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Objective: To provide the mechanism-based pharmacotherapy of the Huatan Qushi formula (HTQS formula), for the health management and treatment of non-alcoholic fatty liver disease (NAFLD). Methods: A rat model of NAFLD was employed to examine the efficacy and safety of the HTQS formula. In vivo active components and potential mechanisms of the HTQS formula were identified using UPLC‒MS/MS combined with network pharmacology. The influence of the HTQS formula on the dominating proteins in PI3K/Akt pathway was validated in vivo using western blot. Finally, 16S rRNA sequencing of the gut microbiome was conducted followed by targeted metabolomics detecting fecal short-chain fatty acids (SCFAs) and bile acids to determine the impact of the HTQS formula on gut microbiota. Results: The HTQS formula reduced weight gain and hepatic steatosis in NAFLD rats and decreased serum total cholesterol (TC), triglycerides, blood glucose, and insulin resistance (IR) without causing liver or kidney injury. We detected 28 components using UPLC‒MS/MS and identified 439 shared targets between NAFLD and the HTQS formula. Primarily, we focused on the PI3K/Akt signaling pathway based on protein‒protein interaction network analysis. We validated that the HTQS formula inhibited liver steatosis and inflammation by increasing the phosphorylation levels of PI3K, AKT, P27, GSK3β in the PI3K/Akt signaling pathway. 16S rRNA sequencing revealed that the HTQS formula reduced the abundance of the genus Family_XIII_AD3011_group, which was positively correlated with IR and taurodeoxycholic acid. In addition, Lachnospiraceae_UCG_010 inversely correlated with TC and five bile acids, which could be essential to the therapeutic effect of the HTQS formula against NAFLD. Conclusions: The HTQS formula proved to be an effective pharmacotherapy for NAFLD without causing liver or kidney injury. Multiple potent components of the HTQS formula could alleviate liver steatosis and lipid metabolism disorder by modulating the PI3K/Akt signaling pathway and restoring gut microbiota composition.

Abstract Extreme ultraviolet (EUV) light is difficult to focus due to strong absorption of most materials. Photon sieves (PS), rather than Fresnel zone plates (FZP), can focus EUV to smaller spot and suppress the higher orders of secondary maxima by several orders of magnitude. The number of pinholes used in PS is far more than that of transparent rings used in FZP, providing a great flexibility to manipulate structured focusing in EUV. In this work we investigate the Fermat-spiral PS to produce focused vortices with different topological charges. Experiment at the wavelength of 46.9 nm is carried out and multi-planar coherent diffractive imaging is used to retrieve the phase map of the focused EUV vortices. These results show the enormous potential of PS for manipulating EUV light. This study not only provides a compact, affordable substitute to focusing vortices where transmissive optics materials are unavailable, but also provides a route of converting various complex light manipulation ranging from visible light to EUV and soft x-ray.

Abstract Temporal transcriptional variation is a major contributor to functional evolution and the developmental process. Parthenogenetic water fleas of the genus Daphnia (Cladocera) provide an ideal model to characterize gene expression patterns across distinct developmental stages. Herein, we report RNA-seq data for female Daphnia mitsukuri at three developmental stages: the embryo, juvenile (three timepoints) and adult. Comparisons of gene expression patterns among these three developmental stages and weighted gene co-expression network analysis based on expression data across developmental stages identified sets of genes underpinning each of the developmental stages of D. mitsukuri. Specifically, highly expressed genes (HEGs) at the embryonic developmental stage were associated with cell proliferation, ensuring the necessary foundation for subsequent development; HEGs at the juvenile stages were associated with chemosensory perception, visual perception and neurotransmission, allowing individuals to enhance detection of potential environmental risks; HEGs at the adult stage were associated with antioxidative defensive systems, enabling adults to mount an efficient response to perceived environmental risks. Additionally, we found a significant overlap between expanded gene families of Daphnia species and HEGs at the juvenile stages, and these genes were associated with visual perception and neurotransmission. Our work provides a resource of developmental transcriptomes, and comparative analyses that characterize gene expression dynamics throughout development of Daphnia.

Aim: To investigate the clinical features, diagnosis and treatment of lymphoepithelioma-like carcinoma (LELC).Materials & methods: The clinical data of 114 LELC patients were retrospectively analyzed.Results: Ninety-eight patients (86.0%) were Epstein-Barr virus-encoded small RNA (EBER) positive detected by situ hybridization. A 67.1% (51/76) patients had PD-L1 expression. The 5-year overall survival rate of EBER negative patients was 51.6% while the rate of positive patients was 84.8% (p = 0.015). The 5-year progression free survival rate of EBER negative patients was 40.2% while the rate of positive patients was 70.2% (p = 0.004).Conclusion: The progression of LELC is relatively slow and present a better prognosis. The occurrence of tumor is closely related to Epstein–Barr virus infection and PD-L1 is highly expressed in tumor cells.

Abstract Extreme-ultraviolet (EUV) radiation is a promising tool, not only for probing microscopic activities but also for processing nanoscale structures and performing high-resolution imaging. In this study, we demonstrate an innovative method to generate free light-shape focusing with self-evolutionary photon sieves under a single-shot coherent EUV laser; this includes vortex focus shaping, array focusing, and structured-light shaping. The results demonstrate that self-evolutionary photon sieves, consisting of a large number of specific pinholes fabricated on a piece of Si3N4 membrane, are capable of freely regulating an EUV light field, for which high-performance focusing elements are extremely lacking, let alone free light-shape focusing. Our proposed versatile photon sieves are a key breakthrough in focusing technology in the EUV region and pave the way for high-resolution soft X-ray microscopy, spectroscopy in materials science, shorter lithography, and attosecond metrology in next-generation synchrotron radiation and free-electron lasers.

Bismuth-based photocatalytic materials have been widely used in the field of photocatalysis in recent years due to their unique layered structure. However, single bismuth-based photocatalytic materials are greatly limited in their photocatalytic performance due to their poor response to visible light and easy recombination of photogenerated charges. At present, constructing semiconductor heterojunctions is an effective modification method that improves quantum efficiency by promoting the separation of photogenerated electrons and holes. In this study, the successful preparation of an In2O3/Bi2WO6 (In2O3/BWO) II-type semiconductor heterojunction composite material was achieved. XRD characterization was performed to conduct a phase analysis of the samples, SEM and TEM characterization for a morphology analysis of the samples, and DRS and XPS testing for optical property and elemental valence state analyses of the samples. In the II-type semiconductor junction system, photogenerated electrons (e−) on the In2O3 conduction band (CB) migrate to the BWO CB, while holes (h+) on the BWO valence band (VB) transfer to the In2O3 VB, promoting the separation of photoinduced charges, raising the quantum efficiency. When the molar ratio of In2O3/BWO is 2:6, the photocatalytic degradation degree of rhodamine B (RhB) is 59.4% (44.0% for BWO) after 60 min illumination, showing the best photocatalytic activity. After four cycles, the degradation degree of the sample was 54.3%, which is 91.4% of that of the first photocatalytic degradation experiment, indicating that the sample has good reusability. The XRD results of 2:6 In2O3/BWO before and after the cyclic experiments show that the positions and intensities of its diffraction peaks did not change significantly, indicating excellent structural stability. The active species experiment results imply that h+ is the primary species. Additionally, this study proposes a mechanism for the separation, migration, and photocatalysis of photoinduced charges in II-type semiconductor junctions.

Abstract Background Inflammatory response of central nervous system is an important component mechanism in the bladder pain of interstitial cystitis/bladder pain syndrome (IC/BPS). Exosomes transfer with microRNAs (miRNA) from mesenchymal stem cell (MSCs) might inhibit inflammatory injury of the central nervous system. Herein, the purpose of our study was to explore the therapeutic effects by which extracellular vesicles （EVs） derived from miR‐9‐edreched MSCs in IC/BPS and further investigate the potential mechanism to attenuate neuroinflammation. Methods On the basis of IC/BPS model, we used various techniques including bioinformatics, cell and molecular biology, and experimental zoology, to elucidate the role and molecular mechanism of TLR4 in regulating the activation of NLRP3 inflammasome in bladder pain of IC/BPS, and investigate the mechanism and feasibility of MSC‐EVs enriched with miR‐9 in the treatment of bladder pain of IC/BPS. Results The inflammatory responses in systemic and central derived by TLR4 activation were closely related to the cystitis‐induced pelvic/bladder nociception in IC/BPS model. Intrathecal injection of miR‐9‐enreched MSCs derived exosomes were effective in the treatment of cystitis‐induced pelvic/bladder nociception by inhibiting TLR4/NF‑κb/NLRP3 signal pathway in central nervous system of IC/BPS mice. Conclusions This study demonstrated that miR‐9‐enreched MSCs derived exosomes alleviate neuroinflammaiton and cystitis‐induced bladder pain by inhibiting TLR4/NF‑κb/NLRP3 signal pathway in interstitial cystitis mice, which is a promising strategy against cystitis‐induced bladder pain.

Purpose This study explores the effects of endometrial thickness (EMT) before embryo transfer on newborn birth weight after in vitro fertilization–frozen embryo transfer (IVF–FET).Methods We collected the medical records related to singleton live births after IVF–FET from June 2015 to February 2019. Pregnant women were aged ≤ 42 years at delivery. Afterward, analyses were performed on outcomes related to newborns (birth weight, gestational age, delivery mode, percentage of newborns with low birth weight, and incidence of macrosomia) and pregnant women (pregnancy-induced hypertension, gestational diabetes mellitus, premature rupture of membranes, and placenta previa).Results The birth weight was higher in singleton newborns delivered by patients with EMT > 12 mm before embryo transfer than those delivered by patients with a thinner endometrium. The mean birth weight was 85.107 g higher in the EMT ≥ 12 mm group and 25.942 g higher in the 8–12 mm EMT group than in the EMT < 8 mm group. Independent predictors of newborn birth weight included pregnancy-induced hypertension, premature rupture of membranes, placenta previa, newborn sex, gestational age, delivery mode, number of implanted embryos, follicle-stimulating hormone levels, estradiol levels, and pre-pregnancy body mass index.Conclusion The weight of newborn singletons is associated with EMT before embryo transfer in patients undergoing the first FET cycle. Specifically, the birth weight is lower for newborns delivered by patients with a thinner endometrium. Accordingly, it is warranted to increase EMT before embryo transfer for improving neonatal outcomes after fertility treatment.

Abstract The relationship between serum uric acid (SUA) and poor cognitive performance in patients with ischemic stroke is unclear. We hypothesized that the severity of renal function mediates the association between SUA and cognitive dysfunction.A retrospective analysis of 608 patients with ischemic stroke was conducted between 2016 and 2020. SUA was obtained from inpatient medical records. Global cognitive function via mini-mental state exam (MMSE) and Montreal Cognitive Assessment (MoCA) was determined one month after hospital discharge. The relationship between SUA and cognitive function was assessed by multiple linear and logistic regression analyses. Patients had a mean age of 66.6 years (SD: 4.1 years), and 52% were male. The mean SUA level was 298.6 ± 75.4 μmol/L. SUA increases were significantly positively associated with lower MMSE and MoCA scores and increased risk of moderate-severe cognitive impairment one month after stroke (p

Objective: To explore the effect of Hupo powder (HP) on autophagy in menstrual blood-derived stem cells (MenSCs) with endometriosis (EMT). Methods: EMT MenSCs (E-MenSCs) and healthy MenSCs (H-MenSCs) were isolated from the menstrual blood of patients with EMT and healthy female participants, respectively. We identified their stem cells’ characteristics via adipogenic and osteogenic differentiation. Twelve male Sprague–Dawley rats received 0.9% NaCl and HP-dispensing granules by gastric irrigation to prepare blank serum and medicated serum, respectively. We used serum concentrations of 5%, 10%, and 20%, each at administered times of 12, 24, and 48 h to select the best condition. These cells were divided into three groups: blank serum of the control group, blank serum of the model group, and medicated serum of the HP group. H-MenSCs were used in the control group, while E-MenSCs were used in the model and HP groups. We analyzed cell viability using a cell counting kit-8 assay, observed cell morphology, evaluated the amounts of autophagosomes and autolysosomes by transmission electron microscopy, and detected the protein expression of autophagy markers (LC3-II and Beclin1) by Western blot. Results: E-MenSCs and H-MenSCs became long fusiform with a diffuse radial pattern, forming lipid droplets and calcium nodules after adipogenic and osteogenic differentiation. We then used the best condition—20% serum and 48 h—for the subsequent experiments. In contrast to the model group, the HP group exhibited lower cell viability (P = .007), larger amounts of autophagosomes and autolysosomes (P

The use of titanium dioxide in the degradation of water pollutants encounters several challenges, including particle agglomeration leading to a reduction in its specific surface area and a high rate of photogenerated electron-hole recombination, resulting in a lower quantum efficiency. Therefore, in this work, we first employed sepiolite to load titanium dioxide, mitigating particle agglomeration. Building upon this, tin dioxide was coupled with it to enhance the photogenerated charge separation. The SnO2/TiO2/sepiolite photocatalytic composites were synthesized using the sol–gel method at 450 ℃. The resulting composites underwent thorough characterization encompassing phase composition, morphology, chemical valence states, specific surface area, optical properties, and photocatalytic activity. The outcomes demonstrate an augmentation in the specific surface area of TiO2/Sep composites following the sepiolite (Sep) loading. Among these, the TiO2/Sep composite (with a Sep: TiO2 mass ratio of 10 %) exhibited the most favorable photocatalytic performance, displaying a first-order reaction rate constant of 0.010 min−1, surpassing that of pure TiO2 by a factor of 2.0. The introduction of SnO2 expedited the migration of photogenerated charge across interfaces, curbing the recombination of photogenerated pairs, thus enhancing quantum efficiency. In light of the presence of sepiolite, the addition of SnO2 further amplified the photocatalytic performance. Optimal results were achieved when the molar ratio of SnO2:TiO2 was set at 1:4, leading to the highest photocatalytic efficiency observed in the SnO2/TiO2/Sep composite. This composite exhibited a first-order reaction rate constant of 0.027 min−1, marking a notable 2.7-fold increase compared to the TiO2/Sep counterpart. The investigation of band potentials, charge transfer pathways, and the photocatalytic mechanism within SnO2/TiO2/Sep composite materials was conducted through a comprehensive analysis involving electrochemical impedance spectroscopy (EIS), X-ray photoelectron spectroscopy (XPS) valence band spectroscopy, electron paramagnetic resonance spectra (EPR) and active radical experiments.

Three-dimensional BiOI/Bi2WO6 Z-scheme photocatalysts were synthesized by one-step hydrothermal method. Detailed characterization via SEM and TEM revealed that these photocatalysts exhibit a unique three-dimensional flower-like structure, composed of two-dimensional sheets. The results of photocatalysis mechanism analysis demonstrated that the BiOI/Bi2WO6 heterojunctions have formed a Z-scheme charge transfer mechanism. Specifically, electrons transfer from the Bi2WO6 conduction band to the BiOI valence band, facilitating both enhanced separation of photogenerated charges and the preservation of the strong reducibility of BiOI conduction band electrons and the strong oxidation of Bi2WO6 valence band holes. This dual effect leads to increased generation of free radicals and a consequent improvement in photocatalytic property. Remarkably, when the molar ratio of BiOI/Bi2WO6 is set at 40%, the first-order reaction rate constant reaches 0.089 min−1, which is nearly 5.9 times that of pure Bi2WO6.

Abstract Introduction Approximately 50% of cases with recurrent spontaneous abortion (RSA) have unexplained etiology. Aberrant expression of transmembrane and ubiquitin‐like domain containing 1 (TMUB1) is closely related to a series of diseases, including RSA. However, the function and underlying mechanism of TMUB1 in the occurrence of RSA has not been described. Methods TMUB1 expression was detected in the placental villous tissues of 30 women with normal miscarriages and 12 women with RSA. The pregnant mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce abortion. Human chorionic trophoblast cells were treated with LPS. Pathological analysis of placental tissues was performed by hematoxylin and eosin staining. Results TMUB1 was highly expressed in the placental villous tissues of RSA patients compared to the patients who underwent induced abortions. After LPS administration, the mice exhibited high embryo absorption and pathological alterations, as well as presented an increase in inflammation and apoptosis (the etiology of RSA induction) in placental tissues. Moreover, the upregulated expression of TMUB1 was also found in placental tissues of LPS‐induced mice, and further investigation showed that TMUB1 deficiency blocked embryo loss as well as inhibited apoptotic rate and inflammation after LPS activation. Furthermore, we found that the loss of TMUB1 suppressed the phosphorylation of IkappaB kinase (IKK) α/β and attenuated cytoplasmic‐nuclear translocation of nuclear factor‐κB (NF‐κB) p65 in LPS‐induced cells. Conclusion Our results indicate that TMUB1 may involve in the modulation of apoptosis and NF‐κB pathway‐mediated inflammation in RSA. Therefore, TMUB1 may develop as a potential biomarker for RSA treatment.

IntroductionCalf diarrhea is a complex disease that has long been an unsolved problem in the cattle industry. Ningxia is at the forefront of China in the scale of cattle breeding, and calf diarrhea gravely restricts the development of Ningxia's cattle industry.MethodsFrom July 2021 to May 2022, we collected diarrhea stool samples from calves aged 1–103 days from 23 farms in five cities in Ningxia, and performed PCR using specific primers for 15 major reported pathogens of calf diarrhea, including bacteria, viruses, and parasites. The effect of different seasons on the occurrence of diarrhea in calves was explored, the respective epidemic pathogens in different seasons were screened, and more detailed epidemiological investigations were carried out in Yinchuan and Wuzhong. In addition, we analyzed the relationship between different ages, river distributions and pathogen prevalence.ResultsEventually, 10 pathogens were detected, of which 9 pathogens were pathogenic and 1 pathogen was non-pathogenic. The pathogens with the highest detection rate were Cryptosporidium (50.46%), Bovine rotavirus (BRV) (23.18%), Escherichia coli (E. coli) K99 (20.00%), and Bovine coronavirus (BCoV) (11.82%). The remaining pathogens such as Coccidia (6.90%), Bovine Astrovirus (BoAstV) (5.46%), Bovine Torovirus (BToV) (4.09%), and Bovine Kobuvirus (BKoV) (3.18%) primarily existed in the form of mixed infection.DiscussionThe analysis showed that different cities in Ningxia have different pathogens responsible for diarrhea, with Cryptosporidium and BRV being the most important pathogens responsible for diarrhea in calves in all cities. Control measures against those pathogens should be enforced to effectively prevent diarrhea in calves in China.

The brain tumor segmentation task with different domains remains a major challenge because tumors of different grades and severities may show different distributions, limiting the ability of a single segmentation model to label such tumors. Semi-supervised models (e.g., mean teacher) are strong unsupervised domain-adaptation learners. However, one of the main drawbacks of using a mean teacher is that given a large number of iterations, the teacher model weights converge to those of the student model, and any biased and unstable predictions are carried over to the student. In this article, we proposed a novel unsupervised domain-adaptation framework for the brain tumor segmentation task, which uses dual student and adversarial training techniques to effectively tackle domain shift with MR images. In this study, the adversarial strategy and consistency constraint for each student can align the feature representation on the source and target domains. Furthermore, we introduced the cross-coordination constraint for the target domain data to constrain the models to produce more confident predictions. We validated our framework on the cross-subtype and cross-modality tasks in brain tumor segmentation and achieved better performance than the current unsupervised domain-adaptation and semi-supervised frameworks.

Abstract Background Necroptosis is a new form of programmed cell death that is associated with cancer initiation, progression, immunity, and chemoresistance. However, the roles of necroptosis-related genes (NRGs) in colorectal cancer (CRC) have not been explored comprehensively. Methods In this study, we obtained NRGs and performed consensus molecular subtyping by “ConsensusClusterPlus” to determine necroptosis-related subtypes in CRC bulk transcriptomic data. The ssGSEA and CIBERSORT algorithms were used to evaluate the relative infiltration levels of different cell types in the tumor microenvironment (TME). Single-cell transcriptomic analysis was performed to confirm classification related to NRGs. NRG_score was developed to predict patients’ survival outcomes with low-throughput validation in a patients’ cohort from Fudan University Shanghai Cancer Center. Results We identified three distinct necroptosis-related classifications (NRCs) with discrepant clinical outcomes and biological functions. Characterization of TME revealed that there were two stable necroptosis-related phenotypes in CRC: a phenotype characterized by few TME cells infiltration but with EMT/TGF-pathways activation, and another phenotype recognized as immune-excluded. NRG_score for predicting survival outcomes was established and its predictive capability was verified. In addition, we found NRCs and NRG_score could be used for patient or drug selection when considering immunotherapy and chemotherapy. Conclusions Based on comprehensive analysis, we revealed the potential roles of NRGs in the TME, and their correlations with clinicopathological parameters and patients’ prognosis in CRC. These findings could enhance our understanding of the biological functions of necroptosis, which thus may aid in prognosis prediction, drug selection, and therapeutics development.

ZnTiO3/TiO2 composite photocatalysts were synthesized via the sol–gel technique, and the impact of varying heat treatment temperatures (470, 570, 670 °C) on their crystalline arrangement, surface morphology, elemental composition, chemical state, specific surface area, optical characteristics, and photocatalytic efficacy was systematically investigated. The outcomes revealed that, as the temperature ascends, pure TiO2 undergoes a transition from anatase to rutile, ultimately forming a hybrid crystal structure at 670 °C. The incorporation of ZnTiO3 engenders a reduction in the TiO2 grain dimensions and retards the anatase-to-rutile phase transition. Consequently, the specimens manifest a composite constitution of anatase and ZnTiO3. In contrast, for pure TiO2, the specimen subjected to 670 °C annealing demonstrates superior photocatalytic performance due to its amalgamated crystal arrangement. The degradation efficacy of methylene blue (MB) aqueous solution attains 91% within a 60-min interval, with a calculated first-order reaction rate constant of 0.039 min−1. Interestingly, the ZnTiO3/TiO2 composite photocatalysts exhibit diminished photocatalytic activity in comparison to pristine TiO2 across all three temperature variations. Elucidation of the photocatalytic mechanism underscores that ZnTiO3 coupling augments the generation of photogenerated charge carriers. Nonetheless, concurrently, it undermines the crystalline integrity of the composite, yielding an excess of amorphous constituents that impede the mobility of photoinduced carriers. This dual effect also fosters escalated recombination of photogenerated charges, culminating in diminished quantum efficiency and reduced photocatalytic performance.

Abstract Background Intrahepatic cholangiocarcinoma (ICC) is a fatal primary liver cancer, and its long-term survival rate remains poor. RNA-binding proteins (RBPs) play an important role in critical cellular processes, failure of any one or more processes can lead to the development of multiple cancers. This study aimed to explore pivotal biomarkers and corresponding mechanisms to predict the prognosis of patients with ICC. Methods The transcriptomic and clinical information of patients were collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. Bioinformatic methods were used to identify survival-related and differentially-expressed biomarkers. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry were used to detect the expression levels of key biomarkers in independent real-world cohorts. Subsequently, a prognostic signature was constructed that effectively distinguished patients in the high- and low-risk groups. Independent prognosis analysis was used to verify the signature’s independent predictive capabilities, and two nomograms were developed to predict survival. Results PIWIL4 and SUPT5H were identified and considered as pivotal biomarkers, and the same expression trends of upregulation in ICC were also validated via qRT-PCR and immunohistochemistry in the separate real-world sample cohorts. The prognostic signature showed good predictive capabilities according to the area under the curve. The correlation of the biomarkers with the tumour microenvironment suggested that the high riskScore was positively related to the enrichment of resting natural killer cells and activated memory CD4 + T cells. Conclusion In the present study, we demonstrated that PIWIL4 and SUPT5H could be used as novel prognostic biomarkers to develop a prognostic signature. This study provides potential biomarkers of prognostic value for patients with intrahepatic cholangiocarcinoma.

BackgroundReliable and individualized biomarkers are crucial for identifying early cognitive impairment in subcortical small-vessel disease (SSVD) patients. Personalized brain age prediction can effectively reflect cognitive impairment. Thus, the present study aimed to investigate the association of brain age with cognitive function in SSVD patients and assess the potential value of brain age in clinical assessment of SSVD.Materials and methodsA prediction model for brain age using the relevance vector regression algorithm was developed using 35 healthy controls. Subsequently, the prediction model was tested using 51 SSVD patients [24 subjective cognitive impairment (SCI) patients and 27 mild cognitive impairment (MCI) patients] to identify brain age-related imaging features. A support vector machine (SVM)-based classification model was constructed to differentiate MCI from SCI patients. The neurobiological basis of brain age-related imaging features was also investigated based on cognitive assessments and oxidative stress biomarkers.ResultsThe gray matter volume (GMV) imaging features accurately predicted brain age in individual patients with SSVD (R2 = 0.535, p < 0.001). The GMV features were primarily distributed across the subcortical system (e.g., thalamus) and dorsal attention network. SSVD patients with age acceleration showed significantly poorer Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA) scores. The classification model based on GMV features could accurately distinguish MCI patients from SCI patients (area under the curve = 0.883). The classification outputs of the classification model exhibited significant associations with MoCA scores, Trail Making Tests A and B scores, Stroop Color and Word Test C scores, information processing speed total scores, and plasma levels of total antioxidant capacity in SSVD patients.ConclusionBrain age can be accurately quantified using GMV imaging data and shows potential clinical value for identifying early cognitive impairment in SSVD patients.

Non-photochemical quenching (NPQ) is an indicator of crop stress. Until now, only a limited number of studies have focused on how to estimate NPQ using remote sensing technology. The main challenge is the complicated regulatory mechanism of NPQ. NPQ can be divided into energy-dependent (qE) and non-energy-dependent (non-qE) quenching. The contribution of these two components varies with environmental factors, such as light intensity and stress level due to the different response mechanisms. This study aims to explore the feasibility of estimating NPQ using photosynthesis-related vegetation parameters available from remote sensing by considering the two components of NPQ. We concurrently measured passive vegetation reflectance spectra by spectrometer, as well as active fluorescence parameters by pulse-amplitude modulated (PAM) of rice (Oryza sativa) leaves. Subsequently, we explored the ability of the selected vegetation parameters (including the photochemical reflectance index (PRI), inverted red-edge chlorophyll index (IRECI), near-infrared reflectance of vegetation (NIRv), and fluorescence quantum yield (ΦF)) to estimate NPQ. Based on different combinations of these remote sensing parameters, empirical models were established to estimate NPQ using the linear regression method. Experimental analysis shows that the contribution of qE and non-qE components varied under different illumination conditions. Under high illumination, the NPQ was attributed primarily to the qE component, while under low illumination, it was equally attributed to the qE and non-qE components. Among all tested parameters, ΦF was sensitive to the qE component variation, while IRECI and NIRv were sensitive to the non-qE component variation. Under high illumination, integrating ΦF in the regression model captured NPQ variations well (R2 > 0.74). Under low illumination, ΦF, IRECI, and NIRv explained 24%, 62%, and 65% of the variation in NPQ, respectively, while coupling IRECI or NIRv with ΦF considerably improved the accuracy of NPQ estimation (R2 > 0.9). For all the samples under both low and high illumination, the combination of ΦF with at least one of the other parameters (including IRECI, NIRv and PAR) offers a more versatile and reliable approach to estimating NPQ than using any single parameter alone. The findings of this study contribute to the further development of remote sensing methods for NPQ estimation at the canopy scale in the future.

The lack of water resources has emerged as a major factor limiting the high-quality economic and ecological development in Hebei Province. Therefore, it is of great significance to understand the dynamic changes in terrestrial water storage for effectively managing water resources in Hebei Province. The evolution pattern and spatial distribution of TWS anomalies (TWSA) were analyzed utilizing gravity recovery and climate experiment (GRACE) solutions and the water balance method from 2003 to 2020, and the missing monthly data during GRACE and GRACE-FO missions were filled by combining the climate-driven model and meteorological products. Moreover, the impact of the south-to-north water-diversion (SNWD) project on alleviating the water-storage deficit was quantified. The results revealed that the water-balance method on the strength of the combination of CMA precipitation and Noahv2.1-simulated evapotranspiration and runoff data matches well with the TWSA data derived from GRACE, with a correlation coefficient up to 0.95. However, the accuracy was unsatisfactory during the process of characterizing the spatial characteristics of TWSA. After the SNWD project, GRACE-derived results showed that the downtrends of TWSA were reduced by 10.93%, especially in mountainous areas: by 79.78%. Concerning the spatial scale, the deficit trends were reduced to a certain extent in northern Hebei Province, while the decreasing trends cannot be reversed for a short time in southern areas where human activities are intensive.

During daily conversations, people prefer indirect replies in face-threatening situations. Existent studies have indicated that recipients tend to perceive the information conveyed by indirect replies as negative and emotion regions are engaged in indirect replies processing in face-threatening situations. In this study, we examined whether indirect replies can reduce recipients’ experience of negative emotion and what are the underlying cerebral structures that may give rise to individual differences in the effectiveness of such replies in attenuating negative emotion. Behavior ratings and resting-stating functional magnetic resonance imaging (rs-fMRI) techniques were combined to explore these questions. We created dialogues expressing refusal or negative opinion with direct/indirect replies. Participants were asked to rate their emotional valence and arousal when they received such replies. The rating scores were used to correlate with spontaneous brain activity. Results showed that indirect replies indeed attenuated recipients’ negative emotion experience. Moreover, the left caudate, the right anterior cingulate cortex (rACC), and the connectivity of rACC and left medial prefrontal cortex (lmPFC) were found to be positively correlated to individual differences in such emotion attenuation. Our findings provide direct empirical evidence for the face-saving function of indirect replies and reveal that the intrinsic brain activities of emotion network and theory of mind (ToM) network are related to individual differences in such emotion attenuation.

Abstract New strategies to decrease risk of relapse after surgery are needed for improving 5‐year survival rate of hepatocellular carcinoma (HCC). To address this need, a wound‐targeted nanodrug is developed, that contains an immune checkpoint inhibitor (anti‐PD‐L1)and an angiogenesis inhibitor (sorafenib)). These nanoparticles consist of highly biocompatible mesoporous silica (MSNP) that is surface‐coated with platelet membrane (PM) to achieve surgical site targeting in a self‐amplified accumulation manner. Sorafenib is introduced into the MSNP pores while covalently attaching anti‐PD‐L1 antibody on the PM surface. The resulting nano‐formulation, abbreviated as a‐PM‐S‐MSNP, can effectively target the surgical margin when intraperitoneally (IP) administered into an immune competent murine orthotopic HCC model. Multiple administrations of a‐PM‐S‐MSNP generate potent anti‐HCC effect and significantly prolong overall mice survival. Immunophenotyping and immunochemistry staining reveal the signatures of favorable anti‐HCC immunity and anti‐angiogenesis effect at tumor sites. More importantly, microscopic inspection of a‐PM‐S‐MSNP treated mice shows that 2 out 6 are histologically tumor‐free, which is in sharp contrast to the control mice where tumor foci can be easily identified. The data suggest that a‐PM‐S‐MSNP can efficiently inhibit post‐surgical HCC relapse without obvious side effects and holds considerable promise for clinical translation as a novel nanodrug.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Here, we identified that increased miR‐23a expression in HCC tissues was associated with worse survival. More importantly, we found that STAT5A was a target of miR‐23a, whose levels significantly decreased in tumor tissues. Stable expression of STAT5A in Huh7 cells suppressed glucose metabolism and tumor growth. Finally, this study showed that increased miR‐23a negatively regulated STAT5A, which further activated AKT signaling to enable rapid metabolism for accelerated tumor growth in HCC. Taken together, our results demonstrated that the miR‐23a‐STAT5A‐AKT signaling pathway is critical to alter glucose metabolism in HCC and may offer new opportunities for effective therapy.

Background: Metabolic diseases pose considerable burden on the healthcare system worldwide, indicating the significance of prevention and treatment. In constitution theory of traditional Chinese medicine, phlegm-dampness constitution (PDC) is the common basis of metabolic diseases. In clinical practice, Huatan Qushi (HTQS) decoction targeting on PDC can effectively improve metabolic indicators. However, its underlying biochemical mechanism still remains unclear. Methods: Eight PDC participants received HTQS decoction for three months. Their blood was collected at baseline and 1 and 3 months after intervention started. Related biomedical indicators were detected. High-throughput sequencing and RT-qPCR were used for validation. Due to the missing data, repeated measures with missing values in mixed models were used. Results: After 3-month treatment, HDL-C level increased (P

In recent years, additive manufacturing (AM) has emerged as a type of efficient manufacturing technology for building ceramic prototypes with increased dimensional accuracy, improved time efficiency, and reduced cost. A wealth of research works have been conducted to uncover the underlying formation mechanism of zirconia ceramic parts manufactured by AM processes and to improve the performance of the parts. In spite of the achievements, there are still some unresolved issues, such as porosity, cracks, coffee staining, which impede the adoption of AM processes for zirconia part manufacturing. This paper aims to review the recent research efforts on zirconia ceramic manufactured using AM techniques. The existing works are mainly categorized in terms of the different AM preparation methods and the applications. More importantly, the challenges and opportunities related to AM of zirconia products are discussed. As such, this review provides not only a comprehensive survey of the existing research, but also an insightful discussion regarding the potential research in the future. Innovations are expected to be stimulated for many critical industrial applications.

Based on the observation data of ground resistivity at Yangyuan seismic station from 1980 to 2017，it is found that the measured value of ground resistivity at Yangyuan seismic station has clear “V” type annual variation characteristics of high values in winter and low values in summer. After eliminating the annual variation information with the appropriate Fourier sliding method，the change of normal background and anomalous characteristics is more remarkable. The relationship between the anomalies and major earthquakes，such as the Fengzhen M5.8 earthquake in 1980，the Datong M6.2 earthquake in 1988 and the Baotou M6.4 earthquake in 1996，the Zhangbei M6.2 earthquake in 1998 and the Zhuolu M4.8 earthquake in 2014 around Yangyuan station，can be identified in the corrected resistivity curves. The indexes of anomalous variation characteristics，duration and deviation amplitude have high reliability，which can provide reliable reference for the study and judgment of seismicity in the border area of Shanxi，Hebei and Mongolia.

ObjectiveTo investigative the diagnostic performance of the morphological model, radiomics model, and combined model in differentiating invasive adenocarcinomas (IACs) from minimally invasive adenocarcinomas (MIAs).MethodsThis study retrospectively involved 307 patients who underwent chest computed tomography (CT) examination and presented as subsolid pulmonary nodules whose pathological findings were MIAs or IACs from January 2010 to May 2018. These patients were randomly assigned to training and validation groups in a ratio of 4:1 for 10 times. Eighteen categories of morphological features of pulmonary nodules including internal and surrounding structure were labeled. The following radiomics features are extracted: first-order features, shape-based features, gray-level co-occurrence matrix (GLCM) features, gray-level size zone matrix (GLSZM) features, gray-level run length matrix (GLRLM) features, and gray-level dependence matrix (GLDM) features. The chi-square test and F1 test selected morphology features, and LASSO selected radiomics features. Logistic regression was used to establish models. Receiver operating characteristic (ROC) curves evaluated the effectiveness, and Delong analysis compared ROC statistic difference among three models.ResultsIn validation cohorts, areas under the curve (AUC) of the morphological model, radiomics model, and combined model of distinguishing MIAs from IACs were 0.88, 0.87, and 0.89; the sensitivity (SE) was 0.68, 0.81, and 0.83; and the specificity (SP) was 0.93, 0.79, and 0.87. There was no statistically significant difference in AUC between three models (p > 0.05).ConclusionThe morphological model, radiomics model, and combined model all have a high efficiency in the differentiation between MIAs and IACs and have potential to provide non-invasive assistant information for clinical decision-making.

Background: We aimed to explore the influencing factors of clinical adverse blood transfusion reactions, to provide theoretical basis and support for clinical safe blood transfusion, and to minimize the occurrence of adverse blood transfusion reactions. Methods: The method was to retrospectively analyze the report of adverse blood transfusion reports from 6 hospitals in Linyi area, Shandong, China to the blood station in Linyi City center from 2013 to 2020. We aimed to classify factors, analyze the occurrence of adverse transfusion reactions, and discuss the correlation between the occurrence of adverse transfusion reactions and the above factors. Results: Overall, 248 patients (77.98%) had a history of blood transfusion. The difference between this group and the group with no history was statistically significant (P

Background: Endometriosis is a hormone- and organ-dependent disease with unclear pathogenesis. Danggui Shaoyao powder (DSP) has been used for the treatment of endometriosis for many years and has been proven to be effective, but its underlying molecular mechanisms remain unclear. In this study, we explored the molecular targets and pathways of DSP in the treatment of endometriosis mainly from the perspective of network pharmacology, and provided some novel ideas for managing this disease. Methods: In the present study, we focused on the underlying mechanisms between DPS and endometriosis, via oral bioavailability screening, drug similarity assessment, target identification, network analysis, drug relocation, and molecular docking using network pharmacology. Results: By bioinformatics, 54 active components of DSP were predicted from the 534 components provided by the TCMSP database. We then found 85 validated targets and 6059 predicted targets for herbal components, and 2241 targets for endometriosis. After mapping, there were 255 targets in common. After that, network analysis was performed to screen key networks and core targets. Ninety-nine indirect targets were collected from 14 direct ones. GO and KEGG analyses identified 63 enriched functions and 10 pathways (P

Thelohanellus Kudo, 1933 is a species rich genus of Myxosporea, sharing many morphological similarities with species of Myxobolus but the former possesses a single polar capsule, and the latter has two. Based on molecular phylogenetic analyses, this single distinguishing feature is not monophyletic, and members of Thelohanellus are intermixed with Myxobolus species, calling into question the validity of genus Thelohanellus. The occurrence of two polar capsules in a small proportion of Thelohanellus spores as observed in this study suggests that these species have the capacity to express this Myxobolus-like trait, clouding the distinction of these two genera further. Herein, using the most comprehensive data set to date, we explored the phylogenetic relationships of Thelohanellus to other myxobolids, to investigate the evolutionary history of the genus Thelohanellus and the origins of single polar capsule in this group. The phylogenetic analyses and statistical tests of topology revealed Thelohanellus as a strongly supported polyphyletic lineage, clustering in five distinct branches within Myxobolus clade. Ancestral state reconstruction for polar capsule number showed that Thelohanellus species have evolved from myxosporean species with two polar capsules at least four times, which could be classified in three possible evolutionary pathways. The polyphyly of Thelohanellus and the multiple evolutionary origins of single polar capsule of Thelohanellus demonstrate that the distinction of this genus from Myxobolus is largely for convenience, and does not reflect their evolutionary history. Keywords: Thelohanellus, Myxobolus, Single polar capsule, Phylogeny, Evolution, SSU rDNA

Abstract Background As the selective inhibitor of BRAF kinase, vemurafenib exhibits effective antitumor activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after its initial treatment. Methods Immunohistochemical staining was performed to detect the expression of iNOS and hTERT, p-p65, Epcam, CD44, PCNA in mice with melanoma xenografts. The proliferation and migration of melanoma cells were detected by MTT, tumorsphere culture, cell cycle, cell apoptosis, AO/EB assay and colony formation, transwell assay and scratch assay in vitro, and tumor growth differences were observed in xenograft nude mice. Changes in the expression of key molecules in the iNOS/hTERT signaling pathways were detected by western blot. Nucleus-cytoplasm separation, and immunofluorescence analyses were conducted to explore the location of p50/p65 in melanoma cell lines. Flow cytometry assay were performed to determine the expression of CD44. Pull down assay and ChIP assay were performed to detect the binding ability of p65 at iNOS and hTERT promoters. Additionally, hTERT promoter-driven luciferase plasmids were transfected in to melanoma cells with indicated treatment to determine luciferase activity of hTERT. Results Melatonin significantly and synergistically enhanced vemurafenib-mediated inhibitions of proliferation, colony formation, migration and invasion and promoted vemurafenib-induced apoptosis, cell cycle arresting and stemness weakening in melanoma cells. Further mechanism study revealed that melatonin enhanced the antitumor effect of vemurafenib by abrogating nucleus translocation of NF-κB p50/p65 and their binding at iNOS and hTERT promoters, thereby suppressing the expression of iNOS and hTERT. The elevated anti-tumor capacity of vemurafenib upon co-treatment with melatonin was also evaluated and confirmed in mice with melanoma xenografts. Conclusions Collectively, our results demonstrate melatonin synergizes the antitumor effect of vemurafenib in human melanoma by inhibiting cell proliferation and cancer-stem cell traits via targeting NF-κB/iNOS/hTERT signaling pathway, and suggest the potential of melatonin in antagonizing the toxicity of vemurafenib and augmenting its sensitivities in melanoma treatment.

Background: Based on the theory of traditional Chinese medicine (TCM) and pre-epidemiological investigation, Professor Qi Wang classified the entire human population into nine constitutions and put forward the theory of “Nine-Constitution Medicine.” Among these constitutions, the main feature of the yang-deficiency constitution (YADC) is intolerance of the cold, which has been proven to reduce quality of life and confer susceptibility to specific diseases. Previous studies explored the genetic and transcriptional bases of YADC. In this experiment, we explored the potential mechanism of YADC using protein microarray, to deepen our understanding of its biological mechanism. Methods: Subjects identified with a YADC (n = 12) or a balance constitution (BC; n = 12) in accordance with the Classification and Determination Standards of Constitutions in Traditional Chinese Medicine were selected. Blood was collected to separate serum and protein microarray technology was used to analyze serum protein expression. Results: The clustering of subjects’ constitutions based on protein expression profiling largely coincided with the TCM classification. Based on false discovery rate correction (P

Photocatalytic degradation of harmful organic matter is a feasible and environmentally friendly method. Bi2WO6 has become a hotspot of photocatalysts because of its unique layered structure and visible light response. In the present study, Sn doping was adopted to modified Bi2WO6 by hydrothermal method. The Sn-doped Bi2WO6 photocatalysts were characterized by XRD, SEM, TEM, BET, XPS, PL, and DRS, respectively. The results show that Sn-doped Bi2WO6 shows three-dimensional (3D) flower-like morphology, which is composed of two-dimensional (2D) nanosheets. Sn4+ ions enter into the Bi2WO6 lattice, producing a degree of Bi2WO6 lattice distortion, which is in favor of reducing the recombination of photogenerated electrons and holes. Moreover, the specific surface area of Bi2WO6 is significantly increased after doping, which is beneficial to providing more active sites. The photocatalytic results show that 2%Sn-Bi2WO6 exhibits the highest photocatalytic activity. After 60 min of irradiation, the photocatalytic degradation degree of methylene blue (MB) increases from 80.6% for pure Bi2WO6 to 92.0% for 2%Sn-Bi2WO6. The first-order reaction rate constant of 2%Sn-Bi2WO6 is 0.030 min−1, which is 1.7 times than that of pure Bi2WO6.

Multiple-drug resistance bacteria containing antimicrobial resistance genes (ARGs) are a concern for public health. Integrons are bacterial genetic elements that can capture, rearrange, and express mobile gene cassettes responsible for the spread of ARGs. Few studies link genotype and phenotype of swine-related ARGs in the context of mobile gene cassette arrays among commensal Escherichia coli (E. coli) in nonclinical livestock isolates from intensive farms. In the present study, a total of 264 isolates were obtained from 330 rectal swabs to determine the prevalence and characteristics of antibiotic-resistant gene being carried by commensal E. coli in the healthy swine from four intensive farms at Anhui, Hebei, Shanxi, and Shaanxi, in China. Antimicrobial resistance phenotypes of the recovered isolates were determined for 19 antimicrobials. The E. coli isolates were commonly nonsusceptible to doxycycline (75.8%), tetracycline (73.5%), sulfamethoxazole-trimethoprim (71.6%), amoxicillin (68.2%), sulfasalazine (67.1%), ampicillin (58.0%), florfenicol (56.1%), and streptomycin (53.0%), but all isolates were susceptible to imipenem (100%). Isolates [184 (69.7%)] exhibited multiple drug resistance with 11 patterns. Moreover, 197 isolates (74.6%) were detected carrying the integron-integrase gene (intI1) of class 1 integrons. A higher incidence of antimicrobial resistance was observed in the intI1-positive E. coli isolates than in the intI1-negative E. coli isolates. Furthermore, there were 17 kinds of gene cassette arrays in the 70 integrons as detected by sequencing amplicons of variable regions, with 66 isolates (94.3%) expressing their gene cassettes encoding for multiple drug resistance phenotypes for streptomycin, neomycin, gentamicin, kanamycin, amikacin, sulfamethoxazole-trimethoprim, sulfasalazine, and florfenicol. Notably, due to harboring multiple, hybrid, and recombination cassettes, complex cassette arrays were attributed to multiple drug resistance patterns than simple arrays. In conclusion, we demonstrated that the prevalence of multiple drug resistance and the incidence of class 1 integrons were 69.7 and 74.6% in commensal E. coli isolated from healthy swine, which were lower in frequency than that previously reported in China.

Porcine circovirus type 2 (PCV2) is the primary causative agent that causing porcine circovirus-associated disease (PCVAD). The open reading frame 5 (ORF5) protein is a newly discovered non-structural protein in PCV2, which the function in viral pathogenesis remains unknown. The aim of this study was to investigate the mechanism of PCV2 ORF5 protein on autophagy and viral replication. The pEGFP-tagged ORF5 gene was ectopic expressed in PK-15 cells and an ORF5-deficient PCV2 mutant strain (PCV2ΔORF5) were used to infected PK-15 cells. This study demonstrated that the ORF5 is essential for the of PCV2-induced autophagy. The ORF5 protein triggers the phosphorylation of PERK, eIF2α and the expression of downstream transcription factor ATF4. In addition, ORF5 protein activated the AMPK-ERK1/2-mTOR signaling pathways. These findings suggest that ORF5 play essential roles in the induction of autophagy by PCV2. We further revealed that PCV2 ORF5 promotes viral replication through PERK-eIF2α-ATF4 and AMPK-ERK1/2-mTOR pathways. In conclusion, we showed that PCV2 ORF5 induces autophagy to promote virus replication in PK-15 cells.

Background/Aims: Based on the theory of constitution in Traditional Chinese Medicine (TCM), the Chinese Han population has been classified into nine constitutions. Of these, Yang deficiency constitution mainly exhibit cold intolerance while Yin deficiency constitution mainly exhibit heat intolerance. Some studies have been carried out to explore the modern genetic and biological basis of such constitution classification, but more remains to be done. MicroRNA (miRNA) serves as post-transcriptional regulators of gene expression and may play a role in the classification process. Here, we examined miRNA expression profile of saliva to further improve the comprehensiveness of constitution classification. Methods: Saliva was collected from Chinese Han individuals with Yang deficiency, Yin deficiency and Balanced constitutions (n=5 each), and miRNA expression profile was determined using the Human miRNA OneArray®v7. Based on 1.5 Fold change, means log2|Ratio|≥0.585 and P-value< 0.05, differentially expressed miRNA was screened. Target genes were predicted using DIANA-TarBasev7.0 and analysis of KEGG pathway was carried out using DIANA-mirPathv.3. Results: We found that 81 and 98 differentially expressed miRNAs were screened in Yang deficiency and Yin deficiency constitution, respectively. Among them, 16 miRNAs were identical and the others were unique. In addition, the target genes that are regulated by the unique miRNAs were significantly enriched in 27 and 20 signaling pathways in Yang deficiency and Yin deficiency constitution, respectively. Thyroid hormone signaling pathway is present in both constitutions. These unique miRNAs that regulated target genes of thyroid hormone signaling pathway may be associated with cold intolerance or heat intolerance. Conclusion: The results of our study show that Yang deficiency and Yin deficiency constitutions exhibit systematic differences in miRNA expression profile. Moreover, the distinct characteristics of TCM constitution may be explained, in part, by differentially expressed miRNAs.

Tadalafil, a long-acting PED-5 inhibitor, is commonly used for the treatment of pulmonary arterial hypertension (PAH). However, its efficacy and clinical application are severely limited by the poor water solubility, low bioavailability and a series adverse effects (e.g. headaches, indigestion). In this study, tadalafil was prepared and loaded into biodegradable PLGA (poly(lactic-co-glycolic acid)) microspheres (TDF-PLGA-MS) via emulsification-solvent evaporation. The resulting microspheres were processed into pulmonary inhalant by freeze drying. The TDF-PLGA-MS was spherical and uniform, with an average particle diameter ~10.29 µm. The encapsulation efficiency and drug loading yield of TDF-PLGA-MS were 81.68% and 8.52%, respectively. The investigation of micromeritics showed that the TDF-PLGA-MS had low moisture content. The fluidity of powders was relatively good. The aerodynamic diameter and emptying rate of microspheres powders were 3.92 µm and 95.41%, respectively. Therefore, the microspheres powders were easy to be atomized, and can meet the requirements of pulmonary administration. In vitro release results showed that the microspheres group released slowly. The cumulative release in 24 h and 10 d was 46.87% and 84.06%, respectively. The in vitro release profile of TDF-PLGA-MS was in accordance with the Weibull model. The results of Pharmacokinetics showed that tadalafil from microspheres slowly released into the blood after intratracheal instillation. The pulmonary drug residue in 0.5 h was 3.5 times compared with solution group. The residual concentration in lung after 10d was still higher than that of solution group in 48 h. The t1/2β and MRT0-∞ were 3.10 times and 3.96 times that of solution group, respectively. Moreover, the Cmax and AUC of drug residues in lung were 3.48 times and 16.36 times that of solution group, respectively. The results of tissue distribution showed that the Re in lung was 16.358, which indicated the lung targeting. In conclusion, the TDF-PLGA-MS for pulmonary administration in this study can significantly improve the pulmonary targeting, increase efficacy of tadalafil and reduce other non-target organs toxicity. This study will have an important clinical significance for PAH patients who need long-term drug therapy.

Abstract Background Myxozoans are a group of cnidarian parasites, the present taxonomy of which favors a more comprehensive characterization strategy combining spore morphology, biological traits (host/organ specificity, tissue tropism), and DNA data over the classical morphology-based taxonomy. However, a systematist might again run into a taxonomic dilemma if more than two of the following exceptional cases were encountered at the same time: extensive intraspecific polymorphism, interspecific morphological similarity, identical interspecific biological traits and blurred small-subunit (SSU) rDNA-based species boundaries. In the present study, spores of a species of Myxobolus Bütschli, 1882 with two morphotypes (wide type and narrow type) were collected from the gills of common carp Cyprinus carpio Linnaeus. Confusingly, the wide type was found to be identical to Myxobolus paratoyamai Kato, Kasai, Tomochi, Li & Sato, 2017 in spore morphology and SSU rDNA sequence, which confidently suggested their conspecificity; while the narrow type, was highly similar to Myxobolus toyamai Kudo, 1917 based on spore morphology and SSU rDNA sequence and thus could not be easily classified. This discordance between wide type and narrow type has caused a taxonomic dilemma. To address this problem, a hypothesis about the conspecificity of the narrow type and M. toyamai was addressed. Results It was found that if the narrow type is conspecific with M. toyamai, it would be paradoxical for the SSU rDNA sequence of the narrow type to be more similar to M. paratoyamai (99.3%), Myxobolus acinosus Nie & Li, 1973 (98.6%) and Myxobolus longisporus Nie & Li, 1992 (98.7%) than to M. toyamai (97.6%). According to the results of the above what-if analysis, the narrow type and M. toyamai were considered to be different species. All in all, the present dual-morphotype species is estimated to be conspecific with M. paratoyamai Kato, Kasai, Tomochi, Li & Sato, 2017. Considering that this species name was preoccupied by Myxobolus paratoyamai Nie & Li, 1992, the replacement name Myxobolus pseudoacinosus nom. nov. is proposed. Conclusions This work addresses the taxonomic dilemma in polymorphic myxozoans and demonstrates that M. pseudoacinosus is a distinct species with two morphotypes. The present study may serve as a baseline for future studies that encounter similar classification complexities.

Tetramethylpyrazine (TMP) is a traditional Chinese herbal medicine with strong anti-inflammatory and cartilage protection activities, and thus a promising candidate for treating osteoarthritis. However, TMP is rapidly cleared from the joint cavity after intra-articular injection and requires multiple injections to maintain efficacy. The aim of this study was to encapsulate TMP into poly (lactic-co-glycolic acid) (PLGA) microspheres to enhance the TMP retention in the joint, reducing injection frequencies and decreasing dosage. TMP microspheres were prepared by emulsion/solvent evaporation method. The intra-articular retention of the drug was assessed by detecting the drug concentration distributed in the joint tissue at different time points. The therapeutic effect of TMP microspheres was evaluated by the swelling of knee joints and histologic analysis in papain-induced OA rat model. The prepared freeze-dried microspheres with a particle size of about 10 µm can effectively prolong the retention time of the drug in the articular cavity to 30 d, which is 4.7 times that of the TMP solution. Intra-articular injection of TMP microspheres efficiently relieved inflammatory symptoms, improved joint lesions and decreased the depletion of proteoglycan. In conclusion, intra-articular injection of TMP loaded microspheres was a promising therapeutic method in the treatment of OA. Keywords: Osteoarthritis, Tetramethylpyrazine, Intra-articular injection, PLGA microspheres, Retention, Pharmacodynamics

The process parameters of selective laser melting (SLM) significantly influence molten pool formation. A comprehensive understanding and analysis, from a macroscopic viewpoint, of the mechanisms underlying these technological parameters and how they affect the evolution of molten pools are presently lacking. In this study, we established a dynamic finite element simulation method for the process of molten pool formation by SLM using a dynamic moving heat source. The molten pool was generated, and the dynamic growth process of the molten pool belt and the evolution process of the thermal field of the SLM molten pool were simulated. Then, a deposition experiment that implemented a new measurement method for online monitoring involving laser supplementary light was conducted using the same process parameters as the simulation, in which high-speed images of the molten pool were acquired, including images of the pool surface and cross-section images of the deposited samples. The obtained experimental results show a good agreement with the simulation results, demonstrating the effectiveness of the proposed algorithm.

The study was conducted to investigate the effects of dietary NFC/NDF ratio change on rumen bacteria in sheep. Twelve Karakul sheep were assigned randomly into four groups fed with four dietary NFC/NDF ratios of 0.54, 0.96, 1.37, and 1.90 and they were assigned into groups 1, 2, 3, and 4, respectively. The experiment was divided into four periods: I (1−18 d), II (19−36 d), III (37−54 d), and IV (55−72 d). In each period, the first 15 d were used for adaption, and then rumen fluid was collected for 3 d from each sheep before morning feeding. The fluid was analyzed with three generations of full-length amplifiers sequencing. Results showed that the bacterial diversity of group 4 was decreased in period III and IV. At the phylum level, Bacteroidetes (37−60%) and Firmicutes (26−51%) were the most dominant bacteria over the four periods. The relative abundance of Bacteroidetes, Firmicutes, Tenericutes, and Spirochaete changed with dietary NFC/NDF ratio change over the four periods, but there was no difference among groups over the four periods (p > 0.05). At the genus level, unidentified-Lachnospiraceae was the dominant genus, and its relative abundance in group 3 was high during the period I and III (p < 0.05). The relative abundance of Mycoplasma in group 4 was high in the period I and II (p < 0.05). The relative abundance of Succiniclasticum was high in group 2 of period II (p < 0.05). At the species level, the relative abundance of Butyrivibrio-fibrisolvens was found to be high in group 3 during periods I and III (p < 0.05). The main semi-cellulose-degrading bacteria and starch-degrading bacteria were low, and there was no significant difference among groups over four periods (p > 0.05). Taken together, the dietary NFC/NDF ratio of 1.90 decreased the diversity of bacteria as a period changed from I to IV. While the main phylum bacteria didn’t change, their relative abundance changed with the dietary NFC/NDF ratio change over the four periods. The most prevalent genus was unidentified-Lachnospiraceae, and its relative abundance was higher in dietary NFC/NDF ratio of 1.37 than other groups. Similarly, the main cellulose-degrading species was higher in the treatment of dietary NFC/NDF ratio of 1.37 than other groups.

Evidence suggests that oxidative stress is involved in the pathogenesis of Parkinson disease (PD). Simvastatin has been suggested to protect against oxidative stress in several diseases. However, the molecular mechanisms by which simvastatin protects against neuropathology and oxidative damage in PD are poorly elucidated. In this study, we aimed to investigate the potential neuroprotective effects of simvastatin owing to its anti-oxidative properties in 6-hydroxydopamine (6-OHDA)-treated SH-SY5Y cells and mice. The results of 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence and CCK-8 assay demonstrated that simvastatin reduced intracellular reactive oxygen species (ROS) levels and reversed apoptosis in 6-OHDA-treated SH-SY5Y cells. Mechanistic studies revealed that 6-OHDA-induced activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/p38 mitogen-activated protein kinase (MAPK) pathway was inhibited and nuclear factor-κB (NF-κB) nuclear transcription decreased in SH-SY5Y cells after simvastatin treatment. Enhanced expression levels of superoxide dismutase (SOD), heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and glutamate-cysteine ligase modifier subunit (GCLM) were observed after simvastatin treatment in 6-OHDA-treated SH-SY5Y cells. In vivo studies revealed that administration of simvastatin by gavage decreased limb-use asymmetry and apomorphine-induced rotations in 6-OHDA-lesioned mice. Simvastatin increased dopaminergic neurons and reduced protein tyrosine nitration and gliosis in the midbrain of PD mice. An inhibitory effect on activation of the NADPH oxidase/p38 MAPK was observed, and increased antioxidant protein expression in the midbrain were seen in the simvastatin plus 6-OHDA group compared with the 6-OHDA-lesioned group. Taken together, these results demonstrate that simvastatin might inhibit the activation of NADPH oxidase/p38 MAPK pathway, enhance antioxidant protein expression and protect against oxidative stress, thereby providing a novel antioxidant mechanism that has therapeutic validity.

Aims. This article performed a retrospective cohort study to estimate the annual incidence rates of diabetes and to assess the utility of HbA1c as a predictor for progression to diabetes in Chinese community adults aged 40 years or older. Methods. In all, 2778 nondiabetic subjects (including 1901 women) underwent HbA1c testing and oral glucose tolerance test (OGTT) measurements at baseline and after 3 years. Diabetes and prediabetes were defined using the WHO criteria. The HbA1c cutoff points were evaluated to predict the future risks of diabetes. Relative risk (RR) was calculated using the chi-square test. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the predictive efficiency of fasting plasma glucose (FPG), 2 hr postprandial plasma glucose (2hPG), and HbA1c for progression to diabetes. A superior cutoff point was defined as the point on the ROC curve with a larger Youden index. Results. Overall, 7.5% (210/2778) of the subjects progressed to diabetes, yielding an annual 2.5% diabetes incidence rate. Additionally, 4.5% (100/2227) of the subjects with normal glucose tolerance (NGT) and 19.6% (110/561) of the subjects with prediabetes progressed to diabetes, and the relative risk of progression to diabetes was 5.188 times higher in subjects with prediabetes than in subjects with NGT (p

Previous studies have suggested that focusing an element can enhance the activation of the focused element and bring about a number of processing benefits. However, whether and how this local prominence of information interacts with global discourse organization remains unclear. In the present study, we addressed this issue in two experiments. Readers were presented with four-sentence discourses. The first sentence of each discourse contained a critical word that was either focused or unfocused in relation to a wh-question preceding the discourse. The second sentence either maintained or shifted the topic of the first sentence. Participants were told to read for comprehension and for a probe recognition task in which the memory of the critical words was tested. In Experiment 1, when the probe words were tested immediately after the point of topic shift, we found shorter response times for the focused critical words than the unfocused ones regardless of topic manipulation. However, in Experiment 2, when the probe words were tested two sentences away from the point of topic shift, we found the facilitation effect of focus only in the topic-maintained discourses, but not in the topic-shifted discourses. This suggests that the facilitation effect of focus was not immediately suppressed at the point of topic shifting, but when additional information was added to the new topic. Our findings provide evidence for the dynamic interplay between global topic structure and local salience of information and have important implications on how activation of information fluctuates in mental representation.

Transforming growth factor β-activated kinase 1 (TAK1), a vital upstream integrator of multiple pro-inflammatory signaling pathways, mediates the production of pro-inflammatory cytokines, chemokines, and adhesion molecules. Investigations targeting TAK1 provide new therapeutic options for chronic inflammatory disorders, autoimmune diseases, and cancer. However, the role and mechanism of the TAK1 inhibitor 5Z-7-oxozeaenol in treating autoimmune demyelinating diseases remain unclear. This work aimed to identify whether 5Z-7-oxozeaenol exerts neuroprotective effects on experimental autoimmune encephalomyelitis (EAE) in mice. Here, we demonstrate that 5Z-7-oxozeaenol efficiently alleviates the symptoms of EAE by decreasing the levels of pro-inflammatory cytokines in splenocytes and central nervous system, diminishing the number of activated microglia and inhibiting the p38MAPK, JNK, and ERK signaling pathways. Furthermore, we demonstrate that administration during the symptomatic time window is required for 5Z-7-oxozeaenol efficacy. These results suggest that TAK1 inhibition may provide a potent approach toward treating autoimmune demyelinating diseases.

Background/Aims: Total saponin extracted from Tribulus terrestris (TSETT) has been reported to protect against atherosclerosis. We here investigate the cellular and molecular mechanisms of TSETT underlying protection against atherosclerosis. Methods: Cell proliferation was measured with Methyl thiazolyl tetrazolium (MTT); Intracellular H2O2 was measured with DCFH-DA, a fluorescent dye; Intracellular free Ca2+ was measured with a confocal laser scanning microscopy; Genes expression was measured with gene array and real-time quantitative polymerase chain reaction (RT-PCR); Phosphorylation of extracellular signal-regulated kinase 1/2 (phospho-ERK1/2) was measured with cell-based enzyme-linked immunosorbent assay (ELISA) and western blotting. Results: TSETT significantly suppressed the increase in cells proliferation induced by angiotensin II, significantly suppressed the increase in the intracellular production of H2O2 induced by angiotensin II, significantly inhibited the increase in intracellular free Ca2+ induced by H2O2, significantly inhibited the increase in phospho-ERK1/2 induced by angiotensin II; significantly inhibited the increase in mRNA expression of c-fos, c-jun and pkc-α induced by angiotensin II. Conclusion: These findings provide a new insight into the antiatherosclerotic properties of TSETT and provide a pharmacological basis for the clinical application of TSETT in anti-atherosclerosis.

Gastric cancer incidence demonstrates a strong etiologic association with smoking. Nicotine, the major component in tobacco, is a survival agonist that inhibits apoptosis induced by certain chemotherapeutic agents, but the precise mechanisms involved remain largely unknown. Recently studies have indicated that α5-nicotinic acetylcholine receptor (α5-nAChR) is highly associated with lung cancer risk and nicotine dependence. Nevertheless, no information has been available about whether nicotine also affects proliferation of human gastric cancer cells through regulation of α5-nAChR. To evaluate the hypothesis that α5-nAChR may play a role in gastric cancer, we investigated its expression in gastric cancer tissues and cell lines. The expression of α5-nAChR increased in gastric cancer tissue compared with para-carcinoma tissues. In view of the results, we proceeded to investigate whether nicotine inhibits cisplatin-induced apoptosis via regulating α5-nAChR in gastric cancer cell. The results showed that nicotine significantly promoted cell proliferation in a dose and time-dependent manner through α5-nAChR activation in human gastric cells. Furthermore, nicotine inhibited apoptosis induced by cisplatin. Silence of α5-nAChR ablated the protective effects of nicotine. However, when co-administrating LY294002, an inhibitor of PI3K/AKT pathway, an increased apoptosis was observed. This effect correlated with the induction of Bcl-2, Bax, Survivin and Caspase-3 by nicotine in gastric cell lines. These results suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutic drugs and that α5-nAChR/AKT signaling plays a key role in the anti-apoptotic activity of nicotine induced by cisplatin.

Objective. To investigate changes in the glycated hemoglobin A1c (A1c) level and those in β cell function and insulin resistance in newly diagnosed and drug naive type 2 diabetes patients and to evaluate the relationship between them. Design and Methods. A total of 818 newly diagnosed diabetic individuals who were ≥40 years of age were recruited. The subjects were grouped by A1c values (