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Whereas some studies suggest that ironic praise necessitates a longer processing time than ironic criticism, others posit that the two are processed at comparable speeds. We hypothesize that the presence of an echoic antecedent within the preceding context may at least partially account for these conflicting findings. To investigate this matter, we analyzed reading times and accuracy stemming from two types of contexts: echoic and non-echoic. Our results demonstrate that ironic criticism was judged to be more ironic in both echoic and non-echoic contexts, while ironic praise was rated as more ironic in an echoic context than in a non-echoic context. Additionally, echoing contexts facilitate the comprehension of ironic criticism, but cause ironic praise to be processed more slowly. There was also an observed asymmetry between the two forms of irony. Ironic criticism demonstrated high accuracy and was rated as more ironic than ironic praise. Furthermore, ironic criticism was read faster in an echoic context, whereas performance was similar in a non-echoic context for both types. These findings suggest that echoing context affects ironic criticism and ironic praise differently, implying that distinct mechanisms may be at work in understanding irony in echoic and non-echoic contexts.

Objective Leg problems including lameness and tibial dyschondroplasia (TD) are one of the most important factors affecting health and animal welfare in meat-type poultry, which are considerably impacted by dietary vitamin regimens. The present study was conducted to investigate the effects of dietary vitamin levels on growth performance and tibia quality in 14-d-old meat ducks. Methods One-d-old Cherry Valley meat-type male ducks were allocated to two vitamin regimens for 14 d, which was formulated according to the recommendation of the National Research Council (NRC, 1994) or China Agricultural Industry Standards (NY/T 2122-2012). Each group included 8 replicates with 16 birds per replicate. Results There was no significant difference in the growth performance of ducks, whereas dietary NY/T vitamin supplementation decreased leg abnormalities as compared to the NRC group, along with similar tibia length, perimeter, and the relative weight of tibia. The tibia from the birds that received the NY/T vitamin diet exhibited markedly higher (p 0.05). Conclusion NY/T vitamin diet improved tibia quality and subsequently decreased leg abnormalities in 14-d-old ducks, which was probably linked with the promoted bone formation.

Abstract Purpose Cervical cancer (CC), a significant global health threat, necessitates comprehensive understanding for improved therapeutic interventions. Many research indicates that dysregulation of the Hippo-YAP1 pathway leads to uncontrolled proliferation and invasion of tumor cells, promoting the progression of various cancers. This article aims to elucidate the role of RNF6 in CC and its regulation of the Hippo-YAP1 signaling pathway. Methods The public tumor dataset analyses, immunohistochemistry, and western blotting were used to explore the expression of RNF6 in CC. Gain- and loss-of-function assays were conducted to elucidate the role of RNF6 in the proliferation and invasion of CC cells. Transcriptome sequencing was used to explore RNF6’s role in cervical cancer, with validation of its regulation of the Hippo-YAP1 pathway through western blotting and RT-qPCR. Co-transfection of YAP overexpression plasmids into RNF6-silenced CC cells were preformed to confirm YAP1’s pivotal role in RNF6-mediated CC progression. Animal experiments were preformed to further validate RNF6 interference’s inhibitory effect on CC proliferation in vivo. Results Clinical samples and bioinformatics analysis revealed high expression of RNF6 in CC, and closely associated with advanced FIGO (International Federation of Gynecology and Obstetrics) stage, larger tumor size, and poor prognosis. Cellular functional experiments demonstrate that RNF6 promotes the proliferation, invasion, and migration of CC cells, while knockdown of RNF6 yields the opposite effect. Transcriptome sequencing further reveals that RNF6 may promote CC progression through the Hippo-YAP signaling pathway. Western blotting and RT-qPCR further unveil that RNF6 enhances the upregulation of YAP1 protein levels, thereby activating downstream oncogenes CTGF and CYR61 transcription. Additionally, exogenous overexpression of YAP1 reverses the inhibitory effect of RNF6 silencing on CC proliferation and invasion. Furthermore, RNF6 interference significantly attenuates tumor growth in vivo experiments. Conclusion Our research reveals that RNF6 is highly expressed in CC, driving malignant progression by upregulating YAP1 protein expression and enhancing the transcription of downstream target genes CTGF and CYR61, offering potential therapeutic targets for CC treatment.

Abstract Despite the importance of radiation therapy as a nonsurgical treatment for non-small cell lung cancer (NSCLC), radiation resistance has always been a concern because of poor patient response and outcomes. Therefore, it is crucial to identify novel targets to increase the effectiveness of radiotherapy and investigate the mechanisms underlying radioresistance. Previously, we demonstrated that Spindlin 1 (SPIN1) was related to tumour initiation and progression. In this study, we found that SPIN1 expression was higher in NSCLC tissues and cell lines than in the corresponding controls. SPIN1 overexpression in NSCLC patients was closely correlated with disease progression and poor prognosis. Functionally, SPIN1 depletion inhibited cell proliferation, decreased the percentage of cells in the G2/M phase and suppressed cell migration and invasion. Moreover, SPIN1 knockdown decreased the clonogenic capacity, impaired double-strand break (DSB) repair and increased NSCLC radiosensitivity. Mechanistically, forkhead box M1 (FOXM1) was identified as a key downstream effector of SPIN1 in NSCLC cells. Furthermore, SPIN1 was found to facilitate MDM2-mediated FOXO3a ubiquitination and degradation, leading to FOXM1 upregulation. Moreover, restoration of FOXM1 expression markedly abolished the inhibitory effects and increased radiosensitivity induced by SPIN1 depletion. These results indicate that the SPIN1-MDM2-FOXO3a/FOXM1 signalling axis is essential for NSCLC progression and radioresistance and could serve as a therapeutic target for increasing radiotherapy efficacy.

Abstract Mobile phone addiction has become a widespread phenomenon in Chinese society, attracting significant social attention. However, there is still limited understanding of complexities and relationships concerning anxiety, depression, self-esteem, and mobile phone addiction (MPA) among college students. To better understand the relationships among depression, anxiety, self-esteem, and mobile phone addiction, the aim of this study was to explore these relationships, analyze the factors influencing mobile phone addiction, and examine the mediating effects of anxiety and self-esteem on the relationship between depression and mobile phone addiction. Data from 2023 were collected, and the SDS depression scale, SAS anxiety scale, mobile phone addiction scale, and Robert self-esteem scale were employed. Pearson correlation analysis and structural equation modeling revealed significant associations between depression, anxiety, self-esteem, and mobile phone addiction. Further analysis indicated that anxiety mediated the relationship between depression and mobile phone addiction, meanwhile, self-esteem mediated the relationship between depression and mobile phone addiction. Self-esteem also mediated the relationship between anxiety and mobile phone addiction. Additionally, anxiety and self-esteem played sequential mediating roles in mobile phone addiction. These findings contribute to a better understanding of the mechanisms underlying the relationship between depression and mobile phone addiction. The discussion provides practical and effective recommendations for the prevention and intervention of mobile phone addiction among college students.

Hydraulic performance and operational stability of submersible drainage pumps can be affected by cavitation and erosion when used for draining water from buildings. A parametric study is essential to improve the suction performance and accurately identify the cavitation and erosion phenomena in the pump, providing a technical reference for monitoring its optimal operation. Therefore, the main objective of this research is to develop an energy-saving, high-efficiency submersible pump capable of emergency response. In this paper, the Reynolds-average Navier-Stokes (RANS) equations were applied to the steady calculation of the submersible pump, which was discretized by the finite volume method. The Reyleigh-Plesset cavitation model was considered for interphase mass transfer to predict and find the cavitation characteristics. Additionally, the discrete phase model (DPM) was adopted as an Eulerian-Eulerian approach combined with Grant and Tabakoff's erosion model to capture the erosion effects in the pump numerically. A test pump was installed, and an experiment was conducted to assess hydraulic performance, validated with computational data. Improving the impeller or casing shape can increase NPSH3 % by at least 3.80 %, with a potential improvement of 4.083 % when only the impeller shape is changed. Erosion rate density increases with particle inflow rate, but model differences decrease as the flow rate increases. Modifying the impeller and casing shapes can reduce the average erosion rate density by at least 25 %. Average efficiency improvements of 4–5 % can be achieved by optimizing the casing shape, though practical implementation is challenging. Optimizing the pump's flow path is essential for improving hydraulic performance and reducing erosion and cavitation.

Abstract The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, S2’s usage as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of the S2 trimer’s opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Informed by molecular simulations and corroborated by experiments, we report an engineered S2 immunogen that exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.

This study aims to investigate the phase composition, microstructure, and mechanical properties of three refractory high-entropy alloys (RHEAs): Al7(NbTiZr)93, Al7(NbTiZrMo)93, and Al7(NbTiZrTa)93. The as-cast Al7(NbTiZr)93 alloy exhibits a single-phase BCC structure, with a yield strength (YS) of 1050 MPa at room temperature. The addition of Mo and Ta leads to the formation of Al7(NbTiZrMo)93 and Al7(NbTiZrTa)93 alloys with BCC-B2 and B2-FCC dual-phase structures, whose YS values reach 1741 MPa and 2350 MPa, respectively. At 800 °C, trace amounts of ordered B2 phase are generated in the Al7(NbTiZr)93 matrix, and the YS decreases from 1050 MPa at room temperature to 219 MPa at 800 °C. In the Al7(NbTiZrMo)93 alloy, the 10 nm B2 precipitates grow to several hundred nanometers, and the YS decreases to 431 MPa after compression at 800 °C. In the Al7(NbTiZrTa)93 alloy, the grid B2-FCC structure at room temperature transforms into a disordered BCC structure at 800 °C, yet possessing the YS of 908 MPa and demonstrating acceptable ductility. Moreover, Ta exhibits the better structural and performance matching than Mo in AlNbTiZr-based RHEAs. Therefore, it opens up new prospects for regulating the structure and high-temperature performance of AlNbTiZr-based RHEAs.

Abstract We perform a phenomenological comparison of the gravitational wave (GW) spectrum expected from cosmic gauge string networks and superstring networks comprised of multiple string types. We show how violations of scaling behavior and the evolution of the number of relativistic degrees of freedom in the early Universe affect the GW spectrum. We derive simple analytical expressions for the GW spectrum from superstrings and gauge strings that are valid for all frequencies relevant to pulsar timing arrays (PTAs) and laser interferometers. We analyze the latest data from PTAs and show that superstring networks are consistent with 32 nHz data from NANOGrav, but are excluded by 3.2 nHz data at 3σ unless the string coupling g s < 0.2 or the strings evolve in only about 10% of the volume of the higher-dimensional space. We also point out that while gauge string networks are excluded by NANOGrav-15 data at 3σ, they are completely compatible with EPTA and PPTA data. Finally, we study correlations between GW signals at PTAs and laser interferometers.

In this paper, a discrete air model (DAM) is developed to capture the discontinuous characteristics of air at different locations during the rapid filling process in long-range, large-scale water pipeline. By introducing the continuity and momentum equations of air and combining them with the water control equation and the interface continuity equation, an improved model based on the uniform air is derived. The accuracy of the model is verified by comparing it with experimental data and the results of the original uniform air model (UAM). Subsequently, a long-range, large-scale pipeline was considered to investigate the dynamic properties of air in large systems, which had not been covered in previous studies. Additionally, the influence of air dynamic characteristics on initial air volume affected by different air lengths and various pipe diameters in large systems – is further studied. Results show that an increased pipe diameter expands the contact area of the air–water interface, often resulting in the UAM underestimating the maximum peak pressure. The propagation process of transient waves in air is divided into three stages: propagation stage with multiple variation, maximum value stage with interface propulsive, and stability stage with several fluctuations, which corresponds to the pressure fluctuation curve. This explains the occurrence of small fluctuations and peaks in the curve. Therefore, the peak pressure simulated by the proposed DAM offers a better understanding of wave behaviours.

Transient flow frequently occurs in water delivery systems, including various flow regimes such as water hammer, free surface flow, and slug flow. Current models often oversimplify these phenomena by simulating single-phase flow or using simplistic one-dimensional assumptions for the gas-water interface, neglecting interface instability. Although two-fluid models can address some of these issues, they cannot simulate open channel flow and have not yet been applied to transient flow scenarios. To date, no single model has been able to simultaneously simulate all these flow regimes while overcoming these limitations. To address this gap, the two-fluid model is enhanced in this paper. For water hammer simulation, a gas volume fraction of zero is assumed, and a TVB unsteady friction model is introduced to enhance numerical accuracy. For open channel flow, a variable wave speed equation and a new state equation are presented. Despite the different state equations required for various flow regimes, a Roe-type scheme is introduced to solve the two-fluid model. This approach accurately simulates water hammer, free surface flow (including open channel flow and stratified flow), and slug flow. An experimental pipeline system is designed to validate the proposed model's ability to simulate water hammer. Additionally, several cases are used to verify the model's capability in simulating open channel flow, stratified flow, and slug flow. The model accurately predicts the occurrence of slug flow, consistent with experimental flow pattern maps, and effectively simulates the evolution of slug flow, closely matching the measured gas-water interface. The effects of gas volume fraction, pipe length, and pipe slope on slug flow are systematically discussed. Results indicate that smaller initial gas volume fractions, longer pipe lengths, and upward pipe slopes increase the likelihood of slug flow generation within the pipeline, which should be minimized during design.Abbreviations: TVB: Trikha-Vardy-Brown model; Cr: Courant number

The traditional one-dimensional (1D) model often fails to accurately predict the dynamic pressure response of large offline air pockets during transients, due to a lack of comprehensive understanding of the underlying mechanisms of transient interaction with offline air pockets. This study investigated dynamic behavior and energy dissipation of offline air pockets through experiments and numerical models. Experimental pressure responses were predicted using a 1D-3D coupling model, which presented superior performance compared to traditional 1D model. The 1D-3D coupling model was further utilized to investigate the air-water interface, internal energy and turbulence distribution of offline air pockets. The results reveal that the stability of the air-water interface depends on the decelerating distance of the jet in offline tube, explaining the instability phenomenon with lower water levels observed in experimental snapshots. The internal energy pattern suggests different energy dissipation mechanisms compared to the inline air pockets. The distribution of turbulence intensity and effective thermal conductivity indicates significant additional energy dissipation at the inlet and outlet of offline neck. By incorporating a minor head loss term for offline neck into traditional 1D model, the pressure response aligns well with the results obtained from 1D-3D coupling model under different flow rates and air volumes.

The diagnostic criteria for preeclampsia do not accurately reflect the pathophysiological characteristics of patients with preeclampsia. Conventional biomarkers and diagnostic approaches have proven insufficient to fully comprehend the intricacies of preeclampsia. This study aimed to screen differentially abundant metabolites as candidate biomarkers for preeclampsia. A propensity score matching method was used to perform a 1:1 match between preeclampsia patients (n = 70) and healthy control individuals (n = 70). Based on univariate and multivariate statistical analysis methods, the different characteristic metabolites were screened and identified. Least absolute shrinkage and selection operator (LASSO) regression analysis was subsequently used to further screen for differentially abundant metabolites. A receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic efficacy of the metabolites. A total of 1,630 metabolites were identified and quantified in maternal serum samples. Fifty-three metabolites were significantly increased, and two were significantly decreased in preeclampsia patients. The area under the curve (AUC) of the model composed of isobutyryl-L-carnitine and acetyl-leucine was 0.878, and the sensitivity and specificity in detecting preeclampsia were 81.4% and 87.1%, respectively. There are significant differences in metabolism between preeclampsia patients and healthy pregnant women, and a range of novel biomarkers have been identified. These findings lay the foundation for the use of metabolomic biomarkers for the diagnosis of preeclampsia.

Background Prognostic factors-based nomograms have been utilised to detect the likelihood of the specific cancer events. We have focused on the roles of aldehyde dehydrogenase 1 (ALDH1) and p-AKT in predicting the prognosis of BC patients. This study was designed to establish nomograms based on the integration of aldehyde dehydrogenase 1 (ALDH1) and p-AKT in predicting the disease-free survival (DFS) and overall survival (OS) of breast cancer (BC) patients.Methods Demographic and clinical data were obtained from BC patients admitted to our hospital between September 2015 and August 2016. Univariate and multivariate Cox regression analyses were utilised to analyse the risk factors of recurrence and mortality. The nomograms for predicting the DFS and OS were established using the screened risk factors. Stratified analysis was performed with the cut-off value of exp (pi) of 4.0-fold in DFS and OS, respectively.Results Multivariate Cox regression analysis indicated that ALDH, p-AKT and pathological stage III were independent risk factors for the recurrence among BC patients. ALDH1, p-AKT, pathological stage III and ER-/PR-/HER2- were independent risk factors for the mortality among BC patients. The established nomograms based on these factors were effective for predicting the DFS and OS with good agreement to the calibration curve and acceptable area under the receiver operating characteristic (ROC) curve. Finally, stratified analyses showed patients with a low pi showed significant decrease in the DFS and OS compared with those of high risk.Conclusion We established nomograms for predicting the DFS and OS of BC patients based on ALDH1, p-AKT and pathological stages. The ER-/PR-/HER2- may be utilised to predict the OS rather than DFS in the BC patients.

A robust comprehensive energy dissipation model is developed to investigate the rapid filling process of a T-shaped bifurcated pipeline with entrapped air pocket, while an experimental system is designed to validate the numerical model. In this work, a self-adapting heat transfer model is proposed to describe the energy exchange during transient event, fully considering the heat transfer of entrapped air pocket and hydraulic losses caused by steady friction and unsteady friction in the section of the filling water column. Importantly, the related heat transfer coefficient is variable and determined by mechanism formula of media characteristics, which is obviously different from the constant heat transfer coefficient in conventional model relying on the trial-and-error method and experimental data. Moreover, the second-order Godunov-type scheme is introduced to solve the governing equations of filling water column, while a virtual plug approach is proposed to track the air–water interface. The resulting predictions are compared to those obtained via a conventional empirical polytropic model and constant coefficient heat transfer model, and to experimental data. The proposed model accurately reproduces the experimental pressure oscillations. The results display that when an air pocket content exceeds a certain threshold (>1.7%), the comprehensive model using forced convection can reproduce the pressure fluctuations. When the air content is lower (

Sewage pumps are widely utilized in various applications, including municipal wastewater treatment plants, industrial processes, and residential sewage systems. These pumps are specifically designed to handle the transportation of mixtures consisting of solid and liquid components, commonly observed as two-phase flow. In this study, semi-open sewage pumps with varying clearance sizes have been examined through adjustment of the geometrical model. Multi-factor analysis of variance is employed to investigate the combined influence of different two-phase flow conditions and tip clearance sizes on the performance of sewage pumps. The results show that the performance of the pump decreases significantly as the clearance size increases. Also, the sensitivity of pump efficiency to variations in tip clearance size is contingent upon the flow rate. Under part-load conditions, both particle concentration and clearance size exhibit a notable effect on efficiency. The two-phase flow will greatly enhance the intensity of the unsteady flow near the inlet and outlet of the semi-open impeller, which is the main reason for the performance degradation of the sewage pump. The findings of this research provide valuable insights for enhancing the hydraulic performance and operational stability of semi-open sewage pumps operating under two-phase flow conditions.

Autoimmune thyroiditis (AIT), also known as Hashimoto’s thyroiditis (HT), is an autoimmune disease that is characterised by elevated thyroid-specific antibody titres. The incidence of AIT is increasing year over year, making it urgent to establish a suitable animal model for this condition, in order to better explore its pathogenesis and potential pharmaceutical mechanisms for treatment. Owing to a lack of basic research on this disease, problems such as disparate modelling methods with unclear and varying success rates make it difficult for researchers to obtain effective information on AIT in the short term. This report summarises and analyzes the current literature on AIT and combines actual operability to explain the selection and specific implementation processes behind the uses of different modelling approaches, to provide a better overall understanding of autoimmune thyroid diseases.

The fluidisation of spherocylindrical particles is often involved in the fields of biomass combustion, drug delivery and food drying. By spherocylindrical particles, we mean elongated spherical particles like non-spherical capsule pills and pulverised biomass fuels. Mastering the fluidisation state of spherocylindrical particles can improve the related industrial processes. In this paper, a coupled CFD–DEM method is used and the reliability of the model in this paper is verified with the help of high-speed photography experiments. Subsequently, the fluidisation characteristics of spherocylindrical particles in a spouted bed were investigated under different operating conditions and compared with the simulation results of spherical particles. The results show that the gas velocity influences the average bed height, axial velocity, volume fraction, orientation angle, and mixing mass of the particles. There are also significant differences in the fluidisation characteristics of particles at different bed heights. The particles in the higher bed region are more dispersed, the gas–solid mixing is more intense, and the gas velocity has a strong influence on the volume fraction/axial velocity of the spherocylindrical particles in the higher bed. In addition, this work also found significant differences in the fluidisation characteristics of different shaped particles.

Bartonella quintana is one of the main causes of blood culture-negative endocarditis, and routine blood culture and serological methods are difficult to achieve early diagnosis. We report a case of blood culture-negative Bartonella quintana endocarditis from southwestern Chongqing. The patient was a 67-year-old male scavenger who presented with heart failure without fever as the main clinical manifestation upon admission. He stated having had contact with stray cats in the past 2 months. The combination of clinical symptoms, echocardiography, and blood mNGS testing confirmed the infection of Bartonella quintana.

Objective To evaluate the prevalence, resistance and risk factors of community-onset urinary tract infections (COUTIs) caused by extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) for providing a basis for the selection of clinical therapeutic agents.Design A retrospective case–control study.Setting The Affiliated Dazu Hospital of Chongqing Medical University (also known as The People’s Hospital of Dazu Chongqing), a 1000-bed tertiary hospital in China.Data and participants This study encompassed adult patients diagnosed with community-acquired urinary tract infections (UTIs) caused by E. coli between May 2017 and December 2022 with exclusion criteria including incomplete clinical data, disagreement to participate in the study, hospitalisation duration exceeding 48 hours prior to confirmation of diagnosis and prior history of urinary tract infection caused by E. coli.Outcome measures The risk factors for COUTIs caused by ESBL-EC were evaluated using a case–control design, defining patients who were diagnosed with UTIs and had an ESBL-positive urine culture as the case group and patients who were diagnosed with UTIs and had an ESBL-negative urine culture as the control group. Perform drug susceptibility testing and resistance analysis on isolated ESBL-EC.Results In total, 394 cases of COUTIs caused by E. coli were included; 192 cases were ESBL-positive with a detection rate of 48.7% (192/394). Parenchymal tumour, history of urolithiasis stone fragmentation, history of urological surgery, hospitalisation within 6 months, indwelling catheter outside the hospital and antibiotic use (mainly third-generation cephalosporins) were the factors significantly associated with COUTIs caused by ESBL-EC (p

Fruit color is an important qualitative trait that greatly influences the marketability of peppers. Fruit color can be divided into two categories. Green fruit color denotes commercial maturity, whereas ripe fruit indicates physiological maturity. Herein, segregation populations were created using the ‘D24’ with pale green in the green fruit stage, orange in the mature fruit stage, and ‘D47’ with green in the green fruit stage and red in the mature fruit stage. BSA-seq and genetic linkage map analysis revealed green fruit color was linked to (gyqtl1.1) on Chr1 and (gyqtl10.1) on Chr10, while mature fruit color was linked to Chr6. Using functional annotation, sequence, and expression analysis, we speculate that an SNP mutation in the CapGLK2 gene at the gyqtl10.1 interval could initiate premature termination of translation, thus yielding green to pale green fruits in D47. Conversely, the orange color in mature D24 fruits is due to the Indel-mediated premature termination of translation of the CapCCS gene. Our research offers a theoretical foundation for choosing different varieties of pepper fruit based on their color.

BackgroundThyroid dysfunction exhibits a heightened prevalence among people with diabetes compared to those without diabetes. Furthermore, TD emerges as a notable correlated risk factor for the onset of diabetic retinopathy.MethodsUsing data from the FinnGen database (R9), we investigated the causal relationship between thyroid dysfunction (TD) and four stages of diabetic retinopathy (DR). A two-sample univariable Mendelian randomization (UVMR) approach was employed to estimate the total causal effect of TD on four stages of DR, while multivariable Mendelian randomization (MVMR) was used to assess the direct causal effect. The meta-analysis was conducted to summarize the collective effect of TD on four stages of DR. The inverse variance weighted (IVW) method was the primary approach for Mendelian randomization analysis, with heterogeneity, horizontal pleiotropy, and leave-one-out sensitivity analyses performed to validate the robustness of the findings.ResultsIn UVMR analysis, thyrotoxicosis (TOS) was significantly associated with an increased risk of diabetic retinopathy across four stages (OR, 1.10–1.19; P

Objectives Previous research has extensively explored the factors associated with psychotic-like experiences (PLEs). However, the characteristics and associated factors of remitted PLEs, which refer to the absence of current PLEs following previous PLEs, remain unclear. Therefore, this study aims to describe the characteristics of adolescents who reported remitted PLEs.Design Cross-sectional study.Setting The survey was conducted from October to December 2020 in three colleges located in Guangzhou, China.Participants A total of 4208 college freshmen aged from 15 to 24 participated in our survey.Primary and secondary outcome measures The 15-item positive subscale of the Community Assessment of the Psychic Experience was used to assess both lifetime and current PLEs. Multivariate logistic regression models were used to examine the associations between remitted PLEs and a range of demographic factors, lifestyle, psychosocial factors, lifetime affective symptoms and sleep problems.Results Three groups of PLEs were observed: non-PLEs (47.27% of the sample), remitted PLEs (40.42%) and current PLEs (12.31%). Several factors have been identified as shared correlates of remission and absence of PLEs, including fewer recent adverse life events, greater resilience, fewer symptoms of depression and anxiety, and early waking. Furthermore, higher levels of social support (OR 1.48, 95% CI 1.01 to 2.17; OR 1.53, 95% CI 1.18 to 1.97) was a specific factor associated with the remission of PLEs. Compared with individuals without PLEs, those with remitted PLEs were more likely to be female (OR 1.50, 95% CI 1.28 to 1.75), less likely to be younger (OR 0.88, 95% CI 0.81 to 0.95) and prone to have more chronic physical illness (OR 1.67, 95% CI 1.29 to 2.16), habitual alcohol intake (OR 1.85, 95% CI 1.19 to 2.88), more childhood trauma (OR for low vs high=0.72, 95% CI 0.57 to 0.91) and the sleep problems of waking up easily (OR 1.36, 95% CI 1.12 to 1.65).Conclusion These findings suggest that remitted PLEs play a vital, unique role among three groups and provide preliminary targets for the intervention for adolescents at risk of mental health problems. Further investigation may shed light on the causality of the relationship between remitted PLEs and associated factors.

Abstract Background The plant-specific YABBY transcription factor family plays important roles in plant growth and development, particularly leaf growth, floral organ formation, and secondary metabolite synthesis. Results Here, we identified a total of 13 OfYABBY genes from the Osmanthus fragrans genome. These 13 OfYABBY genes were divided into five subfamilies through phylogenetic analysis, and genes in the same subfamily showed similar gene structures and conserved protein motifs. Gene duplication promoted the expansion of the OfYABBY family in O. fragrans. Tissue-specific expression analysis showed that the OfYABBY family was mainly expressed in O. fragrans leaves and floral organs. To better understand the role of OfYABBY genes in plant growth and development, OfYABBY12 was selected for heterologous stable overexpression in tobacco, and OfYABBY12-overexpressing tobacco leaves released significantly fewer volatile organic compounds than wild-type tobacco leaves. Overexpression of OfYABBY12 led to the downregulation of NtCCD1/4 and decreased β-ionone biosynthesis. Correspondingly, a dual-luciferase assay showed that OfYABBY12 negatively regulated the expression of OfCCD4, which promotes β-ionone synthesis. Furthermore, tobacco leaves overexpressing OfYABBY12 were curled and wrinkled and had significantly reduced leaf thickness and leaf inclusions and significantly extended flower pistils (styles). Conclusion Overall, the results suggest that the OfYABBY gene family may influence the biosynthesis of the floral scent (especially β-ionone) in O. fragrans and may regulate leaf morphogenesis and lateral organs.

Abstract Background Silicosis represents a paramount occupational health hazard globally, with its incidence, morbidity, and mortality on an upward trajectory, posing substantial clinical dilemmas due to limited effective treatment options available. Trigonelline (Trig), a plant alkaloid extracted mainly from coffee and fenugreek, have diverse biological properties such as protecting dermal fibroblasts against ultraviolet radiation and has the potential to inhibit collagen synthesis. However, it’s unclear whether Trig inhibits fibroblast activation to attenuate silicosis-induced pulmonary fibrosis is unclear. Methods To evaluate the therapeutic efficacy of Trig in the context of silicosis-related pulmonary fibrosis, a mouse model of silicosis was utilized. The investigation seeks to elucidated Trig's impact on the progression of silica-induced pulmonary fibrosis by evaluating protein expression, mRNA levels and employing Hematoxylin and Eosin (H&E), Masson's trichrome, and Sirius Red staining. Subsequently, we explored the mechanism underlying of its functions. Results In vivo experiment, Trig has been demonstrated the significant efficacy in mitigating SiO2-induced silicosis and BLM-induced pulmonary fibrosis, as evidenced by improved histochemical staining and reduced fibrotic marker expressions. Additionally, we showed that the differentiation of fibroblast to myofibroblast was imped in Trig + SiO2 group. In terms of mechanism, we obtained in vitro evidence that Trig inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-β/Smad signaling according to the in vitro evidence. Notably, our finding indicated that Trig seemed to be safe in mice and fibroblasts. Conclusion In summary, Trig attenuated the severity of silicosis-related pulmonary fibrosis by alleviating the differentiation of myofibroblasts, indicating the development of novel therapeutic approaches for silicosis fibrosis.

Introduction In recent years, e-cigarettes as an emerging tobacco product have been favored by college students. Our study aims to explore the factors affecting the use of e-cigarettes among college students and to put forward feasible suggestions for effectively controlling the use of e-cigarettes among college students. Methods The participating students were from three undergraduate and three specialized colleges in Guangdong Province, surveyed from January to March 2022. The Fuzzy-set Qualitative Comparative Analysis (fsQCA) method was used to analyze the influence mechanism and path of five antecedents: selfefficacy, social environment, cognition, sales environment, and negative outcome expectation, on the use of e-cigarettes. The fsQCA used in this study is a novel research methodology that combines the strengths of qualitative and quantitative analyses, through which we can determine which conditions are essential to the outcomes that lead to e-cigarette use among college students, and which combinations of conditions are more important than others. Results The interaction of self-efficacy, social environment, cognition, sales environment, and negative outcome expectation, affected college students’ use of e-cigarettes. Through the fsQCA method, it was found that self-efficacy alone constitutes a necessary condition for college students not to use e-cigarettes. There are four possible pathways for college students not to use e-cigarettes, with higher self-efficacy, correct cognition, and a healthy social environment influencing the most important combination of conditions for college students to use e-cigarettes. Conclusions The use of e-cigarettes by students in Guangdong Province is the result of the synergistic effect of multiple factors. Tobacco control action suggestions focus on improving students' self-efficacy and paying attention to the combination of different factors to achieve more effective tobacco control.

This study explored the protective effect and potential mechanism of carvacrol acetate (CAA) on the oxidation of chlorpyrifos (CPF). A model of oxidative stimulus damage was established in Sprague–Dawley rats by subcutaneous injection of the CPF poison. PC12 cells were used to construct an oxidative injury model using CPF, and the protective effects and mechanism of action of CAA against CPF-induced oxidative damage were explored in vitro. The key role of Nuclear factor erythroid-2-related factor 2 (Nrf2) in alleviating CPF-induced damage via CAA was further confirmed by administering Nrf2 inhibitors to PC12 cells. Administration of CAA significantly enhanced the locomotor ability of the rats, alleviated neuronal pathological alterations, and increased the number of Nissl bodies, while increasing autophagic bodies. In vitro, CAA promoted cell survival and augmented the mitochondrial membrane potential. It decreased both intra- and extracellular levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), while markedly elevating mitochondrial DNA (mtDNA) copy number. Moreover, PC12 cells treated with Nrf2 inhibitors failed to exhibit any improvement in survival rate when treated with CAA after a toxic insult. Furthermore, ROS and MDA levels were not significantly reduced, SOD enzyme activity did not increase, and mitochondrial membrane potential and mtDNA copy number did not improve. Western blot analysis showed that the expression of Tfam, Beclin1, and LC3II/LC3I proteins in the CAA group decreased significantly after Nrf2 inhibition. These findings suggest that CAA modulates mitochondrial function and autophagy by regulating the Nrf2 signalling pathway to mitigate the toxic damage. Finally, the effect of the autophagy inhibitor, 3-MA, on PC12 cells suggests that CAA promotes mitophagy by participating in the Nrf2 pathway, thereby preventing CPF-induced oxidative stress damage.

Abstract Endocrine‐resistant ER+HER2– breast cancer (BC) is particularly aggressive and leads to poor clinical outcomes. Effective therapeutic strategies against endocrine‐resistant BC remain elusive. Here, analysis of the RNA‐sequencing data from ER+HER2– BC patients receiving neoadjuvant endocrine therapy and spatial transcriptomics analysis both show the downregulation of innate immune signaling sensing cytosolic DNA, which primarily occurs in endocrine‐resistant BC cells, not immune cells. Indeed, compared with endocrine‐sensitive BC cells, the activity of sensing cytosolic DNA through the cGAS‐STING pathway is attenuated in endocrine‐resistant BC cells. Screening of kinase inhibitor library show that this effect is mainly mediated by hyperactivation of AKT1 kinase, which binds to kinase domain of TBK1, preventing the formation of a trimeric complex TBK1/STING/IRF3. Notably, inactivation of cGAS–STING signaling forms a positive feedback loop with hyperactivated AKT1 to promote endocrine resistance, which is physiologically important and clinically relevant in patients with ER+HER2– BC. Blocking the positive feedback loop using the combination of an AKT1 inhibitor with a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of endocrine‐resistant tumors in humanized mice models, providing a potential strategy for treating patients with endocrine‐resistant BC.

A lack of access to handwashing facilities is a significant risk factor for lower respiratory infections(LRIs). However, no studies have reported epidemiologic changes in the burden of LRIs attributed to the lack of access to handwashing facilities. We conducted an integrated assessment of the burden of LRIs attributable to the lack of handwashing facilities from 1990 to 2019 using data from the Global Burden of Disease Study 2019. In 2019, 270,000 deaths were attributed to LRIs due to a lack of access to handwashing facilities, with DALYs reaching 14.02 million. The age-standardized mortality rate (ASMR) of LRIs caused by a lack of access to handwashing facilities was approximately 3.74, while the age-standardized DALY rate (ASDR) was reported to be 203.55 in 2019. Over the past 30 years, the burden of LRIs attributed to the lack of access to handwashing facilities has shown a global decline. In 2019, this burden was most pronounced in infants under 1 year of age and in those older than 95 years, reflecting the highest DALY (5591.83) and mortality rates (79.43), respectively. The burden of LRIs caused by the lack of access to handwashing facilities was found to be more severe in males and significantly more pronounced in regions with a low sociodemographic index (SDI), such as the Sahara African region. The development of targeted strategies to address the inadequate and unequal distribution of handwashing facilities holds important value in improving the disease burden of LRIs.

The differentiation of vascular endothelial cells and the formation of new blood vessels are inseparable from the energy supply and regulation of metabolism. The budding of blood vessels is a starting point of glycolysis pathway in angiogenesis. Phosphofructokinase-2/fructose 2,6-biophosphatase 3 (PFKFB3), a key rate-limiting enzyme in glycolysis, exhibits strong kinase activity. Inhibition of PFKFB3 can reduce the rate of glycolysis, thereby inhibiting the budding of blood vessels, resulting in inhibition of pathological angiogenesis. In this review, the role of PFKFB3 in the angiogenesis of inflammatory diseases was summarized, and the endothelial inflammatory diseases associated with PFKFB3 were reviewed.

Objective: This study aimed to clarify the mechanism by which Krüppel-like factor 12 (KLF12) affects progesterone sensitivity in endometrial cancer (EC) through the progesterone receptor PGR signaling pathway. Methods: The relationship of KLF12 with PGR in EC patients was examined by immunohistochemistry, and the expression of KLF12 and PGR in EC cell lines was detected by real-time PCR and western blotting. Cell proliferation assay, plate clone formation, cell apoptosis assay, and cell cycle analysis were conducted to determine the impact of KLF12 intervention on progesterone therapy. CUT&Tag analysis and the dual-luciferase reporter experiment were used to determine the underlying regulatory effect of KLF12 on the PGR DNA sequence. A subcutaneous xenograft nude mouse model was established to validate the in vivo effect of KLF12 on progesterone sensitivity via PGR expression modulation. Results: KLF12 demonstrated decreased progesterone sensitivity and a negative correlation with PGR expression in EC tissues. Progesterone sensitivity was increased by KLF12 deficiency through PGR overexpression, a result that could be significantly reversed by PGR downregulation. PGR was identified as a target gene of KLF12, which could directly bind to the PGR promotor region and inhibit its expression. Conclusion: This study is the first to investigate the effect of KLF12 expression on EC cell resistance to progesterone. Our results offer important mechanistic insight into the direct regulation of the PGR promoter region, demonstrating that KLF12 expression strongly suppressed the PGR signaling pathway and, as a result, reduced progesterone sensitivity in EC patients.

Abstract Background Beta 2‐microglobulin (β2‐MG) is a component of the class I major histocompatibility complex (MHCI) and has recently been reported to be involved in type 2 diabetes mellitus (T2DM) and cardiovascular disease. However, the association of β2‐MG with left ventricular hypertrophy (LVH) in T2DM patients remains unknown. This study aims to investigate the correlation between serum β2‐MG and LVH in T2DM patients. Methods The retrospective analysis included 4602 eligible T2DM patients, divided into LVH and non‐LVH groups based on echocardiography results. Serum β2‐MG levels were measured, and participants were categorized into four groups (Q1–Q4) by their serum β2‐MG quartile. The relationship of serum β2‐MG level with LVH was evaluated using logistic regression, restricted cubic spline (RCS), subgroup analysis, and machine learning. Results The prevalence of LVH in T2DM patients was 31.12%. Each standard deviation increase in serum β2‐MG level corresponded to a 1.17‐fold increase in the prevalence of LVH [OR = 1.17, (95% CI: 1.05–1.31); p = 0.006]. When considering β2‐MG as a categorical variable (quartile), Q3 [OR = 1.36, (95% CI: 1.09–1.69); p = 0.007] and Q4 [OR = 1.77, (95% CI: 1.36–2.31); p

Ethnopharmacological relevance: Vitamin D (VD), selenium preparations (Se), and thyroid hormone replacement therapy are commonly used to treat Hashimoto thyroiditis (HT). Increasing evidence suggests that traditional Chinese medicine (TCM) is an effective therapeutic strategy in the treatment of HT. Aim of the study: This study aimed to investigate the efficacy and safety of commonly-used drugs for HT. Materials and methods: A literature search was performed using PubMed, Web of Science, Cochrane Library, EMBASE, Chinese China National Knowledge Infrastructure (CNKI), Clinical Trial Registry (Chi CTR), China Science and Technology Journal Database (the VIP), Wanfang Database, and China Chinese Biomedical Database (CBM) from January 1, 2003, to December 31, 2022. The outcomes included TPOAb, TgAb, TSH, FT3, FT4, and adverse events. Our study was registered in PROSPERO (CRD42023449705). Results: Sixty trials and 4719 participants were included, comparing 16 treatments: VD, Se, LT-4, Se + LT-4, HM, placebo + LT-4, HM + LT-4, Se + myolnositol, Se + VD, HM + Se, mannan peptide, LT-4+prednisone, Methimazole, Methimazole + HM, Tapazole + Propranolol, and placebo. We found that Chinese herbal medicine has significant effect vs. LT-4 [MD 0.10, 95 % confidence interval 0.02 to 0.50]) and LT-4+placebo [MD 0.10, 95 % confidence interval 0.01 to 0.77]) in reducing TPOAb. Although receiving LT-4+prednisone was not statistically significant, the treatment ranking showed that this combination therapy had the highest probability of reducing TPOAb levels (72.8 %). In addition, the effect of Se plus LT-4 was not statistically significant; however, the treatment ranking showed that this combination therapy had the highest probability (78.6 %) of reducing TgAb levels, followed by HM (64.0 %). Reports on side effects have mainly focused on the digestive and cardiovascular systems. Conclusion: Our analyses showed that HM alone or in combination with other treatments for patients with HT can improve the side effects of other drugs, enhance efficacy, and maybe the most effective option for treating HT. However, there still need further verified using high-quality evidence.

Brown seaweed polysaccharides (BSPs) are potential alternative sources of bioactive compounds. The food and pharmaceutical industries have a great interest in BSPs because of their various bioactivities, such as anticancer, antioxidant, and immunomodulatory activities. Studies have demonstrated that the bioactivities of BSPs are significantly influenced by their structural characteristics and chemical constitution; but, their specific conformational relationships are complex and required further study. However, systematic reviews of the biological activities and mechanisms of action of BSPs are currently inadequate. Thus, this paper summarizes recent studies on the physicochemical and structural features, characterization methods, biological activities, and related action mechanisms of BSPs from different sources. Based on these findings, future prospects include the following three aspects. More advanced research techniques need to be developed to identify the exact main and branch structure of BSPs; in-depth studies of the detailed structure of BSPs are needed to elucidate the conformational relationships between polysaccharides and their activities, and clinical trials should be conducted to verify the effectiveness of BSPs in the prevention and treatment of various diseases. The information provided here aims to offer a theoretical foundation for further research on the structural properties, mechanism of action, and potential applications of BSPs in food and pharmaceutical industries as well as, to increase the economic value of BSPs and extend their application range.

Dolomite formation is a crucial aspect of natural gas reservoirs in the marine strata of the Sichuan Basin, particularly in the exploration of deep carbonate reserved oil and gas resources. Understanding the genetic mechanism of dolomite is essential for predicting the distribution of favorable dolomite reservoirs in deep formations. Taking the third member of the Maokou Formation in the southeastern Sichuan Basin as an example, present work systematically investigates the genetic mechanism of dolomite by analyzing geochemical characteristics such as carbon and oxygen isotopes, strontium isotopes and rare earth elements. The analysis is based on data from outcrops, core samples and thin sections. The results reveal that the dolomites of the third member of the Maokou Formation in the southeastern Sichuan Basin can be categorized into laminated fine-crystalline dolomite, laminated fine to medium-crystalline dolomite, and saddle dolomite cement. Among these, the laminated fine to medium-crystalline dolomite is the most common type. The δ18O values of this dolomite type (-7.04‰ to -6.08‰) appeared unaffected by hydrothermal fluids, and are similar to those of mud-crystal limestone. Additionally, the 87Sr/86Sr ratio (0.707 550 to 0.707 740) locate within the range of contemporaneous seawater, indicating a diagenesis process of quasi-syngenetic to burial-induced restricted marine water infiltration dolomitization. The δ18O values of hydrothermally influenced dolomite range from -7.33‰ to -7.11‰, showing slightly negative compared to those of mud-crystal limestone. These dolomites also showed relatively higher 87Sr/86Sr ratios (0.707 950 to 0.708 171) than those of contemporaneous seawater. The laminated fine-crystalline dolomite, which was not affected by hydrothermal fluids, shares a common genetic mechanism with the previously mentioned laminated fine to medium-crystalline dolomite. Saddle dolomite cement found in caves and fractures is either directly precipitated or recrystallized from hydrothermal fluids. This type of dolomite is characterized by higher 87Sr/86Sr ratios (with a mean value of 0.707 970), significantly negative δ18O values (with a mean value of -7.32‰), and positive Eu anomalies. A gradient change from laminated fine-crystalline dolomite to laminated fine to medium-crystalline dolomite and finally to saddle dolomite cement is observed, controlled by a transition from marine water to hydrothermal fluids. The dolomite in the study area is proposed to be the product of multi-stage fluid-induced diagenesis.

Abstract The development of highly efficient electrocatalysts for direct seawater splitting with bifunctionality for inhibiting anodic oxidation reconstruction and selective oxygen evolution reactions is a major challenge. Herein, we report a direct seawater oxidation electrocatalyst that achieves long-term stability for more than 1000 h at 600 mA/cm2@η600 and high selectivity (Faraday efficiency of 100%). This catalyst revolves an amorphous molybdenum oxide layer constructed on the beaded-like cobalt oxide interface by atomic layer deposition technology. As demonstrated, a new restricted dynamic surface self-reconstruction mechanism is induced by the formation a stable reconstructed Co-Mo double hydroxide phase interface layer. The device assembled into a two-electrode flow cell for direct overall seawater electrolysis maintained at 1 A/cm2@1.93 V for 500 h with Faraday efficiency higher than 95%. Hydrogen generation rate reaches 419.4 mL/cm2/h, and the power consumption (4.62 KWh/m3 H2) is lower than that of pure water (5.0 KWh/m3 H2) at industrial current density.

Abstract Background The aim of this study was to investigate the effects and significance of rituximab (RTX) on the levels of T lymphocyte subsets in patients diagnosed with primary membranous nephropathy (PMN). Methods A total of 58 PMN patients and 25 healthy donors were chosen as the subjects. Among the PMN patients, 40 individuals received RTX treatment and completed at least 6 months of follow-up. All subjects underwent flow cytometry analysis to determine the peripheral blood lymphocyte subsets. The changes in anti-PLA2R antibody titers and 24-hour urinary protein levels were evaluated by ELISA and Biuret method before and after treatment. Results (1) The PMN group exhibited a significantly greater percentage of peripheral blood CD3−CD19+ B cells than the healthy group, which is consistent with the findings of previous reports. Additionally, compared with those in the peripheral blood of healthy individuals, the numbers of CD4+ central memory T cells, CD4+ effector memory T cells, CD4+/CD8+, and CD4+CD25+ T cells in the PMN peripheral blood were markedly greater. However, the number of peripheral blood Treg cells was reduced in the PMN group. (2) After 6 months of RTX treatment, PMN patients exhibited significant decreases in anti-PLA2R antibody titers, 24-hour urinary protein levels, and peripheral blood CD3−CD19+ B cells. Importantly, RTX administration decreased CD4+CD25+ T cells and CD4+/CD8+ in the peripheral blood of PMN patients and improved Treg cell levels. (3) RTX treatment induced alterations in the CD4+ T lymphocyte subsets in PMN patients, which did not correlate with B lymphocyte counts or anti-PLA2R antibody titers. Conclusions RTX treatment might have a beneficial impact on cellular immunity by effectively restoring the balance of CD4+ T lymphocyte subsets in PMN patients, which is beyond its effects on B cells and antibody production. Trial registration The research was registered at the First Affiliated Hospital of Soochow University. Registration Number: MR-32-23-016211. Registration Date: May 31, 2023.

Abstract We study supersymmetric (SUSY) flipped SU(5) × U(1) unification, focussing on its predictions for proton decay, fermion masses and gravitational waves. We performed a two-loop renormalisation group analysis and showed that the SUSY flipped SU(5) model predicts a high GUT scale M GUT > 1016 GeV. We also investigated the restrictions on the M B−L scale which is associated with the U(1) χ breaking scale. We found that the M B−L scale can vary in a broad region with negligible or little effect on the value of M GUT. Proton decay in this model is induced by dimension-6 operators only. The dimension-5 operator induced by SUSY contribution is suppressed due to the missing partner mechanism. We found that the partial decay width p → π 0 e + is high suppressed, being at least one order of magnitude lower than the future Hyper-K sensitivity. We also studied fermion (including neutrino) masses and mixings which can also influence proton decay. We presented two scenarios of flavour textures to check the consistency of the results with fermion masses and mixing. The B − L gauge breaking leads to the generation of cosmic strings. The B − L scale here is not constrained by gauge coupling unification. If this scale is very close that of GUT breaking, strings can be unstable due to the decay to monopole-antimonople pair. Such metastable strings can be used to explain the NANOGrav signals of stochastic gravitational wave background, which may be interpreted here as resulting from the decay of metastable cosmic strings.

Abstract A drug conjugate consists of a cytotoxic drug bound via a linker to a targeted ligand, allowing the targeted delivery of the drug to one or more tumor sites. This approach simultaneously reduces drug toxicity and increases efficacy, with a powerful combination of efficient killing and precise targeting. Antibody‒drug conjugates (ADCs) are the best-known type of drug conjugate, combining the specificity of antibodies with the cytotoxicity of chemotherapeutic drugs to reduce adverse reactions by preferentially targeting the payload to the tumor. The structure of ADCs has also provided inspiration for the development of additional drug conjugates. In recent years, drug conjugates such as ADCs, peptide‒drug conjugates (PDCs) and radionuclide drug conjugates (RDCs) have been approved by the Food and Drug Administration (FDA). The scope and application of drug conjugates have been expanding, including combination therapy and precise drug delivery, and a variety of new conjugation technology concepts have emerged. Additionally, new conjugation technology-based drugs have been developed in industry. In addition to chemotherapy, targeted therapy and immunotherapy, drug conjugate therapy has undergone continuous development and made significant progress in treating lung cancer in recent years, offering a promising strategy for the treatment of this disease. In this review, we discuss recent advances in the use of drug conjugates for lung cancer treatment, including structure-based drug design, mechanisms of action, clinical trials, and side effects. Furthermore, challenges, potential approaches and future prospects are presented.

Abstract Ever-evolving SARS-CoV-2 variants of concern (VOCs) have diminished the effectiveness of therapeutic antibodies and vaccines. Developing a coronavirus vaccine that offers a greater breadth of protection against current and future VOCs would eliminate the need to reformulate COVID-19 vaccines. Here, we rationally engineer the sequence-conserved S2 subunit of the SARS-CoV-2 spike protein and characterize the resulting S2-only antigens. Structural studies demonstrate that the introduction of interprotomer disulfide bonds can lock S2 in prefusion trimers, although the apex samples a continuum of conformations between open and closed states. Immunization with prefusion-stabilized S2 constructs elicits broadly neutralizing responses against several sarbecoviruses and protects female BALB/c mice from mouse-adapted SARS-CoV-2 lethal challenge and partially protects female BALB/c mice from mouse-adapted SARS-CoV lethal challenge. These engineering and immunogenicity results should inform the development of next-generation pan-coronavirus therapeutics and vaccines.

Abstract Purpose The Systemic Immune-inflammatory Index (SII) and Geriatric Nutritional Risk Index (GNRI) have undergone comprehensive examination and validation in forecasting the outcomes of diverse medical conditions. Nevertheless, the correlation between the combined use of GNRI and SII metrics and hip fractures has yet to be elucidated. This study aimed to determine whether the amalgamation of SII and GNRI scores constitutes an independent prognostic factor for elderly patients with hip fractures. Methods We conducted a retrospective analysis of elderly patients admitted to our facility with hip fractures, encompassing both femoral neck and intertrochanteric fractures. Demographic information, experimental parameters, and postoperative complications were systematically recorded. The Geriatric Nutritional Risk Index (GNRI) and Systemic Immunoinflammatory Index (SII) were meticulously computed. Receiver operating characteristic (ROC) curves were generated, and optimal cutoff values for each parameter were determined. Subsequently, a multivariate Cox regression analysis was employed to assess the predictive utility of the SII–GNRI score in relation to 1-year postoperative mortality among elderly patients with hip fractures. Results In a study involving 597 patients, 90 of whom experienced mortality within 1 year, it was observed that the SII-GNRI score in the group of patients who passed away was significantly higher compared to the group that survived. Following a multifactorial adjustment, it was established that a high SII–GNRI score served as an independent predictor of 1-year all-cause mortality in older patients with hip fractures. In addition to the SII–GNRI score, factors such as length of hospital stay, CCI > 2, and blood transfusion were also identified as independent risk factors for survival. Notably, the incidence of postoperative complications in patients with high SII–GNRI scores was significantly greater than in patients with low scores. Conclusion The SII–GNRI score proves valuable in predicting the 1-year survival rate for elderly patients with hip fractures who have undergone surgery.

Abstract Background The incidence of multiple primary cancers (MPC), especially involving primary lung cancer (PLC) and primary hematologic malignancies (PHM), is rising. This study aims to analyze clinicopathological features, gene abnormalities, and prognostic outcomes in individuals diagnosed with PLC-PHM MPC. Methods A retrospective analysis included 89 patients diagnosed with PLC-PHM MPC at the Respiratory or Hematology Departments of Ruijin Hospital from 2003 to 2022 (a total of 842,047 people). Next-generation sequencing (NGS) assessed lung cancer specimens, while Polymerase Chain Reaction (PCR) and NGS were used for hematologic malignancy specimens. Statistical analysis involved survival analysis and Cox regression. Results PLC-PHM MPC incidence surged from 1.67 per year (2011–2013) to 16.3 per year (2020–2022). The primary demographic for PLC-PHM MPC consists predominantly of elderly (average age 66 years) males (59.6%), with a high prevalence of metachronous MPC (89.9%). The prevailing histological types were lung adenocarcinoma (70.8%) in lung cancer (LC) and mature B-cell lymphomas (50.6%) in hematologic malignancies (HM). Notably, in a molecular testing cohort of 38 LC patients, 84.2% of lung cancer cases exhibited driver mutations, in which EGFR mutations frequence prevalent was 74.2%. In total group of 85 cases achieved a median overall survival (mOS) of 46.2 months, with a 5-year survival rate of 37.9% and advanced LC patients with LC gene mutations achieved a mOS was 52.6 months, with a 5-year OS rate of 30.6%. The median progression-free survival (PFS) following first-line treatment of 11 advanced patients with lung cancer-associated driver gene mutations is 26.6 months. Multivariate Cox regression revealed a favorable OS associated with surgery for LC, favorable PS score, adenocarcinoma pathology of LC, and the presence of genetic abnormalities associated with HM. Conclusion PLC-PHM MPC incidence is rising, characterized by a significant proportion of lung adenocarcinoma and a high prevalence of positive driver genes, especially in EGFR. Despite suffering from two primary tumors, the PLC-PHM MPC patients had superior data of both PFS and OS, suggesting an inherently intricate background of genetic abnormalities between the two kinds of tumors.