Design and Evaluation of 3-Phenyloxetane Derivative Agonists of the Glucagon-Like Peptide-1 Receptor.

Various small molecule GLP1R agonists have been developed and tested for treating type 2 diabetes (T2DM) and obesity. However, many of these new compounds have drawbacks, such as potential hERG inhibition, lower activity compared to natural GLP-1, limited oral bioavailability in cynomolgus monkeys, and short duration of action. Recently, a new category of 3-phenyloxetane derivative GLP1R agonists with enhanced hERG inhibition has been discovered. Using an AIDD/CADD method, compound 14 (DD202-114) was identified as a potent and selective GLP1R agonist, which was chosen as a preclinical candidate (PCC). Compound 14 demonstrates full agonistic efficacy in promoting cAMP accumulation and possesses favorable drug-like characteristics compared to the clinical drug candidate Danuglipron. Additionally, in hGLP-1R knock-in mice, compound 14 displayed a sustained pharmacological effect, effectively reducing blood glucose levels and food intake. These findings suggest that compound 14 holds promise as a future treatment option for T2DM and obesity, offering improved properties.

Phytoremediation efficiency of poplar hybrid varieties with diverse genetic backgrounds in soil contaminated by multiple toxic metals (Cd, Hg, Pb, and As).

Fifteen poplar varieties were used in a field trial to investigate the phytoremediation efficiency, stress resistance, and wood property of poplar hybrid varieties with diverse genetic backgrounds under the composite pollution of heavy metals. The coefficient of variation and clone repeatability for growth traits and Cd concentration were large. The Cd accumulation of poplar varieties 107 and QHQ reached 1.9 and 1.7 mg, respectively, followed by QHB, Ti, 69, and Pa, in which Cd accumulation reached 1.3 mg. Most of the intra-specific hybrid varieties (69, QH1, SL4, T3, and ZL46) had low Cd concentrations and small biomass, resulting in weak Cd accumulation and low phytoremediation efficiency for Cd-polluted soil. By contrast, the inter-sectional and inter-specific hybrid varieties exhibited better growth performance and accumulated higher concentrations of heavy metals than the intra-specific hybrids. The bioconcentration factor and translocation factor of Hg, As, and Pb were less than 1, indicating that poplars have low phytoremediation efficiency for these heavy metals. The hybrids between section Aigeiros and Tacamahaca (QHQ and QHB) and the inter-specific hybrid 107 within section Aigeiros were more resistant to composite heavy metal stress than the other poplar varieties were partially because of their high levels of free proline that exceeded 93 µg·g-1 FW. According to the correlation analysis of the concentrations of the different heavy metals, the poplar roots absorbed different heavy metals in a cooperative manner, indicating that elite poplar varieties with superior capacity for accumulating diverse heavy metals can be bred feasibly. Compared with the intra-specific hybrid varieties, the inter-sectional (QHQ and QHB) and inter-specific (107) hybrid varieties had higher pollution remediation efficiency, larger biomass, higher cellulose content, and lower lignin content, which is beneficial for pulpwood. Therefore, breeding and extending inter-sectional (QHQ and QHB) and inter-specific hybrid varieties can improve the phytoremediation of composite pollution.

On-Water Surface Synthesis of Two-Dimensional Polymer Membranes for Sustainable Energy Devices.

ConspectusIon-selective membranes are key components for sustainable energy devices, including osmotic power generators, electrolyzers, fuel cells, and batteries. These membranes facilitate the flow of desired ions (permeability) while efficiently blocking unwanted ions (selectivity), which forms the basis for energy conversion and storage technologies. To improve the performance of energy devices, the pursuit of high-quality membranes has garnered substantial interest, which has led to the exploration of numerous candidates, such as polymeric membranes (e.g., polyamide and polyelectrolyte), laminar membranes (e.g., transition metal carbide (MXene) and graphene oxide (GO)) and nanoporous 2D membranes (e.g., single-layer MoS2 and porous graphene). Despite impressive progress, the trade-off effect between ion permeability and selectivity remains a major scientific and technological challenge for these membranes, impeding the efficiency and stability of the resulting energy devices.Two-dimensional polymers (2DPs), which represent monolayer to few-layer covalent organic frameworks (COFs) with periodicity in two directions, have emerged as a new candidate for ion-selective membranes. The crystalline 2DP membranes (2DPMs) are typically fabricated either by bulk crystal exfoliation followed by filtration or by direct interfacial synthesis. Recently, the development of surfactant-monolayer-assisted interfacial synthesis (SMAIS) method by our group has been pivotal, enabling the synthesis of various highly crystalline and large-area 2DPMs with tunable thicknesses (1 to 100 nm) and large crystalline domain sizes (up to 120 µm2). Compared to other membranes, 2DPMs exhibit well-defined one-dimensional (1D) channels, customizable surface charge, ultrahigh porosity, and ultrathin thickness, enabling them to overcome the permeability-selectivity trade-off challenge. Leveraging these attributes, 2DPMs have established their critical roles in diverse energy devices, including osmotic power generators and metal ion batteries, opening the door for next-generation technology aimed at sustainability with a low carbon footprint.In this Account, we review our achievements in synthesizing 2DPMs through the SMAIS method and highlight their selective-ion-transport properties and applications in sustainable energy devices. We initially provide an overview of the SMAIS method for producing highly crystalline 2DPMs by utilizing the programmable assembly and enhanced reactivity/selectivity on the water surface. Subsequently, we discuss the critical structural parameters of 2DPMs, including pore sizes, charged sites, crystallinity, and thickness, to elucidate their roles in selective ion transport. Furthermore, we present the burgeoning landscape of energy device applications for 2DPMs, including their use in osmotic power generators and as electrode coating in metal ion batteries. Finally, we conclude persistent challenges and future prospects encountered in synthetic chemistry, material science, and energy device applications within this rapidly evolving field.

Application and comparison of several adaptive sampling algorithms in reduced order modeling.

Model Order Reduction (MOR) techniques have extensive applications across scientific and engineering disciplines, such as neutron field reconstruction of nuclear reactor cores, thermoelastic field reconstruction, fluid, and solid mechanics. In the process of building a Reduced Order Model (ROM), the selection of the basis functions in the offline stage is crucial and directly depends on the parameter space sampling strategy. This problem has always been a challenge in MOR. Research into adaptive sampling algorithms has become a hot topic in recent years. To better understand the application of these algorithms to MOR, this paper focuses on three prevalent adaptive sampling algorithms: pseudo-gradient sampling, adaptive sparse grid sampling, adaptive training set extension. These have been successfully applied in various applications, including nuclear reactor cores, molten salt reactor system, power system for convection problems. We systematically assess and compare their performance, finding that adaptive sampling algorithms excel in sampling divergent and oscillating areas and are generally better than the standard sampling strategy. Specifically, the pseudo-gradient sampling algorithm is effective for small-scale scenarios, while the other two algorithms are designed for large-scale sampling. Their practicality is confirmed through successful applications in nuclear reactor cores.

Macrophage membrane-based biomimetic nanocarrier system for enhanced immune activation and combination therapy in liver cancer.

Previous studies have demonstrated that the combination of photodynamic therapy, photothermal therapy and chemotherapy is highly effective in treating hepatocellular carcinoma (HCC). However, the clinical application of this approach has been hindered by the lack of efficient and low-toxicity drug delivery platforms. To address this issue, we developed a novel biomimetic nanocarrier platform named ZID@RM, which utilizes ZIF8 functional nanoparticles encapsulated with macrophage membrane and loaded with indocyanine green and doxorubicin. The bionic nanocarrier platform has good biocompatibility, reducing the risk of rapid clearance by macrophages and improving the targeting ability for HCC cells. Under the dual regulation of acidity and infrared light, ZID@RM stimulated the generation of abundant reactive oxygen species within HCC cells, induced tumor cell pyroptosis and promoted the release of damage-associated molecular patterns to induce immune responses. In the future, this technology platform has the potential to provide personalized and improved healthcare by using patients' own macrophage membranes to create an efficient drug delivery system for tumor therapy.Graphical abstract Scheme 1 Schematic representation of the synthesis of a biomimetic nanomedicine delivery platform (ZID@RM) and its application in tumor imaging-guided combination therapy.

DAZAP1 Phase Separation Regulates Mitochondrial Metabolism to Facilitate Invasion and Metastasis of Oral Squamous Cell Carcinoma.

Tumor invasion and metastasis are the underlying causes of the high mortality rate of oral squamous cell carcinoma (OSCC). Energy metabolism reprogramming has been identified as a crucial process mediating tumor metastasis, thus indicating an urgent need for in-depth investigation of the specific mechanisms of tumor energy metabolism. Here, we identified an RNA-binding protein, DAZ associated protein 1 (DAZAP1), as a tumor-promoting factor with an important role in OSCC progression. DAZAP1 was significantly upregulated in OSCC, which enhanced the migration and invasion of OSCC cells and induced the epithelial-mesenchymal transition (EMT). RNA-seq analysis and experimental validation demonstrated that DAZAP1 regulates mitochondrial energy metabolism in OSCC. Mechanistically, DAZAP1 underwent liquid-liquid phase separation (LLPS) to accumulate in the nucleus where it enhanced cytochrome-c oxidase 16 (COX16) expression by regulating pre-mRNA alternative splicing, thereby promoting OSCC invasion and mitochondrial respiration. In mouse OSCC models, loss of DAZAP1 suppressed EMT, downregulated COX16, and reduced tumor growth and metastasis. In OSCC patient samples, expression of DAZAP1 positively correlated with COX16, and high expression of both proteins was associated with poor patient prognosis. Together, these findings revealed a mechanism by which DAZAP1 supports mitochondrial metabolism and tumor development of OSCC, suggesting the potential of therapeutic strategies targeting DAZAP1 to block OSCC invasion and metastasis.

A modified Goldstein filter for interferogram denoising of interferometric imaging radar altimeter based on multiple quality-guided graphs.

Aiming at the characteristics that the signal noise ratio (SNR) gradually decreases from the near to far range of the swath, an adaptive phase filtering algorithm based on Goldstein filtering and combined with multiple quality-guided graphs was proposed. Firstly, the components used to determine the filtering parameters were obtained through residue density, pseudo-coherence coefficient and pseudo-SNR, the three quality-guided graphs. Then, the filter parameters were calculated by weighting the three components. Finally, the size of filtering window was determined according to the account of residues, and the interferometric phase noise was removed in frequency domain. Simulated data, TSX/TDX data and airborne interferometric imaging radar altimeter data were used to verify the performance of the new algorithm. Compared with the results of Goldstein filtering and its improved algorithms, the results showed that the proposed algorithm can effectively filter out phase noise while maintaining the edge characteristics of interferometric fringe. The section of filtering result can well match with the section of simulated pure interfeometric phase. Moreover, the algorithm proposed in this paper can effectively remove the noise in the interferogram of TSX/TDX sea ice data, and the residues' filtering rate was above 86%, which can effectively remove the phase residues of the sea ice surface while maintaining the characteristics of the sea ice edge. Experimental results showed that the new algorithm provides an effective phase noise filtering method for imaging radar altimeter data processing.

Comprehensive proteomic characterization of urethral stricture disease in the Chinese population.

Background: Male urethral stricture disease (USD) is predominantly characterized by scar formation. There are few effective therapeutic drugs, and comprehensive molecular characterizations of USD formation remain undefined. Methods: The proteomic profiling of twelve scar tissues and five matched normal adjacent tissues (NATs). Proteomic analysis methods were applied to explore the molecular characterizations of USD formation, including uncovering mechanistic pathways and providing novel biomarkers for scar formation. Results: Comparative proteomic analysis showed that the extracellular matrix (ECM) and complement cascade signaling were predominant in scar tissues. COL11A1 and CD248 significantly contributed to the accumulation of ECM components. Our study presented diverse molecular mechanisms of scar formation across different ages and suggested the potential effects of PXK in Age 1 (<45) patients. Furthermore, immune infiltration studies indicated the therapeutic potential of inhibiting the complement system (C4A, C4B) in Age 2 (≥45) patients, providing a potential clinical strategy for USD. Conclusion: This study illustrated the pathogenesis of USD formation and the diverse characteristics of USD patients with different ages, enhancing our understanding of the disease's pathogenesis and providing a valuable resource for USD treatment.

Enhanced Performance of P-Channel CuIBr Thin-Film Transistor by ITO Surface Charge-Transfer Doping.

The process development and optimization of p-type semiconductors and p-channel thin-film transistors (TFTs) are essential for the development of high-performance circuits. In this study, the Br-doped CuI (CuIBr) TFTs are proposed by the solution process to control copper vacancy generation and suppress excess holes formation in p-type CuI films and improve current modulation capabilities for CuI TFTs. The CuIBr films exhibit a uniform surface morphology and good crystalline quality. The on/off current (ION/IOFF) ratio of CuIBr TFTs increased from 103 to 106 with an increase in the Br doping ratio from 0 to 15%. Furthermore, the performance and operational stability of CuIBr TFTs are significantly enhanced by indium tin oxide (ITO) surface charge-transfer doping. The results obtained from the first-principles calculations well explain the electron-doping effect of ITO overlayer in CuIBr TFT. Eventually, the CuIBr TFT with 15% Br content exhibits a high ION/IOFF ratio of 3 × 106 and a high hole field-effect mobility (µFE) of 7.0 cm2 V-1 s-1. The band-like charge transport in CuIBr TFT is confirmed by the temperature-dependent measurement. This study paves the way for the realization of transparent complementary circuits and wearable electronics.

A genome-wide CRISPR screen reveals that antagonism of glutamine metabolism sensitizes head and neck squamous cell carcinoma to ferroptotic cell death.

Glutamine is a conditionally essential amino acid for the growth and survival of rapidly proliferating cancer cells. Many cancers are addicted to glutamine, and as a result, targeting glutamine metabolism has been explored clinically as a therapeutic approach. Glutamine-catalyzing enzymes are highly expressed in primary and metastatic head and neck squamous cell carcinoma (HNSCC). However, the nature of the glutamine-associated pathways in this aggressive cancer type has not been elucidated. Here, we explored the therapeutic potential of a broad glutamine antagonist, DRP-104 (sirpiglenastat), in HNSCC tumors and aimed at shedding light on glutamine-dependent pathways in this disease. We observed a potent antitumoral effect of sirpiglenastat in HPV- and HPV + HNSCC xenografts. We conducted a whole-genome CRISPR screen and metabolomics analyses to identify mechanisms of sensitivity and resistance to glutamine metabolism blockade. These approaches revealed that glutamine metabolism blockade results in the rapid buildup of polyunsaturated fatty acids (PUFAs) via autophagy nutrient-sensing pathways. Finally, our analysis demonstrated that GPX4 mediates the protection of HNSCC cells from accumulating toxic lipid peroxides; hence, glutamine blockade sensitizes HNSCC cells to ferroptosis cell death upon GPX4 inhibition. These findings demonstrate the therapeutic potential of sirpiglenastat in HNSCC and establish a novel link between glutamine metabolism and ferroptosis, which may be uniquely translated into targeted glutamine-ferroptosis combination therapies.

Basic Fibroblast Growth Factor Accumulation in Culture Medium Masks the Direct Antitumor Effect of Anti-VEGF Agent Bevacizumab.

The direct antitumor effect of bevacizumab (BEV) has long been debated. Evidence of the direct antitumor activities of drugs are mainly obtained from in vitro experiments, which are greatly affected by experimental conditions. In this study, we evaluated the effect of BEV-containing medium renewal on the results of in vitro cytotoxicity experiments in A549 and U251 cancer cells. We observed starkly different results between the experiments with and without BEV-containing medium renewal. Specifically, BEV inhibited the tumor cell growth in the timely replacement with a BEV-containing medium but promoted tumor cell growth without medium renewal. Meanwhile, compared with the control, a significant basic fibroblast growth factor (bFGF) accumulation in the supernatant was observed in the group without medium renewal but none in that with replaced medium. Furthermore, bFGF neutralization partially reversed the pro-proliferative effect of BEV in the medium non-renewed group, while exogenous bFGF attenuated the tumor cell growth inhibition of BEV in the medium-renewed group. Our data explain the controversy over the direct antitumor effect of BEV in different studies from the perspective of the compensatory autocrine cytokines in tumor cells.

Nuclear pyruvate dehydrogenase complex regulates histone acetylation and transcriptional regulation in the ethylene response.

Ethylene plays its essential roles in plant development, growth, and defense responses by controlling the transcriptional reprograming, in which EIN2-C-directed regulation of histone acetylation is the first key step for chromatin to perceive ethylene signaling. But how the nuclear acetyl coenzyme A (acetyl CoA) is produced to ensure the ethylene-mediated histone acetylation is unknown. Here we report that ethylene triggers the accumulation of the pyruvate dehydrogenase complex (PDC) in the nucleus to synthesize nuclear acetyl CoA to regulate ethylene response. PDC is identified as an EIN2-C nuclear partner, and ethylene triggers its nuclear accumulation. Mutations in PDC lead to an ethylene hyposensitivity that results from the reduction of histone acetylation and transcription activation. Enzymatically active nuclear PDC synthesizes nuclear acetyl CoA for EIN2-C-directed histone acetylation and transcription regulation. These findings uncover a mechanism by which PDC-EIN2 converges the mitochondrial enzyme-mediated nuclear acetyl CoA synthesis with epigenetic and transcriptional regulation for plant hormone response.

Highly Anion-Conductive Viologen-based Two-Dimensional Polymer Membranes as Nanopower Generators.

Two-dimensional polymers (2DPs) and their layer-stacked 2D covalent organic frameworks (2D COFs) membranes hold great potential for harvesting sustainable osmotic energy. The nascent research has yet to simultaneously achieve high ionic flux and selectivity, primarily due to inefficient ion transport dynamics. This is directly related to ultrasmall pore size (<3 nm), much smaller than the duple Debye length in the diluted electrolyte (6~20 nm), as well as low charge density (<4.5 mC m-2). Here, we introduce a π-conjugated viologen-based 2DP (V2DP) membrane possessing a large pore size of 4.5 nm, strategically enhancing the overlapping of the electric double layer, coupled with an exceptional positive surface charge density (~6 mC m-2). These characteristics enable the membrane to facilitate high anion flux while maintaining ideal selectivity. Notably, V2DP membranes realize an impressive current density of 5.5×103 A m-2, surpassing  previously nanofluidic membranes. In practical application scenario involving the mixing of artificial seawater and river water, the V2DP membranes exhibit a considerable ion transference number of 0.70 towards Cl-, contributing to an outstanding power density of ~55 W m-2. Theoretical calculations reveal that the large quantity of anion transport sites act as binding sites evenly located in the positively charged N-containing pyridine rings.

The liquid-liquid phase separation signature predicts the prognosis and immunotherapy response in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common and fatal malignancy characterized by poor patient prognosis and treatment outcome. The process of liquid-liquid phase separation in tumour cells alters the dysfunction of biomolecular condensation in tumour cells, which affects tumour progression and treatment. We downloaded the data of HCC samples from TCGA database and GEO database, and used a machine learning method to build a new liquid-liquid phase separation index (LLPSI) by liquid-liquid phase separation related genes. The LLPSI-related column line Figure was constructed to provide a quantitative tool for clinical practice. HCC patients were divided into high and low LLPSI groups based on LLPSI, and clinical features, tumour immune microenvironment, chemotherapeutic response, and immunotherapeutic response were systematically analysed. LLPSI, which consists of five liquid-liquid phase separation-associated genes (MAPT, WDR62, PLK1, CDCA8 and TOP2A), is a reliable predictor of survival in patients with HCC and has been validated in multiple external datasets. We found that the high LLPSI group showed higher levels of immune cell infiltration and better response to immunotherapy compared to the low LLPSI group, and LLPSI can also be used for prognostic prediction in various cancers other than HCC. In vitro experiments verified that knockdown of MAPT could inhibit the proliferation and migration of HCC. The LLPSI identified in this study can accurately assess the prognosis of patients with HCC and identify patient populations that will benefit from immunotherapy, providing valuable insights into the clinical management of HCC.

A Kinome-Wide Synthetic Lethal CRISPR/Cas9 Screen Reveals That mTOR Inhibition Prevents Adaptive Resistance to CDK4/CDK6 Blockade in HNSCC.

The comprehensive genomic analysis of the head and neck squamous cell carcinoma (HNSCC) oncogenome revealed the frequent loss of p16INK4A (CDKN2A) and amplification of cyclin D1 genes in most human papillomavirus-negative HNSCC lesions. However, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown modest effects in the clinic. The aberrant activation of the PI3K/mTOR pathway is highly prevalent in HNSCC, and recent clinical trials have shown promising clinical efficacy of mTOR inhibitors (mTORi) in the neoadjuvant and adjuvant settings but not in patients with advanced HNSCC. By implementing a kinome-wide CRISPR/Cas9 screen, we identified cell-cycle inhibition as a synthetic lethal target for mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergism in HNSCC-derived cells in vitro and in vivo. Remarkably, we found that an adaptive increase in cyclin E1 (CCNE1) expression upon palbociclib treatment underlies the rapid acquired resistance to this CDK4/6 inhibitor. Mechanistically, mTORi inhibits the formation of eIF4G-CCNE1 mRNA complexes, with the consequent reduction in mRNA translation and CCNE1 protein expression. Our findings suggest that mTORi reverts the adaptive resistance to palbociclib. This provides a multimodal therapeutic option for HNSCC by cotargeting mTOR and CDK4/6, which in turn may halt the emergence of palbociclib resistance. SIGNIFICANCE: A kinome-wide CRISPR/Cas9 screen identified cell-cycle inhibition as a synthetic lethal target of mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergistic effects in HNSCC. Mechanistically, mTORis inhibited palbociclib-induced increase in CCNE1.

EIF2S2 transcriptionally upregulates HIF1α to promote gastric cancer progression via activating PI3K/AKT/mTOR pathway.

Eukaryotic translation initiation factor 2 subunit beta (EIF2S2) is a protein that controls protein synthesis under various stress conditions and is abnormally expressed in several cancers. However, there is limited insight regarding the expression and molecular role of EIF2S2 in gastric cancer. In this study, we identified the overexpression of EIF2S2 in gastric cancer by immunohistochemical (IHC) staining and found a positive correlation between EIF2S2 expression and shorter overall survival and disease-free survival. Functionally, we revealed that EIF2S2 knockdown suppressed gastric cancer cell proliferation and migration, induced cell apoptosis, and caused G2 phase cell arrest. Additionally, EIF2S2 is essential for in vivo tumor formation. Mechanistically, we demonstrated that EIF2S2 transcriptionally regulated hypoxia induicible factor-1 alpha (HIF1α) expression by NRF1. The promoting role of EIF2S2 in malignant behaviors of gastric cancer cells depended on HIF1α expression. Furthermore, the PI3K/AKT/mTOR signaling was activated upon EIF2S2 overexpression in gastric cancer. Collectively, EIF2S2 exacerbates gastric cancer progression via targeting HIF1α, providing a fundamental basis for considering EIF2S2 as a potential therapeutic target for gastric cancer patients.

Semantic-enhanced graph neural network for named entity recognition in ancient Chinese books.

Named entity recognition (NER) plays a crucial role in the extraction and utilization of knowledge of ancient Chinese books. However, the challenges of ancient Chinese NER not only originate from linguistic features such as the use of single characters and short sentences but are also exacerbated by the scarcity of training data. These factors together limit the capability of deep learning models, like BERT-CRF, in capturing the semantic representation of ancient Chinese characters. In this paper, we explore the semantic enhancement of NER in ancient Chinese books through the utilization of external knowledge. We propose a novel model based on Graph Neural Networks that integrates two different forms of external knowledge: dictionary-level and chapter-level information. Through the Graph Attention Mechanism (GAT), these external knowledge are effectively incorporated into the model's input context. Our model is evaluated on the C_CLUE dataset, showing an improvement of 3.82% over the baseline BAC-CRF model. It also achieves the best score compared to several state-of-the-art dictionary-augmented models.

Fine mapping and candidate gene analysis of CRA8.1.6, which confers clubroot resistance in turnip (Brassica rapa ssp. rapa).

Clubroot disease poses a significant threat to Brassica crops, necessitating ongoing updates on resistance gene sources. In F2 segregants of the clubroot-resistant inbred line BrT18-6-4-3 and susceptible DH line Y510, the genetic analysis identified a single dominant gene responsible for clubroot resistance. Through bulk segregant sequencing analysis and kompetitive allele-specific polymerase chain reaction assays, CRA8.1.6 was mapped within 110 kb (12,255-12,365 Mb) between markers L-CR11 and L-CR12 on chromosome A08. We identified B raA08g015220.3.5C as the candidate gene of CRA8.1.6. Upon comparison with the sequence of disease-resistant material BrT18-6-4-3, we found 249 single-nucleotide polymorphisms, seven insertions, six deletions, and a long terminal repeat (LTR) retrotransposon (5,310 bp) at 909 bp of the first intron. However, the LTR retrotransposon was absent in the coding sequence of the susceptible DH line Y510. Given the presence of a non-functional LTR insertion in other materials, it showed that the LTR insertion might not be associated with susceptibility. Sequence alignment analysis revealed that the fourth exon of the susceptible line harbored two deletions and an insertion, resulting in a frameshift mutation at 8,551 bp, leading to translation termination at the leucine-rich repeat domain's C-terminal in susceptible material. Sequence alignment of the CDS revealed a 99.4% similarity to Crr1a, which indicate that CRA8.1.6 is likely an allele of the Crr1a gene. Two functional markers, CRA08-InDel and CRA08-KASP1, have been developed for marker-assisted selection in CR turnip cultivars. Our findings could facilitate the development of clubroot-resistance turnip cultivars through marker-assisted selection.

Multiple Human Population Movements and Cultural Dispersal Events Shaped the Landscape of Chinese Paternal Heritage.

Large-scale genomic projects and ancient DNA innovations have ushered in a new paradigm for exploring human evolutionary history. However, the genetic legacy of spatiotemporally diverse ancient Eurasians within Chinese paternal lineages remains unresolved. Here, we report an integrated Y-chromosome genomic database encompassing 15,563 individuals from both modern and ancient Eurasians, including 919 newly reported individuals, to investigate the Chinese paternal genomic diversity. The high-resolution, time-stamped phylogeny reveals multiple diversification events and extensive expansions in the early and middle Neolithic. We identify four major ancient population movements, each associated with technological innovations that have shaped the Chinese paternal landscape. First, the expansion of early East Asians and millet farmers from the Yellow River Basin predominantly carrying O2/D subclades significantly influenced the formation of the Sino-Tibetan people and facilitated the permanent settlement of the Tibetan Plateau. Second, the dispersal of rice farmers from the Yangtze River Valley carrying O1 and certain O2 sublineages reshapes the genetic makeup of southern Han Chinese, as well as the Tai-Kadai, Austronesian, Hmong-Mien, and Austroasiatic people. Third, the Neolithic Siberian Q/C paternal lineages originated and proliferated among hunter-gatherers on the Mongolian Plateau and the Amur River Basin, leaving a significant imprint on the gene pools of northern China. Fourth, the J/G/R paternal lineages derived from western Eurasia, which were initially spread by Yamnaya-related steppe pastoralists, maintain their presence primarily in northwestern China. Overall, our research provides comprehensive genetic evidence elucidating the significant impact of interactions with culturally distinct ancient Eurasians on the patterns of paternal diversity in modern Chinese populations.