Search Results (5,341)

Proteasome inhibitors (PIs) are central to multiple myeloma (MM) therapy; however, resistance remains a major clinical challenge, particularly in relapsed/refractory disease. To identify functional mediators of carfilzomib (CFZ) resistance, we performed complementary gain-of-function CRISPR activation and pharmacological screening approaches. These unbiased strategies converged on the E3 ubiquitin ligase MDM2 as a modulator of PI response. MDM2 transactivation enhanced MM cell survival and accelerated recovery following CFZ exposure, supporting a causal role in proteotoxic stress tolerance. Pharmacologic inhibition of MDM2 with NVP-CGM097 synergized with CFZ across multiple PI-sensitive and PI-resistant MM cell lines, irrespective of TP53 status. Mechanistically, MDM2 inhibition induced p21 upregulation, cell-cycle arrest, and reduced c-MYC expression, accompanied by impaired activation of DNA damage response mediators. Genetic silencing of MDM2 phenocopied these effects and increased CFZ sensitivity. Importantly, the combination retained efficacy in MM–stromal co-culture models and in primary patient samples, including cases harboring del(17p), while sparing normal peripheral blood mononuclear cells. Collectively, these findings identify MDM2 as a functional driver of PI resistance and support combined MDM2 and proteasome inhibition as a rational therapeutic strategy in MM, including TP53-deficient contexts. Full article

Black rice is rich in anthocyanins with potential antioxidant benefits, but their specific role in storage stability remains unclear due to confounding genetic backgrounds in previous studies. In this study, we used CRISPR/Cas9-mediated gene editing to generate OsKala4 knockout lines in the black rice cultivar Heizhen (HZ), creating an isogenic system to test whether endogenous anthocyanins contribute to storage-related quality stability. Knockout lines showed blocked anthocyanin biosynthesis (0.5–0.6 vs. 155.6 mg/100 g, p < 0.001) and altered grain composition. Under accelerated aging (45 °C, 90% RH, 2 weeks), HZ maintained higher antioxidant capacity (p < 0.05) and exhibited less pronounced starch aging than the representative knockout line KO2. Apparent amylose content increased less in HZ than in KO2 (16.7% vs. 28.1%, p < 0.05). HZ also showed smaller changes in pasting, thermal, and structural properties. XRD and FTIR analyses further suggested better maintenance of starch crystallinity and molecular order in HZ under accelerated aging conditions. These results suggest that endogenous anthocyanins were associated with storage-related quality stability in black rice. However, direct mechanistic evidence and validation under natural storage conditions are still needed. Full article

Maize is one of the most widely cultivated crops worldwide and is extensively used for animal feed and industrial applications. Plant height (PH) and ear height (EH) are critical determinants of lodging resistance and tolerance to high planting density, and coordinated regulation of these traits is essential for yield improvement. In this study, 479 maize inbred lines from Northeast and North China were genotyped using 7861 single-nucleotide polymorphism (SNP) markers to perform a genome-wide association study (GWAS). After controlling for population structure and relatedness, the mixed linear model (MLM) identified 20 loci significantly associated with PH on chromosomes 2, 4, 5, 6, 7, and 8, and 8 loci associated with EH on chromosomes 2, 3, 4, and 7. A total of 23 candidate genes were identified, including PLATZ8, pectin methylesterase 36, and leucine-rich repeat extensin 14. Gene Ontology (GO) enrichment analysis revealed significant enrichment in biological and molecular functions such as DNA binding, pectinesterase activity, zinc ion binding, ATP binding, and uniporter activity. Bioinformatic characterization of the two most likely candidate genes, Zm00001d002726 and Zm00001d015394, showed that both possess a typical compact four-exon structure. Functional prediction indicated that Zm00001d002726 encodes a pectinesterase/pectinase, potentially regulating cell elongation through pectin degradation and remodeling of the cell wall. Pectinesterase activity may influence PH and EH by mediating pectin demethylation within the cell wall. In contrast, Zm00001d015394 encodes a PLATZ family transcription factor that may regulate downstream gene expression through DNA-binding activity. These findings provide insight into the genetic architecture and potential molecular mechanisms underlying PH and EH in maize and offer a foundation for future breeding efforts. Full article

Rice fungal blast, one of the most devastating diseases caused by Magnaporthe oryzae, poses a severe threat to global rice production. For the breeding and deployment of rice varieties with blast resistance, it is critical to elucidate the frequencies and genetic variations in avirulence genes among M. oryzae populations. In this study, a total of 294 M. oryzae isolates were collected in 2022 from central Jilin Province, China. Pathogenicity assays on 24 monogenic rice lines revealed extensive virulence variations among the 294 isolates, with highly pathogenic strains being dominant and clear geographic differences in pathogenicity profiles. Resistance frequencies differed markedly among 24 monogenic lines, with Pi3, Pit, Pi7, Pikh, Pik, and Pia showing resistance rates over 50% and Pish exhibiting the lowest efficacy. Moreover, resistance profiles varied significantly across four sampling regions in central Jilin Province, with Pit being the most effective in Changchun and Jilin, Pi3 in Tonghua, and Pikm in Liaoyuan. In addition, the Avr genotypes of the isolates were postulated based on phenotypic data from the monogenic rice lines. Among the postulated Avr genotypes, the frequencies of Avr-Pi11 and Avr-Pish were the lowest at 29.25%. Furthermore, molecular characterization of three Avr genes (Avr-Pi9, Avr-Pita2, and Avr-Pizt) was performed by sequencing a subsample of 50 randomly selected isolates. Natural mutation sites were identified in Avr-Pita2 and Avr-Pizt, which were located within the coding sequence regions, leading to non-synonymous mutations and nonsense mutations that cause premature termination. Notably, no mutation was detected within the coding sequences of Avr-Pi9. Collectively, the findings provide a theoretical basis for breeding blast-resistant rice varieties that can be deployed in central Jilin Province, China. Full article

Jacalin-related lectins play crucial roles in plant adaptation to abiotic and biotic stresses. The rice genome encodes four putative jacalin-related lectin kinase genes (OsJacLKs), but their functions toward environmental stresses remain largely uncharacterized. This study demonstrates that a putative jacalin-related lectin kinase, OsJacLK1, conferred resistance to the rice blast fungus Magnaporthe oryzae rather than salt stress. OsJacLK1 protein exhibited agglutination activities and affinity toward chitin, fungal cell wall, and mannose. OsJacLK1 was transcriptionally activated by stress-related phytohormones salicylic acid (SA), methyl jasmonate (MeJA), abscisic acid (ABA), and indoleacetic acid (IAA), as well as salinity, chitin, and M. oryzae inoculation, suggesting its involvement in broad stress-responsive signaling pathways. Overexpression of OsJacLK1 in rice led to reduced susceptibility to rice blast disease, whereas loss-of-function osjaclk1 lines showed no significant phenotypic difference from wild-type plants upon infection. Enhanced resistance in OsJacLK1-overexpressing lines was associated with a stronger reactive oxygen species (ROS) burst and elevated hydrogen peroxide accumulation, accompanied by the up-regulation of defense-related genes (OsRac1, OsSGT1, OsMAPK6, OsPAL1, OsNAC4, OsPBZ1, OsAOS2, and OsJAZ8). Collectively, our findings establish that OsJacLK1 acts as a positive regulator of rice immunity against M. oryzae, modulating the cellular redox state, highlighting its potential as a candidate for genetic improvement of disease resistance in rice. Full article

Acute lymphoblastic leukemia (ALL) is a genetically and epigenetically heterogeneous malignant disease characterized by different subtypes with varying sensitivities to conventional chemotherapy. Despite significant improvements in survival rates, relapse remains the primary cause of treatment failure, often associated with intrinsic or acquired drug resistance. First-line therapy at diagnosis represents a major determinant of relapse in ALL. In this study, we performed a transcriptome and drug response profiling analysis to identify subtype-specific cell surface proteins that are overexpressed in patients with poor response to induction therapy. We summarize the current state of knowledge regarding chemotherapy responses, resistance mechanisms to standard cytostatic drugs and the increasing importance of cell biomarkers as predictors of an adverse disease course and potential therapeutic targets. We discuss the results of clinical and molecular studies linking specific genomic alterations—such as KMT2A-rearrangements, Ph-like, DUX4-rearrangements and T-ALL—to drug resistance and highlight surface antigens like CSPG4, HER2, MCAM and ROR1 that define high-risk leukemia phenotypes. The integration of transcriptomic, immunophenotypic and drug response data could enable a new generation of risk-adapted, surface-directed strategies for relapse treatment in ALL. Our analysis therefore provides subtype-specific predictive therapeutic targets for relapse treatment in ALL. Full article

Background/Objectives: The dark green leaf color trait in bunching onion (Allium fistulosum L.) is an important agronomic trait closely associated with market value; however, its genetic basis remains poorly understood. This study aimed to identify quantitative trait loci (QTLs) associated with leaf color using SPAD values as a phenotypic indicator. Methods: An ${\mathrm{F}}_2$ population derived from a cross between the dark green line YSG1go and the light green line Asagikei-KUJYO was used. A linkage map was constructed based on RNA-seq-derived SNP markers, and SPAD values were measured for QTL analysis. Results: The linkage map consisted of eight linkage groups with a total length of 2103.0 cM and 765 mapped markers. SPAD values showed significant differences between the parental lines, with high broad-sense heritability ($H^2$ = 0.76), indicating a strong genetic contribution to this trait. Multiple significant QTLs were detected on chromosomes 4 and 5, each explaining 27.4–38.1% of the phenotypic variance. The direction of allelic effects differed among QTLs, suggesting that favorable alleles are distributed between the parental lines. In addition, genes related to chloroplast protein translation were identified within the QTL regions. Conclusions: SPAD values are a suitable indicator for genetic analysis of leaf color in bunching onion, and the QTLs identified in this study provide valuable information for molecular breeding aimed at improving dark green leaf color. Full article

Indigenous pig breeds represent valuable reservoirs of genetic diversity but face increasing risks of genetic erosion due to uncontrolled crossbreeding with commercial lines. The Ashanti Dwarf Pig (ADP) of Ghana is an important local genetic resource well-adapted to tropical environments but poorly characterised at the genomic level. Using high-density SNP data from the ADPs and publicly available datasets from other African, European, and Asian pig populations, we examined genetic diversity, population structure, inbreeding, and selection signatures. After quality control, 59,124 SNPs across 875 individuals were retained. ADPs exhibited high polymorphism (~99%) and moderate heterozygosity but also elevated inbreeding (FIS = 0.15; FROH = 0.40), indicating recent inbreeding under free-range management. Population structure revealed that ADPs cluster closely with other African pigs and European breeds more than Chinese breeds. ADMIXTURE analysis, however, indicated recent introgression from both European and Chinese lines. Selection scans revealed candidate genes linked to metabolism-Zinc Finger Ran-Binding Protein 3 (ZRANB3), growth-Sortilin Related VPS10 Domain Containing Receptor 1 (SORCS1), reproduction–Sus Scrofa Chromosome 9 quantitative trait loci (SSC9 QTLs), and immunity-Tudor Domain-Containing Protein 3 and CKLF-like MARVEL transmembrane Domain Containing 7 (TDRD3, CMTM7), reflecting adaptation to tropical production systems. Our results provide a comprehensive genomic characterisation of the ADP within a global context, revealing both genetic richness and vulnerability to genetic erosion. These findings underscore the importance of structured breeding and conservation strategies in preserving this unique African genetic resource and supporting sustainable pig production under changing climatic conditions. Full article

Soil salinization severely restricts rice growth and global grain production, posing a serious threat to food security. Dongxiang wild rice serves as an important genetic resource for improving salt tolerance in rice. In this study, a backcross inbred line (BIL) population derived from Dongxiang wild rice DY80 and an indica restorer line R974 were used to detect QTLs for salt tolerance at the germination and seedling stages. Four QTLs related to germination-stage salt tolerance and three QTLs for seedling-stage salt tolerance were identified, among which qSTS5 on chromosome 5 showed the largest effect with a LOD score of 8.0 and a phenotypic contribution rate of 14.8%. An F_2:3 population was further constructed to validate qSTS5, which increased its LOD value to 10.4 and phenotypic variation explanation rate to 18.5%, and the locus was finally delimited to a 2.3 Mb interval. Transcriptome analysis identified eight differentially expressed genes (DEGs) within the qSTS5 region under salt stress. Sequence comparison between the parents revealed that three DEGs had no coding-region variations, while the other five showed nucleotide polymorphisms leading to amino acid changes. Among them, Os05g0349800 encodes a LEA protein, a typical stress-responsive gene, and harbors a frameshift mutation in DY80. Combined with its induced expression pattern under salt stress, this gene was considered the most promising candidate for qSTS5. This study not only provides a stable major QTL for rice breeding for salt tolerance but also lays a foundation for dissecting the molecular mechanism of salt tolerance in Dongxiang wild rice. Full article

Anaplastic lymphoma kinase (ALK) rearrangement is a well-established oncogenic driver alteration in non-small cell lung cancer (NSCLC), and ALK tyrosine kinase inhibitors (TKIs), particularly lorlatinib, have significantly improved the prognosis of ALK-positive NSCLC patients. Although high programmed death-ligand 1 (PD-L1) expression (≥50%) is generally associated with favorable responses to immune checkpoint inhibitors (ICIs), PD-L1 has not been shown to reliably predict ICI benefit in ALK-rearranged disease, and optimal management after ALK TKI resistance remains challenging. Herein, we report a case of an elderly patient with ALK-rearrangement and exceptionally high PD-L1 expression (TPS ≥ 95%) NSCLC who experienced disease progression following first-line lorlatinib with genetically confirmed MET amplification. The patient subsequently received an exploratory combination of continued lorlatinib plus envafolimab and achieved partial response (PR) with manageable tolerability after 4 months, highlighting a potential sequential strategy that may warrant further investigation in select ALK-positive NSCLC patients exhibiting both bypass pathway activation and exceptionally high PD-L1 expression. Full article

To clarify the regulatory mechanism of NLA on tomato plant architecture and fruit quality, wild-type (WT), nla mutant (narrow leaf angle), and NLA overexpression lines (OE1, OE2) were used as materials, and the study was carried out through genetic analysis, phenotypic and quality determination, and gene expression analysis. The results showed that the tomato leaf angle is controlled by a single gene with semi-dominant inheritance. The nla mutant forms a compact plant architecture due to reduced cell volume at the leaf angle. During vegetative growth, it exhibited significantly increased plant height and decreased stem diameter and crown width. During reproductive growth, it showed significantly higher height of the first inflorescence node and a significantly higher number of the first flowering node. The nla mutant maintained a higher SPAD value during the whole growth period. Mutation of NLA had no significant effect on soluble solids content, but significantly increased flavonoid and titratable acid contents. Meanwhile, the compact architecture optimizes plant spatial distribution, and higher flavonoid content improves antioxidant capacity. Molecular mechanism analysis combined with GA quantification showed that the nla mutant exhibited significantly higher contents of bioactive GA₁ and GA₄, which were closely associated with up-regulated expression of GA biosynthetic genes SlGA20ox1 and SlGA20ox2, as well as down-regulated expression of GA catabolic genes SlGA2ox4 and SlGID1.This study provides a theoretical basis for high-photosynthetic-efficiency breeding and high-quality cultivation of tomato. Full article

Microcystin-LR (MC-LR) is a potent hepatotoxin that has been shown to cause liver damage even at doses lower than the established Low Observable Adverse Effect Level (LOAEL) of 200 μg/kg in animal models. We have previously observed that low-dose exposure to MC-LR in animals with diet-induced Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and subsequent treatment with antioxidants like N-acetylcysteine (NAC) and the Na⁺/K⁺ ATPase-Src kinase inhibitor pNaKtide significantly alleviated hepatic infiltration of immune cells, downregulated markers of inflammation and hepatotoxicity, increased the breakdown of the toxin molecule, and restored phase I and II drug metabolism pathways, including the glutathione pathway. Because the liver is composed of heterogeneous cell types, this study aimed to determine the specific role of hepatocytes in the uptake and metabolism of MC-LR, especially in the setting of MASLD. To address this, we used two well-established hepatocyte cell lines—AML-12 murine hepatocytes and human Hep3B hepatocytes. Preliminary dose comparison studies with AML-12 cells showed that MC-LR at 10 μM concentration showed a significant upregulation in the genetic expression of the markers of hepatotoxicity—OSMR (p ≤ 0.01) and SerpinE (p ≤ 0.0001)—in comparison to Vehicle. Treatment with pNaKtide (1 µM) and/or NAC (10 mM) in the presence of MC-LR significantly reduced the expression of both OSMR (p ≤ 0.0001) and SerpinE (p ≤ 0.01 and p ≤ 0.0001, respectively). To model steatotic hepatocytes characteristic of the MASLD phenotype, Hep3B hepatocytes were first treated with 500 µM of oleic acid (OA) before exposing them to the toxin in the presence and absence of antioxidants. MC-LR exposure, induced markers of inflammation and hepatotoxicity to be elevated significantly in the presence of OA as compared to MC-LR exposure alone. This elevation of the genetic markers of inflammation and hepatotoxicity was significantly attenuated on treatment with pNaKtide (1 µM) and NAC (10 mM). Quantification of human SERPINE1 (PAI1) and 8-OHdG, a stable marker of oxidative stress, in the spent media of Hep3B cells corroborated the trends observed in the genetic markers of hepatotoxicity. These observations support the central role that hepatocytes play in the uptake and metabolism of MC-LR, which is complicated by the presence of MASLD-like conditions and can help in the development of future therapeutic strategies. Full article

To address the challenges of severe surface undulation in mountainous mining areas, significant InSAR geometric distortion, and the inability to directly calculate three-dimensional (3D) displacement from single-track Line-of-Sight (LOS) data, this paper proposes a 3D deformation reconstruction method that integrates Distributed Scatterer Interferometric Synthetic Aperture Radar (DS-InSAR) with an improved Probability Integral Model (PIM) considering topographic sliding effects. The traditional Probability Integral Method (PIM) ignores the additional sliding caused by topographic slope, leading to significant deviations when applied in mountainous areas. This study introduces a nonlinear sliding influence function and constructs a topographic correction model incorporating sliding intensity, position offset, and morphological attenuation parameters to quantitatively describe surface movement patterns under the coupling effect of mining and topography. Based on this, a model parameter-driven single-track InSAR observation equation is established, and the Adaptive Genetic Algorithm (AGA) is employed to invert the complete set of model parameters using high-density LOS deformation obtained from DS-InSAR as constraints, thereby resolving the full-basin 3D displacement field. Experimental results from a typical mountainous coal mine in the Taihang Mountain area of China demonstrate that this method effectively overcomes the ill-posedness of 3D displacement inversion from single-track InSAR data. The maximum vertical subsidence is 1050 mm, and the maximum horizontal displacement was 370 mm, consistent with leveling measurements (vertical RMSE: 75.1 mm; horizontal RMSE: 27.2 mm). Compared with traditional PIM methods without topographic correction, the proposed model reduces 3D displacement RMSE by approximately 35%, significantly improving calculation accuracy in mountainous areas with topographic undulation. Validation against leveling measurement points distributed along strike and dip directions confirms the reliability of reconstructed 3D displacement fields. This method not only restores the physical characteristics of topographic sliding but also provides a low-cost, high-precision solution for mining damage monitoring in complex terrain. Full article

Plant architecture is a critical agronomic trait in watermelon (Citrullus lanatus), with vine length directly influencing planting density, light interception, and field management efficiency. Short-vine forms have become important agronomic targets in breeding due to their advantages of high-density planting, efficient light utilization, and simplified field management. In this study, a dwarf mutant, designated PKH207, was identified from an ethyl methanesulfonate (EMS)-mutagenized population of the watermelon inbred line G42. The mutant exhibited significantly reduced plant height and shortened internodes due to decreased cell expansion in stem tissues. Genetic analysis indicated that the dwarf phenotype in PKH207 is controlled by a single recessive gene, which was named Cldw2 (Citrullus lanatus dwarf mutant 2). Using a population of 558 F₂ plants, bulked segregant analysis sequencing (BSA-seq) and linkage mapping delimited the causal locus to a 540.6 kb region on chromosome 10. Within this interval, a single-nucleotide polymorphism (SNP) mutation was identified in the gene ClG42_10g0100600, encoding an α-tubulin, and this gene was determined to be the candidate gene for the dwarf phenotype. Transcriptome analysis revealed that this mutation significantly disrupts key biological processes, including cell wall biosynthesis, microtubule cytoskeleton organization, and auxin signaling pathways, contributing to the dwarfism phenotype. This study identifies a novel dwarfing allele in cucurbits and provides a direct molecular target for breeding compact watermelon cultivars suited to high-density production. Full article

To improve the assembly efficiency and productivity of complex aircraft components, the optimization of an assembly line was investigated in this study. A hierarchical hybrid multi-objective optimization algorithm (HHMOA) was proposed using an improved non-dominated sorting genetic algorithm II and an enhanced longest processing time algorithm. The algorithm incorporates a two-layer framework for global–local optimization; an information entropy-based problem formulation with three objectives, including line balance rate, load balance index and assembly complexity smoothness index; and a hybrid initialization strategy for high-quality initial solutions. Based on the assembly line datasets of different scales, the algorithm performance was verified by comparing the hypervolume and the calculation efficiency using HHMOA and three benchmark algorithms, and the sensitivity analyses verified the algorithm robustness. For an actual aircraft component assembly line, the optimizations carried out with the given process time, number of workstations and precedence relationships indicate that the balance rate of the optimized line increased 72%, and the load balance index and the assembly complexity smoothing index were reduced by 80.3% and 92% respectively, which proved the reliability of the hybrid algorithm in optimizing the aircraft component assembly line. Finally, the optimization analyses with various workstation numbers and assembly process times suggest that reducing the workstations and adopting robotic automated processing can improve the aircraft component assembly line. Full article