Recently, a review article entitled "Cytoplasmic DNAs: sources, sensing, and roles in the development of lung inflammatory diseases and cancer" was published in Frontiers in Immunology (Official Journal of International Union of Immunological Societies (IUIS), JCR Q1 Journal) by a group of undergraduate students supervised by Jian Liu lab from Zhejiang University - University of Edinburgh Institute (ZJE). This review focuses on recent discoveries and advances in cytoplasmic DNA and its signaling pathways in inflammatory lung disease and lung cancer (Figure 1). The authors find that sustained activation of cytoplasmic DNA sensing pathways contributes to the development of common lung diseases, which can be caused by external factors or mutations in key genes in the body. The interaction of cytoplasmic DNA with anti-inflammatory or antitumor effects and its potential in immunotherapy are further discussed.Mislocated cytoplasmic DNA will be induced by cytoplasmic sensors such as cGAS and inflammatory bodies to induce innate immune responses such as IFN response and inflammatory cell death. A growing number of studies have reported the role of such signaling pathways in the progression of common diseases, including pulmonary inflammatory disease and lung cancer. This article summarizes the latest research results of cytoplasmic DNA sensing in the progression of these lung diseases and proposes the corresponding immunotherapy methods. In addition, the role of pathogens and self-derived cytoplasmic DNA in the development of several types of pulmonary inflammatory diseases, such as COVID-19, has been described. More importantly, the authors note the important contribution of cytoplasmic DNA sensing in some specific genotypes of lung cancer, such as TP53 mutants. This provides a theoretical basis for the accurate treatment of lung cancer. In conclusion, the authors suggest that cytoplasmic DNA plays a crucial role in the progression of common lung diseases, and that its understanding could help explore more therapeutic strategies.Professor Jian Liu is the corresponding author of this paper. He Xintong, Sun Ye and Lu Jianzhang are the co-first authors of this paper. Shenglin Ma is the co-corresponding author of this paper. Co-authors include Faiza Naz, a foreign doctoral student in Jian Liu's lab. Although undergraduate students of ZJE are always busy with their studies, it only took three months from drafting to finishing the article, and only six months from publication. This fully reflects the subjective initiative in research and self-learning ability of ZJE undergraduates. Moreover, these ZJE undergraduate students, the first authors of this publication, conducted some related research in Pro. Jian Liu’s lab, supported by the Zhejiang Province College Students Science and Technology Innovation Activity Plan (New Seedling Talent Program) in 2022.Link of the article：https://www.frontiersin.org/articles/10.3389/fimmu.2023.1117760/full?&utm_source=Email_to_authors_&utm_medium=Email&utm_content=T1_11.5e1_author&utm_campaign=Email_publication&field=&journalName=Frontiers_in_Immunology&id=1117760 About labLiu Jian's research group was founded in November 2020. Currently, its main research interests are tumor biology, AI multi-omics, and gene editing. At present, it focuses on studying the molecular mechanism of lung cancer (lung squamous cell carcinoma) by combining clinical database, transgenic mouse model, and various sequencing methods, aiming at promoting targeted therapy of lung cancer (lung squamous cell carcinoma). Established "groups of databases of lung cancer and other cancers (http://www.canceromics3d.net/ or http://www.lungcancer3d.net/)" and WeChat public account “肺鳞癌”. The leader of the research group can be contacted at JianL@intl.zju.edu.cnLab website: https://person.zju.edu.cn/liujian; Recruit highly motivated postgraduates. Photo of the authorsJian's Lab

Quantitative single-cell analysis has revolutionised our approach to study the molecular events that lead to cell fate decisions. However, a common challenge when performing single-cell analysis is the limited computational tools available to track single-cells over multiple cell generations robustly. This is because when cells undergo cell division, they form daughter cells that can confound the algorithms used to track the cells, leading to high false mother-daughter assignments. This means extensive manual corrections are often required, making it a time-consuming practice.In the recent publication in Bioinformatics, Kuan Yoow Chan's lab developed an application that uses deep learning to classify cells based on the pattern of the well-established fluorescently tagged PCNA protein. By using the PCNA pattern to identify the cell cycle state of cells, we were able to assign mother-daughter relationships rapidly and accurately. This novel approach has high accuracy rates and relatively low computational costs, allowing us to generate high-quality single-cell lineages from large long-term imaging datasets.LINK：https://academic.oup.com/bioinformatics/advance-article/doi/10.1093/bioinformatics/btac602/6680181About labUsing genetic, cell biology and biochemical assays, Kuan Yoow Chan' Lab aim to study how the changes in centrosomal signalling lead to the deregulation of the cell cycle in cancer.

Recently, Dr. Qianting Zhang’s lab from Zhejiang University-University of Edinburgh Institute (ZJE) published a review entitled “Ubiquitin-Proteasome System–Regulated Protein Degradation in Spermatogenesis” on Cells. The review systematically discusses the physiological functions and molecular mechanisms of the components of the ubiquitin-proteasome system (UPS) in regulating spermatogenesis, suggesting that exploring the functions of UPS machineries is critical for the improvement of human Assisted Reproductive Technology (ART) and the popularization of Preimplantation Genetic Diagnosis (PGD). ZJE student Yi Xiong also participated in writing this review. Dr. Qianting Zhang is the corresponding author and Yi Xiong, an undergraduate student (2018 Cohort) from ZJE, is the first author of this article. Spermatogenesis, which maintains sustainable production of male gametes, the spermatozoa, includes more than 40 steps. Spermatogonia, differentiated from the primordial germ cells, undergo meiotic division to form round spermatids, which further mature to become motile, fertile spermatozoa. During this process, male germ cells experience dramatic changes in morphology as well as cellular contents and these changes are tightly regulated through the UPS (Figure 1). According to reports, there are extensive protein degradation events and unique molecular machineries controlling protein homeostasis during spermatogenesis. The UPS plays a broad and precise role in regulating both protein degradation and activity for the step-by-step progression in spermatogenesis. This review includes three main parts: 1. Proteasomes in male germ cells; 2. E3 ubiquitin ligase in spermatogenesis; 3. Protein deubiquitination in spermatogenesis. Exploring the functions of UPS machineries in spermatogenesis provides a global picture of the proteome dynamics during male germ cell production and shed light on the etiology and pathogenesis of human male infertility Figure 1: The processes of mammalian spermatogenesis. (The degradation timing of regulatory proteins involved in meiotic prophase I and histones as substrates of UPS, as well as the expression pattern of 20S proteasome subunits PSMA7 and PSMA8 are labeled with Gradient bar.) Access to the publication: https://www.mdpi.com/2073-4409/11/6/1058 

Stretch, as a form of mechanical force, plays a crucial role in regulating cell behaviors, preventing injuries and repairing tissues such as lung, heart, brain and skeletal system. Among them, stretch in bone tissues has captured the most immense attention in clinical applications, for bone tissues are continuously exposed to stretch stimulation during physiological activities. The structure and function of bone tissues relies on a proper amount of stretch stimulation, while lack of exercises tends to result in the reduction of bone volume and osteoporosis. Under physiological conditions, bone tissues are subjected to micro-stretch with a variable frequency.  Although there has been a massive body of research into the effects of stretch stimulation with a constant frequency, the biological effects of micro-stretch with a variable frequency have not yet been identified. Moreover, commercial stretching devices are unable to generate stretch with a variable frequency similar to the in vivo condition of bone tissues. Against this backdrop, the research team led by Prof. OUYANG Hongwei proposed a novel cell stretcher, named as “musical dish”, which for the first time used the conversion of musical signals to mechanical signals to realize the regulation of stem cell fate by micro-stretch with a variable frequency (NUMS). Their research findings were published in Bioengineering & Translational Medicine, entitled “’Musical dish’ efficiently induces osteogenic differentiation of mesenchymal stem cells through music derived micro-stretch with variable frequency”. In this study, the researchers developed a musical dish with fast response, large deformation, optical transparency and robust controllability, based on dielectric elastomer actuators (DEAs) . This musical dish could convert musical signals into electrical ones, which could further converted into mechanical energy via a flexible dielectric elastomer membrane. It could trigger stretching stably. The actuating strain was featured by homogeneity and equiaxiality. When cells were seeded on the musical dish, they could proliferate normally. The cells showed displacement with the increase of the voltage. To evaluate the effect of NUMS, 1 kV constant voltage with musical signals was applied to cells. The stretch ranged from 0.833% to 0.867% which is close to the stretch condition in bone tissues. Quantitative analysis revealed that cells in the NUMS group exhibited more marked filamentous stress fibers than constant stretch and no stretch groups. Bone development and ossification were up-regulated according to the gene ontology (GO) enrichment analysis. Further, Experiments identified a significant increase in the expression of bone cell-related genes under NUMS, but the expression of stemness-related genes decreased tremendously. The NUMS also promoted osteogenic differentiation of cells in induction medium. These findings highlight a novel “musical dish,” which allows arbitrary strain waveforms to be applied to cells by converting music signals into the stretching force. In comparison with constant stretching, NUMS may have great potential for promoting bone differentiation of cells. For clinical applications, three strategies may contribute to the development of potential therapeutic ways for bone regeneration. First, NUMS could be used in the distraction osteogenesis surgery to replace or assist the current large-scale and slow stretching method for bone regeneration due to its superb performance in promoting osteogenic differentiation. Second, the musical dish could be further developed into a music-derived rehabilitation technology to promote bone healing. Finally, the musical dish could serve as a cell expansion bioreactor to produce cells with a high level of osteogenic differentiation to repair bones by transplantation. Thus, both the new stretching model and the newly-developed stretching device may have a brilliant clinical prospect.  

In Greek mythology, Achilles was the son of the mortal Peleus and Thetis, the goddess of the sea. In order to make his son invulnerable, Thetis carried it upside down and immersed it in the Styx River when he was just born. However, Achilles' heel pinched by his mother was accidentally exposed outside the Styx River, leaving the only fatal weakness in his body. In the Trojan War, Achilles was shot in the ankle by Paris and died.In the human body, there is also such a soft spot- Achilles tendon. As its name suggests, the Achilles tendon is one of the most powerful and fragile tendons in the body. The Achilles tendon could endure a load close to 8 times the body weight during exercise, making it extremely sensitive to injury. Furthermore, due to the unique nature of tendons, failing to consult a doctor soon after an injury can lead to chronic tendon disease, which is characterized by pain, swelling, and movement problems. Heterotopic ossification of tendon is a special type of chronic tendon disease, that is, the bone grows in the place (tendon) where the it shouldn’t, further destroying the morphological structure and function of the tendon tissue. Famous athletes such as Xiang Liu and Kobe Bryant had to retire early from sports due to a lack of a radical solution for Achilles tendon injuries.Figure 1 Achilles tendon - the powerful and fragile Achilles heel of the human body (picture from the Internet)Using single-cell sequencing technology, the Ouyang Hongwei team of Zhejiang University revealed tissue microenvironment changes during tendon heterotopic ossification alters gene expression and cell fate determination of tendon stem progenitor cells, and demonstrated that this process can be blocked by small molecule inhibitor BIBF1120, providing a novel treatment for heterotopic tendon ossification.The authors firstly found that the tendon specific transcription factor MKX decreased significantly in heterotopic ossified human tendon, and knockout of Mkx lead to spontaneous ossification of mouse tendon, suggesting that MKX plays a critical role in heterotopic ossification of tendon.Fig. 2 Heterotopic ossification of tendon caused by decreased MKX expression or Mkx knockoutFurther studies revealed that Mkx knockout mouse tendon cells expressed high levels of angiogenesis related genes, resulting in vascular invasion and tendon extracellular matrix microenvironment remodeling, and abnormal activation of osteogenic and chondrogenic differentiation related genes in tendon stem progenitor cells. These data indicated that inhibition of angiogenesis may improve the tendon tissue microenvironment and prevent HO progression.Figure 3 Single cell sequencing reveals tendon cell subpopulations and altered gene expression patternTherefore, the author focused on finding drugs that can inhibit angiogenesis process. Finally, they found that local injection of BIBF1120 significantly inhibited the neovascularization of tendon after injury, and significantly alleviated the tendon heterotopic ossification.Figure 4 Small molecule inhibitor BIFB1120 significantly improved the microenvironment of tendon injury and inhibited heterotopic ossificationThis work was published in Bone research entitled "Single cell analysis reveals investment of angiogenesis concerns progress of heterotopic ossification in Mkx-/- mice". The first author of the paper is Junxin Lin, a postdoctoral researcher of the Zhejiang University-University of Edinburgh Institute. The corresponding authors are professor Hongwei Ouyang and Wanlu Liu. The research was supported by the National Key R&D Program of China (2017YFA0104900), the National Natural Science Foundation of China (31830029, 81501937, 81522029) and the Fundamental Research Funds for the Central Universities (K20200099).Link：https://www.nature.com/articles/s41413-021-00175-9

Recently, Jian Liu’s group from Zhejiang University-University of Edinburgh Institute (ZJE) in Zhejiang University published their lung cancer metastasis research entitled “Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation” at Nature Communications by collaborating with multiple groups, including the Pro. Xiao Yang from State Key Laboratory of Proteomics in National Center for Protein Sciences (Beijing) and Pro. Xiaotao Li from Shanghai Key Laboratory of Regulatory Biology in East China Normal University, and Pro. Dianwen Song from The First People’s Hospital of Shanghai Jiao Tong University. By developing different genetic mouse models mimicking lung cancer metastasis and the comprehensive mechanism studies, they revealed that the de novo role of SMAD4 in repressing lung cancer metastasis, independent of TGFβ, and the therapeutic targets (SMAD4/miRNA-495/PAK3) for treating lung cancer metastasis. Access to the publication：https://www.nature.com/articles/s41467-021-24898-9Lung cancer is the leading cause of cancer death worldwide and in China1. Over 85% of lung cancer patients harbor overt or subclinical metastases at diagnosis, and therefore most patients die of progressive metastatic disease despite aggressive local and systemic therapies1. SMAD4 is the crucial downstream transcription factor of the TGFβ pathway and has been found to have some somatic mutations and the decreased expression in human lung tumors2,3. Although Jian Liu et al. reported that Smad4 ablation promoted lung cancer development and metastasis, the mechanism of SMAD4 in regulating lung cancer metastasis remains unclear.    Jian Liu et al. have reported that ablation of Smad4 in mouse lungs could not cause cell hyperplasia and tumor formation2,6. This research found that some lung cancer patients harbored the mutations of KRAS, TP53, and SMAD4 in the same tumors by analyzing the TCGA lung cancer datasets. Therefore, this research generated KrasG12DTrp53flox/flox (PK) and KrasG12DTrp53flox/floxSmad4flox/flox (SPK) mouse models to mimic the lung cancer metastasis to investigate the role of SMAD4 in regulating lung cancer under the background of Kras mutation and Trp53 ablation. Moreover, this research found that the ratio of lung tumor metastasis in SPK mice was much higher than that of PK mice. By conducting the transcriptome analysis of the isolated lung tumor cells from PK and SPK mice, followed by the functional analyses (e.g., cell invasion), this research found that Smad4 ablation increased the mRNA and protein expression of PAK3 (Figure 1, Step 3), and consequently activated the JNK-JUN pathway of the downstream of PAK3 (Figure 1, Steps 4 and 5), and eventually promoted lung cancer metastasis. Unexpectedly, the negative regulation of SMAD4 on PAK3 is independent of TGFβ. Analysis of SMAD4 ChIP-Seq data showed that there was no SMAD4 binding on the PAK3 promoter. Furthermore, the exogenous expression of SMAD4 did not alter the luciferase activity driven by the PAK3 promoter. Thus, it indicated that the negative regulation of SMAD4 on PAK3 is independent of TGFβ, belonging to the non-classic role of SMAD4. Some published studies showed that the transcriptional regulation of gene expression could be regulated either by the promoter or the 3’ UTR7. This research further showed that Smad4 loss altered the luciferase activity driven by the PAK3 3’ UTR. Given that miRNA can negatively regulate gene expression by binding on the targeting gene’s 3’ UTR, this research raised a hypothesis that SMAD4 negatively regulates the PAK3 mRNA expression through miRNAs. Through the bioinformatical analysis, as well as the functional validations, this research found that miR-495 and miR-543, directly and positively regulated by SMAD4, mediated the negative regulation of SMAD4 on PAK3 (Figure 1, Steps 1 and 2). Clinically, the negative correlation between SMAD4 and PAK3-JNK-JUN was observed in a group of human lung cancer samples, including the control lungs, early-stage lung tumors, late-stage lung tumors, and metastatic lung tumors. In sum, this research identified SMAD4/miRNA-495/PAK3 to be the de novo targets in treating lung tumor metastases. Figure 1. The TGFβ-independent role of SMAD4 in regulating lung cancer metastasis Of note, the SMAD4 repression on PAK3 is independent of TGFβ since SMAD4 is a typical functional player of the TGFβ pathway. Moreover, they showed that miRNA-495 was able to prevent the lung cancer metastasis induced by Smad4 loss. The biggest challenge of the application of RNA drugs is the in vivo stability of RNA8,9. Given that the mRNA vaccine (Moderna) was successful against COVID-19, it suggested that the concerns of the low stability of RNA drug in vivo have been partially resolved during the clinical applications. Therefore, miRNA-495 against lung cancer metastasis may benefit developing clinical treatment. Dr. Jian Liu is the co-corresponding author of the article. In addition, the master student Feiran Gao (ZJE, 2020 entry) participates in this research. To overcome the difficulties of this research, such as a large number of genetic mouse experiments, the non-classic role of SMAD4, and the different stages of human lung cancer samples, all collaborators effectively communicated with each other and worked together. For example, Dr. Xiao Yang’s group was mainly responsible for generating the mouse models; Drs. Xiaotao Li and Lei Li’s group was mainly in charge of the mechanism investigation and the initial version of the manuscript; Dr. Jian Liu’s group took the responsibility to conduct all bioinformatic analyses, parts of experimental designs, and the whole revision process; Drs. Dianwen Song’s and Junjiang Fu’s groups collected the clinical samples. Meanwhile, the international collaborators also contributed to this research, including Dr. Nabeel Bardeesy from Massachusetts General Hospital of Harvard University, Dr. Kwok-kin Wong from Laura and Isaac Perlmutter Cancer Center of New York University, and Dr. Robb E. Moses from Dan L. Duncan Cancer Center of Baylor College of Medicine.About Jian Liu’s lab (https://person.zju.edu.cn/en/jian_liu) References1.    Rebecca L Siegel, et al. Cancer statistics, 2019. CA Cancer J Clin (2019).2.    Xiaohong Tan, et al. Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation. Nature Communications (2021)3.    Jian Liu. et al. ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis. Cell Reports (2015).4.    Jian Liu, et al. ERBB2 Regulates MED24 during Cancer Progression in Mice with Pten and Smad4 Deletion in the Pulmonary Epithelium. Cells (2019).5.    Ran You, et al. IL17A regulates tumor latency and metastasis in lung adeno and squamous SQ. 2b and AD. 1 cancer. Cancer immunology research (2018)6.    Jian Liu. et al. JNK1/2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression. Nature Communications (2019)7.    Yuval Malka. et al. Post-transcriptional 3´-UTR cleavage of mRNA transcripts generates thousands of stable uncapped autonomous RNA fragments. Nature Communications (2017)8.     Ugur Sahin. et al. mRNA-based therapeutics — developing a new class of drugs. Nature Reviews Drug Discovery (2014)9.     Meirav Segal. Et al. Challenges identifying efficacious miRNA therapeutics for cancer. Expert Opinion on Drug Discovery (2020) 

Recently, ZJE post-doc Prasanth Manohar participated in the International Conference on Bacteriophage Research, delivering a talk on his research: Characterization of a novel bacteriophage PA01_φmotto infecting Pseudomonas aeruginosa, and won the Young Scientist Award.The 2nd International Conference on Bacteriophage Research was held virtually and there are more than 500 participants and 15 guest speakers from various countries./Profile/Prasanth Manohar’s work on bacteriophages focuses mainly on the application of phages in medicine to cure antibiotic-resistant bacterial infections. Mainly working on Klebsiella pneumonia and Pseudomonas aeruginosa phages which are top priority pathogens needing alternative treatments.Contact Email: PrasanthM@intl.zju.edu.cn

Recently, two undergraduate students from Zhejiang University-University of Edinburgh Institute (ZJE) in Dr. Jian Liu’s research group published a review entitled “Comparison of COVID-19 and Lung Cancer Via Reactive Oxygen Species Signaling” at Frontiers in Oncology. This article reviews the role of reactive oxygen species (ROS) and their associated signaling pathways, NRF2, HIF-1, and Nf-κB, in the pathogenesis of COVID-19 and lung cancer (Figure 1) and suggests the interplay between the two diseases. The HIF-1 and Nf-κB pathways are upregulated in both diseases, leading to inflammation, oxidation, tumor cell proliferation, and metastasis. Thus, the authors suggest that targeted therapies to these pathways, such as miRNA and plant-derived chemicals, are attractive and deserve further study in treating both diseases. Given that COVID-19 and lung cancer are two severe pulmonary diseases that cause millions of deaths globally, understanding the dysregulated signaling pathways between them can benefit treating the related patients. Our work emphasizes the significance of ROS in the two mutually impacted pulmonary diseases and would provide a clue in developing more novel preventive and therapeutic strategies for them.Dr. Jian Liu is the corresponding author of the article. Undergraduate students Zilan Zhu and Ziyi Zheng (2018 entry) from ZJE are co-first authors. Of note, although the ZJE undergraduates are almost fulfilled with multiple education tasks, this review was finished by them within six months. Access to the publication:  https://www.frontiersin.org/articles/10.3389/fonc.2021.708263/abstract In June 18th 2021, Dr. Jian Liu published an article entitled “Dependency of human and murine LKB1-inactivated lung cancer on aberrant CRTC-CREB activation” at Elife as a co-author. this study provides direct proof for an essential role of the CRTC-CREB activation in promoting the malignant phenotypes of LKB1-null lung cancer and proposes the CRTC-CREB interaction interface as a novel therapeutic target. Access to the publication: https://elifesciences.org/articles/66095 At the end of March 2021, Jian Liu’s lab and Aifu Lin’s lab in College of Life Science, Zhejiang University, published an article entitled “LncRNAs: Architectural Scaffolds or More Potential Roles in Phase Separation” at Frontiers in Genetics together. This article reviews the functions of phase separation and associated studies of lncRNAs. This review will facilitate our understanding of the formation and function of phase separation and the role of lncRNAs in these processes and related biological activities. A deeper understanding of the formation and maintaining of phase separation will benefit disease diagnosis and treatment. Dr. Jian Liu is the co-corresponding author of the article. Postgraduate student Feiran Gao (2020 entry) from ZJE is a co-author. Access to the publication: https://www.frontiersin.org/articles/10.3389/fgene.2021.626234/full In early March 2021, Dr. Jian Liu published an article entitled “Progesterone receptor isoform B regulates the Oxtr-Plcl2-Trpc3 pathway to suppress uterine contractility” at PNAS as a co-author. In this study, a novel transgenic mouse model was established to reveal the mechanism of uterine contraction. Access to the publication: https://www.pnas.org/content/118/11/e2011643118/tab-article-info In January 2021, Dr. Jian Liu published an article entitled “Mitochondrial long non-coding RNA GAS5 tunes TCA metabolism in response to nutrient stress” at Nature Metabolism as a co-author. In this study, the authors investigated the molecular mechanism of mitochondrial lncRNAs regulating TCA metabolism in response to nutrient stimulation. Access to the publication: https://www.nature.com/articles/s42255-020-00325-z About Jian Liu’s lab (https://person.zju.edu.cn/liujian;）Dr. Jian Liu’s lab studies cancer biology, epigenetics, and gene editing and aims to promote the targeted therapy of squamous cell lung carcinoma. Currently, the lab explores the molecular mechanism of lung cancer (especially squamous cell lung carcinoma) through the combination of clinical database, transgenic mouse models, and sequencing. Dr. Jian Liu’s E-mail address: JianL@intl.zju.edu.cn; Look for the self-motivated Postdocs.

Recently, Dr.Wanlu Liu from Zhejiang University-University of Edinburgh Institute and Prof. Steven E. Jacobsen from UCLA published an article, entitled Ectopic targeting of CG DNA methylation in Arabidopsis with the bacterial SssI methyltransferase, on Nature Communications. The study shows that targeting the CG-specific methyltransferase M.SssI with an artificial zinc finger protein to the promoter of the Arabidopsis FLOWERING WAGENINGEN (FWA) gene can establish heritable CG methylation and silencing of FWA in Arabidopsis (Figure 1). In addition, the author observes highly heritable widespread ectopic CG methylation mainly over euchromatic regions (Figure 2 A, B). By using the techniques including WGBS, ChIP-seq, ATAC-seq, etc., the author identified the Differentially methylated region (DMR), analyze the epigenetic marks on these DMRs, and study the relationship between the CG methylation and other epigenetic modifications. In addition, by analyzing the DMRs across multiple generations of Arabidopsis, the author studies the inheritance pattern of ectopic CG methylation.  Dr.Wanlu Liu is the first author and co-corresponding author of the article. The undergraduate student from Zhejiang University-University of Edinburgh Institute Yuxing Zhou participates in the research. AbstractDNA methylation is an evolutionarily conserved epigenetic modification that plays critical roles in regulating gene expression, silencing transposable elements, genomic imprinting, X-chromosome silencing, etc. In Arabidopsis, DNA methylation occurs within three sequence contexts: CG, CHG, and CHH (where H represents A, T, or C). The maintenance of CG methylation requires the DNA methyltransferase METHYLTRANSFERASE 1 (MET1, the homolog of mammalian DNMT1), while maintenance of CHG and CHH methylation redundantly requires CHROMOMETHYLASE 3 (CMT3), CMT2, and DRM2. Using techniques including zinc fingers (ZF), TAL, or CRISPR/Cas9 to target epigenetic marks like DNA methylation to specific loci is important in both basic research and in crop plant engineering. However, the heritability of targeted DNA methylation, how it impacts gene expression, and which epigenetic features are required for proper establishment is mostly unknown.Figure 1By comparing ectopic CG methylation and other epigenetic modification, the author finds that ectopic methylation occurs preferentially at less open chromatin that lacks positive histone marks. Although the ectopic CG methylation is enriched in the gene body region, this hypermethylation shows little effect on transcription (Figure 2 C-E). The author also observes that the ectopic methylation triggers a mild but significant reduction in the accumulation of H2A.Z and H3K27me3. By analyzing through four generations of Arabidopsis, the author observes the significant heritability of the CG methylation region. These results outline general principles of the heritability and interaction of CG methylation with other epigenomic features that should help guide future efforts to engineer epigenomes.Figure 2

Recently, Aaron T. Irving of ZJU-UoE Institute published a perspective article titled " Lessons from the host defences of bats, a unique viral reservoir " in Nature.Bats are rich reservoirs of many zoonootic viruses, with a unique host defence system. Lessons from the effective host defence of bats would help us to better understand viral evolution and to better predict, prevent and control future viral spillovers.Article:https://www.nature.com/articles/s41586-020-03128-0 Picture: The potential zoonotic transmission cycle for coronaviruses. (published in Nature)Article summary:There have been several major outbreaks of emerging viral diseases, including Hendra,Nipah, Marburg and Ebola virus diseases, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS)—as well as the current pandemic of coronavirus disease 2019 (COVID-19). Notably, all of these outbreaks have been linked to suspected zoonotic transmission of bat-borne viruses. Bats—the only flying mammal—display several additional features that are unique among mammals, such as a long lifespan relative to body size, a low rate of tumorigenesis and an exceptional ability to host viruses without presenting clinical disease. Here the authors discuss the mechanisms that underpin the host defence system and immune tolerance of bats, and their ramifications for human health and disease.Dr Irving’s research group focuses on emerging zoonotic viral infections, the host-pathogen interactions triggered by these viruses and comparative immunology of bats.Email：aaroniriving@intl.zju.edu.cnPersonalPage:https://person.zju.edu.cn/en/aaronirving

The article Encapsulation and Delivery of Therapeutic Phages by Dr. Belinda Loh received the special honour to be featured on the cover of the journal Applied and Environmental Microbiology.https://aem.asm.org/content/early/2020/12/08/AEM.01979-20 AbstractIn the article, the authors describe methods for the encapsulation of bacteriophages that can be used as biological antibiotics. With the increasing number of multidrug resistant bacteria, alternatives to antibiotics are desperately needed and therapeutic phages present a solution to solve the antibiotic crisis. ContactDr.Sebastian LeptihnEmail: leptihn@intl.zju.edu.cnWeb:https://leptihn-lab.org

Bats, the only flying mammal, carry a variety of viruses, many of which are zoonotic. Some of these viruses can spread to humans, often causing severe disease and even death, such as coronavirus, Ebola virus and paramyxovirus. Even though they can host so many viruses, bats maintain a healthy state by producing only a limited inflammatory response. Uncovering the mechanisms by which bats fight off these viruses has important implications for human health. Aaron T. Irving's research team recently published an article in PNAS about the complementary mechanisms by which bats suppress inflammation.Picture：Complementary relationship between M. davidii, E. spelaea, and P. alecto caspase-1 and IL-1β.（Published in PNAS） Caspase-1（or cysteine aspartic protease 1）is the central inflammasome effector for pyroptosis and triggers cytokine ( such as IL-1β) secretion. The team identified residues in caspase-1 which are critical for enzymatic activity yet have been targeted for inhibition in Pteropus bats. Further, they discover cleavage-site flanking residues which led to the loss of IL-1β cleavage in Myotis bats. The team report an inverse relationship between caspase-1 function and IL-1β cleavage in bats within two suborders, with different evolutionary mechanisms resulting in a consistent reduction of downstream signaling by the inflammasome.  https://www.pnas.org/content/early/2020/10/21/2003352117  Dr Aaron Irving trained at the Diamantina Institute (UQ Australia), Monash Institute of Medical Research (Melbourne Australia) and Emerging Infectious Diseases, Duke-NUS Medial School (Singapore). He recently opened his lab at ZJE with a focus on emerging zoonotic viral infections and the host-pathogen interactions triggered by these viruses. There is a special interest in comparative biology using bats as a model organism and identifying key factors from bats that may be utilized to improve the human immune responses to pathogen infections. Other projects in the laboratory include novel diagnostic techniques to identify current or historical infection of wildlife by zoonotic viruses, including SARS-CoV-2, and establishing/evaluating factors that may contribute to zoonotic potential. 

Continuing the success of fruitful collaborations between the ZJE Institute and the University  of Edinburgh, two articles were published in a joint effort of the Leptihn group, together with Prof. Susan Welburn and Dr. Xiaoting Hua from the Sir Run Run Shaw Hospital, in Hangzhou. One article was published in the journal Frontiers in Medicine entitled“ Secondary Bacterial Infections in Patients with Viral Pneumonia”. In a “back-to-back publication” the group published a second review article with the title “Secondary Bacterial Infections during Pulmonary Viral Disease: Phage Therapeutics as Alternatives to Antibiotics?” in the prestigious journal Frontiers in Microbiology.Picture: Comparison of scientific, clinical, and pharmaceutical characteristics of chemical antibiotics, endolysins, and bacteriophages in the treatment of bacterial infections (published in Frontiers in Microbiology).Article summaries:Both articles describe the complex disease progressions of viral pneumonias, which are often complicated by secondary bacterial infections. In the review published in Frontiers in Medicine, the frequency, treatment and impact of secondary bacterial infections during viral pneumonia are discussed, comparing influenza, SARS, MERS and SARS-CoV-2 related infections. Case studies were analysed to interpret the severity of disease progression due to secondary bacterial infections during the global pandemic and antibiotic treatment regimes. The authors reported that up to 15% of the COVID-19 mortality may be caused by secondary bacterial infections, although regional differences do exists.https://www.frontiersin.org/articles/10.3389/fmed.2020.00420/fullIn the publication in Frontiers in Microbiology the authors highlight the use of antibiotic therapy to prevent or cure secondary bacterial infections or co-infections that are occur during viral pulmonary diseases. The authors discuss the potential of using phage therapy or phage-derived compounds as alternatives to antibiotics, in particular for strains that are antibiotic resistant.https://www.frontiersin.org/articles/10.3389/fmicb.2020.01434/fullThe Leptihn’s research group is working on bacteriophage biology and phage therapy. Prof. Sebastian Leptihn’s Research Group (http://leptihn-lab.org/) includes Dr. Belinda Loh (Post-doc) and Dr. Prasanth Manohar (Post-doc), the two lead-authors on the articles.

Recently, Prof. Wenwen Huang has been awarded a ZJU-Cornell Joint Seed Fund to design and synthesize multi-stimuli responsive biomaterials. The funding is provided by Zhejiang University and Cornell China Center to support world-class research, education, collaboration and entrepreneurship across diverse communities in ZJU and Cornell.  About this joint project:China is grappling with demographic shifts due to the global trend of rapid aging that exacerbates the burden of noncommunicable diseases and causes an urgent need to improve preventions and treatments. To address this, we are developing soft, adaptive, and responsive biomaterials using elastin: a major structural protein with high water content, tunable viscoelasticity, and biocompatibility. Using recombinant DNA technology, mechanically weak elastin can be fused with strong silk to adjust the mechanical properties of the dynamic elastin system, dubbed silk-elastin- like proteins (SELPs). We will design and synthesize reconfigurable, self-assembled SELP hydrogels with controllable properties to perform highly specific, pre-programmed functions. We will tightly integrate computational modelling and synthetic biology to design hydrogels that respond to combinatorial changes in temperature, pH, light, and electromagnetic fields. We embed computational modelling into the early stages of material synthesis to achieve time- and cost- efficiencies in generating specific targeted functions from molecular building blocks.Figure. The amino acid sequence in silk-elastin-like proteins can be specifically tailored to imbue the resulting hydrogel with a broad range of stimuli-response About ZJE/Cornell labs:Huang lab (ZJE, China) has extensive knowledge and expertise in the development and integration of de novo designed protein biomaterials with high throughput screening and regenerative medicine. Her lab focuses on the synthesis of tailored proteins with tunable functional properties using recombinant DNA technology and the translation of protein biomaterials for tissue engineering and controlled release systems.Yeo’s lab (Cornell, USA) deploy bio-inspired, bottom-up, computational approaches to rationally design next-generation biomaterials and precisely obtain the desired properties and functions. His lab harness polymeric design principles developed by Nature and combine multiscale modeling with high throughput simulations to rapidly test and validate the properties of these materials for implementation. E-mail: wenwenhuang@intl.zju.edu.cn; jingjieyeo@cornell.eduWebsite: https://person.zju.edu.cn/wenwenhuang; https://www.mae.cornell.edu/faculty-directory/jingjie-yeo