Showing papers in "Science China-life Sciences in 2020"

Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission

Abstract: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China; Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China; National Engineering Research Center for the Emergence Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; The Joint Program in Infection and Immunity: a. Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China; b. Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.

Abstract: The outbreak of the 2019-nCoV infection began in December 2019 in Wuhan, Hubei province, and rapidly spread to many provinces in China as well as other countries. Here we report the epidemiological, clinical, laboratory, and radiological characteristics, as well as potential biomarkers for predicting disease severity in 2019-nCoV-infected patients in Shenzhen, China. All 12 cases of the 2019-nCoV-infected patients developed pneumonia and half of them developed acute respiratory distress syndrome (ARDS). The most common laboratory abnormalities were hypoalbuminemia, lymphopenia, decreased percentage of lymphocytes (LYM) and neutrophils (NEU), elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased CD8 count. The viral load of 2019-nCoV detected from patient respiratory tracts was positively linked to lung disease severity. ALB, LYM, LYM (%), LDH, NEU (%), and CRP were highly correlated to the acute lung injury. Age, viral load, lung injury score, and blood biochemistry indexes, albumin (ALB), CRP, LDH, LYM (%), LYM, and NEU (%), may be predictors of disease severity. Moreover, the Angiotensin II level in the plasma sample from 2019-nCoV infected patients was markedly elevated and linearly associated to viral load and lung injury. Our results suggest a number of potential diagnosis biomarkers and angiotensin receptor blocker (ARB) drugs for potential repurposing treatment of 2019-nCoV infection.

Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China.

Abstract: Previous studies have showed clinical characteristics of patients with the 2019 novel coronavirus disease (COVID-19) and the evidence of person-to-person transmission. Limited data are available for asymptomatic infections. This study aims to present the clinical characteristics of 24 cases with asymptomatic infection screened from close contacts and to show the transmission potential of asymptomatic COVID-19 virus carriers. Epidemiological investigations were conducted among all close contacts of COVID-19 patients (or suspected patients) in Nanjing, Jiangsu Province, China, from Jan 28 to Feb 9, 2020, both in clinic and in community. Asymptomatic carriers were laboratory-confirmed positive for the COVID-19 virus by testing the nucleic acid of the pharyngeal swab samples. Their clinical records, laboratory assessments, and chest CT scans were reviewed. As a result, none of the 24 asymptomatic cases presented any obvious symptoms while nucleic acid screening. Five cases (20.8%) developed symptoms (fever, cough, fatigue, etc.) during hospitalization. Twelve (50.0%) cases showed typical CT images of ground-glass chest and 5 (20.8%) presented stripe shadowing in the lungs. The remaining 7 (29.2%) cases showed normal CT image and had no symptoms during hospitalization. These 7 cases were younger (median age: 14.0 years; P=0.012) than the rest. None of the 24 cases developed severe COVID-19 pneumonia or died. The median communicable period, defined as the interval from the first day of positive nucleic acid tests to the first day of continuous negative tests, was 9.5 days (up to 21 days among the 24 asymptomatic cases). Through epidemiological investigation, we observed a typical asymptomatic transmission to the cohabiting family members, which even caused severe COVID-19 pneumonia. Overall, the asymptomatic carriers identified from close contacts were prone to be mildly ill during hospitalization. However, the communicable period could be up to three weeks and the communicated patients could develop severe illness. These results highlighted the importance of close contact tracing and longitudinally surveillance via virus nucleic acid tests. Further isolation recommendation and continuous nucleic acid tests may also be recommended to the patients discharged.

Plant abiotic stress response and nutrient use efficiency.

Abstract: Abiotic stresses and soil nutrient limitations are major environmental conditions that reduce plant growth, productivity and quality. Plants have evolved mechanisms to perceive these environmental challenges, transmit the stress signals within cells as well as between cells and tissues, and make appropriate adjustments in their growth and development in order to survive and reproduce. In recent years, significant progress has been made on many fronts of the stress signaling research, particularly in understanding the downstream signaling events that culminate at the activation of stress- and nutrient limitation-responsive genes, cellular ion homeostasis, and growth adjustment. However, the revelation of the early events of stress signaling, particularly the identification of primary stress sensors, still lags behind. In this review, we summarize recent work on the genetic and molecular mechanisms of plant abiotic stress and nutrient limitation sensing and signaling and discuss new directions for future studies.

siRNA therapeutics: a clinical reality.

Abstract: Since the revolutionary discovery of RNA interference (RNAi), a remarkable progress has been achieved in understanding and harnessing gene silencing mechanism; especially in small interfering RNA (siRNA) therapeutics. Despite its tremendous potential benefits, major challenges in most siRNA therapeutics remains unchanged—safe, efficient and target oriented delivery of siRNA. Twenty years after the discovery of RNAi, siRNA therapeutics finally charts its way into clinics. As we journey through the decades, we reminisce the history of siRNA discovery and its application in a myriad of disease treatments. Herein, we highlight the breakthroughs in siRNA therapeutics, with special feature on the first FDA approved RNAi therapeutics Onpattro (Patisiran) and the consideration of effective siRNA delivery system focusing on current siRNA nanocarrier in clinical trials. Lastly, we present some challenges and multiple barriers that are yet to be fully overcome in siRNA therapeutics.

A seven-gene-deleted African swine fever virus is safe and effective as a live attenuated vaccine in pigs.

Abstract: African swine fever (ASF) is a devastating infectious disease in swine that is severely threatening the global pig industry. An efficacious vaccine is urgently required. Here, we used the Chinese ASFV HLJ/18 as a backbone and generated a series of gene-deleted viruses. The virulence, immunogenicity, safety, and protective efficacy evaluation in specific-pathogen-free pigs, commercial pigs, and pregnant sows indicated that one virus, namely HLJ/18-7GD, which has seven genes deleted, is fully attenuated in pigs, cannot convert to the virulent strain, and provides complete protection of pigs against lethal ASFV challenge. Our study shows that HLJ/-18-7GD is a safe and effective vaccine against ASFV, and as such is expected to play an important role in controlling the spread of ASFV.

Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19.

Abstract: Coronavirus disease 2019 (COVID-19) is a pandemic with no specific drugs and high fatality. The most urgent need is to find effective treatments. We sought to determine whether hydroxychloroquine (HCQ) application may reduce the death risk of critically ill COVID-19 patients. In this retrospective study, we included 550 critically ill COVID-19 patients who need mechanical ventilation in Tongji Hospital, Wuhan, from February 1, 2020 to April 4, 2020. All 550 patients received comparable basic treatments including antiviral drugs and antibiotics, and 48 of them were treated with oral HCQ treatment (200 mg twice a day for 7-10 days) in addition to the basic treatments. Primary endpoint is fatality of patients, and inflammatory cytokine levels were compared between HCQ and non-hydroxychloroquine (NHCQ) treatments. We found that fatalities are 18.8% (9/48) in HCQ group, which is significantly lower than 47.4% (238/502) in the NHCQ group (P<0.001). The time of hospital stay before patient death is 15 (10-21) days and 8 (4-14) days for the HCQ and NHCQ groups, respectively (P<0.05). The levels of inflammatory cytokine IL-6 were significantly reduced from 22.2 (8.3-118.9) pg mL-1 at the beginning of the treatment to 5.2 (3.0-23.4) pg mL-1 (P<0.05) at the end of the treatment in the HCQ group but there is no change in the NHCQ group. These data demonstrate that addition of HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm. Therefore, HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients, with possible outcome of saving lives. hydroxychloroquine, IL-6, mortalities, COVID-19.

Liquid-liquid phase separation in biology: mechanisms, physiological functions and human diseases.

Abstract: Cells are compartmentalized by numerous membrane-enclosed organelles and membraneless compartments to ensure that a wide variety of cellular activities occur in a spatially and temporally controlled manner. The molecular mechanisms underlying the dynamics of membrane-bound organelles, such as their fusion and fission, vesicle-mediated trafficking and membrane contactmediated inter-organelle interactions, have been extensively characterized. However, the molecular details of the assembly and functions of membraneless compartments remain elusive. Mounting evidence has emerged recently that a large number of membraneless compartments, collectively called biomacromolecular condensates, are assembled via liquid-liquid phase separation (LLPS). Phase-separated condensates participate in various biological activities, including higher-order chromatin organization, gene expression, triage of misfolded or unwanted proteins for autophagic degradation, assembly of signaling clusters and actin- and microtubule-based cytoskeletal networks, asymmetric segregations of cell fate determinants and formation of pre- and post-synaptic density signaling assemblies. Biomacromolecular condensates can transition into different material states such as gel-like structures and solid aggregates. The material properties of condensates are crucial for fulfilment of their distinct functions, such as biochemical reaction centers, signaling hubs and supporting architectures. Cells have evolved multiple mechanisms to ensure that biomacromolecular condensates are assembled and disassembled in a tightly controlled manner. Aberrant phase separation and transition are causatively associated with a variety of human diseases such as neurodegenerative diseases and cancers. This review summarizes recent major progress in elucidating the roles of LLPS in various biological pathways and diseases.

Co-infections of SARS-CoV-2 with multiple common respiratory pathogens in infected patients.

Abstract: Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Department of Pathology Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China; National Clinical Research Center for Infectious Diseases, Guangdong Key Lab for Diagnosis & Treatment of Emerging Infectious Diseases, Shenzhen Third People’s Hospital, Southern University of Science and Technology, Shenzhen 518112, China; Department of Clinical Laboratory, Shenzhen Baoan Hospital, The Second Affiliated Hospital of Shenzhen University, Shenzhen 518071, China

Decreased serum albumin level indicates poor prognosis of COVID-19 patients: hepatic injury analysis from 2,623 hospitalized cases.

Abstract: Coronavirus disease 2019 (COVID-19) is a global pandemic which has caused numerous deaths worldwide The present study investigated the roles of hypoproteinemia in the clinical outcome and liver dysfunction of COVID-19 patients In this retrospective study, we extracted data from 2,623 clinically confirmed adult COVID-19 patients (>18 years old) between January 29, 2020 and March 6, 2020 in Tongji Hospital, Wuhan, China The patients were divided into three groups-non-critically ill, critically ill, and death groups-in accordance with the Chinese Clinical Guideline for COVID-19 Serum albumin, low-density lipoproteins cholesterol (LDL-C), and high-density lipoproteins cholesterol (HDL-C) concentrations and inflammatory cytokines levels were measured and compared among these three groups The median age of these 2,623 patients was 64 years old (interquartile range (IQR), 52-71) Among the patients enrolled in the study, 2,008 (766%) were diagnosed as non-critically ill and 615 (234%) were critically ill patients, including 383 (146%) critically ill survivors and 232 (88%) critically ill deaths in the hospital Marked hypoalbuminemia occurred in 382%, 712%, and 824% patients in non-critically ill, critically ill, and death groups, respectively, on admission and 459%, 777%, and 956% of these three groups, respectively, during hospitalization We also discovered that serum low-density lipoprotein (LDL) and HDL levels were significantly lower in critically ill and death groups compared to non-critically ill group Meanwhile, the patients displayed dramatically elevated levels of serum inflammatory factors, while a markedly prolonged activated partial thromboplastin time (APTT) in critically ill patients reflected coagulopathy This study suggests that COVID-19-induced cytokine storm causes hepatotoxicity and subsequently critical hypoalbuminemia, which are associated with exacerbation of disease-associated inflammatory responses and progression of the disease and ultimately leads to death for some critically ill patients

Bat origin of a new human coronavirus: there and back again.

Abstract: A novel coronavirus reported to cause pneumonia in 41 people during December 2019 in Wuhan, the capital of Hubei province, China, was identified and designated as the 2019 novel coronavirus (2019-nCoV) (Zhu et al., 2020; Li et al., 2020). Infection with 2019-nCoV results in clusters of severe respiratory illness similar to that caused by severe acute respiratory syndrome coronavirus (SARS-CoV) and is associated with high mortality (Chen et al., 2020; Huang et al., 2020). This new coronavirus belongs to genus Betacoronavirus, family Coronaviridae, with a single-stranded, positive-sense RNA genome, but genetically distinct from SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Up to February 4th, 2020, at least 20,630 cases have been confirmed in China and another 23 countries, with 426 deaths (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/). After epidemiological investigation, it was revealed that a local seafood market, where wild animals and live poultry were for sale, was linked to this undiagnosed pneumonia (Wu et al., 2020). Wu et al. collected bronchoalveolar lavage fluid from a patient who worked in the seafood market and performed full genome sequencing of 2019-nCoV. It was shown that 2019-nCoV had a high nucleotide sequence similarity to a bat SARS-related CoV (bat-SL-CoVZC45, accession No. MG772933) and only 79.5% genome sequence similarity to SARS-CoV. Phylogenetic analysis showed that the virus was clustered with SARS-CoV and bat SARSr-CoVs in subgenus Sarbecovirus (Wu et al., 2020; Wei et al., 2020; Yu et al., 2019; Xu et al., 2020). Genomic analysis of 2019-nCoV and four typical coronaviruses (bat SARSr-CoV-Rp3, CoV-ZC45, CoV-ZXC21, and SARS-CoV-Tor2) showed a likelihood of recombination between 2019-nCoV and other coronaviruses among the subgenus (Wu et al., 2020). So how did this novel coronavirus emerge? To investigate the origin of 2019-nCoV, Zhou et al. sequenced samples from seven patients and bats, and found that this new coronavirus shared 96.2% overall genome sequence identity with a bat coronavirus RaTG13 from horseshoe bats (Rhinolophus) (Table 1). This discovery provided further evidence that 2019-nCoV most likely originated from bats (Zhou et al., 2020). Previously, horseshoe bats were identified as natural hosts for SARS-related coronaviruses which were the direct progenitors for the origin of SARS-CoV (Hu et al., 2017). Although some amino acid residues were different in the receptor binding domain (RBD) of 2019-nCoV compared to SARS-CoV, it seems that the structure of the RBD still allowed for the use of ACE2 (angiotensin-converting enzyme 2) as an entry receptor. It was suggested that humans were infected with the virus directly from intermediate (none-bats) hosts via contact (Zhou et al., 2020). Certainly, more field work may be needed to find the inter-

SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells.

Abstract: State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan 430071, China; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology & Wuhan Jinyintan Hospital, CAS, Wuhan 430023, China; The University of Chinese Academy of Sciences, Beijing 100049, China; Center for Translational Medicine, Wuhan Jinyintan Hospital, Wuhan 430040, China; Center for Precision Translational Medicine of Wuhan Institute of Virology and Guangzhou Women and Children’s Medical Center, Guangzhou Women and Children’s Medical Center, Guangzhou 510120, China; Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China

Nanozymes: created by learning from nature

Abstract: Nanozymes, a type of nanomaterials with enzyme-like activity, have shown great potential to replace natural enzymes in many fields such as biochemical detection, environmental management and disease treatment. However, the catalytic efficiency and substrate specificity of nanozymes still need improvement. To further optimize the enzymatic properties of nanozymes, recent studies have introduced the structural characteristics of natural enzymes into the rational design of nanozymes, either by employing small molecules to mimic the cofactors of natural enzymes to boost nanozymes’ catalytic potential, or by simulating the active center of natural enzymes to construct the nanostructure of nanozymes. This review introduces the commonly used bio-inspired strategies to create nanozymes, aiming at clarifying the current progress and bottlenecks. Advances and challenges focusing on the research of bio-inspired nanozymes are outlined to provide ideas for the de novo design of ideal nanozymes.

Detection of serum IgM and IgG for COVID-19 diagnosis.

Abstract: Detection of serum IgM and IgG for COVID-19 diagnosis Ling Zhong, Junlan Chuan, Bo Gong, Ping Shuai, Yu Zhou, Yi Zhang, Zhilin Jiang, Dingding Zhang, Xiaoqi Liu, Shi Ma, Yi Huang, He Lin, Qingwei Wang, Lulin Huang, Dan Jiang, Fang Hao, Juan Tang, Chunqi Zheng, Hua Yu, Zhibin Wang, Qi Jiang, Tao Zeng, Mei Luo, Fanwei Zeng, Fanxin Zeng, Jianghai Liu, Junxi Tian, Yu Xu, Tengxiang Long, Kaiju Xu, Xingxiang Yang, Yuping Liu, Yi Shi, Li Jiang & Zhenglin Yang

Single-cell transcriptome analysis of the novel coronavirus (SARS-CoV-2) associated gene ACE2 expression in normal and non-obstructive azoospermia (NOA) human male testes.

Abstract: Being infected by SARS-CoV-2 may cause damage to multiple organs in patients, such as the lung, liver and heart. Angiotensin-converting enzyme 2 (ACE2), reported as a SARS-CoV-2 receptor, is also expressed in human male testes. This suggests a potential risk in human male reproductive system. However, the characteristics of ACE2-positive cells and the expression of other SARS-CoV-2 process-related genes are still worthy of further investigation. Here, we performed singlecell RNA seq (scRNA-seq) analysis on 853 male embryo primordial germ cells (PGCs) and 2,854 normal testis cells to assess the effects of the SARS-CoV-2 virus on the male reproductive system from embryonic stage to adulthood. We also collected and constructed the scRNA-seq library on 228 Sertoli cells from three non-obstructive azoospermia (NOA) patients to assess the effects at disease state. We found that ACE2 expressing cells existed in almost all testis cell types and Sertoli cells had highest expression level and positive cells ratio. Moreover, ACE2 was also expressed in human male PGCs. In adulthood, the level of ACE2 expression decreased with the increase of age. We also found that ACE2 positive cells had high expressions of stress response and immune activation-related genes. Interestingly, some potential SARS-CoV-2 process-related genes such as TMPRSS2, BSG, CTSL and CTSB had different expression patterns in the same cell type. Furthermore, ACE2 expression level in NOA donors' Sertoli cells was significantly decreased. Our work would help to assess the risk of SARS-CoV-2 infection in the male reproductive system.

Identification of mecciRNAs and their roles in the mitochondrial entry of proteins.

Abstract: Mammalian mitochondria have small genomes encoding very limited numbers of proteins. Over one thousand proteins and noncoding RNAs encoded by the nuclear genome must be imported from the cytosol into the mitochondria. Here, we report the identification of hundreds of circular RNAs (mecciRNAs) encoded by the mitochondrial genome. We provide both in vitro and in vivo evidence to show that mecciRNAs facilitate the mitochondrial entry of nuclear-encoded proteins by serving as molecular chaperones in the folding of imported proteins. Known components involved in mitochondrial protein and RNA importation, such as TOM40 and PNPASE, interact with mecciRNAs and regulate protein entry. The expression of mecciRNAs is regulated, and these transcripts are critical for the adaption of mitochondria to physiological conditions and diseases such as stresses and cancers by modulating mitochondrial protein importation. mecciRNAs and their associated physiological roles add categories and functions to the known eukaryotic circular RNAs and shed novel light on the communication between mitochondria and the nucleus.

Temporal regulation of prenatal embryonic development by paternal imprinted loci

Abstract: Paternal imprinted genes (H19 and Gtl2) are pivotal for prenatal embryonic development in mice. Nongrowing oocytes and sperm- or oocyte-originated haploid embryonic stem cells (haESCs) carrying both H19-DMR (differentially DNA-methylated region) and IG (intergenic)-DMR deletions that partially mimic paternal imprinting of H19-Igf2 and Dlk1-Dio3 can be employed as sperm replacement to efficiently support full-term embryonic development. However, how H19-DMR and IG-DMR act together to regulate embryonic development is still largely unknown. Here, using androgenetic haESC (AG-haESC)-mediated semi-cloned (SC) technology, we showed that paternal H19-DMR and IG-DMR are not essential for pre-implantation development of SC embryos generated through injection of AG-haESCs into oocytes. H19-DMR plays critical roles before 12.5 days of gestation while IG-DMR is essential for late-gestation of SC embryos. Interestingly, we found that combined deletions of H19 and H19-DMR can further improve the efficiency of normal development of SC embryos at mid-gestation compared to DKO SC embryos. Transcriptome and histology analyses revealed that H19 and H19-DMR combined deletions rescue the placental defects. Furthermore, we showed that H19, H19-DMR and IG-DMR deletions (TKO) give rise to better prenatal and postnatal embryonic development of SC embryos compared to DKO. Together, our results indicate the temporal regulation of paternal imprinted loci during embryonic development.

Oxidative stress, nutritional antioxidants and beyond

Abstract: Free radical-induced oxidative stress contributes to the development of metabolic syndromes (Mets), including overweight, hyperglycemia, insulin resistance and pro-inflammatory state. Most free radicals are generated from the mitochondrial electron transport chain; under physiological conditions, their levels are maintained by efficient antioxidant systems. A variety of transcription factors have been identified and characterized that control gene expression in response to oxidative stress status. Natural antioxidant compounds have been largely studied for their strong antioxidant capacities. This review discusses the recent progress in oxidative stress and mitochondrial dysfunction in Mets and highlights the anti-Mets, anti-oxidative, and anti-inflammatory effect of polyphenols as potential nutritional therapy.

Diverse Asgard archaea including the novel phylum Gerdarchaeota participate in organic matter degradation

Abstract: Asgard is an archaeal superphylum that might hold the key to understand the origin of eukaryotes, but its diversity and ecological roles remain poorly understood. Here, we reconstructed 15 metagenomic-assembled genomes from coastal sediments covering most known Asgard archaea and a novel group, which is proposed as a new Asgard phylum named as the “Gerdarchaeota”. Genomic analyses predict that Gerdarchaeota are facultative anaerobes in utilizing both organic and inorganic carbon. Unlike their closest relatives Heimdallarchaeota, Gerdarchaeota have genes encoding for cellulase and enzymes involved in the tetrahydromethanopterin-based Wood–Ljungdahl pathway. Transcriptomics showed that most of our identified Asgard archaea are capable of degrading organic matter, including peptides, amino acids and fatty acids, occupying ecological niches in different depths of layers of the sediments. Overall, this study broadens the diversity of the mysterious Asgard archaea and provides evidence for their ecological roles in coastal sediments.

The completed macronuclear genome of a model ciliate Tetrahymena thermophila and its application in genome scrambling and copy number analyses

Abstract: The ciliate Tetrahymena thermophila has been a powerful model system for molecular and cellular biology. However, some investigations have been limited due to the incomplete closure and sequencing of the macronuclear genome assembly, which for many years has been stalled at 1,158 scaffolds, with large sections of unknown sequences (available in Tetrahymena Genome Database, TGD, http://ciliate.org/ ). Here we completed the first chromosome-level Tetrahymena macronuclear genome assembly, with approximately 300× long Single Molecule, Real-Time reads of the wild-type SB210 cells-the reference strain for the initial macronuclear genome sequencing project. All 181 chromosomes were capped with two telomeres and gaps were entirely closed. The completed genome shows significant improvements over the current assembly (TGD 2014) in both chromosome structure and sequence integrity. The majority of previously identified gene models shown in TGD were retained, with the addition of 36 new genes and 883 genes with modified gene models. The new genome and annotation were incorporated into TGD. This new genome allows for pursuit in some underexplored areas that were far more challenging previously; two of them, genome scrambling and chromosomal copy number, were investigated in this study. We expect that the completed macronuclear genome will facilitate many studies in Tetrahymena biology, as well as multiple lines of research in other eukaryotes.

Nano-bio interactions: the implication of size-dependent biological effects of nanomaterials.

Abstract: Due to their many advantageous properties, nanomaterials (NMs) have been utilized in diverse consumer goods, industrial products, and for therapeutic purposes. This situation leads to a constant risk of exposure and uptake by the human body, which are highly dependent on nanomaterial size. Consequently, an improved understanding of the interactions between different sizes of nanomaterials and biological systems is needed to design safer and more clinically relevant nano systems. We discuss the sizedependent effects of nanomaterials in living organisms. Upon entry into biological systems, nanomaterials can translocate biological barriers, distribute to various tissues and elicit different toxic effects on organs, based on their size and location. The association of nanomaterial size with physiological structures within organs determines the site of accumulation of nanoparticles. In general, nanomaterials smaller than 20 nm tend to accumulate in the kidney while nanomaterials between 20 and 100 nm preferentially deposit in the liver. After accumulating in organs, nanomaterials can induce inflammation, damage structural integrity and ultimately result in organ dysfunction, which helps better understand the size-dependent dynamic processes and toxicity of nanomaterials in organisms. The enhanced permeability and retention effect of nanomaterials and the utility of this phenomenon in tumor therapy are also highlighted.

Functions and mechanisms of plant histone deacetylases

Abstract: Lysine acetylation, one of the major types of post-translational modifications, plays critical roles in regulating gene expression and protein function. Histone deacetylases (HDACs) are responsible for removing acetyl groups from lysines of both histone and non-histone proteins. While tremendous progress has been made in understanding the function and mechanism of HDACs in animals in the past two decades, nearly half of the HDAC studies in plants were reported within the past five years. In this review, we summarize the major findings on plant HDACs, with a focus on the model plant Arabidopsis thaliana, and highlight the components, regulatory mechanisms, and biological functions of HDAC complexes.

Clinical trials for the treatment of Coronavirus disease 2019 (COVID-19): A rapid response to urgent need.

Abstract: Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China; Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China; Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, College of Medicine, Xiamen University, Xiamen 361003, China

Chimeric antigen receptor T cells in solid tumors: a war against the tumor microenvironment

Abstract: Chimeric antigen receptor (CAR) T cell is a novel approach, which utilizes anti-tumor immunity for cancer treatment. As compared to the traditional cell-mediated immunity, CAR-T possesses the improved specificity of tumor antigens and independent cytotoxicity from major histocompatibility complex molecules through a monoclonal antibody in addition to the T-cell receptor. CAR-T cell has proven its effectiveness, primarily in hematological malignancies, specifically where the CD 19 CAR-T cells were used to treat B-cell acute lymphoblastic leukemia and B-cell lymphomas. Nevertheless, there is little progress in the treatment of solid tumors despite the fact that many CAR agents have been created to target tumor antigens such as CEA, EGFR/EGFRvIII, GD2, HER2, MSLN, MUC1, and other antigens. The main obstruction against the progress of research in solid tumors is the tumor microenvironment, in which several elements, such as poor locating ability, immunosuppressive cells, cytokines, chemokines, immunosuppressive checkpoints, inhibitory metabolic factors, tumor antigen loss, and antigen heterogeneity, could affect the potency of CAR-T cells. To overcome these hurdles, researchers have reconstructed the CAR-T cells in various ways. The purpose of this review is to summarize the current research in this field, analyze the mechanisms of the major barriers mentioned above, outline the main solutions, and discuss the outlook of this novel immunotherapeutic modality.

Functional analysis of a novel βV1 gene identified in a geminivirus betasatellite

Abstract: Betasatellites (DNA β) are circular ssDNA molecules that are associated with monopartite geminiviruses and exert a positive effect on the viral infection. Betasatellites encode one protein, named βC1, on the complementary strand; βC1 functions as a pathogenicity factor and RNA silencing suppressor. In this report, we describe the identification of another betasatellite-encoded protein, βVl, which also contributes to symptom development. The βVl open reading frame can be found on the viral strand of approximately 40% of reported betasatellite sequences, and is conserved in position and sequence. The presence of the βVl transcript was observed in plants infected with Tomato yellow leaf curl China virus (TYTCCNV) along with its associated betasatellite Tomato yellow leaf curl China betasatellite (TYTCCNB). Mutant viruses unable to produce βVl showed reduced virulence and decreased viral load. Ectopic expression of the TYTCCNB-PV1 gene in Nicotiana benthamiana plants from a PVX-based vector resulted in leaf mosaic and chlorosis. We further demonstrated that the βVl protein could elicit hypersensitive response (HR)-type cell death in N. benthamiana leaves. Our results uncover a novel betasatellite-encoded protein that contributes to the virus infection, and this discover gives us a more complete view of the plant-geminivirus interaction landscape.

Building a sequence map of the pig pan-genome from multiple de novo assemblies and Hi-C data

Abstract: Pigs were domesticated independently in the Near East and China, indicating that a single reference genome from one individual is unable to represent the full spectrum of divergent sequences in pigs worldwide. Therefore, 12 de novo pig assemblies from Eurasia were compared in this study to identify the missing sequences from the reference genome. As a result, 72.5 Mb of non-redundant sequences (∼3% of the genome) were found to be absent from the reference genome (Sscrofa11.1) and were defined as pan-sequences. Of the pan-sequences, 9.0 Mb were dominant in Chinese pigs, in contrast with their low frequency in European pigs. One sequence dominant in Chinese pigs contained the complete genic region of the tazarotene-induced gene 3 (TIG3) gene which is involved in fatty acid metabolism. Using flanking sequences and Hi-C based methods, 27.7% of the sequences could be anchored to the reference genome. The supplementation of these sequences could contribute to the accurate interpretation of the 3D chromatin structure. A web-based pan-genome database was further provided to serve as a primary resource for exploration of genetic diversity and promote pig breeding and biomedical research.

The brain, another potential target organ, needs early protection from SARS-CoV-2 neuroinvasion.

Abstract: With the outbreak and rapid spread of the novel coronavirus disease (COVID-19) around the world, humans are engaged in a life-and-death battle with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), formerly known as 2019-Novel Coronavirus (2019-nCoV). Based on the existing evidence and lessons from SARS outbreak in 2003, our attention should not be confined to the general organs whose dysfunctions were relatively easy to be observed or examined such as lung, kidney, and liver; at the same time, the brain should not be neglected due to the potential neuroinvasion of SARS-CoV-2, which prompts us to keep an alert on the onset of neurological symptoms, early diagnostics, and neuroprotection. On March 3, the National Health Commission of China issued an updated version of the diagnosis and treatment guidelines for COVID-19 (China NHCotPsRo, 2020). In the latest version of the guidelines, the pathological description was based on a small number of human histopathological samples. These showed that multiple organs are involved, including lungs, spleen and hilar lymph nodes, heart and blood vessels, liver and gallbladder, kidney, brain, adrenal gland, esophagus, stomach, and intestines. Specifically, edema and partial neuronal degeneration were observed in brain tissues (China NHCotPsRo, 2020). A proportion of COVID-19 patients in Wuhan city presented with neurologic signs such as headache (about 8%), nausea and vomiting (1%) (Chen et al., 2020). A retrospective case series of 214 COVID-19 patients reported that up to 36.4% of patients had neurologic symptoms manifested as acute cerebrovascular diseases, consciousness impairment and skeletal muscle symptoms (Mao et al., 2020). Furthermore, a COVID-19 patient was diagnosed with viral encephalitis in Beijing Ditan Hospital by Jingyuan Liu. The presence of SARS-CoV-2 in cerebrospinal fluid was confirmed later by gene sequencing (unpublished data). As shown in Figure 1, these findings suggest that COVID-19 patients should be treated promptly to reduce complications beyond the lungs. This may decrease the mortality rate. As a member of the family of coronaviruses (CoVs), the pathogen SARS-CoV-2 shares a highly homologous sequence with the SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). Previous studies have shown that the brain was a major target organ for infections from almost all the betacoronaviruses, including SARS-CoV and MERS-CoV, both in patients and experimental animals (Li et al., 2020). In light of the structural similarity between SARSCoV2 and betacoronaviruses, it is highly suspected that SARS-CoV-2 also possesses similar neuroinvasive and neurotrophic properties. In addition, SARS-CoV-2 and SARS-CoV shared the same host receptor with the human angiotensin-converting enzyme 2 (ACE2) (Hamming et al., 2004), an important component of the brain renin-angiotensin system (RAS). The existence of an independent intrinsic cerebral RAS with all its components has been well

Analysis of genetic architecture and favorable allele usage of agronomic traits in a large collection of Chinese rice accessions.

Abstract: Genotyping and phenotyping large natural populations provide opportunities for population genomic analysis and genome-wide association studies (GWAS). Several rice populations have been re-sequenced in the past decade; however, many major Chinese rice cultivars were not included in these studies. Here, we report large-scale genomic and phenotypic datasets for a collection mainly comprised of 1,275 rice accessions of widely planted cultivars and parental hybrid rice lines from China. The population was divided into three indica/Xian and three japonica/Geng phylogenetic subgroups that correlate strongly with their geographic or breeding origins. We acquired a total of 146 phenotypic datasets for 29 agronomic traits under multi-environments for different subpopulations. With GWAS, we identified a total of 143 significant association loci, including three newly identified candidate genes or alleles that control heading date or amylose content. Our genotypic analysis of agronomically important genes in the population revealed that many favorable alleles are underused in elite accessions, suggesting they may be used to provide improvements in future breeding efforts. Our study provides useful resources for rice genetics research and breeding.

Dihydroartemisinin regulates the immune system by promotion of CD8+ T lymphocytes and suppression of B cell responses.

Abstract: Artemisia annua is an anti-fever herbal medicine first described in traditional Chinese medicine 1,000 years ago Artemisinin, the extract of A annua, and its derivatives (dihydroartemisinin (DHA), artemether, and artesunate) have been used for the treatment of malaria with substantial efficacy Recently, DHA has also been tested for the treatment of lupus erythematosus, indicating that it may function to balance the immune response in immunocompromised individuals In the present study, the regulatory effect of artemisinin on the murine immune system was systematically investigated in mice infected with two different protozoan parasites (Toxoplasma gondii and Plasmodium berghei) Our results revealed that the mouse spleen index significantly increased (spleen enlargement) in the healthy mice after DHA administration primarily due to the generation of an extra number of lymphocytes and CD8+ T lymphocytes in both the spleen and circulation DHA could increase the proportion of T helper cells and CD8+ T cells, as well as decrease the number of splenic and circulatory B cells Further, DHA could reduce the production of proinflammatory cytokines Our study revealed that apart from their anti-parasitic activity, artemisinin and its derivatives can also actively modulate the immune system to directly benefit the host

Molecular actions of NLR immune receptors in plants and animals.

Abstract: NLRs constitute intracellular immune receptors in both plants and animals. Direct or indirect ligand recognition results in formation of oligomeric NLR complexes to mediate immune signaling. Over the past 20 years, rapid progress has been made in our understanding of NLR signaling. Structural and biochemical studies provide insight into molecular basis of autoinhibition, ligand recognition, and resistosome/inflammasome formation of several NLRs. In this review, we summarize these studies focusing on the structural aspect of NLRs. We also discuss the analogies and differences between plant and animal NLRs in their mechanisms of action and how the available knowledge may shed light on the signaling mechanisms of other NLRs.