Search

Objective: Silk fibroin (SF) hydrogels are of high interest in tissue engineering. However, angiogenesis is one of the major challenges in tissue regeneration and repair. In this study, we present a simple and effective method to develop a 1,2-Dimyristoyl-sn-glycero-3-phosphorylglycerol sodium salt (DMPG)-SF hydrogel. The SF hydrogels had no immunogenicity and approached natural tissues., Materials and Methods: The SF scaffolds were first prepared from Bombyx mori silkworms and DMPG. The SF scaffold was seeded with muscle-derived stem cells derived from sheep embryo and implanted in the tibialis anterior muscle of mature sheep. Gelation time, H&E staining, and histochemistry were conducted and observed. The suitability of the hydrogels for 3D cell culture was assessed by living cell stain CM-Dil., Results: The results showed that the SF hydrogels resembled the mechanical properties of natural soft tissues better. The results of H&E staining and histochemistry revealed that the degradation rate showed an S-type change, and muscle regeneration and angiogenesis were clearly visible. Adverse effects were not observed in the sheep models., Conclusions: DMPG-induced SF hydrogels can be successfully used for in situ cell encapsulation. It provides promising opportunities in biomedical applications, such as in tissue engineering and regeneration.

Objective: To analyze the factors causing failure of primary surgery in congenital scoliosis (CS) patients with single hemivertebra (SHV) undergoing posterior spinal fusion, and to elucidate the revision strategies., Methods: In this retrospective study, a total of 32 CS patients secondary to SHV undergoing revision surgery from April 2010 to December 2017 due to failed primary surgery with more than 2 years follow-up were reviewed. The reasons for failure of primary surgery and revision strategies were analyzed for each patient. The radiographic parameters including coronal Cobb angle, segmental kyphosis (SK), coronal balance (CB), and sagittal vertical axis (SVA) were compared between pre- and post-revision. The complications during revision and follow-up were recorded., Results: The mean age at revision surgery of the 32 CS patients was 15.8 ± 9.7 years and the average duration between primary and revision surgery was 31.0 ± 35.4 months. The reasons for failed primary surgery were severe post-operative curve progression of focal scoliosis in 14 cases (43.8%), implant failure in 17 (53.1%) and trunk imbalance in 12 (37.5%). The candidate revision strategies included thorough resection of residual hemivertebra and adjacent discs, extending fusion levels, complete pseudarthrosis resection, massive bone graft, replacement of broken rods, satellite rod fixation, horizontalization of upper/lower instrumented vertebrae and rigid fusion of structural compensatory curves were performed individually. After revision surgery, the coronal Cobb angle, SK, CB and SVA showed significant improvement (P < 0.05) with no significant correction loss during follow-up (P > 0.05). The intra-operative complications included alarming changes of neurologic monitoring in three (9.4%) patients and dual tear in two, while rod fracture re-occurred was detected in one patient at 18 months after revision., Conclusions: The common reasons for failed primary surgery in CS patients with SHV undergoing posterior spinal fusion were severe post-operative curve progression of focal scoliosis, implant failure and trunk imbalance. The revision strategies including thorough resection of residual hemivertebra and adjacent discs, extended fusion levels to structural curvature, complete pseudarthrosis resection, massive bone graft, replacement of broken internal fixation and horizontalization of upper/lower instrumented vertebrae should be individualized based on the causes of failed primary surgery., (© 2021 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Arabidopsis CHLOROPLAST IMPORT APPARATUS 2 (CIA2) and its paralogous protein CIA2-LIKE (CIL) are nuclear transcription factors containing a C-terminal CCT motif. CIA2 promotes the expression of nuclear genes encoding chloroplast-localized translocons and ribosomal proteins, thereby increasing the efficiency of protein import and synthesis in chloroplasts. We have previously reported that CIA2 and CIL form a homodimer or heterodimer through their C-terminal sequences and interact with other nuclear proteins, such as CONSTANS (CO), via their N-terminal sequences, but the function of CIL had remained unclear. In this study, we verified through transgenic cia2 mutant plants expressing the CIL coding sequence that CIL is partially functionally redundant to CIA2 during vegetative growth. We also compared phenotypes and gene expression profiles of wildtype Col-0, cia2 , cil , and cia2/cil mutants. Our results indicate that CIA2 and CIL coordinate chloroplast biogenesis and function mainly by upregulating the expression of the nuclear factor GOLDEN2-LIKE 1 ( GLK1 ) and chloroplast transcription-, translation-, protein import-, and photosynthesis-related genes, with CIA2 playing a more crucial role. Furthermore, we compared flowering phenotypes in single, double, and triple mutant plants of co , cia2 , and cil . We found that CIA2 and CIL participate in modulating long-day floral development. Notably, CIA2 increases flower number and height of the inflorescence main axis, whereas CIL promotes flowering., Competing Interests: The Authors did not report any conflict of interest., (© 2022 The Authors. Plant Direct published by American Society of Plant Biologists and the Society for Experimental Biology and John Wiley & Sons Ltd.)

Molecularly imprinted polymer nanozyme (MIL-101(Co,Fe)@MIP) with bimetallic active sites and high-efficiency peroxidase-like (POD-like) activity were synthesized for the ratiometric fluorescence and colorimetric dual-mode detection of vanillin with high selectivity and sensitivity. Compared with the monometallic nanozyme, the POD-like activity of bimetallic nanozyme was greatly enhanced by changing the electronic structure and surface structure. Ratiometric fluorescence and colorimetric dual-mode detection of vanillin in aqueous solution was realized by vanillin entering specific imprinted cavities and blocking the molecular channels on the surface of MIL-101(Co,Fe)@MIP and the dual-mode visual detection was also realized. The limits of detection were as low as 104 nM and 198 nM, respectively. The method proposed in this paper was applied to the real samples of ice cream and candy. And the recoveries were between 93.3% and 105.5%, which also reached a satisfactory degree. The further detection of dexamethasone and prednisone, two drugs belonging to glucocorticoid, proved that the nanozyme analysis method based on MIL-101(Co,Fe)@MIP could be developed into a sensing platform., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The application of drug delivery system (DDS) has achieved breakthroughs in many aspects, especially in the field of tumor treatment. In this work, polyethylene glycol (PEG)-modified hollow mesoporous manganese dioxide (HMnO 2 @PEG) nanoparticles were used to load the anti-tumor drug bleomycin (BLM). When the DDS reached the tumor site, HMnO 2 @PEG was degraded and reduced to Mn 2+ by the overexpression of glutathione in the tumor microenvironment, and the drug was released simultaneously. BLM coordinated with Mn 2+ in situ , thereby greatly improving the therapeutic activity of BLM. The results of in vivo and in vitro treatment experiments showed that the DDS had excellent responsive therapeutic activation ability. In addition, Mn 2+ exhibited strong paramagnetism and was used for T 1 -weighted magnetic resonance imaging in vivo . Furthermore, this therapeutic mode of responsively releasing drugs and activating in situ effectively attenuated pulmonary fibrosis initiated by BLM. In short, this DDS could help in avoiding the side effects of drugs.

Background: The anatomical features of the atlantoaxial spine increase the difficulty of complete and safe removal of atlantoaxial intradural extramedullary (IDEM) tumors. Studies concerning surgical interventions via a posterior approach are limited., Aim: To investigate the safety and efficacy of atlantoaxial IDEM tumor resection using a one-stage posterior approach., Methods: We retrospectively analyzed clinical databases for one-stage atlantoaxial IDEM tumor resection via a posterior approach between January 2008 and January 2018. The analyzed data included tumor position, histopathological type, pre- and post-operative Japanese Orthopedic Association (JOA) scores and Nurick grades, postoperative complication and recurrence status., Results: A total of 13 patients who underwent C1-C2 Laminectomy and/or unilateral facetectomy via the posterior approach were enrolled in the study. In all cases reviewed, total tumor resection and concomitant C1-C2 fusion were achieved. The average follow-up was 35.3 ± 6.9 mo (range, 26-49 mo). A statistically significant difference was noted between the preoperative JOA score (11.2 ± 1.1) and the score at the last final follow-up (15.6 ± 1.0) ( P < 0.05). A statistically significant difference was noted between the preoperative Nurick grade (2.3 ± 0.9) and that at the last follow-up (1.2 ± 0.4) ( P < 0.05). However, no statistically significant difference was noted between the preoperative and last follow-up C1-2 Cobb angle and C2-7 Cobb angle ( P > 0.05). No mortalities, severe complications or tumor recurrence were observed during the follow-up period., Conclusion: Total resection of atlantoaxial IDEM tumors is feasible and effective via a posterior approach. Surgical reconstruction should be considered to avoid iatrogenic kyphosis and improve spinal stability and overall clinical outcomes., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Integrase strand transfer inhibitor (InSTI)-based regimens have become the major first-line treatment for HIV-1-infected patients in Taiwan. Transmitted drug resistance (TDR) and several clinical characteristics are associated with time to virological failure or viral suppression; however, these have not been investigated in Taiwan., Objectives: To determine the impact of several factors on treatment outcomes in HIV-1-infected patients in Taiwan., Methods: The cohort included 164 HIV-1 treatment-naive patients in Taiwan from 2018 to 2020. Blood specimens were collected to determine the genotypic drug resistance using the Stanford University HIV drug resistance database. Cox proportional hazards models were used to identify factors associated with time to virological failure or viral suppression., Results: The prevalence of TDR in Taiwan was 27.4% and an increasing trend was seen from 2018 to 2020. TDR mutations related to NNRTIs were the most prevalent (21%) while TDR to InSTIs remained at a relatively low level (1.3%). A baseline HIV-1 viral load of ≥100 000 copies/mL was associated with a shorter time to virological failure [multivariate hazard ratio (mHR) 7.84; P = 0.018] and longer time to viral suppression (mHR 0.46; P < 0.001). Time to viral suppression was shorter in patients receiving InSTI-based regimens (mHR 2.18; P = 0.006). Different InSTI-based regimens as initial treatment did not affect the treatment outcomes., Conclusions: This study found an increasing trend of HIV-1 TDR prevalence from 2018 to 2020 in Taiwan. Baseline HIV-1 viral load and receiving InSTI-based regimens are important factors associated with time to virological failure or viral suppression., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pigs are the main host of Seneca Valley virus (SVV), previously known as Senecavirus A (SVA). Pigs affected by SVV have vesicles in the nose, hooves, and limp and may cause death in some severe cases. Occasionally, SVV has also been detected in mice, houseflies, environmental equipment, and corridors in pig farms. Moreover, it was successfully isolated from mouse tissue samples. In this study, an SVV strain (SVA/GD/China/2018) was isolated from a buffalo with mouth ulcers in the Guangdong province of China using seven mammalian cell lines (including BHK-21, NA, PK-15, ST, Vero, Marc-145, and MDBK). The genome of SVA/GD/China/2018 consists of 7,276 nucleotides. Multiple-sequence alignment showed that SVA/GD/China/2018 shared the highest nucleotide similarity (99.1%) with one wild boar-origin SVV strain (Sichuan HS-01) from the Sichuan province of China. Genetic analysis revealed that SVA/GD/China/2018 clustered with those porcine-origin SVV strains. To the best of our knowledge, this is the first report of SVV infection in buffalo, which might expand the host range of the virus. Surveillance should be expanded, and clinical significance of SVV needs to be further evaluated in cattle., 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 © 2021 Zhou, Liang, Si, Li, Chen, Cai, Lv, Wen, Zhai, Zhai, Liao and He.)

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and intractable complication in chemotherapy-receiving patients. Insulin-like growth factor-1 (IGF-1) is a popular neurotrophin with various functions, such as maintaining neuronal survival and synaptic functioning in the central nervous system. Therefore, we hypothesized that the IGF-1 signaling pathway could be a candidate target for treating CIPN., Methods: We established the CIPN model by injecting mice intraperitoneally with oxaliplatin and assessed IGF-1 protein expression, its receptor IGF1R, phospho-IGF1R (p-IGF1R), interleukin-17A (IL-17A), tumor necrosis factor-α (TNF-α), and calcitonin gene-related peptide (CGRP) in the lumbar spinal cord with Western blot and immunofluorescence. To examine the effect of IGF-1 signaling on CIPN, we injected mice intrathecally or intraperitoneally with mouse recombinant IGF-1 (rIGF-1)., Results: IGF-1 protein expression decreased significantly in the spinal cord on D3 and D10 (the 3rd and 10th days after beginning oxaliplatin chemotherapy) and was co-localized with astrocytes primarily in the lumbar spinal cord, whereas IGF1R was predominantly expressed on neurons. Both intrathecally- and intraperitoneally-administered rIGF-1 relieved the chemotherapy-induced pain-like behavior and reduced IL-17A, TNF-α, and CGRP protein expressions in the spinal cord., Conclusion: Our results indicate a vital role for IGF-1 signaling in CIPN. Targeting IGF-1 signaling could be a potent therapeutic strategy for treating CIPN in clinical settings., (Copyright © 2021 Elsevier Inc. All rights reserved.)

As we all know, inhibiting the activity of dihydrofolate reductase (DHFR) has always been an effective strategy for folate antimetabolites to treat tumors. In the past, it mainly relied on chemical drugs. Here, we propose a new strategy, (3-propanecarboxyl)triphenylphosphonium bromide (CTPB)-modified molecularly imprinted polymer nanomedicine (MIP-CTPB). MIP-CTPB prepared by imprinting the active center of DHFR can specifically bind to the active center to block the catalytic activity of DHFR, thereby inhibiting the synthesis of DNA and ultimately inhibiting the tumor growth. The modification of CTPB allows the nanomedicine to be targeted and enriched in mitochondria, where DHFR is abundant. The confocal laser imaging results show that MIP-CTPB can target mitochondria. Cytotoxicity experiments show that MIP-CTPB inhibits HeLa cell proliferation by 42.2%. In vivo experiments show that the tumor volume of the MIP-CTPB-treated group is only one-sixth of that of the untreated group. The fluorescent and paramagnetic properties of the nanomedicine enable targeted fluorescence imaging of mitochondria and T 2 -weighted magnetic resonance imaging of tumors. This research not only opens up a new direction for the application of molecular imprinting, but also provides a new idea for tumor antimetabolic therapy guided by targeted mitochondrial imaging.

Chemodynamic therapy (CDT) was regarded as a promising approach for tumor treatment. However, owing to the insufficient amount of endogenous hydrogen peroxide (H 2 O 2 ) in tumor cells, the efficacy of CDT was limited. In this study, we designed phosphate-responsive nanoparticles (denoted as MGDFT NPs) based on metal-organic frameworks, which were simultaneously loaded with drug doxorubicin (DOX) and glucose oxidases (GOx). The decorated GOx could act as a catalytic nanomedicine for the response to the abundant glucose in the tumor microenvironment, generating a great deal of H 2 O 2 , which would enhance the Fenton reaction and produce toxic hydroxyl radicals (·OH). Meanwhile, the growth of tumors would also be inhibited by overconsuming the intratumoral glucose, which was the "fuel" for cell proliferation. When the nanoparticles entered into tumor cells, a high concentration of phosphate induced structure collapse, releasing the loaded DOX for chemotherapy. Furthermore, the decoration of target agents endowed the nanoparticles with favorable target ability to specific tumor cells and mitochondria. Consequently, the designed MGDFT NPs displayed desirable synergistic therapeutic effects via combining chemotherapy, starvation therapy, and enhanced Fenton reaction, facilitating the development of multimodal precise antitumor therapy.

Chemodynamic therapy (CDT), the ability to transform H 2 O 2 into a highly toxic hydroxyl radical (˙OH) through a Fenton or Fenton like reaction to kill cancer cells, enables selective tumor therapy. However, the effect is seriously limited by the insufficiency of endogenous H 2 O 2 in cancer cells. Additionally, the specific recognition of epitope imprinting plays an important role in targeting cancer cell markers. In this work, we prepared H 2 O 2 self-supplying degradable epitope molecularly imprinted polymers (MIP) for effective CDT, employing fluorescent calcium peroxide (FCaO 2 ) as an imaging probe and a source of H 2 O 2 , the exposed peptide in the CD47 extracellular region as the template, copper acrylate as one of the functional monomers and N,N'-bisacrylylcystamine (BAC) as a cross-linker. MIP with recognition sites can specifically target CD47-positive cancer cells to achieve fluorescence imaging. Under the reduction of glutathione (GSH), the MIP were degraded and the exposed FCaO 2 reacted with water to continuously produce H 2 O 2 in the slightly acidic environment in cancer cells. The self-supplied H 2 O 2 produced ˙OH through a Fenton like catalytic reaction mediated by copper ions in the MIP framework, inducing cancer cell apoptosis. Therefore, the MIP nano-platform, which was capable of specific recognition of the cancer cell marker, H 2 O 2 self-supply and controlled treatment, was successfully used for targeted CDT.

Neuropathic pain is a chronic condition with little specific treatment. Insulin-like growth factor 1 (IGF1), interacting with its receptor, IGF1R, serves a vital role in neuronal and brain functions such as autophagy and neuroinflammation. Yet, the function of spinal IGF1/IGF1R in neuropathic pain is unclear. Here, we examined whether and how spinal IGF1 signaling affects pain-like behaviors in mice with chronic constriction injury (CCI) of the sciatic nerve. To corroborate the role of IGF1, we injected intrathecally IGF1R inhibitor (nvp-aew541) or anti-IGF1 neutralizing antibodies. We found that IGF1 (derived from astrocytes) in the lumbar cord increased along with the neuropathic pain induced by CCI. IGF1R was predominantly expressed on neurons. IGF1R antagonism or IGF1 neutralization attenuated pain behaviors induced by CCI, relieved mTOR-related suppression of autophagy, and mitigated neuroinflammation in the spinal cord. These findings reveal that the abnormal IGF1/IGF1R signaling contributes to neuropathic pain by exacerbating autophagy dysfunction and neuroinflammation.

The determination approaches of Fe (Ⅲ) in biological samples were developed by a novel water-soluble silicon nanoparticles (SiNPs). The SiNPs were synthesized by a facile microwave-assisted method, and simultaneously featured strong blue fluorescence (photoluminescence quantum yield: 25.2%), long lifetime (~13.29 ns) and good photo-stability. The fluorescence intensities of SiNPs were gradually quenched with Fe (Ⅲ) concentration increasing from 2.0 to 50 μmol/L. The detection limit of the established method was 0.56 μmol/L and the precision for eleven replicate detections of 20 μmol/L Fe (Ⅲ) was 3.2% (relative standard deviation, RSD). The spiked recoveries were 99.0%-104.5%. Results of the lifetime decay and cyclic voltammetry (CV) evidenced that the electron transfer was responsible for the fluorescence quenching mechanism of SiNPs and Fe (Ⅲ). Moreover, the SiNPs were successfully applied in the determination of Fe(Ⅲ) in different environmental waters and human serum. Finally, the resulting SiNPs exhibited the green fluorescence in HeLa cells as the optical probe., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background/purpose: Intentional transmission of HIV-1 is a crime. Identifying the source of transmission between HIV-1 infected cases using phylogenetic analysis has limitations, including delayed examinations after the initiation of infection and ambiguity of phyletic relationships. This study was the first to introduce phylogenetic tree Results as forensic evidence in a trial in Taiwan., Methods: Three lawsuit cases from different district courts in Taiwan were chosen for this study. We identified the source of transmission between individuals in each lawsuit based on the maximum likelihood and Bayesian phylogenetic tree analyses using the HIV-1 sequences from molecular cloning and ultra-deep pyrosequencing (UDPS). Two gene regions of the HIV genome, env and gag, were involved., Results: The results of phylogenetic analysis using sequences from molecular cloning were clear and evidential enough in lawsuits 1 and 3. Due to the delayed sampling time, the result of sequences from molecular cloning in lawsuit 2 was ambiguous. Combined with the analyzed result of sequences from UDPS and epidemiological information, the source of transmission in lawsuit 2 was further identified., Conclusion: Hence phylogenetic analyses cannot exclude the possibility of unsampled intermediaries, the data interpretation should be more careful and conservative, and it should not be considered as the only evidence for the source identification in a trial without epidemiological or serological information. The evaluation of the introduced UDPS method in the identification of transmission source has shown that the validity and evidential effects were still limited and need further optimization., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Glycine- N -methyl transferase (GNMT) downregulation results in spontaneous hepatocellular carcinoma (HCC). Overexpression of GNMT inhibits the proliferation of liver cancer cell lines and prevents carcinogen-induced HCC, suggesting that GNMT induction is a potential approach for anti-HCC therapy. Herein, we used Huh7 GNMT promoter-driven screening to identify a GNMT inducer. Compound K78 was identified and validated for its induction of GNMT and inhibition of Huh7 cell growth. Subsequently, we employed structure-activity relationship analysis and found a potent GNMT inducer, K117. K117 inhibited Huh7 cell growth in vitro and xenograft in vivo . Oral administration of a dosage of K117 at 10 mpk (milligrams per kilogram) can inhibit Huh7 xenograft in a manner equivalent to the effect of sorafenib at a dosage of 25 mpk. A mechanistic study revealed that K117 is an MYC inhibitor. Ectopic expression of MYC using CMV promoter blocked K117-mediated MYC inhibition and GNMT induction. Overall, K117 is a potential lead compound for HCC- and MYC-dependent cancers.

Diabetic neuropathic pain (DNP) is one of the most serious complications of diabetes. Patients with DNP always exhibit spontaneous and stimulus-evoked pain. However, the pathogenesis of DNP remains to be fully elucidated. Non-coding RNAs (ncRNAs) serve important roles in several cellular processes and dysregulated expression may result in the development of several diseases, including DNP. Although ncRNAs have been suggested to be involved in the pathogenesis of DNP, their precise roles remain to be determined. In the present study, sequencing analysis was used to investigate the expression patterns of coding genes, microRNAs (miRNAs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs) in the spinal cord of mice with streptozotocin (STZ)-induced DNP. A total of 30 mRNAs, 148 miRNAs, 9 lncRNAs and 135 circRNAs exhibited significantly dysregulated expression 42 days after STZ injection. Functional enrichment analysis indicated that protein digestion and absorption pathways were the most significantly affected pathways of the differentially expressed (DE) mRNAs. The Rap1 signaling pathway, human T-lymphotropic virus-I infection and the MAPK signaling pathway were the three most significant pathways of the DE miRNAs. A total of 2,118 distinct circRNAs were identified and the length of the majority of the circRNAs was <1,000 nucleotides (nt) (1,552 circRNAs were >1,000 nt) with a median length of 620 nt. In the present study, the expression characteristics of coding genes, miRNAs, lncRNAs and circRNAs in DNP mice were determined; it paves the road for further studies on the mechanisms associated with DNP and potentially facilitates the discovery of novel ncRNAs for therapeutic targeting in the management of DNP., Competing Interests: The authors declare that they have no competing interests., (Copyright: © He et al.)

In this work, we innovatively synthesized homochiral fluorescence nano molecularly imprinted polymers (D-MIP) with dual affinity (metal ion affinity and homochiral affinity) for the specific separation and detection of L-penicillamine (L-PA), which is a core-shell structure with a SiO 2 -covered CDs core and an imprinted layer with L-PA cavities. A switch for fluorescence response was built by chelating grafted Cu 2+ , what's more, the imprinted L-PA was pre immobilized by Cu 2+ to form the directional imprinting with predetermined spatial structure. More importantly, the homochiral affinity of D-galactose in homochiral molecularly imprinted polymers (D-MIP) greatly enhanced the selective adsorption of L-PA, and D-MIP showed a high selectivity factor (α) of 3.45, which is 1.9 times that of the non-homochiral molecularly imprinted polymers (MIP). Meanwhile, D-MIP exhibited a high enantiomeric excess (ee) value of 56% for separation of racemic PA. Additionally, a high sensitive and selective method was established for the detection of L-PA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

To explore the mechanism of anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium based on network pharmacology and inflammatory or pain mouse models. The effective components of Zanthoxyli Pericarpium were screened out by TCMSP database. And their potential corresponding targets were predicted by PharmMapper software. The possible targets relating to inflammation and pain were mainly collected through DrugBank, TTD and DisGeNET databases. The &quot;active ingredient-gene-disease&quot; network diagram was constructed by Cytoscape 3.7.0 software. The network pharmacology results showed 5 potential effective compounds, which were related to 29 targets; 132 targets relating to inflammation and pain were screened out in the DrugBank, TTD and DisGeNET databases. The network analysis results indicated that the phosphatidylinositol 3-kinase catalytic subunit gamma isoform(PIK3 CG) gene may be the key to the anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium. The anti-inflammatory and analgesic effects of essential oil extract and dichloromethane extract of Zanthoxyli Pericarpium were explored through the mouse model of inflammation induced by xylene or carrageenan and the mouse model of pain induced by acetic acid or formalin. The experimental results showed that essential oil extract and dichloromethane extract of Zanthoxyli Pericarpium could reduce xylene-induced ear swelling and carrageenan-induced paw swelling and decrease the number of writhing responses in mice induced by acetic acid and the licking foot time of mice in phase Ⅱ induced by formalin. Western blot results showed that Zanthoxyli Pericarpium extract could inhibit the expressions of PIK3 CG, phosphonated nuclear factor kappaB(p-NF-κB) and phosphonated p38(p-p38 MAPK) protein. The present study showed the anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium through multiple components and targets, so as to provide a pharmacodynamic basis for the study of Zanthoxyli Pericarpium and its mechanism.

Purpose: Plant-derived exogenous microRNAs (miRNAs) regulate human physiological functions by blocking the translation of target mRNAs. Although several computational approaches have been developed to elucidate the interactions of cross-species miRNAs and their targets in mammals, the number of verified plant miRNAs is still limited, and the biological roles of most exogenous plant miRNAs remain unknown., Methods: A miRNA mimic library-based phenotypic screening, which contained 8394 plant mature miRNAs published in the official database miRbase, was performed to identify more novel bioactive plant miRNAs for the prevention of hepatic fibrosis. Inhibition of candidates for the activation of hepatic stellate cells (HSCs) and the underlying mechanisms were evaluated in TGF-β1- and PDGF-exposed HSC models. The protective effects of the candidates against CCl 4 -induced liver fibrosis were evaluated in a mouse model., Results: Among the 8394 plant mature miRNAs reported in the official database miRBase, five candidates were found to effectively inhibit the differentiation of HSCs. gma-miR-159a (miR159a) exerted the strongest inhibitory activities on both TGF-β1- and PDGF-induced HSC activation and proliferation by inhibiting the GSK-3β-mediated NF-κB and TGF-β1 pathways. Moreover, miR159a was mainly accumulated in the liver after intravenous injection, and it reduced CCl 4 -induced hepatic fibrosis and inflammation in mice., Conclusion: Results indicated that miR159a has the therapeutic potential for preventing hepatic fibrosis. This study provides a novel strategy for achieving natural nucleic acid drugs., Competing Interests: The authors declare no conflicts of interest related to this work., (© 2021 Yu et al.)

The selective laser melting (SLM) process, a kind of metal additive manufacturing method, can produce parts with complex geometries that cannot be easily manufactured using material removal processes. With increasing industrial applications, there are still issues such as part quality and productivity that need to be resolved. In this study, maraging steel parts fabricated by synchronized three-spot scanning strategies, i.e., lateral spatial (LS) and spatial inline (SiL), are firstly presented. The LS and SiL represent the three-spot offset direction is perpendicular and parallel to the scanning direction, respectively. A laboratory SLM machine equipped with a fiber laser and three-spot module is used to fabricate the maraging steel parts with two scanning strategies, i.e., LS and SiL. The influence of these scanning strategies on the surface roughness, relative density, hardness, molten pool shapes, and microstructures are investigated. The relative density (~99.02%) and surface hardness (~34.0 HRC) are experimentally found to be higher than the SiL by the LS scanning strategy.

Early and accurate detection of breast cancer plays an important role in improving the survival rates of patients. In this work, we designed and synthesized the Gal-NAc-imprinted nanoparticles (GIPs) via boronate-affinity glycan-oriented surface imprinting strategy. Molecularly imprinted polymers (MIPs) were hybridized with fluorescent silicon nanoparticles (SiNPs) to target Tn antigens. However, the single fluorescent imaging mode is not conducive to obtaining accurate diagnosis, due to its poor tissue penetration. To resolve this obstacle, doping gadolinium (Gd) into SiNPs was adopted to emerge an extra significant magnetic resonance (MR) signal, achieving highly sensitive fluorescence imaging and magnetic resonance imaging (MRI) with high spatial resolution. GIPs had uniform particle size around 31.8 nm, and exhibited satisfactory fluorescence stability. The maximum adsorption capacity of GIPs was 1.15 μM/g with a high imprinting factor (IF) of 7.5. Confocal laser scanning microscope imaging revealed that the GIPs had excellent specific recognition ability with a low cytotoxicity. GIPs also showed an outstanding MR performance on cancer cells. Therefore, the synthesized nanoparticles had desirable performance in dual-model imaging to specifically target recognition cancer cells. It may have a tremendous potential in real biological samples., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Changes in gut microbiota have been linked to systemic lupus erythematosus (SLE), but knowledge is limited. Our study aimed to provide an in-depth understanding of the contribution of gut microbiota to the immunopathogenesis of SLE., Methods: Fecal metagenomes from 117 patients with untreated SLE and 52 SLE patients posttreatment were aligned with 115 matched healthy controls and analyzed by whole-genome profiling. For comparison, we assessed the fecal metagenome of MRL/lpr mice. The oral microbiota origin of the gut species that existed in SLE patients was documented by single-nucleotide polymorphism-based strain-level analyses. Functional validation assays were performed to demonstrate the molecular mimicry of newly found microbial peptides., Results: Gut microbiota from individuals with SLE displayed significant differences in microbial composition and function compared to healthy controls. Certain species, including the Clostridium species ATCC BAA-442 as well as Atopobium rimae, Shuttleworthia satelles, Actinomyces massiliensis, Bacteroides fragilis, and Clostridium leptum, were enriched in SLE gut microbiota and reduced after treatment. Enhanced lipopolysaccharide biosynthesis aligned with reduced branched chain amino acid biosynthesis was observed in the gut of SLE patients. The findings in mice were consistent with our findings in human subjects. Interestingly, some species with an oral microbiota origin were enriched in the gut of SLE patients. Functional validation assays demonstrated the proinflammatory capacities of some microbial peptides derived from SLE-enriched species., Conclusion: This study provides detailed information on the microbiota of untreated patients with SLE, including their functional signatures, similarities with murine counterparts, oral origin, and the definition of autoantigen-mimicking peptides. Our data demonstrate that microbiome-altering approaches may offer valuable adjuvant therapies in SLE., (© 2020, American College of Rheumatology.)

It is difficult for drug delivery systems to release drugs as expected, often leading to undesired side effects. To solve this problem, a CuS@MSN/DOX@MnO 2 @membrane (CMDMm) was reasonably designed. It was introduced to release the drug by a double response, similar to using two keys to open two locks at the same time for one door. CuS@MSN was used as a photothermal therapy (PTT) material and carrier, and then the surface of CuS@MSN/DOX was sealed by MnO 2 to prevent drug release in advance. MnO 2 could be reduced and degraded in a tumor microenvironment. It was applied in MR imaging due to the T 1 magnetism of Mn 2+ following the reduction of MnO 2 . Finally, the 4T1 cell membrane was extracted and coated onto the surface of CuS@MSN/DOX@MnO 2 , which served as a target for 4T1 tumor cells. A noteworthy phenomenon was that the fluorescence of DOX was quenched by the coordination between DOX and CuS, and this greatly improved the interaction between DOX and CuS@MSN. However, the coordination was weakened when DOX was protonated in a tumor microenvironment (∼pH 5.0), leading to the release of DOX and fluorescence recovery. The drug release experiments showed that the release efficiency was higher at pH 5.0 with 10 mmol L -1 GSH. Through in vitro laser confocal imaging, it was successfully observed that DOX was reliably released in specific tumor cells according to the fluorescence recovery, and that there was no leakage in other cells. In short, effective double response drug release was successfully confirmed.

Multimodal imaging-guided accurate tumor-targeting and efficient synergistic therapy are of great importance for cancer therapy in vitro and in vivo. In this study, a biocompatible, tumor-targeted, on-demand chemo-/photothermal therapeutic nanoplatform (HIDSiGdNPs@PDA-HA) based on hollow mesoporous organic silica nanoparticles (HMONs) was used for bimodal imaging and multi-factor stepwise response for drug release and treatment. Targeted molecule hyaluronic acid (HA) promoted the endocytosis of HIDSiGdNPs@PDA-HA in HeLa cancer cells. The gatekeeper pH-/light-sensitive PDA coating was stimulated by the endogenous tumor acidic microenvironment and exogenous NIR laser to release doxorubicin (DOX). Thereafter, HMONs containing S-S bonds were reduced and degraded by endogenous glutathione (GSH), and the drug was further released rapidly to kill cancer cells. Importantly, the photothermal reagent indocyanine green (ICG) was always retained in the carrier, improving the effectiveness of photothermal therapy. The loaded Gd-doped silicon nanoparticles (SiGdNPs) combined with DOX and ICG led to multi-color fluorescence imaging in vitro and magnetic resonance imaging in vivo to realize targeted diagnosis and track drug distribution. The treatment results of tumor-bearing mice also proved the excellent synergistic therapy. It is believed that the multifunctional nanomaterials with dual mode imaging capability and targeted and controlled collaborative therapy would provide an alternative for accurate diagnosis and efficient treatment.

Colored rice is gaining popularity due to its use in creative agriculture and the value of healthy consumption. However, the quality and yield characteristics of most rice varieties still need to be improved. Revealing the genetic background of colored rice is of great significance to promote crop improvement. Here, the completed chloroplast (cp) genome sequence of yellow colored Oryza sativa voucher HSAGSDYD1802 was sequenced and reported. It was a 134,502 bp circular DNA with a typical quadripartite structure, consisting of two reverse repeat regions (IR a and IR b , 20,804 bp) separated by a large single-copy region (LSC, 80,547 bp) and a small single-copy region (SSC, 12,347 bp). The total GC content was 39%. The cp genome encoded 146 genes, containing 100 protein-coding genes, 8 rRNAs, and 38 tRNA genes. Phylogenetic analysis indicated that O. sativa voucher HSAGSDYD1802 was closely related to O. sativa L. TN1, RP Bio-226 and IR8. This study enriches the genetic information of colored rice and is helpful for future molecular breeding., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Benign immunoglobulin G4 (IgG4)-related orbital disease (IgG4-ROD)-characterized as tumors mimicking malignant orbital lymphoma (OL)-responds well to steroids, instead of chemotherapy, radiotherapy and/or surgery of OL. The objective of this study was to report the differences in computed tomography (CT) features and- serum IgG4 levels of IgG4-ROD and OL., Methods: This study retrieved records for patients with OL and IgG4-ROD from a pathology database during an eight-year-and-five-month period. We assessed the differences between 16 OL patients with 27 lesions and nine IgG4-ROD patients with 20 lesions according to prebiopsy CT features of lesions and prebiopsy serum IgG4 levels and immunoglobulin G (IgG) levels This study also established the receiver-operating curves (ROC) of precontrast and postcontrast CT Hounsfield unit scales (CTHU), serum IgG4 levels, serum IgG levels and their ratios., Results: Significantly related to IgG4-ROD (all p < 0.05) were the presence of lesions with regular borders, presence of multiple lesions-involving both lacrimal glands on CT scans-higher median values of postcontrast CTHU, postcontrast CTHU/precontrast CTHU ratios, serum IgG4 levels and serum IgG4/IgG level ratios. Compared to postcontrast CTHU, serum IgG4 levels had a larger area under the ROC curve (0.847 [95% confidence interval (CI): 0.674-1.000, p = 0.005] vs. 0.766 [95% CI: 0.615-0.917, p = 0.002]), higher sensitivity (0.889 [95% CI: 0.518-0.997] vs. 0.75 [95% CI: 0.509-0.913]), higher specificity (0.813 [95% CI: 0.544-0.960] vs. 0.778 [95% CI: 0.578-0.914]) and a higher cutoff value (≥132.5 mg/dL [milligrams per deciliter] vs. ≥89.5)., Conclusions: IgG4-ROD showed distinct CT features and elevated serum IgG4 (≥132.5 mg/dL), which could help distinguish IgG4-ROD from OL.

3-Phosphoinositide-dependent protein kinase-1 (PDK1) plays a critical role in the development of mammalian brain. Here, we investigated the role of PDK1 in Purkinje cells (PCs) by generating the PDK1-conditional knock-out mice (cKO) through crossing PV-cre or Pcp2-cre mice with Pdk1 fl/fl mice. The male mice were used in the behavioral testing, and the other experiments were performed on mice of both sexes. These PDK1-cKO mice displayed decreased cerebellar size and impaired motor balance and coordination. By the electrophysiological recording, we observed the reduced spontaneous firing of PCs from the cerebellar slices of the PDK1-cKO mice. Moreover, the cell body size of PCs in the PDK1-cKO mice was time dependently reduced compared with that in the control mice. And the morphologic complexity of PCs was also decreased after PDK1 deletion. These effects may have contributed to the reduction of the rpS6 (reduced ribosomal protein S6) phosphorylation and the PKCγ expression in PDK1-cKO mice since the upregulation of pS6 by treatment of 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-1, the agonist of mTOR1, partly rescued the reduction in the cell body size of the PCs, and the delivery of recombinant adeno-associated virus-PKCγ through cerebellar injection rescued the reduced complexity of the dendritic arbor in PDK1-cKO mice. Together, our data suggest that PDK1, by regulating rpS6 phosphorylation and PKCγ expression, controls the cell body maintenance and the dendritic development in PCs and is critical for cerebellar motor coordination. SIGNIFICANCE STATEMENT Here, we show the role of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in Purkinje cells (PCs). The ablation of PDK1 in PCs resulted in a reduction of cell body size, and dendritic complexity and abnormal spontaneous firing, which attributes to the motor defects in PDK1-conditional knock-out (cKO) mice. Moreover, the ribosomal protein S6 (rpS6) phosphorylation and the expression of PKCγ are downregulated after the ablation of PDK1. Additionally, upregulation of rpS6 phosphorylation by3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-1 partly rescued the reduction in cell body size of PCs, and the overexpression of PKCγ in PDK1-KO PCs rescued the reduction in the dendritic complexity. These findings indicate that PDK1 contributes to the maintenance of the cell body and the dendritic development of PCs by regulating rpS6 phosphorylation and PKCγ expression., (Copyright © 2020 the authors.)

Metastasis accounts for 90% of cancer death worldwide, and effective therapeutic strategies are lacking. The aim of this work is to identify the key drivers in tumor metastasis and screen therapeutics for treatment of esophageal squamous cell carcinoma (ESCC). Gene Ontology analysis of The Cancer Genome Atlas (TCGA) gene expression datasets of ESCC patients with or without lympy metastasis identifies that TGF β 2 is highly enriched in the pathways essential for tumor metastasis and upregulates in the metastatic ESCC tumors. High TGF β 2 expression in ESCC correlates with metastasis and patient survival, and functionally contributes to tumor metastasis via activating extracellular signal-regulated kinases (ERK) signaling. By screening of a library consisting of 429 bioactive compounds, imperatorin is verified as a novel TGF β 2 inhibitor, with robustly suppressive effect on tumor metastasis in multiple mice models. Mechanistically, direct binding of imperatorin and CREB1 inhibits phosphorylation, nuclear translocation of CREB1, and its interaction with TGF β 2 promoter, represses TGF β 2 expression and fibroblasts-secreted CCL2, and then inactivates ERK signaling to block cancer invasion and abrogates the paracrine effects of fibroblasts on tumor angiogenesis and metastasis. Overall, the findings suggest the use of TGF β 2 as a diagnostic and prognostic biomarker and therapeutic target in ESCC, and supports the potential of imperatorin as a novel therapeutic strategy for cancer metastasis., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

Targeting enrichment of nanocarriers at tumor sites and effective drug release are critical in cancer treatment. Accordingly, we used fluorescent zeolitic imidazolate framework-8 nanoparticles loaded with doxorubicin (FZIF-8/DOX) as the core and a molecularly imprinted polymer (MIP) as the shell to synthesize tumor-sensitive biodegradable FZIF-8/DOX-MIP nanoparticles (FZIF-8/DOX-MIPs). The MIP prepared with the epitope of CD59 cell membrane glycoprotein as the template allowed FZIF-8/DOX-MIPs to be enriched to tumor sites by actively targeting recognition of MCF-7 cancer cells (CD59-positive). Moreover, using N , N '-diacrylylcystamine as the cross-linker and dimethylaminoethyl methacrylate as the main monomer, the MIP's framework will be broken under the stimulation of a tumor microenvironment (high-concentration glutathione and weakly acidic), so that the internal FZIF-8/DOX is exposed to a microacidic environment to release DOX through further degradation. More importantly, the ability of FZIF-8/DOX-MIPs in targeted fluorescence imaging and effective drug release has been validated both in vitro and in vivo. Compared to other cells and nanoparticles, FZIF-8/DOX-MIPs were more capable of being phagocytosed by MCF-7 cells and were more lethal to MCF-7 cells. In the comparative experiments carried out on tumor-bearing mice, FZIF-8/DOX-MIPs had the best inhibitory effect on the growth of MCF-7 tumors. Furthermore, the FZIF-8/DOX-MIPs can serve as a diagnostic agent because of the active targeting of MCF-7 cells and the stronger red fluorescence of the embedded carbon quantum dots. Because of the active targeting ability, good biocompatibility, tumor-sensitive biodegradability, and effective drug release performance, FZIF-8/DOX-MIPs can be widely used in tumor imaging and treatment.

Background and Aim: Patients with leukemia who are isolated in positive pressure rooms for infection prevention usually experience significant physical and psychological distress. This study aimed to examine changes in leukemia patients' comfort level during chemotherapy in isolation wards. Methods: A longitudinal survey was conducted with measures which were repeated four times. Data were collected before chemotherapy, on the first and second week after receiving chemotherapy in positive pressure isolation rooms, and on the third week in the non-isolated hematology ward. Each patient received six questionnaires measuring demographic data, comfort status, functional status, fatigue related to cancer therapy, anxiety level, and distress symptoms. A mixed model with repeated measure analysis was used to examine the changing trajectories in physical and psychological health. Results: Twenty-one patients completed the study. During the process, the highest score for comfort level was shown before chemotherapy, and this decreased from the second week under isolation. Anxiety and uncertainty ( p < 0.05) declined over time, and emotional states improved during the recovery period in the third and fourth weeks outside isolation. Physical well-being ( p < 0.01), cancer-related fatigue ( p < 0.05), hemoglobin ( p < 0.01) and white blood cell count ( p < 0.05) began to rise two weeks after chemotherapy. Conclusion: Comfort levels declined after chemotherapy until the third week of treatment. Anxiety, fatigue and distress symptoms varied across the four time points of chemotherapy from isolation to return to the non-isolated ward. Health care professionals should be aware of psychological symptoms when patients are in isolation rooms, and interventions for promoting a humanized environment, quality of life, and comfort should be considered and provided along with the treatment stages of chemotherapy.

It is a still tough task to precisely target cancer cells and efficiently improve the therapeutic efficacy of various therapies at the same time. Here, dual-template imprinting polymer nanoparticles (MIPs) with a core-shell structure were prepared, in which fluorescent silica nanoparticles (FSiO 2 ) were the core and the imprinted polymer layers were the outermost shell. The imprinted layer was designed and constructed via free-radical precipitation approach on the surface of FSiO 2 , which simultaneously encapsulated gadolinium-doped silicon quantum dots and photosensitizers (Ce6). During the polymerization process, two template molecules were introduced into the mixtures, one was the epitope of CD59 protein (YNCPNPTADCK), which was overexpressed on the surface of a great deal of the solid cancers, and the other was antitumor agent doxorubicin (DOX) to be used for chemotherapy. Furthermore, the embedded Ce6 could generate toxic 1 O 2 under 655 nm laser irradiation to kill cancer cells, combining with the loaded-DOX to obtain a synergistic cancer therapy. Moreover, owing to the introduction of gadolinium-doped silicon quantum dots, Ce6, and DOX, the MIPs were endowed with targeted fluorescence imaging (FI) and MR imaging (MRI). In vitro and in vivo experiments had been conducted to demonstrate the excellent targeting ability and desirable treatment effect with negligible toxicity to healthy tissues and organs. As a consequence, the designed MIPs can promote the development of targeted recognition against biomarkers and precise treatment guided with cell imaging tools.

A carbon dots-embedded epitope imprinted polymer (C-MIP) was fabricated for targeted fluorescence imaging of cervical cancer by specifically recognizing the epidermal growth factor receptor (EGFR). The core-shell C-MIP was prepared by a reverse microemulsion polymerization method. This method used silica nanoparticles embedded with carbon dots as carriers, acrylamide as the main functional monomer, and N-terminal nonapeptides of EGFR modified by palmitic acid as templates. A series of characterizations (transmission electron microscope, dynamic light scattering, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, zeta potential, and energy dispersive X-ray spectroscopy) prove the successful synthesis of C-MIP. The fluorescence of C-MIP is quenched by the epitopes of EGFR due to the specific recognition of epitopes of EGFR through their imprinted cavities (analytical excitation/emission wavelengths, 540 nm/610 nm). The linear range of fluorescence quenching is 2.0 to 15.0 μg mL -1 and the determination limit is 0.73 μg mL -1 . The targeted imaging capabilities of C-MIP are demonstrated through in vitro and in vivo experiments. The laser confocal imaging results indicate that HeLa cells (over-expression EGFR) incubated with C-MIP show stronger fluorescence than that of MCF-7 cells (low-expression EGFR), revealing that C-MIP can target tumor cells overexpressing EGFR. The results of imaging experiments in tumor-bearing mice exhibit that C-MIP has a better imaging effect than C-NIP, which further proves the targeted imaging ability of C-MIP in vivo. Graphical abstract An oriented epitope imprinted polymer embedded with carbon dots was prepared for the determination of the epitopes of epidermal growth factor receptor and targeted fluorescence imaging of cervical cancer.

Methods: Eighty-eight patients undergoing THA were randomized to receive 0.33% ropivacaine (Group QLB, n  = 44) or saline (Group Con, n  = 44) for QL3 block. Spinal anesthesia was then performed. Pain intensity was assessed using the visual analog scale (0: no pain to 10: worst possible pain). The primary outcome was pain scores recorded at rest at 3, 6, 12, 24, 36, and 48 h and on standing and walking at 24, 36, and 48 h postoperatively. Secondary outcomes were analgesic consumption, side effects, the 10-meter walking speed on day 6, and patient satisfaction after surgery., Results: Postoperative pain intensity was significantly lower in Group QLB compared to Group Con at rest after 3, 6, 12, 24, 36, and 48 h ( p < 0.001) and during mobilization after 24, 36, and 48 h ( p < 0.001). Morphine use was significantly lower in Group QLB compared to Group Con during 0-24 h (16.0 ± 7.1 vs. 34.1 ± 7.1 mg, p < 0.001) and during 24-48 h (13.0 ± 4.0 vs. 17.4 ± 4.6 mg, p < 0.001) postoperatively. The 10-meter walking speed was higher in Group QLB compared to Group Con, both at comfortable (0.79 ± 0.13 vs. 0.70 ± 0.14 m/s, p =0.012) and at maximum speeds (1.18 ± 0.26 vs. 1.06 ± 0.22 m/s, p < 0.001). Incidences of nausea (7.3% vs. 31%, p =0.006), vomiting (7.3% vs. 26.2%, p  = 0.022), and urinary retention (9.8% vs. 28.6%, p =0.030) were lower in Group QLB than in Group Con., Conclusions: Ultrasound-guided QL3 block is an effective pain management technique after THA., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Jian He et al.)

Currently, the nanocomposites based on silicon nanoparticles (SiNPs) are usually limited to a single therapeutic modality, and the design of the SiNPs nanohybrids with multi-modal synergistic therapeutic functions is still worth being explored to achieve more effective treatment. Herein, we used mesoporous silica nanoparticle (MSN) as a nanoplatform, SiNPs and the photosensitizer 5,10,15,20-tetrakis (1-methyl 4-pyridinio) porphyrin tetra (p-toluenesulfonate) (TMPyP) were first embedded in the MSN and was further modified with folic acid (FA) to obtain the mesoporous silica nanocomposite (MSN@SiNPs@TMPyP-FA) for targeted two-photon-excited fluorescence imaging-guided photodynamic therapy (PDT) and chemotherapy. The embedded TMPyP could generate singlet oxygen to perform PDT under light irradiation, meanwhile the anticancer drugs doxorubicin (DOX) could be loaded for chemotherapy. Moreover, due to the two-photon excited fluorescence of SiNPs, the nanocomposite successfully achieved targeted two-photon fluorescence cellular imaging at the near-infrared (NIR) laser excitation, which could effectively avoid the interference of biological auto-fluorescence. And in vitro cytotoxicity assays revealed that the synergistic therapy combining PDT and chemotherapy exhibited high therapeutic efficacy for cancer cells., (Copyright © 2019 Elsevier B.V. All rights reserved.)

LysR-type transcriptional regulators are involved in the regulation of numerous cellular metabolic processes in Klebsiella pneumoniae, leading to severe infection. Earlier, we found a novel LysR family gene, named kp05372, in a strain of K. pneumoniae (designated GPKP) isolated from forest musk deer. To study the function of this gene in relation to the biological characteristics of GPKP, we used the suicide plasmid and conjugative transfer methods to construct deletion mutant strain GPKP-Δkp05372; moreover, we also constructed the GPKP-Δkp05372+ complemented strain. The role of this gene was determined by comparing the following characteristics of three strains: growth curves, biofilm formation, drug resistance, stress resistance, median lethal dose (LD 50 ), organ colonization ability, and the histopathology of GPKP. Real-time polymerase chain reaction (RT-PCR) was used to test the expression level of seven genes upstream of kp05372. There was no significant difference in the growth rates when comparing the three bacterial strains, and no significant difference was recorded at different osmotic pressures, temperatures, salt contents, or hydrogen peroxide concentrations. The GPKP-Δkp05372 mutant formed a weak biofilm, and the other two strains formed medium biofilm. The drug resistance of the GPKP-Δkp05372 mutant toward cephalothin, cotrimoxazole, and polymyxin B was changed. The acid tolerance of the deletion strain was stronger than that of the other two strains. The LD 50 values of the wild-type and complemented strains were 174-fold and 77-fold higher than that of the GPKP-Δkp05372 mutant, respectively. The colonization ability of the GPKP-Δkp05372 mutant in the heart, liver, spleen, kidney, and intestine was the weakest. The three strains caused different histopathological changes in the liver and lungs. In the GPKP-Δkp05372 mutant, the relative expression levels of kp05374 and kp05379 were increased to 1.32-fold and 1.42-fold, respectively, while the level of kp05378 was decreased by 42%. Overall, the deletion of kp05372 gene leads to changes in the following: drug resistance and acid tolerance; decreases in virulence, biofilm formation, and colonization ability of GPKP; and regulation of the upstream region of adjacent genes.

Here, staple carbon fiber fabric-reinforced polycarbonate (PC)- and epoxy (EP)-based composites with different impregnating resin levels were fabricated using a modified film stacking process. The effects of surface topographies and resin types on the tribological properties of stable carbon fabric composites (sCFC) were investigated. Friction and wear tests on the carbon composites were conducted under unlubricated sliding using a disk-on-disk wear test machine. Experimental results showed that the coefficient of friction (COF) of the sCFC was dominated by matrix type, followed by peak material portion (S mr1 ) values, and finalized with core height (S k ) values. The COF of composites decreased by increasing the sliding speed and applied pressure. This also relied on surface topography and temperature generated at the worn surface. However, the specific wear rate was strongly affected by resin impregnation. Partially-impregnated composites showed lower specific wear rate, whereas fully-impregnated composites showed a higher wear rate. This substantially increased by increasing the sliding speed and applied pressure. Scanning electron microscopy observations of the worn surfaces revealed that the primary wear mechanisms were abrasion, adhesion, and fatigue for PC-based composites. For EP-based composites, this was primarily abrasion and fatigue. Results proved that partially-impregnated composites exhibited better tribological properties under severe conditions., Competing Interests: The authors declare no conflicts of interest.

Probiotics are intended to provide health benefits when consumed, generally by improving or restoring the gut flora. The health problems of forest musk deer (FMD, Moschus berezovskii), a threatened species currently under conservation, restrict the development of captive musk deer. This study was conducted with the aim of analyzing the effects of forest musk deer compound probiotics (FMDPs) on weight, immunity performance and fecal microbiota in FMD by measuring average daily weight gain (ADG) and immune-related factors and by using high-throughput 16S rRNA sequencing to investigate differences in the fecal microbiota among the control group (4 samples), treatment group A (4 samples) and treatment group B (4 samples). The results showed that the ADG of treatment groups A and B was significantly higher than that of the control group (p = 0.032, p = 0.018). The increase in IgA and IgG levels in treatment group B was significantly higher than that in the control group (p = 0.02, p = 0.011). At the phylum and genus levels, the difference in bacterial community structure was significant between treatment group B and the control group. Both the alpha diversity and beta diversity results showed significant differences in the microbiota of FMD before and after FMDP feeding. In summary, the results indicated that FMDPs could promote the growth of growing FMD, improve immunity and balance the role of intestinal microbes.

Hydrocalumite (Ca-Al-LDHs) is a new type of layered composite metal hydroxide that has a large specific surface area, high anion exchange performance, and high stability. This study focuses on the application of hydrocalumite to remediate different Cd-contaminated farmland soils. These were collected from the Lanping County in the Yunnan Province (highly polluted), Kunshan City in the Jiangsu Province (medium polluted), and Nanjing City in the Jiangsu Province (lowly polluted). Changes in the available Cd, Pb, Zn, and the morphological transformations of these heavy metals in the three soils were investigated through a passivation experiment; moreover, the immobilization mechanism of hydrocalumite was explored by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). The results showed that hydrocalumite could increase the soil pH and reduce the content of available Cd, Pb, and Zn:the maximum reduction in the available Cd reached 97.7%, 96.3%, and 91.8% in each of the three polluted soils, respectively. The easily exchangeable heavy metals were converted into carbonates, as well as into Fe-Mn oxide organic and residual forms following the addition of hydrocalumite:the passivation effect was more evident in the highly Cd-polluted soil than in the low and medium Cd-polluted soils. Since hydrocalumite possess several adsorption sites, the presence of carbonate impurities and reactive groups (e.g., hydroxyl and carboxyl groups) easily coordinated with Cd, Pb, and Zn can lead to a considerable reduction of heavy metal availability in the soils. Therefore, we conclude that hydrocalumite can be effectively applied to the remediation of farmland soils characterized by different Cd pollution levels.

Nanocarriers with both targeting ability and stable loading of drugs can more effectively deliver drugs to precise tumor sites for therapeutic effects. Accordingly, we have rationally designed fluorescent molecularly imprinted polymer nanoparticles (FMIPs), which use N-terminal epitope of P32 membrane protein as the primary template and doxorubicin (DOX) as the secondary template. The DOX imprinted cavity can stably carry the drug and the epitope-imprinted cavity allows FMIPs to actively recognize the P32-positive 4T1 cancer cells. The targeted therapeutic effect of DOX-loaded FMIPs (FMIPs@DOX) is investigated in vitro and in vivo. The FMIPs@DOX only causes apoptosis in 4T1 cancer cells compared to C8161 cells (expressing low level of P32). In addition, highly effective inhibition of 4T1 malignant breast tumors using FMIPs@DOX is achieved in the model of tumor-bearing mice. Importantly, the antitumor effect achieved by intravenous injection of FMIPs@DOX is almost identical to that by intratumoral injection. Furthermore, the FMIPs can serve as a targeted fluorescence imaging agent due to the high specificity of the epitope-imprinted cavity and the stable fluorescence of the embedded silicon nanoparticles. These results demonstrate the effectiveness of the FMIPs for active targeted drug delivery and imaging. Furthermore, the FMIPs provide a direction for drug-loaded nanocarrier.

Targeting is vital for precise positioning and efficient therapy, and integrated platforms for diagnosis and therapy have attracted more and more attention. Herein, we established dual-template molecularly imprinted polymer (MIP) coated fluorescent silicon nanoparticles (Si NPs) by using the linear peptide of the extracellular region of human epidermal growth factor receptor-2 (HER2) and adopting doxorubicin (DOX) as templates for targeted imaging and targeted therapy. Benefiting from the epitope imprinting approach, the imprinted sites generated by peptides on the MIP surface can be employed for recognizing the corresponding protein, which allowed the MIP to specifically and actively target HER2-positive breast cancer cells. Because of its ability to identify breast cancer cells, the MIP was applied for targeted fluorescence imaging by taking advantage of the excellent fluorescence properties of Si NPs, and the DOX-loaded MIP (MIP@DOX) can act as a therapeutic probe to effectively target and kill breast cancer cells. In fluorescence images, the targeting of the MIP promoted more uptake of the nanoparticles by cells than the non-imprinted polymer (NIP), so HER2-positive breast cancer cells incubated with the MIP exhibited stronger fluorescence, and there was no significant difference in fluorescence when HER2-negative cells and normal cells were respectively hatched with the MIP and NIP. Importantly, the cell viability was evaluated to demonstrate targeted accumulation and therapy of MIP@DOX for breast cancer cells. The nanoplatform for diagnosis and therapy combined the high sensitivity of fluorescence with the high selectivity of the molecular imprinting technique, which holds vital potential in targeted imaging and targeted therapy in vitro.

A multifunctional diagnosis and treatment integration platform is crucial in cancer treatments. Here, we show that by integrating Gd-doped silicon nanoparticles (Si-Gd NPs), chlorine e6 (Ce6), doxorubicin (DOX), zeolitic imidazolate framework-8 (ZIF-8), poly(2-(diethylamino)ethyl methacrylate) polymers (HOOC-PDMAEMA-SH), and folic acid-poly(ethylene glycol)-maleimide (MaL-PEG-FA) into one single nanoplatform by a self-assembly method, novel multifunctional MOFs (named FZIF-8/DOX-PD-FA) are synthesized with great biocompatibility and tumor targeting as well as pH responsiveness and no drug leakage for drug delivery. In the design, Si-Gd NPs and Ce6 embedded in the nanocomposites are used for magnetic resonance and fluorescence dual-modal imaging, respectively. DOX loaded by the FZIF-8/DOX-PD-FA porous structure is used for chemotherapy, while Ce6 is excited by near-infrared radiation (NIR) for photodynamic therapy. In addition, the pH-responsive ability of HOOC-PDMAEMA-SH to effectively prevent drug leakage is demonstrated by drug release studies in vitro. From the results of confocal microscopy imaging in vitro and fluorescence/magnetic resonance imaging in vivo, FZIF-8/DOX-PD-FA showed a targeting effect on MCF-7 cancer cells. More importantly, the results of treatment experiments on tumor-bearing mice showed that the tumor volume of the FZIF-8/DOX-PD-FA + NIR group is decreased the most compared to the original volume. Owing to the unique dual-modal imaging capability and excellent chemo-/photodynamic combinational cancer therapy effect, the present hybrid nanocarrier provides a new research platform for a new generation of theranostic nanoparticles.

WD repeat protein 1 (Wdr1), known as a cofactor of actin-depolymerizing factor (ADF)/cofilin, is conserved among eukaryotes, and it plays a critical role in the dynamic reorganization of the actin cytoskeleton. However, the function of Wdr1 in the central nervous system remains elusive. Using Wdr1 conditional knockout mice, we demonstrated that Wdr1 plays a significant role in regulating synaptic plasticity and memory. The knockout mice exhibited altered reversal spatial learning and fear responses. Moreover, the Wdr1 CKO mice showed significant abnormalities in spine morphology and synaptic function, including enhanced hippocampal long-term potentiation and impaired long-term depression. Furthermore, we observed that Wdr1 deficiency perturbed actin rearrangement through regulation of the ADF/cofilin activity. Taken together, these results indicate that Wdr1 in the hippocampal CA1 area plays a critical role in actin dynamics in associative learning and postsynaptic receptor availability., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Molecularly imprinted polymers were commonly used for drug delivery. However, single-template molecularly imprinted polymers often fail to achieve both drug delivery and precise targeting. To address this issue, a dual-template molecularly imprinted polymer nanoparticle used for targeted diagnosis and drug delivery for pancreatic cancer BxPC-3 cells (FH-MIPNPs) was prepared. In the FH-MIPNPs, the 71-80 peptide of human fibroblast growth-factor-inducible 14 modified with glucose (Glu-FH) and bleomycin (BLM) were used as templates simultaneously, so that the FH-MIPNPs could load BLM and bind to the BxPC-3 cells, which overexpress human fibroblast growth-factor-inducible 14 (FN14). Targeted imaging experiments in vitro show that the FH-MIPNPs could specifically target BxPC-3 cells and that there is no targeting effect on cells without expression of FN14. In vivo antitumor experiment results demonstrated that the FH-MIPNP-loaded BLM (FH-MIPNPs/BLM) could inhibit the growth of xenografts tumor of BxPC-3 (tumor volume increased to 1.05×), which shows that FH-MIPNPs/BLM had obvious targeted therapeutic effect compared to the other three control groups of BLM, FH-NIPNPs/BLM, and physiological saline (tumor volume increased to 1.5×, 1.6×, and 2.4×, respectively). What is more, FH-MIPNPs have low biotoxicity through toxicity experiments in vitro and in vivo, which is favorable toward making molecularly imprinted polymers an effective platform for tumor-targeted imaging and therapy.

Background: Augmented renal clearance (ARC) is common in critically ill patients and could result in subtherapeutic antibiotic concentration. However, data in the Asian population are still lacking. The aim of this study was to explore the incidence and risk factors of ARC and its effect on β-lactam pharmacokinetics/pharmacodynamics (PK/PD) in Asian populations admitted to a medical ICU. In addition, we evaluated the appropriateness of using three estimated glomerular filtration (eGFR) formulas [Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] as screening tools., Methods: We measured 2-, 8-, and 24-hr creatinine clearance (CL Cr ) and calculated eGFR by using three formulas for each. ARC was defined as CL Cr24hr >130 mL/min/1.73 m 2 . Concentrations at the mid-dosing interval and prior to the next dose were collected if patients received the β-lactam antibiotic of piperacillin/tazobactam, cefepime, and meropenem, to determine the PK/PD index of fT > MIC. Multiple logistic regression analysis was conducted to identify the risk factors for ARC. Pearson correlation coefficient and the Bland and Altman method were applied to assess the accuracy of CL Cr2hr , CL Cr8hr , and eGFR for predicting ARC., Results: Of 100 patients, 46 (46%) manifested ARC. Younger age (<50 years) and lower Sequential Organ Failure Assessment score increased the likelihood of ARC. ARC resulted in a low chance of achieving 50% fT >4MIC (33% vs 75%, p <0.01), 100% fT > MIC (23% vs 69%, p <0.01), and 100% fT >4MIC (3% vs 25%, p <0.02). CL Cr8hr wielded the best correlation and agreement with CL Cr24hr . eGFR CG was the most appropriate screening tool, and the optimal cutoff value for detecting ARC was 130.5 mL/min/1.73 m 2 ., Conclusion: ARC is associated with inadequate β-lactam PK/PD target in Asian ICU., Competing Interests: The authors report no conflicts of interest in this work.

Enterocytozoon bieneusi , a unicellular enteric microsporidian parasite, can infect humans and a wide range of animals throughout the world. Although E. bieneusi has been identified in many animals, there is no information regarding the genotypes of E. bieneusi in pet birds in China. Birds are important sources of emerging infectious diseases that affect humans, and immunosuppressed individuals can be exposed to potential zoonotic agents shed by birds. The aim of the present study was to determine the prevalence and genotypic diversity of E. bieneusi in pet birds, as well as assessed its zoonotic potential. A total of 387 fecal samples were collected from Psittaciformes (n = 295), Passeriformes (n = 67), and Galliformes (n = 16) from four pet markets in Sichuan province, Southwestern China. The overall prevalence of E. bieneusi in pet birds was 25.1% based on nested polymerase chain reaction analysis of the internal transcribed spacer (ITS) region of the ribosomal RNA (rRNA) gene (Psittaciformes, 21.7%; Passeriformes, 37.3%; Galliformes, 50.0%). Eight genotypes of E. bieneusi were identified, including five known genotypes (D, SC02, BEB6, CHB1, and MJ5) and three novel genotypes (SCB-I, SCB-II, and SCB-III). In phylogenetic analysis, genotypes D and SC02 and one novel genotype SCB-II were clustered within group 1, genotype BEB6 was classified within group 2, and the remaining genotypes (CHB1, MJ5, SCB-I, and SCB-III) clustered with group 10. To the best of our knowledge, this is the first report of E. bieneusi infection in pet birds in China. Genotypes D, SC02, and BEB6 that have been previously identified in humans, were found in pet birds in this study, suggesting that these pet birds can be a potential source of human microsporidiosis in China., (© 2019 The Authors.)

Blastocystis is a common enteric protist that colonizes humans and a wide range of animals. Although some studies have reported incidences of Blastocystis in humans and animals in China, there is no information available on the prevalence of Blastocystis in giant pandas, red pandas, or bird species. The aims of the present study were to determine the prevalence, subtype distribution, and genetic characterizations of Blastocystis in these animals in a captive situation in southwestern China, as well as assess the zoonotic potential of Blastocystis isolates. A total of 168 fecal specimens, including 81 from giant pandas, 23 from red pandas, 38 from black swans, 11 from ruddy shelducks, and 15 from green peafowl were collected at the Chengdu Research Base of Giant Panda Breeding in Sichuan province. The overall minimum prevalence of Blastocystis was 11.3% (19/168) based on PCR amplification of the barcode region of the SSU rRNA gene. The highest prevalence of Blastocystis was observed in ruddy shelduck (18.2%) and the lowest was found in green peafowl (6.7%). The prevalence of Blastocystis in giant pandas >5.5 years of age was higher than that in younger giant pandas. Two potentially zoonotic subtypes (ST1 and ST8) were identified, and ST1 (n = 12) was found to be more prevalent than ST8 (n = 7). To the best of our knowledge, this is the first report of the prevalence and subtypes of Blastocystis in giant pandas, red pandas, and bird species in China. The findings of this study will improve our understanding of the genetic diversity and public health potential of Blastocystis.

Painful diabetic neuropathy (PDN) is among the common complications in diabetes mellitus (DM), with its underlying mechanisms largely unknown. Synapsin II is primarily expressed in the spinal dorsal horn, and its upregulation mediates a superfluous release of glutamate and a deficiency of GABAergic interneuron synaptic transmission, which is directly implicated in the facilitation of pain signals in the hyperalgesic nociceptive response. Recently, synapsin II has been revealed to be associated with the modulation of neurite outgrowth, whereas the process of this neuronal structural neuroplasticity following neuronal hyperexcitability still remains unclear. In this study, we found that under conditions of elevated glucose, TNF-α induced the activation of mTOR, mediating the upregulation of synapsin II and neurite outgrowth in dorsal horn neurons. In vivo, we demonstrated that mTOR and synapsin II were upregulated and coexpressed in the spinal dorsal horn neurons in rats with streptozotocin (STZ)-induced diabetes. Furthermore, the intrathecal administration of the mTOR inhibitor rapamycin or synapsin II shRNA significantly diminished the expression of synapsin II, effectively mitigating hyperalgesia in PDN rats. We are the first to discover that in STZ-induced diabetic rats the activation of mTOR mediates the upregulation of synapsin II and neurite outgrowth, both contributing to hyperalgesia. These findings may benefit the clinical therapy of PDN by provision of a novel target.

Objective: To investigate whether the recombinant FimH-S.T protein could modulate immune response to anti-caries vaccine in vitro and in vivo., Design: Recombinant FimH protein derived from Salmonella was constructed and purified. The expression of dendritic cell maturation markers and cytokines release were performed by flow cytometry, Real-time PCR and ELISA. In addition, BALB/c mice were administered with anti-caries PAc vaccine plus FimH-S.T, antibody responses were evaluated by ELISA. Splenocytes of immunized mice were detected for their proliferative ability in response to in vitro retreatment with PAc antigen by flow cytometry. Caries protection against dental caries formation was also investigated., Results: The purified FimH-S.T induced phenotypic maturation of DC2.4 by up-regulating the expression of costimulatory molecules and MHC II, provoked the production and secretion of cytokines via TLR4-dependent signaling pathway in vitro. Furthermore, the mice immunized with the mixture of FimH-S.T and PAc significantly enhanced the PAc-specific antibodies in the serum along with saliva and promoted splenocyte proliferation. Our results also confirmed that PAc+FimH-S.T decreased the caries lesions formation which provided high protective efficacy against dental caries., Conclusion: Our study demonstrates that recombinant FimH-S.T could enhance specific IgA responses and protection of anti-caries vaccine, possessing mucosal adjuvant ability by activating DC2.4 via TLR4 signaling pathway., (Copyright © 2019. Published by Elsevier Ltd.)

Silicon nanoparticles (SiNPs), especially those emitting red fluorescence, have been widely applied in the field of bioimaging. However, harsh synthetic conditions and strong biological autofluorescence caused by short wavelength excitation restrict the further development of SiNPs in the field of biological applications. Here, we report a method for synthesizing a ruthenium-complex-functionalized two-photon-excited red fluorescence silicon nanoparticle composite (SiNPs-Ru) based on fluorescence resonance energy transfer under mild experimental conditions. In the prepared SiNPs-Ru composite, silicon nanoparticles synthesized by atmospheric pressure microwave-assisted synthesis served as a fluorescence energy donor, which had two-photon fluorescence properties, and tris(4,4'-dicarboxylic acid-2,2-bipyridyl)ruthenium(II) dichloride (L Ru ) acted as a fluorescence energy acceptor, which could emit red fluorescence as well as had the ability to produce singlet-oxygen for photodynamic therapy. Therefore, the synthesized SiNPs-Ru could emit red fluorescence by two-photon excitation based on fluorescence resonance energy transfer, which could effectively avoid the interference of biological autofluorescence. Fluorescence imaging tests in zebrafish and nude mice indicated that the as-prepared SiNPs-Ru could act as a new kind of fluorescence probe for fluorescence imaging in vivo. By coupling folic acid (FA) to SiNPs-Ru, the prepared composite (FA-SiNPs-Ru) could not only serve as a targeted two-photon fluorescence imaging probe but also kill cancer cells via photodynamic therapy in vitro.