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A phase separation-fortified bi-specific adaptor for conditional tumor killing

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Science China(life sciences) 2024年第7期67卷 1385-1397页

作者： Yuyan Liu Yuting Zhu Weifan Xu Pilong Li State Key Laboratory of Membrane biology Frontier Research Center for Biological StructureTsinghua University-Peking University Joint Center for Life SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China

A common approach in therapeutic protein development involves employing synthetic ligands with multivalency,enabling sophisticated control of signal transduction.Leveraging the emerging concept of liquid-liquid phase separation(LLPS)and its ability to organize cell surface receptors into functional compartments,we herein have designed modular ligands with phase-separation modalities to engineer programmable interreceptor communications and precise control of signal pathways,thus inducing the rapid,potent,and specific apoptosis of tumor cells.Despite their simplicity,these“triggers”,named phase-separated Tumor Killers(hereafter referred to as psTK),are sufficient to yield interreceptor clustering of death receptors(represented by DR5)and tumor-associated receptors,with notable features:LLPSmediated robust high-order organization,well-choreographed conditional activation,and broad-spectrum capacity to potently induce apoptosis in tumor cells.The development of novel therapeutic proteins with phase-separation modalities showcases the power of spatially reorganizing signal transduction.This approach facilitates the diversification of cell fate and holds promising potential for targeted therapies against challenging tumors.

关键词： phase separation therapeutic proteins receptor-ligand interactions DR5 tumor apoptosis

Targeting NAD Metabolism for the Therapy of Age-Related Neurodegenerative Diseases

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Neuroscience Bulletin 2024年第2期40卷 218-240页

作者： Feifei Li Chou Wu Gelin Wang School of Pharmaceutical sciences Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical BiologyTsinghua UniversityBeijing 100084China tsinghua-peking Joint center for life sciences Tsinghua UniversityBeijing 100084China

As the aging population continues to grow rapidly, age-related diseases are becoming an increasing burden on the healthcare system and a major concern for the well-being of elderly individuals. While aging is an inevitable process for all humans, it can be slowed down and age-related diseases can be treated or alleviated. Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme or cofactor that plays a central role in metabolism and is involved in various cellular processes including the maintenance of metabolic homeostasis, post-translational protein modifications, DNA repair, and immune responses. As individuals age, their NAD levels decline, and this decrease has been suggested to be a contributing factor to the development of numerous age-related diseases, such as cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. In pursuit of healthy aging, researchers have investigated approaches to boost or maintain NAD levels. Here, we provide an overview of NAD metabolism and the role of NAD in age-related diseases and summarize recent progress in the development of strategies that target NAD metabolism for the treatment of age-related diseases, particularly neurodegenerative diseases.

关键词： Ageing Neuroprotection NAD metabolism Therapeutic strategy Neurodegenerative diseases

Coordinate-wise monotonic transformations enable privacy-preserving age estimation with 3D face point cloud

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Science China(life sciences) 2024年第7期67卷 1489-1501页

作者： Xinyu Yang Runhan Li Xindi Yang Yong Zhou Yi Liu Jing-Dong J.Han School of life sciences Peking UniversityBeijing 100871China peking-tsinghua center for life sciences Academy for Advanced Interdisciplinary StudiesCenter for Quantitative Biology(CQB)Peking UniversityBeijing 100871China Beijing Key Lab of Traffic Data Analysis and Mining School of Computer and Information TechnologyBeijing Jiaotong UniversityBeijing 100044China Clinical Research Institute Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China

The human face is a valuable biomarker of aging,but the collection and use of its image raise significant privacy concerns.Here we present an approach for facial data masking that preserves age-related features using coordinate-wise monotonic transformations.We first develop a deep learning model that estimates age directly from non-registered face point clouds with high accuracy and generalizability.We show that the model learns a highly indistinguishable mapping using faces treated with coordinate-wise monotonic transformations,indicating that the relative positioning of facial information is a low-level biomarker of facial aging.Through visual perception tests and computational3D face verification experiments,we demonstrate that transformed faces are significantly more difficult to perceive for human but not for machines,except when only the face shape information is accessible.Our study leads to a facial data protection guideline that has the potential to broaden public access to face datasets with minimized privacy risks.

关键词： face point cloud age estimation face verification privacy coordinate-wise monotonic transformation

Seeing is believing: observation of migrasomes

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Biophysics Reports 2024年第2期10卷 67-81页

作者： Yuwei Huang Li Yu School of Basic Medical sciences Translational Medicine Institute Xi'an Jiaotong University State Key Laboratory of Membrane biology Tsinghua University-Peking University Joint Center for Life SciencesBeijing Frontier Research Center for Biological Structure School of Life Sciences Tsinghua University

Migrasomes are a novel type of cell organelle that form on the retraction fibers at the rear of migrating cells. In recent years, numerous studies have unveiled the mechanisms of migrasome formation and have highlighted significant roles of migrasomes in both physiological and pathological processes.Building upon the strategies outlined in published works and our own research experiences, we have compiled a comprehensive set of protocols for observing migrasomes. These step-by-step instructions encompass various aspects such as cell culture, labeling, imaging, in vitro reconstitution, and statistical analysis. We believe that these protocols serve as a valuable resource for researchers exploring migrasome biology.

关键词： Migrasome Labeling Imaging In vitro reconstitution

Perspective on new cell-free DNA technologies for early cancer detection

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Cancer biology & Medicine 2024年第2期21卷 139-143页

作者： Jie Li Xun Lan Department of Basic Medical sciences School of MedicineTsinghua UniversityBeijing 100084China MOE Key Laboratory of Bioinformatics Tsinghua UniversityBeijing 100084China tsinghua-peking Joint center for life sciences Tsinghua UniversityBeijing 100084China

High cancer heterogeneity and aggressiveness are major factors contributing to the poor prognosis of patients with advanced cancer~(1-5).Early detection of cancer can significantly improve the prognosis of patients with early-stage cancer after standard treatment.Although traditional cancer detection technologies,such as endoscopy for gastrointestinal cancer,mammography for breast cancer。

关键词： prognosis cancer patients

Recent progress in MOFs-based nanozymes for biosensing

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Nano Research 2024年第1期17卷 39-64页

作者： Imamdin Chandio Yongjian Ai Lei Wu Qionglin Liang MOE Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical biology Department of ChemistryLaboratory of Flexible Electronics TechnologyCenter for Synthetic and Systems BiologyTsinghua University-Peking University Joint Centre for Life SciencesTsinghua UniversityBeijing 100084China

Nanozymes are nanomaterials with enzyme-mimicking catalytic activity.Compared to natural enzymes,nanozymes show various properties such as easy to manufacture,stable,adjustable,and inexpensive.Nanozymes play key roles in biosensing,biocatalysis,and disease treatment.As an important kind of nanozymes,metal-organic framework(MOF)-based nanozymes are receiving a lot of attention due to their structural properties and composition.Rationally developing MOF with enzymes-like catalytic properties has opened new perspectives in biosensing.This review summarizes the up-to-date developments in synthesizing two-dimensional and three-dimensional MOF-based nanozymes and their applications in biosensing.Firstly,classification of nanozymes obtained by MOFs is categorized,and different properties of MOF-based nanozymes are described.Then,the distinctive applications of MOF-based nanozymes in identifying various analytes are thoroughly summarized.Finally,the recent challenges and progressive directions in this area are highlighted.

关键词： metal-organic frameworks nanozymes metal-organic framework (MOF)-based nanozymes biosensing analytes

A commentary of“Initial DNA melting in human DNA replication initiation”:Top 10 Scientific Advances of 2023,China

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Fundamental Research 2024年第3期4卷 701-703页

作者： Ningning Li Ning Gao State Key Laboratory of Membrane biology Peking-Tsinghua Center for Life SciencesSchool of Life SciencesPeking UniversityBeijing 100871China

DNA replication is a complicated process involving several dozens of factors.The molecular machine of eukaryotic DNA replication,replisome,consists of at least three essential modules:one replicative DNA helicase CMG(Cdc45-MCM-GINS)and two sets of DNA polymerase complexes responsible for the synthesis of the leading and lagging strands,respectively.As the core of CMG,MCM is a ring-shaped helicase motor composed of six homologous AAA+ATPase subunits,Mcm2 to Mcm7.The human genome is enormous,with over 3 billion base pairs.To efficiently duplicate the entire genome within a limited time,DNA replication is initiated from more than 25,000 discrete sites simultaneously.

关键词： DNA initiated shaped

CircPTEN-MT from PTEN regulates mitochondrial energy metabolism

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Journal of Genetics and Genomics 2024年第5期51卷 531-542页

作者： Danhui Ruan Jiancheng Xu Yang Liu Juan Luo Xuyang Zhao Yuhua Li Guangxi Wang Jiawen Feng Hui Liang Yue Yin Jianyuan Luo Yuxin Yin Institute of Systems Biomedicine Department of PathologySchool of Basic Medical SciencesBeijing Key Laboratory of Tumor Systems BiologyPeking University International Cancer InstitutePeking-Tsinghua Center of Life SciencesPeking University Health Science CenterBeijing 100191China Institute of Precision Medicine Peking University Shenzhen HospitalShenzhenGuangdong 518036China Department of Pharmacology School of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Department of Medical Genetics Center for Medical GeneticsSchool of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Soochow University Cancer Institute SuzhouJiangsu 215127China

Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins.However,PTEN-related circRNAs are largely unknown.Here,we report that circPTEN-mitochondria(MT)(hsa_circ_0002934)is a circular RNA encoded by exons 3,4,and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism.CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein(LRPPRC),which regulates posttranscriptional gene expression in mitochondria.Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator(SRA)stem-loop interacting RNA binding protein(SLIRP)and inhibits the polyadenylation of mitochondrial mRNA,which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production.Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism.This study expands our understanding of the role of PTEN,which produces both linear and circular RNAs with different and independent functions.

关键词： Circular RNA LRPPRC Mitochondrial energy metabolism mtDNApost-transcriptional regulation

An effective pharmacological hydrogel induces optic nerve repair and improves visual function

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Science China(life sciences) 2024年第3期67卷 529-542页

作者： Lipeng Wang Shan Zhang Yawen Han Shuo Tang Jiarui Li Lina Bu Dongyu Zhao Hongkui Deng Department of Cell biology Schoolof Basic Medical SciencesPeking University Stem Cell Research CenterStateKey Laboratoryof Naturaland Biomimetic DrugsPeking University Health Science Center Beijing 100191China MOE Key Laboratory of Cell Proliferation and Differentiation College of Life SciencesPeking-Tsinghua Center for Life SciencesPeking UniversityBeijing 100871China Academy for Advanced Interdisciplinary Studies Peking UniversityBeijing 100871China Changping Laboratory Beijing 102206China Department of Ophthalmology Peking University People's Hospital Eye Diseases and Optometry InstituteBeijing 100871China Department of Biomedical Informatics School of Basic Medical SciencesPeking UniversityBeijing 100191China

Irreversible eye lesions, such as glaucoma and traumatic optic neuropathy, can cause blindness;however, no effective treatments exist. The optic nerve, in particular, lacks the capacity to spontaneously regenerate, requiring the development of an effective approach for optic nerve repair, which has proven challenging. Here, we demonstrate that a combination of the small molecules 3BDO and trichostatin A(TSA)—which regulate mTOR and HDAC, respectively—packaged in thermosensitive hydrogel for 4-week-sustained release after intravitreal injection, effectively induced optic nerve regeneration in a mouse model of optic nerve crush injury. Moreover, this combination of 3BDO and TSA also protected axon projections and improved visual responses in an old mouse model(11 months old) of glaucoma. Taken together, our data provide a new, local small molecule-based treatment for the effective induction of optic nerve repair, which may represent a foundation for the development of pharmacological methods to treat irreversible eye diseases.

关键词： retinal ganglion cell axon regeneration old-age glaucoma small molecules pharmacological hydrogel visual function repair