Search

Activation of PI3K/AKT pathway is one of the most recurrent resistant mechanisms for BRAF-targeted therapy, and the combination of MAPK and PI3K/AKT inhibitors becomes one of the most promising regimens for BRAF-targeted relapsed melanoma patients. Although the potent drug efficacy was observed in preclinical experiments and early clinical trials, the dual-drug resistance is inevitable observed. In this study, we systematically explored the mechanisms of dual-drug resistance to MAPKi and PI3K/mTORi in melanoma. With transcriptomic dissection of dual-drug resistant models, we identified that the drug tolerance was mediated by ECM-integrins α3β1 and α11β1 signaling. Upon binding ECM, the integrins activated downstream kinase Src rather than FAK, WNT, or TGFβ. Knockdown of integrins α3, α11, and β1 significantly inhibited the proliferation of dual-drug resistant sublines while with trivial effects on parental cells. Although Src inhibition suppressed the phosphorylation of AKT, c-JUN, and p38, none of inhibitors targeting these kinases reversed the dual-drug resistance in model cells. Notably, Src inhibitor promoted the phosphorylations of LATS1 and YAP1, subsequently, re-localized YAP1 from nucleus to cytosol facilitating further degradation. Both small molecule inhibitors and shRNAs targeting YAP1 or Src overcame the MAPKi and PI3K/mTORi dual-drug resistance. In conclusion, our data not only illuminated an integrin-Src-YAP1 pathway mediated MAPKi and PI3K/mTORi dual-drug resistant mechanism but also provided a potential combinatorial regimen for the drug-relapsed melanoma patients.

Background: During the COVID-19 pandemic, the social distancing has significantly affected the healthy lifestyle behaviors of residents. China ended social distancing on January 8, 2023, and the healthy lifestyle behaviors of residents after this time are unclear. The goal of this study was to evaluate the differences in healthy lifestyle behaviors between Chinese urban and rural residency after the termination of social distancing. Methods: From February 1, 2023, to February 8, 2023, a cross-sectional survey which include participants (≥ 18 years old) was carried out in four regions of mainland China (Changzhou in the eastern region, Zhengzhou in the central region, Xining in the western region, and Mudanjiang in the northeastern region). A healthy lifestyle behaviors scale containing 11 items was designed to calculate the healthy lifestyle behaviors scores among urban and rural residents. The healthy lifestyle behaviors scores ranged from 11 to 51. Multivariate linear regression was used to analyze the influencing factors of healthy lifestyle behaviors scores among urban and rural residents. Propensity Score Matching was used to assess the net differences in healthy lifestyle behaviors scores between urban and rural residents. Results: A total of 5780 residents (53.04% females) were included in the study, including 3302(57.13%) urban residents. The average healthy lifestyle behavior score was 38.33(95%CI: 38.18 to 38.49). Healthy lifestyle behaviors score among males was lower than that among females in both urban (β = -1.98, 95%CI: -3.05 to -2.10) and rural residents (β = -2.57, 95%CI: -2.37 to -1.60). Higher education was associated with higher healthy lifestyle behaviors scores in both urban and rural residents. PSM analysis indicated that urban residents still had higher healthy lifestyle behaviors scores (38.72, 95% CI: 38.46 to 38.99) than rural residents (37.85, 95%CI: 37.57 to 38.13), with a net difference of 0.87 points. Conclusions: After the termination of social distancing, the overall healthy lifestyle behaviors of Chinese residents were found to be at a medium level. Urban residents have a better healthy lifestyle behavior compared to their rural counterparts. It is essential to prioritize efforts towards enhancing the healthy lifestyle behaviors of rural residents. [ABSTRACT FROM AUTHOR]

Background: Controversy exists regarding the reconstruction of bone defects in Enneking III. This study aimed to use the finite element analysis (FEA) method to clarify (1) the utility of reconstructing the pelvis Enneking III region and (2) the optimal approach for this reconstruction. Methods: FEA models were generated for three types of Enneking III defects in the pelvis, replacing all the defect areas in region III with a sizable solid box for topology optimization (TO). Based on the defect location and TO results, three reconstruction schemes were designed for each type of defect. We subsequently conducted simulations of static FEA under natural walking loads using ANSYS software (version 2022R1, Canonsburg, Pennsylvania, USA). Results: Compared with Scheme A, reconstruction of the Enneking III region (Schemes B and C) led to a more uniform stress distribution and lower peak stress in the pelvis. Moreover, prostheses and screws exhibit decreased peak stress and deformation, with complex reconstruction schemes (C) outperforming simpler ones (B). Conclusions: The FEA results suggest that reconstructing Enneking Zone III defects improves stress distribution and reduces peak stress in the pelvis compared to non-reconstruction, potentially enhancing stability and reducing fracture risks. Complex reconstruction schemes involving more contralateral pelvis regions demonstrate superior biomechanical performance. However, clinical decisions should be individualized, integrating biomechanical insights with comprehensive patient-specific factors. [ABSTRACT FROM AUTHOR]

ABSTRACT Chimeric antigen receptor (CAR) T‐cell therapy has exhibited remarkable efficacy in the treatment of haematological malignancies, yet its application in solid tumours is hindered by the immunosuppressive tumour microenvironment (TME). In this study, a novel SS1‐TREM1/DAP12‐BB CAR‐T cell was devised to target ovarian cancer and further engineered to co‐express the dominant‐negative TGF‐β receptor 2 (DNR) to combat CAR‐T cell exhaustion in TME. The incorporation of DNR effectively blocked TGF‐β signalling, thereby enhancing CAR‐T cell survival and antitumor activity in a TGF‐β1‐rich environment. In vivo evaluations demonstrated that DNR co‐expression potentiated the antitumor efficacy of TREM1/DAP12‐BB CAR‐T cells and conferred resilience against tumour rechallenge. These findings underscore the broad potential of DNR co‐expression in CAR design, presenting a novel therapeutic strategy for patients with recurrent ovarian cancer. [ABSTRACT FROM AUTHOR]

The operational performance of cereal seeding machinery influences the yield and quality of cereals. In this article, we review the existing literature on intelligent technologies for cereal seeding machinery, encompassing active controllable seeding actuators, intelligent seeding rate control, and intelligent seed position control systems. In this manuscript, (1) the characteristics and innovative structures of existing motor-driven seed-metering devices and ground surface profiling mechanisms are expounded; (2) state-of-the-art detection principles and applications for soil property sensors are described based on different soil properties; (3) optimal seeding rate decision approaches based on soil properties are summarized; (4) the research state of seeding rate measuring and control technologies is expounded in detail; (5) trajectory control methods for seeding machinery and seeding depth control systems are described based on measurement and control principles; and (6) the present state, limitations, and future development directions of intelligent cereal seeding machinery are described. In the future, more advanced multi-algorithm and multi-sensor fusion technologies for soil property detection, optimal seeding rate decisions, seeding rates, and seed position control are likely to evolve. This review not only expounds the latest studies on intelligent actuating, sensing, and control technologies for intelligent cereal seeding machinery, but also discusses the shortcomings of existing intelligent seeding technologies and future developing trends in detail. This review, therefore, offers a reference for future research in the domain of intelligent seeding machinery for cereals. [ABSTRACT FROM AUTHOR]

A new round of monkeypox virus has emerged in the United Kingdom since July 2022 and rapidly swept the world. Currently, despite numerous research groups are studying this virus and seeking effective treatments, the information on the open reading frame, inhibitors, and potential targets of monkeypox has not been updated in time, and the comprehension of monkeypox target ligand interactions remains a key challenge. Here, we first summarized and improved the open reading frame information of monkeypox, constructed the monkeypox inhibitor library and potential targets library by database research as well as literature search, combined with advanced protein modeling technologies (Sequence-based and AI algorithms-based homology modeling). In addition, we build monkeypox virus Docking Server, a web server to predict the binding mode between targets and substrate. The open reading frame information, monkeypox inhibitor library, and monkeypox potential targets library are used as the initial files for server docking, providing free interactive tools for predicting ligand interactions of monkeypox targets, potential drug screening, and potential targets search. In addition, the update of the three databases can also effectively promote the study of monkeypox drug inhibition mechanism and provide theoretical guidance for the development of drugs for monkeypox. [ABSTRACT FROM AUTHOR]

The uniformity of the cultivation environment in a micro-plant factory plays a critical role in ensuring the consistent growth of seedlings, and an optimal airflow pattern is the key to maintaining environmental uniformity. This study applied computational fluid dynamics (CFD) modeling to compare the effects of six different ventilation modes on the microclimate within the cultivation space. In cases 1 and 2, the inlet was positioned at the top, while the outlets were located at both the bottom and the top of the side walls. For cases 3 to 6, a side-inlet and side-outlet ventilation system was employed across the three cultivation layers. Case 4 maintained consistent inlet and outlet airflow speeds, whereas cases 3, 5, and 6 featured airflow settings that either increased or decreased progressively from the top layer to the bottom. Notably, case 6 was characterized by a more compact arrangement of cultivation racks within the space, which were positioned closer to the outlet than in the other cases. In case 1, the air inlets were positioned at the top, while the outlets were located on both side walls at the lower layer of cultivation. In contrast, case 6 used a side-inlet and side-outlet ventilation strategy, in which the airflow speed of the inlets decreases progressively from the top to the bottom of the cultivation layers. Additionally, the cultivation racks in case 6 were arranged more compactly and positioned closer to the outlet of the cultivation space. The relative standard deviation (RSD) was used to evaluate the uniformity of the airflow velocity (m/s), temperature (K), and relative humidity (%) within the crop-growing area. The results indicated that, among all the scenarios, case 6 demonstrated the lowest RSD values for the airflow velocity, temperature, and relative humidity, with reductions of 18.34%, 0.12%, and 2.05%, respectively, compared to the control group (case 1). Based on the ventilation design of case 6, a micro-plant factory was developed featuring a bidirectional flow fan, air conditioning, and PWM fans for the coordinated control of air circulation within the seedling cultivation space, along with adjustable cultivation layer heights and shelf spacing. The accuracy of the CFD model for the micro-plant factory was validated with normalized root mean square error (NMSE) for cultivation layer heights of 250 mm, 300 mm, and 350 mm. The NMSE values comparing the simulated and measured results for the airflow velocity, temperature, and relative humidity were found to be 0.032, 0.0020, and 0.0022; 0.031, 0.0021, and 0.0018; and 0.046, 0.0021, and 0.0021, respectively. These findings indicate that the established CFD model can reliably predict the microenvironment within the micro-plant factory. [ABSTRACT FROM AUTHOR]

Soil tillage is essential for improving soil structure, enhancing fertility, promoting crop growth, and increasing yield. However, precise and efficient standardized methods for quantitatively evaluating post-tillage soil structure are still absent. This study aims to develop a general quantitative evaluation method for post-tillage soil structure using close-range photogrammetry. Six soil surface sample plots of different scales were selected, and two image acquisition methods and three platforms were chosen for image capture and 3D reconstruction. Geomagic Wrap was used for post-processing the models, with indicators such as clod sizes, surface flatness, and cumulative percentage used for quantitative description. Model accuracy was validated using traditional needle plate and vernier caliper measurements. The most effective combinations of image acquisition methods and 3D reconstruction platforms were identified based on modeling efficiency and quality. The results showed that combining image acquisition, 3D reconstruction platforms, and post-processing software enables high-precision 3D reconstruction and accurate digital information retrieval. Image Acquisition Method One and the AgisoftMetashape platform demonstrated the best combination in terms of model completeness, texture detail, and overall quality. This combination is recommended for the 3D reconstruction and digital information retrieval of soil surfaces. This study provides a method for evaluating post-tillage soil structure, including image acquisition, 3D reconstruction, model post-processing, and quantitative metrics. [ABSTRACT FROM AUTHOR]

Introduction In his recent papers, Professor Yong Huang has been attempting to interpret the ethics of Zhuangzi from the perspective of patient moral relativism. Generally speaking, there are two sorts [...]

Let me begin by expressing my sincere gratitude to Professor Huang for his great work on the theory of patient moral relativism and to the editors of Philosophy East and [...]