Evaluation of Influences of Changed Lower Cover Geometry on Kerosene-Air Interaction in a Scramjet Combustor.

The fuel in a scramjet combustor must be injected into a high-speed crossflow and mixed with supersonic air in a very short period of time in order for the scramjet jet to operate reliably. More generally, the supersonic air is produced by the lower cover, similar to a Laval type nozzle, of the scramjet combustor. However, significant variation in lower cover geometry is prone to produce unstable vortexes. The unstable vortexes are accompanied by nonuniform stress and strain and are detrimental to the lower cover, even to the combustor. Inspired by mechanical design, this study proposes to change lower cover geometry by decreasing its sizes and then evaluates effects of these changes on kerosene fuel-air interaction in the combustor. The evaluation is based on three-dimensional computational fluid dynamics with couple level set and volume of fluids, which characterizes the penetration height, span expansion area, shock wave angle, and Sauter mean diameter of kerosene jets for three different injection diameters (0.5, 1.0, and 1.5 mm). The simulated air-kerosene interactions reasonably agree with the past numerical findings at identical working conditions. This result demonstrates the effectiveness of the changed lower cover geometry for the scramjet combustor.

Preoperative computed tomography-guided localization for pulmonary nodules: comparison between hook-wire and anchored needle localization.

Introduction: Both hook-wire (HW) and anchored needle (AN) techniques can be used for preoperative computed tomography (CT)-guided localization for pulmonary nodules (PNs). But the outcomes associated with these two materials remain unclear. Aim: To assess the relative safety and efficacy of preoperative CT-guided HW and AN localization for PNs. Material and methods: This was a retrospective analysis of data collected from two institutions. Consecutive patients with PNs between January 2020 and December 2021 who underwent preoperative CT-guided HW or AN localization followed by video-assisted thoracoscopic surgery (VATS) procedures were included in these analyses, which compared the safety and clinical efficiency of these two localization strategies. Results: In total, 98 patients (105 PNs) and 93 patients (107 PNs) underwent CT-guided HW and AN localization procedures, respectively. The HW and AN groups exhibited similar rates of successful PN localization (95.2% vs. 99.1%, p = 0.117), but the dislodgement rate in the HW group was significantly higher than that for the AN group (4.8% vs. 0.0%, p = 0.029). The mean pain score of patients in the HW group was significantly higher than that for the AN group (p = 0.001). HW and AN localization strategies were associated with comparable pneumothorax (21.4% vs. 16.1%, p = 0.349) and pulmonary hemorrhage (29.6% vs. 23.7%, p = 0.354) rates. All patients other than 1 individual in the HW group successfully underwent VATS-guided limited resection. Conclusions: These data suggest that AN represents a safe, well-tolerated, feasible preoperative localization strategy for PNs that may offer value as a replacement for HW localization.

EC-YOLO: Improved YOLOv7 Model for PCB Electronic Component Detection.

Electronic components are the main components of PCBs (printed circuit boards), so the detection and classification of ECs (electronic components) is an important aspect of recycling used PCBs. However, due to the variety and quantity of ECs, traditional target detection methods for EC classification still have problems such as slow detection speed and low performance, and the accuracy of the detection needs to be improved. To overcome these limitations, this study proposes an enhanced YOLO (you only look once) network (EC-YOLOv7) for detecting EC targets. The network uses ACmix (a mixed model that enjoys the benefits of both self-attention and convolution) as a substitute for the 3 × 3 convolutional modules in the E-ELAN (Extended ELAN) architecture and implements branch links and 1 × 1 convolutional arrays between the ACmix modules to improve the speed of feature retrieval and network inference. Furthermore, the ResNet-ACmix module is engineered to prevent the leakage of function data and to minimise calculation time. Subsequently, the SPPCSPS (spatial pyramid pooling connected spatial pyramid convolution) block has been improved by replacing the serial channels with concurrent channels, which improves the fusion speed of the image features. To effectively capture spatial information and improve detection accuracy, the DyHead (the dynamic head) is utilised to enhance the model's size, mission, and sense of space, which effectively captures spatial information and improves the detection accuracy. A new bounding-box loss regression method, the WIoU-Soft-NMS method, is finally suggested to facilitate prediction regression and improve the localisation accuracy. The experimental results demonstrate that the enhanced YOLOv7 net surpasses the initial YOLOv7 model and other common EC detection methods. The proposed EC-YOLOv7 network reaches a mean accuracy (mAP@0.5) of 94.4% on the PCB dataset and exhibits higher FPS compared to the original YOLOv7 model. In conclusion, it can significantly enhance high-density EC target recognition.

Stably suppressing laser relative intensity noise on a 3 × 3 coupler interferometric system.

A 3 × 3 coupler multiphase demodulation scheme is proposed to eliminate the impact of working point drifting and the laser relative intensity noise (RIN) on a 3 × 3 coupler interferometric system. An ellipse-fitting algorithm (EFA) is applied to fit the two interference signals of the 3 × 3 coupler in order, then the ATAN algorithm is applied to obtain three noise-containing signals with specific trigonometric relationships. By averaging the three signals, the demodulated phase noise induced from RIN can be effectively eliminated. The experimental results show that compared with the asymmetric demodulation scheme without intensity noise control, the noise floor of the proposed scheme decreases from 4.5 to 1 µrad/√Hz at 1 kHz and 2.7 to 0.8 µrad/√Hz at 3 kHz. At high frequencies, the average noise floor level is reduced from 10 to 0.9 µrad/√Hz, a reduction of about 21 dB. Furthermore, the variation range of the average noise floor is reduced from 5.4 to 0.17 µrad /√Hz within 100 s.

Dual-Drug Nanomedicine Assembly with Synergistic Anti-Aneurysmal Effects via Inflammation Suppression and Extracellular Matrix Stabilization.

Abdominal aortic aneurysm (AAA) represents a critical cardiovascular condition characterized by localized dilation of the abdominal aorta, carrying a significant risk of rupture and mortality. Current treatment options are limited, necessitating novel therapeutic approaches. This study investigates the potential of a pioneering nanodrug delivery system, RAP@PFB, in mitigating AAA progression. RAP@PFB integrates pentagalloyl glucose (PGG) and rapamycin (RAP) within a metal-organic-framework (MOF) structure through a facile assembly process, ensuring remarkable drug loading capacity and colloidal stability. The synergistic effects of PGG, a polyphenolic antioxidant, and RAP, an mTOR inhibitor, collectively regulate key players in AAA pathogenesis, such as macrophages and smooth muscle cells (SMCs). In macrophages, RAP@PFB efficiently scavenges various free radicals, suppresses inflammation, and promotes M1-to-M2 phenotype repolarization. In SMCs, it inhibits apoptosis and calcification, thereby stabilizing the extracellular matrix and reducing the risk of AAA rupture. Administered intravenously, RAP@PFB exhibits effective accumulation at the AAA site, demonstrating robust efficacy in reducing AAA progression through multiple mechanisms. Moreover, RAP@PFB demonstrates favorable biosafety profiles, supporting its potential translation into clinical applications for AAA therapy.

A prediction nomogram for fractured vertebra re-collapse after posterior reduction and pedicle screw fixation in thoracolumbar fractures.

OBJECTIVE: This study aimed to establish a predictive nomogram model for re-collapse of fractured vertebra after posterior pedicle screw fixation in thoracolumbar fractures (TLFs). METHODS: Patients undergoing posterior pedicle screw fixation for TLFs at our hospital between January 2016 and December 2021 were retrospectively reviewed. Patients were divided into two groups according to the presence or absence of re-collapse of the fractured vertebra at the final follow-up. The predictors for fractured vertebra re-collapse were identified by univariate and multivariable logistic regression analysis, and a nomogram model was developed. The prediction performance and internal validation were established. RESULTS: A total of 224 patients were included in this study. Of these, 46 (20.5%) patients developed re-collapse of fractured vertebra. Age, thoracic and lumbar injury severity score (TLICS), screw distribution in the fractured vertebra, and anterior vertebral height compression (AVHC) ratio were associated with vertebral re-collapse. These predictors were used to construct a predictive nomogram. The area under the receiver operating characteristic curve (AUC) of the nomogram model was 0.891. The concordance index (C-index) was 0.891, and it was 0.877 with bootstrapping validation. The calibration curves and decision curve analysis (DCA)also suggested that the nomogram model had excellent predictive performances for fractured vertebra re-collapse. CONCLUSIONS: A clinical nomogram incorporating four variables was constructed to predict fractured vertebra re-collapse after posterior pedicle screw fixation for TLFs. The nomogram demonstrated good calibration and discriminative abilities, which may help clinicians to make better treatment decisions.

SiO 2 Induces Iron Overload and Ferroptosis in Cardiomyocytes in a Silicosis Mouse Model.

Objective: The aim of this study was to explore the role and mechanism of ferroptosis in SiO 2-induced cardiac injury using a mouse model. Methods: Male C57BL/6 mice were intratracheally instilled with SiO 2 to create a silicosis model. Ferrostatin-1 (Fer-1) and deferoxamine (DFO) were used to suppress ferroptosis. Serum biomarkers, oxidative stress markers, histopathology, iron content, and the expression of ferroptosis-related proteins were assessed. Results: SiO 2 altered serum cardiac injury biomarkers, oxidative stress, iron accumulation, and ferroptosis markers in myocardial tissue. Fer-1 and DFO reduced lipid peroxidation and iron overload, and alleviated SiO 2-induced mitochondrial damage and myocardial injury. SiO 2 inhibited Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes, while Fer-1 more potently reactivated Nrf2 compared to DFO. Conclusion: Iron overload-induced ferroptosis contributes to SiO 2-induced cardiac injury. Targeting ferroptosis by reducing iron accumulation or inhibiting lipid peroxidation protects against SiO 2 cardiotoxicity, potentially via modulation of the Nrf2 pathway.

Role of Trace Cadmium Exposure on the Development of Occlusal Traumatic Temporomandibular Arthritis.

OBJECTIVE: To investigate whether heavy metal cadmium acts as a risk factor for temporomandibular joint disorder disease and to study its pathogenic mechanism. METHODS: A total of 57 rats were allocated into 6 distinct groups, distinguished by 2 interventions: occlusal elevation and cadmium water gavage. These groups included a blank control group, occlusal elevation group, occlusal elevation + 0.42 mg/mL cadmium water gavage group, occlusal elevation + 4.2 mg/mL cadmium water gavage group, no occlusal elevation + 0.42 mg/mL cadmium water gavage group, and no occlusal elevation + 4.2 mg/mL cadmium water gavage group. The impact of cadmium exposure on cartilage oxidative stress was evaluated through the assessment of SOD, CAT, GST, and GSH-Px enzyme activities. In addition, the influence of cadmium exposure on alterations in the extracellular matrix and inflammatory mediators was examined by analyzing the expression levels of type II collagen, protein aggregation polysaccharide, glycosaminoglycan, IL1ß, IL-6, and TNF-α. Histologic examination of the condylar process cartilage of rats in the occlusal elevation + cadmium water gavage group was conducted to ascertain the occurrence of osteoarthritis. RESULTS: The variance in the expression levels of inflammatory factors did not demonstrate statistical significance between the occlusal elevation group and the blank control group; however, statistical significance was observed between the occlusal elevation + cadmium water gavage group and both the control and occlusal elevation groups. CONCLUSION: The severity of inflammation and condylar lesions correlates directly with the concentration of cadmium.

Population structure and selection signal analysis of indigenous sheep from the southern edge of the Taklamakan Desert.

Analyzing the genetic diversity and selection characteristics of sheep (Ovis aries) holds significant value in understanding their environmental adaptability, enhancing breeding efficiency, and achieving effective conservation and rational utilization of genetic resources. In this study, we utilized Illumina Ovine SNP 50 K BeadChip data from four indigenous sheep breeds from the southern margin of the Taklamakan Desert (Duolang sheep: n = 36, Hetian sheep: n = 74, Kunlun sheep: n = 27, Qira black sheep: n = 178) and three foreign meat sheep breeds (Poll Dorset sheep: n = 105, Suffolk sheep: n = 153, Texel sheep: n = 150) to investigate the population structure, genetic diversity, and genomic signals of positive selection within the indigenous sheep. According to the Principal component analysis (PCA), the Neighbor-Joining tree (NJ tree), and Admixture, we revealed distinct clustering patterns of these seven sheep breeds based on their geographical distribution. Then used Cross Population Extended Haplotype Homozygosity (XP-EHH), Fixation Index (FST), and Integrated Haplotype Score (iHS), we identified a collective set of 32 overlapping genes under positive selection across four indigenous sheep breeds. These genes are associated with wool follicle development and wool traits, desert environmental adaptability, disease resistance, reproduction, and high-altitude adaptability. This study reveals the population structure and genomic selection characteristics in the extreme desert environments of native sheep breeds from the southern edge of the Taklimakan Desert, providing new insights into the conservation and sustainable use of indigenous sheep genetic resources in extreme environments. Additionally, these findings offer valuable genetic resources for sheep and other mammals to adapt to global climate change.

Smell loss is associated with cognitive impairment in amyotrophic lateral sclerosis patients.

BACKGROUND: Smell loss significantly impacts the quality of life in patients. However, there is limited research on smell loss in individuals with amyotrophic lateral sclerosis (ALS), and the correlation between smell loss and cognitive impairment is unclear. This study aimed to investigate the correlation between smell loss and cognition impairment in ALS patients. METHODS: The study included 216 ALS patients. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and smell identification test specifically for the Chinese population (CSIT) were administered to evaluate participants' cognitive and olfactory function, respectively. RESULTS: After covarying for age, sex, BMI, education level, degree of hunger, dietary bias, eagerness for food, stress, smoking status, alcohol consumption, and upper respiratory tract infection (URTI) or rhinitis, CSIT scores were significantly correlated with ECAS scores (r = 0.162, p = 0.028), especially the ALS-specific scores (r = 0.158, p = 0.031). Even after excluding patients with URTI or rhinitis, the results were similar. CSIT scores were significantly correlated with ECAS scores (r = 0.224, p = 0.011), especially the ALS-specific scores (r = 0.205, p = 0.019). CONCLUSION: In patients with ALS, smell loss is significantly correlated with cognitive impairment, particularly frontotemporal dysfunction. Cognitive dysfunction may lead to worse olfactory performance in ALS patients.

Effectiveness of Low-level Red Light for Controlling Progression of Myopia in Children and Adolescents.

OBJECTIVE: To evaluate the effectiveness of low-level red light (LRL) in controlling the progression of myopia in children and adolescents. METHODS: A randomized controlled trial was conducted from March 2022 to June 2022 at the Xuzhou First People's Hospital. A total of 73 children and adolescents with myopia, between the ages of 6 and 14, and meeting the inclusion criteria, were randomly divided into two groups. The experimental group wore single vision spectacles with LRL intervention, while the control group wore single vision spectacles alone. Spherical equivalent refraction (SER), axial length (AL), subfoveal choroidal thickness (SFCT), and best-corrected visual acuity (BCVA) were measured for the participants. Data analysis was performed using chi-square test, independent samples t-test, and Mann-Whitney U test. To compare the changes in SER and AL between groups, we utilized the Generalized Estimating Equations (GEE) model. RESULTS: The experimental group was composed of 36 individuals, while the control group had 37. The mean age of the participants was 8.9 ± 2.0 years. No statistically significant distinctions in SER, AL and SFCT were observed between the two groups at baseline (P > 0.05). After 6 months of intervention, the experimental group's increase in SER (-0.01D; 95% CI: -0.09, 0.06) was higher than that of the control group (-0.41D; 95% CI: -0.51, -0.32), with a significance level of P < 0.001. Furthermore, the changes over time revealed significant differences between the two groups (Wald χ2group×time: 31.576, P < 0.001). The experimental group's AL increase (-0.02mm; 95% CI: -0.07, 0.03) was less than the control group's (0.22mm; 95% CI: 0.19, 0.25) (P < 0.001), with a significant difference over time between them (wald χ2group×time: 62.305, P < 0.001). SFCT change after 6 months in the experimental group was significantly greater (29.19µm; 95% CI: 18.48, 39.91) compared to that of the control group (-6.59µm; 95% CI: -14.28, 1.09) (P < 0.001). No adverse events were observed, and there was no evidence of fundus structural damage on OCT imaging. CONCLUSIONS: The findings suggest that low-level red light can effectively control myopia progression in children and adolescents within 6 months. No adverse reactions were observed.

Increasing GSH-Px Activity and Activating Wnt Pathway Promote Fine Wool Growth in FGF5-Edited Sheep.

Fibroblast growth factor 5 (FGF5) plays key roles in promoting the transition from the anagen to catagen during the hair follicle cycle. The sheep serves as an excellent model for studying hair growth and is frequently utilized in various research processes related to human skin diseases. We used the CRISPR/Cas9 system to generate four FGF5-edited Dorper sheep and only low levels of FGF5 were detected in the edited sheep. The density of fine wool in GE sheep was markedly increased, and the proportion of fine wool with a diameter of 14.4-20.0 µm was significantly higher. The proliferation signal in the skin of gene-edited (GE) sheep was stronger than in wild-type (WT) sheep. FGF5 editing decreased cortisol concentration in the skin, further activated the activity of antioxidant enzymes such as Glutathione peroxidase (GSH-Px), and regulated the expression of Wnt signaling pathways containing Wnt agonists (Rspondins, Rspos) and antagonists (Notum) in hair regeneration. We suggest that FGF5 not only mediates the activation of antioxidant pathways by cortisol, which constitutes a highly coordinated microenvironment in hair follicle cells, but also influences key signals of the Wnt pathway to regulate secondary hair follicle (SHF) development. Overall, our findings here demonstrate that FGF5 plays a significant role in regulating SHF growth in sheep and potentially serves as a molecular marker of fine wool growth in sheep breeding.

Analysis of PD-1/PD-L1 variations in lung cancer and association with immunotherapeutic efficacy and prognosis: A nonrandomized controlled trial.

INTRODUCTION: This study aims to explore Programmed Death Receptor-1 (PD-1) and Programmed Death Ligand-1 (PD-L1) variations in Lung Cancer (LC) tissues and Peripheral Blood (PPB) and their association with immunotherapy efficacy and prognosis. METHOD: 72 patients with LC were included in the LC group and 39 patients with concurrent benign lung disease were included in the benign group. PD-1/PDL-1 was compared in PPB and lung tissue. All LC patients were treated with immunotherapy. The relationship between PD-1/PDL-1 in LC tissue and PPB and immunotherapy efficacy was analyzed. Patients were divided into death and survival groups, and PD-1/PDL-1 in tumor tissues and PPB were compared. RESULTS: The authors found that PD-1 and PDL-1 positive expression in lung tissue and PPB in LC patients was elevated. Combined detection of PD-1 and PDL-1 was effective in diagnosing LC and evaluating the prognosis of LC patients. PD-1 and PDL-1 positive expression was reduced after disease remission while elevated in dead patients. The 3-year survival rate of patients with PD-1 positive expression was 45.45 % (25/55), which was lower (82.35 %, 14/17) than those with PD-1 negative expression. The 3-year survival rate of patients with positive and negative expression of PDL-1 was 48.78 % (20/41) and 61.29 % (19/31), respectively. DISCUSSION: The present results demonstrated that PD-1 and PDL-1 are abnormal in cancer tissue and PPB of LC patients. The combined detection of PD-1 and PDL-1 has diagnostic value for LC and evaluation value for the efficacy and prognosis of immunotherapy.

Genetic variation analysis of Guanling cattle based on whole-genome resequencing.

Objective: The objective of this study was to unravel the genetic traits of Guanling cattle, pinpoint genes advantageous for muscle growth, and lay a foundation for the preservation of genetic diversity and further analysis of regulation mechanism of important economic traits in local cattle breed. Methods: In this study, we sequenced the whole genome of 3 Guanling cattle in Guizhou province using the Illumina HiSeq cBo sequencing platform. And, high- multiplex PCR technology was employed to detect high-quality SNP sites of other 55 Guanling cattle. Results: Our study identified 166,411 non-synonymous SNPs (nsSNPs) and 42,423 insertions and deletions (indels). Through SNP annotation, gene function enrichment analysis, and comparing with Simmental, Angus, and Limousin cattle, we identified six genes (LEPR, AKAP9, SIX4, SPIDR, PRG4, FASN) which are potentially influential on meat quality traits, playing crucial roles in muscle growth, fat metabolism, and bodily support. We also examined polymorphisms at seven SNP sites in Guanling cattle and found that all seven were in Hardy-Weinberg equilibrium. Conclusion: These findings suggested that these gene sites are stable and widespread in the Guanling cattle population. Our research lays the groundwork for future genetic enhancement and variety identification of Guanling cattle.

Inhibiting mitochondrial citrate shuttling induces hepatic triglyceride deposition in Nile tilapia (Oreochromis niloticus) through lipid anabolic remodeling.

The solute carrier family 25 member 1 (Slc25a1)-dependent mitochondrial citrate shuttle is responsible for exporting citrate from the mitochondria to the cytoplasm for supporting lipid biosynthesis and protein acetylation. Previous studies on Slc25a1 concentrated on pathological models. However, the importance of Slc25a1 in maintaining metabolic homeostasis under normal nutritional conditions remains poorly understood. Here, we investigated the mechanism of mitochondrial citrate shuttle in maintaining lipid metabolism homeostasis in male Nile tilapia (Oreochromis niloticus). To achieve the objective, we blocked the mitochondrial citrate shuttle by inhibiting Slc25a1 under normal nutritional conditions. Slc25a1 inhibition was established by feeding Nile tilapia with 250 mg/kg 1,2,3-benzenetricarboxylic acid hydrate for 6 weeks or intraperitoneal injecting them with dsRNA to knockdown slc25a1b for 7 days. The Nile tilapia with Slc25a1 inhibition exhibited an obesity-like phenotype accompanied by fat deposition, liver damage and hyperglycemia. Moreover, Slc25a1 inhibition decreased hepatic citrate-derived acetyl-CoA, but increased hepatic triglyceride levels. Furthermore, Slc25a1 inhibition replenished cytoplasmic acetyl-CoA through enhanced acetate pathway, which led to hepatic triglycerides accumulation. However, acetate-derived acetyl-CoA caused by hepatic Slc25a1 inhibition did not activate de novo lipogenesis, but rather modified protein acetylation. In addition, hepatic Slc25a1 inhibition enhanced fatty acids esterification through acetate-derived acetyl-CoA, which increased Lipin1 acetylation and its protein stability. Collectively, our results illustrate that inhibiting mitochondrial citrate shuttle triggers lipid anabolic remodeling and results in lipid accumulation, indicating the importance of mitochondrial citrate shuttle in maintaining lipid metabolism homeostasis.

Schadenfreude or empathy? Children's emotional responses to the physical pain and pleasure of prosocial and antisocial others.

Adults' emotional reactions to the pain and pleasure of others are influenced by the moral character of those individuals. However, it remains unclear whether children's emotional responses also show such selectivity. To investigate this, we compared 4- to 8-year-old children's emotional responses to the physical pain and pleasure of prosocial versus antisocial puppets. In Study 1, children reported unhappiness after witnessing the pain of the prosocial and antisocial puppets but reported less unhappiness after witnessing the pain of the antisocial puppet. In Study 2, children reported happiness after witnessing the pleasure of both puppets but reported being less happy for the antisocial puppet. These results suggest that children are less likely to empathize with antisocial individuals. Meanwhile, children did not display Schadenfreude (pleasure at others' pain) or Gluckschmerz (displeasure at others' pleasure) toward antisocial individuals in our studies. Moreover, the selectivity of children's emotional responses disappeared after we manipulated the physical competence rather than the moral character of the puppets in Study 3. Our findings help to reveal the moral selectivity of emotional responses to others' pleasure and pain during early childhood.

Phase separation as a new form of regulation in innate immunity.

Innate immunity is essential for the host against pathogens, cancer, and autoimmunity. The innate immune system encodes many sensor, adaptor, and effector proteins and relies on the assembly of higher-order signaling complexes to activate immune defense. Recent evidence demonstrates that many of the core complexes involved in innate immunity are organized as liquid-like condensates through a mechanism known as phase separation. Here, we discuss phase-separated condensates and their diverse functions. We compare the biochemical, structural, and mechanistic details of solid and liquid-like assemblies to explore the role of phase separation in innate immunity. We summarize the emerging evidence for the hypothesis that phase separation is a conserved mechanism that controls immune responses across the tree of life. The discovery of phase separation in innate immunity provides a new foundation to explain the rules that govern immune system activation and will enable the development of therapeutics to treat immune-related diseases properly.

Nitazoxanide synergizes polymyxin B against Escherichia coli by depleting cellular energy.

The rapid expansion of antibiotic-resistant bacterial diseases is a global burden on public health. It makes sense to repurpose and reposition already-approved medications for use as supplementary agents in synergistic combinations with existing antibiotics. Here, we demonstrate that the anthelmintic drug nitazoxanide (NTZ) synergistically enhances the effectiveness of the lipopeptide antibiotic polymyxin B in inhibiting gram-negative bacteria, including those resistant to polymyxin B. Mechanistic investigations revealed that nitazoxanide inhibited calcium influx and cell membrane depolarization, enhanced the affinity between polymyxin B and the extracellular membrane, and promoted intracellular ATP depletion and an increase in reactive oxygen species (ROS), thus enhancing the penetration and disruption of the Escherichia coli cell membrane by polymyxin B. The transcriptomic analysis revealed that the combination resulted in energy depletion by inhibiting both aerobic and anaerobic respiration patterns in bacterial cells. The increased bactericidal effect of polymyxin B on the E. coli ∆nuoC strain further indicates that NuoC could be a promising target for nitazoxanide. Furthermore, the combination of nitazoxanide and polymyxin B showed promising therapeutic effects in a mouse infection model infected with E. coli. Taken together, these results demonstrate the potential of nitazoxanide as a novel adjuvant to polymyxin B, to overcome antibiotic resistance and improve therapeutic outcomes in refractory infections.IMPORTANCEThe rapid spread of antibiotic-resistant bacteria poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue. Here, the synergistic activity of the FDA-approved agent nitazoxanide (NTZ) combined with polymyxin B was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of the combination of nitazoxanide and polymyxin B were explored by fluorescent dye, transmission electron microscopy (TEM), and transcriptomic analysis. The synergistic efficacy was evaluated in vivo by the Escherichia coli and mouse sepsis models. These results suggested that nitazoxanide, as a promising antibiotic adjuvant, can effectively enhance polymyxin B activity, providing a potential strategy for treating multidrug-resistant bacteria.

The therapeutic potential of circular RNA in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is among the most aggressive subtypes of the disease that does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Circular RNAs (circRNAs) are a type of non-coding RNA with a circular shape formed by non-standard splicing or reverse splicing. Numerous circRNAs exhibit abnormal expression in various malignancies, showing their critical role in the emergence and growth of tumors. Recent studies have shown evidence supporting the idea that certain circRNAs regulate the proliferation and metastasis of TNBC. In addition, circRNAs alter metabolism and the immune microenvironment to promote or inhibit the development of TNBC. Notably, circRNAs may affect the efficacy of clinical drug therapy, serve as therapeutic targets, and be used as molecular biomarkers in the future. Herein, we will first summarize the biogenesis and function of circRNAs. Then, we will explain current research on circRNAs related to TNBC and their potential to serve as therapeutic targets or biomarkers for future drug development, providing a new direction and idea for TNBC therapy.

Plasma EBV quantification is associated with the efficacy of immune checkpoint blockade and disease monitoring in patients with primary pulmonary lymphoepithelioma-like carcinoma.

Objectives: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein-Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation. Methods: We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB-treated PLELC. Viral EBNA-1 and BamHI-W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction. Results: Progression-free survival (PFS) was significantly longer in EBNA-1 high or BamHI-W high groups. A longer PFS was also observed in patients with both high plasma EBNA-1 or BamHI-W and PD-L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA-1 and BamHI-W. Plasma EBV load was negatively associated with intratumoral CD8+ immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months. Conclusions: Plasma EBV DNA could be a useful and easy-to-use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging.