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Xiangyang Cheng,1,* Dejian Li,2,* Aiqi Lin,3 Jun Xu,1 Liang Wu,1 Huijie Gu,1 Zhongyue Huang,1 Jiangyi Liu,1 Yiming Zhang,1 Xiaofan Yin1 1Department of Orthopedics, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai 201199, China; 2Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201301, China; 3Department of Retired, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai 201199, China *These authors contributed equally to this work Introduction: For an ideal drug delivery system, the outstanding drug-loading capacity and specific control of the release of therapeutics at the desired lesions are crucial. In this work, we developed a triple-responsive nanoplatform based on copper sulfide (CuS)-capped yolk-shell-structured periodic mesoporous organosilica nanoparticles (YSPMOs) for synergetic chemo-photothermal therapy. Methods: Herein, the YSPMOs were employed as a drug carrier, which exhibited a high doxorubicin (DOX) loading capacity of 386 mg/g. In this controlled-release drug delivery system, CuS serves as a gatekeeper to modify YSPMOs with reduction-cleavable disulfide bond (YSPMOs@CuS). CuS could not only avoid premature leakage in the delivery process, but also endowed the excellent photothermal therapy (PTT) ability. Results: Upon entering into cancer cells, the CuS gatekeeper was opened with the breaking of disulfide bonds and the DOX release from YSPMOs(DOX)@CuS in response to the intracellular acidic environment and external laser irradiation. Such a precise control over drug release, combined with the photothermal effect of CuS nanoparticles, is possessed by synergistic chemo-photothermal therapy for cancer treatment. Both in vitro and in vivo experimental data indicated that the synergistic effect of YSPMOs(DOX)@CuS showed efficient antitumor effect. In addition, low systemic toxicity was observed in the pathologic examinations of liver, spleen, lungs, and kidneys. Conclusion: This versatile nanoplatform combination of PTT, chemotherapeutics, and gating components shows general potential for designing multifunctional drug delivery systems. Keywords: periodic mesoporous organosilica, CuS, triple-responsive release, chemo-photothermal therapy

Lu Cao,1,* Qian Chen,1,* Li-Bo Jiang,1,* Xiao-Fan Yin,1,2 Chong Bian,1 Hui-Ren Wang,1 Yi-Qun Ma,1 Xiang-Qian Li,1 Xi-Lei Li,1 Jian Dong1 1Department of Orthopaedic Surgery, Zhongshan Hospital, 2Department of Orthopaedic Surgery, Minhang Hospital, Fudan University, Shanghai, China *These authors contributed equally to this work Study design: This is an experimental animal study.Objective: The objective of this study was to compare an anterior cervical discectomy and interbody fusion of a novel polylactide/nano-sized β-tricalcium phosphate (PLA/nβ-TCP) bioabsorbable self-retaining cervical fusion cage (BCFC) with an autologous bone graft and polyetheretherketone (PEEK) cages.Background: Although PLA cervical cages have potential advantages compared with traditional materials, they are not currently routinely used in spine surgery because of undesirable effects such as the lack of osteoconductivity and osteolysis around the implant. This study involved the manufacturing of a bioabsorbable cage from PLA/nβ-TCP that was then used as a device for anterior cervical discectomy and fusion (ACDF) on a goat cervical spine fusion model.Materials and methods: Eighteen goats underwent C3/C4 discectomy and were randomly divided into three groups based on the following methods: Group A (n=6), an autologous bone graft; Group B (n=6), PEEK cage filled with an autologous graft; and Group C (n=6), BCFC filled with an autologous iliac bone. Radiography was performed preoperatively and postoperatively and at 1, 4, 8, and 12 weeks after the operation. Disc space height (DSH) was measured at the same time. After 12 weeks, the fused segments were harvested and evaluated with functional radiographic views, biomechanical testing, and histological analyses.Results: Over a 12-week period, the BCFC and PEEK cage groups exhibited significantly higher DSH values than the bone graft group. Additionally, the BCFC group yielded a significantly lower range of motion in axial rotation than both the autologous bone graft and PEEK cage groups. A histologic evaluation revealed an increased intervertebral bone volume/total volume ratio and better interbody fusion in the BCFC group than in the other groups.Conclusion: The BCFC device exhibited better results than the autologous bone graft and PEEK cages in single-level ACDF models in vivo. This device may be a potential alternative to the current PEEK cages. Keywords: goat, cervical spine cages, bioabsorbable, PLA, β-TCP, self-retaining

Purpose: To report the use of anterior segment optical coherence tomography (AS-OCT) for superficial keratectomy (SK) in anterior corneal opacity., Methods: The characteristics of 43 eyes (39 patients) with various lesions responsible for anterior corneal opacity were included in this retrospective non-comparative study. AS-OCT was performed on all eyes before surgery. The thickness of corneal opacity and the underlying healthy stroma were measured. SK was performed on each individual., Results: Four types of anterior corneal opacity were evaluated, including corneal degeneration (26/43), Reis-Bücklers corneal dystrophy (8/43), alkali burn (1/43) and corneal tumors (8/43). Based on AS-OCT images, all eyes showed abnormal hyper-reflective signals in the superficial cornea to less than one-third of the normal corneal thickness in the deepest corneal opacity. All 43 eyes underwent an SK procedure. In addition, 1 eye with alkali burns and 7 eyes with corneal tumors were combined with amniotic membrane transplantation. All eyes restored transparency without significant complications., Conclusion: AS-OCT is a valuable method for objective preoperative and noninvasive assessments of anterior corneal opacities and is useful for guiding SK., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Although the pathogenesis of osteoarthritis (OA) is unclear, inflammatory cytokines are related to its occurrence. However, few studies focused on the therapeutic strategies of regulating joint homeostasis by simultaneously remodeling the anti-inflammatory and immunomodulatory microenvironments. Fibroblast growth factor 18 (FGF18) is the only disease-modifying OA drug (DMOAD) with a potent ability and high efficiency in maintaining the phenotype of chondrocytes within cell culture models. However, its potential role in the immune microenvironment remains unknown. Besides, information on an optimal carrier, whose interface and chondral-biomimetic microenvironment mimic the native articular tissue, is still lacking, which substantially limits the clinical efficacy of FGF18. Herein, to simulate the cartilage matrix, chondroitin sulfate (ChS)-based nanoparticles (NPs) are integrated into poly(D, L-lactide)-poly(ethylene glycol)-poly(D, L-lactide) (PLEL) hydrogels to develop a bionic thermosensitive sustainable delivery system. Electrostatically self-assembled ChS and ε-poly-l-lysine (EPL) NPs are prepared for the bioencapsulation of FGF18. This bionic delivery system suppressed the inflammatory response in interleukin-1β (IL-1β)-mediated chondrocytes, promoted macrophage M2 polarization, and inhibited M1 polarization, thereby ameliorating cartilage degeneration and synovitis in OA. Thus, the ChS-based hydrogel system offers a potential strategy to regulate the chondrocyte-macrophage crosstalk, thus re-establishing the anti-inflammatory and immunomodulatory microenvironment for OA therapy., (© 2024 Wiley‐VCH GmbH.)

Single-nucleotide polymorphism (SNP) is one of the core mechanisms that respond to antibiotic resistance of Escherichia coli (E. coli), which is a major issue in environmental pollution. A specific type of SNPs, synonymous SNPs, have been generally considered as the "silent" SNPs since they do not change the encoded amino acid. However, the impact of synonymous SNPs on mRNA splicing, nucleo-cytoplasmic export, stability, and translation was gradually discovered in the last decades. Figuring out the mechanism of synonymous SNPs in regulating antibiotic resistance is critical to improve antimicrobial therapy strategies in clinics and biological treatment strategies of antibiotic-resistant E. coli-polluted materials. With our newly designed antibiotic resistant SNPs prediction algorithm, Multilocus Sequence Type based Identification for Phenotype-single nucleotide polymorphism Analysis (MIPHA), and in vivo validation, we identified 2 important synonymous SNPs 522 G>A and 972 C>T, located at hisD gene, which was previously predicted as a fluoroquinolone resistance-related gene without a detailed mechanism in the E. coli samples with environmental backgrounds. We first discovered that hisD causes gyrA mutation via the upregulation of sbmC and its downstream gene umuD. Moreover, those 2 synonymous SNPs of hisD cause its own translational slowdown and further reduce the expression levels of sbmC and its downstream gene umuD, making the fluoroquinolone resistance determining region of gyrA remains unmutated, ultimately causing the bacteria to lose their ability to resist drugs. This study provided valuable insight into the role of synonymous SNPs in mediating antibiotic resistance of bacteria and a new perspective for the treatment of environmental pollution caused by drug-resistant bacteria., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: To the best of our knowledge, no studies have been performed to determine the optimal parameters of photodynamic therapy (PDT) combined with subconjunctival injection of bevacizumab for corneal neovascularization. This study aimed to compare the effect of photodynamic therapy with two different sets of parameters combined with subconjunctival injection of bevacizumab for corneal neovascularization., Methods: Patients with stable corneal neovascularization (CNV) unresponsive to conventional treatment (topical steroid) were included in this study. Patients were divided into two groups, receiving PDT with two different sets of parameters (group 1 receiving fluence of 50 J/cm 2 at 15 min after intravenous injection of verteporfin with, group 2 receiving fluence of 150 J/cm 2 at 60 min after intravenous injection of verteporfin with). Subconjunctival injection of bevacizumab was performed immediately after PDT. All patients were followed for 6 months. Best-corrected visual acuity and intraocular pressure were evaluated, and slit-lamp biomicroscopy as well as digital photography were performed. Average diameter and cumulative length of corneal neovascular were measured to evaluate the corneal neovascularization., Results: Seventeen patients (20 eyes) were included in this study. At the last visit, the vision was improved in 12 eyes (60 %), steady in 4 eyes (20 %) and worsen in 4 eyes (20 %). The intraocular pressure (IOP) of all patients remained in normal range. A significant decrease in corneal neovascularization was showed in all the eyes after treatment. At 6 months after the combined treatment, the average diameter and cumulative length of vessels significantly decreased to 0.041 ± 0.023 mm (P < 0.05) and 18.78 ± 17.73 mm (P < 0.05), respectively, compared with the pretreatment data (0.062 ± 0.015 mm, 31.48 ± 18.21 mm). The reduction was more remarkable in group 2 compared to group 1.In group 1, the average diameter was 0.062 ± 0.013mm before and 0.056 ± 0.017mm after, the cumulative length of vessels was 38.66 ± 22.55mm before and 31.21 ± 17.30 after. In group 2, the date were 0.061 ± 0.016mm before and 0.029 ± 0.020mm after, 25.60 ± 8.95 mm before and 8.61 ± 8.26 mm. The reported complications included epithelial defect in four eyes, small white filaments in two eyes and corneal epithelial erosion in two eyes., Conclusion: The PDT combined with subconjunctival injection of bevacizumab was effective for the chronic corneal neovascularization. A more promising treatment outcome was observed when PDT was performed at 60 min after intravenous injection of verteporfin with fluence of 150 J/cm 2 . No serious complications or systemic events were observed throughout the follow-up period., Competing Interests: Declaration of competing interest None of the authors has financial interests in this topic., (Copyright © 2024. Published by Elsevier B.V.)

Background: Chorioamnionitis (CA) can cause multiple organ injuries in premature neonates, particularly to the lungs. Different opinions exist regarding the impact of intrauterine inflammation on neonatal respiratory distress syndrome (NRDS) and bronchopulmonary dysplasia (BPD). We aim to systematically review the relationship between CA or Funisitis (FV) and lung injury among preterm infants., Methods: We electronically searched PubMed, EMbase, the Cochrane library, CNKI, and CMB for cohort studies from their inception to March 15, 2023. Two reviewers independently screened literature, gathered data, and did NOS scale of included studies. The meta-analysis was performed using RevMan 5.3., Results: Sixteen observational studies including 68,397 patients were collected. Meta-analysis showed CA or FV increased the lung injury risk (OR = 1.43, 95%CI: 1.06-1.92). Except for histological chorioamnionitis (HCA) (OR = 0.72, 95%CI: 0.57-0.90), neither clinical chorioamnionitis (CCA) (OR = 1.86, 95%CI: 0.93-3.72) nor FV (OR = 1.23, 95%CI: 0.48-3.15) nor HCA with FV (OR = 1.85, 95%CI: 0.15-22.63) had statistical significance in NRDS incidence. As a result of stratification by grade of HCA, HCA (II) has a significant association with decreased incidence of NRDS (OR = 0.48, 95%CI: 0.35-0.65). In terms of BPD, there is a positive correlation between BPD and CA/FV (CA: OR = 3.18, 95%CI: 1.68-6.03; FV: OR = 6.36, 95%CI: 2.45-16.52). Among CA, HCA was positively associated with BPD (OR = 2.70, 95%CI: 2.38-3.07), whereas CCA was not associated with BPD (OR = 2.77, 95%CI: 0.68-11.21). HCA and moderate to severe BPD (OR = 25.38, 95%CI: 7.13-90.32) showed a positive correlation, while mild BPD (OR = 2.29, 95%CI: 0.99-5.31) did not., Conclusion: Currently, evidence suggests that CA or FV increases the lung injury incidence in premature infants. For different types of CA and FV, HCA can increase the incidence of BPD while decreasing the incidence of NRDS. And this "protective effect" only applies to infants under 32 weeks of age. Regarding lung injury severity, only moderate to severe cases of BPD were positively correlated with CA., (© 2024. The Author(s).)

The aim of this study was to explore the effects of different sulfur fertilizers combined with sulfate-reducing bacteria on the accumulation of cadmium and arsenic in rice and the formation of iron plaque under long-term flooding conditions and to provide a reference for the safe production of rice fields polluted by moderate and mild cadmium and arsenic. We adopted a pot experiment, selecting two sulfur fertilizers, sulfur and calcium sulfate, and Enterobacter M5 with sulfate-reducing ability, and designed six treatments of single application and combined application of different sulfur fertilizers and M5. The results showed that the combined application of calcium sulfate and M5(CM5) had the best effect on reducing available cadmium and arsenic in rice rhizosphere soil. The combined application of sulfur fertilizer or M5 could reduce the content of cadmium and inorganic arsenic in early season rice grains by 8%-51% and 42%-61%, respectively, under flooding conditions. The content of cadmium and inorganic arsenic in late rice grains decreased by 81%-92% and 41%-62%, respectively. The treatment of the combined application of sulfur and M5(SM5) and CM5 had the best effect on reducing cadmium and arsenic content in both early and late season rice grains. SM5 and CM5 could promote the adsorption of cadmium and arsenic by iron plaque, and the extracted cadmium and arsenic content of ACA in both treatments was significantly higher than that of CK. The extracted iron content of ACA in the CM5 treatment was also significantly higher than that of CK, which indicates that the combined application of calcium sulfate and M5 would promote the formation of iron plaque. The results showed that the combined application of sulfur fertilizer and M5 was better than single application in reducing the content of cadmium and arsenic in grains, whereas the combined application of calcium sulfate and M5 was the best and most stable method.

Competing Interests: The authors declare that they have no conflict of interest.

Background: There is a paucity of research investigating the application of machine learning techniques for distinguishing between lipid-poor adrenal adenoma (LPA) and subclinical pheochromocytoma (sPHEO) based on radiomic features extracted from non-contrast and dynamic contrast-enhanced computed tomography (CT) scans of the abdomen., Methods: We conducted a retrospective analysis of multiphase spiral CT scans, including non-contrast, arterial, venous, and delayed phases, as well as thin- and thick-thickness images from 134 patients with surgically and pathologically confirmed. A total of 52 patients with LPA and 44 patients with sPHEO were randomly assigned to training/testing sets in a 7:3 ratio. Additionally, a validation set was comprised of 22 LPA cases and 16 sPHEO cases from two other hospitals. We used 3D Slicer and PyRadiomics to segment tumors and extract radiomic features, respectively. We then applied T-test and least absolute shrinkage and selection operator (LASSO) to select features. Six binary classifiers, including K-nearest neighbor (KNN), logistic regression (LR), decision tree (DT), random forest (RF), support vector machine (SVM), and multi-layer perceptron (MLP), were employed to differentiate LPA from sPHEO. Receiver operating characteristic (ROC) curves and area under the curve (AUC) values were compared using DeLong's method., Results: All six classifiers showed good diagnostic performance for each phase and slice thickness, as well as for the entire CT data, with AUC values ranging from 0.706 to 1. Non-contrast CT densities of LPA were significantly lower than those of sPHEO (P < 0.001). However, using the optimal threshold for non-contrast CT density, sensitivity was only 0.743, specificity 0.744, and AUC 0.828. Delayed phase CT density yielded a sensitivity of 0.971, specificity of 0.641, and AUC of 0.814. In radiomics, AUC values for the testing set using non-contrast CT images were: KNN 0.919, LR 0.979, DT 0.835, RF 0.967, SVM 0.979, and MLP 0.981. In the validation set, AUC values were: KNN 0.891, LR 0.974, DT 0.891, RF 0.964, SVM 0.949, and MLP 0.979., Conclusions: The machine learning model based on CT radiomics can accurately differentiate LPA from sPHEO, even using non-contrast CT data alone, making contrast-enhanced CT unnecessary for diagnosing LPA and sPHEO., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Isthmin-1 (Ism-1) is a newly identified insulin-like adipokine that increases glucose uptake by adipocytes and inhibits hepatic lipid synthesis. Recent studies have shown that Ism-1 can improve the metabolic disorders associated with type 2 diabetes mellitus (T2DM) and improve lipid metabolism. The classic function of high-density lipoprotein cholesterol (HDL-C) is to transport cholesterol from extra-hepatic tissues to the liver for metabolism. In contrast, disorders of lipid metabolism and inflammation are the leading causes of atherosclerosis (As). Atherosclerosis often manifests as loss of elasticity, lipid accumulation, fibrous tissue proliferation and calcium deposits in the affected arteries, eventually forming plaques., Aim: To illustrate the correlation between HDL-C and Ism-1 in T2DM, and the relationship between lipoprotein cholesterol and carotid plaque., Methods: A total of 128 patients with T2DM were enrolled in the study and basic information was collected. HDL-C levels were measured chemically. Serum Ism-1 levels were measured using an enzyme-linked immunosorbent assay (ELISA). Linear regression analysis was used to assess the correlation between serum Ism-1 levels and HDL-C in patients with T2DM. Basic information was again collected from 226 patients with T2DM. Independent sample t-tests were performed to explore the relationship between carotid plaque formation and lipids., Results: HDL-C was divided into four groups according to quartiles and there was a between-group difference in Ism-1 (p = 0.040). Multivariable linear regression showed a negative association between Ism-1 and HDL-C in T2DM (β = -0.235, p < 0.001), even after adjusting for related factors (β = -0.165, p = 0.009). Low-density lipoprotein cholesterol (LDL-C) and HDL-C showed significant differences between the carotid plaque group and the non-carotid plaque group (p LDL-C  = 0.007, p HDL-C  = 0.003)., Conclusion: Serum Ism-1 and HDL-C are negatively correlated in T2DM. LDL-C is significantly higher in carotid plaque group than non-carotid plaque group, while HDL-C is significantly lower than in the non-carotid plaque group., Competing Interests: Declaration of competing interest All authors report having no relevant conflicts of interest for this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Poly(A)-binding protein nuclear 1 (PABPN1) is an RNA-binding protein localized in nuclear speckles, while its alanine (Ala)-expanded variants accumulate as intranuclear aggregates in oculopharyngeal muscular dystrophy. The factors that drive PABPN1 aggregation and its cellular consequences remain largely unknown. Here, we investigated the roles of Ala stretch and poly(A) RNA in the phase transition of PABPN1 using biochemical and molecular cell biology methods. We have revealed that the Ala stretch controls its mobility in nuclear speckles, and Ala expansion leads to aggregation from the dynamic speckles. Poly(A) nucleotide is essential to the early-stage condensation that thereby facilitates speckle formation and transition to solid-like aggregates. Moreover, the PABPN1 aggregates can sequester CFIm25, a component of the pre-mRNA 3'-UTR processing complex, in an mRNA-dependent manner and consequently impair the function of CFIm25 in alternative polyadenylation. In conclusion, our study elucidates a molecular mechanism underlying PABPN1 aggregation and sequestration, which will be beneficial for understanding PABPN1 proteinopathy., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the effect and timing of subconjunctival bevacizumab injection on inhibiting corneal neovascularization (CorNV) in patients after chemical burns., Methods: Patients with CorNV secondary to chemical burns were involved. Two subconjunctival injections of bevacizumab (2.5 mg/0.1 mL per involved quadrant) with an interval of 4 weeks were administered, and followed up a year. The area occupied by neovascular vessels (NA), accumulative neovascular length (NL), mean neovascular diameter (ND), best-corrected visual acuity (BCVA) and intraocular pressure (IOP) were evaluated. Complication was also recorded., Results: Eleven patients with CorNV were involved. Eight patients had a history of surgery (four had amniotic grafts, one had keratoplasty, and three had amniotic grafts and keratoplasty). Decreasing in NA, NL, and ND were statistically significant at each time point compared to the baseline ( p < 0.01). CorNV that developed within 1 month was considerably regressed, and vessels with fibrovascular membranes were found to be narrower and shorter than pretreatment. BCVA improved in five patients (from one to five lines), remained unchanged in five patients, and decreased in one patient compared to pretreatment., Conclusion: Subconjunctival bevacizumab injection has a particular potential for the regression of CorNV, especially newly formed within 1 month in patients after chemical burns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Peng, He, Yin, Zhou, Zhou and Zhou.)

An independent set (IS) is a set of vertices in a graph such that no edge connects any two vertices. In adiabatic quantum computation [E. Farhi, et al ., Science 292, 472-475 (2001); A. Das, B. K. Chakrabarti, Rev. Mod. Phys. 80, 1061-1081 (2008)], a given graph G ( V , E ) can be naturally mapped onto a many-body Hamiltonian [Formula: see text], with edges [Formula: see text] being the two-body interactions between adjacent vertices [Formula: see text]. Thus, solving the IS problem is equivalent to finding all the computational basis ground states of [Formula: see text]. Very recently, non-Abelian adiabatic mixing (NAAM) has been proposed to address this task, exploiting an emergent non-Abelian gauge symmetry of [Formula: see text] [B. Wu, H. Yu, F. Wilczek, Phys. Rev. A 101, 012318 (2020)]. Here, we solve a representative IS problem [Formula: see text] by simulating the NAAM digitally using a linear optical quantum network, consisting of three C-Phase gates, four deterministic two-qubit gate arrays (DGA), and ten single rotation gates. The maximum IS has been successfully identified with sufficient Trotterization steps and a carefully chosen evolution path. Remarkably, we find IS with a total probability of 0.875(16), among which the nontrivial ones have a considerable weight of about 31.4%. Our experiment demonstrates the potential advantage of NAAM for solving IS-equivalent problems.

Quantum sensing can provide the superior sensitivity for sensing a physical quantity beyond the shot-noise limit. In practice, however, this technique has been limited to the issues of phase ambiguity and low sensitivity for small-scale probe states. Here, we propose and demonstrate a full-period quantum phase estimation approach by adopting the Kitaev's phase estimation algorithm to eliminate the phase ambiguity and using the GHZ states to obtain phase value, simultaneously. For an N-party entangled state, our approach can achieve an upper bound of sensitivity of δθ=sqrt[3/(N^{2}+2N)], which beats the limit of adaptive Bayesian estimation. By performing an eight-photon experiment, we demonstrate the estimation of unknown phases in a full period, and observe the phase superresolution and sensitivity beyond the shot-noise limit. Our Letter provides a new way for quantum sensing and represents a solid step towards its general applications.

Circadian rhythm (CR) disruption contributes to tumor initiation and progression, however the pharmacological targeting of circadian regulators reversely inhibits tumor growth. Precisely controlling CR in tumor cells is urgently required to investigate the exact role of CR interruption in tumor therapy. Herein, based on KL001, a small molecule that specifically interacts with the clock gene cryptochrome (CRY) functioning at disruption of CR, we fabricated a hollow MnO 2 nanocapsule carrying KL001 and photosensitizer BODIPY with the modification of alendronate (ALD) on the surface (H-MnSiO/K&B-ALD) for osteosarcoma (OS) targeting. The H-MnSiO/K&B-ALD nanoparticles reduced the CR amplitude in OS cells without affecting cell proliferation. Furthermore, nanoparticles-controlled oxygen consumption by inhibiting mitochondrial respiration via CR disruption, thus partially overcoming the hypoxia limitation for photodynamic therapy (PDT) and significantly promoting PDT efficacy. An orthotopic OS model demonstrated that KL001 significantly enhanced the inhibitory effect of H-MnSiO/K&B-ALD nanoparticles on tumor growth after laser irradiation. CR disruption and oxygen level enhancement induced by H-MnSiO/K&B-ALD nanoparticles under laser irradiation were also confirmed in vivo. This discovery first demonstrated the potential of CR controlling for tumor PDT ablation and provided a promising strategy for overcoming tumor hypoxia., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

A strain of Enterobacter was screened from cadmium and arsenic contaminated farmland soil and its passivation mechanism of cadmium and arsenic were explored through removing performance and characterization experiments. The results showed that the screened strain M5 was identified as Enterobacter sp. with a sulfate-reduction function, and its maximum resistance concentration was approximately 1 mmol·L -1 to cadmium and arsenic. In the simulation system, the maximum removal efficiencies of cadmium and arsenic were 94.13% and 27.26% by strain M5, respectively. The results of SEM-EDS and XRD confirmed that Cd and As were fixed to CdS and As 2 S 3 , and XPS results showed that carboxyl groups, hydroxyl groups, and amide groups on the surface of the bacteria were mainly involved in biological adsorption. These results can provide new ideas and a theoretical basis for microbial applications to soil remediations for heavy metal pollution.

A higher ratio of M1/M2 macrophages and an elevated chemerin level are both related to increased risk of preeclampsia. However, the crosstalk between these two events and their collective contribution to preeclampsia are not well understood. In this study, we assessed the impacts of chemerin chemokine-like receptor 1 (CMKLR1)/p-Akt/CEBPα axis in regulating macrophage polarization and mediating the pathogenic effects of chemerin on preeclampsia. We showed that chemerin, in a dose- and time-dependent manner, stimulated M1 macrophage polarization, inhibited macrophage-induced trophoblast invasion and migration, and suppressed macrophage-mediated angiogenesis. All these chemerin-induced phenotypes are essentially mediated by sequentially CMKLR1, Akt activation, and CEBPα. Mechanistically, CEBPα acted as a transcriptional activator for both IRF8 and chemerin. In vivo, chemerin aggravated preeclampsia, while α-NETA, an inhibitor for CMKLR1, significantly suppressed M1 macrophage polarization and alleviated preeclampsia. In summary, chemerin, by activating CMKLR1/Akt/CEBPα axis, forms a positive feedback loop, promotes M1 macrophage polarization, suppresses trophoblast migration/invasion and angiogenesis, and contributes to preeclampsia. Therefore, targeting chemerin signaling may benefit the prevention and/or treatment of preeclampsia., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

MicroRNAs can regulate the function of ion channels in many organs. Based on our previous study we propose that miR-142a-39, which is highly expressed in denervated skeletal muscle, might affect cell excitability through similar mechanisms. In this study, we overexpressed or knocked down miR-142a-3p in C2C12 cells using a lentivirus method. After 7 days of differentiation culture, whole-cell currents were recorded. The results showed that overexpression of miR-142a-3p reduced the cell membrane capacitance, increased potassium current density and decreased calcium current density. Knockdown of miR-142a-3p reduced sodium ion channel current density. The results showed that change in miR-142a-3p expression affected the ion channel currents in C2C12 cells, suggesting its possible roles in muscle cell electrophysiology. This study was approved by the Animal Ethics Committee of Peking University in July 2020 (approval No. LA2017128)., Competing Interests: None

Sirtuin-1 (SIRT1) is a critical nuclear deacetylase that participates in a wide range of biological processes. We hereby employed quantitative acetyl-proteomics to globally reveal the landscape of SIRT1-dependent acetylation in colorectal cancer (CRC) cells stimulated by specific SIRT1 inhibitor Inauhzin (INZ). We strikingly observed that SIRT1 inhibition enhances protein acetylation levels, with the multisite-acetylated proteins (acetyl sites >4/protein) mainly enriched in mitochondria. INZ treatment increases mitochondrial fission and depolarization in CRC cells. The acetylation of mitochondrial proteins promoted by SIRT1 inhibition prevents the recruitment of ubiquitin and LC3 for mitophagic degradation. We then found that, SIRT1 inhibition increases the acetylation of mitochondrial calcium uniporter (MCU) at residue K332, resulting in mitochondrial Ca 2+ overload and depolarization, and ultimately CRC apoptosis. Arginine substitution of the K332 (K332R) dramatically decreases the mitochondrial Ca 2+ influx, mitochondrial membrane potential loss and ROS burst induced by INZ. This finding uncovers a non-canonical role of SIRT1 in regulating mitochondrial function and implicates a possible way for anticancer intervention through SIRT1 inhibition., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Infections caused by drug-resistant bacteria are a serious threat to public health worldwide, and the discovery of novel antibacterial compounds is urgently needed. Here, we screened an FDA-approved small-molecule library and found that crizotinib possesses good antimicrobial efficacy against Gram-positive bacteria. Crizotinib was found to increase the survival rate of mice infected with bacteria and decrease pulmonary inflammation activity in an animal model. Furthermore, it showed synergy with clindamycin and gentamicin. Importantly, the Gram-positive bacteria showed a low tendency to develop resistance to crizotinib. Mechanistically, quantitative proteomics and biochemical validation experiments indicated that crizotinib exerted its antibacterial effects by reducing ATP production and pyrimidine metabolism. A drug affinity responsive target stability study suggested crizotinib targets the CTP synthase PyrG, which subsequently disturbs pyrimidine metabolism and eventually reduces DNA synthesis. Subsequent molecular dynamics analysis showed that crizotinib binding occurs in close proximity to the ATP binding pocket of PyrG and causes loss of function of this CTP synthase. Crizotinib is a promising antimicrobial agent and provides a novel choice for the development of treatment for Gram-positive infections. IMPORTANCE Infections caused by drug-resistant bacteria are a serious problem worldwide. Therefore, there is an urgent need to find novel drugs with good antibacterial activity against multidrug-resistant bacteria. In this study, we found that a repurposed drug, crizotinib, exhibits excellent antibacterial activity against drug-resistant bacteria both in vivo and in vitro via suppressing ATP production and pyrimidine metabolism. Crizotinib was found to disturb pyrimidine metabolism by targeting the CTP synthase PyrG, thus reducing DNA synthesis. This unique mechanism of action may explain the decreased development of resistance by Staphylococcus aureus to crizotinib. This study provides a potential option for the treatment of drug-resistant bacterial infections in the future.

The recognition of entanglement states is a notoriously difficult problem when no prior information is available. Here, we propose an efficient quantum adversarial bipartite entanglement detection scheme to address this issue. Our proposal reformulates the bipartite entanglement detection as a two-player zero-sum game completed by parameterized quantum circuits, where a two-outcome measurement can be used to query a classical binary result about whether the input state is bipartite entangled or not. In principle, for an N-qubit quantum state, the runtime complexity of our proposal is O(poly(N)T) with T being the number of iterations. We experimentally implement our protocol on a linear optical network and exhibit its effectiveness to accomplish the bipartite entanglement detection for 5-qubit quantum pure states and 2-qubit quantum mixed states. Our work paves the way for using near-term quantum machines to tackle entanglement detection on multipartite entangled quantum systems.

Poor immunogenicity and compromised T cell infiltration impede the application of immune-checkpoint blockade (ICB) immunotherapy for osteosarcoma (OS). Although autophagy is involved in enhancing the immune response, the synergistic role of autophagy in ICB immunotherapy and the accurate control of autophagy levels in OS remain elusive and challenging. Here, we designed a pH-sensitive autophagy-controlling nanocarrier, CUR-BMS1166@ZIF-8@PEG-FA (CBZP), loading a natural derivative, curcumin (CUR), to boost the immunotherapeutic response of PD-1/PD-L1 blockade by activating immunogenic cell death (ICD) via autophagic cell death, and BMS1166 to inhibit the PD-1/PD-L1 interaction simultaneously, enhancing the tumor immunogenicity and sensitizing the antitumor T cell immunity. After entering tumor cells, the pH-sensitive nanoparticles induced autophagy and decreased the intracellular pH, which in turn further facilitated the release of CUR to enhance autophagic activity. Transferring CBZP to orthotopic OS tumor-bearing mice showed powerful antitumor effects and established long-term immunity against tumor recurrence, accompanied by enhanced dendritic cell maturation and tumor infiltration of CD8 + T lymphocytes. Collectively, CBZP exhibited synergistic effects in treating OS by combining ICD induction with checkpoint blockade, thereby shedding light on the use of autophagy control as a potential clinical therapy for OS., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Motor endplates (MEPs) are important sites of information exchange between motor neurons and skeletal muscle, and are distributed in an organized pattern of lamellae in the muscle. Delayed repair of peripheral nerve injury typically results in unsatisfactory functional recovery because of MEP degeneration. In this study, the mouse tibial nerve was transected and repaired with a biodegradable chitin conduit, immediately following or 1 or 3 months after the injury. Fluorescent α-bungarotoxin was injected to label MEPs. Tissue optical clearing combined with light-sheet microscopy revealed that MEPs were distributed in an organized pattern of lamellae in skeletal muscle after delayed repair for 1 and 3 months. However, the total number of MEPs, the number of MEPs per lamellar cluster, and the maturation of single MEPs in gastrocnemius muscle gradually decreased with increasing denervation time. These findings suggest that delayed repair can restore the spatial distribution of MEPs, but it has an adverse effect on the homogeneity of MEPs in the lamellar clusters and the total number of MEPs in the target muscle. The study procedures were approved by the Animal Ethics Committee of the Peking University People's Hospital (approval No. 2019PHC015) on April 8, 2019., Competing Interests: None

Detecting pesticide residues in human serum is a challenging process due to trace-level chronic exposure. Several methods using magnetic adsorbents have been developed for analyzing pesticide residue levels in human serum, but it is still difficult to achieve lower quantitative levels, and the adsorption mechanism for extracting pesticides is unclear. Herein, we propose a feasibility concept of using C 18 -functionalized magnetic nanoparticles for the adsorption of target pesticides, focusing on the extensively used weakly polar pesticides based on molecular dynamics (MD) simulations. To support this, the facilitated target nanoparticles of Fe 3 O 4 @SiO 2 -C 18 were synthesized at a size of 12-13 nm with a magnetic saturation of 40 emu/g. After optimizing and establishing the extraction conditions (1.8 mL C 18 modifier, 10 mg sorbents, 3 min adsorption time, 1000 μL ACN for desorption eluent at pH 3.8 and 5 min desorption time), which exhibited recovery = 72.3%-118.3% with RSDs = 0.03-6.57, linearity at 0.01-10 ng/mL with R 2  = 0.9561-0.9993, and LODs = 0.01-0.30 ng/mL for the 11 weakly polar pesticides in human serum. Furthermore, the mechanism by which the C 18 group selectively extracts weakly polar pesticides was confirmed by binding van der Waals and electrostatic interactions under stable and strong binding energy. The extraction process of efficient adsorption and desorption with C 18 functional magnetite nanoparticles suggests a simple method for detecting weakly polar pesticides. The concept may lead to a general approach to analyzing multiple pesticide residues in human serum at trace levels., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In the conventional view a muscle is composed of intermediate structures before its further division into microscopic muscle fibers. Our experiments in mice have confirmed this intermediate structure is composed of the lamella cluster formed by motor endplates, the innervating nerve branches and the corresponding muscle fibers, which can be viewed as an independent structural and functional unit. In this study, we verified the presence of these muscle construction units in rabbits. The results showed that the muscular branch of the femoral nerve sent out 4-6 nerve branches into the quadriceps and the tibial nerve sent out 4-7 nerve branches into the gastrocnemius. When each nerve branch of the femoral nerve was stimulated from the most lateral to the medial, the contraction of the lateral muscle, intermediate muscle and medial muscle of the quadriceps could be induced by electrically stimulating at least one nerve branch. When stimulating each nerve branch of the tibial nerve from the lateral to the medial, the muscle contraction of the lateral muscle 1, lateral muscle 2, lateral muscle 3 and medial muscle of the gastrocnemius could be induced by electrically stimulating at least one nerve branch. Electrical stimulation of each nerve branch resulted in different electromyographical waves recorded in different muscle subgroups. Hematoxylin-eosin staining showed most of the nerve branches around the neuromuscular junctions consisted of one individual neural tract, a few consisted of two or more neural tracts. The muscles of the lower limb in the rabbit can be subdivided into different muscle subgroups, each innervated by different nerve branches, thereby allowing much more complex muscle activities than traditionally stated. Together, the nerve branches and the innervated muscle subgroups can be viewed as an independent structural and functional unit. This study was approved by the Animal Ethics Committee of Peking University People's Hospital (approval No. 2019PHE027) on October 20, 2019., Competing Interests: None

Ultraviolet B (UVB) is one of the most common exogenous factors in skin aging, especially photoaging. Once a large amount of UVB accumulates within a short period of time, skin tissue can become inflamed. It has also been found in clinics that platelet-rich plasma (PRP) can promote wound repair; therefore, the aim of this study was to identify the mechanism by which PRP repairs UVB-induced skin photodamage. We used PRP of Sprague-Dawley rats with the two-spin technique in the established acute UVB radiation photodamage model and harvested the corresponding skin after 1, 7, and 28 d. Hematoxylin and eosin staining was used to observe tissue inflammation. We found that PRP reduces inflammation in the early stages of UVB-induced acute skin damage, and then promotes the proliferation of collagen in the middle and late stages. Moreover, PRP can stimulate Act A and M1 polarization in the early stage, while inhibiting activin A (Act A) and inducing M2 polarization in the middle and late stages. In conclusion, this study demonstrates that PRP plays an important regulatory role in helping reduce UVB-induced acute skin tissue inflammation by adjusting macrophage polarization, which alleviates skin inflammation and stimulates collagen regeneration.

This study evaluated the adverse effects of low-dose imidacloprid (IMI) on the characteristics of sperm from male Wistar rats. Thirty mature male rats were equally divided into three groups and orally administered vehicle (Control Group), acceptable daily intake (ADI) concentration of IMI (Group 1), and IMI at a dose 10-fold that of the ADI (Group 2) for 90 days. The findings revealed that IMI caused abnormalities in sperm concentrations and morphologies, accompanied by an imbalance of the gonadal hormone testosterone. Histopathological damage and decrease of testosterone levels were observed in testes from rats treated with IMI. However, estradiol and gonadotropin levels were unchanged after IMI treatment. IMI inhibited the activity of cytochrome P450 3A4 (CYP3A4) and left itself existed in the organism of rats. The indicators relating to sperms and CYP3A4 activity were recovered when rats were co-treated with IMI and CYP3A4 inducer rifampicin together. These results indicated that low-dose IMI exposure caused sperm abnormalities through affecting on the spermiogenesis in testis. Inhibition of CYP3A4 activity by IMI largely contributed to its sperm toxicity. Thus, IMI exposure at doses close to real-world settings resulted in sperm toxicity on rats, which might be a potential risk factor for human reproductive diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Colorectal cancer (CRC) is one of the most common malignancies worldwide, and effective therapy remains a challenge. In this study, we take advantage of a drug repurposing strategy to screen small molecules with novel anticancer activities in a small-molecule library consisting of 1056 FDA-approved drugs. We show, for the first time, that lomitapide, a lipid-lowering agent, exhibits antitumor properties in vitro and in vivo. Activated autophagy is characterized as a key biological process in lomitapide-induced CRC repression. Mechanistically, lomitapide stimulated mitochondrial dysfunction-mediated AMPK activation, resulting in increased AMPK phosphorylation and enhanced Beclin1/Atg14/Vps34 interactions, provoking autophagy induction. Autophagy inhibition or AMPK silencing significantly abrogated lomitapide-induced cell death, indicating the significance of AMPK-regulated autophagy in the antitumor activities of lomitapide. More importantly, PP2A was identified as a direct target of lomitapide by limited proteolysis-mass spectrometry (LiP-SMap), and the bioactivity of lomitapide was attenuated in PP2A-deficient cells, suggesting that the anticancer effect of lomitapide occurs in a PP2A-dependent manner. Taken together, the results of the study reveal that lomitapide can be repositioned as a potential therapeutic drug for CRC treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Trans -Cinnamaldehyde (TC) is a widely used food additive, known for its sterilization, disinfection, and antiseptic properties. However, its antibacterial mechanism is not completely understood. In this study, quantitative proteomics was performed to investigate differentially expressed proteins (DEPs) in Escherichia coli in response to TC treatment. Bioinformatics analysis suggested aldehyde toxicity, acid stress, oxidative stress, interference of carbohydrate metabolism, energy metabolism, and protein translation as the bactericidal mechanism. E. coli BW25113Δ yqhD , Δ gldA , Δ betB , Δ tktB , Δ gadA , Δ gadB , Δg adC , and Δ rmf were used to investigate the functions of DEPs through biochemical methods. The present study revealed that TC exerts its antibacterial effects by inducing the toxicity of its aldehyde group producing acid stress. These findings will contribute to the application of TC in the antibacterial field.

Complex pathological changes occur during the development of spinal cord injury (SCI), and determining the underlying molecular events that occur during SCI is necessary for the development of promising molecular targets and therapeutic strategies. This study was designed to explore differentially expressed genes (DEGs) associated with the acute and chronic stages of SCI using bioinformatics analysis. Gene expression profiles (GSE45006, GSE93249, and GSE45550) were downloaded from the Gene Expression Omnibus database. SCI-associated DEGs from rat samples were identified, and Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. In addition, a protein-protein interaction network was constructed. Approximately 66 DEGs were identified in GSE45550 between 3-14 days after SCI, whereas 2418 DEGs were identified in GSE45006 1-56 days after SCI. Moreover, 1263, 195, and 75 overlapping DEGs were identified between these two expression profiles, 3, 7/8, and 14 days after SCI, respectively. Additionally, 16 overlapping DEGs were obtained in GSE45006 1-14 days after SCI, including Pank1, Hn1, Tmem150c, Rgd1309676, Lpl, Mdh1, Nnt, Loc100912219, Large1, Baiap2, Slc24a2, Fundc2, Mrps14, Slc16a7, Obfc1, and Alpk3. Importantly, 3882 overlapping DEGs were identified in GSE93249 1-6 months after SCI, including 3316 protein-coding genes and 567 long non-coding RNA genes. A comparative analysis between GSE93249 and GSE45006 resulted in the enrichment of 1135 overlapping DEGs. The significant functions of these 1135 genes were correlated with the response to the immune effector process, the innate immune response, and cytokine production. Moreover, the biological processes and KEGG pathways of the overlapping DEGs were significantly enriched in immune system-related pathways, osteoclast differentiation, the nuclear factor-κB signaling pathway, and the chemokine signaling pathway. Finally, an analysis of the overlapping DEGs associated with both acute and chronic SCI, assessed using the expression profiles GSE93249 and GSE45006, identified four overlapping DEGs: Slc16a7, Alpk3, Lpl and Nnt. These findings may be useful for revealing the biological processes associated with SCI and the development of targeted intervention strategies., Competing Interests: None

Growing experimental and clinical evidence suggests that a chronic inflammatory response induced by gut microbiome critically contribute to the development of rheumatoid arthritis (RA). Previous studies demonstrated the disturbance of lymphocyte subpopulations in RA patients. The purpose of this study was to explore the characteristics of gut microbiome and the associations between bacterium and lymphocyte subpopulations as well as cytokines in patients with RA. Fecal samples from 205 RA patients and 199 healthy controls (HCs) were collected for bacterial DNA extraction and 16S ribosomal RNA (rRNA) gene sequencing. The levels of peripheral lymphocyte subpopulation such as T, B, CD4 + T, CD8 + T, NK, T helper 1 (Th1), Th2, Th17, and regulatory T cells (Tregs) of these subjects were detected by flow cytometry combined with standard absolute counting beads. The serum levels of cytokines interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-17, tumour necrosis factor- α (TNF- α ), and interferon- γ (INF- γ ) were tested by flow cytometric bead array (CBA). Alpha and beta diversity of gut microbiome were explored by bioinformatics analysis. Spearman rank correlation test was used to explore the relationships between gut microbiome and lymphocyte subsets as well as serum cytokines. The diversity and relative abundance of intestinal microbiota in patients with RA were significantly different from those in HCs. Detailly, the abundant of phylum Proteobacteria in RA patients was more than that in HCs, while Firmicutes was less than in HCs. There was increased relative abundance of genus Clostridium&#95;XlVa as well as genus Blautia , more abundance of Ruminococcus2 in patients with lower levels of T, B, CD4 + T, and Tregs. In addition, the relative abundances of Pelagibacterium , Oxalobacter , ClostridiumXlVb , and ClostridiumXVIII were correlated with cytokines. Gut microbiome of RA patients was clearly different from that of HCs. Abnormal bacteria communities are associated with the altered levels of lymphocyte subpopulation and cytokines, which might be one of the pathogenesis of RA., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Yuan Li et al.)

This study aimed to screen novel anticancer strategies from FDA-approved non-cancer drugs and identify potential biomarkers and therapeutic targets for colorectal cancer (CRC). Methods: A library consisting of 1056 FDA-approved drugs was screened for anticancer agents. WST-1, colony-formation, flow cytometry, and tumor xenograft assays were used to determine the anticancer effect of azelastine. Quantitative proteomics, confocal imaging, Western blotting and JC-1 assays were performed to examine the effects on mitochondrial pathways. The target protein of azelastine was analyzed and confirmed by DARTS, WST-1, Biacore and tumor xenograft assays. Immunohistochemistry, gain- and loss-of-function experiments, WST-1, colony-formation, immunoprecipitation, and tumor xenograft assays were used to examine the functional and clinical significance of ARF1 in colon tumorigenesis. Results: Azelastine, a current anti-allergic drug, was found to exert a significant inhibitory effect on CRC cell proliferation in vitro and in vivo , but not on ARF1-deficient or ARF1-T48S mutant cells. ARF1 was identified as a direct target of azelastine. High ARF1 expression was associated with advanced stages and poor survival of CRC. ARF1 promoted colon tumorigenesis through its interaction with IQGAP1 and subsequent activation of ERK signaling and mitochondrial fission by enhancing the interaction of IQGAP1 with MEK and ERK. Mechanistically, azelastine bound to Thr-48 in ARF1 and repressed its activity, decreasing Drp1 phosphorylation. This, in turn, inhibited mitochondrial fission and suppressed colon tumorigenesis by blocking IQGAP1-ERK signaling. Conclusions: This study provides the first evidence that azelastine may be novel therapeutics for CRC treatment. ARF1 promotes colon tumorigenesis, representing a promising biomarker and therapeutic target in CRC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Introduction: A dome-shaped macula (DSM) is an inward convexity or anterior deviation of the macular area. DSM is believed as a protective factor in maintaining visual acuity in highly myopic eyes., Objective: To investigate the correlation between best-corrected visual acuity (BCVA), choroidal neovascularization (CNV), and a dome-shaped macula (DSM) in highly myopic eyes., Methods: In this retrospective and observational case series study, BCVA tests and optical coherence tomography (OCT) were performed in a total of 472 highly myopic eyes (refractive error ≥6.5 diopters or axial length ≥26.5 mm). CNV was detected by fundus fluorescein angiography (FFA), and the CNV area was measured by ImageJ software. BCVA, central retinal thickness (CRT), and the CNV area were compared between highly myopic eyes with and without DSM., Results: The data revealed 13 eyes with DSM complicated by CNV, for an estimated prevalence of 25%. The eyes with CNV in the DSM group showed worse BCVA than those in the non-DSM group (1.59 ± 0.69 and 0.63 ± 0.64, respectively, p < 0.05), and the CNV area in the DSM group was larger than that in the non-DSM group (2793.91 ± 2181.24 and 1250.71 ± 1210.36 pixels, respectively, p < 0.05). After excluding the eyes with CNV, the DSM group had better BCVA than the non-DSM group (0.33 ± 0.17 and 0.44 ± 0.48, respectively, p < 0.05); however, no significant difference was observed in the CRT of eyes with CNV between the DSM group and the non-DSM group., Conclusion: These results show that DSM might be a protective mechanism for visual acuity, but its protective capability is limited. DSM eyes have better visual acuity within the protective capability. If a more powerful pathogenic factor exceeding the protective capability is present, then the eye will have more severe CNV and worse visual acuity., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Lu Wang et al.)

Neutrophil peptide 1 belongs to a family of peptides involved in innate immunity. Continuous intramuscular injection of neutrophil peptide 1 can promote the regeneration of peripheral nerves, but clinical application in this manner is not convenient. To this end, the effects of a single intraoperative administration of neutrophil peptide 1 on peripheral nerve regeneration were experimentally observed. A rat model of sciatic nerve crush injury was established using the clamp method. After model establishment, a normal saline group and a neutrophil peptide 1 group were injected with a single dose of normal saline or 10 μg/mL neutrophil peptide 1, respectively. A sham group, without sciatic nerve crush was also prepared as a control. Sciatic nerve function tests, neuroelectrophysiological tests, and hematoxylin-eosin staining showed that the nerve conduction velocity, sciatic functional index, and tibialis anterior muscle fiber cross-sectional area were better in the neutrophil peptide 1 group than in the normal saline group at 4 weeks after surgery. At 4 and 8 weeks after surgery, there were no differences in the wet weight of the tibialis anterior muscle between the neutrophil peptide 1 and saline groups. Histological staining of the sciatic nerve showed no significant differences in the number of myelinated nerve fibers or the axon cross-sectional area between the neutrophil peptide 1 and normal saline groups. The above data confirmed that a single dose of neutrophil peptide 1 during surgery can promote the recovery of neurological function 4 weeks after sciatic nerve injury. All the experiments were approved by the Medical Ethics Committee of Peking University People's Hospital, China (approval No. 2015-50) on December 9, 2015., Competing Interests: None

Detecting pesticide residues in human serum is a challenging process. In this study we developed and validated a method for the extraction and recovery of residues of multiple classes of pesticides from serum using one reagent. Salt-assisted acetonitrile extraction and high-performance liquid chromatography with quadrupole time of flight tandem mass spectrometry were used to quantitate 34 pesticides classified in nine groups of chemicals in human serum samples, which are frequently detected in food. The recoveries for 33 of analyzed pesticides ranged from 86 to 112% with relative standard deviations below 15%. The limits of quantitation and linearity of 31 of the pesticides were 1 µg/L and >0.990, respectively. The lower limit of quantitation has been reported in the literature particularly for multi-classes pesticide mixtures in human serum. The salt-acetonitrile reagent was allowed to achieve good recoveries and detection limits, which could be attributed to salt altering the solvent polarity, preferentially collecting the organic phase in the solution, and promoting the extraction. The developed method was applied for two organophosphate pesticide metabolites, diethylphosphate and 3,5,6-trichloro-2-pyridinol, in serum from rats that were fed a nonlethal quantity of chlorpyrifos. The concentrations of these two were 252.18 ± 15.47 and 0.63 ± 0.23 µg/L, respectively., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Peripheral nerve injury may trigger changes in mRNA levels in the spinal cord. Finding key mRNAs is important for improving repair after nerve injury. This study aimed to investigate changes in mRNAs in the spinal cord following sciatic nerve injury by transcriptomic analysis. The left sciatic nerve denervation model was established in C57BL/6 mice. The left L4-6 spinal cord segment was obtained at 0, 1, 2, 4 and 8 weeks after severing the sciatic nerve. mRNA expression profiles were generated by RNA sequencing. The sequencing results of spinal cord mRNA at 1, 2, 4, and 8 weeks after severing the sciatic nerve were compared with those at 0 weeks by bioinformatic analysis. We identified 1915 differentially expressed mRNAs in the spinal cord, of which 4, 1909, and 2 were differentially expressed at 1, 4, and 8 weeks after sciatic nerve injury, respectively. Sequencing results indicated that the number of differentially expressed mRNAs in the spinal cord was highest at 4 weeks after sciatic nerve injury. These mRNAs were associated with the cellular response to lipid, ATP metabolism, energy coupled proton transmembrane transport, nuclear transcription factor complex, vacuolar proton-transporting V-type ATPase complex, inner mitochondrial membrane protein complex, tau protein binding, NADH dehydrogenase activity and hydrogen ion transmembrane transporter activity. Of these mRNAs, Sgk1, Neurturin and Gpnmb took part in cell growth and development. Pathway analysis showed that these mRNAs were mainly involved in aldosterone-regulated sodium reabsorption, oxidative phosphorylation and collecting duct acid secretion. Functional assessment indicated that these mRNAs were associated with inflammation and cell morphology development. Our findings show that the number and type of spinal cord mRNAs involved in changes at different time points after peripheral nerve injury were different. The number of differentially expressed mRNAs in the spinal cord was highest at 4 weeks after sciatic nerve injury. These results provide reference data for finding new targets for the treatment of peripheral nerve injury, and for further gene therapy studies of peripheral nerve injury and repair. The study procedures were approved by the Ethics Committee of the Peking University People's Hospital (approval No. 2017PHC004) on March 5, 2017., Competing Interests: None

Purpose: To investigate whether subconjunctival bevacizumab help prevent corneal graft neovascularization and prolong the graft survival of patients with chemical burns., Methods: We performed a prospective nonrandomized comparative case series study. Twenty-six eyes received subconjunctival bevacizumab (10 mg/0.4 mL) once and topical immunosuppressive agents after sclerocorneal lamellar keratoplasty as the treatment, and 13 eyes received a topical immunosuppressant alone and served as the control group. The main outcomes were a cumulative probability of graft survival, development of corneal neovascularization, and complications., Results: The postoperative follow-up time was 14.3 months (range, 2-62 mo). The cumulative graft survival time was significantly longer in the treatment group than that in the control group (42.9 ± 5.9 vs. 4.8 ± 0.7 mo; log rank < 0.001). In the treatment group, 19 of the 26 grafts (73.1%) survived as transparent with a mean follow-up of 18.7 ± 3.0 months. At the end of the follow-up, 4 grafts remained free of neovascularization, 2 developed edema without neovascularization, and 15 remained transparent with a stable ocular surface and some neovascular vessels in the peripheral transplant interface. The other 5 grafts became opaque and neovascularized. In the control group, all grafts became opaque and neovascularized within the follow-up period (5.5 ± 0.7 mo). During the follow-up, a corneal epithelial defect developed in 9 eyes in the treatment group and 7 in the control group., Conclusions: Early application of subconjunctival bevacizumab after sclerocorneal lamellar keratoplasty can significantly prevent corneal neovascularization and promote graft survival for severe late-stage ocular chemical burns.

Quantum networks illustrate the use of connected nodes of quantum systems as the backbone of distributed quantum information processing. When the network nodes are entangled in graph states, such a quantum platform is indispensable to almost all the existing distributed quantum tasks. Unfortunately, real networks unavoidably suffer from noise and technical restrictions, making nodes transit from quantum to classical at worst. Here, we introduce a figure of merit in terms of the number of classical nodes for quantum networks in arbitrary graph states. Such a network property is revealed by exploiting a novel Einstein-Podolsky-Rosen steerability. Experimentally, we demonstrate photonic quantum networks of n&#95;{q} quantum nodes and n&#95;{c} classical nodes with n&#95;{q} up to 6 and n&#95;{c} up to 18 using spontaneous parametric down-conversion entanglement sources. We show that the proposed method is faithful in quantifying the classical defects in prepared multiphoton quantum networks. Our results provide novel identification of generic quantum networks and nonclassical correlations in graph states.

Hepatocellular carcinoma (HCC) ranks as the fifth most common cancer worldwide, and it is the primary histologic subtype of liver cancer, with high incidence and poor prognosis. Recently, numerous long noncoding RNAs have been reported to be associated with the tumorigenesis of HCC; however, the underlying mechanisms of long intergenic nonprotein coding RNA 0152 (LINC00152) action in HCC are poorly understood. Herein, we identified a significant up-regulation of LINC00152 in both HCC tissues and cell lines. Functional studies showed that knockdown of LINC00152 inhibited cell proliferation, migration, and invasion, but promoted cell apoptosis, indicating its oncogenic functions in HCC tumorigenesis. Mechanistically, LINC00152 functioned as an efficient miR-139 sponge, thereby releasing the suppression of PIK3CA (a target gene of miR-139). Anti-miR-139 rescued the inhibition of cell proliferation, migration, and invasion induced by LINC00152 knockdown. Similarly, PIK3CA-overexpressing plasmid also reversed miR-139-mediated biological functions in HCC cells. Taken together, our study revealed a crucial regulatory network of LINC00152/miR-139/PIK3CA axis in the tumorigenesis of HCC, implying that LINC00152 may be a biomarker and novel therapeutic target for further clinical therapy of HCC., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Entanglement witness is of great importance in characterizing quantum systems. The imperfections in conventional entanglement witness schemes could lead to the misidentification of a separated state as an entangled state. Measurement-device-independent entanglement witness (MDIEW) has been proposed and demonstrated to resolve the imperfect measurement devices. So far, however, the MDIEW has been restricted to a two-party qubit entangled state. Here, for the first time, we demonstrate MDIEW for multipartite entangled states. We experimentally detect the genuine entanglement and the entanglement structure of a tripartite entangled state based on an eight-photon interferometry. Furthermore, with the verified multipartite entangled state, we demonstrate quantum randomness generation and open-destination quantum key distribution in an measurement-device-independent manner. Our research presents an important step toward building a robust and secure quantum network.

Objective: Endoplasmic reticulum stress (ERS) is present in chondrocytes of osteoarthritis, and the intensity of ERS is related to the degree of cartilage degeneration. In vitro intervention strategies can change the status of ERS and induce the inhibition of ERS-related pathway. Therefore, this study is designed to explore the role and molecular mechanism of cartilage stem cells (ACSCs) of ERS in chondrocytes after hip replacement., Methods: Human cartilage cell lines C28/I2 were cultured as the control group. The ERS inducer was added into C28/I2 as ERS group. The third ERS + stem cells group was formed by adding cartilage stem cells into ERS group, and further transfection of si-PERK was defined as si-PERK + ERS + stem cells group. Cell cycle and apoptosis in the four groups were determined by flow cytometry. The protein expression of GRP78, PERK, ATF4, TMEM119, CDK4, Cyclin D, and BMP6 in chondrocytes in the four groups were investigated by western blot, and the distribution of PERK, TMEM119, and BMP6 in chondrocytes were observed by immunofluorescence assay. In addition, the transcriptional levels of Bcl2, Bax, and Caspase 3 were also determined by RT-PCR., Results: In cell cycle assay, ERS increased the accumulation of cells in G 0 /G 1 and G 2 /M, while cartilage stem cells weakened the effects. The apoptosis rates in control group, ERS, ERS + stem cells, si-PERK + ERS + stem cells were 0%, 21.3%, 18.9%, and 15.9%, respectively, and the difference of apoptosis rate between the latter three groups and control group was statistically significant (P < 0.01). Stem cells could weaken the ERS-induced cell apoptosis, especially reducing the number of cells in the late stage of apoptosis from 5.4% to 1.1%. The protein level of GRP78, PERK, ATF4, TMEM119, and BMP6 in the group of ERS, ERS + stem cells, and si-PERK + ERS + stem cells were all significantly higher than those in control group, and the group of ERS + stem cells was the highest, all of the differences were significant (P < 0.01). However, the protein level of CDK4 and Cyclin D presented an absolutely opposite trend and the difference was still significant (P < 0.05). The group of si-PERK + ERS + stem cell was lower than those in the group of ERS + stem cell but higher than those in the group of ERS (P < 0.05). The level of Caspase 3 in the latter three groups was significantly higher than those in the control group, and the group of ERS was the highest (P < 0.01). Besides, the relative level of Bcl-2/Bax in control group was 1, but the group of ERS was about 0.5, and there was significant difference (P < 0.01). The ratio of Bcl-2/Bax in the group of ERS + stem cells was more than 2 and significantly higher than those of other groups., Conclusion: ACSCs could reduce ERS-induced chondrocyte apoptosis by PERK and Bax/Bcl-2 signaling pathway., (© 2020 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

We report three cases of neck accessory tragus, which is the largest number of cases with dermatologists reported in China. Neck accessory tragus belongs to special accessory auricular anomaly. Case 1: A 5-year-old girl presented with a skin-colored mass above her right clavicle since birth. Physical examination revealed a pea-sized mass positioned above the right clavicle. Case 2 and case 3 were a 3-month-old female infant and a 4-month-old male infant, respectively. Both of their parents complained that the masses gradually increased in front of the neck. Histopathologically, all of the three cases showed cartilage beneath the subcutaneous tissue. All cases were diagnosed as cervical auricles., (© 2019 Wiley Periodicals, Inc.)

Lung cancer is the leading cause of cancer-related deaths worldwide, but effective therapeutics is limited. This study aims to identify novel anticancer strategy from a Food and Drug Administration (FDA)-approved drug library consisting of 528 compounds. Benzethonium Chloride (BZN), a FDA-approved drug for anti-infective, was found to markedly induce apoptosis and inhibit proliferation and colony formation ability of lung cancer cells in dose- and time-dependent manners. BZN also enhanced the sensitivity of lung cancer cells to gefitinib, the first-line treatment strategy for selected lung cancer patients. Furthermore, BZN significantly delayed the growth of tumor xenografts in nude mice by increasing apoptosis and decreasing Ki-67 proliferation index, without obvious toxic effects to the vital organs of animals. Mechanistically, quantitative proteomics coupled with bioinformatics analyses and a series of functional assays demonstrated that BZN induced cell cycle arrest at G1 phase, and this was associated with an increase in p38-mediated phosphorylation at threonine 286 (T286) and accelerated degradation of cyclin D1. Our findings provide the first evidence that BZN could be a promising therapeutic agent in lung cancer treatment., Competing Interests: None., (AJCR Copyright © 2019.)

Background: Laser systems are a common treatment choice for onychomycosis. They exert their effects on inhibiting the growth of the fungus by selective photothermolysis but efficacy is dependent on the specific type of apparatus used. To systematically review the available published literature on the curative effects and safety of laser treatment for onychomycosis., Methods: Databases including PubMed, web of science, China National Knowledge Internet (CNKI), WanFang Database and VIP were searched systematically to identify relevant articles published up to July 2018. Potentially relevant articles were sourced, assessed against eligibility criteria by 2 researchers independently and data were extracted from included studies. A meta-analysis was performed using R software., Results: Thirty-five articles involving 1723 patients and 4278 infected nails were included. Meta-analysis of data extracted from these studies revealed that: the overall mycological cure rate was 63.0% (95%CI 0.53-0.73); the mycological cure rate associated with the 1064-nm Nd: YAG laser was 63.0% (95%CI 0.51-0.74); and that of CO2 lasers was 74.0% (95%CI 0.37-0.98). The published data indicate that laser treatment is relatively safe, but can cause tolerable pain and occasionally lead to bleeding after treatment., Conclusion: Laser treatment of onychomycosis is effective and safe. The cumulative cure rate of laser treatment was significantly higher for CO2 lasers than other types of laser. Laser practitioners should be made aware of potential adverse effects such as pain and bleeding.

Rationale: Atopic dermatitis (AD) is a chronic recurrent dermatitis with profound itching, which could be the first manifestation of acute myeloid leukemia (AML)., Patient Concerns: A 53-year-old Chinese man suffered a 6-month history of systemic symmetrical dermatitis, accompanied with profound itching. The patient was diagnosed as "eczema" in several hospitals, and the effects of antihistamine and topical steroid creams were poor. Nocturnal sleep was seriously affected by aggravating pruritus. Laboratorial examination was compatible with AML-M4., Diagnoses: AML-M4 with AD as first manifestation., Interventions: IA regimen (ayninen and cytarabine) were used in induction chemotherapy. However, the patient did not achieve complete remission, and although his rash had improved, he still experienced severely general body itching. On the seventh day of chemotherapy, the patient entered the period of granulocyte deficiency with infection., Outcomes: The patient died due to septic shock after chemotherapy., Lessons: The case strengthens the awareness of AML with AD as first manifestation and raises oncological vigilance in patients with AD refractory.