Pharmacological manipulation of TRPC5 by kaempferol attenuates metastasis of gastrointestinal cancer via inhibiting calcium involved in the formation of filopodia.

The thermo-sensory receptor, transient receptor potential channel 5 (TRPC5), a non-selective calcium ion (Ca2+)-permeable ion channel, has been implicated in cancer initiation and progression. However, its specific role in gastrointestinal cancer remains unclear. This study demonstrates that TRPC5 is significantly overexpressed in gastrointestinal tumors and is inversely associated with patient prognosis. TRPC5 overexpression triggers a substantial elevation in intracellular Ca2+ levels ([Ca2+]i), driving actin cytoskeleton reorganization and facilitating filopodia formation. Furthermore, kaempferol, a compound sourced from traditional Chinese medicine, is identified as a TRPC5 inhibitor that effectively suppresses its activity, thereby impeding gastrointestinal cancer metastasis. These findings underscore the potential of TRPC5 as a therapeutic target for metastasis inhibition, with kaempferol emerging as a promising natural inhibitor that could be optimized for clinical use in preventing cancer metastasis.

NEDD4 family ubiquitin ligase AIP4 interacts with Alix to enable HBV naked capsid egress in an Alix ubiquitination-independent manner.

Hepatitis B virus (HBV) exploits the endosomal sorting complexes required for transport (ESCRT)/multivesicular body (MVB) pathway for virion budding. In addition to enveloped virions, HBV-replicating cells nonlytically release non-enveloped (naked) capsids independent of the integral ESCRT machinery, but the exact secretory mechanism remains elusive. Here, we provide more detailed information about the existence and characteristics of naked capsid, as well as the viral and host regulations of naked capsid egress. HBV capsid/core protein has two highly conserved Lysine residues (K7/K96) that potentially undergo various types of posttranslational modifications for subsequent biological events. Mutagenesis study revealed that the K96 residue is critical for naked capsid egress, and the intracellular egress-competent capsids are associated with ubiquitinated host proteins. Consistent with a previous report, the ESCRT-III-binding protein Alix and its Bro1 domain are required for naked capsid secretion through binding to intracellular capsid, and we further found that the ubiquitinated Alix binds to wild type capsid but not K96R mutant. Moreover, screening of NEDD4 E3 ubiquitin ligase family members revealed that AIP4 stimulates the release of naked capsid, which relies on AIP4 protein integrity and E3 ligase activity. We further demonstrated that AIP4 interacts with Alix and promotes its ubiquitination, and AIP4 is essential for Alix-mediated naked capsid secretion. However, the Bro1 domain of Alix is non-ubiquitinated, indicating that Alix ubiquitination is not absolutely required for AIP4-induced naked capsid secretion. Taken together, our study sheds new light on the mechanism of HBV naked capsid egress in viral life cycle.

Phosphorylation of the transcription factor SlBIML1 by SlBIN2 kinases delays flowering in tomato.

Brassinosteroids (BRs) are well known for their important role in the regulation of plant growth and development. Plants with deficiency in BR signaling show delayed plant development and exhibit late flowering phenotypes. However, the precise mechanisms involved in this process require investigation. In this study, we cloned homologs of BRASSINOSTEROID INSENSITIVE 2 (SlBIN2), the GSK3-like protein kinase in tomato (Solanum lycopersicum). We characterized growth-related processes and phenotypic changes in the transgenic lines and found that SlBIN2s transgenic lines have delayed development and slow growing phenotypes. SlBIN2s work redundantly to negatively regulate BR signaling in tomato. Furthermore, the transcription factor SlBIN2.1-INTERACTING MYB-LIKE 1 (SlBIML1) was identified as a downstream substrate of SlBIN2s that SlBIN2s interact with and phosphorylate to synergistically regulate tomato developmental processes. Specifically, SlBIN2s modulated protein stability of SlBIML1 by phosphorylating multiple amino acid residues, including the sites Thr266 and Thr280. This study reveals a branch of the BR signaling pathway that regulates the vegetative growth phase and delays floral transition in tomato without the feedback affecting BR signaling. This information enriches our understanding of the downstream transduction pathway of BR signaling and provides potential targets for adjusting tomato flowering time.

Health lifestyles of six Zhiguo ethnic groups in China: a latent class analysis.

BACKGROUND: Zhiguo ethnic groups, commonly known as "the directly-entering-socialism ethnic groups", represent Chinese ethnic minorities who have undergone a unique social development trajectory by transforming directly from primitive societies to the socialist stage. In recent decades, significant lifestyle transformations have occurred among Zhiguo ethnic groups. Understanding their health lifestyles can play a strategic role in China's pursuit of universal health coverage. This study aims to examine patterns of health-related lifestyle among Zhiguo ethnic groups and explore whether sociodemographic features and specific indicators related to health status are associated with particular classes. METHODS: A cross-sectional study was conducted in Yunnan Province, China, from July to December 2022. Stratified random sampling method was employed to recruit residents belonging to six Zhiguo ethnic groups aged between 15 and 64. Latent class analysis was performed to identify clusters of health-related behaviors within each ethnic group. Logistic regression was utilized to determine the predictors of health lifestyles. RESULTS: A total of 1,588 individuals from the Zhiguo ethnic groups participated in this study. Three latent classes representing prevalent health lifestyles among the Zhiguo ethnic groups were identified: "unhealthy lifestyle" (31.80%), "mixed lifestyle" (57.37%), and "healthy lifestyle" (10.83%). In the overall population, individuals belonging to the "healthy lifestyle" group exhibited a higher likelihood of being non-farmers (OR: 2.300, 95% CI: 1.347-3.927), women (OR: 21.459, 95% CI: 13.678-33.667), married individuals (OR: 1.897, 95% CI: 1.146-3.138), and those residing within a walking distance of less than 15 min from the nearest health facility (OR: 2.133, 95% CI: 1.415-3.215). Conversely, individuals in the age cohorts of 30-39 years (OR: 0.277, 95% CI: 0.137-0.558) and 40-49 years (OR: 0.471, 95% CI: 0.232-0.958) showed a decreased likelihood of adopting a healthy lifestyle. CONCLUSIONS: A considerable proportion of the Zhiguo ethnic groups have not adopted healthy lifestyles. Targeted interventions aimed at improving health outcomes within these communities should prioritize addressing the clustering of unfavorable health behaviors, with particular emphasis on single male farmers aged 30-49, and expanding healthcare coverage for individuals residing more than 15 min away from accessible facilities.

EEGNet classification of sleep EEG for individual specialization based on data augmentation.

Sleep is an essential part of human life, and the quality of one's sleep is also an important indicator of one's health. Analyzing the Electroencephalogram (EEG) signals of a person during sleep makes it possible to understand the sleep status and give relevant rest or medical advice. In this paper, a decent amount of artificial data generated with a data augmentation method based on Discrete Cosine Transform from a small amount of real experimental data of a specific individual is introduced. A classification model with an accuracy of 92.85% has been obtained. By mixing the data augmentation with the public database and training with the EEGNet, we obtained a classification model with significantly higher accuracy for the specific individual. The experiments have demonstrated that we can circumvent the subject-independent problem in sleep EEG in this way and use only a small amount of labeled data to customize a dedicated classification model with high accuracy.

Plastic particles and fluorescent brightener co-modify Chlorella pyrenoidosa photosynthesis and a machine learning approach predict algae growth.

Global release of plastics exerts various impacts on the ecological cycle, particularly on primary photosynthesis, while the impacts of plastic additives are unknown. As a carrier of fluorescent brightener, plastic particles co-modify Chlorella pyrenoidosa (C. pyrenoidosa) growth and its photosynthetic parameters. In general, adding to the oxidative damage induced by polystyrene, fluorescent brightener-doped polystyrene produces stronger visible light and the amount of negative charge is more likely to cause photodamage in C. pyrenoidosa leading to higher energy dissipation through conditioning than in the control group with a date of ETR (II) inhibition rate of 33 %, Fv/Fm inhibition rate of 8.3 % and Pm inhibition rate of 48.8 %. To elucidate the ecological effect of fluorescent brightener doping in plastic particles, a machine learning method is performed to establish a Gradient Boosting Machine model for predicting the impact of environmental factors on algal growth. Upon validation, the model achieved an average fitting degree of 88 %. Relative concentration of plastic particles and algae claimed the most significant factor by interpretability analysis of the machine learning. Additionally, both Gradient Boosting Machine prediction and experimental results indicate a matching result that plastic additives have an inhibitive effect on algal growth.

L-Glutamate treatment alleviates chilling injury of prune (Prunus domestica L.) fruit by regulating ROS homeostasis, GABA shunt, and energy metabolism.

The impacts of L-glutamate (L-Glu) treatment on chilling injury (CI), Ca2+ signaling, mitochondrial ultrastructure, and metabolisms of reactive oxygen species (ROS), γ-aminobutyric acid (GABA), energy of prune fruit under chilling stress were studied. The results found that the optimal concentration of L-Glu to suppress CI occurrence and maintain quality in prune fruit was 0.1 g L-1, which also enhanced the PdGLRs expression, cytoplasmic Ca2+ concentration, the contents of CaM, and CML under cold stress. Moreover, L-Glu treatment could reduce ROS accumulation and increase GABA content, and energy level, contributing to maintaining the integrity of the mitochondrial structure in cold-stored prune fruit. More importantly, PdGLRs expression and CaM/CML content positively correlated with antioxidant enzyme activities, GABA shunt, and energy status in prune fruit. These results indicated that the enhanced cold resistance of L-Glu-treated prunes might be attributed to the activated Ca2+ signaling, thus improving the antioxidant capacity, GABA, and energy levels.

Gender-specific factors of suicidal ideation among high school students in Yunnan province, China: A machine learning approach.

BACKGROUND: Suicidal ideation (SI) assumes a pivotal role in predicting suicidal behaviors. The incidence of SI among high (junior and senior) school students is significantly higher than that of other age groups. The aim of this study is to explore the gender differences in SI among high school students in Yunnan Province. METHOD: A total of 6180 students in grades 7-12 in Yunnan province, China from May 2021 to May 2022 participated in this survey. Univariate analysis was employed to describe the influencing factors of male and female students' SI. Subsequently, data were stratified by gender. Adopting machine learning technique, including Least Absolute Shrinkage and Selection Operator (Lasso) and Boruta algorithm, and logistic regression model to estimate the direction and effect magnitude of the influencing factors. RESULTS: The prevalence of SI was significantly higher for females (31.34 %) than males (16.73 %). The logistic regression model was established using the variables screened by Boruta algorithm, indicated that anxiety, depression, suffering emotion abuse or emotion neglect in childhood, non-suicidal self-injury, evening chronotype are common risk factors for SI in male and female students. Notably, female students who exhibited aggressive behavior, have experienced bullying, and were in the junior high school learning stage were more likely to report SI than their male counterparts. CONCLUSIONS: Females showed more vulnerability to SI than males especially among females in junior high school, reporting aggressive behavior and bullying experiences. Tailored prevention strategies, informed by these gender-related distinctions, should be developed and implemented.

Wavelength Modulation and Fast Response of Mixed-Phase ß-Ga2O3:Zn/SnO2 in-Plane Heterojunction Ultraviolet Photodetectors.

Ultraviolet photodetectors based on wide bandgap mixed-phase ß-Ga2O3:Zn/SnO2 thin films formed through doping on the c-sapphire substrate (c-Al2O3) are prepared to construct in-plane heterojunctions employing a low-cost and simple preparation method. The mixed-phase thin film photodetectors have a low dark current of 0.74 nA, and the photo-to-dark current ratio ranges from 36.43 to 642.38 at 10 V. The photodetectors also have wavelength modulation, with response peaks ranging from 260 nm (4 mA/W) to 295 nm (1.63 A/W). Furthermore, the photodetectors have a fast response time with a rise time of 0.07 s/0.22 s and a decay time of 0.04 s/0.22 s at 1 V. The excellent performance of the devices is attributed to the reduction of VO and the establishment of multiple electric fields in the mixed-phase films, which indicates the feasibility of implementing wavelength-modulated and fast-response ß-Ga2O3 photodetectors using the sol-gel method.

Case report: A case of Savolitinib in the treatment of MET amplification mutation advanced lung adenocarcinoma with rare bilateral breast metastasis.

Background: The distant metastasis of lung cancer primarily occurs in the bones, liver, brain, and lungs, while the breast is an extremely rare site of metastasis. There is very limited literature on the occurrence of breast metastasis from lung cancer, and metastatic lesions in the breast are prone to being misdiagnosed as primary breast cancer, requiring careful attention and differentiation in the clinical diagnostic and treatment process. Case summary: The patient, a 63-year-old female, initially presented with an EGFR exon 21 L858R mutated left lung adenocarcinoma in 2017, treated successfully with surgical resection and subsequent monitoring. The relapse of disease occurred in January 2020. Despite maintaining a prolonged progression-free survival (PFS) with first-generation EGFR-TKI Afatinib, disease progression occurred in 2022 without detectable resistance mutations. Transition to second-generation TKI Furmonertinib resulted in poor control, with rapid progression including unusual bilateral breast metastases that exhibited inflammatory breast cancer-like peau d'orange changes. Standard chemotherapy achieved only short-term stability. Upon detecting a MET amplification mutation, treatment with Savolitinib was initiated. Remarkably, this led to significant clinical and radiographic improvement, notably resolving the peau d'orange appearance and reducing multiple lesions across the body. Conclusion: This case underscores the importance of continuous genetic profiling and tailored treatment approaches in managing advanced lung adenocarcinoma, particularly when presenting with rare metastatic sites and complex genetic landscapes. The successful application of Savolitinib following the identification of a MET amplification mutation highlights its potential in overcoming resistance mechanisms in NSCLC, providing a significant therapeutic option for similarly challenging cases.

Integrative Analyses Reveal the Physiological and Molecular Role of Prohexadione Calcium in Regulating Salt Tolerance in Rice.

Salinity stress severely restricts rice growth. Prohexadione calcium (Pro-Ca) modulation can effectively alleviate salt stress in rice. In this study, we explored the effects of Pro-Ca on enhancing salt tolerance in two rice varieties, IR29 and HD96-1. The results revealed that Pro-Ca markedly enhanced root and shoot morphological traits and improved plant biomass under salt stress. Chlorophyll a and b content were significantly increased, which improved photosynthetic capacity. Transcriptomic and metabolomic data showed that Pro-Ca significantly up-regulated the expression of genes involved in E3 ubiquitin ligases in IR29 and HD96-1 by 2.5-fold and 3-fold, respectively, thereby maintaining Na+ and K+ homeostasis by reducing Na+. Moreover, Pro-Ca treatment significantly down-regulated the expression of Lhcb1, Lhcb2, Lhcb3, Lhcb5, and Lhcb6 in IR29 under salt stress, which led to an increase in photosynthetic efficiency. Furthermore, salt stress + Pro-Ca significantly increased the A-AAR of IR29 and HD96-1 by 2.9-fold and 2.5-fold, respectively, and inhibited endogenous cytokinin synthesis and signal transduction, which promoted root growth. The current findings suggested that Pro-Ca effectively alleviated the harmful effects of salt stress on rice by maintaining abscisic acid content and by promoting oxylipin synthesis. This study provides a molecular basis for Pro-Ca to alleviate salt stress in rice.

Temperature-Driven Activated Sludge Bacterial Community Assembly and Carbon Transformation Potential: A Case Study of Industrial Plants in the Yangtze River Delta.

Temperature plays a critical role in the efficiency and stability of industrial wastewater treatment plants (WWTPs). This study focuses on the effects of temperature on activated sludge (AS) communities within the A2O process of 19 industrial WWTPs in the Yangtze River Delta, a key industrial region in China. The investigation aims to understand how temperature influences AS community composition, functional assembly, and carbon transformation processes, including CO2 emission potential. Our findings reveal that increased operating temperatures lead to a decrease in alpha diversity, simplifying community structure and increasing modularity. Dominant species become more prevalent, with significant decreases in the relative abundance of Chloroflexi and Actinobacteria, and increases in Bacteroidetes and Firmicutes. Moreover, higher temperatures enhance the overall carbon conversion potential of AS, particularly boosting CO2 absorption in anaerobic conditions as the potential for CO2 emission during glycolysis and TCA cycles grows and diminishes, respectively. The study highlights that temperature is a major factor affecting microbial community characteristics and CO2 fluxes, with more pronounced effects observed in anaerobic sludge. This study provides valuable insights for maintaining stable A2O system operations, understanding carbon footprints, and improving COD removal efficiency in industrial WWTPs.

Knowledge, attitude, and practice of e-cigarette use among undergraduate students: A comparative study between China and Indonesia.

INTRODUCTION: The health risks associated with e-cigarettes are currently the focus of tobacco control efforts and public health initiatives. Given that China and Indonesia have the highest rates of adult smoking worldwide, it is imperative to gain a comprehensive understanding of e-cigarette prevalence among college students in these two nations. METHODS: From May to June 2023, a cross-sectional study was employed to conduct an online questionnaire survey among college students in three universities located in Kunming (China) and Jakarta (Indonesia), respectively. The chi-squared test was utilized to compare the rates/ratios, while binary logistic regression analysis was applied to examine the factors influencing e-cigarette knowledge, attitude, and practice. RESULTS: A total of 1327 individuals were included in the investigation. The proportion of Indonesian students (75.6%) with a high level of e-cigarette knowledge was lower than that observed among Chinese students (87.4%) (χ2=29.7, p<0.001). Additionally, the prevalence of e-cigarette use among Indonesian students (9.4%) was higher compared to their Chinese counterparts (3.0%) (χ2=22.32, p<0.001). Binary logistic regression analysis revealed that age, place of residence, studies, gender, and e-cigarette use by friends and family, significantly influenced knowledge levels and attitudes toward e-cigarettes in both countries (p<0.05). CONCLUSIONS: Despite the positive knowledge, attitudes, and practices towards e-cigarettes among undergraduate students in both countries, a notable knowledge gap exists concerning the harmful effects of e-cigarettes. Chinese students had better e-cigarette knowledge and demonstrated lower usage rates, suggesting that heightened awareness plays a favorable role in preventing e-cigarette use. Furthermore, it becomes imperative for policymakers and health educators to focus on specific factors, such as the influence of close friends and family members, as well as the area of residence.

The concentrations and behavior of classic phthalates and emerging phthalate alternatives in different environmental matrices and their biological health risks.

Because of their excellent plasticity, phthalates or phthalic acid esters (PAEs) are widely used in plastic products. However, due to the recognized toxicity of PAEs and legislative requirements, the production and use of emerging PAE alternatives have rapidly grown, such as di-isononyl cyclohexane-1,2-dicarboxylate (DINCH) and di(2-ethylhexyl) terephthalate (DEHTP) which are the primary replacements for classic PAEs. Nowadays, PAEs and emerging PAE alternatives are frequently found in a variety of environmental media, including the atmosphere, sludge, rivers, and seawater/sediment. PAEs and emerging PAE alternatives are involved in endocrine-disrupting effects, and they affect the reproductive physiology of different species of fish and mammals. Therefore, their presence in the environment is of considerable concern due to their potential effects on ecosystem function and public health. Nevertheless, current research on the prevalence, destiny, and conduct of PAEs in the environment has primarily focused on classic PAEs, with little attention given to emerging PAE alternatives. The present article furnishes a synopsis of the physicochemical characteristics, occurrence, transport, fate, and adverse effects of both classic PAEs and emerging PAE alternatives on organisms in the ecosystem. Our analysis reveals that both classic PAEs and emerging PAE alternatives are widely distributed in all environmental media, with emerging PAE alternatives increasingly replacing classic PAEs. Various pathways can transform and degrade both classic PAEs and emerging PAE alternatives, and their own and related metabolites can have toxic effects on organisms. This research offers a more extensive comprehension of the health hazards associated with classic PAEs and emerging PAE alternatives.

Hotspots lurking underwater: Insights into the contamination characteristics, environmental fates and impacts on biogeochemical cycling of microplastics in freshwater sediments.

The widespread presence of microplastics (MPs) in aquatic environments has become a significant concern, with freshwater sediments acting as terminal sinks, rapidly picking up these emerging anthropogenic particles. However, the accumulation, transport, degradation and biochemical impacts of MPs in freshwater sediments remain unresolved issues compared to other environmental compartments. Therefore, this paper systematically revealed the spatial distribution and characterization information of MPs in freshwater (rivers, lakes, and estuaries) sediments, in which small-size (<1 mm), fibers, transparent, polyethylene (PE), and polypropylene (PP) predominate, and the average abundance of MPs in river sediments displayed significant heterogeneity compared to other matrices. Next, the transport kinetics and drivers of MPs in sediments are summarized, MPs transport is controlled by the particle diversity and surrounding environmental variability, leading to different migration behaviors and transport efficiencies. Also emphasized the spatio-temporal evolution of MPs degradation processes and biodegradation mechanisms in sediments, different microorganisms can depolymerize high molecular weight polymers into low molecular weight biodegradation by-products via secreting hydrolytic enzymes or redox enzymes. Finally, discussed the ecological impacts of MPs on microbial-nutrient coupling in sediments, MPs can interfere with the ecological balance of microbially mediated nutrient cycling by altering community networks and structures, enzyme activities, and nutrient-related functional gene expressions. This work aims to elucidate the plasticity characteristics, fate processes, and potential ecological impact mechanisms of MPs in freshwater sediments, facilitating a better understanding of environmental risks of MPs in freshwater sediments.

Discovery of L15 as a novel Vif PROTAC degrader with antiviral activity against HIV-1.

Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15, Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS).

Channel modeling for NLoS visible light networks with integrated sensing and communication.

Inspired by the advanced integrated sensing and communication (ISAC), in this Letter, we explore the non-line-of-sight (NLoS) optical channels formed by reflections from the ground or objects to establish an integrated channel model for simultaneous communication and sensing. The integrated channel model can, on the one hand, perceive the changes in the surrounding environment and, on the other hand, determine whether these changes positively or negatively affect the quality of communication simultaneously. To validate the effectiveness of the proposed model, from sensing, we analyze the impact of various floor materials and visible light communication (VLC) users on the integrated channel; from communication, we characterize the influence of perceived environmental changes on communication performance by calculating throughput. Experimental results confirm the capability of the derived model, which can support the design and deployment of VL-based ISAC networks.

Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation.

Advancements in anticancer strategies spotlight proteolysis targeting chimera (PROTAC) technology, yet it is hindered by poor water solubility and bioavailability. This study introduces a novel amphiphilic PROTAC, B1-PEG, synthesized through PEGylation of an optimized PROTAC molecule, B1, to enhance its properties. B1-PEG is engineered to self-organize into micelles in water and releases its active form in response to the tumor-specific high GSH environment. Comparative pharmacokinetic analysis revealed B1-PEG's superior bioavailability at 84.8%, outperforming the unmodified PROTAC molecule B1. When tested in a H3122 xenograft mouse model, B1-PEG significantly regressed tumors, underscoring its potential as a formidable candidate in targeted cancer therapy. Our findings offer a promising direction for overcoming bioavailability limitations in PROTAC drug design.

Discovery of Novel Proteolysis-Targeting Chimera Molecules as Degraders of Programmed Cell Death-Ligand 1 for Breast Cancer Therapy.

The immune checkpoint blockade represents a pivotal strategy for tumor immunotherapy. At present, various programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies have been successfully applied to tumor treatment. Additionally, numerous small molecule inhibitors of the PD-1/PD-L1 interaction have also been developed, with some advancing into clinical trials. Here, a novel PD-L1 proteolysis-targeting chimera (PROTAC) library was designed and synthesized utilizing the PD-L1 inhibitor BMS202 and the E3 ligand PG as foundational components. Among these, we identified a highly potent molecule PA8 for PD-L1 degradation in 4T1 cells (DC50 = 0.609 µM). Significantly, compound PA8 potentially inhibits 4T1 cell growth both in vitro and in vivo. Further mechanistic studies revealed that PA8 effectively promoted the immune activation of model mice. Thus, these results suggest that PA8 could be a novel strategy for cancer immunotherapy in the 4T1 tumor model. Although PA8 exhibits weaker degradation activity in some human cancer cells, it still provides a certain basis for further research on PD-L1 PROTAC.

The brassinosteroid receptor StBRI1 promotes tuber development by enhancing plasma membrane H+-ATPase activity in potato.

The brassinosteroid (BR) receptor BRASSINOSTEROID-INSENSITIVE 1 (BRI1) plays a critical role in plant growth and development. Although much is known about how BR signaling regulates growth and development in many crop species, the role of StBRI1 in regulating potato (Solanum tuberosum) tuber development is not well understood. To address this question, a series of comprehensive genetic and biochemical methods were applied in this investigation. It was determined that StBRI1 and Solanum tuberosum PLASMA MEMBRANE (PM) PROTON ATPASE2 (PHA2), a PM-localized proton ATPase, play important roles in potato tuber development. The individual overexpression of StBRI1 and PHA2 led to a 22% and 25% increase in tuber yield per plant, respectively. Consistent with the genetic evidence, in vivo interaction analysis using double transgenic lines and PM H+-ATPase activity assays indicated that StBRI1 interacts with the C-terminus of PHA2, which restrains the intramolecular interaction of the PHA2 C-terminus with the PHA2 central loop to attenuate autoinhibition of PM H+-ATPase activity, resulting in increased PHA2 activity. Furthermore, the extent of PM H+-ATPase autoinhibition involving phosphorylation-dependent mechanisms corresponds to phosphorylation of the penultimate Thr residue (Thr-951) in PHA2. These results suggest that StBRI1 phosphorylates PHA2 and enhances its activity, which subsequently promotes tuber development. Altogether, our results uncover a BR-StBRI1-PHA2 module that regulates tuber development and suggest a prospective strategy for improving tuberous crop growth and increasing yield via the cell surface-based BR signaling pathway.