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Abstract In patients with abdominal or pelvic tumors, radiotherapy can result in radiation-induced intestinal injury (RIII), a potentially severe complication for which there are few effective therapeutic options. Sitagliptin (SI) is an oral hypoglycemic drug that exhibits antiapoptotic, antioxidant, and anti-inflammatory activity, but how it influences RIII-associated outcomes has yet to be established. In this study, a pH-responsive metal-organic framework-based nanoparticle platform was developed for the delivery of SI (SI@ZIF-8@MS NP). These NPs incorporated mPEG-b-PLLA (MS) as an agent capable of resisting the effects of gastric acid, and are capable of releasing Zn2+ ions. MS was able to effectively shield these SI@ZIF-8 NPs from rapid degradation when exposed to an acidic environment, enabling the subsequent release of SI and Zn2+ within the intestinal fluid. Notably, SI@ZIF-8@MS treatment was able to mitigate radiation-induced intestinal dysbiosis in these mice. restored radiation-induced changes in bacterial composition. In summary, these data demonstrate the ability of SI@ZIF-8@MS to protect against WAI-induced intestinal damage in mice, suggesting that these NPs represent a multimodal targeted therapy that can effectively be used in the prevention or treatment of RIII.

Background: It is well known that cognitive function is associated with gender differences. However, the effect of sex differences on the relationship between lipids fractions and cognitive function in older adults has been contentious. Methods: 2,170 participants from the U.S. National Health and Nutrition Examination Surveys (1999-2002 and 2011-2014) were included. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST). Multiple linear regression models and restricted cubic spline curve fitting were used. Results: Overall, low HDL-C levels were negatively associated with DSST scores in every group. The levels of TC, TG, and LDL-C were not significantly associated with DSST scores, not only in the total population but also in the males. In the females, after adjustment for potential confounding factors, high TC levels were negatively related to DSST scores (OR = −3.590, 95% CI: – 6.343 to – 0.837), and high TG levels were found positively associated with DSST scores (OR = 2.323, 95% CI: 0.159–4.488). Conclusion: Low plasma HDL is associated with cognitive dysfunction in older adults. In older women, high TC levels are positively associated with cognitive decline while high TG levels may protect cognitive function.

Abstract Exosomes are nanoscale vesicles of cellular origin. One of the main characteristics of exosomes is their ability to carry a wide range of biomolecules from their parental cells, which are important mediators of intercellular communication and play an important role in physiological and pathological processes. Exosomes have the advantages of biocompatibility, low immunogenicity, and wide biodistribution. As researchers’ understanding of exosomes has increased, various strategies have been proposed for their use in diagnosing and treating diseases. Here, we provide an overview of the biogenesis and composition of exosomes, describe the relationship between exosomes and disease progression, and focus on the use of exosomes as biomarkers for early screening, disease monitoring, and guiding therapy in refractory diseases such as tumors and neurodegenerative diseases. We also summarize the current applications of exosomes, especially engineered exosomes, for efficient drug delivery, targeted therapies, gene therapies, and immune vaccines. Finally, the current challenges and potential research directions for the clinical application of exosomes are also discussed. In conclusion, exosomes, as an emerging molecule that can be used in the diagnosis and treatment of diseases, combined with multidisciplinary innovative solutions, will play an important role in clinical applications.

Reduction of endogenous hydrogen sulfide (H2S) is considered to have an important impact on the progress of Parkinson's disease (PD), thus exogenous H2S supplementation is expected to become one of the key means to treat PD. However, at present, it is difficult for H2S donors to effectively penetrate the blood brain barrier (BBB), selectively release H2S in brain, and effectively target the mitochondria of neuron cells. Herein, we report a kind of nanomotor-based H2S donor, which is obtained by free radical polymerization reaction between l-cysteine derivative modified-polyethylene glycol (PEG-Cys) and 2-methacryloyloxyethyl phosphorylcholine (MPC). This kind of H2S donor can not only effectively break through BBB, but also be specifically catalyzed by cystathionine β-synthase (CBS) in neurons of PD site in brain and 3-mercaptopyruvate sulfurtransferase (3-MST) in mitochondria to produce H2S, endowing it with chemotaxis/motion ability. Moreover, the unique chemotaxis effect of nanomotor can realize the purpose of precisely targeting brain and the mitochondria of damaged neuron cytopathic diseases. This kind of nanomotor-based H2S donor is expected to enrich the current types of H2S donors and provide new ideas for the treatment of PD.

Transparent wood is a promising material with many advantages, including high optical transmittance, adjustable optical haze, and excellent mechanical properties. However, the manufacture of transparent wood always requires polymer filling, which affects its sustainability; the flammability of transparent wood also limits its development and application in more fields. Herein, a flame retardant transparent wood film (FR-TWF) was prepared by a top-down chemical treatment. Delignification and TEMPO-mediated oxidation can effectively remove lignin from natural wood and introduce carboxyl groups into the cellulose for further chelation with Al ions. Then, FR-TWF was obtained through self-densification by forming fully collapsed wood cell walls and elastic lumen after drying. The obtained FR-TWF had high optical transmittance (∼76.1%) and haze (∼75.2%); its tensile strength reached 354.3 MPa, exceeding most existing plastic films. Compared with natural wood, the peak of heat release rate and total heat release of FR-TWF decreased by 91.4% and 77.1%, respectively. The excellent flame retardant property of FR-TWF is attributed to the generation of graphitized carbon layers during combustion and the release of more water vapor at high temperatures. Furthermore, the FR-TWF merits being price moderate, sustainable, and biodegradable, which can be widely used in flexible device substrates or optical management devices.

ObjectHospital sewage have been associated with incorporation of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) into microbes, which is considered as a key indicator for the spread of antimicrobial resistance (AMR). The compositions of dental waste water (DWW) contain heavy metals, the evolution of AMR and its effects on the water environment in the context of heavy metal environment have not been seriously investigated. Thus, our major aims were to elucidate the evolution of AMR in DWW.MethodsDWW samples were collected from a major dental department. The presence of microbial communities, ARGs, and MGEs in untreated and treated (by filter membrane and ozone) samples were analyzed using metagenomics and bioinformatic methods.ResultsDWW-associated resistomes included 1,208 types of ARGs, belonging to 29 antibiotic types/subtypes. The most abundant types/subtypes were ARGs of multidrug resistance and of antibiotics that were frequently used in the clinical practice. Pseudomonas putida, Pseudomonas aeruginosa, Chryseobacterium indologenes, Sphingomonas laterariae were the main bacteria which hosted these ARGs. Mobilomes in DWW consisted of 93 MGE subtypes which belonged to 8 MGE types. Transposases were the most frequently detected MGEs which formed networks of communications. For example, ISCrsp1 and tnpA.5/4/11 were the main transposases located in the central hubs of a network. These significant associations between ARGs and MGEs revealed the strong potential of ARGs transmission towards development of antimicrobial-resistant (AMR) bacteria. On the other hand, treatment of DWW using membranes and ozone was only effective in removing minor species of bacteria and types of ARGs and MGEs.ConclusionDWW contained abundant ARGs, and MGEs, which contributed to the occurrence and spread of AMR bacteria. Consequently, DWW would seriously increase environmental health concerns which may be different but have been well-documented from hospital waste waters.

Brain-wide axonal projections of single neurons have been extensively reconstructed without any functional characterization. The authors present a method that allows for developing a precise one-to-one map of both projection patterns and functional features of single neurons in mice.

Abstract A filtering algorithm based on frequency domain spline type, frequency domain spline adaptive filters (FDSAF), effectively reducing the computational complexity of the filter. However, the FDSAF algorithm is unable to suppress non-Gaussian impulsive noises. To suppression non-Gaussian impulsive noises along with having comparable operation time, a maximum correntropy criterion (MCC) based frequency domain spline adaptive filter called frequency domain maximum correntropy criterion spline adaptive filter (FDSAF-MCC) is developed in this paper. Further, the bound on learning rate for convergence of the proposed algorithm is also studied. And through experimental simulations verify the effectiveness of the proposed algorithm in suppressing non-Gaussian impulsive noises. Compared with the existing frequency domain spline adaptive filter, the proposed algorithm has better performance.

Objective Sepsis is a systemic and deleterious host reaction to severe infection. Cardiac dysfunction is an established serious outcome of multiorgan failure associated with this condition. Therefore, it is important to develop drugs targeting sepsis-induced cardiac damage and inflammation. Thymoquinone (TQ) has anti-inflammatory, anti-oxidant, anti-fibrotic, anti-tumor, and anti-apoptotic effects. This study examined the effects of thymoquinone on sepsis-induced cardiac damage. Methods Male BALB/c mice were randomly segregated into four groups: control, TQ, cecal ligation and puncture (CLP), and CLP + TQ groups. CLP was performed after gavaging the mice with TQ for 2 weeks. After 48 hours, we estimated the histopathological changes in the cardiac tissue and the serum levels of cardiac troponin-T. We evaluated the expression of factors associated with inflammation, apoptosis, oxidative stress, and the PI3K/AKT pathway. Results TQ significantly reduced intestinal histological alterations and inhibited the upregulation of interleukin-6, tumor necrosis factor-α, Bax, NOX4, p-PI3K, and p-AKT. TQ also increased Bcl-2, HO-1, and NRF2 expression. Conclusion These results suggest that TQ effectively modulates pro-inflammatory, apoptotic, oxidative stress, and PI3K/AKT pathways, making it indispensable in the treatment of sepsis-induced cardiac damage.

Link prediction is one of the most important and challenging tasks in complex network analysis, which aims to predict the existence of unknown links based on the known information in the network. As critical topological properties in the network, node’s degree and clustering coefficient are well-suited for describing the tightness of connection between nodes. The importance of node can affect the possibility of link existence to a certain extent. By analyzing the impact of different centrality on links, which concluded that the degree centrality and proximity centrality have the greatest influence on network link prediction. A link prediction algorithm combines importance of node and network topological properties, called DCCLP, is proposed in this paper, the symmetry of the adjacency matrix is considered in the DCCLP link prediction algorithm to further describe the structural similarity of network nodes. In the training phase of the DCCLP algorithm, the maximized AUC indicator in the training set as the objective, and the optimal parameters are estimated by utilizing the White Shark Optimization algorithm. Then the prediction accuracy of the DCCLP algorithm is evaluated in the test set. By experimenting on twenty-one networks with different scales, and comparing with existing algorithms, the experimental results show that the effectiveness and feasibility of DCCLP algorithm, and further illustrate the importance of the degree centrality of node pairs and proximity centrality of nodes to improve the prediction accuracy of link prediction.

An interactive artificial ecological optimization algorithm (SIAEO) based on environmental stimulus and a competition mechanism was devised to find the solution to a complex calculation, which can often become bogged down in local optimum because of the sequential execution of consumption and decomposition stages in the artificial ecological optimization algorithm. Firstly, the environmental stimulus defined by population diversity makes the population interactively execute the consumption operator and decomposition operator to abate the inhomogeneity of the algorithm. Secondly, the three different types of predation modes in the consumption stage were regarded as three different tasks, and the task execution mode was determined by the maximum cumulative success rate of each individual task execution. Furthermore, the biological competition operator is recommended to modify the regeneration strategy so that the SIAEO algorithm can provide consideration to the exploitation in the exploration stage, break the equal probability execution mode of the AEO, and promote the competition among operators. Finally, the stochastic mean suppression alternation exploitation problem is introduced in the later exploitation process of the algorithm, which can tremendously heighten the SIAEO algorithm to run away the local optimum. A comparison between SIAEO and other improved algorithms is performed on the CEC2017 and CEC2019 test set.

Sorafenib, lenvatinib and regorafenib, the multi-RTK inhibitors with potent anti-angiogenesis effects, are currently therapeutic drugs generally recommended for the patients with advanced hepatocellular carcinoma (HCC). To date, however, there have been no published studies on the mechanism underling differential effects of the three drugs on HCC cell proliferation, and the proteomic analysis in HCC cell lines treated by regorafenib or lenvatinib. The present study for the first time performed a direct comparison of the cell cycle arrest and apoptosis induction in the Huh-7 cells caused by sorafenib, regorafenib and lenvatinib at respective IC50 using flow cytometry technique, as well as their pharmacological interventions for influencing whole cell proteomics using tandem mass tag-based peptide-labeling coupled with the nLC-HRMS technique. Sorafenib, regorafenib and lenvatinib at respective IC50 drove the remaining surviving Huh-7 cells into a G0/G1 arrest, but lenvatinib and regorafenib were much more effective than sorafenib. Lenvatinib produced a much stronger induction of Huh-7 cells into early apoptosis than sorafenib and regorafenib, while necrotic cell proportion induced by regorafenib was 2.4 times as large as that by lenvatinib. The proteomic study revealed 419 proteins downregulated commonly by the three drugs at respective IC50. KEGG pathway analysis of the downregulated proteins indicated the ranking of top six signaling pathways including the spliceosome, DNA replication, cell cycle, mRNA surveillance, P53 and nucleotide excision repair involved in 33 proteins, all of which were directly related to their pharmacological effects on cell cycle and cell apoptosis. Notably, lenvatinib and regorafenib downregulated the proteins of PCNA, Cyclin B1, BCL-xL, TSP1, BUD31, SF3A1 and Mad2 much more strongly than sorafenib. Moreover, most of the proteins in the P53 signaling pathway were downregulated with lenvatinib and regorafenib by more than 36% at least. In conclusion, lenvatinib and regorafenib have much stronger potency against Huh-7 cell proliferation than sorafenib because of their more potent effects on cell cycle arrest and apoptosis induction. The underling mechanism may be at least due to the 33 downregulated proteins centralizing the signal pathways of cell cycle, p53 and DNA synthesis based on the present proteomics study.

Doxazosin (DOX) is prescribed as a racemic drug for the clinical treatment of benign prostatic hyperplasia and hypertension. Recent studies found that the two enantiomers of DOX exhibit differences in blood concentration and pharmacological effects. However, the stereoselective metabolic characteristics and mechanisms for DOX are not yet clear. Herein, we identified 34 metabolites of DOX in rats based on our comprehensive and effective strategy. The relationship among the metabolites and the most discriminative metabolites between (−)-DOX and (+)-DOX administration was analyzed according to the kinetic parameters using state-of-the-art multivariate statistical methods. To elucidate the enantioselective metabolic profile in vivo and in vitro, we carefully investigated the metabolic characteristics of metabolites after optically pure isomers administration in rat plasma, rat liver microsomes (RLMs) or human liver microsomes (HLMs), and recombinant human cytochrome P450 (CYP) enzymes. As a result, the differences of these metabolites were found based on their exposure and elimination rate, and the metabolic profile of (±)-DOX was more similar to that of (+)-DOX. Though the metabolites identified in RLMs and HLMs were the same, the metabolic profiles of the metabolites from (−)-DOX and (+)-DOX were greatly different. Furthermore, four human CYP enzymes could catalyze DOX to produce metabolites, but their preferences seemed different. For example, CYP3A4 highly specifically and selectively catalyzed the formation of the specific metabolite (M22) from (−)-DOX. In conclusion, we established a comprehensive metabolic system using pure optical isomers from in vivo to in vitro, and the complicated enantioselectivity of the metabolites of DOX was clearly shown. More importantly, the comprehensive metabolic system is also suitable to investigate other chiral drugs.

Emergency response plans are regarded as effective guidance for natural disasters and these plans describe emergency response processes in natural language. More specifically, they are textual process descriptions and describe not only how all departments perform their own response tasks, but also how different departments interact with each other. Analyzing text quality of emergency response plans as a typical evaluation approach is an important concern in emergency responses. Because of the flexibility of natural language, emergency response plans normally contain unwanted ambiguities, and it is difficult to check consistency and completeness. Automatic text quality analysis of emergency response plans written in Chinese from the perspective of process descriptions is proposed in this paper. Firstly, three types of response tasks including message sending tasks, message receiving tasks and regular tasks are extracted through Bi-LSTM-CRF networks (a Conditional Random Fields network is combined with a Bidirectional Long Short-Term Memory network). Then, a series of text quality analysis rules associated with extracted response tasks are created. These rules focus on the progressive relationship of four levels of emergency responses, completeness of response tasks, ambiguity and redundancy of emergency response plans. Finally, real-world data is collected to validate the proposed approach, which consists of four types of emergency response plans of natural disasters including district, municipal, provincial and national emergency response plans. It is demonstrated that the proposed approach can be used to facilitate revisions and improvements of emergency response plans.

Whisker detection is crucial to adapt to the environment for some animals, but how the nervous system processes and integrates whisker information is still an open question. It is well-known that two main parallel pathways through Ventral posteromedial thalamic nucleus (VPM) ascend to the barrel cortex, and classical theory suggests that the cross-talk from trigeminal nucleus interpolaris (Sp5i) to principal nucleus (Pr5) between the main parallel pathways contributes to the multi-whisker integration in barrel columns. Moreover, some studies suggest there are other cross-streams between the parallel pathways. To confirm their existence, in this study we used a dual-viral labeling strategy and high-resolution, large-volume light imaging to get the complete morphology of individual VPM neurons and trace their projections. We found some new thalamocortical projections from the ventral lateral part of VPM (VPMvl) to barrel columns. In addition, the retrograde-viral labeling and imaging results showed there were the large trigeminothalamic projections from Sp5i to the dorsomedial section of VPM (VPMdm). Our results reveal new cross-streams between the parallel pathways through VPM, which may involve the execution of multi-whisker integration in barrel columns.

Due to the acceleration of urbanization in China, the land use and new building construction in mining subsidence areas are increasing. However, a large high-rise building (100 m × 80 m × 100 m) was planned to be built above gob areas in the Xiangcheng Mine subsidence area. According to the analysis of the borehole exploration data, borehole TV observations, and theoretical calculations, there were broken bedrock and developmental fractures in the fracture and caved zones above the gob areas. In addition, the depth affected by the building load is less than 9 m from the top of the fracture zone; thus, the stabilities of the gobs are low. Then, through the theoretical analysis of the space stress, compression settlement of foundation soil, and residual settlement of the gob and coal pillar under loads, combining the similar simulation study on settlement characteristics of foundation soil and gobs, the total settlement of the foundation can be regarded as the vector superposition of the compression settlement and residual settlement; then, the maximum settlement is calculated as 555 mm and the maximum tilt is 14.9 mm/m under the building load, which are greater than the permissible values of 200 mm and 2 mm/m, indicating that the foundation’s stability is inadequate. Therefore, the treatment measures of the deep pile group foundations in the soil layer and grouting reinforcement in the gobs were simultaneously put forward to effectively improve the stability of the building foundations.

Emergency plans can be regarded as the effective guidance of hazard emergency responses, and they include the textual descriptions of emergency response processes in terms of natural language. In this paper, we propose an approach to automatically extract emergency response process models from Chinese emergency plans. First, the emergency plan is represented as a text tree according to its layout markups and sentence-sequential relations. Then, process model elements, including four-level response condition formulas, executive roles, response tasks, and flow relations, are identified by rule-based approaches. Finally, an emergency response process tree is generated from both the text tree and extracted process model elements, and is transformed to an emergency response process that is modeled as business process modeling notation. Extensive experiments on real-world emergency plans demonstrate that the proposed approach is capable of extracting emergency response process models that are highly consistent with both the manually extracted models and the textual plans.

There are more than 14,000 square kilometers of mining subsidence areas in China, most of which have been reclaimed for the construction of new buildings. In the past, few special measures were required for the foundations of small buildings above old gob areas. But a plan was created to construct a large office building 100 m in length, 90 m in width, and 100 m in height, above old gob areas in the Huaibei subsidence area. However, the results of exploration borehole data and borehole TV observation indicated a broken bedrock stratum and developmental fractures above the old gob areas, and thus, the space stabilities of the building foundation were poor. Therefore, grouting reinforcement measure was adopted for the old gob and foundation areas. And the grouting effect was examined using borehole TV observation and the water injection test, where the detection results of boreholes TV observation showed that the filling ratio of the stratum fracture was over 85%, and the stability of the foundation was obviously enhanced. In addition, we monitored the settlement of the foundation continuously for 930 days. The results show that the maximum cumulative subsidence was 15.3 mm and the maximum slope was 0.05 mm/m, which verifies that grouting reinforcement is feasible in terms of the safety of large buildings constructed over old gob areas using bedrock stratum grouting in the Huaibei subsidence area.