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Macrophages and neutrophils are the main components of the innate immune system and play important roles in promoting angiogenesis, extracellular matrix remodeling, cancer cell proliferation, and metastasis in the tumor microenvironment (TME). They can also be harnessed to mediate cytotoxic tumor killing effects and orchestrate effective anti-tumor immune responses with proper stimulation and modification. Therefore, macrophages and neutrophils have strong potential in cancer immunotherapy. In this review, we briefly outlined the applications of macrophages or neutrophils in adoptive cell therapies, and focused on chimeric antigen receptor (CAR)-engineered macrophages (CAR-Ms) and neutrophils (CAR-Ns). We summarized the construction strategies, the preclinical and clinical studies of CAR-Ms and CAR-Ns. In the end, we briefly discussed the limitations and challenges of CAR-Ms and CAR-Ns, as well as future research directions to extend their applications in treating solid tumors.

In this study, we constructed novel brain-targeting complexes (U2-AuNP) by conjugating aptamer U2 to the gold nanoparticle (AuNPs) surface as a promising option for GBM therapy. The properties of the U2-AuNP complexes were thoroughly characterized. Then, we detected the in vitro effects of U2-AuNP in U87-EGFRvIII cell lines and the in vivo antitumor effects of U2-AuNP in GBM-bearing mice. Furthermore, we explored the inhibition mechanism of U2-AuNP in U87-EGFRvIII cell lines. We found that U2-AuNP inhibits the proliferation and invasion of U87-EGFRvIII cell lines and prolongs the survival time of GBM-bearing mice. We found that U2-AuNP can inhibit the EGFR-related pathway and prevent DNA damage repair in GBM cells. These results reveal the promising potential of U2-AuNP as a drug candidate for targeted therapy in GBM.

Glioma is the most malignant cancer in the brain. As a major vitamin-K-dependent protein in the central nervous system, PROS1 not only plays a vital role in blood coagulation, and some studies have found that it was associated with tumor immune infiltration. However, the prognostic significance of PROS1 in glioma and the underlying mechanism of PROS1 in shaping the tumor immune microenvironment (TIME) remains unclear. The raw data (including RNA-seq, sgRNA-seq, clinicopathological variables and prognosis, and survival data) were acquired from public databases, including TCGA, GEPIA, CGGA, TIMER, GEO, UALCAN, and CancerSEA. GO enrichment and KEGG pathway analyses were performed using \"cluster profiler\" package and visualized by the \"ggplot2\" package. GSEA was conducted using R package \"cluster profiler\". Tumor immune estimation resource (TIMER) and spearman correlation analysis were applied to evaluate the associations between infiltration levels of immune cells and the expression of PROS1. qRT-PCR and WB were used to assay the expression of PROS1. Wound-healing assay, transwell chambers assays, and CCK-8 assays, were performed to assess migration and proliferation. ROC and KM curves were constructed to determine prognostic significance of PROS1 in glioma. The level of PROS1 expression was significantly increased in glioma in comparison to normal tissue, which was further certificated by qRT-PCR and WB in LN-229 and U-87MG glioma cells. High expression of PROS1 positively correlated with inflammation, EMT, and invasion identified by CancerSEA, which was also proved by downregulation of PROS1 could suppress cells migration, and proliferation in LN-229 and U-87MG glioma cells. GO and KEGG analysis suggested that PROS1 was involved in disease of immune system and T cell antigen receptor pathway. Immune cell infiltration analysis showed that expression of PROS1 was negatively associated with pDC and NK CD56 bright cells while positively correlated with Macrophages, Neutrophils in glioma. Immune and stromal scores analysis indicated that PROS1 was positively associated with immune score. The high level of PROS1 resulted in an immune suppressive TIME the recruitment of immunosuppressive molecules. In addition, Increased expression of PROS1 was correlated with T-cell exhaustion, M2 polarization, poor Overall-Survival (OS) in glioma. And it was significantly related to tumor histological level, age, primary therapy outcome. The results of our experiment and various bioinformatics approaches validated that PROS1 was a valuable poor prognostic marker. Increased expression of PROS1 was correlated with malignant phenotype and associated with poor prognosis in glioma. Besides, PROS1 could be a possible biomarker and potential immunotherapeutic target through promoting the glioma immunosuppressive microenvironment and inducing tumor-associated macrophages M2 polarization.

Background Cancer‐associated fibroblasts (CAFs) are potential targets for cancer therapy. Due to the heterogeneity of CAFs, the influence of CAF subpopulations on the progression of lung cancer is still unclear, which impedes the translational advances in targeting CAFs. Methods We performed single‐cell RNA sequencing (scRNA‐seq) on tumour, paired tumour‐adjacent, and normal samples from 16 non‐small cell lung cancer (NSCLC) patients. CAF subpopulations were analyzed after integration with published NSCLC scRNA‐seq data. SpaTial enhanced resolution omics‐sequencing (Stereo‐seq) was applied in tumour and tumour‐adjacent samples from seven NSCLC patients to map the architecture of major cell populations in tumour microenvironment (TME). Immunohistochemistry (IHC) and multiplexed IHC (mIHC) were used to validate marker gene expression and the association of CAFs with immune infiltration in TME. Results A subcluster of myofibroblastic CAFs, POSTN+ CAFs, were significantly enriched in advanced tumours and presented gene expression signatures related to extracellular matrix remodeling, tumour invasion pathways and immune suppression. Stereo‐seq and mIHC demonstrated that POSTN+ CAFs were in close localization with SPP1+ macrophages and were associated with the exhausted phenotype and lower infiltration of T cells. POSTN expression or the abundance of POSTN+ CAFs were associated with poor prognosis of NSCLC. Conclusions Our study identified a myofibroblastic CAF subpopulation, POSTN+ CAFs, which might associate with SPP1+ macrophages to promote the formation of desmoplastic architecture and participate in immune suppression. Furthermore, we showed that POSTN+ CAFs associated with cancer progression and poor clinical outcomes and may provide new insights on the treatment of NSCLC. POSTN+ CAFs were enriched in advanced NSCLC tumours and presented gene expression signatures related to extracellular matrix remodeling, tumour invasion and immune suppression. POSTN+ CAFs were in close localization with SPP1+ macrophages and associated with the exhausted phenotype and lower infiltration of T cells. POSTN expression and POSTN+ CAFs were prognostic factors for NSCLC.

Background Parkinson's disease (PD) affects approximately 1% of individuals aged 60 and older, with prevalence projected to double by 2030 amid global aging. Traditional assessments using the Unified Parkinson's Disease Rating Scale (UPDRS) rely heavily on subjective clinical evaluation, producing inconsistent and non-reproducible outcomes. Accumulating evidence demonstrates that PD involves systemic inflammatory responses, making serological biomarkers promising candidates for objective severity assessment in routine clinical settings Methods We analysed serological data from 2,614 individuals to investigate correlations with motor symptom severity and Hoehn and Yahr (H&Y) staging. Thirty clinically relevant biomarkers were selected, including inflammatory markers (NLR, LMR, SII) and biochemical indicators (albumin, ALT, uric acid). We developed multiple machine learning models—XGBoost, CatBoost, Random Forest, and Decision Tree—for H&Y classification and MDS-UPDRS motor score prediction (total and itemized). Feature selection was conducted using XGBoost importance rankings. Additionally, we constructed a deep neural network incorporating adaptive feature selection and learning rate adjustment strategies to evaluate deep learning performance with the same feature set. Results Among traditional machine learning models, XGBoost achieved the highest performance for H&Y classification (accuracy: 0.816, weighted F1-score: 0.813), followed by CatBoost (accuracy: 0.812, F1-score: 0.811) and Random Forest (accuracy: 0.803, F1-score: 0.801). XGBoost also demonstrated superior performance in regression tasks for predicting motor scores. The DNN model significantly outperformed all classifiers, attaining accuracy of 0.885 and weighted F1-score of 0.881 for H&Y staging. Feature importance analysis revealed that inflammatory markers—particularly neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR)—emerged as critical predictors across all tasks. Removal of these markers resulted in notable performance decline, confirming their essential role in disease severity assessment and highlighting the relevance of systemic inflammation in PD progression. Conclusion Serological biomarkers, particularly inflammatory markers, can serve as effective non-invasive indicators for assessing PD severity and staging. Machine learning and deep learning algorithms, enhanced by adaptive optimization strategies, significantly improve the accuracy and objectivity of clinical evaluations. These findings establish a foundation for developing scalable, accessible diagnostic tools that support early PD detection, progression monitoring, and treatment planning in routine clinical practice.

Leptin is an adipocytokine that is primarily secreted by white adipose tissue, and it contributes to the pathogenesis of neuropathic pain in collaboration with N-methyl-D-aspartate receptors (NMDARs). Functional NMDARs are a heteromeric complex that primarily comprise two NR1 subunits and two NR2 subunits. NR2A is preferentially located at synaptic sites, and NR2B is enriched at extrasynaptic sites. The roles of synaptic and extrasynaptic NMDARs in the contribution of leptin to neuropathic pain are not clear. The present study examined whether the important role of leptin in neuropathic pain was related to synaptic or extrasynaptic NMDARs. We used a rat model of spared nerve injury (SNI) and demonstrated that the intrathecal administration of the NR2A-selective antagonist NVP-AAM077 and the NR2B-selective antagonist Ro25-6981 prevented and reversed mechanical allodynia following SNI. Administration of exogenous leptin mimicked SNI-induced behavioral allodynia, which was also prevented by NVP-AAM077 and Ro25-6981. Mechanistic studies showed that leptin enhanced NR2B- but not NR2A-mediated currents in spinal lamina II neurons of naïve rats. Leptin also upregulated the expression of NR2B, which was blocked by the NR2B-selective antagonist Ro25-6981, in cultured dorsal root ganglion (DRG) neurons. Leptin enhanced neuronal nitric oxide synthase (nNOS) expression, which was also blocked by Ro25-6981, in cultured DRG cells. However, leptin did not change NR2A expression, and the NR2A-selective antagonist NVP-AAM077 had no effect on leptin-enhanced nNOS expression. Our data suggest an important cellular link between the spinal effects of leptin and the extrasynaptic NMDAR-nNOS-mediated cellular mechanism of neuropathic pain.

The Himalayas is currently rising due to the collision of the Indian and Asian plates and hosts frequent earthquakes, some of which are devastating, such as the 2015 Mw7.8 Gorkha earthquake. Despite the importance of deep dynamic processes to understand the uplift of the Himalayas and the occurrence of large earthquakes, it remains limitedly constrained due to the lack of a detailed three‐dimensional subsurface image under this region. Here, we construct new models of shear‐wave velocity and radial anisotropy down to the 150 km depth from Rayleigh‐ and Love‐wave tomography in the Nepal Himalayas. We find that the 2015 Gorkha earthquake and its main aftershock occurred in a velocity contrast that is presumably interpreted as Main Himalayan Thrust (MHT). A duplex structure, imaged as relatively high velocities, is inferred to exist above MHT under the Lesser Himalayas. This duplex shows heterogeneous features along the strike of the Himalayas that may control the rupture behavior during the occurrence of a large earthquake. Additionally, a low‐velocity anomaly is observed at depths from Moho to 100 km under the Lhasa Terrane and north of the Himalayan Terrane between 85° and 88°E. We interpret this low‐velocity anomaly to be likely caused by mantle upwelling resulting from either possible Indian slab tearing, or northward subduction of the Indian plate. If this is the case, the north‐south trending rifts that situate within the dispersal of the low‐velocity anomaly are probably associated with the mantle upwelling. This study provides a new independent constraint on the geometry of the MHT system and deep dynamic processes occurring in the Nepal Himalaya. Plain Language Summary The 2015 Mw7.8 Gorkha (Nepal) earthquake caused great damages to property and lives. It is widely suggested that the motion of a megathrust (i.e, the Main Himalayan Thrust (MHT) is responsible for the large earthquake. In order to understand the geometry of this thrust system and associated deep dynamics, in this study we constructed a three‐dimensional subsurface image of the Nepal Himalayas using surface wave that travels at the surface of the Earth. Our seismic image, together with previous studies of coseismic slip distribution, reveals that rupture behavior of the 2015 Gorkha earthquake and its main aftershock is controlled by the heterogeneous duplex structure (i.e., a system of imbricate thrust faults) of the megathrust. Additionally, we offer seismic velocity evidence for the occurrence of asthenospheric upwelling beneath the north of the Himalayan Terrane between 85° and 88°E that is likely linked with the variable MHT geometry along the strike of the Himalayas and surface exposed north‐south trending rifts. This study provides a new independent constraint on the geometry of the MHT system and deep dynamic processes occurring in the Nepal Himalayas. Key Points New lithospheric‐scale shear‐wave velocity and radial anisotropy models are constructed using surface‐wave tomography A duplex structure of Main Himalayan Thrust is imaged as relatively high velocities under the Lesser Himalayas, controlling earthquake rupture propagation Mantle upwelling is inferred to occur beneath north of the Himalayan Terrane between 85° and 88°E

Cytokinin (CTK) is an important plant hormone that promotes cell division, controls cell differentiation, and regulates a variety of plant growth and development processes. Cytokinin oxidase/dehydrogenase (CKX) is an irreversible cytokinin‐degrading enzyme that affects plant growth and development by regulating the dynamic balance of CTKs synthesis and degradation. There are presumed 11 members of the CKX gene family in rice (Oryza sativa L.), but limited members have been reported. In this study, based on CRISPR‐Cas9 and CRISPR‐Cas12a genome‐editing technology, we established a complete set of OsCKX1‐OsCKX11 single‐gene mutants, as well as double‐gene and triple‐gene mutants of different OsCKXs gene combinations with high similarity. The results revealed that CRISPR‐Cas12a outperformed Cas9 to generate biallelic mutations, multi‐gene mutants, and more diverse genotypes. And then, we found, except the reported OsCKX2, OsCKX4, OsCKX9 and OsCKX11, OsCKX5, OsCKX6, OsCKX7, and OsCKX8 also had significant effects on agronomic traits such as plant height, panicle size, grain size, and grain number per panicle in rice. In addition, the different loss‐of‐function of the OsCKX genes also changed the seed appearance quality and starch composition. Interestingly, by comparing different combinations of multi‐gene mutants, we found significant functional redundancy among OsCKX gene members in the same phylogenetic clade. These data collectively reveal the diversified regulating capabilities of OsCKX genes in rice, and also provide the valuable reference for further rice molecular breeding. Core Ideas CRISPR‐Cas12a outperformed CRISPR‐Cas9 to generate multi‐gene mutants. There was significant functional redundancy among the OsCKX members in the same clade. OsCKXs affected plant development, seed appearance quality, and starch composition by regulating endogenous cytokinins. OsCKX1/2 and OsCKX3/8/10 gene clades played key roles in the control of panicle architecture and grain number. OsCKX4/5/9 gene clade regulated the development of roots and plant architecture such as plant height and tillers.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a critical maternal complication in some pre-eclampsia (PE) and nearly all eclampsia patients; RPLS is associated with high blood pressure (BP). However, the effect of BP on RPLS and the different characteristics of RPLS in PE or eclampsia are largely unknown. We consecutively collected data from 69 patients who were diagnosed with RPLS in PE or eclampsia between 2013 and 2017. The BP and biochemical indicators at onset and post onset of RPLS were examined to explore their likely correlation with RPLS. We grouped patients into PE (n=40) and eclampsia (n=29) groups according to whether a seizure had occurred. Information regarding BP, clinical symptoms and imaging features was collected retrospectively to explore the differences between groups. BP measurements (moderate and severe hypertension, systolic pressure (SBP), diastolic pressure (DBP) and mean arterial pressure (MAP) levels) and biochemical indicators (uric acid, lactate dehydrogenase (LDH), C-reactive protein and WBC) were higher at the onset of RPLS than post-onset of RPLS (P<0.001), whereas normal BP and serum albumin levels were lower (P<0.001). Moreover, the BP values (SBP, DBP and MAP) and LDH levels were significantly correlated with the degree of edema (Spearman's correlation, P<0.01). These results suggest that hypertension and LDH are likely factors in the development of RPLS in PE or eclampsia. Moreover, BP and LDH were closely related to the degree of brain edema, However, no significant differences were found between the PE and eclampsia groups with the exception of age and consciousness impairment.

Strictosidine synthase (STR) plays an important role in the biosynthesis of terpenoid indole alkaloids (TIAs) and is expressed in a range of active meristematic tissues of higher plants. STR proteins are involved in different physiological and biochemical pathways. However, the function of STR proteins in rice development remains poorly understood. In this study, we identified 21 possible STR-like ( OsSTRL ) family members in rice genome and found that only one gene, OsSTRL2 , exhibited a pre-emergency specific florescence expression pattern. Tissue-specific expression profile analysis, β-glucuronidase histochemical (GUS) staining and RNA in situ hybridization confirmed that OsSTRL2 was highly expressed in tapetal cells and microspores. Comparative protein sequence analysis indicated that OsSTRL2 lacked the key catalytic residue found in a typical STR (STR1), although it possessed conserved β-propellers and α-helices formed the basic structure of STR1. OsSTRL2 knockout mutant resulted to male sterility because of the defects in anther development and pollen wall formation. Subcellular localization of OsSTRL2-YFP revealed that the OsSTRL2 protein was primarily localized in the endoplasmic reticulum (ER). Therefore, OsSTRL2 is an atypical strictosidine synthase that plays crucial roles in regulating anther development and pollen wall formation in rice.