miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells.

JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

Revealing spatial distribution and accessibility of cell wall polymers in bamboo through chemical imaging and mild chemical treatments.

Understanding the distribution and accessibility of polymers within plant cell walls is crucial for addressing biomass recalcitrance in lignocellulosic materials. In this work, Imaging Fourier Transform Infrared (FTIR) and Raman spectroscopy, coupled with targeted chemical treatments, were employed to investigate cell wall polymer distribution in two bamboo species at both tissue and cell wall levels. Tissue-level Imaging FTIR revealed significant disparities in the distribution and chemical activity of cell wall polymers between the fibrous sheath and fibrous strand. At the cell wall level, Imaging Raman spectroscopy delineated a distinct difference between the secondary wall and intercellular layer, with the latter containing higher levels of lignin, hydroxycinnamic acid (HCA), and xylan, and lower cellulose. Mild acidified sodium chlorite treatment led to partial removal of lignin, HCA, and xylan from the intercellular layer, albeit to a lesser extent than alkaline treatment, indicating susceptibility of these polymers to chemical treatment. In contrast, lignin in the secondary wall exhibited limited reactivity to acidified sodium chlorite but was slightly removed by alkaline treatment, suggesting stable chemical properties with slight alkaline intolerance. These findings provide valuable insights into the inherent design mechanism of plant cells and their efficient utilization.

Latest insights into the global epidemiological features, screening, early diagnosis and prognosis prediction of esophageal squamous cell carcinoma.

As a highly invasive carcinoma, esophageal cancer (EC) was the eighth most prevalent malignancy and the sixth leading cause of cancer-related death worldwide in 2020. Esophageal squamous cell carcinoma (ESCC) is the major histological subtype of EC, and its incidence and mortality rates are decreasing globally. Due to the lack of specific early symptoms, ESCC patients are usually diagnosed with advanced-stage disease with a poor prognosis, and the incidence and mortality rates are still high in many countries, especially in China. Therefore, enormous challenges still exist in the management of ESCC, and novel strategies are urgently needed to further decrease the incidence and mortality rates of ESCC. Although the key molecular mechanisms underlying ESCC pathogenesis have not been fully elucidated, certain promising biomarkers are being investigated to facilitate clinical decision-making. With the advent and advancement of high-throughput technologies, such as genomics, proteomics and metabolomics, valuable biomarkers with high sensitivity, specificity and stability could be identified for ESCC. Herein, we aimed to determine the epidemiological features of ESCC in different regions of the world, especially in China, and focused on novel molecular biomarkers associated with ESCC screening, early diagnosis and prognosis prediction.

ARRB1 inhibits extracellular matrix degradation and apoptosis of nucleus pulposus cells by promoting autophagy and attenuates intervertebral disc degeneration.

OBJECTIVE: Intervertebral disc degeneration (IVDD) is the leading cause of lower back pain (LBP). ß-arrestin 1 (ARRB1) is a multifunctional protein that regulates numerous pathological processes. The aim of this study was to investigate the role of ARRB1 in IVDD. METHODS: The expression of ARRB1 in nucleus pulposus (NP) of rats with IVDD was assayed. Next, rat nucleus pulposus cells (NPCs) were infected with lentiviruses containing shArrb1 (LV-shArrb1) and overexpressing Arrb1 (LV-oeArrb1). The roles of Arrb1 in serum-deprived NPCs were investigated by measuring apoptosis, extracellular matrix degradation, and autophagic flux. For experiments in vivo, LV-oeArrb1 lentivirus was injected into the NP tissues of IVDD rats to evaluate the effects of Arrb1 overexpression on NP. RESULTS: In the NP tissues of IVDD rats, ARRB1 and cleaved caspase-3 expression increased, and the ratio of LC3II/LC3I protein expression was upregulated. Arrb1 knockdown aggravated extracellular matrix degradation, cellular apoptosis, and impairment of autophagic flux in rat NPCs under serum-deprived conditions, whereas Arrb1 overexpression significantly reversed these effects. ARRB1 interacted with Beclin 1, and Arrb1 knockdown suppressed the formation of the Beclin1-PIK3C3 core complex. The autophagy inhibitor 3-methyladenine (3-MA) offset the protective effects of Arrb1 overexpression in serum-deprived NPCs. Furthermore, Arrb1 overexpression inhibited apoptosis and extracellular matrix degradation, promoted autophagy in NP, and delayed the development of IVDD in rats. CONCLUSION: ARRB1 prevents extracellular matrix degradation and apoptosis of NPCs by upregulating autophagy and ameliorating IVDD progression, presenting an innovative strategy for the treatment of IVDD.

Molecular distinctions of bronchoalveolar and alveolar organoids under differentiation conditions.

The bronchoalveolar organoid (BAO) model is increasingly acknowledged as an ex-vivo platform that accurately emulates the structural and functional attributes of proximal airway tissue. The transition from bronchoalveolar progenitor cells to alveolar organoids is a common event during the generation of BAOs. However, there is a pressing need for comprehensive analysis to elucidate the molecular distinctions characterizing the pre-differentiated and post-differentiated states within BAO models. This study established a murine BAO model and subsequently triggered its differentiation. Thereafter, a suite of multidimensional analytical procedures was employed, including the morphological recognition and examination of organoids utilizing an established artificial intelligence (AI) image tracking system, quantification of cellular composition, proteomic profiling and immunoblots of selected proteins. Our investigation yielded a detailed evaluation of the morphologic, cellular, and molecular variances demarcating the pre- and post-differentiation phases of the BAO model. We also identified of a potential molecular signature reflective of the observed morphological transformations. The integration of cutting-edge AI-driven image analysis with traditional cellular and molecular investigative methods has illuminated key features of this nascent model.

Genetically programmable cell membrane-camouflaged nanoparticles for targeted combination therapy of colorectal cancer.

Cell membrane-camouflaged nanoparticles possess inherent advantages derived from their membrane structure and surface antigens, including prolonged circulation in the bloodstream, specific cell recognition and targeting capabilities, and potential for immunotherapy. Herein, we introduce a cell membrane biomimetic nanodrug platform termed MPB-3BP@CM NPs. Comprising microporous Prussian blue nanoparticles (MPB NPs) serving as both a photothermal sensitizer and carrier for 3-bromopyruvate (3BP), these nanoparticles are cloaked in a genetically programmable cell membrane displaying variants of signal regulatory protein α (SIRPα) with enhanced affinity to CD47. As a result, MPB-3BP@CM NPs inherit the characteristics of the original cell membrane, exhibiting an extended circulation time in the bloodstream and effectively targeting CD47 on the cytomembrane of colorectal cancer (CRC) cells. Notably, blocking CD47 with MPB-3BP@CM NPs enhances the phagocytosis of CRC cells by macrophages. Additionally, 3BP, an inhibitor of hexokinase II (HK2), suppresses glycolysis, leading to a reduction in adenosine triphosphate (ATP) levels and lactate production. Besides, it promotes the polarization of tumor-associated macrophages (TAMs) towards an anti-tumor M1 phenotype. Furthermore, integration with MPB NPs-mediated photothermal therapy (PTT) enhances the therapeutic efficacy against tumors. These advantages make MPB-3BP@CM NPs an attractive platform for the future development of innovative therapeutic approaches for CRC. Concurrently, it introduces a universal approach for engineering disease-tailored cell membranes for tumor therapy.

Inhibiting the Jahn-Teller Effect of Manganese Hexacyanoferrate via Ni and Cu Codoping for Advanced Sodium-Ion Batteries.

Manganese (Mn)-based Prussian blue analogs (PBAs) are of great interest as a prospective cathode material for sodium-ion batteries (SIBs) due to their high redox potential, easy synthesis, and low cost. However, the Jahn-Teller effect and low electrical conductivity of Mn-based PBA cause poor structure stability and unsatisfactory performance during the cycling. Herein, a novel nickel- and copper-codoped K2Mn[Fe(CN)6] cathode is developed via a simple coprecipitation strategy. The doping elements improve the electrical conductivity of Mn-based PBA by reducing the bandgap, as well as suppress the Jahn-Teller effect by stabilizing the framework, as verified by the density functional theory calculations. Simultaneously, the substitution of sodium with potassium in the lattice is beneficial for filling vacancies in the PBA framework, leading to higher average operating voltages and superior structural stability. As a result, the as-prepared Mn-based cathode exhibits excellent reversible capacity (116.0 mAh g-1 at 0.01 A g-1) and superior cycling stability (81.8% capacity retention over 500 cycles at 0.1 A g-1). This work provides a profitable doping strategy to inhibit the Jahn-Teller structural deformation for designing stable cathode material of SIBs.

A 32-Month Follow-Up Study of the Effect of APOE ε4 on the Whole Brain Connection in Young Healthy Individuals.

APOE ε4 is risk for cognitive decline even in normal aging, but its effect on the whole-brain functional connectivity (FC) among time in young adults remain elusive. This study aimed to validate the time-by-APOE ε4 interaction on brain FC of this specific population. Longitudinal changes in neuropsychological assessments and resting-state functional magnetic resonance imaging in 26 ε4 carriers and 26 matched non-ε4 carriers were measured for about 3 years. Whole-brain FC was calculated, and a full factorial design was used to compare the difference among groups. Two-sample t test was used for post-hoc analysis. Pearson's correlation analysis was conducted to investigate the relationships between FC and cognitive tests. Of 26 specially appointed ROIs, left superior temporal gyrus (TG) was most sensitive to the effect of time-by-gene interaction. Specifically, the alteration of FC was distributed between the left TG and right TG with GRF correction (voxel-P < 0.001, cluster-P < 0.05), and decreased in ε4 carriers while increased in non-ε4. The main effect of gene showed ε4 carriers has lower FC between left TG and right middle frontal gyrus as compared with non-ε4 both at baseline and follow-up study; ε4 carriers has lower FC between left TG and right supramarginal as compared with non-ε4 at baseline, but no difference in follow-up study. The time-by-APOE ε4 interaction on brain FC was demonstrated at a young age, and left TG was the earliest affected brain regions. The young adult ε4 carriers experience decreased FC among time in the absence overt clinical symptoms.

Cholesterol-Dependent Membrane Deformation by Metastable Viral Capsids Facilitates Entry.

Nonenveloped viruses employ unique entry mechanisms to breach and infect host cells. Understanding these mechanisms is crucial for developing antiviral strategies. Prevailing perspective suggests that nonenveloped viruses release membrane pore-forming peptides to breach host membranes. However, the precise involvement of the viral capsid in this entry remains elusive. Our study presents direct observations elucidating the dynamically distinctive steps through which metastable reovirus capsids disrupt host lipid membranes as they uncoat into partially hydrophobic intermediate particles. Using both live cells and model membrane systems, our key finding is that reovirus capsids actively deform and permeabilize lipid membranes in a cholesterol-dependent process. Unlike membrane pore-forming peptides, these metastable viral capsids induce more extensive membrane perturbations, including budding, bridging between adjacent membranes, and complete rupture. Notably, cholesterol enhances subviral particle adsorption, resulting in the formation of pores equivalent to the capsid size. This cholesterol dependence is attributed to the lipid condensing effect, particularly prominent at an intermediate cholesterol level. Furthermore, our results reveal a positive correlation between membrane disruption extent and efficiency of viral variants in establishing infection. This study unveils the crucial role of capsid-lipid interaction in nonenveloped virus entry, providing new insights into how cholesterol homeostasis influences virus infection dynamics.

Dynamic changes in key factors of the blood-brain barrier in early diabetic mice.

Chronic hyperglycemia can result in damage to the hippocampus and dysfunction of the blood-brain barrier (BBB), potentially leading to neurological disorders. This study examined the histological structure of the hippocampus and the expression of critical genes associated with the BBB at 2 early stage time points in a streptozotocin-induced diabetes mellitus (DM) mouse model. Routine histology revealed vascular congestion and dilation of Virchow-Robin spaces in the hippocampal CA1 region of the DM group. Neuronal alterations included rounding and swelling and reduction in Nissl bodies and increased apoptosis. Compared to the control group, TJP1 mRNA expression in the DM group was significantly lower (P < .05 or P < .01), while mRNA levels of JAM3, TJP3, CLDN5, CLDN3, and OCLN initially increased and then decreased. At 7, 14, and 21 days, mRNA levels of the receptor for advanced glycation end products (AGER) were greater in the DM group than in the control group (P < .05 or P < .01). These findings indicate that early-stage diabetes may cause structural and functional impairments in hippocampal CA1 in mice. These abnormalities may parallel alterations in the expression of key BBB tight junction molecules and elevated AGER expression in early DM patients.

The efficacy of the combination of venetoclax and hypomethylating agents versus HAG agents in patients with acute myeloid leukemia: a retrospective study.

OBJECTIVES: The purpose of this study was to compare the effectiveness of the combination of venetoclax and hypomethylating agents with the HAG regimen. METHODS: We studied 52 cases of newly diagnosed AML and 26 cases of relapsed refractory AML, (including AML patients with treatment-related and ELN-adverse risk disease (n = 50)). These patients were treated with venetoclax and hypomethylating agents and HAG regimens, respectively. RESULTS: Twenty-nine patients newly diagnosed with acute myeloid leukemia were treated with VEN-HMA (venetoclax-hypomethylating agent), while 23 patients were treated with HAG. The median age of the VEN-HMA group was 70 years, while the HAG group had a median age of 69 years. The VEN-HMA group achieved a significantly higher rate of complete remission (82.7%) compared to the cohort treated with the HAG regimen (21.7%) (P < 0.001). At the same time, the VEN-HMA group exhibited a significant survival advantage compared to the HAG treatment group(HR = 0.328, 95%CI: 0.158-0.683, P = 0.003).In patients with relapsed and refractory acute myeloid leukaemia, 43.8% of patients in the VEN-HMA treatment group achieved complete remission, which was similar to the 50% in the HAG treatment group (P > 0.99). The median overall survival was similar between the VEN-HMA and HAG groups, with 4 and 3.67 months, respectively (P = 0.290). CONCLUSIONS: In conclusion, our analyses indicated that VEN-HMA resulted in better therapeutic outcomes compared to HAG for newly diagnosed AML patients, with higher rates of complete remission and overall survival. In relapsed/refractory AML patients, there was no significant difference in the efficacy of the two treatments and further studies with larger sample sizes are warranted.

Global Emergence and Genomic Epidemiology of blaNDM-Carrying Klebsiella variicola.

Purpose: Klebsiella variicola has emerged as a human pathogen in the past decade. Here, we present findings related to a K. variicola strain carrying the blaNDM-1 gene, which was isolated from a urinary tract infection in China. Global transmission dynamics and genomic epidemiology of blaNDM-carrying K. variicola were further investigated. Material and Methods: The complete genome sequence of the strain was determined using the Illumina NovaSeq 6000 and Nanopore MinION sequencer. Genomic features and resistance mechanisms were analyzed through diverse bioinformatics approaches. Additionally, genome sequences of K. variicola strains carrying blaNDM were retrieved from the NCBI database, and a comprehensive analysis of the global dissemination trends of these strains was conducted. Results: K. variicola strain 353 demonstrated resistance to multiple antimicrobials, including carbapenems. Within its genome, we identified fourteen antimicrobial resistance genes associated with ß-lactam, aminoglycoside, fosfomycin, quinolone, trimethoprim, rifamycin, and sulfonamide resistance. The carbapenem-resistant gene blaNDM-1 was located on an IncU-type plasmid spanning 294,608 bp and flanked by ISCR1 and IS26. Downstream of blaNDM-1, we identified an Intl1 element housing numerous antibiotic resistance genes. A comprehensive search of the NCBI database revealed 72 K. variicola strains carrying blaNDM from twelve different countries, predominantly from clinical sources, with the highest prevalence observed in the USA and China. A total of 28 distinct sequence types (STs) were identified, with ST115 being the most prevalent, followed by ST60. Conclusion: In summary, this study presents the genomic characterization of a K. variicola strain carrying blaNDM-1 on an IncU-type plasmid. The research highlights the global dissemination of blaNDM-carrying K. variicola, observed in both healthcare settings and natural environments. Our data have revealed a diverse array of antimicrobial resistance determinants in K. variicola, providing valuable insights that could aid in the development of strategies for the prevention, diagnosis, and treatment of K. variicola infections.

Andrographolide Attenuates NLRP3 Inflammasome Activation and Airway Inflammation in Exacerbation of Chronic Obstructive Pulmonary Disease.

Purpose: The aim of this study is to uncover the anti-inflammatory propertity of andrographolide (AGP) in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and the underlying mechanisms related to the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome pathway. Methods: An in vivo experiment was conducted on murine model of AECOPD through endotracheal atomization of elastase and lipopolysaccharide (LPS). Intraperitoneal AGP was administered four times. NLRP3 inflammasome pathway molecules were examined using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. By using enzyme-linked immunosorbent assay (ELISA), we tested interleukin (IL)-1ß levels in bronchoalveolar lavage fluid. An in vitro study was conducted to determine how AGP impacts the NLRP3 inflammasome in THP-1 derived macrophages. The levels of molecules involved in the pathway were measured. Furthermore, molecular docking analyses were carried out to investigate the interactions between AGP and pathway targets. Results: In the in vivo study, NLRP3 inflammasome activation was observed in mice experiencing AECOPD. The administration of high-dose AGP demonstrated a mitigating effect on inflammatory cells infiltration in the lungs. Moreover, AGP administration effectively suppressed the expression of NLRP3, apoptosis associated speck-like protein that contains a CARD (PYCARD), cysteinyl aspartate-specific protease-1 (Caspase-1), IL-1ß, and IL-18 at both the genetic and protein levels. In the in vitro experiment, IL-1ß levels were significantly elevated in THP-1 derived macrophages with activated inflammasome compared to the control group. Furthermore, the downregulation of NLRP3, CASP1, and IL1B genes was observed upon the inhibition of NLRP3 expression through small interfering RNA (siRNA). AGP demonstrated inhibitory effects on the gene expression and protein levels of NLRP3, Caspase-1, and IL-1ß. Additionally, molecular docking analysis confirmed that AGP exhibited a favorable binding affinity with all five targets of the pathway. Conclusion: AGP effectively inhibited NLRP3 inflammasome activation and mitigated the inflammatory reaction of AECOPD both in animal models and in vitro experiments, highlighting the potential of AGP as a treatment for AECOPD with anti-inflammatory properties.

Abnormal expression of serum miR-4746-5p in liver cancer patients after interventional chemotherapy and its possible mechanism.

Interventional chemotherapy is a common operation in the clinical treatment of liver cancer. The aim of this study was to investigate the expression and molecular mechanism of serum miR-4746-5p in liver cancer patients before and after interventional chemotherapy. The levels of miR-4746-5p and CDKN1C in serum samples from liver cancer patients were detected using real-time fluorescence quantitative polymerase chain reaction. Receiver operating characteristic curves revealed the diagnostic value of miR-4746-5p in tumors. Differences in clinical indicators between liver cancer patients and healthy controls were assessed using Pearson correlation analysis. Luciferase reporter gene assays confirmed the targeted interaction between miR-4746-5p and CDKN1C. In vitro cellular assays were validated by Cell Counting Kit-8, Transwell assay, and chemoresistance assay. Serum miR-4746-5p levels were increased in liver cancer patients but were downregulated after chemotherapy intervention. CDKN1C expression showed the opposite trend. Low levels of miR-4746-5p mediated cell growth and metastasis by targeting and negatively regulating CDKN1C expression, while silencing CDKN1C restored cell activity. Inhibition of miR-4746-5p reduced chemoresistance, while downregulation of CDKN1C affected cell sensitivity. miR-4746-5p may be a potential therapeutic factor for liver cancer diagnosis and interventional chemotherapy.

A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.

[Determination of nine components of fried Ziziphi Spinosae Semen extract in beagle dog plasma by UPLC-MS/MS and its application in pharmacokinetic research].

This study established a convenient, rapid, and sensitive ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of magnoflorine,(R)-coclaurine, vicenin Ⅱ, isospinosin, spinosin, swertisin, N-nornuciferine, 6-feruloylspinosin, and jujuboside B in beagle dog plasma after oral administration of fried Ziziphi Spinosae Semen(FZSS) extract. The Waters HSS-T3 C_(18) column(2.1 mm×100 mm, 1.8 µm) was used. The methanol-aqueous solution(containing 0.01% formic acid) was adopted as the mobile phase for gradient elution. The nine components and two internal standards were completely separated within 8 min. The mass spectrometry detection was performed in multiple reaction monitoring(MRM) mode by positive and negative ion switching of electrospray ionization. The analytical method was validated in terms of specificity, selectivity, linear range, accuracy, precision, recovery, matrix effect, and stability. It could meet the requirement of pharmacokinetic research after oral administration of FZSS extract to beagle dogs. The results showed that the time to reach the peak concentration(T_(max)) of magnoflorine,(R)-coclaurine, vicenin Ⅱ, isospinosin, spinosin, 6-feruloylspinosin, and jujuboside B was 2.40-3.20 h, and the elimination halflife(t_(1/2)) was 2.08-6.79 h after a single-dose oral administration of FZSS to beagle dogs. The exposure of magnoflorine and spinosin was high, with a peak concentration(C_(max)) of 76.7 and 31.5 ng·mL~(-1) and an area under the curve(AUC_(0-∞)) of 581 and 315 ng·h·mL~(-1), respectively. The exposure of the remaining five compounds was lower, with a C_(max) of 0.81-13.0 ng·mL~(-1) and an AUC_(0-∞) of 6.00-106 ng·h·mL~(-1). This study provides a reference for the follow-up research of FZSS.

Multiomics and biotechnologies for understanding and influencing cadmium accumulation and stress response in plants.

Cadmium (Cd) is one of the most toxic heavy metals faced by plants and, additionally, via the food chain, threatens human health. It is principally dispersed through agro-ecosystems via anthropogenic activities and geogenic sources. Given its high mobility and persistence, Cd, although not required, can be readily assimilated by plants thereby posing a threat to plant growth and productivity as well as animal and human health. Thus, breeding crop plants in which the edible parts contain low to zero Cd as safe food stuffs and harvesting shoots of high Cd-containing plants as a route for decontaminating soils are vital strategies to cope with this problem. Recently, multiomics approaches have been employed to considerably enhance our understanding of the mechanisms underlying (i) Cd toxicity, (ii) Cd accumulation, (iii) Cd detoxification and (iv) Cd acquisition tolerance in plants. This information can be deployed in the development of the biotechnological tools for developing plants with modulated Cd tolerance and detoxification to safeguard cellular and genetic integrity as well as to minimize food chain contamination. The aim of this review is to provide a current update about the mechanisms involved in Cd uptake by plants and the recent developments in the area of multiomics approach in terms of Cd stress responses, as well as in the development of Cd tolerant and low Cd accumulating crops.

Effectiveness of high-risk human papillomavirus genotyping for cervical cancer screening. A multicentre screening cohort study in rural China.

BACKGROUND: This study aimed to assess the effectiveness of high-risk human papillomavirus (HR-HPV) primary testing for cervical cancer screening in China's rural areas. METHODS: Women aged 21-64 years were recruited. Cervical cytology was diagnosed following the Bethesda 2001 classification system, HPV infection (HR-HPV, HPV-16, HPV-18, and other 12 genotypes) identified by Cobas-4800, and colposcopy and biopsy performed when required. Primary outcomes were defined as the cumulative incidence of cervical intraepithelial neoplasia grade 2/3/higher (CIN2/3+) and its relative risk at baseline and at the 36-month follow-up. RESULTS: The study included 9,218 women; mean age was 45.15 years (SD: 8.74); 81% completed the follow-up. The most frequent type of cytological lesions (12.4% ) were ASCUS (8.4%) and LSIL (2.2%). HR-HPV infection (16.3%) was more prevalent in HPV-16 than in HPV-18 (3 vs 1.5%); a positive relationship with the severity of the lesions, from 29.8% in ASCUS to 89.6% in HSIL was found. At baseline, 3.5% of the patients underwent colposcopy; 20% had a positive diagnosis. At the 36-month follow-up, the cumulative incidences of CIN2+ and CIN3+ were higher in women with HR-HPV infection (16.9 vs 0.5% and 8.2 vs 0.2%). The relative risk of CIN2/3+ was lower in HR-HPV-negative women compared to those with a negative cytology at baseline (0.4; 95%CI: 0.3-0.4). CONCLUSIONS: High-risk HPV-based screening may significantly reduce the risk of CIN2/3+ compared with cytology testing. This may be a new resource for public health demands in China's rural areas.

Charge Transport Approaches in Photocatalytic Supramolecular Systems Composing of Semiconductor and Molecular Metal Complex for CO2 Reduction.

The design of photocatalytic supramolecular systems composing of semiconductors and molecular metal complexes for CO2 reduction has attracted increasing attention. The supramolecular system combines the structural merits of semiconductors and metal complexes, where the semiconductor harvests light and undertakes the oxidative site, while the metal complex provides activity for CO2 reduction. The intermolecular charge transfer plays crucial role in ensuring photocatalytic performance. Here, we review the progress of photocatalytic supramolecular systems in reduction of CO2 and highlight the interfacial charge transfer pathways, as well as their state-of-the-art characterization methods. The remaining challenges and prospects for further design of supramolecular photocatalysts are also presented.

Effect of Insertional Direction of Pedicle Screw on Screw Loosening: A Biomechanical Study on Synthetic Bone Vertebra under a Physiology-like Load.

OBJECTIVES: It is now understood that pedicle screw loosening at the implant-bone interface can lead to poor screw-bone interface purchase and decreased fixation stability. Previous biomechanical tests used cadaveric vertebrae and pull-out or torque loads to assess the effect of the insertional direction of pedicle screws on screw loosening. However, these tests faced challenges in matching biomechanical differences among specimens and simulating in vivo loads applied on pedicle screws. This study aimed to evaluate the effect of the insertional direction of pedicle screws on screw loosening using tension-compression-bending loads and synthetic bone vertebrae. METHODS: Polyaxial pedicle screws were inserted into nine synthetic bone vertebrae in three directions (three samples per group): cranial, parallel, and caudad (-10°, 0°, +10° of the pedicle screw rod to the upper plane of the vertebra, respectively). Pedicle screws in the vertebrae were loaded using a polyethylene block connected to a material testing machine. Tension-compression-bending loads (100N-250N) with 30,000 cycles were applied to the pedicle screws, and displacements were recorded and then cycle-displacement curve was drawn based on cycle number. Micro-CT scans were performed on the vertebrae after removing the pedicle screws to obtain images of the screw hole, and the screw hole volume was measured using imaging analysis software. Direct comparison of displacements was conducted via cycle-displacement curve. Screw hole volume was analyzed using analysis of variance. The correlation between the displacement, screw hole volume and the direction of pedicle screw was assessed by Spearman correlation analysis. RESULTS: The smallest displacements were observed in the caudad group, followed by the parallel and cranial groups. The caudad group had the smallest screw hole volume (p < 0.001 and p = 0.009 compared to the cranial and parallel groups, respectively), while the volume in the parallel group was greater than that in the cranial group (p = 0.003). Correlation analysis revealed that the insertional direction of the pedicle screw was associated with the displacement (p = -0.949, p < 0.001) and screw hole volume (p = -0.944, p < 0.001). CONCLUSION: Strong correlations were found between the insertional direction of the pedicle screw and relevant parameters, including displacement and screw hole volume. Pedicle screw insertion in the caudad direction resulted in the least pedicle screw loosening.