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Abstract Background The association of body mass index (BMI) with survival outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with first-line chemotherapy, immunotherapy, or chemoimmunotherapy is controversial. We aimed to investigate these associations, including associations in male and female patients specifically, in a multicenter cohort study. Methods We retrospectively analyzed data from seven cohorts comprising 7021 advanced non-small cell lung cancer patients who received chemotherapy (three cohorts), immunotherapy (two cohorts), and chemoimmunotherapy (two cohorts) from five data sources, including a de-identified nationwide (US-based) NSCLC clinico-genomic database and two randomized, double-blind, phase 3 clinical trials. BMI was categorized as underweight, normal weight, overweight, or obese. Underweight patients were excluded because of their small proportion. The primary endpoints were the associations between BMI and progression-free survival (PFS) and overall survival (OS) stratified by treatment type and sex, which were assessed using Kaplan–Meier methods and adjusted Cox modeling. Meta-analyses were performed to combine the adjusted hazard ratios. Results In the pooled analysis, obesity was significantly associated with improved OS in patients receiving chemotherapy (hazard ratios [HR] = 0.84, 95% confidence interval (CI) 0.76–0.93), but there was no association with PFS (HR = 0.91, 95% CI 0.82–1.02). The association of BMI with OS for patients receiving chemotherapy differed by sex, with an inverse association in men (HR = 0.74, 95% CI 0.64–0.84), but no association observed in women (HR = 0.96, 95% CI 0.81–1.13, Pinteraction = 0.018). No impact of BMI on OS or PFS was detected in patients receiving immunotherapy or chemoimmunotherapy. Obese patients had the lowest level of tumor mutational burden, similar level of programmed death-ligand 1 expression and ESTIMATE scores. Conclusions Obesity may be associated with an increased overall survival among male patients treated with chemotherapy, whereas not associated with the outcomes in patients treated with immunotherapy or chemoimmunotherapy.

Abstract Higher-order topological insulators (HOTIs) are unique materials hosting topologically protected states, whose dimensionality is at least by 2 lower than that of the bulk. Topological states in such insulators may be strongly confined in their corners which leads to considerable enhancement of nonlinear processes involving such states. However, all nonlinear HOTIs demonstrated so far were built on periodic bulk lattice materials. Here, we demonstrate the first nonlinear photonic HOTI with the fractal origin. Despite their fractional effective dimensionality, the HOTIs constructed here on two different types of the Sierpiński gasket waveguide arrays, may support topological corner states for unexpectedly wide range of coupling strengths, even in parameter regions where conventional HOTIs become trivial. We demonstrate thresholdless spatial solitons bifurcating from corner states in nonlinear fractal HOTIs and show that their localization can be efficiently controlled by the input beam power. We observe sharp differences in nonlinear light localization on outer and multiple inner corners and edges representative for these fractal materials. Our findings not only represent a new paradigm for nonlinear topological insulators, but also open new avenues for potential applications of fractal materials to control the light flow.

Abstract Objective To analyze primary angle closure suspect (PACS) patients’ anatomical characteristics of anterior chamber configuration, and to establish artificial intelligence (AI)-aided diagnostic system for PACS screening. Methods A total of 1668 scans of 839 patients were included in this cross-sectional study. The subjects were divided into two groups: PACS group and normal group. With anterior segment optical coherence tomography scans, the anatomical diversity between two groups was compared, and anterior segment structure features of PACS were extracted. Then, AI-aided diagnostic system was constructed, which based different algorithms such as classification and regression tree (CART), random forest (RF), logistic regression (LR), VGG-16 and Alexnet. Then the diagnostic efficiencies of different algorithms were evaluated, and compared with junior physicians and experienced ophthalmologists. Results RF [sensitivity (Se) = 0.84; specificity (Sp) = 0.92; positive predict value (PPV) = 0.82; negative predict value (NPV) = 0.95; area under the curve (AUC) = 0.90] and CART (Se = 0.76, Sp = 0.93, PPV = 0.85, NPV = 0.92, AUC = 0.90) showed better performance than LR (Se = 0.68, Sp = 0.91, PPV = 0.79, NPV = 0.90, AUC = 0.86). In convolutional neural networks (CNN), Alexnet (Se = 0.83, Sp = 0.95, PPV = 0.92, NPV = 0.87, AUC = 0.85) was better than VGG-16 (Se = 0.84, Sp = 0.90, PPV = 0.85, NPV = 0.90, AUC = 0.79). The performance of 2 CNN algorithms was better than 5 junior physicians, and the mean value of diagnostic indicators of 2 CNN algorithm was similar to experienced ophthalmologists. Conclusion PACS patients have distinct anatomical characteristics compared with health controls. AI models for PACS screening are reliable and powerful, equivalent to experienced ophthalmologists.

Abstract Microtubule-based vesicle trafficking usually relies upon kinesin and dynein motors and few reports describe microtubule polymerisation driving directional vesicle trafficking. Here we show that Arabidopsis END BINDING1b (EB1b), a microtubule plus-end binding protein, directly interacts with SYP121, a SNARE protein that mediates the trafficking of the K+ channel KAT1 and its distribution to the plasma membrane (PM) in Arabidopsis guard cells. Knockout of AtEB1b and its homologous proteins results in a modest but significant change in the distribution of KAT1 and SYP121 in guard cells and consequently delays light-induced stomatal opening. Live-cell imaging reveals that a portion of SYP121-associated endomembrane compartments co-localise with AtEB1b at the growing ends of microtubules, trafficking along with the growth of microtubules for targeting to the PM. Our study reveals a mechanism of vesicle trafficking driven by microtubule growth, which is involved in the redistribution of PM proteins to modulate guard cell movement.

AbstractContext Liuwei Dihuang pill (LWDH) has been used to treat postmenopausal osteoporosis (PMOP).Objective To explore the effects and mechanisms of action of LWDH in PMOP.Materials and methods Forty-eight female Sprague-Dawley rats were divided into four groups: sham-operated (SHAM), ovariectomized (OVX), LWDH high dose (LWDH-H, 1.6 g/kg/d) and LWDH low dose (LWDH-L, 0.8 g/kg/d); the doses were administered after ovariectomy via gavage for eight weeks. After eight weeks, the bone microarchitecture was evaluated. The effect of LWDH on the differentiation of bone marrow mesenchymal stem cells (BMSCs) was assessed via osteogenesis- and lipogenesis-induced BMSC differentiation. The senescence-related biological indices were also detected using senescence staining, cell cycle analysis, quantitative real-time polymerase chain reaction and western blotting. Finally, the expression levels of autophagy-related proteins and Yes-associated protein (YAP) were evaluated.Results LWDH-L and LWDH-H significantly modified OVX-induced bone loss. LWDH promoted osteogenesis and inhibited adipogenesis in OVX-BMSCs. Additionally, LWDH decreased the positive ratio of senescence OVX-BMSCs and improved cell viability, cell cycle, and the mRNA and protein levels of p53 and p21. LWDH upregulated the expression of autophagy-related proteins, LC3, Beclin1 and YAP, in OVX-BMSCs and downregulated the expression of p62.Discussion and conclusions LWDH improves osteoporosis by delaying the BMSC senescence through the YAP-autophagy axis.

Abstract The combination of micron zero-valent iron (mZVI) and microorganisms is an effective method for trichloroethylene (TCE) degradation, but electron transfer efficiency needs improvement. A new chem-bio hybrid process using a composite material (S-ZVI@biochar) was developed, consisting of sulfurized mZVI and biochar as a chemical remover, and Shewanella oneidensis MR-1 and dechlorinating bacteria (DB) as a biological agent for TCE degradation. S-ZVI@biochar showed improved stability, biocompatibility, and TCE removal compared to ZVI and S-ZVI. The hybrid system DB + MR-1 + S-ZVI@biochar exhibited the highest TCE removal efficiency at 96.5% after 30 days, which was 3.7 times higher than that of bare ZVI. The study revealed that the enhanced dechlorination performance was due to improved electron transfer efficiency, adjustment of microbial community structure, and iron recycling. S-ZVI@biochar constructed electron transport channels in the composite system, improving the overall dechlorination capacity. This system shows promise for long-term TCE removal in anaerobic environments.

Abstract Ultra-low-power consumption and high-speed integrated switches are highly desirable for future data centers and high-performance optical computers. In this study, we proposed an ultra-low-power consumption silicon electro-optic switch based on photonic crystal nanobeam cavities on a foundry platform. The proposed switch showed an ultra-low static-tuning power of 0.10 mW and a calculated dynamic switching power of 6.34 fJ/bit, with a compact footprint of 18 μm × 200 μm. Additionally, a 136-Gb/s four-level pulse amplitude modulation signal transmission experiment was carried out to verify the capability of the proposed electro-optic switch to support high-speed data transmission. The proposed device has the lowest static-tuning power consumption among silicon electro-optic switches and the highest data transmission rate. The results demonstrate the potential applications of this switch in high-performance optical computers, data center interconnects, optical neural networks, and programmable photonic circuits.

Abstract To gain a deeper understanding of the flowering pattern and reproductive characteristics of Epimedium sagittatum, to enrich the research on the flower development of E. sagittatum and its reproductive regulation, and to screen the methods suitable for the rapid detection of pollen viability of E. sagittatum and to promote its cross-breeding. The characteristics of its flower parts were observed, recorded and measured, and the pollen viability of E. sagittatumwas determined by five methods, including TTC staining, I2-KI staining, red ink staining, peroxidase method and in vitro germination method. The flowering process of E. sagittatum can be divided into five stages: calyx dehiscence, bract spathe, petal outgrowth, pollen dispersal, and pollination and withering. The results of I2-KI staining and peroxidase method were significantly higher than those of other methods; the in vitro germination method was intuitive and accurate, but the operation was complicated and time-consuming; the red ink staining method was easy to operate and had obvious staining effect, and the results were the closest to those of the in vitro germination method; and it was found that the pollen of E. sagittatum was not as effective as the in vitro germination method at the bud stamen stage, the flower stigma and the flower bud. It was also found that the pollen viability and germination rate of E. sagittatum pollen were higher in the three periods of bud spitting, petal adductor and pollen dispersal. Comparing the five methods, the red ink staining method was found to be a better method for the rapid detection of pollen viability; the best pollination periods of E. sagittatum were the bud stamen stage, petal adductor stage, and pollen dispersal stage of flowers at the peak of bloom. This study on the flowering and fruiting pattern of E. sagittatum, and the related mechanism of sexual reproduction, can be used as a reference for the next step of research on the breeding of E. sagittatum.

Abstract The increasing prevalence of myopia worldwide presents a significant public health challenge. A key strategy to combat myopia is with early detection and prediction in children as such examination allows for effective intervention using readily accessible imaging technique. To this end, we introduced DeepMyopia, an artificial intelligence (AI)-enabled decision support system to detect and predict myopia onset and facilitate targeted interventions for children at risk using routine retinal fundus images. Based on deep learning architecture, DeepMyopia had been trained and internally validated on a large cohort of retinal fundus images (n = 1,638,315) and then externally tested on datasets from seven sites in China (n = 22,060). Our results demonstrated robustness of DeepMyopia, with AUCs of 0.908, 0.813, and 0.810 for 1-, 2-, and 3-year myopia onset prediction with the internal test set, and AUCs of 0.796, 0.808, and 0.767 with the external test set. DeepMyopia also effectively stratified children into low- and high-risk groups (p

Abstract Background Abdominal CT scans are vital for diagnosing abdominal diseases but have limitations in tissue analysis and soft tissue detection. Dual-energy CT (DECT) can improve these issues by offering low keV virtual monoenergetic images (VMI), enhancing lesion detection and tissue characterization. However, its cost limits widespread use. Purpose To develop a model that converts conventional images (CI) into generative virtual monoenergetic images at 40 keV (Gen-VMI40keV) of the upper abdomen CT scan. Methods Totally 444 patients who underwent upper abdominal spectral contrast-enhanced CT were enrolled and assigned to the training and validation datasets (7:3). Then, 40-keV portal-vein virtual monoenergetic (VMI40keV) and CI, generated from spectral CT scans, served as target and source images. These images were employed to build and train a CI-VMI40keV model. Indexes such as Mean Absolute Error (MAE), Peak Signal-to-Noise Ratio (PSNR), and Structural Similarity (SSIM) were utilized to determine the best generator mode. An additional 198 cases were divided into three test groups, including Group 1 (58 cases with visible abnormalities), Group 2 (40 cases with hepatocellular carcinoma [HCC]) and Group 3 (100 cases from a publicly available HCC dataset). Both subjective and objective evaluations were performed. Comparisons, correlation analyses and Bland-Altman plot analyses were performed. Results The 192nd iteration produced the best generator mode (lower MAE and highest PSNR and SSIM). In the Test groups (1 and 2), both VMI40keV and Gen-VMI40keV significantly improved CT values, as well as SNR and CNR, for all organs compared to CI. Significant positive correlations for objective indexes were found between Gen-VMI40keV and VMI40keV in various organs and lesions. Bland-Altman analysis showed that the differences between both imaging types mostly fell within the 95% confidence interval. Pearson’s and Spearman’s correlation coefficients for objective scores between Gen-VMI40keV and VMI40keV in Groups 1 and 2 ranged from 0.645 to 0.980. In Group 3, Gen-VMI40keV yielded significantly higher CT values for HCC (220.5HU vs. 109.1HU) and liver (220.0HU vs. 112.8HU) compared to CI (p

Abstract Background Resistance to immune checkpoint inhibitors (ICIs) represents a major unmet medical need in non-small cell lung cancer (NSCLC) patients. Vascular endothelial growth factor (VEGF) inhibition may reverse a suppressive microenvironment and recover sensitivity to subsequent ICIs. Methods This phase Ib/IIa, single-arm study, comprised dose-finding (Part A) and expansion (Part B) cohorts. Patients with ICIs-refractory NSCLC were enrolled to receive anlotinib (a multi-target tyrosine kinase inhibitor) orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360 mg every 3 weeks, intravenously) on a 21-day treatment cycle. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort. The primary objectives were recommended phase 2 dose (RP2D, part A), safety (part B), and objective response rate (ORR, part B), respectively. Results Between November 2020 and March 2022, 34 patients were screened, and 21 eligible patients were enrolled (6 patients in Part A). The RP2D of anlotinib is 12 mg/day orally (14 days on and 7 days off) and nivolumab (360 mg every 3 weeks). Adverse events (AEs) of any cause and treatment-related AEs (TRAEs) were reported in all treated patients. Two patients (9.5%) experienced grade 3 TRAE. No grade 4 or higher AEs were observed. Serious AEs were reported in 4 patients. Six patients experienced anlotinib interruption and 4 patients experienced nivolumab interruption due to TRAEs. ORR and disease control rate (DCR) was 19.0% and 76.2%, respectively. Median PFS and OS were 7.4 months (95% CI, 4.3-NE) and 15.2 months (95% CI, 12.1-NE), respectively. Conclusion Our study suggests that anlotinib combined with nivolumab shows manageable safety and promising efficacy signals. Further studies are warranted. Trial registration NCT04507906 August 11, 2020.

Abstract Background There is inconclusive evidence to suggest that the expression of programmed cell death ligand 1 (PD-L1) is a putative predictor of response to EGFR-TKI therapy in advanced EGFR-mutant non-small cell lung cancer (NSCLC). We evaluated the heterogeneity in PD-L1 expression in the primary lung site and metastatic lymph nodes to analyze the association between PD-L1 expression and response for patients treated with EGFR-TKI. Methods This study reviewed 184 advanced NSCLC patients with EGFR mutations who received first-generation EGFR-TKI as first-line treatment from 2020 to 2021 at Shanghai Chest Hospital. The patients were divided into the primary lung site group (n = 100) and the metastatic lymph nodes group (n = 84) according to the biopsy site. The patients in each group were divided into TPS

BackgroundImmunotherapy has significantly advanced lung cancer treatment, particularly in nonsquamous non–small cell lung cancer (NSCLC), with overall response rates between 50% and 60%. However, about 30% of patients only achieve a stable disease state. Cryoablation has shown potential to enhance immunotherapy by modifying the tumor’s immune microenvironment through the release of antigens and immune factors. Addressing how to boost the immune response in these patients is critical. ObjectiveThis study aims to investigate the efficacy and safety of immunochemotherapy in combination with cryoablation as a first-line treatment for advanced NSCLC. MethodsThis is a phase II, pilot, open-label, single arm, single center, interventional study. Patients with stage IIIB to IIIC or IV NSCLC with T staging ranging from T1 to T2b will receive sintilimab (200 mg/m2 every 3 weeks) and chemotherapy. After 2 cycles, the feasibility of cryoablation will be considered for those with stable disease by a multidisciplinary team. Cryoablation with 3 freeze-thaw cycles will be performed for the main lesion. The third cycle of systemic therapy will begin 7 (SD 3) days after cryoablation. A total of 20 patients will be enrolled. Treatment will continue until the disease progresses, there is unacceptable toxicity, a participant withdraws consent, other discontinuation criteria are met, or the study reaches completion. The primary objective is to assess progression-free survival (PFS). The secondary objective is to assess efficacy through duration of response, disease control rate, overall survival (OS), and the safety profile. The exploratory objective is to investigate and compare immune factor changes after 2 cycles of immunochemotherapy and at 1, 3, and 7 days after cryoablation. Survival time will be estimated using the Kaplan-Meier method to calculate median PFS and OS. Any adverse events that occur during the trial will be promptly recorded. ResultsThe project was funded in 2024, and enrollment will be completed in 2025. The first results are expected to be submitted for publication in 2027. ConclusionsThis study will provide evidence for the efficacy and safety of the combination of immunochemotherapy and cryoablation as a first-line treatment for advanced NSCLC. Although it has a limited sample size, the findings of this study will be used in the future to inform the design of a fully powered, 2-arm, larger-scale study. Trial RegistrationClinicalTrials.gov NCT06483009; https://clinicaltrials.gov/study/NCT06483009 International Registered Report Identifier (IRRID)PRR1-10.2196/64950

This study was conducted from June to September 2020 and conducted a population-based study of 2149 rural Dai residents aged 50 years or above in Xishuangbanna. The definition of hypertension was a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg, or a current treatment plan with an antihypertensive medication. High blood pressure (HBP) included the following subtypes: SDH, ISH and IDH. All participants were interviewed, had physical examinations performed, and had blood pressure measurements taken. Multivariable logistic regression analysis was applied to analyse the risk factors for hypertension. The prevalence of HBP was 43.2 %. The subtype-specific prevalence of hypertension was 16.5 % for SDH, 24.2 % for ISH and 2.5 % for IDH. Among hypertensive participants, 38.2 % were SDH, 56.0 % were ISH and 5.8 % were IDH. Older age is a risk factor for HBP and ISH. Obesity, smoking, drinking and history of hypertension are risk factors for HBP and its subtypes including SDH and ISH (OR >1). Among all the hypertensive participants, only 25.0 % of the participants were aware of their hypertension while 34.7 % of SDH participants, 20.0 % of ISH participants and 9.3 % of IDH participants knew the individual subtype of hypertension. Among Dai people, the prevalence of hypertension is high, while the awareness and the rate of adequate treatment of hypertension is low. ISH stood out as the most prevalent type of HBP among the rural elderly. Rising ageing population in China, ISH remains an important public health problem and a challenging management issue in rural China.

Abstract Alzheimer's disease (AD) is a type of dementia characterized by a decline in brain function, which leads to the inability to perform activities independently. Many researchers recognize abnormalities related to beta‐amyloid as the main cause of the disease (i.e., the beta‐amyloid hypothesis), but aging, genetics, coronary heart disease, environmental factors, gender, and other risk factors may also contribute to AD development. Three drugs with different mechanisms are available for AD treatment: cholinesterase inhibitors, N‐methyl d‐aspartate, and aducanumab. This study reviewed the therapies that are already applied in clinical practice and those that are currently being investigated for clinical use. These therapies include not only pharmacological treatments but also non‐pharmacological treatments, such as gut flora therapy and music therapy. A comprehensive understanding of these therapies is necessary to enable early intervention, improve patients' physical and mental conditions, delay the occurrence and development of AD, and extend patients' healthy lifespans.

Abstract Background The 9th edition of the TNM Classification for lung cancer delineates M1c into two subcategories: M1c1 (Multiple extrathoracic lesions within a single organ system) and M1c2 (Multiple extrathoracic lesions involving multiple organ systems). Existing research indicates that patients with lung cancer in stage M1c1 exhibit superior overall survival compared to those in stage M1c2. The primary frontline therapy for patients with advanced non‐small cell lung cancer (NSCLC), lacking driver gene mutations, involves the use of immune checkpoint inhibitors (ICIs) combined with chemotherapy. Nevertheless, a dearth of evidence exists regarding potential survival disparities between NSCLC patients with M1c1 and M1c2 undergoing first‐line immune‐chemotherapy, and reliable biomarkers for predicting treatment outcomes are elusive. Serum metabolic profiles may elucidate distinct prognostic mechanisms, necessitating the identification of divergent metabolites in M1c1 and M1c2 undergoing combination therapy. This study seeks to scrutinize survival discrepancies between various metastatic patterns (M1c1 and M1c2) and pinpoint metabolites associated with treatment outcomes in NSCLC patients undergoing first‐line ICIs combined with chemotherapy. Method In this study, 33 NSCLC patients lacking driver gene mutations diagnosed with M1c1, and 22 similarly diagnosed with M1c2 according to the 9th edition of TNM Classification, were enrolled. These patients received first‐line PD‐1 inhibitor plus chemotherapy. The relationship between metastatic patterns and progression‐free survival (PFS) in patients undergoing combination therapy was analyzed using univariate and multivariate Cox regression models. Serum samples were obtained from all patients before treatment initiation for untargeted metabolomics analysis, aiming to identify differential metabolites. Results In the univariate analysis of PFS, NSCLC patients in M1c1 receiving first‐line PD‐1 inhibitor plus chemotherapy exhibited an extended PFS (HR = 0.49, 95% CI, 0.27–0.88, p = 0.017). In multivariate PFS analyses, these M1c1 patients receiving first‐line PD‐1 inhibitor plus chemotherapy also demonstrated prolonged PFS (HR = 0.45, 95% CI, 0.22–0.92, p = 0.028). The serum metabolic profiles of M1c1 and M1c2 undergoing first‐line PD‐1 inhibitors plus chemotherapy displayed notable distinctions. In comparison to M1c1 patients, M1c2 patients exhibited alterations in various pathways pretreatment, including platelet activation, linoleic acid metabolism, and the VEGF signaling pathway. Diminished levels of lipid‐associated metabolites (diacylglycerol, sphingomyelin) were correlated with adverse outcomes. Conclusion NSCLC patients in M1c1, devoid of driver gene mutations, receiving first‐line PD‐1 inhibitors combined with chemotherapy, experienced superior outcomes compared to M1c2 patients. Moreover, metabolomic profiles strongly correlated with the prognosis of these patients, and M1c2 patients with unfavorable outcomes manifested distinct changes in metabolic pathways before treatment. These changes predominantly involved alterations in lipid metabolism, such as decreased diacylglycerol and sphingomyelin, which may impact tumor migration and invasion.

ABSTRACTCandida albicans is a common fungal pathogen that can cause life-threatening infections. MIR1 is considered to be a mitochondrial phosphate carrier of C. albicans, while its role in virulence has not been fully elucidated. In this study, we found that mir1Δ/Δ mutant exhibited severe virulence defect in both nematode and murine models. Further mechanism studies revealed that the mir1Δ/Δ mutant grew more slowly than the wild-type strain and showed severe filamentation defects on the hypha-inducing agar media, including YPD + serum, Lee, Spider + glucose, SLAD, SLD, and YPS. Furthermore, the loss of MIR1 resulted in unfermentable carbon utilisation defect, ATP decrease, and reactive oxygen species (ROS) accumulation in C. albicans. Antioxidant proanthocyanidins, vitamin E, and N-acetyl cysteine (NAC) could reduce intracellular ROS levels and partially rescue the filamentation defects of the mir1Δ/Δ mutant. Accordingly, hypha-specific genes, as well as CEK1 and RIM101 were down-regulated in the mir1Δ/Δ mutant, and this down-regulation could be partially rescued by the addition of the antioxidant NAC. Collectively, MIR1 plays an important role in C. albicans mitochondrial function, filamentation and virulence, and would be a promising antifungal target.

Many transmission channels of monetary policy have been proposed to enrich and deepen the understanding of its mechanisms. However, some channels have not been clarified, particularly for those unconventional quantitative policies implemented after 2008 financial crisis. In this paper, we develop a unified model of a credit economy where bank regulations and decisions and loanable funds market are placed at a central position, while stocks and flows are incorporated with each other to formulate banks' credit creation and circulation. We find that bank regulations can induce some new channels of monetary transmission by imposing credit constraints, including the new bank capital channel, the credit supply channel, the new bank balance sheet channel, and the new bank risk-taking channel. Comparing these channels with the traditional ones, we underscore the impact of bank regulations on monetary transmission. As aggregate demand can be decomposed into two monetary flows generated by money circulation and bank lending respectively, the direct channels of monetary transmission to aggregate demand can be renewed as follows: the money channel, the narrow money circulation channel, the new bank lending channel, and the repayment channel. In addition, based on the relevant data from the United States, we have conducted vector autoregressive (VAR) impulse response analysis to confirm the effectiveness of some direct channels. Our work not only aids in revisiting the monetary transmission from a credit view but also facilitates the assessment of efficiency of monetary policy.

Objectives The TP53 mutation, a prevalent tumor suppressor gene alteration, is linked to chemotherapy resistance, increased relapse rates and diminished overall survival (OS) in acute myeloid leukemia (AML) patients.Methods In this study, we characterize the TP53 mutation phenotypes across various AML cohorts utilizing The Cancer Genome Atlas (TCGA) data. We devised a TP53-related prognostic signature derived from differentially expressed genes between mutated and wild-type TP53 AML specimens. In-depth analyses were conducted, encompassing genetic variation, immune cell infiltration and prognostic stratification.Results A six-gene TP53-related signature was established using least absolute shrinkage and selection operator (LASSO)–Cox regression, demonstrating robust prognostic predictability. This signature exhibited strong performance in both the OHSU validation cohorts, an independent Gene Expression Omnibus (GEO) validation cohort (GSE71014) and proved by results of the in vivo experiment. Finally, we used single cell database (GSE198681) to observe the characteristics of these six genes.Discussion Our study may facilitate the development of efficacious therapeutic approaches and provide a novel idea for future research. Conclusion: The TP53-related signature and pattern hold the potential to refine prognostic stratification and underscore emerging targeted therapies.

Abstract Heat treatment is carried out on 20MnCr5 gear steel using a cycle carburizing process. The dispersed carbide precipitation mechanism in the carburized layer of 20MnCr5 gear steel is revealed, and the metallographic organization, microhardness, wear resistance, and fatigue properties are tested. The precipitation mechanism of two kinds of dispersed carbides at grain boundary and inside grain in carburized layer of gear steel was observed by experiment. The size of dispersed carbide particles is 0–5 μm, and 90% of the dispersed carbide is appropriately smaller than 1 μm. Compared to gears without dispersed carbide, gears with dispersed carbide have high microhardness within a 0.4 mm depth below the surface and a low friction coefficient. It has been verified by bench test that the presence of diffuse carbides dramatically improves the fatigue life of the gears after shot blasting and shot peening.

Under high-temperature and high-load operational conditions, inadequate ventilation and suboptimal cooling arrangements within indoor substations result in high oil temperatures, posing a threat to the secure and steady operation of transformers. In this paper, the ventilation and heat dissipation effect of a 110 kV indoor substation is studied by the computational fluid dynamics method. Initially, the three-dimensional simulation model of the main transformer chamber is constructed to mirror the actual substation structure. Subsequently, the impact of the upper outlet on ventilation and heat dissipation is explored. The results show that the proximity of the upper outlet to the fan on the side wall prompts the fan to draw air from the upper outlet, diminishing the air volume entering the lower intake outlet by 38.8 %. It proves detrimental to the transformer's heat dissipation efficiency. Lastly, with the upper outlet closed, the study delves into the impact of various configurations of intake and exhaust ports on optimizing ventilation and heat dissipation. A total of six cases of two scenarios for the air inlet location and three exhaust vent positions are explored. According to the simulation results, the optimal case of substation ventilation and heat dissipation is obtained by considering four evaluation parameters.

This paper investigates the ventilation and heat dissipation performance of a 110 kV indoor substation under natural ventilation conditions using computational fluid dynamics (CFD). The objectives are to evaluate the influences of air inlet design parameters including location and size, and transformer load, on the airflow distribution, temperature field, and cooling efficiency. The study finds that staggered opposite inlets optimize cooling uniformity without airflow attenuation. Compared to a single inlet, the maximum transformer temperature is reduced by 1.3 °C and energy utilization increases by 9.1 % with staggered inlets. Increasing the inlet length ratio initially improves cooling until an optimal point (The length ratio is 1.10), while reducing the inlet height ratio decreases airflow and efficiency. With load increasing, the intake airflow rises but at a reduced rate, and the temperature difference can exceed 15 °C under high loads. In summary, optimizing inlet design enhances natural ventilation performance in indoor substations, but limitations exist at high loads, indicating supplemental mechanical ventilation may be required.

Green and low-carbon development is an important part of global sustainable development. Green power trading provides strong support and assurance for promoting green and low-carbon development. Due to the long cycle of green power data chains and their susceptibility to malicious tampering, the integrity and traceability of data are difficult to guarantee. Therefore, this paper first proposes a security provenance model with enhanced relations based on the core structure of PROV and blockchain technology, which can securely capture provenance records, use the transfer time and number of transactions between various links in the traceability network as reasoning clues, realize the correlation tracing of the green electricity transfer process. Under the model, a traceability mechanism of green electricity is designed based on smart contracts. Trustworthy green electricity data collection is achieved through data filling and data verification techniques. Traceability query technique is adopted to achieve trustworthy traceability of green electricity. And the effectiveness of the proposed solution is demonstrated through simulation experiments.

Abstract This research explores the potential of multimodal fusion for the differential diagnosis of early-stage lung adenocarcinoma (LUAD) (tumor sizes < 2 cm). It combines liquid biopsy biomarkers, specifically extracellular vesicle long RNA (evlRNA) and the computed tomography (CT) attributes. The fusion model achieves an impressive area under receiver operating characteristic curve (AUC) of 91.9% for the four-classification of adenocarcinoma, along with a benign-malignant AUC of 94.8% (sensitivity: 89.1%, specificity: 94.3%). These outcomes outperform the diagnostic capabilities of the single-modal models and human experts. A comprehensive SHapley Additive exPlanations (SHAP) is provided to offer deep insights into model predictions. Our findings reveal the complementary interplay between evlRNA and image-based characteristics, underscoring the significance of integrating diverse modalities in diagnosing early-stage LUAD.

Abstract Background Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer’s disease (AD). However, the roles of additional novel protein biomarkers in AD etiology remains elusive. The availability of large-scale AD GWAS and plasma proteomic data provide the resources needed for the identification of causally relevant circulating proteins that may serve as risk factors for AD and potential therapeutic targets. Methods We established and validated genetic prediction models for protein levels in plasma as instruments to investigate the associations between genetically predicted protein levels and AD risk. We studied 71,880 (proxy) cases and 383,378 (proxy) controls of European descent. Results We identified 69 proteins with genetically predicted concentrations showing associations with AD risk. The drugs almitrine and ciclopirox targeting ATP1A1 were suggested to have a potential for being repositioned for AD treatment. Conclusions Our study provides additional insights into the underlying mechanisms of AD and potential therapeutic strategies.

AbstractBackground Phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) are involved in the clearance of Mycobacterium tuberculosis (MTB) by macrophages.Aim This study aimed to investigate the effects of polymorphisms in the PI3K/AKT genes and the gene-smoking interaction on susceptibility to TB.Methods This case-control study used stratified sampling to randomly select 503 TB patients and 494 control subjects. Logistic regression analysis was used to determine the association between the polymorphisms and TB. Simultaneously, the marginal structure linear dominance model was used to estimate the gene-smoking interaction.Results Genotypes GA (OR 1.562), AA (OR 2.282), and GA + AA (OR 1.650) at rs3730089 of the PI3KR1 gene were significantly associated with the risk to develop TB. Genotypes AG (OR 1.460), GG (OR 2.785), and AG + GG (OR 1.622) at rs1130233 of the AKT1 gene were significantly associated with the risk to develop TB. In addition, the relative excess risk of interaction (RERI) between rs3730089 and smoking was 0.9608 (95% CI: 0.5959, 1.3256, p

Abstract Introduction Durvalumab is a check‐point inhibitor against programmed death ligand‐1 (PD‐L1), and anlotinib is a new orally administered multitarget tyrosine kinase inhibitor (TKI). Both agents have been approved in China. Preclinical and clinical trials have suggested that antiangiogenic therapy has the potential to alleviate immunosuppression and showed synergetic effect when combined with ICIs. However, it is unclear that whether this combination is effective when initiated as maintenance treatment in ES‐SCLC patients. Methods This is a multicenter, randomized, phase II study. A total of 64 eligible patients who do not experience disease progression after four cycles platinum‐based chemotherapy combined with durvalumab will be randomized to durvalumab with anlotinib or durvalumab alone until disease progression, withdrawal of consent, or unacceptable toxicity. The primary endpoint is PFS (from randomization); secondary endpoint was OS and PFS (from diagnosis), objective response rate (ORR); disease control rate (DCR) and duration of response (DOR), safety and tolerability assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Discussion We conduct a phase II study to investigate the safety and efficacy of durvalumab combined with anlotinib as maintenance treatment in ES‐SCLC patients.

Abstract Alzheimer disease (AD) is a common neurodegenerative disease with a late onset. It is critical to identify novel blood-based DNA methylation biomarkers to better understand the extent of the molecular pathways affected in AD. Two sets of blood DNA methylation genetic prediction models developed using different reference panels and modelling strategies were leveraged to evaluate associations of genetically predicted DNA methylation levels with AD risk in 111,326 (46,828 proxy) cases and 677,663 controls. A total of 1,168 cytosine-phosphate-guanine (CpG) sites showed a significant association with AD risk at a false discovery rate (FDR)

Objectives Circular RNAs (circRNAs) serve a crucial regulatory role in ovarian cancer (OC). Circular RNA ArfGAP with FG repeats 1 (circAGFG1) has been shown to be involved in promoting the progression of several cancers, containing triple-negative breast cancer, esophageal cancer and colorectal cancer. However, the function of circAGFG1 in OC is unclear. Methods Quantitative real-time reverse transcription PCR (RT-qPCR) was conducted to determine the expression levels of circAGFG1 and miR-409-3p. The proliferation and metastasis of cells were determined by colony formation assays, EdU assays, transwell assays and wound healing assays. In addition, a dual-luciferase reporter assay was performed to validate the mechanism between circAGFG1, miR-409-3p, and ZEB1. Results Our data suggested that circAGFG1 was significantly overexpressed in OC tissues compared to normal ovarian epithelial tissues. Overexpression of circAGFG1 was correlated with intraperitoneal metastasis, tumor recurrence and advanced stage. Additionally, circAGFG1 overexpression revealed a poor prognosis in OC patients. Knockdown of circAGFG1 suppressed the proliferation, invasion and migration of OC cells. Mechanistically, circAGFG1 acted as a sponge of miR-409-3p to enhance the expression level of zinc finger E-box binding homeobox 1 (ZEB1), thereby conferring OC cell proliferation, invasion and migration. Importantly, re-expression of ZEB1 effectively reversed the effects of circAGFG1 knockdown on OC cells. Conclusions In summary, our study indicated that circAGFG1 may act as a prognostic biomarker and potential therapeutic target for patients with OC.

Background Combining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene mutations. Reliable biomarkers are essential for predicting treatment outcomes. Emerging evidence from various cancers suggests that early assessment of serum metabolites could serve as valuable biomarkers for predicting outcomes. This study aims to identify metabolites linked to treatment outcomes in patients with advanced NSCLC undergoing first-line or second-line therapy with programmed cell death 1 (PD-1) inhibitors plus chemotherapy.Method 200 patients with advanced NSCLC receiving either first-line or second-line PD-1 inhibitor plus chemotherapy, and 50 patients undergoing first-line chemotherapy were enrolled in this study. The 200 patients receiving combination therapy were divided into a Discovery set (n=50) and a Validation set (n=150). These sets were further categorized into respond and non-respond groups based on progression-free survival PFS criteria (PFS≥12 and PFS1 and p

The lungs are a key organ in the respiratory system. They are regulated by a complex network of nerves that control their development, structure, function, and response to various pathological stimuli. Accumulating evidence suggests the involvement of a neural mechanism in different pathophysiological conditions in the lungs and the development and progression of common respiratory diseases. Lung diseases are the chief source of death globally. For instance, lung cancer is the second most commonly diagnosed malignancy, after prostate cancer in men and breast cancer in women, and is the most lethal cancer worldwide. However, although airway nerves are accepted as a mechanistically and therapeutically important feature that demands appropriate emphasizing in the context of many respiratory diseases, significantly less is known about the role of the neuroglial cells in lung physiology and pathophysiology, including lung cancer. New data have uncovered some cellular and molecular mechanisms of how Schwann cells, as fundamental components of the peripheral nervous system, may regulate lung cancer cells’ survival, spreading, and invasiveness in vitro and in vivo. Schwann cells control the formation and maintenance of the lung cancer microenvironment and support metastasis formation. It was also reported that the number of lung cancer-associated Schwann cells correlates with patients’ survival. Different factors secreted by Schwann cells, including microRNA, are known to sharpen the lung cancer environment by regulating the tumor-neuro-immune axis. Further clinical and experimental studies are required to elucidate the detailed role of Schwann cells in creating and maintaining pulmonary tumor-neuro-immune axis, which will advance our understanding of the pathogenesis of lung cancer and may inform therapeutic hypotheses aiming neoplasms and metastases in the lung.

AIM:To investigate the neuroprotective effect of 17β-estradiol(E2)on retina light damage in BALB/c and C57BL/6 mice and provide experimental data for the successful construction of a research model for E2 against retinal light damage.METHODS:Totally 40～45 adult female BALB/c or C57BL/6 mice were divided into six groups, 6 for each group: normal control, ovariectomized control, ovariectomized light(mice were stimulated with continuous white light at 10000 lx for 4, 8, 12, 16, and 24h after 14d of ovariectomy), intravitreal administration sham operation, saline and E2 pre-treatment groups(2μL saline or 10-5mol/L E2 were intravitreal injected respectively after 14d of ovariectomy operation and 24h of dark adaptation). The morphological and functional changes of the retina were detected by paraffin section HE staining, TUNEL staining and electroretinogram.RESULTS:In the ovariectomized light group, the thickness of the inner/outer nuclear layer decreased significantly from the 4h stimulation of 10000 lx white light group. Intravitreal administration of E2 significantly inhibited the apoptosis of retinal cells in the two strains of mice(P

Abstract Pleural contact in lung cancers does not always imply pleural invasion (PI). This study was designed to determine whether specific invasive CT characteristics or iodine uptake can aid in the prediction of PI. The sample population comprised patients with resected solid lung adenocarcinomas between April 2019 and May 2022. All participants underwent a contrast enhanced spectral CT scan. Two proficient radiologists independently evaluated the CT features and iodine uptake. Logistic regression analyses were employed to identify predictors for PI, via CT features and iodine uptake. To validate the improved diagnostic efficiency, accuracy analysis and ROC curves were subsequently used. A two-tailed P value of less than 0.05 was considered statistically significant. We enrolled 97 consecutive patients (mean age, 61.8 years ± 10; 48 females) in our study. The binomial logistic regression model revealed that a contact length > 10 mm (OR 4.80, 95% CI 1.92, 11.99, p = 0.001), and spiculation sign (OR 2.71, 95% CI 1.08, 6.79, p = 0.033) were independent predictors of PI, while iodine uptake was not. Enhanced sensitivity (90%) and a greater area under the curve (0.73) were achieved by integrating the two aforementioned CT features in predicting PI. We concluded that the combination of contact length > 10 mm and spiculation sign can enhance the diagnostic performance of PI.

Abstract Diabetic retinopathy is one of the most common and serious microvascular complications of diabetes mellitus. There are many factors leading to diabetic retinopathy, and its pathogenesis is still unclear. At present, there are still no effective measures for the early treatment of diabetic retinopathy, and the treatment options available when diabetes progresses to advanced stages are very limited, and the treatment results are often unsatisfactory. Detailed studies on the molecular mechanisms of diabetic retinopathy pathogenesis and the development of new therapeutic agents are of great importance. This review describes the potential pathogenesis of diabetic retinopathy for experimental studies and clinical practice.

Thickness affects the electrical breakdown strength (EBD) of insulation materials, and the variation of EBD with thickness (d) is an important basis for insulation design. In this paper, the effect of d on three kinds of organic insulation materials (OIMs), namely polymethyl methacrylate (PMMA), polyetheretherketone (PEEK), and polyethylene terephthalate (PET), on their breakdown characteristics under microsecond pulse voltage (MSPV) was studied, and a breakdown probability prediction model was established based on Weibull distribution. The breakdown mechanisms of the OIMs under MSPV were also discussed. The results showed that the EBD of all three materials decreased with increasing d. The relationship between characteristic EBD and d all satisfied the inverse power model, and their inverse power coefficients were all close to 1/2.3, which was much larger than 1/8 for that under nanosecond pulse voltage. A general breakdown probability prediction model of the OIMs was established by combining the Weibull distribution and β = 2.3 so as to guide engineering design in the absence of basic test data under MSPV. The breakdown mechanism of the OIMs under MSPV was an energy-related composite physical breakdown mechanism, which was verified by analysis of energy accumulation characteristics and experimental evidence of the little influence of pulse width on EBD under MSPV. The research results lay the foundation for the insulation design and further study on the breakdown modeling of OIM under MSPV.

Abstract Objective Immunotherapy extensively treats advanced non‐small‐cell lung cancer (NSCLC). Although immunotherapy is generally better tolerated than chemotherapy, it can cause multiple immune‐related adverse events (irAEs) involving multiple organs. Checkpoint inhibitor‐related pneumonitis (CIP) is a relatively uncommon irAE that, in severe cases, can be fatal. Potential risk factors for the occurrence of CIP are currently poorly understood. This study sought to develop a novel scoring system for predicting the risk of CIP based on a nomogram model. Methods We retrospectively collected advanced NSCLC patients who received immunotherapy at our institution between January 1, 2018, and December 30, 2021. All patients who met the criteria were randomly divided into the training set and testing set (in a ratio of 7:3), and cases fulfilling the CIP diagnostic criteria were screened. The patients' baseline clinical characteristics, laboratory tests, imaging, and treatment information were extracted from the electronic medical records. The risk factors associated with the occurrence of CIP were identified based on the results of logistic regression analysis on the training set, and a nomogram prediction model was developed. The discrimination and prediction accuracy of the model was evaluated using the receiver operating characteristic (ROC) curve, the concordance index (C‐index), and the calibration curve. Decision curve analysis (DCA) was used to evaluate the clinical applicability of the model. Results The training set comprised 526 (CIP: 42 cases), and the testing set comprised 226 (CIP: 18 cases) patients, respectively. In the training set, the final multivariate regression analysis revealed that age (p = 0.014; odds ratio [OR] = 1.056; 95% Confidence Interval [CI] =1.011–1.102), Eastern Cooperative Oncology Group performance status (p = 0.002; OR = 6.170; 95% CI = 1.943–19.590), history of prior radiotherapy (p

Abstract Background To assess the anxiety and depression levels in patients with Posner-Schlossman syndrome (PSS) and to determine the potential risk factors. Methods In this cross-sectional study, a total of 195 participants, including 93 PSS patients and 102 healthy controls were recruited. Sociodemographic and clinical information were collected for all participants. Hospital Anxiety and Depression scale (HADS) was administered to evaluate the anxiety and depression levels. Visual function (VF) and quality-of-life (QOL) questionnaires were administered to assess variables potentially associated with anxiety and depression. Results Increased anxiety level was observed in 22 (23.7%) PSS patients as compared to 10 (9.8%) of controls (P = 0.009). While the frequency of depression between the two groups was not significantly different (P = 0.349). The mean anxiety and depression scores were 6.98 ± 4.20 and 6.44 ± 3.66 in PSS patients as compared to 6.67 ± 3.21 (P = 0.564) and 5.96 ± 2.93 (P = 0.311) in controls. Logistic regression analysis showed mental well-being was significantly associated with anxiety (odds ratio [OR] = 0.920, 95% confidence interval [CI] = 0.881–0.962, P

Abstract Background Long non-coding RNA (lncRNA) closely associates with numerous biological processes, and with many diseases. Therefore, lncRNA-disease association prediction helps obtain relevant biological information and understand pathogenesis, and thus better diagnose preventable diseases. Results Herein, we offer the LDAF_GAN method for predicting lncRNA-associated disease based on association filtering and generative adversarial networks. Experimentation used two types of data: lncRNA-disease associated data without lncRNA sequence features, and fused lncRNA sequence features. LDAF_GAN uses a generator and discriminator, and differs from the original GAN by the addition of a filtering operation and negative sampling. Filtering allows the generator output to filter out unassociated diseases before being fed into the discriminator. Thus, the results generated by the model focuses only on lncRNAs associated with disease. Negative sampling takes a portion of disease terms with 0 from the association matrix as negative samples, which are assumed to be unassociated with lncRNA. A regular term is added to the loss function to avoid producing a vector with all values of 1, which can fool the discriminator. Thus, the model requires that generated positive samples are close to 1, and negative samples are close to 0. The model achieved a superior fitting effect; LDAF_GAN had superior performance in predicting fivefold cross-validations on the two datasets with AUC values of 0.9265 and 0.9278, respectively. In the case study, LDAF_GAN predicted disease association for six lncRNAs-H19, MALAT1, XIST, ZFAS1, UCA1, and ZEB1-AS1-and with the top ten predictions of 100%, 80%, 90%, 90%, 100%, and 90%, respectively, which were reported by previous studies. Conclusion LDAF_GAN efficiently predicts the potential association of existing lncRNAs and the potential association of new lncRNAs with diseases. The results of fivefold cross-validation, tenfold cross-validation, and case studies suggest that the model has great predictive potential for lncRNA-disease association prediction.

Abstract Rectal cancer is one of the most common lower gastrointestinal diseases worldwide. Currently, the common treatment is low anterior resection (LAR) of the rectum, which preserves the anus of the patient. However, it is easy to cause low anterior resection syndrome after surgery, which has a significant negative impact on the life of patients, and there is no unified evaluation standard for postoperative rectal function. To solve this problem, a multi‐sensor fusion rectal information acquisition system is designed in this paper, and a rectal signal processing method is proposed to theoretically evaluate the rectal function of postoperative patients. The method uses the complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) to decompose the one‐dimensional rectal signal to solve the underdetermined ICA problem, uses the Fast independent component analysis (Fast‐ICA) to separate the pure rectal signal, uses the wavelet packet to extract features, and uses the particle swarm optimization optimizes support vector machine (PSO‐SVM) to classify and evaluate postoperative function. According to the experimental results, the rectal signal preprocessing effect is good, the evaluation prediction rate is 99.5565%, and the algorithm classification results are accurate, which provides a certain preliminary theoretical basis and reference value for the evaluation of rectal function after LAR.

Background. Antihypertensive therapy is crucial for preventing stroke in hypertensive patients. However, the efficacy of antihypertensive therapy varies across individuals, partially due to therapy-related genetic variations among individuals. We investigated the association of antihypertensive drug-related gene polymorphism with stroke in patients with hypertension. Methods. Demographic information, medication, and outcome data were obtained from a hypertensive patient management system, and a PCR fluorescence probe technique was used to detect 7 gene polymorphic loci (CYP2D6∗10, ADRB1, CYP2C9∗3, AGTR1, ACE, CYP3A5∗3, and NPPA), and these loci were compared between patients with and without stroke. Logistic regression was performed to analyze the association of these genetic variations with stroke risk in hypertensive patients while controlling for potential factors. Results. The prevalence of stroke in the hypertensive population in Changsha County of Hunan Province was 2.75%. The mutation frequencies of ADRB1 (1165G > C), CYP2D6∗10, CYP2C9∗3, AGTR1 (1166A > C), ACE (I/D), NPPA (2238T > C), and CYP3A5∗3 were 74.43%, 57.23%, 4.26%, 5.71%, 31.62%, 1.17%, and 69.58%, respectively. Univariate analysis revealed that ADRB1 polymorphism was associated with stroke (χ2 = 8.659, P C), ACE (I/D), CYP3A5∗3, and NPPA (2238T > C) polymorphisms and stroke. Conclusions. ADRB1 (1165G > C) gene polymorphism is associated with the risk of stroke in Chinese hypertensive patients. The CC genotype is correlated with a higher risk of stroke than the GC + GG genotype.

Abstract Major depressive disorder (MDD) is the most prevalent form of depression and is becoming a great challenge for public health and medical practice. Although first-line antidepressants offer therapeutic benefits, about 35% of depressed patients are not adequately treated, creating a substantial unmet medical need. A multicenter, double-blind, randomized, placebo-controlled phase 3 clinical trial was conducted in patients with MDD in China to assess the efficacy and safety of ansofaxine (LY03005), a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine. Eligible 588 MDD patients were included and randomly assigned (1:1:1) to 8-week treatment with ansofaxine 80 mg/day(n = 187), ansofaxine 160 mg/day(n = 186), or placebo(n = 185). The primary efficacy endpoint was the Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from baseline to the end of the study. Safety indexes included adverse events, vital signs, physical examination, laboratory tests, 12-lead electrocardiogram (ECG), and evaluation of suicide tendency and sexual function. Significant differences were found in mean changes in MADRS total score at week 8 in the two ansofaxine groups (80 mg, −20.0; 160 mg, −19.9) vs. placebo (−14.6; p

Abstract Objectives Treatments for advanced small‐cell lung cancer (SCLC) patients who are resistant to first‐line chemotherapy are limited. Given that antiangiogenic agents and immune‐checkpoint inhibitors (ICIs) can confer synergistic therapeutic benefits, combination therapy should be considered. We explored the efficacy and safety of combination therapy with anlotinib and programmed cell death protein 1 (PD‐1)/programmed cell death‐ligand 1 (PD‐L1) inhibitors as second‐line and subsequent therapy for advanced SCLC. Materials and Methods We reviewed advanced SCLC patients at Shanghai Chest Hospital who had received anlotinib in combination with ICIs from November 2016 to November 2020 as second‐ and subsequent‐line treatment. Patients with advanced SCLC who had received paclitaxel monotherapy as second‐line treatment were included as the control group. Results A total of 141 patients were included in the final analysis (40 in the combination therapy group and 101 in the paclitaxel monotherapy group). The median progression‐free survival (PFS) times for the combination therapy and paclitaxel monotherapy groups were 3.40 and 2.83 months (p = 0.022), respectively, while the median overall survival (OS) times for the combination therapy and paclitaxel monotherapy groups were 8.20 and 5.87 months (p = 0.048), respectively. Hypertension and hepatic dysfunction were the most pronounced adverse events of combination therapy and two patients changed regimens due to severe fatigue and anorexia. Conclusion The combination of anlotinib and PD‐1/PD‐L1 blockade has promising efficacy and safety as a second‐line or subsequent therapy for SCLC.

The widespread use of orthopedic implants to support or replace bones is increasingly threatened by the risk of incurable bacterial infections, impenetrable microbial biofilms, and irreversible antibiotic resistance. In the past, the development of anti-infective biomaterials focused solely on direct antibacterial properties while ignoring the host's immune response. Inspired by the clearance of infection by the innate neutrophil response and participation in anti-infectious immunity of Zn ions, we report an innovative neutrophil extracellular traps (NETs) strategy, induced by biodegradable pure Zn, which achieved therapeutic efficacy toward biomaterial-related infections. Our in vitro and in vivo data showed that pure Zn was favorable for NETs formation by promoting the release of DNA fibers and granule proteins in a reactive oxygen species (ROS)-dependent manner, thereby retraining and degrading bacteria with an efficiency of up to 99.5%. Transcriptome analysis revealed that cytoskeletal rearrangement and toll-like receptor (TLR) signaling pathway were also involved in Zn-induced NETs formation. Furthermore, the in vivo results of a Staphylococcus aureus (S. aureus)-infected rat model verified that pure Zn potentiated the bactericidal capability of neutrophils around implants, and promoted osseointegration in S. aureus-infected rat femurs. This antibacterial immunity concept lays a foundation for the development of other antibacterial biomaterials and holds great promise for treating orthopedic infections.

Macrobrachium rosenbergii is a warm water species, and low temperature is a limiting factor for its growth and survival. In order to explore the role of the acetyl-CoA-carboxylase (ACC) gene in response to the cold stress of M. rosenbergii, we investigated the effects of RNA interference (RNAi) with the ACC gene on the expression of fatty acid metabolism-related genes and the mortality of M. rosenbergii under cold stress. The results showed that different siRNA sequences and different injection concentrations had different inhibiting effects on ACC gene expression, and siRNA-III with an injection concentration of 2.0 μg/g (siRNA/prawn body weight) had the best interference effect. With the optimal siRNA and the optimal concentration under cold stress, the expressions of three fatty acid metabolism-related genes, FabD, echA, and ACOT, were generally significantly down-regulated. Compared to negative (scrambled-siRNA) and blank (PBS) control groups, the expression of FabD in the interference group was extremely significantly down-regulated at 12 h in the hepatopancreas and at 18 h in the muscles and gills; EchA was highly significantly down-regulated at 6 and 12 h in the muscles and gills; and ACOT was extremely significantly down-regulated and kept declining in the gills. Within 6–18 h after injection under cold stress, the mortality rate of the siRNA interference group (75%) was much lower than that of the negative (95%) or blank control group (97.5%), and all prawns died after 24 h. In conclusion, RNA interference with the ACC gene inhibited the expression of some fatty acid metabolism-related genes, and could partly improve the tolerance of M. rosenbergii to cold stress, indicating that the ACC gene might play an important role in the response of M. rosenbergii to cold stress.

Extremely preterm infants are often treated with supraphysiological oxygen, which contributes to the development of bronchopulmonary dysplasia (BPD). These same infants exhibit compromised antioxidant capacities due in part to selenium (Se) deficiency. Se is essential for basal and inducible antioxidant responses. The present study utilized a perinatal Se deficiency (SeD) mouse model to identify the combined effects of newborn hyperoxia exposure and SeD on alveolarization and antioxidant responses, including the identification of affected developmental pathways. Se-sufficient (SeS) and SeD C3H/HeN breeding pairs were generated, and pups were exposed to room air or 85% O2 from birth to 14 d. Survival, antioxidant protein expression, and RNA seq analyses were performed. Greater than 40% mortality was observed in hyperoxia-exposed SeD pups. Surviving SeD pups had greater lung growth deficits than hyperoxia-exposed SeS pups. Gpx2 and 4 protein and Gpx activity were significantly decreased in SeD pups. Nrf2-regulated proteins, Nqo1 and Gclc were increased in SeD pups exposed to hyperoxia. RNA seq revealed significant decreases in the Wnt/β-catenin and Notch pathways. Se is a biologically relevant modulator of perinatal lung development and antioxidant responses, especially in the context of hyperoxia exposure. The RNA seq analyses suggest pathways essential for normal lung development are dysregulated by Se deficiency.

Objective Recently, a new subtype of granzyme B (GrB)-producing Breg cells has been identified, which was proven to be involved in autoimmune disease. Our recent report demonstrated that GrB-producing Breg cells were correlated with clinical and immunological features of SLE. However, the effect of GrB-producing Breg cells in lupus mice is unclear.Methods GrB expression in naïve and lupus mouse B cells was analysed using flow cytometry, PCR, ELISA and ELISpot assays. To study the role of GrB-producing B cells in a lupus model, GrB knockout (KO) and wild-type (WT) mice were intraperitoneally injected with monoclonal cells from the mutant mouse strain B6.C-H-2bm12 (bm12) for 2 weeks. In addition, the function of GrB-producing Breg cells in naïve and lupus mice was further explored using in vitro B cells-CD4+CD25− T cell co-culture assays with GrB blockade/KO of B cells.Results B cells from the spleens of WT C57BL/6 (B6) mice could express and secret GrB (p

Abstract Permanent magnet eddy current couplers have been widely used in large fan and pump loads to achieve the purpose of speed regulation and energy saving. In order to reduce the coupler axial volume and simplify the actuator, a novel flux adjustable axial flux permanent magnet eddy current coupler (FAAF‐PMECC) is proposed in this paper. The permanent magnet rotor is divided into three parts: the inner, middle and outer parts, where the permanent magnets are embedded in the core and the adjacent poles are magnetised in opposite directions. The middle part is the adjusting permanent magnet ring (AR), which can rotate around the shaft. The inner part and outer part are fixed permanent magnet rings (FR) that are fixed with the shaft, and the output torque can be controlled by adjusting the relative angle of AR and FR. The structure and working principle of FAAF‐PMECC are described in detail, and the output torque analytical model of the whole regulating process is established based on the magnetic equivalent circuit method. The AR regulation process is simulated by the variable reluctance model. The validation results show that the proposed structure can achieve a good speed regulation effect, and the output torque calculated by the analytical model in a certain slip speed range matches well with the output torque obtained using the 3D finite element method and experimental measurements. The sensitivity analysis of the structure parameters is also carried out. The analysis shows that the proposed coupler can achieve a wide speed range.