation characteristics of argillaceous dolomite and mudstone are significantly different. Mudstone starts hydrocarbon generation later and has a shorter hydrocarbon generation cycle, while argillaceous dolomite starts hydrocarbon generation earlier and has a longer hydrocarbon generation period. Due to the difference in hydrocarbon generation characteristics, when the burial depth is below 3000 m (EasyRo <0.85%), the oil-generation overpressure in the mudstone is smaller than that in argillaceous dolomite, and the tight oil in the argillaceous dolomite reservoir is mainly generated by and stored in the argillaceous dolomite itself. However, when the burial depth exceeds 3000 m (EasyRo >0.85%), the oil-generation overpressure in the mudstone surpasses that in argillaceous dolomite, and the tight oil has mixed source characteristics. The biomarker characteristics observed in extracts and crude oil confirm the above view. Whether tight oil exploration in argillaceous dolomite reservoir requires attention to the hydrocarbon supply capacity of adjacent mudstone depends on the maturity of organic matter.

Understanding the spatio-temporal variations of temperature and precipitation in the arid and semiarid region of China (ASRC) is of great significance for promoting regional eco-environmental protection and policy-making. In this study, the annual and seasonal spatio-temporal patterns of change in average temperature and precipitation and their influencing factors in the ASRC were analyzed using the Mann-Kendall test, linear tendency estimation, accumulative anomaly and the Pearson’s correlation coefficient. The results showed that both annual average temperature and average annual precipitation increased in the ASRC during 1951–2019. The temperature rose by about 1.93°C and precipitation increased by about 24 mm. The seasonal average temperature presented a significant increase trend, and the seasonal precipitation was conspicuous ascension in spring and winter. The spatio-temporal patterns of change in temperature and precipitation differed, with the southwest area showing the most obvious variation in each season. Abrupt changes in annual and seasonal average temperature and precipitation occurred mainly around the 1990s and after 2000, respectively. Atmospheric circulation had an important effect on the trends and abrupt changes in temperature and precipitation. The East Asian summer monsoon had the largest impact on the trend of average annual temperature, as well as on the abrupt changes of annual average temperature and precipitation. Temperature and precipitation changes in the ASRC were influenced by long-term and short-term as well as direct and indirect anthropogenic and natural factors. This study identifies the characteristics of spatio-temporal variations in temperature and precipitation in the ASRC and provides a scientific reference for the formulation of climate change responses.

The electronic structures, phonon dispersions, and electron–phonon coupling of Nb2CT2(T = O, S, Se, or Te) MXenes were investigated via first-principles calculations. Different models of Nb2CT2were constructed, and the results show that the low-energy models of Nb2CT2are intrinsic phonon-mediated superconductors. Of the four Nb2CT2MXenes, Nb2CO2MXene exhibits the largest superconducting critical temperature (Tc) of 14.43 K. The existence of soft modes induced by Kohn anomalies and the contribution of Nb atoms to the Fermi level lead to strong electron–phonon coupling (λ = 0.92) in Nb2CO2MXene. The Tcof Nb2CO2is further enhanced by biaxial tensile strain and reaches up to 18.28 K under 4% tensile strain. The predicted Tcof Nb2CS2is 4.5 K, which is comparable with experimental data. These findings will further stimulate the search for superconducting MXenes.

Nicotine salts, formed by nicotine and organic acids, are commonly added to electronic cigarette liquids for their ability to provide desirable sensory effects. Analytical strategies have been developed to detect the types of organic acids and nicotine levels, but methods for directly measuring nicotine salts are still desirable. Herein, a novel approach is presented for the simultaneous quantification of non-volatile and volatile nicotine salts vialiquid chromatography/tandem mass spectroscopy (LC-MS/MS) and gas chromatography/mass spectroscopy (GC-MS). This approach was validated with recovery experiments, which yielded recovery values between 92.0% and 110.8%. This method is the first technique for quantifying multiple nicotine salts that could be present in commercial e-liquids. Without using derivatization steps, different nicotine salts could be detected rapidly and conveniently. This new method was demonstrated with 10 e-cigarette liquid samples, providing satisfactory outcomes. It could be used to study organic acids and protonated nicotine in e-liquids and the release behaviour of nicotine salts in electronic cigarettes.

As a taxoid agent, docetaxel (DTX) exhibits potent antitumor activity. However, severe toxic side effects and acquired multidrug resistance represent its clinical challenges. Herein, a novel docetaxel derivative (DTX-AI) is synthesized viathe nucleophilic addition reaction of 4-acetylphenyl carbamate at the C10 position of the DTX framework. DTX-AI exhibits superior cytotoxicity and a higher apoptotic ratio in vitroagainst DTX-sensitive tumor cells (MCF-7, HeLa and A549 cells) and even DTX-resistant ones (HeLa/PTX cells), but displays less toxicity against normal cells (MRC-5 and L929 cells) compared with DTX. DTX-AI can effectively suppress the growth of HeLa-tumor xenografts in vivoand even induce complete tumor regression. Furthermore, DTX-AI shows sustained effects on the inhibition of A549-tumor xenograft growth and no obvious recurrence, even after the drug administration was stopped for 30 d. More importantly, DTX-AI has significantly reduced long-term and short-term animal toxicity and extended the survival of mice (100%) compared with DTX (0%). DTX-AI is expected to be a promising ‘me-better’ anti-tumor drug with higher efficiency and lower toxicity for improved chemotherapy in the clinic.

ABSTRACTHepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and chemoprevention represents a feasible treatment to reduce the mortality of this carcinoma. Mulberry fruit polysaccharides (MFP) possess immunoregulatory and anti-inflammatory effects, which have been reported to alleviate liver damage evoked by CCl4 or alcohol in previous reports. However, its chemopreventive effect against liver carcinogenesis is insufficient. The present study was aimed to investigate the possible role of MFP as a pro-apoptosis, and anti-inflammatory agent to possess its chemoprevention property. Hepatocarcinogenesis was induced by diethylnitrosamine/phenobarbital (DEN/PB) for 14 weeks. The DEN/PB-administered rats were co-treated with different doses of MFP (50 or 100 mg/kg body weight) by oral gavage for 14 weeks. Basic hepatic function indexes (AST, ALT, ALP, GGT, total bilirubin, and albumin), and hepatic tumor biomarkers (AFP, CEA, and CA19.9), together with histological assessment were performed. Besides, the hepatic apoptosis markers (Bcl-2, Bax, caspase3, and caspase9), inflammation markers (IL-1β, TNF-α, and NF-κB), and mutT homologue gene 1 (MTH1) were examined. Oral gavage of MFP inhibited the elevations of hepatic function indexes and hepatic tumor biomarkers and alleviated pathological changes in hepatic tissue. In addition, the hepatic apoptosis markers, inflammation markers, and the mRNA level of MTH1 were abnormal in DEN/PB group, which were reversed by MFP treatment. In conclusion, MFP is an effective agent that provides chemoprevention against DEN/PB-evoked hepatocarcinogenesis via inhibition of inflammation and induction of apoptosis.

ABSTRACTPurposeTo compare the pharmacokinetics, pharmacodynamics and safety of the new prolonged-release leuprorelin acetate microspheres for injection (3.75 mg) with the reference product Enantone® (3.75 mg).Method48 healthy male volunteers were enrolled and randomly received a single 3.75 mg dose of the test drug or Enantone®.ResultsThere were no significant differences in Cmax, AUC0-tand AUC0-48between the test group and reference group (P > 0.05). The 90% confidence intervals of the two groups were 87.49%~112.74%, 97.15%~154.25%, and 80.85%~109.01%, respectively. Twenty-eight days after administration, both groups reached 100.0% castration level; there was no difference in the time from administration to reaching castration level between the two groups (P > 0.05); However, the difference between the two groups in the duration of castration level was statistically significant (P < 0.05). There were no major or serious adverse events, and the severity was mild to moderate.ConclusionThe pharmacokinetic characteristics of leuprorelin in two groups were consistent. The two groups exhibited similar inhibitory effects on testosterone and more subjects in the test group maintained a longer castration time than those in the reference group.

As the gold standard for stealth polymer materials, poly(ethylene glycol) (PEG) has been widely used in drug delivery with excellent properties such as low toxicity, reduced immunogenicity, good water solubility, and so forth. However, lack of understanding for the fate of PEG and PEGylated delivery systems at the cellular level has limited the application of PEGylated molecules in diagnosis and therapy. Here, we chose linear PEG 5k as a representative model and focused on the internalization behavior and mechanism, intracellular trafficking, sub-cellular localization, and cellular exocytosis of PEG and PEGylated molecules in living cells. Our investigation showed that PEG could be internalized into cells in 1 h. The internalized PEG was localized to lysosome, cytosol, endoplasmic reticulum (ER) and mitochondria. Importantly, the fate of PEG in cells could be regulated by conjugating different small molecules. PEGylated rhodamine B (PEG-RB) as the positively charged macromolecule was internalized into cells by micropinocytosis and then transported in lysosomes, ER, and mitochondria via vesicles sequentially. In contrast, PEGylated pyropheophorbide-a (PEG-PPa) as the negatively charged macromolecule was internalized into cells and transported to lysosomes ultimately. PEGylation slowed down the exocytosis process of RB and PPa and significantly prolonged their residence time inside the cells. These findings improve the understanding of how PEG and PEGylated molecules interact with the biological system at cellular and sub-cellular levels, which is of significance to rational PEGylation design for drug delivery.

Accumulating evidences have suggested that extracellular vesicles (EVs) are crucial players in the pathogenesis of ischemic brain injury. This study was designed to explore the specific functions of M2 phenotype microglia-derived EVs in ischemic brain injury progression. The expression of microRNA-135a-5p (miR-135a-5p) in M2 microglia-derived EVs was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), followed by the identification of expression relationship among miR-135a-5p, thioredoxin-interacting protein (TXNIP), and nod-like receptor protein 3 (NLRP3) by dual luciferase reporter gene assay. After construction of an oxygen-glucose deprivation/reperfusion (OGD/R) cell model, the effects of miR-135a-5p on the biological characteristics of HT-22 cells were assessed by cell counting kit 8 (CCK-8) assay and flow cytometry. Finally, a mouse model of transient middle cerebral artery occlusion (tMCAO) was established and cerebral infarction volume was determined by triphenyltetrazolium chloride (TTC) staining and the expression of IL-18 and IL-1β in the brain tissue was determined by enzyme-linked immunosorbent assay (ELISA). We found that M2 microglia-derived EVs had high expression of miR-135a-5p, and that miR-135a-5p in M2 microglia-derived EVs negatively regulated the expression of NLRP3 via TXNIP. Overexpression of miR-135a-5p promoted the proliferation but inhibited the apoptosis of neuronal cells, and inhibited the expression of autophagy-related proteins. M2 microglia-derived EVs delivered miR-135a-5p into neuronal cells to inhibit TXNIP expression, which further inhibited the activation of NLRP3 inflammasome, thereby reducing neuronal autophagy and ischemic brain injury. Hence, M2 microglia-derived EVs are novel therapeutic targets for ischemic brain injury treatment.