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Abstract Background Some species of Culicoides (Diptera, Ceratopogonidae) are major vectors for arboviruses, and Yunnan Province is a key area for arbovirus prevalence in China. Therefore, this study attempts to search for potential Culicoides vectors for the common orbiviruses bluetongue virus (BTV), epizootic hemorrhagic disease virus (EHDV), Palyam virus (PALV) and Tibet orbivirus (TIBOV) in Yunnan Province, China. Methods Culicoides specimens were collected from 16 counties in Yunnan Province, China, using UV traps and tested for BTV, EHDV, PALV and TIBOV through one-step reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A total of 543 conspecific pools of Culicoides containing 9895 specimens were tested. Results A total of 46 species belonging to 8 subgenera and 2 groups were recognized. A total of 19 species and a Culicoides subgenus Trithecoides complex were tested using RT-qPCR. One pool of Culicoides shortti Smith & Swaminath and one pool of Culicoides orientalis Macfie tested positive for BTV, one pool of Culicoides oxystoma Kieffer tested positive for PALV, and four pools of Culicoides jacobsoni Macfie tested positive for TIBOV. All the tested samples were negative for EHDV, and all the tested C. subgenus Trithecoides midges were negative for any virus. Conclusions Culicoides shortti was identified as a potential BTV vector for the first time. Culicoides jacobsoni was confirmed as a potential TIBOV vector and C. orientalis as a potential BTV vector. Culicoides oxystoma was also shown to be a natural carrier of PALV using the RT-qPCR method. Graphical Abstract

Abstract Most of the species in Paris have important medicinal values in China. Polyphyllins are the key components in Paris, with varying levels and compositions among different species. This study investigated polyphyllin compositions of 206 Paris samples from 16 different producing areas. 9 Paris polyphylla var. yunnanensis, 3 Paris fargesii, and 3 Paris forrestii were selected based on polyphyllin levels and composition for metabolome and transcriptome analysis. A total of 1,243 metabolites were identified among these samples, along with 92.11 Gb of full-length transcriptome data. This study provides potential candidate genes involved in polyphyllins synthesis in Paris, aiming to facilitate the biosynthesis of different polyphyllins.

BackgroundThe global impact of SARS-CoV-2 and its associated coronavirus disease (COVID-19) has necessitated urgent characterization of prognostic biomarkers. This study aimed to delineate the epidemiological and clinical predictors of mortality among hospitalized COVID-19 patients.MethodsA retrospective cohort study was conducted on 123 patients with laboratory-confirmed COVID-19 admitted to Huoshenshan Hospital (Wuhan, China) from 1 February 2020 to 30 April 2020. Kaplan–Meier curve and multivariate Cox regression were used to assess the independent factors with survival time. Statistical significance was set at a p-value of

Abstract Background The initial randomized, double‐blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first‐line therapy in epidermal growth factor receptor (EGFR)‐mutated advanced non‐small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. Methods Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double‐blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow‐up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological‐BICR). The primary endpoint for this subgroup analysis was CNS progression‐free survival (PFS). Results Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological‐BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17‐0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11‐0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non‐CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. Conclusions These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR‐mutated advanced NSCLC with baseline CNS metastases. Trial registration ClinicalTrials.gov number, NCT03849768

Abstract Background Iron deficiency (ID) is the most prevalent nutritional deficiency disease in preterm infants, significantly affecting their growth and development. For preterm infants to flourish physically and neurologically, timely iron supplementation is essential. The main goals of this study were to determine whether the present iron supplementation regimen results in iron overload in late preterm infants and whether it can meet the growth requirements of early preterm infants for catch-up. Methods We conducted a prospective follow-up study on preterm infants at the Department of Child Health, West China Second University Hospital, Sichuan University, from January 1, 2020, to August 31, 2020. In this study, 177 preterm infants were divided into two groups based on gestational age—early preterm infants (gestational age

Abstract Lysosomes are important cellular structures for human health as centers for recycling, signaling, metabolism and stress adaptation. However, the potential role of lysosomes in stress‐related emotions has long been overlooked. Here, it is found that lysosomal morphology in astrocytes is altered in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social defeat stress. A screen of lysosome‐related genes revealed that the expression of the mucolipin 1 gene (Mcoln1; protein: mucolipin TRP channel 1) is decreased in susceptible mice and depressed patients. Astrocyte‐specific knockout of mucolipin TRP channel 1 (TRPML1) induced depressive‐like behaviors by inhibiting lysosomal exocytosis‐mediated adenosine 5′‐triphosphate (ATP) release. Furthermore, this stress response of astrocytic lysosomes is mediated by the transcription factor EB (TFEB), and overexpression of TRPML1 rescued depressive‐like behaviors induced by astrocyte‐specific knockout of TFEB. Collectively, these findings reveal a lysosomal stress‐sensing signaling pathway contributing to the development of depression and identify the lysosome as a potential target organelle for antidepressants.

The increasing demand for indoor positioning information has led to a growing emphasis on indoor localization. Non-Line-of-Sight (NLOS) conditions diminish the accuracy of Ultra-Wide Band (UWB) system positioning, while over time, Inertial Navigation Systems (INS) suffer from accumulating positioning errors. To address these issues, this paper proposes a method that combines UWB and INS sensors. Compared to individual system positioning methods, this approach effectively enhances localization precision, leveraging the complementary strengths of both systems. The paper utilizes Extended Kalman Filtering (EKF) to fuse residual positioning information, and the obtained residual position results are processed using the Multiple Fading Factor Square Root Kalman Filter technique (MSTSCKF). Moreover, during temporal asynchrony, it updates INS positioning and yaw angle information using EKF output for subsequent INS positioning until the next data correction. To further mitigate NLOS effects, a k-means preprocessing method is applied to UWB data. Root Mean Square Error (RMSE) is used as an evaluation metric. Simulation and experimental results demonstrate that the proposed method effectively accounts for NLOS error influences, thereby enhancing navigation and positioning accuracy.

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

Combining inertial navigation system (INS) and ultra-wideband (UWB) technologies can effectively compensate for their respective shortcomings, thus significantly enhancing the accuracy of indoor positioning systems. However, in the process of fusing these two technologies, signal fading under non-line-of-sight (NLOS) conditions, multipath effects, and errors accumulated by the INS over a long period of time are still key issues that need to be addressed. To cope with these challenges, a new fusion localization algorithm is proposed in this study. The algorithm employs a combination of fuzzy C-mean (FCM) and K-Medoids algorithms for UWB for position computation on the one hand, and an Implicit Unscented Particle Filter (IUPF)-enhanced INS for navigation information processing on the other. In addition, based on the INS error equation, this algorithm realizes the effective fusion of UWB and INS positioning information through the Minimum Error Entropy Extended Kalman Filter (MEE-EKF) technique. This integrated approach significantly improves the accuracy and stability when dealing with the localization problem in complex indoor environments. After simulation experiments under different noise conditions and real environment experiments, the algorithm proposed in this study shows significant advantages in terms of localization performance over the traditional UWB/INS localization methods in recent years. In real experiments, the algorithm achieves an average of 36.15% improvement in positioning accuracy.

Abstract Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain. Due to the advancement of immuno-oncology, an increasing number of novel immunoregulatory targets and mechanisms are being revealed, with relevant therapies promising to improve clinical immunotherapy in the foreseeable future. Therefore, comprehending the larger picture is important. In this review, we analyze and summarize the current landscape of preclinical and translational mechanistic research, drug development, and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors. Along with further clarification of cancer immunobiology and advances in antibody engineering, agents targeting additional inhibitory immune checkpoints, including LAG-3, TIM-3, TIGIT, CD47, and B7 family members are becoming an important part of cancer immunotherapy research and discovery, as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells. Exemplified by bispecific T cell engagers, newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits. Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics. Cell therapies, cancer vaccines, and oncolytic viruses are not covered in this review. This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.

To optimize the control of fan coil unit (FCU) systems under model-free conditions, researchers have integrated reinforcement learning (RL) into the control processes of system pumps and fans. However, traditional RL methods can lead to significant fluctuations in the flow of pumps and fans, posing a safety risk. To address this issue, we propose a novel FCU control method, Fluctuation Suppression–Deep Deterministic Policy Gradient (FS-DDPG). The key innovation lies in applying a constrained Markov decision process to model the FCU control problem, where a penalty term for process constraints is incorporated into the reward function, and constraint tightening is introduced to limit the action space. In addition, to validate the performance of the proposed method, we established a variable operating conditions FCU simulation platform based on the parameters of the actual FCU system and ten years of historical weather data. The platform’s correctness and effectiveness were verified from three aspects: heat transfer, the air side and the water side, under different dry and wet operating conditions. The experimental results show that compared with DDPG, FS-DDPG avoids 98.20% of the pump flow and 95.82% of the fan flow fluctuations, ensuring the safety of the equipment. Compared with DDPG and RBC, FS-DDPG achieves 11.9% and 51.76% energy saving rates, respectively, and also shows better performance in terms of operational performance and satisfaction. In the future, we will further improve the scalability and apply the method to more complex FCU systems in variable environments.

Introduction: Previous results from the phase 3 ALESIA study (NCT02838420) revealed that alectinib (a central nervous system [CNS]-active, ALK inhibitor) had clinical benefits in treatment-naïve Asian patients with advanced ALK-positive NSCLC, consistent with the global ALEX study. We present updated data after more than or equal to 5 years of follow-up from the “last patient in” date. Methods: Adult patients with treatment-naïve, advanced ALK-positive NSCLC from mainland China, South Korea, and Thailand were randomized 2:1 to receive twice-daily 600 mg alectinib (n = 125) or 250 mg crizotinib (n = 62). The primary endpoint was investigator-assessed progression-free survival. Secondary or exploratory endpoints included overall survival, objective response rate, time to CNS progression, and safety. Results: At the data cutoff (May 16, 2022), the median survival follow-up was 61 and 51 months in the alectinib and crizotinib arms, respectively. Median progression-free survival was 41.6 months with alectinib versus 11.1 months with crizotinib (stratified hazard ratio = 0.33, 95% confidence interval: 0.23–0.49). Overall survival data remain immature; 5-year overall survival rates were 66.4% (alectinib arm) versus 56.1% (crizotinib arm). Objective response rate was 91.2% versus 77.4% with alectinib and crizotinib, respectively. CNS progression was delayed with alectinib versus crizotinib (cause-specific hazard ratio = 0.16, 95% confidence interval: 0.08–0.32). Median treatment duration was longer with alectinib versus crizotinib (42.3 versus 12.6 mo). No new safety signals were observed. Conclusions: With four additional years of follow-up, these updated results confirm the clinical benefit and manageable safety of alectinib in Asian patients with advanced ALK-positive NSCLC, and confirm alectinib as a standard-of-care treatment for patients with advanced ALK-positive NSCLC.

Abstract The SEL1L-HRD1 protein complex represents the most conserved branch of endoplasmic reticulum (ER)-associated degradation (ERAD). Despite recent advances in both mouse models and humans, in vivo evidence for the importance of SEL1L in the ERAD complex formation and its (patho-)physiological relevance in mammals remains limited. Here we report that SEL1L variant p.Ser658Pro (SEL1L S658P ) is a pathogenic hypomorphic mutation, causing partial embryonic lethality, developmental delay, and early-onset cerebellar ataxia in homozygous mice carrying the bi-allelic variant. Biochemical analyses reveal that SEL1L S658P variant not only reduces the protein stability of SEL1L, but attenuates the SEL1L-HRD1 interaction, likely via electrostatic repulsion between SEL1L F668 and HRD1 Y30 residues. Proteomic screens of SEL1L and HRD1 interactomes reveal that SEL1L-HRD1 interaction is a prerequisite for the formation of a functional HRD1 ERAD complex, as SEL1L is required for the recruitment of E2 enzyme UBE2J1 as well as DERLIN to HRD1. These data not only establish the disease relevance of SEL1L-HRD1 ERAD, but also provide additional insight into the formation of a functional HRD1 ERAD complex.

Abstract Endoplasmic reticulum-associated degradation (ERAD) plays indispensable roles in many physiological processes; however, the nature of endogenous substrates remains largely elusive. Here we report a proteomics strategy based on the intrinsic property of the SEL1L-HRD1 ERAD complex to identify endogenous ERAD substrates both in vitro and in vivo. Following stringent filtering using a machine learning algorithm, over 100 high-confidence potential substrates are identified in human HEK293T and mouse brown adipose tissue, among which ~88% are cell type-specific. One of the top shared hits is the catalytic subunit of the glycosylphosphatidylinositol (GPI)-transamidase complex, PIGK. Indeed, SEL1L-HRD1 ERAD attenuates the biogenesis of GPI-anchored proteins by specifically targeting PIGK for proteasomal degradation. Lastly, several PIGK disease variants in inherited GPI deficiency disorders are also SEL1L-HRD1 ERAD substrates. This study provides a platform and resources for future effort to identify proteome-wide endogenous substrates in vivo, and implicates SEL1L-HRD1 ERAD in many cellular processes including the biogenesis of GPI-anchored proteins.

Two-way fluid–structure interaction (FSI) simulation of wind turbines has gained significant attention in recent years due to the growth of offshore wind energy development. Strong coupling procedures in these simulations predict realistic behavior with higher accuracy but result in increased computational costs and potential numerical instabilities. This paper proposes a mixed weak and strong coupling approach for the FSI simulation of a 5 MW wind turbine. The deformation of the turbine blade is calculated using a weak coupling approach, ensuring blade deflection meets a convergence criterion before rotating to the next azimuthal position. Fluid and solid solvers are partitioned, utilizing the commercial software packages STAR-CCM+ and Abaqus, respectively. Flexible and rigid blade cases are modeled, and the calculated loads, power, and blade tip displacement for the rotor at a constant rotating speed are compared. The proposed model is validated, showing good agreement with the existing literature and results comparable to those from another validated wind turbine simulator. The effect of rotor–tower interaction is evident in the results. Based on our calculations, the power production of flexible blades is evaluated to be 9.6% lower than that of rigid blades.

LiDAR and cameras, often regarded as the “eyes” of intelligent driving vehicles, are vulnerable to adverse weather conditions like haze, rain, and snow, compromising driving safety. In order to solve this problem and enhance the environmental sensing capability under severe weather conditions, this paper proposes a multimodal back-end fusion object detection method, Sec-CLOCs, which is specifically optimized for vehicle detection under heavy snow. This method achieves object detection by integrating an improved YOLOv8s 2D detector with a SECOND 3D detector. First, the quality of image data is enhanced through the Two-stage Knowledge Learning and Multi-contrastive Regularization (TKLMR) image processing algorithm. Additionally, the DyHead detection head and Wise-IOU loss function are introduced to optimize YOLOv8s and improve 2D detection performance.The LIDROR algorithm preprocesses point cloud data for the SECOND detector, yielding 3D object detection results. The CLOCs back-end fusion algorithm is then employed to merge the 2D and 3D detection outcomes, thereby enhancing overall object detection capabilities. The experimental results show that the Sec-CLOCs algorithm achieves a vehicle detection accuracy of 82.34% in moderate mode (30–100 m) and 81.76% in hard mode (more than 100 m) under heavy snowfall, which demonstrates the algorithm’s high detection performance and robustness.

Phosphorus (P) is a nonrenewable resource and a critical element for plant growth that plays an important role in improving crop yield. Excessive P fertilizer application is widespread in agricultural production, which not only wastes phosphate resources but also causes P accumulation and groundwater pollution. Here, we hypothesized that the apparent P balance of a crop system could be used as an indicator for identifying the critical P input in order to obtain a high yield with high phosphorus use efficiency (PUE). A 12-year field experiment with P fertilization rates of 0, 45, 90, 135, 180, and 225 kg P2O5 ha−1 was conducted to determine the crop yield, PUE, and soil Olsen-P value response to P balance, and to optimize the P input. Annual yield stagnation occurred when the P fertilizer application exceeded a certain level, and high yield and PUE levels were achieved with annual P fertilizer application rates of 90–135 kg P2O5 ha−1. A critical P balance range of 2.15–4.45 kg P ha−1 was recommended to achieve optimum yield with minimal environmental risk. The critical P input range estimated from the P balance was 95.7–101 kg P2O5 ha−1, which improved relative yield (>90%) and PUE (90.0–94.9%). In addition, the P input–output balance helps in assessing future changes in Olsen-P values, which increased by 4.07 mg kg−1 of P for every 100 kg of P surplus. Overall, the P balance can be used as a critical indicator for P management in agriculture, providing a robust reference for limiting P excess and developing a more productive, efficient and environmentally friendly P fertilizer management strategy.

As the most common degenerative joint disease, osteoarthritis (OA) contributes significantly to pain and disability during aging. Several genes of interest involved in articular cartilage damage in OA have been identified. However, the direct causes of OA are poorly understood. Evaluating the public human RNA-seq dataset showed that CBFB (subunit of a heterodimeric Cbfβ/Runx1, Runx2, or Runx3 complex) expression is decreased in the cartilage of patients with OA. Here, we found that the chondrocyte-specific deletion of Cbfb in tamoxifen-induced Cbfbf/f;Col2a1-CreERT mice caused a spontaneous OA phenotype, worn articular cartilage, increased inflammation, and osteophytes. RNA-sequencing analysis showed that Cbfβ deficiency in articular cartilage resulted in reduced cartilage regeneration, increased canonical Wnt signaling and inflammatory response, and decreased Hippo/Yap signaling and Tgfβ signaling. Immunostaining and western blot validated these RNA-seq analysis results. ACLT surgery-induced OA decreased Cbfβ and Yap expression and increased active β-catenin expression in articular cartilage, while local AAV-mediated Cbfb overexpression promoted Yap expression and diminished active β-catenin expression in OA lesions. Remarkably, AAV-mediated Cbfb overexpression in knee joints of mice with OA showed the significant protective effect of Cbfβ on articular cartilage in the ACLT OA mouse model. Overall, this study, using loss-of-function and gain-of-function approaches, uncovered that low expression of Cbfβ may be the cause of OA. Moreover, Local admission of Cbfb may rescue and protect OA through decreasing Wnt/β-catenin signaling, and increasing Hippo/Yap signaling and Tgfβ/Smad2/3 signaling in OA articular cartilage, indicating that local Cbfb overexpression could be an effective strategy for treatment of OA.

Abstract Background The immune system may influence prognosis, and lymphopenia is a frequent side effect of concurrent chemoradiotherapy (CCRT). Radical irradiation for locally advanced esophageal cancer (LA‐EC) exposes significant vascular and heart volumes. In this study, we hypothesized that lymphopenia is linked to cardiac and pericardial doses and affects patient prognosis. Methods and Materials We identified 190 LA‐EC patients who received radical CCRT. Multivariate analysis (MVA) was performed to correlate clinical factors and dosimetric parameters with overall survival (OS). We collected lymphocyte‐related variables and ratios before and during CCRT. MVA was performed to correlate hematologic toxicity with OS. The relationship between dosimetric parameters and G4 lymphopenia was determined using logistic stepwise regression. Finally, a nomogram of G4 lymphopenia was developed and validated externally. Results Median follow‐up time for all patients was 27.5 months. On MVA for OS, higher pericardial V30 (PV30) was linked to worse survival (HR: 1.013, 95% CI: 1.001–1.026, p = 0.039). The median OS stratified by PV30 > 55.3% and PV30 ≤ 55.3% was 24.0 months and 54.0 months, respectively (p = 0.004). G4 lymphopenia was shown to be linked with worse OS in the MVA of hematological toxicity with OS (HR: 2.042, 95% CI: 1.335–3.126, p = 0.001). Thirty of the 100 patients in the training set had G4 lymphopenia. Logistic stepwise regression was used to identify variables associated with G4 lymphopenia, and the final model consisted of stage‐IVA (p = 0.017), platelet‐to‐lymphocyte ratio during CCRT (p = 0.008), Heart V50 (p = 0.046), and PV30 (p = 0.048). Finally, a nomogram predicting G4 lymphocytopenia were constructed and externally validated. The ROC curve showed an AUC for internal validation of 0.775 and external validation of 0.843. Conclusion Higher doses of pericardial radiation might affect LA‐EC patients' prognosis by inducing G4 lymphopenia during CCRT. Further prospective studies are warranted to confirm these findings, especially in the era of immune‐checkpoint inhibitor treatment.