Host traits shape virome composition and virus transmission in wild small mammals.

Bats, rodents, and shrews are the most important animal sources of human infectious diseases. However, the evolution and transmission of viruses among them remain largely unexplored. Through the meta-transcriptomic sequencing of internal organ and fecal samples from 2,443 wild bats, rodents, and shrews sampled from four Chinese habitats, we identified 669 viruses, including 534 novel viruses, thereby greatly expanding the mammalian virome. Our analysis revealed high levels of phylogenetic diversity, identified cross-species virus transmission events, elucidated virus origins, and identified cases of invertebrate viruses in mammalian hosts. Host order and sample size were the most important factors impacting virome composition and patterns of virus spillover. Shrews harbored a high richness of viruses, including many invertebrate-associated viruses with multi-organ distributions, whereas rodents carried viruses with a greater capacity for host jumping. These data highlight the remarkable diversity of mammalian viruses in local habitats and their ability to emerge in new hosts.

A Genomic Perspective on the Origin and Emergence of SARS-CoV-2.

The ongoing pandemic of a new human coronavirus, SARS-CoV-2, has generated enormous global concern. We and others in China were involved in the initial genome sequencing of the virus. Herein, we describe what genomic data reveal about the emergence SARS-CoV-2 and discuss the gaps in our understanding of its origins.

Using Metagenomics to Characterize an Expanding Virosphere.

We know less about viruses than any other lifeform. Fortunately, metagenomics has led to a massive expansion in the known diversity of the virosphere. Here, we discuss how metagenomics has changed our understanding of RNA viruses and present some of the remaining challenges, including characterization of the "dark matter" of divergent viral genomes.

Author Correction: A new coronavirus associated with human respiratory disease in China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A new coronavirus associated with human respiratory disease in China.

Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health1-3. Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here 'WH-Human 1' coronavirus (and has also been referred to as '2019-nCoV'). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China5. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.

Phosphorylation-Regulated Dynamic Phase Separation of HIP-55 Protects Against Heart Failure.

BACKGROUND: Heart failure (HF), which is the terminal stage of many cardiovascular diseases, is associated with low survival rates and a severe financial burden. The mechanisms, especially the molecular mechanism combined with new theories, underlying the pathogenesis of HF remain elusive. We demonstrate that phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 (hematopoietic progenitor kinase 1-interacting protein of 55 kDa) protects against HF. METHODS: Fluorescence recovery after photobleaching assay, differential interference contrast analysis, pull-down assay, immunofluorescence, and immunohistochemical analysis were used to investigate the liquid-liquid phase separation capacity of HIP-55 and its dynamic regulation in vivo and in vitro. Mice with genetic deletion of HIP-55 and mice with cardiac-specific overexpression of HIP-55 were used to examine the role of HIP-55 on ß-adrenergic receptor hyperactivation-induced HF. Mutation analysis and mice with specific phospho-resistant site mutagenesis were used to identify the role of phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 in HF. RESULTS: Genetic deletion of HIP-55 aggravated HF, whereas cardiac-specific overexpression of HIP-55 significantly alleviated HF in vivo. HIP-55 possesses a strong capacity for phase separation. Phase separation of HIP-55 is dynamically regulated by AKT-mediated phosphorylation at S269 and T291 sites, failure of which leads to impairment of HIP-55 dynamic phase separation by formation of abnormal aggregation. Prolonged sympathetic hyperactivation stress induced decreased phosphorylation of HIP-55 S269 and T291, dysregulated phase separation, and subsequent aggregate formation of HIP55. Moreover, we demonstrated the important role of dynamic phase separation of HIP-55 in inhibiting hyperactivation of the ß-adrenergic receptor-mediated P38/MAPK (mitogen-activated protein kinase) signaling pathway. A phosphorylation-deficient HIP-55 mutation, which undergoes massive phase separation and forms insoluble aggregates, loses the protective activity against HF. CONCLUSIONS: Our work reveals that the phosphorylation-regulated dynamic phase separation of HIP-55 protects against sympathetic/adrenergic system-mediated heart failure.

Improved characterization of aminoglycoside penetration into human lung epithelial lining fluid via population pharmacokinetics.

Aminoglycosides are important treatment options for serious lung infections, but modeling analyses to quantify their human lung epithelial lining fluid (ELF) penetration are lacking. We estimated the extent and rate of penetration for five aminoglycosides via population pharmacokinetics from eight published studies. The area under the curve in ELF vs plasma ranged from 50% to 100% and equilibration half-lives from 0.61 to 5.80 h, indicating extensive system hysteresis. Aminoglycoside ELF peak concentrations were blunted, but overall exposures were moderately high.

Comprehensive stability analysis of 13 ß-lactams and ß-lactamase inhibitors in in vitro media, and novel supplement dosing strategy to mitigate thermal drug degradation.

Non-clinical antibiotic development relies on in vitro susceptibility and infection model studies. Validating the achievement of the targeted drug concentrations is essential to avoid under-estimation of drug effects and over-estimation of resistance emergence. While certain ß-lactams (e.g., imipenem) and ß-lactamase inhibitors (BLIs; clavulanic acid) are believed to be relatively unstable, limited tangible data on their stability in commonly used in vitro media are known. We aimed to determine the thermal stability of 10 ß-lactams and 3 BLIs via LC-MS/MS in cation-adjusted Mueller Hinton broth at 25 and 36°C as well as agar at 4 and 37°C, and in water at -20, 4, and 25°C. Supplement dosing algorithms were developed to achieve broth concentrations close to their target over 24 h. During incubation in broth (pH 7.25)/agar, degradation half-lives were 16.9/21.8 h for imipenem, 20.7/31.6 h for biapenem, 29.0 h for clavulanic acid (studied in broth only), 23.1/71.6 h for cefsulodin, 40.6/57.9 h for doripenem, 46.5/64.6 h for meropenem, 50.8/97.7 h for cefepime, 61.5/99.5 h for piperacillin, and >120 h for all other compounds. Broth stability decreased at higher pH. All drugs were ≥90% stable for 72 h in agar at 4°C. Degradation half-lives in water at 25°C were >200 h for all drugs except imipenem (14.7 h, at 1,000 mg/L) and doripenem (59.5 h). One imipenem supplement dose allowed concentrations to stay within ±31% of their target concentration. This study provides comprehensive stability data on ß-lactams and BLIs in relevant in vitro media using LC-MS/MS. Future studies are warranted applying these data to antimicrobial susceptibility testing and assessing the impact of ß-lactamase-related degradation.

Blood molecular markers associated with COVID-19 immunopathology and multi-organ damage.

COVID-19 is characterized by dysregulated immune responses, metabolic dysfunction and adverse effects on the function of multiple organs. To understand host responses to COVID-19 pathophysiology, we combined transcriptomics, proteomics, and metabolomics to identify molecular markers in peripheral blood and plasma samples of 66 COVID-19-infected patients experiencing a range of disease severities and 17 healthy controls. A large number of expressed genes, proteins, metabolites, and extracellular RNAs (exRNAs) exhibit strong associations with various clinical parameters. Multiple sets of tissue-specific proteins and exRNAs varied significantly in both mild and severe patients suggesting a potential impact on tissue function. Chronic activation of neutrophils, IFN-I signaling, and a high level of inflammatory cytokines were observed in patients with severe disease progression. In contrast, COVID-19-infected patients experiencing milder disease symptoms showed robust T-cell responses. Finally, we identified genes, proteins, and exRNAs as potential biomarkers that might assist in predicting the prognosis of SARS-CoV-2 infection. These data refine our understanding of the pathophysiology and clinical progress of COVID-19.

Total infectome characterization of respiratory infections in pre-COVID-19 Wuhan, China.

At the end of 2019 Wuhan witnessed an outbreak of "atypical pneumonia" that later developed into a global pandemic. Metagenomic sequencing rapidly revealed the causative agent of this outbreak to be a novel coronavirus denoted SARS-CoV-2. To provide a snapshot of the pathogens in pneumonia-associated respiratory samples from Wuhan prior to the emergence of SARS-CoV-2, we collected bronchoalveolar lavage fluid samples from 408 patients presenting with pneumonia and acute respiratory infections at the Central Hospital of Wuhan between 2016 and 2017. Unbiased total RNA sequencing was performed to reveal their "total infectome", including viruses, bacteria and fungi. We identified 35 pathogen species, comprising 13 RNA viruses, 3 DNA viruses, 16 bacteria and 3 fungi, often at high abundance and including multiple co-infections (13.5%). SARS-CoV-2 was not present. These data depict a stable core infectome comprising common respiratory pathogens such as rhinoviruses and influenza viruses, an atypical respiratory virus (EV-D68), and a single case of a sporadic zoonotic pathogen-Chlamydia psittaci. Samples from patients experiencing respiratory disease on average had higher pathogen abundance than healthy controls. Phylogenetic analyses of individual pathogens revealed multiple origins and global transmission histories, highlighting the connectedness of the Wuhan population. This study provides a comprehensive overview of the pathogens associated with acute respiratory infections and pneumonia, which were more diverse and complex than obtained using targeted PCR or qPCR approaches. These data also suggest that SARS-CoV-2 or closely related viruses were absent from Wuhan in 2016-2017.

Design and tribological performance of graphene nanofluids dispersed by dragging effect of bicomponent gelator.

Nanofluids have excellent lubrication and high thermal conductivity. However, the agglomeration and sedimentation produced by the large surface energy of nanoparticles in base liquid threaten the long-term dispersion stability and impact the wide application of nanofluid. In this work, based on the self-assemble behavior and continuous network structure formed by low molecular weight organic gelator, the uniform clusters were formed through regulating the kinetics behavior in the gelling process. The dragging effect was demonstrated by oleic acid - sodium dodecyl sulfate (OA-SDS) bicomponent gelator and graphene oxide (GO) nanosheets. The results showed that GO nanofluids dispersed by OA-SDS were stable for more than 12 months. The well-dispersed GO nanofluid exhibited better anti-friction and anti-wear properties under both immersion and electrostatic minimum quantity lubrication conditions. Moreover, the lower contact angle, surface tension and droplet size of nanofluids after charging improved the wettability on the frictional interface. The GO adsorption film formed on the friction interface protected the tribochemical reaction film of iron oxide and prevented the occurrence of sintering of base oil.

The evolutionary history of vertebrate RNA viruses.

Our understanding of the diversity and evolution of vertebrate RNA viruses is largely limited to those found in mammalian and avian hosts and associated with overt disease. Here, using a large-scale meta-transcriptomic approach, we discover 214 vertebrate-associated viruses in reptiles, amphibians, lungfish, ray-finned fish, cartilaginous fish and jawless fish. The newly discovered viruses appear in every family or genus of RNA virus associated with vertebrate infection, including those containing human pathogens such as influenza virus, the Arenaviridae and Filoviridae families, and have branching orders that broadly reflected the phylogenetic history of their hosts. We establish a long evolutionary history for most groups of vertebrate RNA virus, and support this by evaluating evolutionary timescales using dated orthologous endogenous virus elements. We also identify new vertebrate-specific RNA viruses and genome architectures, and re-evaluate the evolution of vector-borne RNA viruses. In summary, this study reveals diverse virus-host associations across the entire evolutionary history of the vertebrates.

Author Correction: The evolutionary history of vertebrate RNA viruses.

Change history: In this Article, author Li Liu should be associated with affiliation number 5 (College of Marine Sciences, South China Agricultural University, Guangzhou, Guangdong, China), rather than affiliation number 4 (Wenzhou Center for Disease Control and Prevention, Wenzhou, Zhejiang, China). This has been corrected online.

ICTV Virus Taxonomy Profile: Discoviridae 2023.

Discoviridae is a family of negative-sense RNA viruses with genomes of 6.2-9.7 kb that have been associated with fungi and stramenopiles. The discovirid genome consists of three monocistronic RNA segments with open reading frames (ORFs) that encode a nucleoprotein (NP), a nonstructural protein (Ns), and a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Discoviridae, which is available at ictv.global/report/discoviridae.

ICTV Virus Taxonomy Profile: Mypoviridae 2023.

Mypoviridae is a family of negative-sense RNA viruses with genomes of about 16.0 kb that have been found in myriapods. The mypovirid genome consists of three monocistronic RNA segments that encode a nucleoprotein (NP), a glycoprotein (GP), and a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Mypoviridae, which is available at: ictv.global/report/mypoviridae.

ICTV Virus Taxonomy Profile: Tulasviridae 2023.

Tulasviridae is a family of ambisense RNA viruses with genomes of about 12.2 kb that have been found in fungi. The tulasvirid genome is nonsegmented and contains three open reading frames (ORFs) that encode a nucleoprotein (NP), a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain, and a protein of unknown function (X). This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Tulasviridae, which is available at ictv.global/report/tulasviridae.

ICTV Virus Taxonomy Profile: Wupedeviridae 2023.

Wupedeviridae is a family of negative-sense RNA viruses with genomes of about 20.5 kb that have been found in myriapods. The wupedevirid genome consists of three monocistronic RNA segments with open reading frames (ORFs) that encode a nucleoprotein (NP), a glycoprotein (GP), and a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Wupedeviridae, which is available at ictv.global/report/wupedeviridae.

ICTV Virus Taxonomy Profile: Cruliviridae 2023.

Cruliviridae is a family of negative-sense RNA viruses with genomes of 10.8-11.5 kb that have been found in crustaceans. The crulivirid genome consists of three RNA segments with ORFs that encode a nucleoprotein (NP), a glycoprotein (GP), a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain, and in some family members, a zinc-finger (Z) protein of unknown function. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Cruliviridae, which is available at ictv.global/report/cruliviridae.

Dietary patterns and severity of symptom with the risk of esophageal squamous cell carcinoma and its histological precursor lesions in China: a multicenter cross-sectional latent class analysis.

BACKGROUND: Dietary patterns and symptoms research among Chinese with esophageal squamous cell carcinoma (ESCC) and its precursor lesions is limited, especially as it relates to multiple food consumption and multiple co-occurring symptoms. The aim of our study was to identify the dietary patterns and severity of symptom classes with the risk of esophageal squamous cell carcinoma and its histological precursor lesions, and develop a risk prediction model for different stages of esophageal disease. METHODS: We analyzed data from a multicenter cross-sectional study carried out in ESCC high incidence areas between 2017 and 2018, which included 34,707 individuals aged 40-69 years. Dietary patterns and severity of symptom classes were derived by applying a latent class analysis (LCA). A multiple logistic regression model was used to derive the odds ratio (ORs) and corresponding 95% confidence intervals (CIs) for ESCC and the different stages of esophageal disease according to the dietary patterns and severity of symptom classes identified. We built the risk prediction model by using a nomogram. RESULTS: We identified five dietary patterns and three severity of symptom classes. The dietary patterns were classified as follows: "Healthy", "Western", "Lower consumers-combination", "Medium consumers-combination" and "Higher consumers-combination" patterns based on the intake of foods such as red meat, vegetables and fruits. The severity of symptoms was categorized into "Asymptomatic", "Mild symptoms" and "Overt symptoms" classes based on health-related symptoms reported by the participants. Compared to the "Healthy" pattern, the other four patterns were all associated with an increased risk of esophageal disease. Similarly, the other two symptom classes present different degrees of increased risk of esophageal disease compared to the "Asymptomatic". The nomograms reflect the good predictive ability of the model. CONCLUSION: Among individuals aged 40-69 years in high incidence regions of upper gastrointestinal cancer, the results supplied that subjects with diets rich in livestock and poultry meat and low in fruits and vegetables and subjects with typical symptoms were at increased ESCC risk. The findings highlight the importance of considering food and symptom combinations in cancer risk evaluation.

Evaluate the Correlation between the TIMI Frame Count, IMR, and CFR in Coronary Microvascular Disease.

OBJECTIVE: To evaluate the correlation between the TIMI frame count, IMR, and CFR in coronary microvascular disease (slow flow phenomenon). METHODS: TFC and IMR were recorded in the nitroglycerin and ATP administration states, and the relationship between TFC, IMR, and CFR in specific states was analyzed. RESULTS: A total of 41 patients with baseline TFC >25 frames on coronary angiography were enrolled, and nitroglycerin reduced TFC by 50% from baseline in 24 (58.54%) patients; 16 of the remaining 17 patients were able to achieve a 50% reduction in TFC by further intracoronary ATP injection. 10 patients were further tested for IMR, and the results showed significant correlations between baseline TFC and IMR (r = 0.775, P=0.008), TFC and IMR after nitroglycerin (r = 0.875, P=0.001), and the minimal TFC and IMR that could be obtained with nitroglycerin or ATP administration (r = 0.890, P=0.001). There was also a significant correlation between the proportional improvement in TFC and CFR before and after nitroglycerin injection (r = 0.685, P=0.029). In addition, we observed a lower IMR measured after nitroglycerin than after ATP in three patients, suggesting that CMD may be dominated by NO-sensitive vascular such as prearterioles and that an extensive analysis of the target site of CMD may be achieved by stepwise drug administration. CONCLUSION: Induction of TFC in different states by a stepwise drug approach may serve as a potential primary screening method for coronary microcirculatory dysfunction, thereby reducing the need for further IMR or CFR testing.