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    Tao Wen, Guoqing Niu, Tong Chen, Qirong Shen, Jun Yuan, Yong-Xin Liu
    Protein & Cell, 2023, 14(10): 713-725.

    With the gradual maturity of sequencing technology, many microbiome studies have published, driving the emergence and advance of related analysis tools. R language is the widely used platform for microbiome data analysis for powerful functions. However, tens of thousands of R packages and numerous similar analysis tools have brought major challenges for many researchers to explore microbiome data. How to choose suitable, efficient, convenient, and easy-to-learn tools from the numerous R packages has become a problem for many microbiome researchers. We have organized 324 common R packages for microbiome analysis and classified them according to application categories (diversity, difference, biomarker, correlation and network, functional prediction, and others), which could help researchers quickly find relevant R packages for microbiome analysis. Furthermore, we systematically sorted the integrated R packages (phyloseq, microbiome, MicrobiomeAnalystR, Animalcules, microeco, and amplicon) for microbiome analysis, and summarized the advantages and limitations, which will help researchers choose the appropriate tools. Finally, we thoroughly reviewed the R packages for microbiome analysis, summarized most of the common analysis content in the microbiome, and formed the most suitable pipeline for microbiome analysis. This paper is accompanied by hundreds of examples with 10,000 lines codes in GitHub, which can help beginners to learn, also help analysts compare and test different tools. This paper systematically sorts the application of R in microbiome, providing an important theoretical basis and practical reference for the development of better microbiome tools in the future. All the code is available at GitHub

    Hainan Zhang, Xiangfeng Kong, Mingxing Xue, Jing Hu, Zikang Wang, Yinghui Wei, Haoqiang Wang, Jingxing Zhou, Weihong Zhang, Mengqiu Xu, Xiaowen Shen, Fengcai Yin, Zhiyuan Ai, Guangyan Huang, Junhui Xia, Xueqiong Song, Hengbin Li, Yuan Yuan, Jinhui Li, Na Zhong, Meiling Zhang, Yingsi Zhou, Hui Yang
    Protein & Cell, 2023, 14(7): 538-543.
    Shunping He, Yiyu Chen
    Protein & Cell, 2023, 14(7): 471-473.
    Ying Jing, Yuesheng Zuo, Yang Yu, Liang Sun, Zhengrong Yu, Shuai Ma, Qian Zhao, Guoqiang Sun, Huifang Hu, Jingyi Li, Daoyuan Huang, Lixiao Liu, Jiaming Li, Zijuan Xin, Haoyan Huang, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Si Wang, Jing Qu, Guang-Hui Liu
    Protein & Cell, 2023, 14(7): 497-512.

    Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia, and increases the risk of many aging-related metabolic diseases. Here, we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging. A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types, indicating a higher susceptibility of skeletal muscle fiber to aging. We found a downregulation of FOXO3 in aged primate skeletal muscle, and identified FOXO3 as a hub transcription factor maintaining skeletal muscle homeostasis. Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model, we revealed that silence of FOXO3 accelerates human myotube senescence, whereas genetic activation of endogenous FOXO3 alleviates human myotube aging. Altogether, based on a combination of monkey skeletal muscle and human myotube aging research models, we unraveled the pivotal role of the FOXO3 in safeguarding primate skeletal muscle from aging, providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-related disorders.

    Lan-Zhu Li, Kuan Yang, Yaobin Jing, Yanling Fan, Xiaoyu Jiang, Si Wang, Guang-Hui Liu, Jing Qu, Shuai Ma, Weiqi Zhang
    Protein & Cell, 2023, 14(8): 623-628.
    Gaoxiang Zhao, Qian Lin, Zhaoyuan Meng, Xinlei Sheng, Leina Ma, Yingming Zhao
    Protein & Cell, 2023, 14(7): 474-476.
    Alexander Stevens, Yanxiang Cui, Sakar Shivakoti, Z. Hong Zhou
    Protein & Cell, 2023, 14(7): 544-548.
    Ya-Hui Zhao, Wei Jiang, Hai Gao, Guo-Zheng Pang, Yu-Shuang Wu, Yuan-Xian Wang, Meng-Yao Sheng, Jia-Ying Xie, Wan-Ling Wu, Zhi-Jian Ji, Ya-Rui Du, Lei Zhang, Xiao-Qin Wang, Colum P. Walsh, Hai Jiang, Guo-Liang Xu, Dan Zhou
    Protein & Cell, 2023, 14(7): 532-537.
    Yuhan Chen, Jiansen Lu, Yanwen Xu, Yaping Huang, Dazhuang Wang, Peiling Liang, Shaofang Ren, Xuesong Hu, Yewen Qin, Wei Ke, Ralf Jauch, Andrew Paul Hutchins, Mei Wang, Fuchou Tang, Xiao-Yang Zhao
    Protein & Cell, 2023, 14(7): 477-496.

    Although somatic cells can be reprogrammed to pluripotent stem cells (PSCs) with pure chemicals, authentic pluripotency of chemically induced pluripotent stem cells (CiPSCs) has never been achieved through tetraploid complementation assay. Spontaneous reprogramming of spermatogonial stem cells (SSCs) was another non-transgenic way to obtain PSCs, but this process lacks mechanistic explanation. Here, we reconstructed the trajectory of mouse SSC reprogramming and developed a five-chemical combination, boosting the reprogramming efficiency by nearly 80- to 100-folds. More importantly, chemical induced germline-derived PSCs (5C-gPSCs), but not gPSCs and chemical induced pluripotent stem cells, had authentic pluripotency, as determined by tetraploid complementation. Mechanistically, SSCs traversed through an inverted pathway of in vivo germ cell development, exhibiting the expression signatures and DNA methylation dynamics from spermatogonia to primordial germ cells and further to epiblasts. Besides, SSC-specific imprinting control regions switched from biallelic methylated states to monoallelic methylated states by imprinting demethylation and then re-methylation on one of the two alleles in 5C-gPSCs, which was apparently distinct with the imprinting reprogramming in vivo as DNA methylation simultaneously occurred on both alleles. Our work sheds light on the unique regulatory network underpinning SSC reprogramming, providing insights to understand generic mechanisms for cell-fate decision and epigenetic-related disorders in regenerative medicine.

    Yingrui Wang, Qianru Zhu, Rui Sun, Xiao Yi, Lingling Huang, Yifan Hu, Weigang Ge, Huanhuan Gao, Xinfu Ye, Yu Song, Li Shao, Yantao Li, Jie Li, Tiannan Guo, Junping Shi
    Protein & Cell, 2023, 14(9): 668-682.

    Although the development of COVID-19 vaccines has been a remarkable success, the heterogeneous individual antibody generation and decline over time are unknown and still hard to predict. In this study, blood samples were collected from 163 participants who next received two doses of an inactivated COVID-19 vaccine (CoronaVac®) at a 28-day interval. Using TMT-based proteomics, we identified 1,715 serum and 7,342 peripheral blood mononuclear cells (PBMCs) proteins. We proposed two sets of potential biomarkers (seven from serum, five from PBMCs) at baseline using machine learning, and predicted the individual seropositivity 57 days after vaccination (AUC = 0.87). Based on the four PBMC’s potential biomarkers, we predicted the antibody persistence until 180 days after vaccination (AUC = 0.79). Our data highlighted characteristic hematological host responses, including altered lymphocyte migration regulation, neutrophil degranulation, and humoral immune response. This study proposed potential blood-derived protein biomarkers before vaccination for predicting heterogeneous antibody generation and decline after COVID-19 vaccination, shedding light on immunization mechanisms and individual booster shot planning.

    Chen Zhu, Yanfeng Shi, Jing Yu, Wenhao Zhao, Lingqiao Li, Jingxi Liang, Xiaolin Yang, Bing Zhang, Yao Zhao, Yan Gao, Xiaobo Chen, Xiuna Yang, Lu Zhang, Luke W. Guddat, Lei Liu, Haitao Yang, Zihe Rao, Jun Li
    Protein & Cell, 2023, 14(12): 919-923.
    Yunyun Gao, Danyi Li, Yong-Xin Liu
    Protein & Cell, 2023, 14(10): 709-712.
    Pingping Nie, Weihong Zhang, Yan Meng, Moubin Lin, Fenghua Guo, Hui Zhang, Zhenzhu Tong, Meng Wang, Fan Chen, Liwei An, Yang Tang, Yi Han, Ruixian Yu, Wenjia Wang, Yuanzhi Xu, Linxin Wei, Zhaocai Zhou, Shi Jiao
    Protein & Cell, 2023, 14(7): 513-531.

    As an important part of tumor microenvironment, neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis. Here we defined, at single-cell resolution, CD44CXCR2 neutrophils as tumor-specific neutrophils (tsNeus) in both mouse and human gastric cancer (GC). We uncovered a Hippo regulon in neutrophils with unique YAP signature genes (e.g., ICAM1, CD14, EGR1) distinct from those identified in epithelial and/or cancer cells. Importantly, knockout of YAP/TAZ in neutrophils impaired their differentiation into CD54+ tsNeus and reduced their antitumor activity, leading to accelerated GC progression. Moreover, the relative amounts of CD54+ tsNeus were found to be negatively associated with GC progression and positively associated with patient survival. Interestingly, GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+ tsNeus. Furthermore, pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC, with no significant inflammation-related side effects. Thus, our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus, opening a new possibility to develop neutrophil-based antitumor therapeutics.

    Yujing Qian, Xiazhao Yu, Yangqing Sun, Qun Xie, Ge Liang, Gaiping Bai
    Protein & Cell, 2023, 14(9): 629-631.
    Yuxia Wang, Lijie Wu, Tian Wang, Junlin Liu, Fei Li, Longquan Jiang, Zhongbo Fan, Yanan Yu, Na Chen, Qianqian Sun, Qiwen Tan, Tian Hua, Zhi-Jie Liu
    Protein & Cell, 2024, 15(3): 230-234.
    Shanshan Yang, Chengyu Liu, Mengmeng Jiang, Xiaoqian Liu, Lingling Geng, Yiyuan Zhang, Shuhui Sun, Kang Wang, Jian Yin, Shuai Ma, Si Wang, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Guang-Hui Liu
    Protein & Cell, 2024, 15(2): 98-120.

    Aging increases the risk of liver diseases and systemic susceptibility to aging-related diseases. However, cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized. Here, we constructed the first single-nucleus transcriptomic landscape of primate liver aging, in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell–cell interactions between hepatocytes and niche cells. Upon in-depth dissection of this rich dataset, we identified impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging. In particular, hyperactivated sterol regulatory element-binding protein (SREBP) signaling was a hallmark of the aged liver, and consequently, forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes, manifesting as impaired detoxification and accelerated cellular senescence. This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

    Liyuan Jiang, Xin Wang, Leyun Wang, Sinan Ma, Yali Ding, Chao Liu, Siqi Wang, Xuan Shao, Ying Zhang, Zhikun Li, Wei Li, Guihai Feng, Qi Zhou
    Protein & Cell, 2023, 14(12): 924-928.
    Zhimei Que, Zhujun Su, Yuanyuan Meng
    Protein & Cell, 2023, 14(12): 861-865.
    Ting Tian, Sensen Zhang, Maojun Yang
    Protein & Cell, 2023, 14(9): 635-652.

    Spinal cord injury (SCI) disrupts the structural and functional connectivity between the higher center and the spinal cord, resulting in severe motor, sensory, and autonomic dysfunction with a variety of complications. The pathophysiology of SCI is complicated and multifaceted, and thus individual treatments acting on a specific aspect or process are inadequate to elicit neuronal regeneration and functional recovery after SCI. Combinatory strategies targeting multiple aspects of SCI pathology have achieved greater beneficial effects than individual therapy alone. Although many problems and challenges remain, the encouraging outcomes that have been achieved in preclinical models offer a promising foothold for the development of novel clinical strategies to treat SCI. In this review, we characterize the mechanisms underlying axon regeneration of adult neurons and summarize recent advances in facilitating functional recovery following SCI at both the acute and chronic stages. In addition, we analyze the current status, remaining problems, and realistic challenges towards clinical translation. Finally, we consider the future of SCI treatment and provide insights into how to narrow the translational gap that currently exists between preclinical studies and clinical practice. Going forward, clinical trials should emphasize multidisciplinary conversation and cooperation to identify optimal combinatorial approaches to maximize therapeutic benefit in humans with SCI.

    Maomao Pu, Wenhui Zheng, Hongtao Zhang, Wei Wan, Chao Peng, Xuebo Chen, Xinchang Liu, Zizhen Xu, Tianhua Zhou, Qiming Sun, Dante Neculai, Wei Liu
    Protein & Cell, 2023, 14(9): 653-667.

    Lipophagy, the selective engulfment of lipid droplets (LDs) by autophagosomes for lysosomal degradation, is critical to lipid and energy homeostasis. Here we show that the lipid transfer protein ORP8 is located on LDs and mediates the encapsulation of LDs by autophagosomal membranes. This function of ORP8 is independent of its lipid transporter activity and is achieved through direct interaction with phagophore-anchored LC3/GABARAPs. Upon lipophagy induction, ORP8 has increased localization on LDs and is phosphorylated by AMPK, thereby enhancing its affinity for LC3/GABARAPs. Deletion of ORP8 or interruption of ORP8-LC3/GABARAP interaction results in accumulation of LDs and increased intracellular triglyceride. Overexpression of ORP8 alleviates LD and triglyceride deposition in the liver of ob/ob mice, and Osbpl8-/- mice exhibit liver lipid clearance defects. Our results suggest that ORP8 is a lipophagy receptor that plays a key role in cellular lipid metabolism.

    Xiaoyang Dou, Lulu Huang, Yu Xiao, Chang Liu, Yini Li, Xinning Zhang, Lishan Yu, Ran Zhao, Lei Yang, Chuan Chen, Xianbin Yu, Boyang Gao, Meijie Qi, Yawei Gao, Bin Shen, Shuying Sun, Chuan He, Jun Liu
    Protein & Cell, 2023, 14(9): 683-697.

    METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell (mESC). While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-independent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification. Mechanistically, METTL14, but not METTL3, binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression. The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs. This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance, and differentiation of mESCs.

    Juan Zhang, Dingfeng Li, Keqiang He, Qiang Liu, Zhongwen Xie
    Protein & Cell, 2024, 15(2): 149-155.
    Huan Liu, Jianliang Huang, Wanying Gao, Hao Cheng
    Protein & Cell, 2023, 14(8): 551-555.
    Zheng Wang, Hong Zhang
    Protein & Cell, 2023, 14(9): 632-634.
    Jiewei Zhu, Vasily Giannakeas, Steven A. Narod, Mohammad R. Akbari
    Protein & Cell, 2023, 14(8): 556-559.
    Liangwen Zhong, Miriam Gordillo, Xingyi Wang, Yiren Qin, Yuanyuan Huang, Alexey Soshnev, Ritu Kumar, Gouri Nanjangud, Daylon James, C. David Allis, Todd Evans, Bryce Carey, Duancheng Wen
    Protein & Cell, 2023, 14(8): 591-602.

    While Mek1/2 and Gsk3β inhibition (“2i”) supports the maintenance of murine embryonic stem cells (ESCs) in a homogenous naïve state, prolonged culture in 2i results in aneuploidy and DNA hypomethylation that impairs developmental potential. Additionally, 2i fails to support derivation and culture of fully potent female ESCs. Here we find that mouse ESCs cultured in 2i/LIF supplemented with lipid-rich albumin (AlbuMAX) undergo pluripotency transition yet maintain genomic stability and full potency over long-term culture. Mechanistically, lipids in AlbuMAX impact intracellular metabolism including nucleotide biosynthesis, lipid biogenesis, and TCA cycle intermediates, with enhanced expression of DNMT3s that prevent DNA hypomethylation. Lipids induce a formative-like pluripotent state through direct stimulation of Erk2 phosphorylation, which also alleviates X chromosome loss in female ESCs. Importantly, both male and female “all-ESC” mice can be generated from de novo derived ESCs using AlbuMAX-based media. Our findings underscore the importance of lipids to pluripotency and link nutrient cues to genome integrity in early development.

    Hai Zheng, Qianwei Jin, Xinxin Wang, Yilun Qi, Weida Liu, Yulei Ren, Dan Zhao, Fei Xavier Chen, Jingdong Cheng, Xizi Chen, Yanhui Xu
    Protein & Cell, 2023, 14(9): 698-702.
    Hui Sun, Tingting Deng, Yali Zhang, Yanling Lin, Yanan Jiang, Yichao Jiang, Yang Huang, Shuo Song, Lingyan Cui, Tingting Li, Hualong Xiong, Miaolin Lan, Liqin Liu, Yu Li, Qianjiao Fang, Kunyu Yu, Wenling Jiang, Lizhi Zhou, Yuqiong Que, Tianying Zhang, Quan Yuan, Tong Cheng, Zheng Zhang, Hai Yu, Jun Zhang, Wenxin Luo, Shaowei Li, Qingbing Zheng, Ying Gu, Ningshao Xia
    Protein & Cell, 2024, 15(2): 121-134.

    Continual evolution of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus has allowed for its gradual evasion of neutralizing antibodies (nAbs) produced in response to natural infection or vaccination. The rapid nature of these changes has incited a need for the development of superior broad nAbs (bnAbs) and/or the rational design of an antibody cocktail that can protect against the mutated virus strain. Here, we report two angiotensin-converting enzyme 2 competing nAbs—8H12 and 3E2—with synergistic neutralization but evaded by some Omicron subvariants. Cryo-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472–489 loop in the receptor-binding domain to avoid steric clashing. Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5. Together, these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.

    Junmo Wu, Yu Kang, Xiang Luo, Shaoxing Dai, Yuxi Shi, Zhuoyao Li, Zengli Tang, Zhenzhen Chen, Ran Zhu, Pengpeng Yang, Zifan Li, Hong Wang, Xinglong Chen, Ziyi Zhao, Weizhi Ji, Yuyu Niu
    Protein & Cell, 2024, 15(3): 207-222.

    Non-human primates (NHPs) are increasingly used in preclinical trials to test the safety and efficacy of biotechnology therapies. Nonetheless, given the ethical issues and costs associated with this model, it would be highly advantageous to use NHP cellular models in clinical studies. However, developing and maintaining the naïve state of primate pluripotent stem cells (PSCs) remains difficult as does in vivo detection of PSCs, thus limiting biotechnology application in the cynomolgus monkey. Here, we report a chemically defined, xeno-free culture system for culturing and deriving monkey PSCs in vitro. The cells display global gene expression and genome-wide hypomethylation patterns distinct from monkey-primed cells. We also found expression of signaling pathways components that may increase the potential for chimera formation. Crucially for biomedical applications, we were also able to integrate bioluminescent reporter genes into monkey PSCs and track them in chimeric embryos in vivo and in vitro. The engineered cells retained embryonic and extra-embryonic developmental potential. Meanwhile, we generated a chimeric monkey carrying bioluminescent cells, which were able to track chimeric cells for more than 2 years in living animals. Our study could have broad utility in primate stem cell engineering and in utilizing chimeric monkey models for clinical studies.

    Dan Cao, Mengyue Lv, Chi Hu, Shukai Li, Siwen Wang, Chao Xu, Wen Pan
    Protein & Cell, 2024, 15(3): 223-229.