新时代科教兴国战略:内在逻辑、现实证据与实现路径

党的二十大报告全面系统地阐述了新时代科教兴国战略,凸显了在中国开启第二个百年新征程的背景下,立足教育、科技、人才对于社会主义现代化强国建设的重要意义。深刻理解科教兴国的时代意涵,充分把握科教兴国战略的内在逻辑,必须认识到科教兴国战略的底层逻辑、新经济逻辑、创新逻辑与国际竞争逻辑。面对新的数字革命的特点、中国经济发展的阶段性特征以及复杂多变的国际政治经济形势对实施科教兴国战略提出的全新战略需求,必须要依托自主创新体系的建立,以及教育体系的高质量重构培养创新型人才来完善落实科教兴国战略的实施路径。

初中生的同伴效应:基于发育成熟度的自然实验

同伴是影响初中生学业成绩的重要因素。国内已有研究对这一问题进行过探讨,但在解决内生性方面还有一定的不足。因此,本文利用同一班级相邻两年的初中生发育成熟度的自然变化这一随机效应来识别由于青春期发育成熟度变化带来的同伴效应,采用一阶差分和分位数回归的策略,解决了一般回归分析中存在的内生性问题。研究发现:女生发育成熟度与学生成绩为显著的负向关联,男生发育成熟度与学生成绩为显著的正向关联,这说明男女生发育成熟度对初中生学业成绩的影响具有性别差异。此外,同伴效应还具有异质性,总体来看,班级女生发育成熟度越低,越有利于学生成绩的提高;班级男生发育成熟度越高,越有利于学生成绩的提高。本研究的发现对于适龄儿童入学年龄的调整有一定的政策含义。

新时代教育体制机制设计:公益性的坚守与微观活力的激发

中国教育发展进入高质量教育体系建设新阶段,新阶段的教育发展需要与之相适应的教育体制机制做保障。针对过去教育治理体系建设落后于教育发展的问题,文章从体制机制设计的视角分析了新时代教育体制机制设计的基本遵循和行为逻辑,提出新时代教育体制机制的设计要坚持教育的公益性,坚持激发微观主体活力以及坚持规则制定与行为选择并重;提出新时代教育机制设计要从信息不对称下的博弈思路出发,以激励相容为目标,制定清晰的规则,更好发挥政府监管的作用,形成微观主体有活力的公平竞争的运行机制;提出新时代的教育新机制要避免激励与监管的错位。

TMPRSS2 and SARS-CoV-2 SPIKE interaction assay for uHTS

SARS-CoV-2,the coronavirus that causes the disease COVID-19,has claimed millions of lives over the past 2 years.This demands rapid development of effective therapeutic agents that target various phases of the viral replication cycle.The interaction between host transmembrane serine protease 2(TMPRSS2)and viral SPIKE protein is an important initial step in SARS-CoV-2 infection,offering an opportunity for therapeutic development of viral entry inhibitors.Here,we report the development of a time-resolved fluorescence/Förster resonance energy transfer(TR-FRET)assay for monitoring the TMPRSS2–SPIKE interaction in lysate from cells co-expressing these proteins.The assay was configured in a 384-well-plate format for high-throughput screening with robust assay performance.To enable large-scale compound screening,we further miniaturized the assay into 1536-well ultrahigh-throughput screening(uHTS)format.A pilot screen demonstrated the utilization of the assay for uHTS.Our optimized TR-FRET uHTS assay provides an enabling platform for expanded screening campaigns to discover new classes of small-molecule inhibitors that target the SPIKE and TMPRSS2 protein–protein interaction.

Development of a miniaturized 3D organoid culture platform for ultra-high-throughput screening

The recent advent of robust methods to grow human tissues as 3D organoids allows us to recapitulate the 3D architecture of tumors in an in vitro setting and offers a new orthogonal approach for drug discovery.However,organoid culturing with extracellular matrix to support 3D architecture has been challenging for high-throughput screening(HTS)-based drug discovery due to technical difficulties.Using genetically engineered human colon organoids as a model system,here we report our effort to miniaturize such 3D organoid culture with extracellular matrix support in high-density plates to enable HTS.We first established organoid culturing in a 384-well plate format and validated its application in a cell viability HTS assay by screening a 2036-compound library.We further miniaturized the 3D organoid culturing in a 1536-well ultra-HTS format and demonstrated its robust performance for large-scale primary compound screening.Our miniaturized organoid culturing method may be adapted to other types of organoids.By leveraging the power of 3D organoid culture in a high-density plate format,we provide a physiologically relevant screening platform to model tumors to accelerate organoid-based research and drug discovery.

NSD3S stabilizes MYC through hindering its interaction with FBXW7

The MYC transcription factor plays a key role in cell growth control. Enhanced MYC protein stability has been found to promote tumorigenesis. Thus, understanding how MYC stability is controlled may have significant implications for revealing MYC-driven growth regulatory mechanisms in physiological and pathological processes. Our previous work identified the histone lysine methyltransferase nuclear receptor binding SET domain protein 3 (NSD3) as a MYC modulator. NSD3S, a noncatalytic isoform of NSD3 with oncogenic activity, appears to bind, stabilize, and activate the transcriptional activity of MYC. However, the mechanism by which NSD3S stabilizes MYC remains to be elucidated. To uncover the nature of the interaction and the underlying mechanism of MYC regulation by NSD3S, we characterized the binding interface between both proteins by narrowing the interface to a 15-amino acid region in NSD3S that is partially required for MYC regulation. Mechanistically, NSD3S binds to MYC and reduces the association of F-box and WD repeat domain containing 7 (FBXW7) with MYC, which results in suppression of FBXW7-mediated proteasomal degradation of MYC and an increase in MYC protein half-life. These results support a critical role for NSD3S in the regulation of MYC function and provide a novel mechanism for NSD3S oncogenic function through inhibition of FBXW7-mediated degradation of MYC.

A multiplexed time-resolved fluorescence resonance energy transfer ultrahigh-throughput screening assay for targeting the SMAD4–SMAD3–DNA complex

The transforming growth factor-beta(TGFβ)signaling pathway plays crucial roles in the establishment of an immunosuppressive tumor microenvironment,making anti-TGFβagents a significant area of interest in cancer immunotherapy.However,the clinical translation of current anti-TGFβagents that target upstream cytokines and receptors remains challenging.Therefore,the development of small-molecule inhibitors specifically targeting SMAD4,the downstream master regulator of the TGFβpathway,would offer an alternative approach with significant therapeutic potential for anti-TGFβsignaling.In this study,we present the development of a cell lysate-based multiplexed time-resolved fluorescence resonance energy transfer(TR-FRET)assay in an ultrahigh-throughput screening(uHTS)1536-well plate format.This assay enables simultaneous monitoring of the protein–protein interaction between SMAD4 and SMAD3,as well as the protein–DNA interaction between SMADs and their consensus DNA-binding motif.The multiplexed TR-FRET assay exhibits high sensitivity,allowing the dynamic analysis of the SMAD4–SMAD3–DNA complex at single-amino acid resolution.Moreover,the multiplexed uHTS assay demonstrates robustness for screening small-molecule inhibitors.Through a pilot screening of an FDA-approved bioactive compound library,we identified gambogic acid and gambogenic acid as potential hit compounds.These proof-of-concept findings underscore the utility of our optimized multiplexed TR-FRET platform for large-scale screening to discover small-molecule inhibitors that target the SMAD4–SMAD3–DNA complex as novel antiTGFβsignaling agents.