Exploring the impact of ITGB2 on glioma progression and treatment: Insights from non-apoptotic cell death and immunotherapy.

In the realm of glioma treatment, our groundbreaking research has uncovered the pivotal role of Integrin Beta 2 (ITGB2) in non-apoptotic cell death and its profound implications for immunotherapy efficacy. Gliomas, known for their aggressive and infiltrative nature, demand innovative therapeutic strategies for improved patient outcomes. Our study bridges a critical gap by examining the interplay between non-apoptotic cell death and immunotherapy response in gliomas. Through comprehensive analysis of ten diverse glioma datasets, we developed a unique death enrichment score and identified ITGB2 as a significant risk marker. This study demonstrates that ITGB2 can predict immune activity, mutation characteristics, and drug response in glioma patients. We reveal that ITGB2 not only mediates glioma proliferation and migration but also crucially influences immunotherapy responses by modulating the interaction between gliomas and macrophages by single-cell sequencing analysis (iTalk and ICELLNET). Employing a variety of molecular and cellular methodologies, including in vitro models, our findings highlight ITGB2 as a potent marker in glioma biology, particularly impacting macrophage migration and polarization. We present compelling evidence of ITGB2's dual role in regulating tumor cell behavior and shaping the immune landscape, thereby influencing therapeutic outcomes. The study underlines the potential of ITGB2-targeted strategies in enhancing the efficacy of immunotherapy and opens new avenues for personalized treatment approaches in glioma management. In conclusion, this research marks a significant stride in understanding glioma pathology and therapy, positioning ITGB2 as a key biomarker and a promising target in the quest for effective glioma treatments.

IGFBP2 from a novel copper metabolism-associated biomarker promoted glioma progression and response to immunotherapy.

Introduction: Copper metabolism encompasses all cellular metabolic processes involving copper ions and plays a significant role in the pathogenesis of diseases, including cancer. Furthermore, copper is intricately involved in various processes related to nucleotide metabolism. However, a comprehensive analysis of copper metabolism in gliomas remains lacking despite its importance. Methods: To address this gap, glioma patients were stratified based on the expression levels of copper metabolism-related genes. By utilizing machine learning techniques, a novel copper metabolism-associated biomarker was developed. The potential of this biomarker in prognosis, mutation analysis, and predicting immunotherapy response efficiency in gliomas was systematically investigated. Results: Notably, IGFBP2, identified as a glioma tumor promoter, was found to promote disease progression and influence immunotherapy response. Additionally, glioma-derived IGFBP2 was observed to enhance microglial migration. High IGFBP2 expression in GBM cells facilitated macrophage interactions through the EGFR, CD63, ITGB1, and CD44 signaling pathways. Discussion: Overall, the copper metabolism-associated biomarker shows promising potential to enhance the clinical management of gliomas, offering valuable insights into disease prognosis and treatment strategies.

Coronatine promotes maize water uptake by directly binding to the aquaporin ZmPIP2;5 and enhancing its activity.

Water uptake is crucial for crop growth and development and drought stress tolerance. The water channel aquaporins (AQP) play important roles in plant water uptake. Here, we discovered that a jasmonic acid analog, coronatine (COR), enhanced maize (Zea mays) root water uptake capacity under artificial water deficiency conditions. COR treatment induced the expression of the AQP gene Plasma membrane intrinsic protein 2;5 (ZmPIP2;5). In vivo and in vitro experiments indicated that COR also directly acts on ZmPIP2;5 to improve water uptake in maize and Xenopus oocytes. The leaf water potential and hydraulic conductivity of roots growing under hyperosmotic conditions were higher in ZmPIP2;5-overexpression lines and lower in the zmpip2;5 knockout mutant, compared to wild-type plants. Based on a comparison between ZmPIP2;5 and other PIP2s, we predicted that COR may bind to the functional site in loop E of ZmPIP2;5. We confirmed this prediction by surface plasmon resonance technology and a microscale thermophoresis assay, and showed that deleting the binding motif greatly reduced COR binding. We identified the N241 residue as the COR-specific binding site, which may activate the channel of the AQP tetramer and increase water transport activity, which may facilitate water uptake under hyperosmotic stress.

CircUCK2 regulates HECTD1-mediated endothelial-mesenchymal transition inhibition by interacting with FUS and protects the blood-brain barrier in ischemic stroke.

Ischemic stroke (IS) has become a cerebrovascular disease of widespread concern. Overexpression of circUCK2 alleviates neuronal damage in IS. However, the specific regulatory mechanisms of circUCK2 are not fully understood. In this study, we found that circUCK2 and HECT domain E3 ubiquitin ligase 1 (HECTD1) were downregulated in IS models in vitro and in vivo. Overexpression of circUCK2 or HECTD1 inhibited endothelial-mesenchymal transition (EndoMT) and protected the blood-brain barrier (BBB) in transient middle cerebral artery occlusion mice from damage. It was further discovered that circUCK2 regulated HECTD1 expressions by interacting with fused in sarcoma (FUS). Moreover, FUS overexpression partially restored the effect of circUCK2 on EndoMT, and overexpression of HECTD1 weakened the effect of FUS on EndoMT. Collectively, circUCK2 upregulates the expression of HECTD1 by combining with FUS and inhibits EndoMT to alleviate BBB damage in IS both in vivo and in vitro.

Natural variations of ZmSRO1d modulate the trade-off between drought resistance and yield by affecting ZmRBOHC-mediated stomatal ROS production in maize.

While crop yields have historically increased, drought resistance has become a major concern in the context of global climate change. The trade-off between crop yield and drought resistance is a common phenomenon; however, the underlying molecular modulators remain undetermined. Through genome-wide association study, we revealed that three non-synonymous variants in a drought-resistant allele of ZmSRO1d-R resulted in plasma membrane localization and enhanced mono-ADP-ribosyltransferase activity of ZmSRO1d toward ZmRBOHC, which increased reactive oxygen species (ROS) levels in guard cells and promoted stomatal closure. ZmSRO1d-R enhanced plant drought resilience and protected grain yields under drought conditions, but it led to yield drag under favorable conditions. In contrast, loss-of-function mutants of ZmRBOHC showed remarkably increased yields under well-watered conditions, whereas they showed compromised drought resistance. Interestingly, by analyzing 189 teosinte accessions, we found that the ZmSRO1d-R allele was present in teosinte but was selected against during maize domestication and modern breeding. Collectively, our work suggests that the allele frequency reduction of ZmSRO1d-R in breeding programs may have compromised maize drought resistance while increased yields. Therefore, introduction of the ZmSRO1d-R allele into modern maize cultivars would contribute to food security under drought stress caused by global climate change.

A dirigent family protein confers variation of Casparian strip thickness and salt tolerance in maize.

Plant salt-stress response involves complex physiological processes. Previous studies have shown that some factors promote salt tolerance only under high transpiring condition, thus mediating transpiration-dependent salt tolerance (TDST). However, the mechanism underlying crop TDST remains largely unknown. Here, we report that ZmSTL1 (Salt-Tolerant Locus 1) confers natural variation of TDST in maize. ZmSTL1 encodes a dirigent protein (termed ZmESBL) localized to the Casparian strip (CS) domain. Mutants lacking ZmESBL display impaired lignin deposition at endodermal CS domain which leads to a defective CS barrier. Under salt condition, mutation of ZmESBL increases the apoplastic transport of Na+ across the endodermis, and then increases the root-to-shoot delivery of Na+ via transpiration flow, thereby leading to a transpiration-dependent salt hypersensitivity. Moreover, we show that the ortholog of ZmESBL also mediates CS development and TDST in Arabidopsis. Our study suggests that modification of CS barrier may provide an approach for developing salt-tolerant crops.

A natural variation in Ribonuclease H-like gene underlies Rht8 to confer "Green Revolution" trait in wheat.

Rht8 is a gibberellin-sensitive Reduced height (Rht) locus that has been widely used in crop wheat semi-dwarfing breeding. In this study, the authors reported the map-based cloning of Rht8 candidate gene, and confirmed that loss of Ribonuclease H-Like 1 (RNHL-D1) is responsible for Rht8 semi-dwarfing effect.

MAPK-like protein 1 positively regulates maize seedling drought sensitivity by suppressing ABA biosynthesis.

Mitogen-activated protein kinase (MAPK) cascades play vital roles in regulating plant growth, development, and stress responses. MAPK-like (MPKL) proteins are a group of kinases containing the MAPK signature TxY motif and showing sequence similarity to MAPKs. However, the functions of plant MPKL proteins are currently unknown. The maize (Zea mays) genome contains four genes encoding MPKL proteins, here named ZmMPKL1 to ZmMPKL4. In this study, we show that ZmMPKL1 possesses kinase activity and that drought-induced ZmMPKL1 expression, ZmMPKL1 overexpression and knockout maize seedlings exhibited no visible morphological difference from wild-type B73 seedlings when grown under normal conditions. By contrast, under drought conditions, ZmMPKL1-overexpressing seedlings showed increased stomatal aperture, water loss, and leaf wilting and knockout seedlings showed the opposite phenotypes. Moreover, these drought-sensitive phenotypes in ZmMPKL1-overexpressing seedlings were restored by exogenous abscisic acid (ABA). ZmMPKL1 overexpression reduced drought-induced ABA production in seedlings and the knockout showed enhanced ABA production. Drought-induced transcription of ABA biosynthetic genes were suppressed and ABA catabolic genes were enhanced in ZmMPKL1-overexpressing seedlings, while their transcription were reversely regulated in knockout seedlings. These results suggest that ZmMPKL1 positively regulates seedlings drought sensitivity by altering the transcription of ABA biosynthetic and catabolic genes, and ABA homeostasis.