Utility of real-time 3D visualization system in the early stage of phacoemulsification training.

AIM: To determine the teaching effects of a real-time three dimensional (3D) visualization system in the operating room for early-stage phacoemulsification training. METHODS: A total of 10 ophthalmology residents of the first-year postgraduate were included. All the residents were novices to cataract surgery. Real-time cataract surgical observations were performed using a custom-built 3D visualization system. The training lasted 4wk (32h) in all. A modified International Council of Ophthalmology's Ophthalmology Surgical Competency Assessment Rubric (ICO-OSCAR) containing 4 specific steps of cataract surgery was applied. The self-assessment (self) and expert-assessment (expert) were performed through the microsurgical attempts in the wet lab for each participant. RESULTS: Compared with pre-training assessments (self 3.2±0.8, expert 2.5±0.6), the overall mean scores of post-training (self 5.2±0.4, expert 4.7±0.6) were significantly improved after real-time observation training of 3D visualization system (P<0.05). Scores of 4 surgical items were significantly improved both self and expert assessment after training (P<0.05). CONCLUSION: The 3D observation training provides novice ophthalmic residents with a better understanding of intraocular microsurgical techniques. It is a useful tool to improve teaching efficiency of surgical education.

Online sequential analysis of volatile and semivolatile organic compounds in water matrices by double robotic sample preparations and dual-channel mono and comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry system.

The monitoring of organic compounds in aquatic matrices poses challenges due to its complexity and time-intensive nature. To address these challenges, we introduce a novel approach utilizing a dual-channel mono (1D) and comprehensive two-dimensional (2D) gas chromatography coupled with time-of-flight mass spectrometry (GC × GC-TOFMS) system, integrated with a robotic pretreatment platform, for online monitoring of both volatile organic compounds (VOCs) and semivolatile organic compounds (SVOCs) in water matrices. Employing the robotic platform, we establish a suite of online liquid-liquid extraction (LLE) pretreatment processes for water samples, marking the first instance of such procedures. Leveraging the automatic headspace (HS) module, dual robotic preparations of HS and LLE are sequentially executed to extract VOCs and SVOCs from water matrices. The GC × GC-TOFMS system is distinguished by its dual-channel analytical column configuration, facilitating sequential analysis of VOCs in GC-TOFMS mode and SVOCs in GC × GC-TOFMS mode. Quantitative detection of 55 target VOCs and 104 SVOCs is achieved in a water sample using the instrument system. Our method demonstrates excellent correlation coefficients ranging from 0.990 to 1.000, method detection limits ranging from 0.08 to 4.78 µg L-1, relative standard deviations below 19.3 %, and recovery rates ranging from 50.0 % to 124.0 %. To validate the online monitoring capabilities of our system, we assess target SVOCs at three different concentration levels over a 3-day period. Most compounds exhibit recovery rates ranging from 70.0 % to 130.0 %. Furthermore, we apply our method to analyze a real water sample, successfully identifying over 100 target and nontarget VOCs/SVOCs, including alcohols, aldehydes, ketones, acids, esters, and phenols. These results highlight the efficacy of the proposed analysis system, capable of conducting two distinct analyses in automatic sequence, thereby enhancing the efficiency and accuracy of organic compound analysis in water matrices.

Reduced Graphene Oxide Modified Nitrogen-Doped Chitosan Carbon Fiber with Excellent Electromagnetic Wave Absorbing Performance.

Lightweight and low-cost one-dimensional carbon materials, especially biomass carbon fibers with multiple porous structures, have received wide attention in the field of electromagnetic wave absorption. In this paper, graphene-coated N-doped porous carbon nanofibers (PCNF) with excellent wave absorption properties were successfully synthesized via electrostatic spinning, electrostatic self-assembly, and high-temperature carbonization. The obtained results showed that the minimum reflection loss of the absorbing carbon fiber obtained under the carbonization condition of 800 °C is -51.047 dB, and the absorption bandwidth of reflection loss below -20 dB is 10.16 GHz. This work shows that carbonization temperature and filler content have a certain effect on the wave-absorbing properties of fiber, graphene with nanofiber, and the design and preparation of high-performance absorbing materials by combining the characteristics of graphene and nanofibers and multi-component coupling to provide new ideas for the research of absorbing materials.

Mechanisms of vemurafenib-induced anti-tumor effects in ATC FRO cells.

Background: Anaplastic Thyroid Carcinoma (ATC) is a rare and deadly malignant tumor in humans. It is prone to developing resistance to radiotherapy and chemotherapy. Molecular targeted therapy offers a novel way to treat ATC. The BRAF mutation is closely associated with many cancers, including thyroid carcinoma. Vemurafenib, a small-molecule inhibitor, is specifically designed to target the mutant serine/threonine kinase BRAF. The objective of this study is to elucidate the regulatory mechanisms underlying the effects of vemurafenib on human anaplastic thyroid carcinoma cell line FRO and to assess its potential therapeutic role. Methods: The effects of vemurafenib on the proliferation of FRO cells were assessed by the CCK-8 method and Colony-forming assay. Transwell chambers and scratch tests were employed to examine the impact of vemurafenib on the invasion and migration of FRO cells. Apoptosis and cycle distribution of FRO cells were analyzed by tunel assay and flow cytometry. The effects of vemurafenib on the expression of BRAF-activated non-protein coding RNA (BANCR), Bax, Bcl2, and E-cadherin were evaluated by qRT-PCR. Furthermore, the effects of vemurafenib on the expression of phosphoinositol-3-kinase (PI3K)/phosphoinositol-3-kinase (AKT) pathway-related proteins, BRAF, CyclinD1, Bcl-2, Bax, and E-cadherin proteins in FRO cells were investigated through the western-blot method. All experiments were conducted in three replicates. Results: Vemurafenib was observed to inhibit proliferation and induce apoptosis in a dose- and time-dependent manner (P < 0.05). The formation of FRO cell colonies, as well as migration and invasion, all showed a dose-dependent reduction (P < 0.05). Flow cytometric analysis indicated G0/G1 cell cycle arrest (P < 0.05). QRT-PCR revealed that vemurafenib could suppress the expression of BANCR and Bcl2 while increasing the expression of Bax and E-cadherin in a dose-dependent manner (P < 0.05). The protein expression levels of Bax and E-cadherin were up-regulated significantly, and the expression levels of BRAF, CyclinD1, Bcl-2, p-PI3K, p-AKT, and p-mTOR were markedly down-regulated with increasing concentrations of vemurafenib (P < 0.05). Conclusions: The proliferation and metastasis of FRO cells can be suppressed by vemurafenib through the silencing of BRAF and BANCR expression, inhibition of PI3K/AKT signaling pathway activation, induction of apoptosis, and cell cycle arrest.

Neutrophils-mediated bioinspired nanoagents for noninvasive monitoring of inflammatory recruitment dynamics and navigating phototherapy in rheumatoid arthritis.

Neutrophils play a crucial role in inflammatory immune responses, but their in vivo homing to inflammatory lesions remains unclear, hampering precise treatment options. In this study, we employed a biomineralization-inspired multimodal nanoagent to label neutrophils, enabling noninvasive monitoring of the dynamic process of inflammatory recruitment and guiding photothermal therapy in rheumatoid arthritis. Our nanoagents allowed visualization of neutrophil fate through magnetic resonance imaging, photoacoustic imaging, and fluorescence imaging in the first and second near-infrared windows. Histopathology and immunofluorescence analysis revealed pronounced inflammatory cell infiltration in rheumatoid arthritis compared to the normal limb. Furthermore, the recruitment quantity of neutrophils positively correlated with the inflammatory stage. Additionally, the inherent photothermal effect of the nanoagents efficiently ablated inflammatory cells during the optimal homing time and inflammatory phase. This neutrophil imaging-guided photothermal therapy precisely targeted inflammatory nuclei in rheumatoid arthritis and downregulated pro-inflammatory cytokines in serum. These results demonstrate that in vivo tracking of inflammatory immune response cells can significantly optimize the treatment of inflammatory diseases, including rheumatoid arthritis.

Research progress on animal models of corneal epithelial-stromal injury.

A corneal epithelial-stromal defect is recognized as a major contributor to corneal scarring. Given the rising prevalence of blindness caused by corneal scarring, increasing attention has been focused on corneal epithelial-stromal defects. Currently, the etiology and pathogenesis of these defects remain inadequately understood, necessitating further investigation through experimental research. Various modeling methods exist both domestically and internationally, each with distinct adaptive conditions, advantages, and disadvantages. This review primarily aims to summarize the techniques used to establish optimal animal models of corneal epithelial-stromal injury, including mechanical modeling, chemical alkali burns, post-refractive surgery infections, and genetic engineering. The intention is to provide valuable insights for studying the mechanisms underlying corneal epithelial-stromal injury and the development of corresponding therapeutic interventions.

In vivo clinical molecular imaging of T cell activity.

Tumor immunotherapy is refashioning traditional treatments in the clinic for certain tumors, especially by relying on the activation of T cells. However, the safety and effectiveness of many antitumor immunotherapeutic agents are suboptimal due to difficulties encountered in assessing T cell responses and adjusting treatment regimens accordingly. Here, we review advances in the clinical visualization of T cell activity in vivo, and focus particularly on molecular imaging probes and biomarkers of T cell activation. Current challenges and prospects are also discussed that aim to achieve a better strategy for real-time monitoring of T cell activity, predicting prognoses and responses to tumor immunotherapy, and assessing disease management.

Real-world effectiveness and safety of RC48-ADC alone or in combination with PD-1 inhibitors for patients with locally advanced or metastatic urothelial carcinoma: A multicenter, retrospective clinical study.

INTRODUCTION: Previous RC48 (Disitamab Vedotin) studies established that the safety and efficacy of RC48-antibody-drug conjugate (ADC), either alone or combined with toripalimab, for metastatic urothelial carcinoma (mUC) patients exhibiting human epidermal growth factor receptor 2 (HER2)-positive or even HER2-negative status after standard chemotherapy failure. METHODS: With locally advanced or metastatic urothelial carcinoma (la/mUC), patients who received RC48-ADC monotherapy or a combination with programmed cell death protein 1 (PD-1) inhibitors between August 2021 and October 2022 were enrolled in this retrospective observational study to evaluate the real-world antitumor effectiveness and safety. RESULTS: Among the 38 enrolled patients (29 males; median age 67.5 years [38-93]), 8 received RC48-ADC monotherapy, while 30 received combination therapy. Initially, 63.2% (24/38) of the patients had received ≥1 line of prior treatment, and 63.2% (24/38) had visceral metastasis. UC of the bladder represented the majority type in 68.4% (26/38) of cases. By the data cutoff in March 2023, the overall objective response rate (ORR) was 63.2% (95% CI, 47.1%-79.2%), with a disease control rate (DCR) of 89.5% (95% CI, 79.3%-99.7%). Median follow-up time was 10.6 months. The median progression-free survival (PFS) was 8.2 months (95% CI, 5.9-10.5), with a 6-month PFS rate of 63.2% and a 12-month PFS rate of 34.1%. Median overall survival (OS) was not reached, with a 12-month OS rate of 76.7%. The median duration of response was 7.3 months (95% CI, 4.6-10.0) among 24 patients evaluated as partial response (PR). The most common treatment-related adverse events (TRAEs) included anemia (71.1%), anorexia (57.9%), asthenia (52.6%), hypoesthesia (52.6%), bone marrow suppression (47.4%), alopecia (47.4%), nausea (44.7%), proteinuria (36.8%), vomiting (34.2%), and hypoalbuminemia (31.6%). No patient experienced TRAEs of Grade ≥3. One patient had an immune-related adverse event (irAE) of rash related to toripalimab. CONCLUSIONS: Both as monotherapy and in combination with PD-1 inhibitors, RC48-ADC exhibits promising effectiveness and manageable safety profile for mUC patients in real-world settings.

MicroRNA-989 targets 5-hydroxytryptamine receptor1 to regulate ovarian development and eggs production in Culex pipiens pallens.

BACKGROUND: Female mosquitoes need a blood meal after mating for their eggs to develop, and this behavior leads to the spread of pathogens. Therefore, understanding the molecular regulation of reproduction in female mosquitoes is essential to control mosquito vector populations. In this study, we reported that microRNA-989 (miR-989), which targets 5-HTR1 (encoding secreted 5-hydroxytryptamine receptor1), is essential for mosquito reproduction. METHODS: The spatiotemporal expression profile of miR-989 was detected using quantitative real-time reverse transcription PCR (RT-qPCR). miR-989 antagomirs and antagomir-negative control (NC) were designed and synthesized to knock down the expression of endogenous miR-989 in female mosquitoes. RNA sequencing was used to analyze the ovarian response to miR-989 deletion. The targets of miR-989 were predicted and confirmed using RNAhybrid and dual-luciferase assays. RESULTS: miR-989 is exclusively expressed in female mosquito ovaries and responds to blood feeding. Injection of the miR-989 antagomir resulted in smaller ovaries and reduced egg production. 5-HTR1 was demonstrated as a target of miR-989. The deletion of miR-989 contributed to the upregulation of 5-HTR1 expression. Knockdown of 5-HTR1 rescued the adverse egg production caused by miR-989 silencing. Thus, miR-989 might play an essential role in female reproduction by targeting 5-HTR1. CONCLUSIONS: We found that miR-989 targets 5-HTR1 and participates in the regulation of reproduction in female mosquitoes. These findings expand our understanding of reproduction-related miRNAs and promote new control strategies for mosquitoes.

Degradation of Levofloxacin by a green zero-valent iron-loaded carbon composite activating peroxydisulfate system: Reactivity, products and mechanism.

In this study, a green zero-valent iron-loaded carbon composite (ZVI-SCG) was synthesized using coffee grounds and FeCl3 solution through two-steps method, and the synthesized ZVI-SCG was used in the activation of peroxydisulfate (PDS) to degrade Levofloxacin (LEX). Results revealed that ZVI-SCG exhibited a great potential for LEX removal by adsorption and catalytic degradation in the ZVI-SCG/PDS system, and 99% of LEX was removed in the ZVI-SCG/PDS system within 60 min. ZVI-SCG/PDS system showed a high reactivity toward LEX degradation under realistic environmental conditions. Also, the ZVI-SCG/PDS system could effectively degrade several quinolone antibiotics including gatifloxacin, ciprofloxacin and LEX in single and simultaneous removal modes. A potential reaction mechanism of LEX degradation by ZVI-SCG/PDS system was proposed, SO4•-, HO•, O2•- and 1O2 involved in radical and non-radical pathways took part in catalytic degradation of LEX by ZVI-SCG/PDS system, but HO• might be the main reactive species for LEX degradation. The possible degradation pathway of LEX was also proposed based on the identified ten intermediate products, LEX degradation was successfully achieved through decarboxylation, opening ring and hydroxylation processes. The potential toxicity of LEX and its oxidation products decreased significantly after treatment. This study provides a promising strategy of water treatment for the antibiotics-containing wastewater.

Pyrotinib plus capecitabine for trastuzumab-resistant, HER2-positive advanced breast cancer (PICTURE): a single-arm, multicenter phase 2 trial.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer and primary resistance to trastuzumab have a poor clinical outcome and lack good evidence to inform clinical decision. This study investigated the efficacy and safety of pyrotinib plus capecitabine in this population. METHODS: This phase 2 trial was conducted at 16 sites in China. Patients received oral pyrotinib 400 mg once daily and capecitabine 1000 mg/m2 twice a day on days 1-14 of each 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: Between June 2019 and September 2021, 100 patients were enrolled with a median age of 51 years (range, 24-69). All patients had been treated with trastuzumab and 21 (21.0%) patients had prior use of pertuzumab. As of August 31, 2022, the median follow-up duration was 20.1 months (range, 1.3-38.2). The median PFS was 11.8 months (95% confidence interval [CI], 8.4-15.1), which crossed the pre-specified efficacy boundary of 8.0 months. The objective response rate was 70.0% (70/100), with a median duration of response of 13.8 months (95% CI, 10.2-19.3). The disease control rate was 87.0% (87/100). The median overall survival was not reached. The most common grade ≥ 3 treatment-emergent adverse event was diarrhea (24 [24.0%]). No treatment-related deaths occurred. CONCLUSIONS: Pyrotinib plus capecitabine can be considered to be a treatment option in HER2-positive advanced breast cancer patients who have shown primary resistance to trastuzumab. Even in the era of modern anti-HER2 treatments, this clinical setting warrants more investigations to meet unmet needs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04001621. Retrospectively registered on June 28, 2019.

Adverse effects of knocking down chitin synthase A on female reproduction in Culex pipiens pallens (Diptera: Culicidae).

BACKGROUND: Current mosquito-borne disease vector control strategies, largely based on chemical insecticides, are seriously threatened by increasing resistance worldwide. There is also growing concerned about the adverse effects of insecticides on nontarget organisms and the environment, therefore effective and ecologically friendly alternative approaches are urgently needed. Targeting critical steps of reproduction is considered a potential way to control mosquito populations. Herein, we focused on the roles of chitin synthase A (encoded by chsa) in the reproduction of female mosquitoes. RESULTS: The injection of small interfering RNA targeting Cpchsa in female Culex pipiens pallens (Diptera: Culicidae) had antireproductive effects, including decreased follicle numbers, egg-laying, and hatching rate. Scanning electron microscopy observations showed that Cpchsa silencing caused a defective egg envelope, including absence of the vitelline membrane and cracked chorion layers, which resulted in abnormal permeability. Widely distributed nurse cell apoptosis and follicular epithelial cell autophagy were observed in Cpchsa-silenced ovaries during the vitellogenesis phase. Consistent with the detective egg envelope formation during oogenesis, the exochorionic eggshell structures were also affected in eggs deposited by Cpchsa-silenced mosquitoes. CONCLUSION: This study provided fundamental evidence for the role of chitin synthase A in the female reproductive process of mosquitoes and might result in a novel alternative strategy for mosquito control. © 2023 Society of Chemical Industry.

SMSP Mainlobe Jamming Suppression with FDA-MIMO Radar Based on FastICA Algorithm.

In the electronic warfare environment, the performance of ground-based radar target search is seriously degraded due to the existence of smeared spectrum (SMSP) jamming. SMSP jamming is generated by the self-defense jammer on the platform, playing an important role in electronic warfare, making traditional radars based on linear frequency modulation (LFM) waveforms face great challenges in searching for targets. To solve this problem, an SMSP mainlobe jamming suppression method based on a frequency diverse array (FDA) multiple-input multiple-output (MIMO) radar is proposed. The proposed method first uses the maximum entropy algorithm to estimate the target angle and eliminate the interference signals from the sidelobe. Then, the range-angle dependence of the FDA-MIMO radar signal is utilized, and the blind source separation (BSS) algorithm is used to separate the mainlobe interference signal and the target signal, avoiding the impact of mainlobe interference on target search. The simulation verifies that the target echo signal can be effectively separated, the similarity coefficient can reach more than 90% and the detection probability of the radar is significantly enhanced at a low signal-to-noise ratio.

Light-initiated aggregation of gold nanoparticles for synergistic chemo-photothermal tumor therapy.

The combination of chemotherapy with photothermal therapy (PTT) has attracted extensive attention due to its excellent synergetic effect attributing to the fact that hyperthermia can effectively promote the tumor uptake of chemotherapeutic drugs. Herein, we propose a light-initiated gold nanoparticle (AuNP) aggregation boosting the uptake of chemotherapeutic drugs for enhanced chemo-photothermal tumor therapy. Novel light-responsive AuNPs (tm-AuNPs) were rationally designed and fabricated by conjugating both 2,5-diphenyltetrazole (Tz) and methacrylic acid (Ma) onto the surface of AuNPs with small size (∼20 nm). Upon the irradiation of 405 nm laser, AuNPs could be initiated to form aggregates specifically within tumors through the covalent cycloaddition reaction between Tz and Ma. Taking advantage of the controllable photothermal effect of Au aggregates under NIR excitation, improved enrichment of doxorubicin (DOX) in tumor tissues was realized, combined with PTT, resulting in outstanding synergetic anti-tumor efficacy in living mice. We thus believe that this light-initiated AuNP aggregation approach would offer a valuable and powerful tool for precisely synergistic chemo-photothermal tumor therapy.

Three-dimensional heterogeneous electro-Fenton system with reduced graphene oxide based particle electrode for Acyclovir removal.

New pollutant pharmaceutical and personal care products (PPCPs), especially antiviral drugs, have received increasing attention not only due to their increase in usage after the outbreak of COVID-19 epidemics but also due to their adverse impacts on water ecological environment. Electro-Fenton technology is an effective method to remove PPCPs from water. Novel particle electrodes (MMT/rGO/Fe3O4) were synthesized by depositing Fe3O4 nanoparticles on reduced graphene oxide modified montmorillonite and acted as catalysts to promote oxidation performance in a three-dimensional Electro-Fenton (3D-EF) system. The electrodes combined the catalytic property of Fe3O4, hydrophilicity of montmorillonite and electrical conductivity of graphene oxides, and applied for the degradation of Acyclovir (ACV) with high efficiency and ease of operation. At optimal condition, the degradation rate of ACV reached 100% within 120 min, and the applicable pH range could be 3 to 11 in the 3D-EF system. The stability and reusability of MMT/rGO/Fe3O4 particle electrodes were also studied, the removal rate of ACV remained at 92% after 10 cycles, which was just slightly lower than that of the first cycle. Potential degradation mechanisms were also proposed by methanol quenching tests and FT-ICR-MS.

Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting. METHODS: DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18-75 years, of any menopausal status, had an ECOG performance status of 0-1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov, NCT03966898, and is ongoing but closed to recruitment. FINDINGS: Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3-25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6-not reached] vs 18·2 months [16·5-22·5]; stratified hazard ratio 0·51 [95% CI 0·38-0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes). INTERPRETATION: Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape. FUNDING: Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Identification and functional analysis of ABC transporter genes related to deltamethrin resistance in Culex pipiens pallens.

BACKGROUND: Pathogens that reproduce or develop in mosquitoes can transmit several diseases, endanger human health, and overwhelm health systems. Synthetic pyrethroids are the most widely used insecticides against adult mosquitoes, but their widespread use has led to resistance. The adenosine triphosphate (ATP)-binding cassette (ABC) transporters are involved in the resistance monitoring of insects, but their role and underlying mechanisms in insecticide resistance have not been fully elucidated. In the present study, we identified ABC transporter genes in Culex pipiens and investigated their role in the development of insecticide resistance. RESULTS: We identified 63 ABC transporter genes in Cx. pipiens and classified them as per the ABC transporter subfamilies. We also performed phylogenetic analysis. The knockdown rate of the mosquitoes orally fed with the ABC transporter inhibitor verapamil increased after deltamethrin treatment compared with that of the control group. Several genes from the ABCB, ABCC, and ABCG subfamilies were highly expressed in resistant mosquitoes. Immunofluorescence analysis revealed that ABCG6032427 was expressed in the head, chest, abdomen, wings, and legs, and the expression was the highest in the legs. Subsequently, knockdown of ABCG6032427 using RNA interference (RNAi) increased the sensitivity of the mosquitoes to deltamethrin, and scanning and transmission electron microscopy revealed that ABCG6032427 knockdown reduced cuticle thickness and the cuticle became loose and irregular. CONCLUSIONS: ABCG6032427 may modulate cuticle thickness and structure, thus play an important role in the development of deltamethrin resistance in mosquitoes. Thus, it could be a potential target for deltamethrin resistance management in Cx. pipiens. © 2023 Society of Chemical Industry.

Exploration and validation of the hub genes involved in hypoxia-induced endothelial-mesenchymal transition of systemic sclerosis.

OBJECTIVES: During the development of systemic sclerosis (SSc), endothelial-mesenchymal transition (EndoMT) has been shown to be one of the mechanisms leading to pulmonary fibrosis. However, the correlation between hypoxia and EndoMT was mostly unknown. METHODS: R software was used to analyse differentially expressed genes (DEGs) in vascular endothelial cells under hypoxic conditions, and fibroblasts derived from SSc-related pulmonary fibrotic tissues, respectively. Using a web-based online Venn diagram tool, we analysed overlapping genes of DEGs between endothelial cells and fibroblasts. Finally, the protein-protein interaction network of EndoMT hub genes were constructed using the STRING database. The hub genes were knockdown by transfection of siRNAs in the hypoxia model of HULEC-5a cells constructed by liquid paraffin closure and then used to detect the effect on EndoMT-related biomarkers by western blot. RESULTS: In this study, we found that INHBA, DUSP1, NOX4, PLOD2, BHLHE40 were upregulated in SSc fibroblasts and hypoxic-treated endothelial cells, while VCAM1, RND3, CCL2, and TXNIP were downregulated. In the hypoxia model of HULEC-5a cells, the expression of these 9 hub genes was confirmed by western blot. In addition, through Spearman's correlation analysis and Western blot, we confirmed that these hub genes were closely related to the EndoMT-related markers. The mechanisms of these hypoxia-induced EndoMT hub genes may be related to TGF-ß, Notch, Wnt, NF-κ B, TNF and mTOR signalling pathways. CONCLUSIONS: Our study provides new insights into the occurrence and development of SSc-related pulmonary fibrosis resulting from hypoxia-induced EndoMT.

Toxic Effects of Perilla frutescens (L.) Britt. Essential Oil and Its Main Component on Culex pipiens pallens (Diptera: Culicidae).

Sustainable control of mosquitoes, vectors of many pathogens and parasites, is a critical challenge. Chemical insecticides are gradually losing their effectiveness because of development of resistance, and plant metabolites are increasingly being recognized as potential alternatives to chemical insecticides. This study aimed to analyze the main components of Perilla frutescens essential oil (PE-EO), investigate the specific activity of PE-EO as a botanical insecticide and mosquito repellent, and explore whether its main constituents are potential candidates for further research. The larvicidal activity assay showed that LC50 of PE-EO and 2-hexanoylfuran was 45 and 25 mg/L, respectively. In the ovicidal activity assay, both 120 mg/L PE-EO and 80 mg/L 2-hexanoylfuran could achieve 98% egg mortality. Moreover, PE-EO and 2-hexanoylfuran showed repellency and oviposition deterrence effects. Notably, 10% PE-EO maintained a high rate of protection for 360 min. Although PE-EO and its main component had certain toxic effects on zebrafish, no significant harmful effects were detected in human embryonic kidney cells. Therefore, perilla essential oil is an effective agent for mosquito control at several life stages and that its main component, 2-hexanoylfuran, is a potential candidate for developing novel plant biopesticides.

The effect of thinning intensity on the soil carbon pool mediated by soil microbial communities and necromass carbon in coastal zone protected forests.

Thinning is a common forest management measure that can effectively maintain the ecological service function of protected forests. However, the effect of thinning on the soil carbon (C) pool remains uncertain. In particular, we lack an understanding of the complete link between thinning and microbial communities, microbial necromass C, and consequently, soil C pools in coastal zone protected forests. In this study, three thinning intensities, i.e., a control treatment (CT, i.e., no thinning), light thinning (LT) and heavy thinning (HT), were established in three types of forests (Quercus acutissima Carruth, Pinus thunbergii Parl and mixed Quercus acutissima Carruth and Pinus thunbergii Parl, i.e., QAC, PTP and QP, respectively). Two years after the completion of thinning, we investigated the changes in the soil organic carbon (SOC) fractions, soil microbial community and soil microbial necromass C in the surface layer (0-20 cm) and thoroughly evaluated the relationship between the potential change in SOC and the microbial community. Compared with CT, there was no change in the SOC content under LT and HT, but thinning conducted in QAC increased the proportion of mineral-associated organic C (MAOC) in SOC. Moreover, both LT and HT reduced the soil carbon lability (CL) in the QAC and QP forests. Different thinning intensities changed the soil microbial community structure, and most of the variation was explained by thinning and the soil physicochemical properties. The proportion of soil bacterial and fungal necromass C to SOC increased with increasing thinning intensity. The content of soil bacterial and fungal necromass C was mainly controlled by the relative abundance of the core phylum (relative abundance>10 %). Thinning affected the soil C pool by affecting the content of soil bacterial and fungal necromass C, but their accumulation pathways was different. The results showed that thinning was beneficial to the stability of SOC. The microbial C pool, total organic C pool and even bacterial and fungal C pools should be distinguished when studying the soil C pool, which can effectively deepen our understanding of the mechanism by which soil microorganisms affect the soil C pool.