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Self-healing coatings mainly include externally assisted self-healing coatings based on the addition of repair agent and intrinsic selfhealing coatings based on reversible bond crosslinking polymers.The intrinsic self-healing coatings have attracted extensive attention due to their multiple repairable properties.In this paper，the self-healing technology based on crosslinking polymers containing reversible covalent bonds such as reversible imine bond，reversible disulfide bond，reversible Diels-Alder reaction and reversible urea bond，as well as the selfhealing mechanism，performance characteristics and difficulties of supramolecular crosslinked polymers based on reversible non-covalent bonds such as hydrogen bond，metal-ligand coordination bond and π - π stacking were discussed in detail.Besides，the application of self-healing technology based on reversible crosslinking polymers in coatings was also discussed.

Abstract Background Chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) has been studied in patients with head and neck cancer. Its impact on patients with oral cavity cancer was not specified. Methods We consecutively reviewed medical files of patients with untreated oral cavity cancer who received neoadjuvant TPF chemotherapy in our department from January 2017 to April 2020. Outcomes included the objective response to TPF chemotherapy, factors associated with the response, and progression and survival in different response groups. Results A total of 167 patients were included, with half of stage IV disease. Complete or partial response was observed in 51 patients. A total of 91 patients had stable disease, and 25 patients had progressive disease. The response was not associated with age, sex, anatomic subsite, and the tumor's T stage. It was related with N stage (p

Abstract Background The importance of multidisciplinary team (MDT) centred on pregnant women with pulmonary hypertension (PH) has been highlighted. However, rare studies have explored its effects on pregnancy outcomes. This study seeks to investigate whether and how the MDT has an effect on the treatment and outcomes of PH pregnant women. Methods A pre- and post-intervention study was conducted based on an interrupted time series design to compare the treatment and outcomes of patients with PH before (pre-MDT) and after (post-MDT) implementation of the MDT. PH was defined as pulmonary artery systolic pressure (sPAP) ≥ 35 mmHg measured by echocardiography or right heart catheterization and sPAP at 35–60 mmHg and over 60 mmHg was defined as mild and severe PH, respectively. All results were analyzed by T-tests, Chi square tests or Fisher exact test and two-sided p value

Abstract Background XRCC4 is a NHEJ factor identified recently that plays a vital role in repairing DNA double-stranded breaks. Studies have reported the associations between abnormal expression of XRCC4 and tumor susceptibility and radiosensitivity, but the potential biological mechanisms by which XRCC4 exerts effects on tumorigenesis are not fully understood. This study aimed to systematically investigate the role of XRCC4 across cancer types. Methods The TIMER, GTEX and Xiantao Academic database were used to interpret the expression of XRCC4. Genomic alterations and protein expression in human organic and tumor tissues were applied in cBioPortal and the Human Protein Atlas databases. Correlations between XRCC4 expression and immune and molecular subtypes were analyzed by using the TISIDB database. Protein–protein interactions, GO and KEGG enrichment were also applied for XRCC4-related genes. The TIMER and the Tumor Immune Single Cell Hub (TISCH) online databases were used to explore the relationship between XRCC4 and tumor immune microenvironment. Drug sensitivity information was acquired from the CellMiner database to analyze the effect of XRCC4 on sensitivity analysis. Results The XRCC4 expression was significantly upregulated in 15 tumor types and downregulated in two tumor types compared with the normal tissues, most of which were validated by the results of Xiantao academic platform. XRCC4 was expressed at intermediate level in malignant cells. The XRCC4 expression was related to the molecular and immune subtypes of human cancers, and the survival outcome of 11 types of cancers, including KIRC, STAD and LIHC. The main type of frequent genetic alteration is amplification. Strong correlations were also found between XRCC4 and immune checkpoint genes in 33 human cancers. Furthermore, the abnormal expression of XRCC4 was related to immune cell infiltration and drug sensitivity. Enrichment analysis showed that XRCC4 was significantly correlated with DNA damage response. Conclusions This comprehensive pan-cancer analysis suggested that XRCC4 may play a vital role in the prognosis and immunotherapy response in cancer patients, and it is a promising therapy target in the future.

Abstract Background The COVID-19 pandemic has disproportionately impacted racial and ethnic minorities in the United States, including Asian Americans, Native Hawaiians and Pacific Islanders (Asian Americans and NH/PIs). However, few studies have highlighted nor disaggregated these disparities by Asian Americans and NH/PIs ethnic subgroups. Methods This retrospective, cross-sectional observational study aimed to assess variation of Asian Americans and NH/PIs COVID-19 testing and outcomes compared to non-Hispanic Whites (NHW). The study utilized data from the electronic health records (EHR) and the COVID-19 Universal Registry for Vital Evaluations (CURVE) from all patients tested for SARS-CoV-2 (n = 556,690) at a large, health system in Northern and Central California between February 20, 2020 and March 31, 2021. Chi-square tests were used for testing differences in the severity of COVID-19 (hospitalization, ICU admission, death) and patient demographic and clinical characteristics across the Asian Americans and NH/PIs subgroups and NHW. Unadjusted and adjusted Odds Ratios (ORs) were estimated for measuring effect of race ethnicity on severity of COVID-19 using multivariable logistic regression. Results Of the entire tested population, 70,564/556,690 (12.7%) tested positive for SARS-CoV-2. SARS-CoV-2 positivity of Asian subgroups varied from 4% in the Chinese and Korean populations, to 11.2%, 13.5%, and 12.5% for Asian Indian, Filipino, and “other Asian” populations respectively. Pacific Islanders had the greatest subgroup test positivity at 20.1%. Among Asian Americans and NH/PIs patients with COVID-19 disease, Vietnamese (OR = 2.06, 95% CI = 1.30–3.25), “Other Asian” (OR = 2.13, 95% CI = 1.79–2.54), Filipino (OR = 1.78, 95% CI = 1.34–2.23), Japanese (OR = 1.78, 95% CI = 1.10–2.88), and Chinese (OR = 1.73, 95% CI = 1.34–2.23) subgroups had almost double the odds of hospitalization compared to NHW. Pacific Islander (OR = 1.58, 95% CI = 1.19–2.10) and mixed race subgroups (OR = 1.55, 95% CI = 1.10–2.20) had more than one and a half times odds of hospitalization compared to NHW. Adjusted odds of ICU admission or death among hospitalized patients by different Asian subgroups varied but were not statistically significant. Conclusions Variation of COVID-19 testing and hospitalization by Asian subgroups was striking in our study. A focus on the Asian Americans and NH/PIs population with disaggregation of subgroups is crucial to understand nuances of health access, utilization, and outcomes among subgroups to create health equity for these underrepresented populations.

Abstract Background Gonadotrophic pituitary adenoma is a major subtype of pituitary adenoma in the sellar region, but it is rarely involved in the hypersecretion of hormones into blood; thus, it is commonly regarded as “non-functioning.” Its tumorigenic mechanisms remain unknown. The aim of this study was to identify human gonadotrophic pituitary adenoma stem cells (hPASCs) and explore the underlying gene expression profiles. In addition, the potential candidate genes involved in the invasive properties of pituitary adenoma were examined. Methods The hPASCs from 14 human gonadotrophic pituitary adenoma clinical samples were cultured and verified via immunohistochemistry. Genetic profiling of hPASCs and the matched tumor cells was performed through RNA-sequencing and subjected to enrichment analysis. By aligning the results with public databases, the candidate genes were screened and examined in invasive and non-invasive gonadotrophic pituitary adenomas using Real-time polymerase chain reaction. Results The hPASCs were successfully isolated and cultured from gonadotrophic pituitary adenoma in vitro, which were identified as positive for generic stem cell markers (Sox2, Oct4, Nestin and CD133) via immunohistochemical staining. The hPASCs could differentiate into the tumor cells expressing follicle-stimulating hormone in the presence of fetal bovine serum in the culture medium. Through RNA-sequencing, 1352 differentially expressed genes were screened and identified significantly enriched in various gene ontologies and important pathways. The expression levels of ANXA2, PMAIP1, SPRY2, C2CD4A, APOD, FGF14 and FKBP10 were significantly upregulated while FNDC5 and MAP3K4 were downregulated in the invasive gonadotrophic pituitary adenomas compared to the non-invasive ones. Conclusion Genetic profiling of hPASCs may explain the tumorigenesis and invasiveness of gonadotrophic pituitary adenoma. ANXA2 may serve as a potential therapeutic target for the treatment of gonadotrophic pituitary adenoma.

The traditional dynamic weapon target assignment model is a combination of multiple static weapon target assignment stages. The assignment of the next stage is carried out after the result of the previous static weapon target assignment is settled. However, between two static weapon target assignment stages, the threat ranking of multiple targets may change with time, and the traditional dynamic weapon target assignment model does not take this time issue into consideration. This paper proposes a “time sampling dynamic weapon assignment model”. This model divides the decision-making stage by setting the time interval of data collection, and it can capture the real-time changes in the target threat degree and make timely decisions. With this model, this study designed a dynamic weapon target assignment method based on the reinforcement learning algorithm. Additionally, according to this method, a comparative experiment with different sampling time divisions was designed, and a better sampling time division method was obtained. Finally, a comparative experiment between the reinforcement learning algorithm and the traditional heuristic algorithm was designed in this study. The simulation results show that, compared with the traditional heuristic algorithm, the proposed assignment model and the reinforcement learning algorithm are better in terms of decision-making timeliness and global considerations.

It is the key research object of electronic warfare to use UAV (Unmanned Aerial Vehicle) clusters to carry out electronic countermeasure tasks. The UAV carries loads such as reconnaissance and interference at the same time, which makes it necessary to simultaneously decide multiple types of actions—namely, compound actions—which poses a challenge to intelligent decision-making algorithms. Considering the problem of action-space dimensional complexity and weak collaboration between decisions in multi-agent scenarios with composite actions, this study proposed a decision algorithm involving a multi-agent reinforcement-learning sequence, which combined joint composite actions into sequential decision, reducing the difficulty of a single decision and enhancing the collaboration between various agents and their individual decisions. Because long decision sequences required better depth modeling and had high variance, a DeLighT module was added to the naïve transformer model to increase the depth and baseline techniques, which were used to reduce the variance in the value estimation. The simulated results verified the effectiveness of the proposed algorithm in the UAV cooperative combat scenario, where each agent had a composite action space and showed better performance than the existing algorithms.

Stromal cells in the tumour microenvironment are reported to regulate cancer stemness via biomechanical signals. Here the authors show that TAZ activated by biomechanical cues enhanced cancer stem cell properties via phase separation with Nanog.

Abstract Layer actions response time is a critical indicator of cloud geographical information services (cloud GIS Services), which is of great significance to resource allocation and schedule optimization. However, since cloud GIS services are highly dynamic, uncertain, and uncontrollable, the response time of layer actions is influenced by spatiotemporal intensity and concurrent access intensity, posing significant challenges in predicting layer action response time.To predict the response time of layer actions more accurately, we analyzed the data association of cloud GIS services. Furthermore, based on the characteristics of long-term stable trends and short-term random fluctuations in layer actions response time series, a wavelet transforms-based ARIMA-XGBoost hybrid method for cloud GIS services is proposed to improve the one-step and multi-step prediction results of layer actions response time.We generate a multivariate time series feature matrix using the historical value of the layer actions response time, the predicted value of the linear component, and the historical value of the non-linear component. There is no need to meet the traditional assumption that the linear and nonlinear components of the time series are additive, which minimizes the model’s time series requirements and enhances its flexibility. The experimental results demonstrate the superiority of our approach over previous models in the prediction of layer actions response time of cloud GIS services.

Head and neck squamous cell carcinoma (HNSC) is one of most common malignancies with high mortality worldwide. Importantly, the molecular heterogeneity of HNSC complicates the clinical diagnosis and treatment, leading to poor overall survival outcomes. To dissect the complex heterogeneity, recent studies have reported multiple molecular subtyping systems. For instance, HNSC can be subdivided to four distinct molecular subtypes: atypical, basal, classical, and mesenchymal, of which the mesenchymal subtype is characterized by upregulated epithelial-mesenchymal transition (EMT) and associated with poorer survival outcomes. Despite a wealth of studies into the complex molecular heterogeneity, the regulatory mechanism specific to this aggressive subtype remain largely unclear. Herein, we developed a network-based bioinformatics framework that integrates lncRNA and mRNA expression profiles to elucidate the subtype-specific regulatory mechanisms. Applying the framework to HNSC, we identified a clinically relevant lncRNA LNCOG as a key master regulator mediating EMT underlying the mesenchymal subtype. Five genes with strong prognostic values, namely ANXA5, ITGA5, CCBE1, P4HA2, and EPHX3, were predicted to be the putative targets of LNCOG and subsequently validated in other independent datasets. By integrative analysis of the miRNA expression profiles, we found that LNCOG may act as a ceRNA to sponge miR-148a-3p thereby upregulating ITGA5 to promote HNSC progression. Furthermore, our drug sensitivity analysis demonstrated that the five putative targets of LNCOG were also predictive of the sensitivities of multiple FDA-approved drugs. In summary, our bioinformatics framework facilitates the dissection of cancer subtype-specific lncRNA regulatory mechanisms, providing potential novel biomarkers for more optimized treatment of HNSC.

Particle impact, a new drilling technology, has been applied in drilling and gas and oil exploitation. Also, it is considerably promising as an assisting rock-breaking method for the excavation of tunnels in extremely hard rocks. In this paper, an experimental study was conducted to investigate the effects of particle impact number, particle strength, and particle impact velocity on the damage and fragmentation characteristics of surface impact crater in extremely hard granite. The three-dimensional morphology, rock fragments, and mineral fragmentation properties in the impact crater were quantitatively analyzed. The results indicate that the maximum depth of the impact crater increases in a parabolic way, while both the volume and surficial area of the impact crater grow linearly with the impact number. Moreover, the impact crater volume first increases and then decreases with the particle impact velocity, with a critical velocity of nearly 82.5 m /s. In addition, the difference in mesoscopic fragmentation mechanism inside and outside the crater center causes the double-peak characteristics of average size of rock fragments. The volume, surficial area and maximum depth of the impact crater increase linearly with the kinetic energy of impacting particles in the double logarithmic coordinate system. The fractal dimension variations of internal crack distribution in main minerals around the impact crater under different impact velocities and numbers were obtained through image processing method. The experimental results manifest that the damage scale of rock crater is enlarged through improving particle velocity and impact number, while particle velocity exerts a more significant effect than impact number does.

A large-span steel–concrete composite beam with precast hollow core slabs (CBHCSs) is a relatively new floor structure that can be applied to various long-span structures. However, human-induced vibrations may present serviceability issues in such structures. To alleviate vibrations, both the walking forces excited by humans and the associated floor responses must be elucidated. In this study, 150 load–time histories of walking, excited by 25 test participants, are obtained using a force measuring plate. The dynamic loading factors and phase angles in the Fourier series functions for one-step walking are determined. Subsequently, walking tests are performed on seven CBHCS specimens to capture the essential dynamic properties of mode shapes, natural frequencies, damping ratios, and acceleration time histories. The CBHCS floor system generally exhibits a high frequency (> 10 Hz) and low damping (damping ratio

High melting point paraffin wax (HPW) is a novel desensitizer that has the potential to achieve low sensitivity of energetic crystals, such as 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX). However, first-principles calculations confirmed that interface deterioration occurred due to a weak interfacial connection. In this work, the polydopamine (PDA)/HPW/PDA with a sandwich-like interfacial structure was prepared using three simple steps to improve safety performance, thermal stability, and mechanical properties. The theoretical and experimental results suggested that the PDA acted as a double-sided tape to adhere to the adjacent HMX/HPW layer or HPW/polymer binder layer, thus substantially enhancing the interfacial interaction. While maintaining higher safety performance (impact energy: 11∼13 ​J) than that of HMX (5 ​J), the new design improved the β-δ polymorphic transition temperature of HMX to 219.4 ​°C for HMX@PDA@HPW@PDA, which was higher than that of HMX@HPW (202.8 ​°C) and core@double-shell HMX@PDA@HPW (208.9 ​°C). Among the modified energetic composites, polymer-bonded explosives (PBXs) based on HMX@PDA@HPW@PDA exhibited the optimum mechanical performance, including the storage modulus and tensile fracture energy, which were 43.5% and 77.1% higher than those of PBXs based on raw HMX, respectively. The achieved favorable systematical enhancement in thermal stability, mechanical properties, and safety performance shows that such a sandwich-like interfacial structure has great potential for application for HMX-based formulation used in complex environments.

Abstract Background Sjogren’s syndrome (SS) is an autoimmune disorder characterized by the destruction of exocrine glands, resulting in dry mouth and eyes. Currently, there is no effective treatment for SS, and the mechanisms associated with inadequate salivary secretion are poorly understood. Methods In this study, we used NOD mice model to monitor changes in mice’s salivary secretion and water consumption. Tissue morphology of the submandibular glands was examined by H&E staining, and Immunohistochemical detected the expression of AQP5 (an essential protein in salivary secretion). Global gene expression profiling was performed on submandibular gland tissue of extracted NOD mice model using RNA-seq. Subsequently, a series of bioinformatics analyses of transcriptome sequencing was performed, including differentially expressed genes (DEGs) identification, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, PPI network construction, hub gene identification, and the validity of diagnostic indicators using the dataset GSE40611. Finally, IFN-γ was used to treat the cells, the submandibular gland tissue of NOD mice model was extracted, and RT-qPCR was applied to verify the expression of hub genes. Results We found that NOD mice model had reduced salivary secretion and increased water consumption. H&E staining suggests acinar destruction and basement membrane changes in glandular tissue. Immunohistochemistry detects a decrease in AQP5 immunostaining within acinar. In transcriptome sequencing, 42 overlapping DEGs were identified, and hub genes (REN, A2M, SNCA, KLK3, TTR, and AZGP1) were identified as initiating targets for insulin signaling. In addition, insulin signaling and cAMP signaling are potential pathways for regulating salivary secretion and constructing a regulatory relationship between target-cAMP signaling-salivary secretion. Conclusion The new potential targets and signal axes for regulating salivary secretion provide a strategy for SS therapy in a clinical setting.

Abstract Lung cancer remains the leading cause of cancer-related deaths for both men and women in the U.S., yet uptake of preventive cancer screening for people with a heavy smoking history remains low. This qualitative interview study of patients and providers from a large ambulatory healthcare system in northern and central California reevaluated perceptions of lung cancer screening with low-dose computed tomography (LCS-LDCT) 5 years after Medicare coverage. We hypothesized that initial attitudes and barriers within the LCS-LDCT discussion and process have likely persisted with little change since Medicare coverage and we sought to understand how these attitudes continue to impact effective implementation and uptake of screening with the goal of identifying opportunities for improvement. Between 2019 and 2020, interviews were conducted with 10 primary care physicians and 30 patients using semi-structured interview guides. Providers and patients expressed that they were both aware and supportive of LCS-LDCT, a change from earlier studies, but continued to report little to no shared decision making nor use of a decision aid despite being Medicare requirements. Creation and incorporation of a single-page, graphic heavy decision aid may help address many of the persistent barriers around implementation for both providers and patients. Given recently expanded guidelines from the U.S. Preventive Services Task Force for LCS-LDCT screening and their coverage by Medicare, it is important for healthcare systems to understand provider and patient perceptions to further improve the implementation of LCS-LDCT to ultimately reduce lung cancer mortality.

Abstract Background It is critical to find optimal forms to identify perinatal depression (PND) and its vulnerable factors and make them more applicable to depression screening. This study aims to evaluate the reliability and validity of the Chinese version of the Leiden Index of Depression Sensitivity (LEIDS-RR-CV) among perinatal women in China and determine the cut-off values for screening for high-risk depression. Methods Women in their third trimester of pregnancy and six weeks postpartum completed the LEIDS-RR-CV and a diagnostic reference standard online. We assessed the LEIDS-RR-CV using classical test theory (CTT) and item response theory (IRT). We also assessed the test performance for cut-off scores using receiver operator characteristic analysis to further screen for high-risk depression at each time point. Results In total, 396 (third trimester) and 321 (six weeks postpartum) women participated. Cronbach’s alpha, two-week test–retest reliability, and marginal reliability for the scale were all greater than 0.8. It showed a five-factor model; the cut-off values were 58 (third trimester) and 60 (six weeks postpartum). The areas under the curve were acceptable (≥ 0.7), and the LEIDS-RR-CV was positively correlated with the total Edinburgh Postnatal Depression Scale (EPDS) score (r = 0.52 and 0.56, p = 0.00), indicating its predictive validity. An IRT analysis further confirmed its discriminative validity. Conclusions The LEIDS-RR-CV was found to be reliable, valid, and can be used to quantify cognitive reactivity among perinatal Chinese women and for screening for high-risk depression during this period.

Lung cancer is one of the leading causes of cancer incidence and mortality worldwide. While smoking, radon, air pollution, as well as occupational exposure to asbestos, diesel fumes, arsenic, beryllium, cadmium, chromium, nickel, and silica are well-established risk factors, many lung cancer cases cannot be explained by these known risk factors. Over the last two decades the incidence of adenocarcinoma has risen, and it now surpasses squamous cell carcinoma as the most common histologic subtype. This increase warrants new efforts to identify additional risk factors for specific lung cancer subtypes as well as a comprehensive review of current evidence from epidemiologic studies to inform future studies. Given the myriad exposures individuals experience in real-world settings, it is essential to investigate mixture effects from complex exposures and gene-environment interactions in relation to lung cancer and its subtypes.

Abstract Background The pathophysiology of hepatitis B-related liver cirrhosis (HBV-LC) remains unclear. This study aimed to explore the disease mechanisms using topological analysis of the miRNA/mRNA network. Methods Paired miRNA/mRNA sequencing was performed with thirty-three peripheral blood mononuclear cell samples (LC, n = 9; chronic hepatitis B, n = 12; normal controls, n = 12) collected from a prospective cohort to identify the miRNA/mRNA network. Topological features and functional implications of the network were analyzed to capture pathophysiologically important miRNAs/mRNAs, whose expression patterns were confirmed in the validation group (LC, n = 15; chronic hepatitis B, n = 15; normal controls, n = 10), and functional potentials initiating fibrogenesis were demonstrated in vitro. Results The miRNA/mRNA network contained 3121 interactions between 158 differentially expressed (DE) miRNAs and 442 DE-mRNAs. The topological analysis identified a core module containing 99 miRNA/mRNA interactions and two hub nodes (miR-20a-5p/miR-340-5p), which connected to 75 DE-mRNAs. The expression pattern along the disease progression of the core module was found associated with a continuous increase in wound healing, inflammation, and leukocyte migration but an inflection of immune response and lipid metabolic regulation, consistent with the pathophysiology of HBV-LC. MiR-20a-5p/miR-340-5p were found involved in macrophage polarization and hepatic stellate cell (HSC) activation in vitro (THP-1, LX-2 cell lines), and their expression levels were confirmed in the validation group independently. Conclusion Topological analysis of the miRNA/mRNA network in HBV-LC revealed the association between fibrosis and miR-20a-5p/miR-340-5p involving initiating activations of macrophage and HSC. Further validations should be performed to confirm the HSC/macrophage activations and the interactions between miR-20a-5p/miR-340-5p and their potential targets, which may help to develop non-invasive prognostic markers or intervention targets for HBV-LC.

Flexomagnetism refers to the modification of the magnetic properties of a material due to inhomogeneous strain, and offers a promising pathway to the control and manipulation of magnetism. Here, Makushko et al. explore flexomagnetism in antiferromagnetic thin films of Cr2O3, demonstrating a gradient of the Néel temperature as a result of an inhomogeneous strain.

The hot deformation behavior of Mg-9.16Gd-3.03Y-1.44Zn-0.61Zr alloy was examined by hot compression experiments at 623–753 K with strain rates 0.1–20 s−1. Flow stress-strain curves developed an Arrhenius-type equation with adjustment for strain. The influence of strain on microstructure evolution was studied by optical microscope. The results showed that with the increase of deformation, LPSO phase broken and kinked and interacted with dislocations to promote nucleation of dynamic recrystallization (DRX) grains. In addition, the effects of temperature and strain rate on DRX during hot compression were examined using electron back-scatter diffraction. The results demonstrated that the volume fraction of DRX grains improved as temperature and strain rate increased. The alloys could adapt to plastic deformation caused mostly by continuous and discontinuous dynamic recrystallization. Transmission electron microscopy was then utilized to observe the phase structure. The dynamic precipitates occurred after hot compression, and the LPSO phase was broken and kinked, which coordinated the plastic deformation. Using the Avrami equation, the DRX dynamic model of the alloy at 0.1 s−1 was established for the first time.

In patients with locally advanced resectable oral squamous cell carcinoma (OSCC), the risk of recurrence and metastasis following treatment is high. Here, a phase I clinical trial reports safety and pathological response of neoadjuvant camrelizumab and apatinib in patients with locally advanced resectable OSCC.

Muddy water irrigation has been widely practiced in the Yellow River Basin for agricultural production and is an important method of economical and intensive utilization of water resources. In this study, the effects of sediment gradation, sand content, and soil moisture content on nitrogen (N) transformation were studied through a series of experimental tests. The results indicated that muddy water irrigation significantly affected agricultural soil physical and biological properties as well as N transformation. Soil bulk density, total porosity, pH, and microbial enzyme activities significantly correlated with N transformation as affected by the interaction between sediment and soil moisture. Sediment addition generally increased the soil bulk density and reduced the soil porosity and pH significantly, and the optimum moisture for promotion of the N transformation rate was 80% of the water-filled pore space. Therefore, muddy water irrigation has a potentially long-term influence on agricultural N cycles in semi-arid regions of northwestern China. This could provide a theoretical basis for scientific and rational use of muddy water for irrigation.

Seaweed is a rich source of phycocolloids, which include agar, alginate, and carrageenan. Low molecular weight polysaccharides, namely oligomers or oligosaccharides, can be produced from seaweed polysaccharides through enzymatic degradation. Most of these enzymes are produced by microorganisms closely associated with seaweed. This study aimed to isolate and select polysaccharidases-producing (SPases) bacteria associated with wild seaweed from the sea around Ambon Island, an area famous for its high marine biodiversity index. A total of 11 types of marine algae samples could be collected, and as many as 92 bacterial isolates could be cultured from all these algae samples. Screening used a clear zone method on a solid medium containing substrates agar, alginate, or carrageenan and followed by Lugol’s iodine staining solution showed that a total of 74 of the 92 bacterial isolates obtained were SPases-producing with the composition: agarase-producing (28 isolates), and alginate lyase-producing (26 isolates), and carrageenaseproducing (20 isolates). The 16S rRNA identification results showed that the 74 bacterial isolates were representative of 13 species and belong to 2 classes, namely Gammaproteobacteria and Bacillus. The bacterial isolates in the Gammaproteobacteria class obtained consisted of three genera: Pseudoalteromonas (32 isolates), Cobetia (18 isolates), and Microbulbifer (15 isolates). Bacterial isolates in the Bacillus class obtained only contain a genus consisting of 8 isolates. In conclusion, the sea around Ambon Island is a potential source of polysaccharidases-producing algal symbiont bacteria.

Background: Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular disease that negatively impacts quality of life, exercise capacity, and mortality. This study sought to investigate the relationship between serum uric acid (UA) level and the disease severity and treatment response of patients with PAH and congenital heart disease (PAH-CHD).Methods: This study included 225 CHD patients and 40 healthy subjects. Serum UA was measured in all patients, and UA levels and haemodynamic parameters were re-evaluated in 20 patients who had received PAH-specific drug treatment for at least 7 ± 1 month.Results: Serum UA levels were significantly higher in PAH-CHD patients than in CHD patients with a normal pulmonary artery pressure and normal subjects (347.7 ± 105.7 μmol/L vs. 278.3 ± 84.6 μmol/L; 347.7 ± 105.7 μmol/L vs. 255.7 ± 44.5 μmol/L, p < 0.05). UA levels in the intermediate and high risk groups were significantly higher than those in the low-risk group (365.6 ± 107.8 μmol/L vs. 311.2 ± 82.8 μmol/L; 451.6 ± 117.6 μmol/L vs. 311.2 ± 82.8 μmol/L, p < 0.05). Serum UA levels positively correlated with mean pulmonary arterial pressure, WHO functional class, pulmonary vascular resistance, and NT-proBNP (r = 0.343, 0.357, 0.406, 0.398; p < 0.001), and negatively with mixed venous oxygen saturation (SvO2) and arterial oxygen saturation (SaO2) (r = −0.293, −0.329; p < 0.001). UA significantly decreased from 352.7 ± 97.5 to 294.4 ± 56.8 μmol/L (p = 0.001) after PAH-specific drug treatment for at least 6 months, along with significant decreases in mean pulmonary arterial pressure and pulmonary vascular resistance and increases in cardiac index and mixed SvO2.Conclusion: Serum UA can be used as a practical and economic biomarker for risk stratification and the evaluation of PAH-specific drug treatment effects for patients with PAH-CHD.

IntroductionRepetitive transcranial magnetic stimulation (rTMS) is an effective non-invasive cortical stimulation technique in the treatment of neuropathic pain. As a new rTMS technique, intermittent theta burst stimulation (iTBS) is also effective at relieving pain. We aimed to establish the pain-relieving effectiveness of different modalities on neuropathic pain. The study was conducted in individuals with spinal cord injury (SCI) and different modalities of rTMS.MethodsThirty-seven individuals with SCI were randomly allocated to three groups, in which the “iTBS” group received iTBS, the “rTMS” group received 10 Hz rTMS, and the “iTBS + rTMS” group received iTBS and 10 Hz rTMS successively of the primary motor cortex 5 days a week for 4 weeks, and they all underwent the full procedures. The primary outcome measure was change in the visual analog scale (VAS), and the secondary outcomes were measured using the Hamilton Rating Scale for Depression (HAM-D) and the Pittsburgh Sleep Quality Index (PSQI). All the outcomes were evaluated at 1 day before stimulation (baseline), 1 day after the first week of stimulation (S1), and 1 day after the last stimulation (S2).ResultsThe VAS scores showed significant pain improvement after 4 weeks of stimulation (p = 0.0396, p = 0.0396, and p = 0.0309, respectively) but not after 1 week of stimulation. HAM-D scores declined, but the decreases were not significant until 4 weeks later (p = 0.0444, p = 0.0315, and p = 0.0447, respectively). PSQI scores were also significantly decreased after 4 weeks of stimulation (p = 0.0446, p = 0.0244, and p = 0.0088, respectively). Comparing the three modalities, VAS, HAM-D, and PSQI scores at S1 showed no differences, and, at S2, VAS scores showed significant differences (p = 0.0120; multiple comparisons showed significant differences between iTBS and iTBS + rTMS, p = 0.0091), while the HAM-D and PSQI scores showed no differences.DiscussionThe primary and secondary outcomes all showed significant improvement, indicating that the three different modalities were all effective at relieving the pain. However, not all the three stimulations were of same effectiveness after treatment; there were statistical differences in the treatment of neuropathic pain between iTBS as a priming stimulus and as a single procedure.

Background: Idiopathic pulmonary arterial hypertension (PAH) is a potentially fatal pulmonary vascular disease with an extremely poor natural course. The limitations of current treatment and the unclear etiology and pathogenesis of idiopathic PAH require new targets and avenues of exploration involved in the pathogenesis of PAH. tRNA-derived small RNAs (tsRNAs), a new type of small non-coding RNAs, have a significant part in the progress of diverse diseases. However, the potential functions behind tsRNAs in idiopathic PAH remain unknown.Methods: Small RNA microarray was implemented on three pairs of plasma of idiopathic PAH patients and healthy controls to investigate and compare tsRNAs expression profiles. Validation samples were used for real-time polymerase chain reaction (Real-time PCR) to verify several dysregulated tsRNAs. Bioinformatic analysis was adopted to determine potential target genes and mechanisms of the validated tsRNAs in PAH.Results: Microarray detected 816 statistically significantly dysregulated tsRNAs, of which 243 tsRNAs were upregulated and 573 were downregulated in PAH. Eight validated tsRNAs in the results of Real-time PCR were concordant with the small RNA microarray: four upregulated (tRF3a-AspGTC-9, 5’tiRNA-31-GluCTC-16, i-tRF-31:54-Val-CAC-1 and tRF3b-TyrGTA-4) and four downregulated (5’tiRNA-33-LysTTT-4, i-tRF-8:32-Val-AAC-2, i-tRF-2:30-His-GTG-1, and i-tRF-15:31-Lys-CTT-1). The Gene Ontology analysis has shown that the verified tsRNAs are related to cellular macromolecule metabolic process, regulation of cellular process, and regulation of cellular metabolic process. It is disclosed that potential target genes of verified tsRNAs are widely involved in PAH pathways by Kyoto Encyclopedia of Genes and Genomes.Conclusion: This study investigated tsRNA profiles in idiopathic PAH and found that the dysregulated tsRNAs may become a novel type of biomarkers and possible targets for PAH.

N6-methyladenosine (m6A) is a post-transcriptional epigenetic change with transcriptional stability and functionality regulated by specific m6A-modifying enzymes. However, the significance of genes modified by m6A and enzymes specific to m6A regulation in the context of pulmonary arterial hypertension (PAH) remains largely unexplored. MeRIP-seq and RNA-seq were applied to explore variances in m6A and RNA expression within the pulmonary artery tissues of control and monocrotaline-induced PAH rats. Functional enrichments were analyzed using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. To screen candidate m6A-related genes, the STRING and Metascape databases were used to construct a protein–protein interaction network followed by a real-time PCR validation of their expression. The expression level of an m6A regulator was further investigated using immunohistochemical staining, immunofluorescence, and Western blot techniques. Additionally, proliferation assays were conducted on primary rat pulmonary artery smooth muscle cells (PASMCs). We identified forty-two differentially expressed genes that exhibited either hypermethylated or hypomethylated m6A. These genes are predominantly related to the extracellular matrix structure, MAPK, and PI3K/AKT pathways. A candidate gene, centromere protein F (CENPF), was detected with increased expression in the PAH group. Additionally, we first identified an m6A reader, leucine rich pentatricopeptide repeat containing (LRPPRC), which was downregulated in the PAH rat model. The in vitro downregulation of Lrpprc mediated by siRNA resulted in the enhanced proliferation and elevated expression of Cenpf mRNA in primary rat PASMCs. Our study revealed a modified transcriptome-wide m6A landscape and associated regulatory mechanisms in the pulmonary arteries of PAH rats, potentially offering a novel target for therapeutic strategies in the future.

Hyperuricemia has become a global burden with the increasing prevalence and risk of associated metabolic disorders and cardiovascular diseases. Uricosurics act as a vital urate-lowering therapy by promoting uric acid excretion via the kidneys. However, potent and safe uricosurics are still in urgent demand for use in the clinic. In this study, we aimed to establish in vitro and in vivo models to aid the discovery of novel uricosurics, and to search for potent active compounds, especially targeting urate transporter 1 (URAT1), the major urate transporter in the kidney handling uric acid homeostasis. As a result, for preliminary screening, the in vitro URAT1 transport activity was assessed using a non-isotopic uric acid uptake assay in hURAT1-stably expressed HEK293 cells. The in vivo therapeutic effect was evaluated in a subacute hyperuricemic mouse model (sub-HUA) and further confirmed in a chronic hyperuricemic mouse model (Ch-HUA). By utilizing these models, compound CC18002 was obtained as a potent URAT1 inhibitor, with an IC50 value of 1.69 μM, and favorable uric acid-lowering effect in both sub-HUA and Ch-HUA mice, which was comparable to that of benzbromarone at the same dosage. Moreover, the activity of xanthine oxidoreductase, the key enzyme catalyzing uric acid synthesis, was not altered by CC18002 treatment. Taken together, we have developed a novel screening system, including a cell model targeting URAT1 and two kinds of mouse models, for the discovery of novel uricosurics. Utilizing this system, compound CC18002 was investigated as a candidate URAT1 inhibitor to treat hyperuricemia.

Abstract Background Pulmonary arterial hypertension (PAH) is a chronic, progressive lung vascular disease accompanied by elevated pulmonary vascular pressure and resistance, and it is characterized by increased pulmonary artery smooth muscle cell (PASMC) proliferation. Apolipoprotein A5 (ApoA5) improves monocrotaline (MCT)-induced PAH and right heart failure; however, the underlying mechanism remains unknown. Here we speculate that ApoA5 has a protective effect in pulmonary vessels and aim to evaluate the mechanism. Methods ApoA5 is overexpressed in an MCT-induced PAH animal model and platelet-derived growth factor (PDGF)-BB-induced proliferating PASMCs. Lung vasculature remodeling was measured by immunostaining, and PASMC proliferation was determined by cell counting kit‐8 and 5‐ethynyl‐2'‐deoxyuridine5‐ethynyl‐2'‐deoxyuridine incorporation assays. Coimmunoprecipitation-mass spectrometry was used to investigate the probable mechanism. Next, its role and mechanism were further verified by knockdown studies. Results ApoA5 level was decreased in MCT-induced PAH lung as well as PASMCs. Overexpression of ApoA5 could help to inhibit the remodeling of pulmonary artery smooth muscle. ApoA5 could inhibit PDGF-BB-induced PASMC proliferation and endoplasmic reticulum stress by increasing the expression of glucose-regulated protein 78 (GRP78). After knocking down GRP78, the protecting effects of ApoA5 have been blocked. Conclusion ApoA5 ameliorates MCT-induced PAH by inhibiting endoplasmic reticulum stress in a GRP78 dependent mechanism.

Abstract We aim to determine whether ischemic stroke(IS)-related PRSs are also associated with and further predict 3-year all-cause mortality. 1756 IS patients with European ancestry were randomly split into training (n = 1226) and testing (n = 530) groups with 3-year post-event observations. Univariate Cox proportional hazards regression model (CoxPH) was used for primary screening of individual prognostic PRSs. Only the significantly associated PRSs and clinical risk factors with the same direction for a causal relationship with IS were used to construct a multivariate CoxPH. Feature selection was conducted by the LASSO method. After feature selection, a prediction model with 11 disease-associated pathway-specific PRSs outperformed the base model, as demonstrated by a higher concordance index (0.751, 95%CI [0.693–0.809] versus 0.729, 95%CI [0.676–0.782]) in the testing sample. A PRS derived from endothelial cell apoptosis showed independent predictability in the multivariate CoxPH (Hazard Ratio = 1.193 [1.027–1.385], p = 0.021). These PRSs fine-tuned the model by better stratifying high, intermediate, and low-risk groups. Several pathway-specific PRSs were associated with clinical risk factors in an age-dependent manner and further confirmed some known etiologies of IS and all-cause mortality. In conclusion, Pathway-specific PRSs for IS are associated with all-cause mortality, and the integrated multivariate risk model provides prognostic value in this context.

Abstract Fine grained 8 mol% yttria-stabilized zirconia (8YSZ) transparent ceramics with high optical and mechanical properties were fabricated by air pre-sintering and hot isostatic pressing (HIP) using commercial 8YSZ powders as the raw material. The pre-sintered ceramics with fine grains and appropriate relative density play a key role to achieve high transparency and suppressed grain size after HIP post-treatment at relatively low temperatures. With the increase of HIP temperature from 1350 to 1550 °C, the in-line transmittance of 8YSZ ceramics at 600 nm increases from 56.9% to 71.5% (2.5 mm in thickness), and the average grain size increases from 2.4 to 16.3 µm. The corresponding bending strength of 8YSZ transparent ceramics decreases from 328±20 to 289±19 MPa, the hardness (H) decreases from 12.9±0.1 to 12.5±0.2 GPa, and the fracture toughness (K IC) decreases from 1.30±0.02 to 1.26±0.03 MPa·m1/2. Systematical investigations were carried out to study the combination of high optical transparency and excellent mechanical properties in 8YSZ ceramics.

Abstract Background Mucosal melanoma has characteristically distinct genetic features and typically poor prognosis. The lack of representative mucosal melanoma models, especially cell lines, has hindered translational research on this melanoma subtype. In this study, we aimed to establish and provide the biological properties, genomic features and the pharmacological profiles of a mucosal melanoma cell line that would contribute to the understanding and treatment optimization of molecularly‐defined mucosal melanoma subtype. Methods The sample was collected from a 67‐year‐old mucosal melanoma patient and processed into pieces for the establishment of cell line and patient‐derived xenograft (PDX) model. The proliferation and tumorigenic property of cancer cells from different passages were evaluated, and whole‐genome sequencing (WGS) was performed on the original tumor, PDX, established cell line, and the matched blood to confirm the establishment and define the genomic features of this cell line. AmpliconArchitect was conducted to depict the architecture of amplified regions detected by WGS. High‐throughput drug screening (HTDS) assay including a total of 103 therapeutic agents was implemented on the established cell line, and selected candidate agents were validated in the corresponding PDX model. Results A mucosal melanoma cell line, MM9H‐1, was established which exhibited robust proliferation and tumorigenicity after more than 100 serial passages. Genomic analysis of MM9H‐1, corresponding PDX, and the original tumor showed genetic fidelity across genomes, and MM9H‐1 was defined as a triple wild‐type (TWT) melanoma subtype lacking well‐characterized “driver mutations”. Instead, the amplification of several oncogenes, telomerase reverse transcriptase (TERT), v‐Raf murine sarcoma viral oncogene homolog B1 (BRAF), melanocyte Inducing transcription factor (MITF) and INO80 complex ATPase subunit (INO80), via large‐scale genomic rearrangement potentially contributed to oncogenesis of MM9H‐1. Moreover, HTDS identified proteasome inhibitors, especially bortezomib, as promising therapeutic candidates for MM9H‐1, which was verified in the corresponding PDX model in vivo. Conclusions We established and characterized a new mucosal melanoma cell line, MM9H‐1, and defined this cell line as a TWT melanoma subtype lacking well‐characterized “driver mutations”. The MM9H‐1 cell line could be adopted as a unique model for the preclinical investigation of mucosal melanoma.

Objective To summarize the characteristics and changes of traumatic brain injury (TBI) in Tongzhou district of Beijing with the rapid development of social economy, in order to provide the theoretical basis for adjustment of the prevention and treatment strategies in high risk population. Methods The home pages of electronic health record (EHR) of patients with TBI from December 1, 2004 to October 22, 2018 were automatically extracted from the EHR of Beijing Luhe Hospital, Capital Medical University. The clinical characteristics were retrospectively analyzed, and the risk factors related to death at discharge were screened by univariate and multivariate forward Logistic regression analysis. Results A total of 4058 patients with TBI were screened out, of which 3683 cases (90.76%) survived and 375 cases (9.24%) died at discharge. The mortality at discharge was significantly different among different age (χ2 = 51.526, P = 0.000), causes of injury (χ2 = 82.349, P = 0.000), treatment modalities (χ2 = 186.270, P = 0.000) and hospital length (χ2 = 9.842, P = 0.000). The mortality of patients aged 45-64, 65-74 and ≥ 75 years was higher than that of patients aged 15-24 and 25-44 years (P < 0.01, for all), and the mortality of patients aged ≥ 75 years was higher than that of patients aged 45-64 years (P = 0.001). The mortality of patients with traffic accident injury was higher than that of fall injury (P = 0.000), and the mortality of patients with traffic accident injury, fall injury and other cases was higher than that of violent injury (P = 0.000, for all). The mortality of patients received neurosurgery and non-neurosurgery was higher than that of conservative treatment (P = 0.000, for all). The mortality of patients with hospital lengh of 1-14 d was higher than that of 15-30 d and > 30 d (P = 0.000, for all). Logistic regression analysis showed that 45-64 years old (OR = 2.285, 95%CI: 1.428-3.657; P = 0.001), 65-74 years old (OR = 4.025, 95%CI: 2.334-6.941; P = 0.000), ≥ 75 years old (OR = 5.757, 95%CI: 3.317-9.991; P = 0.000), hospital admission in year 2007-2010 (OR = 1.856, 95%CI: 1.376-2.504; P = 0.000), treatment with neurosurgery (OR = 6.465, 95%CI: 4.991-8.376; P = 0.000) and non-neurosurgical procedures (OR = 3.389, 95%CI: 1.828 - 6.283; P = 0.000), hospital length 1- 14 d (OR = 6.023, 95%CI: 3.822-9.490; P = 0.000) were risk factors for death at discharge of TBI patients, and violent injury was a protective factor for death at discharge (OR = 0.245, 95%CI: 0.112-0.537; P = 0.000). Conclusions The mortality of TBI is still high, patients over 45 years, hospital admission in year 2007-2010, traffic accident injury, treatment with neurosurgery and non-neurosurgery, and hospital length of 1-14 d had a higher mortality at discharge.

Aiming at the local overheating phenomenon of the contact position caused by the large current operation in the complex environment in the design of the DC transmission busbar of the CRAFT (Comprehensive Research Facility for Fusion Technology) converter power supply, based on the contact resistance measured by a certain contact torque and contact area, this paper proposes a method based on transmission Thermal theory and ANSYS thermoelectric coupling module method. The busbar temperature range is determined by considering and not considering the contact resistance, and the maximum temperature of the flexible connection is obtained through simulation, and the maximum temperature of the flexible connection is obtained by simulation. Finally, the temperature rise experiment was carried out on the linear flexible connection and the L-shaped flexible connection, and compared with the simulation results, it showed a good consistency and met the engineering design requirements.

Abstract. Background:. Non-smokers account for a large proportion of lung cancer patients, especially in Asia, but the attention paid to them is limited compared with smokers. In non-smokers, males display a risk for lung cancer incidence distinct from the females—even after excluding the influence of smoking; but the knowledge regarding the factors causing the difference is sparse. Based on a large multicenter prospective cancer screening cohort in China, we aimed to elucidate the interpretable sex differences caused by known factors and provide clues for primary and secondary prevention. Methods:. Risk factors including demographic characteristics, lifestyle factors, family history of cancer, and baseline comorbidity were obtained from 796,283 Chinese non-smoking participants by the baseline risk assessment completed in 2013 to 2018. Cox regression analysis was performed to assess the sex difference in the risk of lung cancer, and the hazard ratios (HRs) that were adjusted for different known factors were calculated and compared to determine the proportion of excess risk and to explain the existing risk factors. Results:. With a median follow-up of 4.80 years, 3351 subjects who were diagnosed with lung cancer were selected in the analysis. The lung cancer risk of males was significantly higher than that of females; the HRs in all male non-smokers were 1.29 (95% confidence interval [CI]: 1.20–1.38) after adjusting for the age and 1.38 (95% CI: 1.28–1.50) after adjusting for all factors, which suggested that known factors could not explain the sex difference in the risk of lung cancer in non-smokers. Known factors were 7% (|1.29–1.38|/1.29) more harmful in women than in men. For adenocarcinoma, women showed excess risk higher than men, contrary to squamous cell carcinoma; after adjusting for all factors, 47% ([1.30–1.16]/[1.30–1]) and 4% ([7.02–6.75]/[7.02–1])) of the excess risk was explainable in adenocarcinoma and squamous cell carcinoma. The main causes of gender differences in lung cancer risk were lifestyle factors, baseline comorbidity, and family history. Conclusions:. Significant gender differences in the risk of lung cancer were discovered in China non-smokers. Existing risk factors did not explain the excess lung cancer risk of all non-smoking men, and the internal causes for the excess risk still need to be explored; most known risk factors were more harmful to non-smoking women; further exploring the causes of the sex difference would help to improve the prevention and screening programs and protect the non-smoking males from lung cancers.

Abstract Background Gait disability affects the daily lives of patients with stroke in both home and community settings. An abnormal foot–ankle position can cause instability on the supporting surface and negatively affect gait. Our research team explored the ability of a portable peroneal nerve-targeting electrical stimulator to improve gait ability by adjusting the foot–ankle position during walking in patients with chronic stroke undergoing home-based rehabilitation. Methods This was a double-blinded, parallel-group randomized controlled trial. Thirty-one patients with chronic stroke and ankle–foot motor impairment were randomized to receive 3 weeks of gait training, which involved using the transcutaneous peroneal nerve stimulator while walking (tPNS group; n = 16, mean age: 52.25 years), or conventional home and/or community gait training therapy (CT group; n = 15, mean age: 54.8 years). Functional assessments were performed before and after the 3-week intervention. The outcome measures included spatiotemporal gait parameters, three-dimensional kinematic and kinetic data on the ankle–foot joint, and a clinical motor and balance function assessment based on the Fugl–Meyer Assessment of Lower Extremity (FMA-LE) and Berg Balance scales (BBS). Additionally, 16 age-matched healthy adults served as a baseline control of three-dimensional gait data for both trial groups. Results The FMA-LE and BBS scores improved in both the tPNS groups (p = 0.004 and 0.001, respectively) and CT groups (p = 0.034 and 0.028, respectively) from before to after training. Participants in the tPNS group exhibited significant differences in spatiotemporal gait parameters, including double feet support, stride length, and walking speed of affected side, and the unaffected foot off within a gait cycle after training (p = 0.043, 0.017, 0.001 and 0.010, respectively). Additionally, the tPNS group exhibited significant differences in kinematic parameters, such as the ankle angle at the transverse plane (p = 0.021) and foot progression angle at the frontal plane (p = 0.009) upon initial contact, and the peak ankle joint angle at the transverse plane (p = 0.023) and foot progression angle (FPA) at the frontal and transverse planes (p = 0.032 and 0.046, respectively) during gait cycles after 3 weeks of training. Conclusions Use of a portable tPNS device during walking tasks appeared to improve spatiotemporal gait parameters and ankle and foot angles more effectively than conventional home rehabilitation in patients with chronic stroke. Although guidelines for home-based rehabilitation training services and an increasing variety of market devices are available, no evidence for improvement of motor function and balance was superior to conventional rehabilitation. Trial registration Chictr, ChiCTR2000040137. Registered 22 November 2020, https://www.chictr.org.cn/showproj.aspx?proj=64424

ObjectivesThe current standard nonsurgical treatment for locally advanced head and neck squamous cell cancer (LA-HNSCC) is concomitant chemoradiotherapy (CRT). Neoadjuvant chemotherapy combined with CRT has been explored in HNSCC patients and is an acceptable strategy. However, the occurrence of adverse events (AEs) restricts its application. We conducted a clinical study to explore the efficacy and feasibility of a novel induction therapy with orally administered apatinib and S-1 in LA-HNSCC.Materials and methodsThis nonrandomized, single-arm, prospective clinical trial included patients with LA-HNSCCs. The eligibility criteria included histologically or cytologically confirmed HNSCC, with at least one radiographically measurable lesion detected by magnetic resonance imaging (MRI) or computerized tomography (CT) scan, age 18–75 years, and a diagnosis of stage III to IVb according to the 7th edition of the American Joint Committee of Cancer (AJCC). Patients received induction therapy with apatinib and S-1 for three cycles (3 weeks/cycle). The primary endpoint of this study was the objective response rate (ORR) to induction therapy. The secondary endpoints included progression-free survival (PFS), overall survival (OS), and AEs during induction treatment.ResultsFrom October 2017 to September 2020, 49 patients with LA-HNSCC were screened consecutively and 38 were enrolled. The median age of the patients was 60 years (range, 39-75). Thirty-three patients (86.8%) had stage IV disease according to the AJCC staging system. The ORR after induction therapy was 97.4% (95% confidence interval [CI]: 86.2%-99.9%). the 3-year OS rate was 64.2% (95% CI: 46.0%-78.2%) and 3-year PFS was 57.1% (95% CI: 40.8%-73.6%). The most common AEs during induction therapy were hypertension and hand-foot syndrome, which were manageable.ConclusionApatinib combined with S-1 as novel induction therapy for LA-HNSCC patients resulted in a higher-than-anticipated ORR and manageable adverse effects. With the associated safety profile and preferable oral administration route, apatinib combined with S-1 is an attractive exploratory induction regimen in outpatient settings. However, this regimen failed to show a survival benefit.Clinical trial registrationhttps://clinicaltrials.gov/show/NCT03267121, identifier NCT03267121.

Obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Sex differences in immune cell activation drive obesity-mediated pathologies where males are more susceptible to obesity comorbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELMα critically protects females against high-fat diet (HFD)-induced obesity. Compared to male mice, serum RELMα levels were higher in both control and HFD-fed females and correlated with frequency of adipose macrophages and eosinophils. RELMα-deficient females gained more weight and had proinflammatory macrophage accumulation and eosinophil loss in the adipose stromal vascular fraction (SVF), while RELMα treatment or eosinophil transfer rescued this phenotype. Single-cell RNA-sequencing of the adipose SVF was performed and identified sex and RELMα-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283/Gm21887, correlated with increased obesity, while eosinophil chemotaxis and response to amyloid-beta were protective. Monocyte-to-macrophage transition was also dysregulated in RELMα-deficient animals. Collectively, these studies implicate a RELMα–macrophage–eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.

Objectives: The role of re-irradiation after salvage surgery for recurrent oral cavity cancer (OCC) is controversial. We evaluated the efficacy and safety of adjuvant toripalimab (PD-1 antibody) in this patient setting. Materials and methods: In this phase II study, patients after salvage surgery with OCC occurring in an area of previously irradiated were enrolled. Patients received toripalimab 240 mg once every 3 weeks for 12 months, or combined with S-1 orally for 4–6 cycles. The primary endpoint was 1-year progression-free survival (PFS). Results: Between April 2019 and May 2021, 20 patients were enrolled. Sixty percent patients had ENE or positive margins, 80% were restaged as stage IV, and 80% were previously treated with chemotherapy. The 1-year PFS and overall survival (OS) were 58.2%, and 93.8%, respectively, for patients with CPS ≥ 1, which was significantly better than those of the real-world reference cohort (p = 0.001 and 0.019). No grade 4–5 toxicities were reported, and only one patient experienced grade 3 immune related adrenal insufficiency and discontinued treatment. The 1-year PFS and OS were significantly different for patients with CPS

Abstract Electrostatic electron cyclotron harmonic (ECH) waves which can efficiently produce scattering loss of electrons, are frequently observed in the first band. Here we present new results on the global occurrence of higher‐band ECH waves in the radiation belts from Van Allen Probes data. We develop a novel noise reduction algorithm which can be widely applied to various plasma waves to better identify naturally occurring waves during periods of instrument interference. The occurrence rate of ECH waves in higher harmonic bands is comparable to that in the first harmonic band, except in the noon‐to‐dusk sector. As the level of geomagnetic activity increases, ECH waves in all bands can be observed at lower L‐shells. The occurrence rates of weak (moderate, strong) waves in all four bands increase 3–4 (4–6, 5–10) times during disturbed periods compared to those during quiet periods. The current results may provide better understanding of ECH‐driven magnetosphere‐ionosphere coupling.

BackgroundSepsis is a leading cause of death in patients with trauma, and the risk of mortality increases significantly for each hour of delay in treatment. A hypermetabolic baseline and explosive inflammatory immune response mask clinical signs and symptoms of sepsis in trauma patients, making early diagnosis of sepsis more challenging. Machine learning–based predictive modeling has shown great promise in evaluating and predicting sepsis risk in the general intensive care unit (ICU) setting, but there has been no sepsis prediction model specifically developed for trauma patients so far. ObjectiveTo develop a machine learning model to predict the risk of sepsis at an hourly scale among ICU-admitted trauma patients. MethodsWe extracted data from adult trauma patients admitted to the ICU at Beth Israel Deaconess Medical Center between 2008 and 2019. A total of 42 raw variables were collected, including demographics, vital signs, arterial blood gas, and laboratory tests. We further derived a total of 485 features, including measurement pattern features, scoring features, and time-series variables, from the raw variables by feature engineering. The data set was randomly split into 70% for model development with stratified 5-fold cross-validation, 15% for calibration, and 15% for testing. An Extreme Gradient Boosting (XGBoost) model was developed to predict the hourly risk of sepsis at prediction windows of 4, 6, 8, 12, and 24 hours. We evaluated model performance for discrimination and calibration both at time-step and outcome levels. Clinical applicability of the model was evaluated with varying levels of precision, and the potential clinical net benefit was assessed with decision curve analysis (DCA). A Shapley additive explanation algorithm was applied to show the effect of features on the prediction model. In addition, we trained an L2-regularized logistic regression model to compare its performance with XGBoost. ResultsWe included 4603 trauma patients in the study, 1196 (26%) of whom developed sepsis. The XGBoost model achieved an area under the receiver operating characteristics curve (AUROC) ranging from 0.83 to 0.88 at the 4-to-24-hour prediction window in the test set. With a ratio of 9 false alerts for every true alert, it predicted 73% (386/529) of sepsis-positive timesteps and 91% (163/179) of sepsis events in the subsequent 6 hours. The DCA showed our model had a positive net benefit in the threshold probability range of 0 to 0.6. In comparison, the logistic regression model achieved lower performance, with AUROC ranging from 0.76 to 0.84 at the 4-to-24-hour prediction window. ConclusionsThe machine learning–based model had good discrimination and calibration performance for sepsis prediction in critical trauma patients. Using the model in clinical practice might help to identify patients at risk of sepsis in a time window that enables personalized intervention and early treatment.

Myocardial ischemia is a predominant cardiovascular disorder that can result in a series of life-threatening cardiovascular diseases. Carthami flos (CF), the flower of Carthamus tinctorius L., is a commonly used herbal medicine in Chinese medicine for treating coronary atherosclerotic heart diseases based on its anti-myocardial ischemia (MI) effects. This paper aimed to investigate the active substances and mechanisms of the anti-MI effects of CF by network pharmacology and in vitro experiments. The results indicated that 9 constituents showed high degree of association with multiple targets of MI, including quercetin, kaempferol, β-sitosterol, luteolin, baicalein, safflomin A, safflomin C, safflower-yellow-B and hydroxysafflor yellow A. In addition, AKT1, EGFR, CASP3, MYC, JUN, ALB, CTNNB1, VEGFA, ESR1, and IL1B were screened as the leading targets with a degree number ≥50. Bioinformatic annotation of GO-MF and KEGG showed that the anti-MI effects of CF are related to apoptosis and response to antioxidative stress pathways. The in vitro results showed that CF reduced LDH and CK levels, alleviated cell cycle arrest, and decreased ROS levels in H2O2-treated H9c2 cells. In addition, CF also promoted the nuclear shift of Nrf2 and the mRNA expressions of Akt, Nrf2 and Bcl-2 but decreased the expression of caspase-3 in H2O2-treated H9c2 cells. Collectively, the anti-MI effects of CF involve inhibiting apoptosis and antioxidative stress in cardiomyoblasts by regulating Akt/Nrf2/Caspase-3/Bcl-2, and the possible active substances of CF are quercetin, kaempferol, β-sitosterol, luteolin, baicalein, safflomin C, safflower-yellow-B, and hydroxysafflor yellow A. The results of this study will be helpful for further drug development of CF and its active monomers.

Abstract Targeting CD96 that originates in immune cells has shown potential for cancer therapy. However, the role of intrinsic CD96 in solid tumor cells remains unknown. Here, it is found that CD96 is frequently expressed in tumor cells from clinical breast cancer samples and is correlated with poor long‐term prognosis in these patients. The CD96+ cancer cell subpopulations exhibit features of both breast cancer stem cells and chemoresistance. In vivo inhibition of cancer cell‐intrinsic CD96 enhances the chemotherapeutic response in a patient‐derived tumor xenograft model. Mechanistically, CD96 enhances mitochondrial fatty acid β‐oxidation via the CD155‐CD96‐Src‐Stat3‐Opa1 pathway, which subsequently promotes chemoresistance in breast cancer stem cells. A previously unknown role is identified for tumor cell‐intrinsic CD96 and an attractive target in improving the chemotherapeutic response.

Abstract At present, dental implant surgery mainly relies on the clinical experience of the doctor and the assistance of preoperative medical imaging. However, there are some problems in dental implant surgery, such as narrow space, sight obstruction, inaccurate positioning, and high requirements of doctors' proficiency. Therefore, a dental implant robot system (DIRS) guided by optical navigation is developed in this study, with an x-shaped tool and an irregular pentagonal tracer are designed for spatial registration and needle tip positioning strategy respectively. The coordinate system of each unit in DIRS is unified through system calibration, spatial registration, and needle tip positioning strategy. Then the surgical path is planned on the computed tomography (CT) images in the navigation software before operation. The automatic positioning method and the auxiliary positioning method can be used in the operation to achieve accurate positioning and assist doctors to complete the operation. The errors of spatial registration, needle tip positioning strategy, and the overall accuracy of the system were evaluated respectively, and the results showed that they all met the needs of clinical surgery. This study preliminarily verified the feasibility of the precise positioning method for dental surgery robots and provided certain ideas for subsequent related research.

Abstract Background Deregulation of cell-cycle pathway is ubiquitously observed in human papillomavirus negative (HPVneg) head and neck squamous cell carcinoma (HNSCC). Despite being an attractive target, CDK4/6 inhibition using palbociclib showed modest or conflicting results as monotherapy or in combination with platinum-based chemotherapy or cetuximab in HPVneg HNSCC. Thus, innovative agents to augment the efficacy of palbociclib in HPVneg HNSCC would be welcomed. Methods A collection of 162 FDA-approved and investigational agents was screened in combinatorial matrix format, and top combinations were validated in a broader panel of HPVneg HNSCC cell lines. Transcriptional profiling was conducted to explore the molecular mechanisms of drug synergy. Finally, the most potent palbociclib-based drug combination was evaluated and compared with palbociclib plus cetuximab or cisplatin in a panel of genetically diverse HPVneg HNSCC cell lines and patient-derived xenograft models. Results Palbociclib displayed limited efficacy in HPVneg HNSCC as monotherapy. The high-throughput combination drug screening provided a comprehensive palbociclib-based drug-drug interaction dataset, whereas significant synergistic effects were observed when palbociclib was combined with multiple agents, including inhibitors of the PI3K, EGFR, and MEK pathways. PI3K pathway inhibitors significantly reduced cell proliferation and induced cell-cycle arrest in HPVneg HNSCC cell lines when combined with palbociclib, and alpelisib (a PI3Kα inhibitor) was demonstrated to show the most potent synergy with particularly higher efficacy in HNSCCs bearing PIK3CA alterations. Notably, when compared with cisplatin and cetuximab, alpelisib exerted stronger synergism in a broader panel of cell lines. Mechanistically, RRM2-dependent epithelial mesenchymal transition (EMT) induced by palbociclib, was attenuated by alpelisib and cetuximab rather than cisplatin. Subsequently, PDX models with distinct genetic background further validated that palbociclib plus alpelisib had significant synergistic effects in models harboring PIK3CA amplification. Conclusions This study provides insights into the systematic combinatory effect associated with CDK4/6 inhibition and supports further initiation of clinical trials using the palbociclib plus alpelisib combination in HPVneg HNSCC with PIK3CA alterations.

A two-step fermentation method was used to prepare Hovenia dulcis Thunb Huangjiu, its physical and chemical indexes were tested, and its antioxidant capacity was evaluated. To explore the reasons for its antioxidant, the total phenols and total flavonoids in soaked and fermented Hovenia dulcis Thunb Huangjiu were compared, and the differences in the content of the main active ingredients dihydromyricetin and myricetin were further analyzed by high-performance liquid chromatography. The results showed that Huangjiu fermented with Hovenia dulcis Thunb (HFH) belonged to special type semi-dry Huangjiu. It had medicinal aroma, improved bitterness and astringency, and better taste. Its VC milligram equivalents on DPPH, ABTS, OH free radical scavenging ability and reducing power were 0.727, 33.60, 9.07 and 0.823 mg VC/mL, which were higher than those of Huangjiu. After comparison, it was found that the total phenol content of HFH was 1120.20 mg/L, which was significantly higher than that of the soaked type (P

AIM: To explore the current situation of myopia among children and adolescents in Mengzi city and the possible influencing factors of myopia.METHODS: A multi-stage cluster sampling method was used to select students in 7 schools(2 primary schools, 2 junior high schools, 2 high schools, and 1 vocational high school)in Mengzi city, Yunnan Province in October 2019. A total of 1 837 students were selected for questionnaire surveys, and examination of distance visual acuity and noncycloplegic autorefraction. There were 1 622 valid questionnaires were finally collected after checking the integrity and rationality of the questionnaires. RESULTS: The prevalence of myopia among primary and secondary students in Mengzi city in 2019 was 61.34%. The prevalence of myopia in girls(71.36%)was higher than that in boys(50.45%), and the prevalence of myopia in Han nationality(70.19%)was higher than that in ethnic minorities(57.70%). With the grade growth, the prevalence of myopia showed an upward trend. Multivariate Logistic regression analysis showed that the risk factors of myopia were female(OR=2.308), Han nationality(OR=1.712), higher learning stage(junior high school: OR=1.579, high school: OR=5.538), the time of doing homework daily in the past 1wk(1-

In order to provide accurate meteorological services for grain storage and ensure the safety of grain storage, based on the grain situation data of three grain depot in Jiamusi and the observation data of local meteorological stations from 2017 to 2020, the temperature, relative humidity and their correlation inside and outside the station and the granary were explored and analyzed by using mathematical statistics method. The results showed that the real-time temperature of meteorological stations was mostly lower than that outside the granary, and the two showed synchronous oscillation changes with little difference. R was above 0.996. The relative humidity of meteorological stations was higher than that outside the granary, and the two basically showed consistent changes. The relative humidity inside the granary was generally controlled below 70%. The daily maximum temperature of meteorological stations had a good correlation with the temperature in the warehouse and the maximum grain temperature in the surface layer, and R reached above 0.90. The change of warehouse temperature and the maximum grain temperature in the surface layer lagged behind the change of daily maximum temperature for about 1 d and 30 d, respectively. The regression equations of the daily maximum temperature of meteorological stations with the warehouse temperature and the maximum grain temperature in the surface layer were all positively correlated, and increased with the increase of the daily maximum temperature. The maximum grain temperature in other layers was less affected by temperature. According to the regression equation, the warehouse temperature and the maximum grain temperature in each layer were predicted, and the high temperature index of meteorological service in large warehouses was 28 ℃, and the ventilation and humidity service index was less than 70%.