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Abstract Tumor embolization therapy has attracted great attention due to its high efficiency in inhibiting tumor growth by cutting off tumor nutrition and oxygen supply by the embolic agent. Although transcatheter arterial embolization (TAE) is the mainstream technique in the clinic, there are still some limitations to be considered, especially the existence of high risks and complications. Recently, nanomaterials have drawn wide attention in disease diagnosis, drug delivery, and new types of therapies, such as photothermal therapy and photodynamic therapy, owing to their unique optical, thermal, convertible and in vivo transport properties. Furthermore, the utilization of nanoplatforms in tumor non-interventional embolization therapy has attracted the attention of researchers. Herein, the recent advances in this area are summarized in this review, which revealed three different types of nanoparticle strategies: (1) nanoparticles with active targeting effects or stimuli responsiveness (ultrasound and photothermal) for the safe delivery and responsive release of thrombin; (2) tumor microenvironment (copper and phosphate, acidity and GSH/H2O2)-responsive nanoparticles for embolization therapy with high specificity; and (3) peptide-based nanoparticles with mimic functions and excellent biocompatibility for tumor embolization therapy. The benefits and limitations of each kind of nanoparticle in tumor non-interventional embolization therapy will be highlighted. Investigations of nanoplatforms are undoubtedly of great significance, and some advanced nanoplatform systems have arrived at a new height and show potential applications in practical applications.

Abstract The potential role of DNA methylation from paracancerous tissues in cancer diagnosis has not been explored until now. In this study, we built classification models using well-known machine learning models based on DNA methylation profiles of paracancerous tissues. We evaluated our methods on nine cancer datasets collected from The Cancer Genome Atlas (TCGA) and utilized fivefold cross-validation to assess the performance of models. Additionally, we performed gene ontology (GO) enrichment analysis on the basis of the significant CpG sites selected by feature importance scores of XGBoost model, aiming to identify biological pathways involved in cancer progression. We also exploited the XGBoost algorithm to classify cancer types using DNA methylation profiles of paracancerous tissues in external validation datasets. Comparative experiments suggested that XGBoost achieved better predictive performance than the other four machine learning methods in predicting cancer stage. GO enrichment analysis revealed key pathways involved, highlighting the importance of paracancerous tissues in cancer progression. Furthermore, XGBoost model can accurately classify nine different cancers from TCGA, and the feature sets selected by XGBoost can also effectively predict seven cancer types on independent GEO datasets. This study provided new insights into cancer diagnosis from an epigenetic perspective and may facilitate the development of personalized diagnosis and treatment strategies.

Elderly individuals frequently report cognitive decline, while various studies indicate hippocampal functional declines with advancing age. Hippocampal function is influenced by ghrelin through hippocampus-expressed growth hormone secretagogue receptor (GHSR). Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous GHSR antagonist that attenuates ghrelin signaling. Here, we measured plasma ghrelin and LEAP2 levels in a cohort of cognitively normal individuals older than 60 and found that LEAP2 increased with age while ghrelin (also referred to in literature as “acyl-ghrelin”) marginally declined. In this cohort, plasma LEAP2/ghrelin molar ratios were inversely associated with Mini-Mental State Examination scores. Studies in mice showed an age-dependent inverse relationship between plasma LEAP2/ghrelin molar ratio and hippocampal lesions. In aged mice, restoration of the LEAP2/ghrelin balance to youth-associated levels with lentiviral shRNA Leap2 downregulation improved cognitive performance and mitigated various age-related hippocampal deficiencies such as CA1 region synaptic loss, declines in neurogenesis, and neuroinflammation. Our data collectively suggest that LEAP2/ghrelin molar ratio elevation may adversely affect hippocampal function and, consequently, cognitive performance; thus, it may serve as a biomarker of age-related cognitive decline. Moreover, targeting LEAP2 and ghrelin in a manner that lowers the plasma LEAP2/ghrelin molar ratio could benefit cognitive performance in elderly individuals for rejuvenation of memory.

Purine adenosine pathway exists widely in the body metabolism, and is involved in regulating various physiological processes. It is one of the important pathways of environmental regulation in human body. CD73 is essentially a protease that catalyzes further dephosphorylation of extracellular adenine nucleotides, hydrolyzing extracellular AMP to adenosine and phosphate. CD73 is an important part of the adenosine signaling pathway. Studies have shown that CD73-mediated adenosine pathway can convert the inflammatory ATP into the immunosuppressant adenosine. This paper aims to summarize the relevant effects of CD73 in the occurrence, development and prognosis of liver diseases such as viral hepatitis, highlight the important role of CD73 in liver diseases, especially in viral hepatitis such as HBV and HCV, and explore new clinical ideas for future treatment targets of liver diseases.

With the widespread prevalence of drug-resistant pathogens, traditional antibiotics have limited effectiveness and do not yield the desired outcomes. Recently, alternative antibacterial therapies based on ultrasound (US) have been explored to overcome the crisis of bacterial pathogens. Antimicrobial sonodynamic therapy (aSDT) offers an excellent solution that relies on US irradiation to produce reactive oxygen species (ROS) and achieve antibiotic-free mediated antimicrobial effects. In addition, aSDT possesses the advantage of superior tissue penetrability of US compared to light irradiation, demonstrating great feasibility in treating deep infections. Although existing conventional sonosensitizers can produce ROS for antimicrobial activity, some limitations, such as low penetration rate, nonspecific distribution and poor ROS production under hypoxic conditions, result in suboptimal sterilization in aSDT. Recently, emerging nanosonosensitizers have enormous advantages as high-performance agents in aSDT, which overcome the deficiencies of conventional sonosensitizers as described above. Thus, nanosonosensitizer-mediated aSDT has a bright future for the management of bacterial infections. This review classifies the current available nanosonosensitizers and provides an overview of the mechanisms, biomedical applications, recent advances and perspectives of aSDT.

Objectives In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting. Methods Using the International Metastatic Renal Cell Carcinoma Database Consortium (imdc) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (mrcc) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (vegfr) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (os) and time to treatment failure (ttf) were calculated using Kaplan-Meier curves. Overall response rates (orrs) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment. Results The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median os was observed: 22.10 months [95% confidence interval (ci): 17.18 months to not reached] with nivolumab and 23.70 months (95% ci: 15.52 months to not reached) with cabozantinib (p = 0.61). The ttf was also similar at 6.90 months (95% ci: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% ci: 5.52 months to 12.85 months) with cabozantinib (p = 0.20). The adjusted hazard ratio (hr) for nivolumab compared with cabozantinib was 1.30 (95% ci: 0.73 to 2.3), p = 0.38. When adjusted by imdc criteria and age, the hr was 1.32 (95% ci: 0.74 to 2.38), p = 0.35. Conclusions Real-world imdc data indicate comparable os and ttf for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line vegfr-targeted therapy. [ABSTRACT FROM AUTHOR]

Abstract Albumin-biomineralized copper sulfide nanoparticles (Cu2−xS NPs) have attracted much attention as an emerging phototheranostic agent due to their advantages of facile preparation method and high biocompatibility. However, comprehensive preclinical safety evaluation is the only way to meet its further clinical translation. We herein evaluate detailedly the safety and hepatotoxicity of bovine serum albumin-biomineralized Cu2−xS (BSA@Cu2−xS) NPs with two different sizes in rats. Large-sized (LNPs, 17.8 nm) and small-sized (SNPs, 2.8 nm) BSA@Cu2−xS NPs with great near-infrared absorption and photothermal conversion efficiency are firstly obtained. Seven days after a single-dose intravenous administration, SNPs distributed throughout the body are cleared primarily through the feces, while a large amount of LNPs remained in the liver. A 14-day subacute toxicity study with a 28-day recovery period are conducted, showing long-term hepatotoxicity without recovery for LNPs but reversible toxicity for SNPs. Cellular uptake studies indicate that LNPs prefer to reside in Kupffer cells, leading to prolonged and delayed hepatotoxicity even after the cessation of NPs administration, while SNPs have much less Kupffer cell uptake. RNA-sequencing analysis for gene expression indicates that the inflammatory pathway, lipid metabolism pathway, drug metabolism-cytochrome P450 pathway, cholesterol/bile acid metabolism pathway, and copper ion transport/metabolism pathway are compromised in the liver by two sizes of BSA@Cu2−xS NPs, while only SNPs show a complete recovery of altered gene expression after NPs discontinuation. This study demonstrates that the translational feasibility of small-sized BSA@Cu2−xS NPs as excellent nanoagents with manageable hepatotoxicity. Graphical Abstract

Alternative splicing is dysregulated in hepatocellular carcinoma. Here, the authors investigate the role of the splice variant of Splicing Regulatory Glutamic Acid and Lysine Rich Protein 1 (SREK1) and its upstream regulator, Serine/arginine-rich splicing factor 10 (SRSF10) in sustaining the oncogenic signal.

BackgroundArsenic is a well-known environmental toxicant. Hepatic fibrosis could occur dueto excessive or long-term exposure to arsenic, while associated molecular mechanisms remain undefined. Mitogen-inducible gene 6 (Mig-6) exhibits a protective effect on numerous diseases or cancers. However, the specific role of Mig-6 in the mechanisms of arsenite-induced hepatic fibrosis remains indistinct.ObjectiveTo investigate the specific role of Mig-6 in the activation of hepatic stellate cells (HSC) and the deposition of extracellular matrix (ECM) induced by sodium arsenite (NaAsO2).MethodsHuman hepatic stellate cells (Lx-2) were treated with 0, 1.875, 3.75, 7.5, and 15 μmol·L−1 of NaAsO2 for 24 h, or with 7.5 μmol·L−1 NaAsO2 for 0, 12, 24, 48, and 72 h. Additionally, Lx-2 cells were transfected by pcDNA3.1(+)/Mig-6, then treated with 7.5 μmol·L−1 NaAsO2 for 24 h; a blank control group, a pcDNA3.1(+)-control group, a pcDNA3.1(+)/Mig-6 group, and an arsenic (7.5 μmol·L−1 NaAsO2) group were also set up. After transfection, the cells and culture supernatants were collected, and the protein levels of Mig-6, α-smooth muscle actin (α-SMA), and transforming growth factor-β1 (TGF-β1) in Lx-2 cells were identified by Western blotting analysis; moreover, the secretion levels of main ECM components in supernatants such as hyaluronic acid (HA), laminin (LN), collagens IV (COL-IV), and procollagen-III (PIIINP) were tested by ELISA. ResultsThe Mig-6 expression decreased in the 3.75, 7.5, and 15 μmol·L−1 NaAsO2 groups (0.561±0.095, 0.695±0.048, and 0.401±0.030) compared to the control group (1.000±0.000) in Lx-2 cells (P

IntroductionThe community structure of groundwater microorganisms has a significant impact on groundwater quality. However, the relationships between the microbial communities and environmental variables in groundwater of different recharge and disturbance types are not fully understood.MethodsIn this study, measurements of groundwater physicochemical parameters and 16S rDNA high-throughput sequencing technology were used to assess the interactions between hydrogeochemical conditions and microbial diversity in Longkou coastal aquifer (LK), Cele arid zone aquifer (CL), and Wuhan riverside hyporheic zone aquifer (WH). Redundancy analysis indicated that the primary chemical parameters affecting the microbial community composition were NO3–, Cl–, and HCO3–.ResultsThe species and quantity of microorganisms in the river–groundwater interaction area were considerably higher than those in areas with high salinity [Shannon: WH (6.28) > LK (4.11) > CL (3.96); Chao1: WH (4,868) > CL (1510) > LK (1,222)]. Molecular ecological network analysis demonstrated that the change in microbial interactions caused by evaporation was less than that caused by seawater invasion under high-salinity conditions [(nodes, links): LK (71,192) > CL (51,198)], whereas the scale and nodes of the microbial network were greatly expanded under low-salinity conditions [(nodes, links): WH (279,694)]. Microbial community analysis revealed that distinct differences existed in the classification levels of the different dominant microorganism species in the three aquifers.DiscussionEnvironmental physical and chemical conditions selected the dominant species according to microbial functions. Gallionellaceae, which is associated with iron oxidation, dominated in the arid zones, while Rhodocyclaceae, which is related to denitrification, led in the coastal zones, and Desulfurivibrio, which is related to sulfur conversion, prevailed in the hyporheic zones. Therefore, dominant local bacterial communities can be used as indicators of local environmental conditions.

Arsenic is a well known environmental hazardous material, chronic arsenic exposure results in different types of liver damage. Among them, liver fibrosis has become a research hotspot because of its reversibility, while the underlying mechanism is still unclear. Previous studies revealed that EGFR/ERK signaling appears to play an important role in fibrosis diseases. In this study, sprague-dawley rats were exposed to different doses of arsenite for 36 weeks to investigate the roles of EGFR/ERK signaling on arsenite-induced liver fibrogenesis. Our results showed that long-term arsenite exposure induced liver fibrosis, accompanied by hepatic stellate cells (HSCs) activation, excessive serum secretion of extracellular matrix (ECM), and hepatocytes epithelial-mesenchymal transformation (EMT). In addition, arsenite exposure caused hyperphosphorylation of EGFR/ERK signaling in liver tissue of rats, indicating that EGFR/ERK signaling may be involved in arsenite-induced liver fibrosis. Indeed, erlotinib (a specific phosphorylation inhibitor of EGFR) intervention significantly decreased arsenite induced hyperphosphorylation of EGFR/ERK signaling, thereby suppressed hepatocytes EMT process and alleviated liver fibrogenesis in arsenite exposed rats. In summary, the present study provides evidences showing that hyperphosphorylation of EGFR/ERK signaling facilitates long-term arsenite-induced hepatocytes EMT and liver fibrosis in rats, which brings new insights into the pathogenesis of arsenic-induced liver injury.

Background Thrombolysis is the first-line treatment for patients with acute ischemic stroke. Previous studies leveraged machine learning to assist neurologists in selecting patients who could benefit the most from thrombolysis. However, when designing the algorithm, most of the previous algorithms traded interpretability for predictive power, making the algorithms hard to be trusted by neurologists and be used in real clinical practice. Methods Our proposed algorithm is an advanced version of classical k-nearest neighbors classification algorithm (KNN). We achieved high interpretability by changing the isotropy in feature space of classical KNN. We leveraged a cohort of 189 patients to prove that our algorithm maintains the interpretability of previous models while in the meantime improving the predictive power when compared with the existing algorithms. The predictive powers of models were assessed by area under the receiver operating characteristic curve (AUC). Results In terms of interpretability, only onset time, diabetes, and baseline National Institutes of Health Stroke Scale (NIHSS) were statistically significant and their contributions to the final prediction were forced to be proportional to their feature importance values by the rescaling formula we defined. In terms of predictive power, our advanced KNN (AUC 0.88) outperformed the classical KNN (AUC 0.75, p = 0.0192 ). Conclusions Our preliminary results show that the advanced KNN achieved high AUC and identified consistent significant clinical features as previous clinical trials/observational studies did. This model shows the potential to assist in thrombolysis patient selection for improving the successful rate of thrombolysis.

Salmonella: mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models, but the detailed mechanism remains unsolved. In this report, the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma allografts. Since flagella are key inducers of the host immune response during bacterial infection, flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer therapy. The results showed that flagellum-deficient strains failed to induce significant anti-tumor effects, even when more bacteria were administered to offset the difference in invasion efficiency. Flagella mainly activate immune cells via Flagellin/Toll-like receptor 5 (TLR5) signalling pathway. Indeed, we showed that exogenous activation of TLR5 signalling by recombinant Flagellin and exogenous expression of TLR5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against melanoma. Our study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/TLR5 signalling pathway during Salmonella-mediated cancer therapy, thereby suggesting the potential application of TLR5 agonists in the cancer immune therapy.

In the treatment of ischemic stroke, timely and efficient recanalization of occluded brain arteries can successfully salvage the ischemic brain. Thrombolysis is the first-line treatment for ischemic stroke. Machine learning models have the potential to select patients who could benefit the most from thrombolysis. In this study, we identified 29 related previous machine learning models, reviewed the models on the accuracy and feasibility, and proposed corresponding improvements. Regarding accuracy, lack of long-term outcome, treatment option consideration, and advanced radiological features were found in many previous studies in terms of model conceptualization. Regarding interpretability, most of the previous models chose restrictive models for high interpretability and did not mention processing time consideration. In the future, model conceptualization could be improved based on comprehensive neurological domain knowledge and feasibility needs to be achieved by elaborate computer science algorithms to increase the interpretability of flexible algorithms and shorten the processing time of the pipeline interpreting medical images.

Abstract Therapeutic vaccines, an exciting development in cancer immunotherapy, share the goal of priming of personalized antigen‐specific T‐cell response by precise antigen presentation of dendritic cells (DCs), but major obstacles include insufficient antigen loading and off‐target to DCs remain to their success. Here, we developed an imageable therapeutic vaccine with whole‐antigen loading and target delivery constructed by ovalbumin (OVA)‐biomineralized Bi2S3 nanoparticles‐pulsed DCs. Relying on the strong X‐ray absorption and fluorescence labeling performance of Bi2S3@OVA nanoparticles, the in vivo spatiotemporal fate of the vaccine (Bi2S3@OVA@DC) can be noninvasively monitored by computed tomography and near‐infrared fluorescence imaging in real time. The Bi2S3@OVA@DC can rapidly and durably accumulate in draining lymph nodes and thus trigger stronger T‐cell responses compared to OVA‐pulsed DCs. Meanwhile, Bi2S3@OVA@DC can further achieve in vivo antitumor effects against OVA‐expressing B16F10 melanoma when combined with fractionated radiotherapy, resulting from the upregulation of cytotoxic CD8+ T cells and restraint of regulatory T cells in the tumor microenvironment, and the systemical secretion of OVA‐specific IgG1/IgG2α antibody. Overall, we successfully fabricated an engineered DC vaccine featured in high whole‐antigen loading capacity that can be precisely delivered to the lymphatic system for visualization, serving as a powerful therapeutic platform for cancer radioimmunotherapy.

Background: As warthogs (Phacochoerus africanus) have innate immunity against African swine fever (ASF), it is critical to understand the evolutionary novelty of warthogs to explain their specific ASF resistance. Methods: Here, we present two completed new genomes of one warthog and one Kenyan domestic pig as fundamental genomic references to elucidate the genetic mechanisms of ASF tolerance. Results: Multiple genomic variations, including gene losses, independent contraction, and the expansion of specific gene families, likely molded the warthog genome to adapt to the environment. Importantly, the analysis of the presence and absence of genomic sequences revealed that the DNA sequence of the warthog genome had an absence of the gene lactate dehydrogenase B (LDHB) on chromosome 2 compared with the reference genome. The overexpression and siRNA of LDHB inhibited the replication of the African swine fever virus. Combined with large-scale sequencing data from 42 pigs worldwide, the contraction and expansion of tripartite motif-containing (TRIM) gene families revealed that TRIM family genes in the warthog genome are potentially responsible for its tolerance to ASF. Conclusion: Our results will help improve the understanding of genetic resistance to ASF in pigs.

Abstract Background Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms in part, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms. Methods Sprague–Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II (1 μM) with or without the indicated concentration (0.5, 1, 10 μM) of DAPA. The protein levels of collagen and TGF-β1/Smad signaling were measured along with body weight, and blood biochemical indexes. Results DAPA pretreatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA pretreatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-β1/Smads signaling. Conclusion DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a non-glucose-lowering dependent manner.

The biological macromolecule Nocardia rubra cell-wall skeleton (Nr-CWS) has well-established immune-stimulating and anti-tumor activities. However, the role of Nr-CWS on natural killer (NK) cells remains unclear. Here, we explore the function and related mechanisms of Nr-CWS on NK cells. Using a tumor-bearing model, we show that Nr-CWS has slightly effect on solid tumor. In addition, using a tumor metastasis model, we show that Nr-CWS suppresses the lung metastasis induced by B16F10 melanoma cells in mice, which indicates that Nr-CWS may up-regulate the function of NK cells. Further investigation demonstrated that Nr-CWS can increase the expression of TRAIL and FasL on spleen NK cells from Nr-CWS treated B16F10 tumor metastasis mice. The spleen index and serum levels of TNF-α, IFN-γ, and IL-2 in B16F10 tumor metastasis mice treated with Nr-CWS were significantly increased. In vitro, the studies using purified or sorted NK cells revealed that Nr-CWS increases the expression of CD69, TRAIL, and FasL, decreases the expression of CD27, and enhances NK cell cytotoxicity. The intracellular expression of IFN-γ, TNF-α, perforin (prf), granzyme-B (GrzB), and secreted TNF-α, IFN-γ, IL-6 of the cultured NK cells were significantly increased after treatment with Nr-CWS. Overall, the findings indicate that Nr-CWS could suppress the lung metastasis induced by B16F10 melanoma cells, which may be exerted through its effect on NK cells by promoting NK cell terminal differentiation (CD27lowCD11bhigh), and up-regulating the production of cytokines and cytotoxic molecules.

Head and neck squamous cell carcinoma (HNSCC) have a high incidence and mortality rate, and investigating the pathogenesis and potential therapeutic strategies of HNSCC is required for further progress. Immunotherapy is a considerable therapeutic strategy for HNSCC due to its potential to produce a broad and long-lasting antitumor response. However, immune escape, which involves mechanisms including dyregulation of cytokines, perturbation of immune checkpoints, and recruitment of inhibitory cell populations, limit the efficacy of immunotherapy. Currently, multiple immunotherapy strategies for HNSCC have been exploited, including immune checkpoint inhibitors, costimulatory agonists, antigenic vaccines, oncolytic virus therapy, adoptive T cell transfer (ACT), and epidermal growth factor receptor (EGFR)-targeted therapy. Each of these strategies has unique advantages, and the appropriate application of these immunotherapies in HNSCC treatment has significant value for patients. Therefore, this review comprehensively summarizes the mechanisms of immune escape and the characteristics of different immunotherapy strategies in HNSCC to provide a foundation and consideration for the clinical treatment of HNSCC.

Background: For patients who treated with tacrolimus after kidney transplant, therapeutic drug monitoring is essential to improve their prognosis. However, previous detection methods have limitations, such as the overestimation and unacceptable bias in the immunoassays. Precision medicine has been challenged. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is recognized as the gold standard due to its accuracy and specificity, but lack of throughput and complex process limits its clinical application. Therefore, an accurate, simple and high throughput method for tacrolimus monitoring is needed for clinical practice. Methods: A modified LC-MS/MS method was introduced and validated. Whole blood samples were prepared by a one-step protein precipitation method. Chromatographic separation was achieved using a Phenomenex Kinetex 2.6 μm XB-C18 2.1 × 50 mm column with a total run time of 3.5 min to avoid matrix effect. An electrospray ionization source (ESI) was used in positive ion multiple reaction monitoring (MRM) mode for mass spectrometric detection. In order to protect the mass spectrometer, only part of the sample after LC separation was allowed to enter the mass spectrum, through a two HPLC systems coupled one mass spectrometry design. In this way, the instrument throughput is also improved and realizing the detection of 2 samples within 3.5 min and carried out a shorter analyzing time for each sample of 1.75 min. Additionally, we calculated tacrolimus-intrapatient variant (Tac-IPV) based on this modified method and assessed the prognostic value of Tac-IPV in Chinese kidney transplant patients. Results: The LC-MS/MS was modified by streamlining the procedure and increasing the throughput. The method proved to be accurate and reproducible with all performance parameters suitably meeting the clinical requirements over a calibration ranged from 0.37 to 42.90 ng/mL. Parameters such as linearity, limit of quantification (LoQ) and dilution integrity were validated with a clinical reportable range from 0.37 to 343.20 ng/mL, which was particularly useful for high drug concentrations patients (rare but very serious). Both cross-contamination and matrix effects were negligible. Clinical data of 83 patients showed that Tac-IPV was associated with poor kidney transplant outcome in Chinese (Hazard Ratio (HR) = 3.96, 4.75; 95% Cl: 1.10–14.21, 1.23–18.36; P < 0.05). Conclusions: This modified LC-MS/MS method possessed high throughput and simple sample preparation, allowing it to meet daily clinical needs. At the same time, Tac-IPV based on this modified LC-MS/MS had excellent prognostic value in kidney transplantation. These advantages have great significance for the individualized treatment of Chinese kidney transplant patients and broad application of Tac-IPV.

ABSTRACT Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever acquired by tick bites. Whether mast cells (MCs), the body’s first line of defense against pathogens, might influence immunity or pathogenesis during SFTS virus (SFTSV) infection remained unknown. Here, we found that SFTSV can cause MC infection and degranulation, resulting in the release of the vasoactive mediators, chymase, and tryptase, which can directly act on endothelial cells, break the tight junctions of endothelial cells and threaten the integrity of the microvascular barrier, leading to microvascular hyperpermeability in human microvascular endothelial cells. Local activation of MCs (degranulation) and MC-specific proteases-facilitated endothelial damage were observed in mouse models. When MC-specific proteases were injected subcutaneously into the back skin of mice, signs of capillary leakage were observed in a dose-dependent manner. MC-specific proteases, chymase, and tryptase were tested in the serum collected at the acute phase of SFTS patients, with the higher level significantly correlated with fatal outcomes. By performing receiver operator characteristic curve (ROC) analysis, chymase was determined as a biomarker with the area under the curve value of 0.830 (95% CI = 0.745 to 0.915) for predicting fatal outcomes in SFTS. Our findings highlight the importance of MCs in SFTSV-induced disease progression and outcome. An emerging role for MCs in the clinical prognosis and blocking MC activation as a potential drug target during SFTSV infection was proposed. IMPORTANCE We revealed a pathogenic role for MCs in response to SFTSV infection. The study also identifies potential biomarkers that could differentiate patients at risk of a fatal outcome for SFTS, as well as novel therapeutic targets for the clinical management of SFTS. These findings might shed light on an emerging role for MCs as a potential drug target during infection of other viral hemorrhagic fever diseases with similar host pathology as SFTS.

Background To evaluate the prognostic significance of systemic inflammation score (SIS) for patients undergoing video-assisted thoracoscopic surgery (VATS) lobectomy for non-small-cell lung cancers (NSCLCs). Methods: This retrospective cohort study was conducted on the prospectively maintained database in our institution during the study period. Preoperative SIS comprising serum albumin (sALB) and lymphocyte-to-monocyte ratio (LMR) was graded into 0, 1 and 2. Survival analysis was performed to distinguish differences in postoperative survival between three groups of SIS. Finally, multivariate Cox proportional hazards regression analyses were conducted to determine independent prognostic factors. Results: There were 390 patients with operable NSCLCs included. We applied sALB at 40 g/L and our median LMR at 3.91 as the cutoffs for modified SIS scoring criteria. Both overall survival (OS) and disease-free survival (DFS) were significantly shortened in a step-wise fashion with each 1-point increase in SIS (Log-rank p

Abstract The striatum is structurally highly diverse, and its organ functionality critically depends on normal embryonic development. Although several studies have been conducted on the gene functional changes that occur during striatal development, a system-wide analysis of the underlying molecular changes is lacking. Here, we present a comprehensive transcriptome profile that allows us to explore the trajectory of striatal development and identify the correlation between the striatal development and Huntington’s disease (HD). Furthermore, we applied an integrative transcriptomic profiling approach based on machine learning to systematically map a global landscape of 277 transcription factor (TF) networks. Most of these TF networks are linked to biological processes, and some unannotated genes provide information about the corresponding mechanisms. For example, we found that the Meis2 and Six3 were crucial for the survival of striatal neurons, which were verified using conditional knockout (CKO) mice. Finally, we used RNA-Seq to speculate their downstream targets.

In this work, two Ni-based superalloys with 13 wt.% and 35 wt.% Co were prepared via selective laser melting (SLM), and the effects of Co on the microstructure and mechanical properties of the additively manufactured superalloys were investigated. As the Co fraction increased from 13 wt.% to 35 wt.%, the average grain size decreased from 25.69 μm to 17.57 μm, and the size of the nano-phases significantly increased from 80.54 nm to 230 nm. Moreover, the morphology of the γ′ phase changed from that of a cuboid to a sphere, since Co decreased the γ/γ′ lattice mismatch from 0.64% to 0.19%. At room temperature, the yield strength and ultimate tensile strength of the 13Co alloy reached 1379 MPa and 1487.34 MPa, and those of the 35Co alloy were reduced to 1231 MPa and 1350 MPa, while the elongation increased by 52%. The theoretical calculation indicated that the precipitation strengthening derived from the γ′ precipitates made the greatest contribution to the strength.

In computer vision, fine-grained classification has become an important issue in recognizing objects with slight visual differences. Usually, it is challenging to generate good performance when solving fine-grained classification problems using traditional convolutional neural networks. To improve the accuracy and training time of convolutional neural networks in solving fine-grained classification problems, this paper proposes a tree-structured framework by eliminating the effect of differences between clusters. The contributions of the proposed method include the following three aspects: (1) a self-supervised method that automatically creates a classification tree, eliminating the need for manual labeling; (2) a machine-learning matcher which determines the cluster to which an item belongs, minimizing the impact of inter-cluster variations on classification; and (3) a pruning criterion which filters the tree-structured classifier, retaining only the models with superior classification performance. The experimental evaluation of the proposed tree-structured framework demonstrates its effectiveness in reducing training time and improving the accuracy of fine-grained classification across various datasets in comparison with conventional convolutional neural network models. Specifically, for the CUB 200 2011, FGVC aircraft, and Stanford car datasets, the proposed method achieves a reduction in training time of 32.91%, 35.87%, and 14.48%, and improves the accuracy of fine-grained classification by 1.17%, 2.01%, and 0.59%, respectively.

In this work, a method concerning thermal consolidation is proposed to simulate the traditional powder metallurgy process and accomplish the composition screening of powder metallurgy Ni-based superalloys U720Li and RR1000 with rare metal scandium, and superalloys with zero scandium addition, medium scandium addition and high scandium addition are selected. Then effects of scandium on the microstructure and mechanical properties of superalloys are further investigated through fast hot pressed sintering. The results indicate that scandium doping can effectively refine the grain through modifying the size and volume fraction of primary γ’ precipitates at the grain boundary. Meanwhile, scandium can promote the growth and precipitation of secondary γ’ precipitates to some extent. Due to the comprehensive effects of γ’ precipitate modification and grain boundary strengthening, as-sintered U720Li with 0.043 wt.% scandium presents an excellent combination of tensile strength and ductility at ambient and elevated temperature while as-sintered RR1000 with 0.064 wt.% scandium has a good performance at elevated temperature.

The distribution grid is undergoing profound changes nowadays, and state estimator has become an essential part in the control room to enable future smart grid. The newly deployed micro phase measurement units (μPMU) and advanced metering infrastructure (AMI) devices make the real-time state estimation possible for distribution system. Therefore, this paper studies the incorporation and process of the multi-source measurements and proposes a fast three-phase state estimation based on the hybrid measurements scheme. By the process of μPMU measurements, pseudo voltage measurements are added, which significantly increases the estimation redundancy. For AMI measurements, the harmonic components model is used to overcome the asynchronicity problem. An improved sequential state estimation based on the changed measurements is proposed to enable a fast estimation. IEEE 13-node and 390-node systems are simulated to verify the efficacy and efficiency of the proposed method.

Abstract Background Porcine epidemic diarrhea virus (PEDV) is a causative agent of serious viral enteric disease in suckling pigs. Such diseases cause considerable economic losses in the global swine industry. Enhancing our knowledge of PEDV-induced transcriptomic responses in host cells is imperative to understanding the molecular mechanisms involved in the immune response. Here, we analyzed the transcriptomic profile of intestinal porcine epithelial cell line J2 (IPEC-J2) after infection with a classical strain of PEDV to explore the host response. Results In total, 854 genes were significantly differentially expressed after PEDV infection, including 716 upregulated and 138 downregulated genes. Functional annotation analysis revealed that the differentially expressed genes were mainly enriched in the influenza A, TNF signaling, inflammatory response, cytokine receptor interaction, and other immune-related pathways. Next, the putative promoter regions of the 854 differentially expressed genes were examined for the presence of transcription factor binding sites using the MEME tool. As a result, 504 sequences (59.02%) were identified as possessing at least one binding site of signal transducer and activator of transcription (STAT), and five STAT transcription factors were significantly induced by PEDV infection. Furthermore, we revealed the regulatory network induced by STAT members in the process of PEDV infection. Conclusion Our transcriptomic analysis described the host genetic response to PEDV infection in detail in IPEC-J2 cells, and suggested that STAT transcription factors may serve as key regulators in the response to PEDV infection. These results further our understanding of the pathogenesis of PEDV.

Responsive soft materials which can exhibit various three-dimensional (3D) shapes under the same stimulus are desirable for applications in adaptive and reconfigurable soft robots. Here, the authors report a laser rewritable magnetic composite film, whose responsive shape-morphing behaviors induced by a magnetic field can be digitally and repeatedly reprogrammed by a facile method of direct laser writing.

BackgroundThe internal orifice plays an important role in the pathogenesis and treatment of the most complex fistula-in-ano. The treatment of the internal orifice is considered to be the key to the success of anal fistula surgery. The objective of this study is to evaluate the feasibility of a new sphincter-sparing surgical approach for anal fistula.Materials and MethodsAll hospitalized anal fistula patients were included in this study. Preoperative anorectal ultrasound was done on all the patients. Transanal internal orifice alloy closure (IOAC) was performed through a disposable titanium nickel alloy anal fistula stapler. The external sphincter was not cut. An anal fistula brush was used to curette and clean fistulas. Postoperative anorectal color ultrasound was used for evaluation 2 months postoperatively.ResultsTwenty-one patients (male/female: 18/3, age: 39.7 ± 10.5 years) with fistula-in-ano were included (follow-up: 6–11 months).In total, 38.1% (8) had multiple tracts, and 9.5% (2) belonged to a high anal fistula. In total, 23.8% (5) of anal fistula patients were complicated by Crohn’s disease. The fistula healed completely in 85.7% (18/21) and did not heal in 14.3% (3/21). Three patients who did not heal had conventional surgery reperformed and eventually healed. Except for three patients undergoing additional traditional anal fistula surgery, the Wexner incontinence scores of other patients did not change after surgery compared with before surgery.ConclusionsIOAC is a novel sphincter-saving technique that is simply effective in treating anal fistula containing Crohn’s anal fistula.

Mukawa virus (MKWV), a novel tick-borne virus (TBV) of the genus Phlebovirus of family Phenuiviridae, has been firstly reported in Ixodes persulcatus in Japan. In this study, we made an epidemiological investigation in China to obtain the geographic distribution and genetic features of this virus outside Japan. We screened 1,815 adult ticks (665 I. persulcatus, 336 Dermacentor silvarum, 599 Haemaphysalis longicornis, 170 Rhipicephalus microplus, 45 Haemaphysalis concinna) and 805 wild small mammals collected from eight provinces. The positive rate of 6.77% (45/665, including 18 female and 27 male I. persulcatus) and 2.22% (1/45, 1 male H. concinna) were obtained from I. persulcatus and H. concinna in Heilongjiang province, respectively. No evidence of MKWV infection was found in other three tick species or any of the mammalian species. The virus can infect the Vero cells successfully, indicating the ability of MKWV to replicate in mammalian cells. A phylogenetic tree based on the nucleotide sequences of L, M, and S segments demonstrated that the Japanese MKWV variant, our two MKWV variants, and KURV were clustered with the members of the mosquito/sandfly-borne phleboviruses and distant from other tick-borne phenuiviruses. A phylogenetic analysis based on 895 bp partial L gene sequences (n = 46) showed that all MKWV sequences were separated into three lineages. Our results showed the presence of MKWV in I. persulcatus and H. concinna in northeast of China, highlighting the necessity of epidemiological study in wider regions. Due to the ability of MKWV to replicate in mammalian cells, the potential for zoonosis, and wide distribution of I. persulcatus and H. concinna in China, the important vectors of MKWV, further screening to more tick species, wild animals, domestic animals, and humans raises up practical significance.

Beijing Black pig is an excellent cultivated black pig breed in China, with desirable body shape, tender meat quality and robust disease resistance. To explore the level of admixture and selection signatures of Beijing Black pigs, a total number of 90 individuals covering nine pig breeds were used in our study, including Beijing Black pig, Large White, Landrace, Duroc, Lantang pig, Luchuan pig, Mashen pig, Huainan pig and Min pig. These animals were resequenced with 18.19 folds mapped read depth on average. Generally, we found that Beijing Black pig was genetically closer to commercial pig breeds by population genetic structure and genetic diversity analysis, and was also affected by Chinese domestic breeds Huainan pig and Min pig. These results are consistent with the cross-breeding history of Beijing Black pig. Selection signal detections were performed on three pig breeds, Beijing Black pig, Duroc and Large White, using three complementary methods (FST, θπ, and XP-EHH). In total, 1,167 significant selected regions and 392 candidate genes were identified. Functional annotations were enriched to pathways related to immune processes and meat and lipid metabolism. Finally, potential candidate genes, influencing meat quality (GPHA2, EHD1, HNF1A, C12orf43, GLTP, TRPV4, MVK, and MMAB), reproduction (PPP2R5B and MAP9), and disease resistance (OASL, ANKRD13A, and GIT2), were further detected by gene annotation analysis. Our results advanced the understanding of the genetic mechanism behind artificial selection of Beijing Black pigs, and provided theoretical basis for the subsequent breeding and genetic research of this breed.