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

On June 23, 2020, Prof. Wenwen Huang’s lab published their collaborative research on bioinspired actuators in Proceedings of the National Academy of Sciences of the United States of America (PNAS). This research provides a novel approach to build smart biocompatible actuators for in vivo biomedical soft robotics and bionic devices.Figure. Schematic of the fabrication of thermo-responsive and ionic strength responsive SELP/CNF actuators.About this research article:‘Smart’ stimuli-responsive materials, which are sensitive to environmental triggers or biological signals, are appealing platforms for the development of biomedical devices. However, most smart materials are synthetic polymers that are not biocompatible and biodegradable, limiting their use in vivo. In this study, the researchers at ZJE and Tufts designed and built a new class of bionic actuator entirely out of biocompatible and biodegradable materials, using genetically engineered silk–elastin-like proteins (SELPs) and cellulose nanofibers (CNFs). Programmable and reversible deformations in response to the stimuli have been achieved with the SELP/CNF actuator. This novel bioinspired actuator can provide an avenue to customized responsiveness toward applications for in vivo biomedical devices.  Movie. The transformation process of the SELP/CNF actuators over time in 1M NaCl solutions at room temperature.Link of this article: https://www.pnas.org/content/117/25/14602About Huang Lab:Huang lab focuses on predictive design, synthesis and functionalization of protein-based biomaterials for regenerative medicine and sustainable technology innovations. The ultimate goal of the lab is to advance the basic research in biomedical science, promote sustainable technologies, and translate biomaterials to the clinic.E-mail: wenwenhuang@intl.zju.edu.cnHome page of Prof. Wenwen Huang: https://person.zju.edu.cn/en/wenwenhuang

On April 7, 2020, Prof. Zhi Hong’s lab from the Joint College of Edinburgh University and Zhejiang University together with Cong Yi’s lab from the Basic Medical College of Zhejiang University published a research article on Frontiers in Cell and Developmental Biology，titled "Mitochondrial Fusion Machinery Specifically Involved in Energy Deprivation-Induced Autophagy". This research expounded the relationship between mitochondrial morphology and energy deprivation-induced autophagy.  Main idea:Autophagy is a process in which cells degrade intracellular substances for reuse when facing internal and external environmental changes. Autophagy can be classified into non-selective autophagy and selective autophagy according to different degradation substrates. Non-selective autophagy, commonly known as macroautophagy or autophagy, has no selectivity for degradation substrates. Selective autophagy relies on the interaction between specific autophagy receptors with LC3 / Atg8 to degrade damaged organelles. Numerous studies have shown that autophagy plays an important role in maintenance of cellular homeostasis and development of biological organisms. Dysfunctional autophagy contributes to various human diseases such as neurodegenerative diseases, typeⅡdiabetes, fatty liver, cancer etc.Mitochondria, as the center of cell metabolism and signal transduction networks, regulate ATP synthesis, intracellular calcium homeostasis, oxidative phosphorylation and cellular apoptosis, and are one of the most important organelles for maintaining normal physiological functions of cells. Mitochondria vary in different cells and show dynamic changes. The dynamic balance of fusion and division affects the distribution and morphology of mitochondria, which in turn determines their physiological functions. Mitochondria form a dynamic network that is mainly regulated by mitochondrial fusion, fission, and tubulation machinery, which play an important role in maintaining the integrity of mitochondrial genetic material and DNA in living organisms. Mitochondrial damage will rapidly initiate mitophagy, but the link between mitochondrial morphology and non-selective autophagy remains poorly understood.Drawn by Yuling Qin (PhD student in Prof. Zhi Hong’s lab)In this study, they found that the mitochondria fusion machinery Ugo1, Fzo1, etc. regulate the interaction between Snf1 (AMPK homolog in yeast cells) and Mec1 (ATR homolog in yeast) by participating in aerobic respiration in an energy-deficient state. Depletion of Ugo1, Fzo1, etc. leads to a decrease in Snf1 activity and Mec1 phosphorylation level, which fails to recruit Atg1/ULK1 and other autophagic proteins to the pre-autophagosomal structure (PAS), therefore inhibits the occurrence of energy-deficient induced autophagy. Interestingly, the molecular machineries responsible for mitochondrial fission and tubulation are not involved in energy deprivation-induced autophagy.Associate professor Choufei Wu and assistant researcher Weijing Yao are the co-first authors of this article. Researcher Cong Yi (left) and researcher Zhi Hong (right) are the co-corresponding authors of this article.This research was supported by the National Natural Science Foundation of China and National Key R&D Program of China.Lab info:Zhi Hong’s research team has been focusing on spatiotemporal regulation of vesicle transport, organelle crosstalk network and cell homeostasis maintenance, and is keen to solve biological problems by using different disciplines. If you are also interested in freely exploring and risk taking, welcome to join us! E-mail: zhihong@intl.zju.edu.cnHome page of Prof. Zhi Hong: https://person.zju.edu.cn/hongzhi

The innate immune system is the body's first line of defense against viruses. The tripartite motif containing 25 (TRIM25) is an E3 ubiquitin ligase thought to be a key component in the activation of innate immune response.TRIM25 has recently been identified as an RNA-binding protein, raising the question of whether its RNA-binding activity is important for its role in innate immunity. Here, we review TRIM25's mechanisms and pathways in non-infected and infected cells.  This protein represents a large group of proteins with newly identified RNA-binding potential and can serve as an exemplar towards critical evaluation of protein functions in biological systems.Original publicationNila Roy Choudhury, Gregory Heikel and Gracjan Michlewski. WIREs RNA. 2020;e1588https://doi.org/10.1002/wrna.1588TRIM25 and its emerging RNA‐binding roles in antiviral defenseE3 ubiquitin ligase TRIM25 is newly identified RNA‐binding protein which is emerging as a key factor in the innate immune response to RNA viruses.doi.orgFigure. E3 ubiquitin ligase TRIM25 is newly identified RNA‐binding protein which is emerging as a key factor in the innate immune response to RNA viruses.

Recently, one review paper “Current advances in microsphere based cell culture and tissue engineering” published in Biotechnology Advances (IF=11.452). Prof. Hongwei Ouyang is corresponding author of the paper. Co-first authors are Doctoral candidate Qiulin He (Zhejiang University-University of Edinburgh Institute) and Dr. Jingwei Zhang (Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine).Cell-based regenerative therapy has a great prospect in tissue repair. There are many clinical trials and preclinical animal experiments reported cell therapy for complex diseases. Effective cell culture and delivery is a necessary requirement to achieve the clinical applications of cell therapy. Recently, microsphere (MS) based system has attracted and more attention in cell culture and tissue repair (Figure 1A, B). MSs can not only serve as supportive carriers for cell culture, providing different chemical and physical environment for cell growth, but also be excellent delivery carriers for cell therapy in vivo, realizing non-invasive injectable therapy, alleviating the pain of patients, and improving the treatment effect. The main advantages of MSs are: (a) Simple method for large-scale fabrication, which is easy to realize; (b) Uniform and regular porous structure can be formed between MSs; (c) The specific surface area is large, and the size is varied and controllable; (d) MSs are able to control the release of drugs and biomolecules.Figure 1. (A) Number of papers of “microsphere AND (tissue engineering)” from 1980 to 2018; (B) Citation frequency of papers about “((microsphere) AND tissue engineering)” from 2000 to 2018; (C) Schematic illustrating topics covered in this review.In this review, MS system has been divided into two categories：(a) Cells cultured on the surface of MSs (cell-on system); and (b) Cells encapsulated in MSs (cell-in system) (Figure 1C). Firstly, in the cell-on system, often used for cell expansion, the final yield depends on cell adhesion ratio, proliferation rate and harvest rate; “low input and high output” should be a criterion for effective cell expansion in vitro. This review summarized three main factors for cell adhesion and proliferation in the cell-on system: chemical property, physical property and surface modification of MSs, as well as three methods for cell detachment: enzymatic treatment, non-enzymatic degradation and temperature-responsive detachment. Secondly, in cell-in system, used to protect encapsulated cells and control cell distribution after in vivo transplantation, is prudent to consider the influential factors so that cells can be supported in high cell viability and proliferation. Factors such as procedures of MS fabrication and architectures of MSs have been introduced in detail. Thirdly, in MS system, stem cells can differentiate into different mature cells, including chondrocytes, osteocytes, adipocytes, neurocytes. Both inherent properties of MSs and biomolecules released from MSs can regulate cell differentiation. At last, cell-loaded MSs provide a revolutionized approach to cell delivery in vivo, in addition to being biomolecule delivery systems, they have the characteristic of being injectableand the capacity to improve cell efficiency. On the one hand, cell-loaded MSs with a specific function serve as small building blocks (microtissues) to be assembled into macroscopic tissues (macrotissues) through a bottom-up approach. On the other hand, MSs can serve as a part of bulk scaffolds to improve biological functions of scaffolds. This review summarized researches about applications of MSs in cell culture and tissue engineering, which provides guidance and reference for future development.Link of the paper: https://www.sciencedirect.com/science/article/pii/S0734975019301594?from=groupmessage&via%3Dihub=   

Dr Gracjan Michlewski has been awarded a grant worth £510,000 to investigate the role of novel RNA-binding protein TRIM25 in viral nucleic acids sensing and signalling.Dr Gracjan Michlewski of Infection Medicine is leading a £510k project, funded by the UK Government’s Biotechnology and Biological Sciences Research Council, which aims to investigate the role of novel RNA-binding protein TRIM25 in viral nucleic acids sensing and signalling.Investigating the role of novel RNA-binding protein TRIM25 in viral nucleic acids sensing and signallingE3 ubiquitin ligase TRIM25 is emerging as a key factor in the innate immune response to RNA viruses, including influenza A virus (IAV), HIV, SARS, dengue virus and many others. We have recently discovered that TRIM25 possesses RNA-binding activity. Despite the essential involvement of TRIM25 in viral RNA-induced innate immune pathways, its RNA-binding functions are still poorly understood. In this project we will study the role of RNA-binding activity of TRIM25 in innate immune pathways in the context of IAV infections.The importance of the projectRNA viruses are an important class of pathogen that continue to cause devastating epidemics in the 21st century. Taking IAV as an exemplar, it threatens periodic pandemics, kills 250,000 to 500,000 people annually even in epidemic phases, generating a significant socioeconomic burden. The impact of IAV infections on livestock animals is equally tremendous. During a 2005 bird flu outbreak the total economic losses in South East Asia alone were calculated at around $10 billion. However, we still do not know all of the molecular mechanisms of key host proteins that sense and restrict human and animal IAV infections.

ZJE Associate Professor Gracjan Michlewski publishes a great paper in Nature CommunicationsTitle – Loss of 5-methylcytosine alters the biogenesis of Vault-derived small RNAs to coordinate epidermal differentiation.Journal – Nature CommunicationsThe presence and absence of RNA modifications regulates RNA metabolism which contributes to cellular and organismal development and function. Here, we decipher the consequences of 5-methylcytosine (m5C) deposition by NOP2/Sun RNA Methyltransferase 2 (NSUN2) into the abundant non-coding vault RNA VTRNA1.1. We identify the serine/arginine rich splicing factor 2 (SRSF2) as a novel VTRNA1.1-binding protein. Finally, we demonstrate a functional relationship between SRSF2, m5C and VTRNA1.1 processing into small vault RNA (svRNA) in regulating the epidermal differentiation programme.This study is important as m5C modification in RNA is very common. However, it is largely unknown what are the functional consequences in terms of molecular mechanisms as well as cellular and organismal functions of this RNA modification.URL for paper (if available)https://www.nature.com/articles/s41467-019-10020-7Please attach any striking images associated with the study Summary of VTRNA1.1 processing into svRNA4. A) Expression of both NSUN2 and SRSF2 (e.g. in progenitor cells) result in high levels of VTRNA1.1 methylation (CH3 – m5C) and high levels of svRNA4 and repressed differentiation. B) No NSUN2 in the presence of SRSF2 suppresses formation of svRNA4 and allows differentiation. C) Lack of expression of both NSUN2 and SRSF2 release VTRNA1.1 from SRSF2 binding and increases the levels of svRNA4. 

Dean of ZJE, Professor of Zhejiang University Hongwei Ouyang lead his lab in publishing two papers in High Level International Academic Journals: Nature Communications and The American Journal of Sports Medicine.The first paper is entitled “A strongly adhesive haemostatic hydrogel for the repair of arterial and heart bleeds” published in Nature Communications.The hydrogel can stop high pressure bleeding from pig carotid arteries with 4~5 mm long incision wounds and from pig hearts with 6 mm diameter cardiac penetration holes within 30 seconds. While clinically used Fibrin Glue and SurgifloTM failed to stop such bleeding. Treated pigs survived carotid artery and heart bleeding after hemostatic treatments with this hydrogel, which is well-tolerated and appears to offer significant clinical advantage as a traumatic wound sealant.Uncontrollable bleeding is a major problem in surgical procedures and after major trauma. Existing hemostatic agents poorly control  haemorrhaging from traumatic arterial and cardiac wounds because of their weak adhesion to wet and mobile tissues.The paper is available at the link belowhttps://www.nature.com/articles/s41467-019-10004-7  The second paper published by the lab is  “Single-Cell Profiles and Clinically Useful Properties of Human Mesenchymal Stem Cells of Adipose and Bone Marrow Origin” in the The American Journal of Sports Medicine.Single-cell RNA sequencing analysis showed that the population of ADSCs showed lower transcriptomic heterogeneity when compared with BMSCs. Additionally, as compared with BMSCs, ADSCs were less dependent on mitochondrial respiration for energy production and had a lower expression level of human leukocyte antigen class I antigen as well as higher immunosuppression capacity. Meta-analysis of current clinical trials of osteoarthritis treatment with MSCs consistently showed that ADSCs are more stable than BMSCs in their therapeutic effect.These results provide basic biological insights into human ADSCs and BMSCs at the single-cell resolution. Findings indicated that ADSCs may be a more controllable stem cell source, may be more adaptable to surviving in the hypoxic articular cavity niche, and may exhibit superiority in regulating inflammation.This paper is available to read at the link belowhttps://journals.sagepub.com/doi/abs/10.1177/0363546519848678    

Associate Professor Gracjan Michlewski publishes a collaborative paper in Molecular Cell on the dynamics and roles of RNA-bound proteome during viral infections.An international group of researchers led by University of Oxford developed ‘comparative RNA-interactome capture’ to analyse the RNA-bound proteome during virus infection. >200 cellular RNA-binding proteins change their binding activity in response to this challenge, mainly driven by transcript availability. Many of these RNA-binding proteins regulate viral replication and can be targeted to influence infection outcome.SummaryThe compendium of RNA-binding proteins (RBPs) has been greatly expanded by the development of RNA-interactome capture (RIC). However, it remained unknown if the complement of RBPs changes in response to environmental perturbations and whether these rearrangements are important. To answer these questions, we developed “comparative RIC” and applied it to cells challenged with an RNA virus called sindbis (SINV). Over 200 RBPs display differential interaction with RNA upon SINV infection. These alterations are mainly driven by the loss of cellular mRNAs and the emergence of viral RNA. RBPs stimulated by the infection redistribute to viral replication factories and regulate the capacity of the virus to infect. For example, ablation of XRN1 causes cells to be refractory to SINV, while GEMIN5 moonlights as a regulator of SINV gene expression. In summary, RNA availability controls RBP localization and function in SINV-infected cells. Original publicationGarcia-Moreno et al., System-wide Profiling of RNA-Binding Proteins Uncovers Key Regulators of Virus Infection. Molecular Cell 74, 1–16 April 4, 2019You can access the full paper here:https://www.cell.com/molecular-cell/fulltext/S1097-2765(19)30037-1

Reprint from Official Wechat of School of Basic Medical Sciences, Zhejiang UniversityOn Dec.29，the Proceedings of the National Academy of Sciences (PNAS) published online the latest research result from Professor Linrong Lu’s group "Phosphatase PP2A is essential for TH17 differentiation". The study revealed the essential role of phosphatase PP2A in regulating TH17 cell differentiation and the development of related autoimmune diseases.Clinical analysis showed that the expression level of phosphatase PP2A was positively correlated with the severity of disease and IL17A expression in patients with systemic lupus erythematosus, suggesting the involvement of PP2A in the regulation of TH17 differentiation and related inflammatory responses. By using a gene knockout that leads to T cell-specific deletion, Prof. Lu and his colleagues revealed the essential role of Ser/Thr phosphatase PP2A in TH17 differentiation. They also showed that this works through the regulation of SMAD2/3 phosphorylation status, which elucidates molecular pathways by which PP2A modulates the expression of TH17 phenotypes. This finding extends our understanding of the close relationship between PP2A overexpression and inflammatory disease. PP2A is a Ser/Thr phosphatase shown to be capable of controlling TH17 differentiation via modulating R-SMADs activity. This work also demonstrated the translational potential of these findings by showing a therapeutic effect of PP2A inhibitors in controlling autoimmune disease in the encephalomyelitis model.Ph.D. students Qin Xu and Xuexiao Jin from the Institute of Immunology are the first authors of this study. Other co-authors include Zheng Mingzhu, Deepak Rohila, Fu Guotong, Wen Zhuoyu, and Qi Jun. This is a collaborative research with Professor Wu Songquan from Lishui Medical College, Professor Richard Sloan from Zhejiang University-Edinburgh University, Professor Lie Wang from the Institute of Immunology,Professor Hu Hu from the Department of Pathology and Pathophysiology and Professor Xiang Gao from the Model anima research center in Nanjing University. The corresponding authors of this article is Professor Linrong Lu and Professor Xiang Gao. This study was supported by the National Natural Science Foundation.Figure1: PP2A promotes TH17 cell differentiation through differential regulation of SMAD2 and SMAD3 Phosphorylation ( Adapted from Gustavo J. Martinez, JEM 2017）. Link of the paper：https://www.pnas.org/content/early/2018/12/27/1807484116Lab link：https://person.zju.edu.cn/llr