Long-term toxicity evaluation of aristolochic acid-IIIa in mice.

Aristolochic acid (AA)-IIIa is an AA analog present in Aristolochiaceae plants. To evaluate the chronic toxicity of AA-IIIa, mice were intragastrically administered with media control, 1 mg/kg AA-IIIa, and 10 mg/kg AA-IIIa, and designated as the control (CTL), AA-IIIa low dose (AA-IIIa-L), and AA-IIIa high dose (AA-IIIa-H) groups, respectively. AA-IIIa was administered three times a week, every other day, for 24 weeks (24-week time point). Thereafter, some mice were sacrificed immediately, while others were sacrificed 29 or 50 weeks after AA-IIIa withdrawal (53- or 74-week time point). Serum and organs were collected for biochemical and pathological analyses, respectively. Whole-genome sequencing was performed on the kidney, liver, and stomach tissues of AA-IIIa-treated mice for single-nucleotide polymorphism (SNP) detection. AA-IIIa-H mice died at 66 weeks, and the remaining mice showed moribund conditions at the 69 weeks. AA-IIIa induced minor kidney tubule injury, fibroblast hyperplasia, and forestomach carcinoma in mice. Bladder, intestine, liver, heart, spleen, lung, and testis tissues were not pathologically altered by AA-IIIa. In addition, AA-IIIa increased the C:G > A:T mutation in the kidney; however, no SNP mutation changes were observed in the liver and forestomach tissues of AA-IIIa-H mice at the 24-week time point compared with control mice. Therefore, we suspect that AA-IIIa is potentially mutagenic for mice after overdose and long-term administration. On the other hand, the forestomach is a unique organ in mice, but it does not exist in humans; thus, we hypothesize that the stomach toxicity induced by AA-IIIa is not a suitable reference for toxicological evaluation in humans. We recommend that Aristolochiaceae plants containing AA-IIIa should be properly supervised, and overdosing and long-term administration of drugs containing AA-IIIa should be avoided.

Copper-Catalyzed Difunctionalization of Propargylic Carbonates through Tandem Nucleophilic Substitution/Boroprotonation.

Highly functionalized organic molecules are in high demand, but their preparation is challenging. Copper-catalyzed transformation of alkynyl- and allenyl-containing substrates has emerged as a powerful tool to achieve this objective. Herein, an efficient copper-catalyzed difunctionalization of propargylic carbonates through tandem nucleophilic substitution/boroprotonation has been developed, affording the formation of thiol-, selenium-, and boron-functionalized alkenes with high yield and stereoselectivity. Two distinct catalytic mechanisms involving a single reaction without any requirement of catalyst change were successfully demonstrated.

A novel data fusion based intelligent identification approach for working cycle stages of hydraulic excavators.

Accurately identifying the stage of the excavator working cycle is the prerequisite to achieve the staged energy-saving control. However, current identification methods often overlook the influence of hydraulic system latency on identification results and depend on a single model, resulting in poor generalization performance of the identification approaches. Moreover, expert calibration system remains a necessary factor for improving identification accuracy. Aiming at these issues, a hybrid multi-scale feature extractor and a decision-level data fusion classifier approach (HMSFE-DFC) is proposed to identify the working cycle stages of excavator. The input signal employs mixed signals from the main pump pressure and the control current of the proportional solenoid valve to reduce the response delay caused by the single main pump pressure signal. A hybrid multi-scale feature extractor is constructed using a convolutional neural network temporal self-attention feature extraction mechanism and one-dimensional ResNet-50 architecture to extract multiscale features. To prevent overfitting, a decision-level data fusion classifier is used to fuse the decisions information of numerous classifiers. The accuracy of stage identification for 10 consecutive working cycles reaches 95.21%, which verifies its effectiveness.

Enhanced Sensing Mechanism Based on Shifting an Exceptional Point.

Non-Hermitian systems associated with exceptional points (EPs) are expected to demonstrate a giant response enhancement for various sensors. The widely investigated enhancement mechanism based on diverging from an EP should destroy the EP and further limits its applications for multiple sensing scenarios in a time sequence. To break the above limit, here, we proposed a new enhanced sensing mechanism based on shifting an EP. Different from the mechanism of diverging from an EP, our scheme is an EP nondemolition and the giant enhancement of response is acquired by a slight shift of the EP along the parameter axis induced by perturbation. The new sensing mechanism can promise the most effective response enhancement for all sensors in the case of multiple sensing in a time sequence. To verify our sensing mechanism, we construct a mass sensor and a gyroscope with concrete physical implementations. Our work will deepen the understanding of EP-based sensing and inspire designing various high-sensitivity sensors in different physical systems.

Long noncoding RNA PVT1 predicts poor prognosis and promotes the progression of colorectal cancer through the miR-24-3p/NRP1 axis in zebrafish xenografts.

Long noncoding RNAs (lncRNAs) play important roles in the progression of human cancer. It is reported that lncRNA plasmacytoma variant translocation 1 (PVT1) is involved in colorectal cancer (CRC), however, the underlying mechanism remains to be explored deeply, especially by in vivo models. In the present study, bioinformatics analysis showed that the expression level of PVT1 was upregulated in CRC tissues and highly associated with poor prognosis of CRC patients. In cultured CRC cells, knockdown of PVT1 inhibited cell proliferation and migration of CRC cells, while overexpression of PVT1 promoted the progression of CRC cells. In zebrafish xenografts, the silencing of PVT1 also suppressed the growth and metastasis of CRC cells. For mechanism studies, the binding relationships among PVT1, miR-24-3p, and Neuropilin 1 (NRP1) were predicted by starBase firstly. The luciferase reporter assays verified that PVT1 and NRP1 could bind with miR-24-3p directly. Further studies showed miR-24-3p negatively regulated the progression of CRC cells, the inhibition of miR-24-3p counteracted the repression effects of CRC progression when knocking down PVT1. In addition, the expression of NRP1 was regulated by PVT1, and NRP1 overexpression could partially rescue the inhibition effects of CRC progression when knocking down PVT1 in vitro and in vivo. Our study reveals that PVT1 promotes the proliferation and metastasis of CRC via regulating the miR-24-3p/NRP1 axis, which provides a prognosis biomarker and a potential therapeutic target for CRC patients.

Postpartum depression literacy in Chinese perinatal women: a cross-sectional study.

Background: Postpartum depression literacy is a specific mental health literacy that can help perinatal women identify, manage, and prevent postpartum depression. However, the current status and associated factors of postpartum depression literacy among Chinese perinatal women are still unclear. This study investigated postpartum depression literacy and its associated factors among this group. Methods: A cross-sectional survey was conducted involving 386 cases of perinatal women using the convenience sampling method. Participants completed four questionnaires to evaluate their general characteristics, postpartum depression literacy, perceived social support, and general self-efficacy. The SPSS 24.0 software was used for descriptive statistical analysis, univariate analysis, and multivariate analysis. Results: The total PoDLiS score was (3.56 ± 0.32). The factors that composed the final multiple regression equation included planned pregnancy condition (ß = -0.137, p = 0.003), education (ß = 0.127, p < 0.001), history of depression (ß = -0.271, p < 0.001), social support (ß = 0.0012, p < 0.001), self-efficacy (ß = 0.030, p < 0.001), and complications (ß = -0.0191, p = 0.0019). They accounted for 32.8% of the total postpartum depression literacy variation (R2 = 0.328, F = 24.518, p < 0.001). Conclusion: The findings of this study improved our understanding of perinatal women's postpartum depression literacy and its associated factors. Women with low postpartum depression literacy urgently need to be identified. Comprehensive nursing intervention measures should be taken from six dimensions of mental health literacy, social support, and self-efficacy to improve the postpartum depression literacy of perinatal women.

A secreted phospholipase A2 (BmsPLA2 ) regulates melanization of immunity through BmDDC in the silkworm Bombyx mori.

Insect immune-associated phospholipase A2 (PLA2 ) is an important target of pathogen invasion. Melanization, an effective defense response, has significant correlations with other immune responses to coordinate immune attack against invaders. However, the effect of PLA2 on melanization has not yet been reported in insects or other arthropods. In this work, we cloned a PLA2 gene (BmsPLA2 ), and its protein had characteristic features of secreted PLA2 (sPLA2 ). After injection of bacteria, BmsPLA2 expression and sPLA2 activity in hemolymph significantly increased. BmsPLA2 fluorescence was transferred from the cytoplasm to the cell membranes of circulating hemocytes. These results indicated that BmsPLA2 was related to hemolymph immunity in silkworms. Interestingly, reducing BmsPLA2 by RNA interference decreased melanosis (melanistic hemocytes) levels in vivo and in vitro, while BmsPLA2 overexpression had the opposite effect. The larval survival and melanization rate in the hemocoel both slowed depending on the PLA2 inhibitor dosage. These results demonstrated that BmsPLA2 plays a role in melanization during the immune process of silkworms. Surprisingly, the level of BmDDC matched the degree of melanization in various observations. BmDDC expression showed a significant increase, with the peak occurring later than that of BmsPLA2 after injection of bacteria, implying that BmsPLA2 was activated prior to BmDDC. Moreover, the alteration of BmsPLA2 by RNA interference or overexpression led to altered BmDDC levels. These results suggested that BmsPLA2 regulates the melanization response in silkworms through BmDDC. Our study proposes a new regulatory mechanism of the melanization response and new directions for understanding the complex immune networks of insects.

Copper-Catalyzed Asymmetric Boroprotonation of Phosphinylallenes.

Synthesis of chiral phosphorus compounds from readily available substrates by a facile method is an attractive strategy. In this study, an efficient route for copper-catalyzed asymmetric boroprotonation of phosphinylallenes with bis(pinacolato)diboron with high regioselectivity was developed, affording chiral allylphosphine oxides in high yields with high enantioselectivities of up to 98% ee. The synthetic utility was further demonstrated by the facile transformation of the chiral allylphosphine oxides to several stereospecific products.

Tuning the Quantum Properties of ZnO Devices by Modulating Bulk Length and Doping.

The quantum transport properties of ZnO devices with five different bulk configurations are investigated with numerical methods. The calculation results reveal that the transport property at a higher energy range can be tuned by changing the length of central scattering. By substituting some Zn atoms with Cu atoms, it is found that the doped Cu atoms have an obvious effect on the quantum properties at the entire energy range investigated, and could result in different transmission. The properties of ZnO devices are also influenced by the doping positions of Cu atoms. The tuning mechanism relies on the shifting of carrier distributions in the scattering center of the device.

Heterodyne detection of backscattering for whispering-gallery-mode sensors.

Whispering-gallery-mode (WGM) microcavities have shown significant applications in nanoparticle sensing for environmental monitoring and biological analysis. However, the enhancement of detection resolution often calls for active cavities or elaborate structural designs, leading to an increase of fabrication complexity and cost. Herein, heterodyne amplification is implemented in WGM microsensors based on backscattering detection mechanism. By interfering with an exotic reference laser, the reflecting light backscattered by perturbation targets can be strongly enlarged, yielding an easy-to-resolve and consequently sensitive microsensor. The dependence of detection laser frequency has also been characterized with the assistance of optothermal dynamics. We show that exploiting heterodyne interferometry boosts the detection of weak signals in microresonator systems and provides a fertile ground for optical microsensor development.

Simultaneous ground-state cooling of multiple degenerate mechanical modes through the cross-Kerr effect.

Simultaneous ground-state cooling of multiple degenerate mechanical modes is a difficult issue in optomechanical systems, owing to the existence of the dark mode effect. Here we propose a universal and scalable method to break the dark mode effect of two degenerate mechanical modes by introducing cross-Kerr (CK) nonlinearity. At most, four stable steady states can be achieved in our scheme in the presence of the CK effect, unlike the bistable behavior of the standard optomechanical system. Under a constant input laser power, the effective detuning and mechanical resonant frequency can be modulated by the CK nonlinearity, resulting in an optimal CK coupling strength for cooling. Similarly, there will be an optimal input laser power for cooling when the CK coupling strength stays fixed. Our scheme can be extended to break the dark mode effect of multiple degenerate mechanical modes by introducing more than one CK effect. To fulfill the requirement of the simultaneous ground-state cooling of N multiple degenerate mechanical modes, N - 1 CK effects with different strengths are needed. Our proposal provides new, to the best of our knowledge. insights into dark mode control and might pave the way to manipulating multiple quantum states in a macroscopic system.

The rfbN gene of Salmonella Typhimurium mediates phage adsorption by modulating biosynthesis of lipopolysaccharide.

The study of the interaction mechanism between bacteriophage and host is helpful in promoting development of bacteriophage applications. The mechanism of the interaction with the phage was studied by constructing the rfbN gene deletion and complemented with strains of Salmonella enterica subspecies enterica serovar Typhimurium (Salmonella Typhimurium, S. Typhimurium) D6. The rfbN gene deletion strain could not be lysed by phage S55 and led to a disorder of lipopolysaccharide (LPS) biosynthesis, which changed from the smooth type to rough type. Also, the RfbN protein lacking any of the three-segment amino acid (aa) sequences (90-120 aa, 121-158 aa, and 159-194 aa) produces the same result. Transmission electron microscopy and confocal microscopy assays demonstrated that phage S55 dramatically reduced adsorption to the rfbN deletion strain as compared to the wild strain D6. After co-incubation of the S55 with the purified smooth LPS, D6 could not be lysed, indicating that the smooth LPS binds to the S55 in vitro and then inhibits the cleavage activity of the S55. To sum up, the rfbN gene affects phage adsorption by regulating LPS synthesis. Furthermore, the functioning of the RfbN protein requires the involvement of multiple structures. To the best of our knowledge, this study is the first report of the involvement of the bacterial rfbN gene involved in the phage-adsorption process.

Phase-controlled dual-wavelength resonance in a self-coupling whispering-gallery-mode microcavity.

We report a novel, to the best of our knowledge, way to achieve phase-controlled dual-wavelength resonance based on whispering-gallery-mode (WGM) microcavities experimentally. With the help of a feedback waveguide, not only two optical pathways but also a unidirectional coupling between counter-propagating waves are formed, which is the requirement of all-optical analogues of electromagnetically induced transparency and Autler-Townes splitting. By adjusting the accumulating phase introduced from the fiber waveguide, we observe the signal lineshape changes from symmetric to asymmetric, i.e., the resonant transmission and extinction ratio of two splitting modes can be controlled, which brings a new degree of freedom to the WGM resonator system. These results may boost the development of quantum state control and pave the way for reconfiguring devices such as narrow-band filters.

Shuxuening injection, derived from Ginkgo biloba leaf, induced pseudo-allergic reactions through hyperactivation of mTOR.

Context: Shuxuening injection (SXNI), derived from the leaf of Ginkgo biloba L. (Ginkgoaceae), is widely used to treat cardio-cerebral vascular system related disease due to the efficacy of dilating the blood vessels and improving the function of microcirculation. Nevertheless, SXNI induces immediate hypersensitivity reactions in clinics and the molecular mechanisms are unknown.Objective: The present study investigates the molecular mechanism of SXNI mediated hypersensitivity reactions.Materials and methods: Naive male ICR mice (n = 10) were administered (i.v.) with negative control combined with Evans blue (EB) (CTL-EB), SXNI (14 or 70 mg/kg) combined with EB (SXNI/1-EB or SXNI/4-EB), vascular leakage was evaluated, ears and lungs were collected for histopathological analysis. In vitro, TSC1 was knockdown in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated with SXNI, and the alterations of endothelial cell permeability were observed. Rapamycin (mTOR inbibitor) was used to investigate SXNI-induced hypersensitivity reactions both in mice and HUVECs.Results: SXNI (70 mg/kg) induced vascular leakage in mice. Slight oedema and microvascular dilation in the ears, and broaden of alveolar septal and monocyte infiltration in the lungs were observed in SXNI (70 mg/kg) treated mice. mTOR inhibitor alleviates SXNI mediated vascular endothelial hyperpermeability both in vitro and in vivo.Discussion and conclusions: SXNI stimulates pseudo-allergic reactions through hyperactivation of mTOR signalling pathway. Our work provides the new molecular mechanism of drug related pseudo-allergic reactions, and a potential drug to prevent and treat SXNI mediated hypersensitivity reactions.

Genome-wide transcriptional analysis of Aristolochia manshuriensis induced gastric carcinoma.

Context: Aristolochia manshuriensis Kom (Aristolochiaceae) (AMK) is known for toxicity and mutagenicity.Objective: The tumorigenic role of AMK has yet to be understood.Materials and methods: AMK extracts were extracted from root crude drug. SD (Sprague Dawley) rats underwent gavage with AMK (0.92 g/kg) every other day for 10 (AMK-10) or 20 (AMK-20) weeks. Stomach samples were gathered for histopathological evaluation, microarray and mRNA analysis.Results: The gastric weight to body weight ratio (GW/BW) is 1.7 in the AMK-10 cohort, and 1.8 in AMK-20 cohort compared to control (CTL) cohort. Liver function was damaged in AMK-10 and AMK-20 rats compared to CTL rats. There were no significant changes of CRE (creatinine) in AMK-10 and AMK-20 rats. Histopathological analysis revealed that rats developed dysplasia in the forestomach in AMK-10 rats, and became gastric carcinoma in AMK-20 rats. Genes including Mapk13, Nme1, Gsta4, Gstm1, Jun, Mgst2, Ggt6, Gpx2, Gpx8, Calml3, Rasgrp2, Cd44, Gsr, Dgkb, Rras, and Amt were found to be critical in AMK-10 and AMK-20 rats. Pik3cb, Plcb3, Tp53, Hras, Myc, Src, Akt1, Gnai3, and Fgfr3 worked in AMK-10 rats, and PDE2a and PDE3a played a pivotal role in AMK-20 rats.Discussion and conclusions: AMK induced benign or malignant gastric tumours depends on the period of AMK administration. Genes including Mapk13, Nme1, Gsta4, Gstm1, Jun, Mgst2, Ggt6, Gpx2, Gpx8, Calml3, Rasgrp2, Cd44, Gsr, Dgkb, Rras, Amt, Pik3cb, Plcb3, Tp53, Hras, Myc, Src, Akt1, Gnai3, Fgfr3, PDE2a, and PDE3a were found to be critical in aristolochic acid-induced gastric tumour process.

The efficacy and safety of one-stage endoscopic treatment for ascending acute cholangitis caused by choledocholithiasis with severe comorbidities.

BACKGROUND: Emergency endoscopic retrograde cholangiopancreatography (ERCP) for ascending acute cholangitis in patients with severe comorbidities is challenging. Here, we evaluated the efficacy and safety of one-stage ERCP in such patients by performing a retrospective study. METHODS: We included all patients with ascending acute cholangitis and undergoing ERCP between January 2017 and March 2019. In total, we recruited 212 patients: 74 and 138 with and without severe comorbidities, respectively. We collected and analyzed data related to basal characteristics, ERCP, and clinical outcomes. RESULTS: Elderly age (76.20 ± 9.99 years vs. 66.52 ± 8.16 years, P = 0.000), higher levels of leukocyte count (15.86 ± 2.47 × 109/ml vs. 13.49 ± 1.65 × 109/ml, P = 0.000), and serum bilirubin (3.11 ± 1.29 mg/dl vs. 1.94 ± 0.90 mg/dl, P = 0.000) were present in patients with severe comorbidities. A significantly higher proportion of these patients were severe cases (32.4% vs. 6.5%, P = 0.000), American Society of Anesthesiologists (ASA) stage V status (37.8% vs. 10.1%, P = 0.000) and had undergone general anesthesia (56.8% vs. 18.8%, P = 0.000). Successful biliary cannulation and complete stone clearance in one session were achieved in 207 and 202 patients, respectively. Mean length of hospital stay was 8.02 ± 2.71 days. Forty-three patients required ICU stay with the mean length of 3.26 ± 3.51 days. In-hospital mortality occurred in seven patients; all these patients had severe comorbidities. ERCP details, including urgent and early ERCP, biliary cannulation, complete stone clearance in one session, stent insertion, and complications were not significantly different between the two groups. Patients with severe comorbidities had a longer in-hospital stay (9.39 ± 3.15 days vs. 7.29 ± 2.11 days, P = 0.000), a higher proportion of ICU admission (45.9% vs. 6.5%, P = 0.000), and a longer ICU stay length (4.88 ± 4.37 days vs. 1.44 ± 0.52 days, P = 0.000). Our data also revealed that early diagnosis is an important predictor associated with clinical outcomes. CONCLUSIONS: One-stage ERCP is safe and effective for ascending acute cholangitis caused by choledocholithiasis. Early diagnosis is a significant predictor of clinical outcomes.

The Involvement of the RhoA/ROCK Signaling Pathway in Hypersensitivity Reactions Induced by Paclitaxel Injection.

A high incidence of hypersensitivity reactions (HSRs) largely limits the use of paclitaxel injection. Currently, these reactions are considered to be mediated by histamine release and complement activation. However, the evidence is insufficient and the molecular mechanism involved in paclitaxel injection-induced HSRs is still incompletely understood. In this study, a mice model mimicking vascular hyperpermeability was applied. The vascular leakage induced merely by excipients (polyoxyl 35 castor oil) was equivalent to the reactions evoked by paclitaxel injection under the same conditions. Treatment with paclitaxel injection could cause rapid histamine release. The vascular exudation was dramatically inhibited by pretreatment with a histamine antagonist. No significant change in paclitaxel injection-induced HSRs was observed in complement-deficient and complement-depleted mice. The RhoA/ROCK signaling pathway was activated by paclitaxel injection. Moreover, the ROCK inhibitor showed a protective effect on vascular leakage in the ears and on inflammation in the lungs. In conclusion, this study provided a suitable mice model for investigating the HSRs characterized by vascular hyperpermeability and confirmed the main sensitization of excipients in paclitaxel injection. Histamine release and RhoA/ROCK pathway activation, rather than complement activation, played an important role in paclitaxel injection-induced HSRs. Furthermore, the ROCK inhibitor may provide a potential preventive approach for paclitaxel injection side effects.

SOX9 promotes epithelial-mesenchymal transition via the Hippo-YAP signaling pathway in gastric carcinoma cells.

SRY-box 9 (SOX9) is overexpressed in a number of human tumors, including gastric cancer (GC). However, the function of SOX9 in the development of GC remains unknown. In the present study, SOX9 activated the Hippo-yes-associated protein (YAP) signaling pathway to enhance the epithelial-mesenchymal transition in GC cell lines. The results suggested that SOX9 knockdown inhibited invasion, proliferation and migration of GC cells. Furthermore, SOX9 silencing upregulated the expression of E-cadherin, an epithelial marker, and downregulated the expression of mesenchymal markers, including snail family transcriptional repressor 1, vimentin and N-cadherin. SOX9 overexpression increased the expression of the aforementioned markers. SOX9 significantly affected YAP phosphorylation and total YAP protein levels, suggesting that SOX9 is involved in the Hippo-YAP signaling pathway. The current study revealed that SOX9 may be involved in the pathogenesis of GC, and further elucidation of the pathways involved may support the development of novel therapeutic options for the treatment of GC.

RNA Sequencing Analysis of Molecular Basis of Sodium Butyrate-Induced Growth Inhibition on Colorectal Cancer Cell Lines.

Butyrate is a short-chain fatty acid decomposed from dietary fiber and has been shown to have effects on inhibition of proliferation but induction of apoptosis in colorectal cancer cells. However, clinical trials have yielded ambiguous outcomes with regard to its antitumor activities. In this study, we aimed to explore the molecular mechanisms underlying the sensitivity of colorectal cancer cells to sodium butyrate (NaB). RNA sequencing was used to establish the whole-transcriptome profile in NaB-treated versus untreated colorectal cancer cells. Differentially expressed genes were bioinformatically analyzed to predict their possible involvement in NaB-triggered cell death, and the expression of eight dysregulated genes was validated by quantitative real-time PCR. We found that there were a total of 7192 genes (5720 upregulated and 1472 downregulated, fold-change ≥ 2 or ≤ 0.5 for upregulation or downregulation, q-value < 0.05) differentially expressed in NaB-treated cells as compared with the untreated controls. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that the differentially expressed genes were enriched in DNA replication, cell cycle, homologous recombination, pyrimidine metabolism, mismatch repair, and other signaling pathways and may take part in NaB-induced cell death. Among the identified factors, the MCM2-7 complex might be a target of NaB. Our findings provide an important basis for further studies of the complicate network that might regulate sensitivity of colorectal cancer cells to NaB.