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Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity of reagents to translate this for cancer therapy. Here, we report that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1α-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa. XBP1s is necessary for optimal c-MYC mRNA and protein expression, establishing, for the first time, a direct link between UPR and oncogene activation. In addition, an XBP1-specific gene expression signature is strongly associated with PCa prognosis. Our data establish IRE1α-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies. ER stress and UPR are implicated in various cancers. Here, the authors show that one of the canonical UPR pathways, IRE1α-XBP1 regulates c-MYC signaling to promote prostate tumorigenesis, and pharmacological inhibition of IRE1α with MKC8866 inhibits prostate cancer growth and synergizes with clinically used prostate cancer drugs.

The relationship between socioeconomic status and cardiovascular disease among the general Chinese population is inconclusive. This study aims to investigate the relationship between socioeconomic status and cardiovascular disease in the Chinese general population through a large sample. We retrospectively analyzed data from the 2015 and 2018 waves of the China Health and Retirement Longitudinal Study (CHARLS). Participants were required to be at least 45 years old and have cardiovascular disease (CVD) data. The study was divided into two parts: a cross-sectional analysis using 2015 data, and a longitudinal analysis of participants without CVD in 2015 but with complete follow-up data in 2018. Socioeconomic status (SES) was assessed using self-reported household income, occupation, education level, and health insurance. CVD events were identified through participant-reported diagnoses of heart disease or stroke. Logistic and Cox proportional hazards regression models were used to estimate the association between SES and CVD. 16,560 participants were included in the cross-sectional analysis and 11,587 in the longitudinal analysis. Socioeconomic status. Cardiovascular disease, heart disease, and stroke. In the cross-sectional analysis, 16% of the 16,560 participants had CVD, with higher prevalence in lower SES groups. After adjustments, middle SES was significantly associated with increased CVD risk (OR 1.77, 95% CI 1.21-2.58). In the longitudinal analysis, during a 3-year follow-up, 12.1% of 11,587 participants developed CVD. Middle SES was associated with a 67% higher risk of new-onset CVD (HR 1.67, 95% CI 1.02-2.74). Sensitivity analysis confirmed these findings, with middle SES showing a significant association with CVD risk (HR 1.32, 95% CI 1.04-1.67). In the general population of China, middle socioeconomic status is positively associated with cardiovascular disease and is more likely to be associated with new-onset cardiovascular disease. Our findings support the need for trade-offs between socioeconomic status groups to benefit different populations, especially considering the middle socioeconomic status group, which is an easily overlooked group. However, more long-term prospective studies are needed to further elucidate the relationship between changes in socioeconomic status and cardiovascular disease in China.

Electrolyte disturbances are relatively common in patients with depression, but they are often overlooked, and the relationship between electrolyte changes and adverse outcomes in depression is not yet clear. This study aims to explore the impact of serum electrolyte levels on the all-cause and cardiovascular disease (CVD) mortality rates in patients with depression. This prospective cohort study included 3127 patients with depression who participated in the National Health and Nutrition Examination Survey (NHANES) from 2005 through 2018. Depression was assessed using the Patient Health Questionnaire (PHQ-9), with a PHQ-9 score ≥10 defined as depression. The data were analyzed from April 1 to July 30, 2024. Multivariable Cox proportional hazards regression model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) between serum sodium, potassium, and chloride levels and the CVD risk and all-cause mortality in patients with depression. Three multivariable models were constructed. We further stratified the analysis by age, gender, hypertension, smoking, alcohol consumption, diabetes, and drinking status. Interaction significance was estimated using P-values for the product terms between serum sodium, potassium, chloride, and stratification factors. This cohort study included data from 2946 participants in the analysis (mean [SD] age, 50.13 [16.48] years; 1116 men [37.88]); During a median (IQR) follow-up of 7.2 (3.6-10.5) years, 398 deaths were recorded, of which 117 were attributed to CVD.After multivariable adjustment, compared with participants in the first quartile of serum sodium levels, the HRs of CVD mortality were 0.90(95% CI, 0.53-1.53) in the fourth quartile (p for trend = 0.484). The HRs of all-cause mortality were 0.73(95% CI, 0.55-0.99) for the fourth quartile (p for trend = 0.003). A nonlinear association was observed between serum sodium levels and all-cause mortality in patients with depression (p for overall = 0.003, p for nonlinear = 0.047). Compared with participants in the first quartile of serum potassium levels, the HRs of CVD mortality were and 1.58(95% CI, 0.98-2.54) in the fourth quartile (p for trend = 0.050), the HRs of all-cause mortality were 1.52(95% CI, 1.16-1.99) for the fourth quartile (p for trend <0.001). A nonlinear association was observed between serum potassium levels and all-cause (p for overall<0.001, p for nonlinear = 0.005) and CVD (p for nonlinear = 0.003) mortality in patients with depression. Compared with participants in the first quartile of serum chlorine levels, the HRs of CVD mortality were 0.84(95% CI, 0.49-1.46) in the fourth quartile(p for trend = 0.284). The HRs of all-cause mortality were 0.70(95% CI, 0.51-0.95) for the fourth quartile(p for trend <0.001). A nonlinear association was observed between serum chlorine levels and all-cause (p for nonlinear<0.001) and CVD (p for nonlinear<0.001) mortality in patients with depression. This cohort study found that in patients with depression, higher sodium is significantly correlated with lower all-cause mortality, higher potassium is significantly correlated with higher all-cause and CVD mortality, and higher chloride is significantly correlated with lower all-cause and CVD mortality.

Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics. IRE1/XBP-1 activation has a major role in Triple negative breast cancer (TNBC). Here, the authors show that inhibition of IRE1’s RNase activity attenuates autocrine and paracrine signaling of pro-tumorigenic cytokines and synergizes with paclitaxel to confer potent anti-tumor effects in TNBC.

The unfolded protein response (UPR) is a cellular homeostatic mechanism that is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the molecular mechanisms for UPR activation and regulation in cancer cells remain elusive. Here, we show that oncogenic MYC regulates the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) branch of the UPR in breast cancer via multiple mechanisms. We found that MYC directly controls IRE1 transcription by binding to its promoter and enhancer. Furthermore, MYC forms a transcriptional complex with XBP1, a target of IRE1, and enhances its transcriptional activity. Importantly, we demonstrate that XBP1 is a synthetic lethal partner of MYC. Silencing of XBP1 selectively blocked the growth of MYC-hyperactivated cells. Pharmacological inhibition of IRE1 RNase activity with small molecule inhibitor 8866 selectively restrained the MYC-overexpressing tumor growth in vivo in a cohort of preclinical patient-derived xenograft models and genetically engineered mouse models. Strikingly, 8866 substantially enhanced the efficacy of docetaxel chemotherapy, resulting in rapid regression of MYC-overexpressing tumors. Collectively, these data establish the synthetic lethal interaction of the IRE1/XBP1 pathway with MYC hyperactivation and provide a potential therapy for MYC-driven human breast cancers.

Soil organic carbon fractions and pool management indices are critical for the ecosystem function of bamboo forests; however, their response to varying degrees of expansion of Chimonobambusa utilis (EDCU) and altitudinal gradients remains poorly understood in high-altitude karst regions. In this study, 225 samples (three replicate soil samples, each with five duplicate samples) were collected from 45 typical soil sites in the Jinfo high-altitude karst mountains, China. This study investigated the effects of three EDCUs (low, moderate, and high expansion) and five altitudinal gradients (1300–1500 m, 1500–1700 m, 1700–900 m, 1900–2100 m, and 2100–2300 m) on root elemental composition, soil properties, soil organic fractions, and pool management indices. The results revealed that root total C, N, RC:P, and RN:P decreased with increasing altitude, whereas root total C, N, P, and RC:N also increased significantly with increasing EDCU. Compared with those at low and moderate EDCU, the POC:SOC (34.12%), HFOC (32.73 g kg−1), and HFOC:SOC (37.07%) ratios were highest at high EDCU along the altitudinal gradient of 1700–1900 m. Meanwhile, the L (2.38), LI (2.01), and CMI (174.55) ratios reached their highest values at moderate expansion degrees of Chimonobambusa utilis within the altitudinal gradient of 1900–2100 m. Moreover, redundancy discriminant analysis (RDA) and structural equation modeling (SEM) revealed that the soil carbon pool management index was significantly positively associated with soil properties through direct pathways and negatively correlated with root elemental composition through indirect pathways. In general, the quality of the carbon pool in Chimonobambusa utilis is optimal within the moderate expansion degrees of Chimonobambusa utilis within the altitudinal gradient of 1900–2100 m. The findings of this study establish a theoretical basis for the expansion of Chimonobambusa utilis in high-altitude karst regions and provide scientific evidence to support the increase in the carbon sequestration capacity of bamboo forest ecosystems in these mountainous areas.

The expansion ratio of bamboo forests has significantly influenced soil nutrient cycling in broad-leaved forests through alterations in vegetation composition. However, the extent to which varying expansion ratios of bamboo within broad-leaved forest areas (MRB) affect soil enzyme activities and stoichiometric ratio in karst regions with yellow limestone soil remains poorly understood. Therefore, we examined five MRB levels (<20%, 20-40%, 40-60%, 60-80%, and >80%) and three soil depths (0-20 cm, 20-40 cm, and 40-60 cm) to analyze variations in soil microbial resource limitation within a field experiment conducted in a karst region. The results revealed showed that root morphology was significantly less developed at both low (<20%) and high (≥80%) expansion ratios than at moderate expansion ratios (40-60%) and exhibited a decreasing trend with increasing soil depth. The soil TC (46.43 g·kg ), SOC (80.05 g·kg ) and N:P (0.96) reached their highest values in the 40-60% MRB, whereas the pH (4.61), BD (0.42 g·cm ), AN (20.28 g·kg ) and C:N (45.51) were lowest at 0-20 cm. Moreover, the CBH and the E ratio at 40-60 cm depth in the 0-20% MRB were significantly 2.64 and 1.31 times greater than those at 0-20 cm depth in the 40-60% MRB. Mantel and structural equation modeling (SEM) analyses revealed that soil enzyme activity and stoichiometric ratios are indirectly influenced by soil bulk density (β = -0.156) and root characteristics (β = -0.630). Overall, both C and P limitations are present at the lowest MRB (<20%), whereas other MRB ranges exhibit only P limitation without C limitation. Our results highlight that soil nutrient availability in karst regions of Southwest China is influenced by vegetation structure. These findings provide a scientific foundation for achieving the green and sustainable management of bamboo forests within broad-leaved forest ecosystems.

The sheaths of bamboo shoots, characterized by distinct colors and spotting patterns, are key phenotypic markers influencing species classification, market value, and genetic studies. This study introduces YOLOv8-BS, a deep learning model optimized for detecting these traits in Chimonobambusa utilis using a dataset from Jinfo Mountain, China. Enhanced by data augmentation techniques, including translation, flipping, and contrast adjustment, YOLOv8-BS outperformed benchmark models (YOLOv7, YOLOv5, YOLOX, and Faster R-CNN) in color and spot detection. For color detection, it achieved a precision of 85.9%, a recall of 83.4%, an F1-score of 84.6%, and an average precision (AP) of 86.8%. For spot detection, it recorded a precision of 90.1%, a recall of 92.5%, an F1-score of 91.1%, and an AP of 96.1%. These results demonstrate superior accuracy and robustness, enabling precise phenotypic analysis for bamboo germplasm evaluation and genetic diversity studies. YOLOv8-BS supports precision agriculture by providing a scalable tool for sustainable bamboo-based industries. Future improvements could enhance model adaptability for fine-grained varietal differences and real-time applications.

Heavy metal (HM) contamination poses a serious threat to safe crop production and human health, and different maize inbred lines respond differently to cadmium (Cd) stress. However, the morphological and physiological characteristics of maize inbred lines seedlings are not clear under Cd stress. In this study, we analyzed the agronomic traits and physiological and biochemical indices of inbred maize seedlings under Cd stress in the seedling stage using the inbred lines Kui3, CML118, Mo17, B73, and B77 as the materials. These five inbred maizes were treated with five different concentrations of Cd (0, 1, 3, 5, and 7 mg L−1, respectively) were applied and the indices of the maize seedlings determined on day 15. The aboveground and belowground biomass of five maize inbred lines seedlings showed a decreasing trend under Cd stress. Leaf relative water content and SPAD values also decreased, but the overall decrease in relative water content was small, and the differences were not significant. Surprisingly, Cd stress affected the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), leading to enhanced mem-brane lipid peroxidation. The cadmium content varied greatly between varieties under Cd stress, but all of them had lower Cd content above ground than below ground, and the varieties with the highest and lowest transfer coefficients were Mo17 (0.33–0.83) and B73 (0.06–0.44), respectively. Kui3 had the greatest difference in soluble protein content under Cd stress, which showed a de-creasing trend, and the soluble sugar content was significantly decreased in general compared to that of CK. The soluble sugar content was higher than CK under Cd treatment, and the proline content of the maize seedlings of all of the inbred lines showed an increasing trend compared to CK. Overall, there were significant genotypic differences in the Cd stress response to Cd toxicity in the maize inbred lines seedlings, and, in general, this study helps us to understand the mechanism of maize inbred lines seedlings response to Cd stress. It provides a theoretical basis for the se-lection and breeding of varieties, and food safety.

Phenolamides are important secondary metabolites in plant species. They play important roles in plant defense responses against pathogens and insect herbivores, protection against UV irradiation and floral induction and development. However, the accumulation and variation in phenolamides content in diverse maize lines and the genes responsible for their biosynthesis remain largely unknown. Here, we combined genetic mapping, protein regulatory network and bioinformatics analysis to further enhance the understanding of maize phenolamides biosynthesis. Sixteen phenolamides were identified in multiple populations, and they were all significantly correlated with one or several of 19 phenotypic traits. By linkage mapping, 58, 58, 39 and 67 QTLs, with an average of 3.9, 3.6, 3.6 and 4.2 QTLs for each trait were mapped in BBE1, BBE2, ZYE1 and ZYE2, explaining 9.47%, 10.78%, 9.51% and 11.40% phenotypic variation for each QTL on average, respectively. By GWAS, 39 and 36 significant loci were detected in two different environments, 3.3 and 2.8 loci for each trait, explaining 10.00% and 9.97% phenotypic variation for each locus on average, respectively. Totally, 58 unique candidate genes were identified, 31% of them encoding enzymes involved in amine and derivative metabolic processes. Gene Ontology term analysis of the 358 protein-protein interrelated genes revealed significant enrichment in terms relating to cellular nitrogen metabolism, amine metabolism. GRMZM2G066142, GRMZM2G066049, GRMZM2G165390 and GRMZM2G159587 were further validated involvement in phenolamides biosynthesis. Our results provide insights into the genetic basis of phenolamides biosynthesis in maize kernels, understanding phenolamides biosynthesis and its nutritional content and ability to withstand biotic and abiotic stress.