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Zhao, C.

Publications and source records attributed to Zhao, C..

At least 217 records · Page 12Linked to original sources

Comparison of urine proteomes from tumor-bearing mice with those from tumor-resected mice

[Objective]This study focuses on the most important concern of surgeons - whether they resected all of the tumor. Urine can reflect early changes associated with physiological or pathophysiological processes. Based on the above ideas, we conducted experiments to explore changes in the urine proteome between tumor-bearing mice and tumor-resected mice. [Method]The tumor-bearing mouse model was established with MC38 mouse colon cancer cells, and the mice were divided into the healthy control group, complete resection group, and nonresection group. Urine was collected 7 days and 30 days after resection. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to identify the urine proteome and then analyze differentially expressed proteins and biological pathways. [Results](1) Seven days after tumor resection, there were 20 differentially expressed proteins that could distinguish between the complete resection group and the nonresection group. The biological process includes circadian rhythm, Notch signaling pathway, leukocyte cell-cell adhesion, and heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules. (2) Thirty days after tumor resection, there were 33 differentially expressed proteins that could distinguish between the complete resection group and the nonresection group. The biological process includes cell adhesion, complement activation, the alternative pathway, the immune system process, and angiogenesis. (3) There was no significant difference between the two groups at 30 days after tumor resection between the complete resection group and the healthy control group. [Conclusion]Changes in the urine proteome can reflect tumors with or without complete resection.

biochemistry↗

Contrasting autoimmune and treatment effects reveals baseline set points of immune toxicity following checkpoint inhibitor treatment

Immune checkpoint inhibitors (ICIs) have changed the cancer treatment landscape, but severe immune-related adverse events (irAEs) can be life-threatening or fatal and may prohibit patients from receiving further ICI treatment. While the clinical features of irAEs are well documented, molecular signatures, predictive biomarkers, and mechanisms of impending irAEs are largely unknown. In addition, the markers and mechanisms of ICI-induced antitumor immunity often overlap with those for irAEs. It is thus critical to uncover signatures associated specifically with irAEs but not with antitumor immunity. To identify circulating immune cell states associated with irAEs, we applied multimodal single cell analysis (CITE-seq) to simultaneously measure the transcriptome and surface proteins from peripheral blood mononuclear cells (PBMCs) collected before and after treatment with an anti-PD-L1 antibody (avelumab) in patients with thymic cancers (thymic epithelial tumors). All patients had an antitumor response, yet a subset developed muscle autoimmunity (myositis), a potentially life-threatening irAE. Mixed-effect modeling disentangled cell type-specific transcriptional states associated with ICI treatment responses from those of irAEs to identify temporally stable pre-treatment immune set points associated with irAEs only. These pre-treatment baseline signatures of irAE developed post-avelumab irAEs reflect correlated transcriptional states of multiple innate and adaptive immune cell populations, including elevation of metabolic genes downstream of mTOR signaling in T-cell subsets. Together these findings suggest putative pre-treatment biomarkers for irAEs following ICI therapy in thymic cancer patients and raise the prospect of therapeutically dampening autoimmunity while sparing antitumor activity in cancer patients treated with ICIs. Together, pre-treatment biomarkers and interventional therapeutics could help mitigate treatment discontinuation and improve clinical outcomes.

immunology↗

Saturated cell lysing is critical for high sensitivity microbiome analysis

Introductory paragraphFor robust DNA-based gut microbiome analysis, all cells in the stool samples need to be lysed. However, no standards have been developed to evaluate a DNA extraction protocols capability of lysing all cells and its sensitivity on detecting microbial structural differences among samples. In this study, we incrementally increased the intensity of mechanical lysis and integrated lysozyme pretreatment to Protocol Q (PQ), which was recommended as the best from 21 protocols1. A new protocol (LPQ) was optimized when DNA yield, Gram-positive bacteria ratio, and beta diversity all reached to a plateau with no further significant changes, indicating the achievement of saturated lysing. LPQ detected significant differences among three groups of fiber-treated human stool samples and identified 64 responsive ASVs, while a commercial kit failed to detect any significant treatment effects and PQ only detected 17 responsive ASVs. Therefore, saturated lysing as defined in this study should be adopted for evaluating microbiome DNA extraction protocols.

microbiology↗

Elemental diet enriched in amino acids alters gut microbial community and prevents colonic mucus degradation in mice with colitis

The role of dietary amino acids or intact proteins in the progression of colitis remains controversial, and the mechanism involving gut microbes is unclear. Here, we investigated the effects of an elemental diet (ED) enriched in amino acids and a polymeric diet enriched in intact protein on the pathogenesis of DSS-induced colitis in mice. Our results showed that ED induced remission of colitis in mice. Notably, ED treatment reduced the abundance of the mucolytic bacteria Akkermansia and Bacteroides, which was attributed to the decreased colonic protein fermentation. Consistently, the activities of mucolytic enzymes were decreased, leading to the protection of mucus layer degradation and microbial invasion. The fecal microbiota transplantation of ED-fed mice reshaped microbial ecology and alleviated intestinal inflammation in recipient mice. ED failed to induce remission of colitis in pseudo-germ-free mice. Together, we convincingly demonstrated the critical role of gut microbiota in the prevention of ED on colitis. ImportanceThe prevalence of inflammatory bowel disease is rapidly increasing and has become a global burden. Several specific amino acids have been shown to benefit mucosal healing and colitis remission. However, the role of amino acids or intact proteins in diets and enteral nutrition formulas is controversial, and the mechanisms involving gut microbes remain unclear. In this study, we investigated the effects of an elemental diet (ED) enriched in amino acids and a polymeric diet enriched in intact protein on the pathogenesis of colitis in mice. The underlying mechanisms were explored by utilizing fecal microbiota transplantation and pseudo-germ-free mice. ED treatment reduced the abundance of mucolytic bacteria, thereby protecting the mucus layer from microbial invasion and degradation. For the first time, we convincingly demonstrated the critical role of gut microbiota in the effects of ED. This study may provide new insights into the gut microbiota-diet interaction in human health.

microbiology↗

Neural mechanisms underlying distractor suppression guided by spatial cues

A growing body of research demonstrates that distracting inputs can be proactively suppressed via spatial cues, nonspatial cues, or experience, which are governed by more than one top-down mechanism of attention. However, how the neural mechanisms underlying spatial distractor cues guide proactive suppression of distracting inputs remains unresolved. Here, we recorded electroencephalography signals from 110 subjects in three experiments to identify the role of alpha activity in proactive distractor suppression induced by spatial cues and its influence on subsequent distractor inhibition. Behaviorally, we found novel spatial changes in spatial distractor cues: cueing distractors far away from the target improves search performance for the target while cueing distractors close to the target hampers performance. Crucially, we found dynamic characteristics of spatial representation for distractor suppression during anticipation. This result was further verified by alpha power increased relatively contralateral to the cued distractor. At both the between- and within-subjects levels, we found that these activities further predicted the decrement of subsequent PD component, which was indicative of reduced distractor interference. Moreover, anticipatory alpha activity and its link with subsequent PD component were specific to the high predictive validity of distractor cue. Together, these results provide evidence for the existence of proactive suppression mechanisms of spatial distractors, support the role of alpha activity as gating by proactive suppression and reveal the underlying neural mechanisms by which cueing the spatial distractor may contribute to reduced distractor interference. (235). SignificanceIn space, the attention-capturing distractors are obstacles to successfully identifying targets. How to sidestep task-irrelevant distractors that stand between the target and our focus in advance is essential but still unclear. This research investigated how dynamic spatial cues can help us proactively eliminate attention-capturing distractors. Using three cue-distractor tasks that manipulate the predictive validity of distractor occurrence, we provide a series of evidence for the presence of alpha power activity related to distractor anticipation. Critically, this was the first study linking cue-elicited alpha power and distractor-elicited PD, indicating that spatial modulation of alpha power may reduce distractor interference. These findings delineate the neural mechanisms of proactive suppression for spatial distractors. (109)

neuroscience↗

A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-cell Leukemia

T-cell Acute Lymphoblastic Leukemia (T-ALL) is a NOTCH1-driven disease in need of novel therapies. Here, we identify a NOTCH1-SIRT1-KAT7 link as a therapeutic vulnerability in T-ALL, in which SIRT1 is overexpressed downstream of a novel NOTCH1-bound enhancer. SIRT1 loss impairs leukemia generation, while SIRT1 overexpression accelerates leukemia and confers resistance to NOTCH1 inhibition in a deacetylase-dependent manner. Moreover, secondary SIRT1 loss extends survival and synergizes with NOTCH1 inhibition. Global acetyl-proteomics upon SIRT1 loss uncovered hyperacetylation of KAT7 and BRD1, subunits of a histone acetyltransferase complex targeting H4K12. Metabolic and gene expression profiling revealed a metabolic crisis together with a transcriptional signature resembling KAT7 deletion. Consistently, SIRT1 loss resulted in reduced H4K12ac, and overexpression of a non-acetylatable KAT7 mutant partly rescued SIRT1 loss-induced proliferation defects. The newly unveiled NOTCH1-SIRT1-KAT7 axis uncovers novel therapeutic targets in T-ALL and reveals a circular feedback mechanism balancing deacetylase/acetyltransferase activation with potentially broad relevance in cancer. Statement of significanceWe identified a novel axis in T-ALL whereby NOTCH1 activates SIRT1 through an enhancer region, and SIRT1 deacetylates and activates KAT7. Targeting SIRT1 shows antileukemic effects, partly mediated by KAT7 inactivation. Our results identify novel therapeutic targets and uncover a rheostat mechanism between deacetylase/acetyltransferase activities with potentially broader cancer relevance.

cancer biology↗

Comparative genomics of five Valsa species gives insights on their pathogenicity evolution

Valsa is a genus of ascomycetes fungi within the family Valsaceae that includes many wood destructive pathogens. The species such as Valsa mali and Valsa pyri that colonize fruit trees are threatening the global fruit production. Rapid host adaptation and fungicide resistance emergence are the main characteristics that make them devastating and hard to control. Efficient disease management can be achieved from early infection diagnosis and fungicide application, but lack of understandings of their genetic diversity and genomic features that underpin their pathogenicity evolution and drug resistance is essentially impeding the progress of effective and sustainable disease control. Here, we report genome assemblies of Valsa malicola, Valsa persoonii and Valsa sordida which represents close relatives of the two well known Valsa mali and Valsa pyri that cause canker disease with different host preferences. Comparative genomics analysis revealed that segmental rearrangements, inversions and translocations frequently occurred among Valsa spp. genomes. Genes identified in highly active regions exhibited high sequence differentiation and are enriched in membrane transporter proteins involved in anti-drug and nutrient transportation activities. Consistently, we also found membrane transporter gene families have been undergoing significant expansions in Valsa clade. Furthermore, unique genes that possessed or retained by each of the five Valsa species are more likely part of the secondary metabolic (SM) gene clusters which suggests SM one of the critical components that diverge along with the evolution of Valsa species. Repeat sequence content contributes significantly to genome size variation across the five species. The wide spread AT-rich regions resulted from repeat induced point C to T mutation (RIP) exhibited a specific proximity to secondary metabolic gene clusters and this positional proximity is correlated with the diversification of SM clusters suggesting a potential companion evolution between repeat sequence and secondary metabolism cluster. Lastly, we show that LaeA, the global regulator of secondary metabolic gene cluster, exhibiting diverged manner of regulation on the expression of clusters in vegetative and invasive mycelia of the devastating V. mali indicating the complexity of secondary metabolism in fungal species.

bioinformatics↗

In situ architecture and membrane fusion of SARS-CoV-2 Delta variant

Among the current five Variants of Concern, infections caused by the SARS-CoV-2 B.1.617.2 (Delta) variant are often associated with the greatest severity. Despite recent advances on the molecular basis of elevated pathogenicity using recombinant proteins, architecture of intact Delta virions remains veiled. Moreover, molecular evidences for the detailed mechanism of S-mediated membrane fusion are missing. Here we reported the in situ structure and distribution of S on the authentic Delta variant, and discovered invagination in the distinctive Delta architecture. We also captured fusion snapshots from the virus-virus fusion events, provided structural evidences for Deltas attenuated dependency on cellular factors for fusion activation, and proposed a model of S-mediated membrane fusion. Site-specific glycan analysis revealed increased oligomannose-type glycosylation of native Delta S over that of the Wuhan-Hu-1 S. Together, these results disclose distinctive factors of Delta being the most virulent SARS-CoV-2 variant. In BriefCryo-ET of intact SARS-CoV-2 Delta variant revealed its distinctive architecture and captured snapshots of its membrane fusion in action.

biophysics↗

Curation of BIDS (CuBIDS): a workflow and software package for streamlining reproducible curation of large BIDS datasets

The Brain Imaging Data Structure (BIDS) is a specification accompanied by a software ecosystem that was designed to create reproducible and automated workflows for processing neuroimaging data. BIDS Apps flexibly build workflows based on the metadata detected in a dataset. However, even BIDS valid metadata can include incorrect values or omissions that result in inconsistent processing across sessions. Additionally, in large-scale, heterogeneous neuroimaging datasets, hidden variability in metadata is difficult to detect and classify. To address these challenges, we created a Python-based software package titled "Curation of BIDS" (CuBIDS), which provides an intuitive workflow that helps users validate and manage the curation of their neuroimaging datasets. CuBIDS includes a robust implementation of BIDS validation that scales to large samples and incorporates DataLad--a version control software package for data--to ensure reproducibility and provenance tracking throughout the entire curation process. CuBIDS provides tools to help users perform quality control on their images metadata and identify unique combinations of imaging parameters. Users can then execute BIDS Apps on a subset of participants that represent the full range of acquisition parameters that are present, accelerating pipeline testing on large datasets. HIGHLIGHTSO_LICuBIDS is a workflow and software package for curating BIDS data. C_LIO_LICuBIDS summarizes the heterogeneity in a BIDS dataset. C_LIO_LICuBIDS prepares BIDS data for successful preprocessing pipeline runs. C_LIO_LICuBIDS helps users perform metadata-based quality control. C_LI

neuroscience↗

Drivers of nematode diversity in forest soils across climatic zones

Nematodes are the most abundant multi-cellular animals in soil, influencing key processes and functions in terrestrial ecosystems. Yet, little is known about the drivers of nematode abundance and diversity in forest soils across climatic zones. This is despite forests cover approximately 30% of the earths land surface, provide many crucial ecosystem services but strongly vary in hydrothermal conditions and associated ecosystem properties across climatic zones. Here, we collected nematode samples from 13 forests across a latitudinal gradient. We divided this gradient in temperate, warm-temperate, and tropical climatic zones. Using boosted regression trees, we showed that across the gradient, nematode abundance and diversity were mainly influenced by soil organic carbon. However, within climatic zones, other factors were more important in driving nematode alpha-diversity, nematode biomass and the abundance of different trophic groups: mean annual temperature and total soil phosphorus in temperate zones, soil pH in warm-temperate zones, and mean annual precipitation in tropical zones. Additionally, nematode beta-diversity was higher in temperate than in warm-temperate and tropical zones, and we did not find significant differences among climatic zones in nematode gamma diversity. Together, our findings indicate a latitudinal shift in the main climatic variables controlling soil nematode communities and demonstrate that the drivers of soil nematode diversity in forested ecosystems are affected by the spatial scale and climatic conditions considered. This implies that high resolution studies are needed to accurately predict how soil functions respond if climate conditions move beyond the coping range of soil organisms. Our results also emphasize the importance of studying the area-diversity relationship of soil organisms under different climatic conditions.

ecology↗

Integrated platform for multi-scale molecular imaging andphenotyping of the human brain

Understanding cellular architectures and their connectivity is essential for interrogating system function and dysfunction. However, we lack technologies for mapping the multi-scale details of individual cells in the human organ-scale system. To address this challenge, we developed a platform that simultaneously extracts spatial, molecular, morphological, and connectivity information of individual cells from the same human brain, by integrating novel chemical, mechanical, and computational tools. The platform includes three key tools: (i) a vibrating microtome for ultra-precision slicing of large-scale tissues without losing cellular connectivity (MEGAtome), (ii) a polymer hydrogel-based tissue processing technology for multiplexed multiscale imaging of human organ-scale tissues (mELAST), and (iii) a computational pipeline for reconstructing 3D connectivity across multiple brain slabs (UNSLICE). We demonstrated the transformative potential of our platform by analyzing human Alzheimers disease pathology at multiple scales and demonstrating scalable neural connectivity mapping in the human brain. One-Sentence SummaryWe developed an integrated, scalable platform for highly multiplexed, multi-scale phenotyping and connectivity mapping in the same human brain tissue, which incorporated novel tissue processing, labeling, imaging, and computational technologies.

bioengineering↗

Boosting transformation in wheat by BBM-WUS

Agrobacterium-mediated transformation is a cost-effective and convenient way to introduce foreign genetic elements to plants. However, only limited protocols successfully generates transgenic plants with fielder, a spring wheat variety. Wheat transformation method with higher efficiency and without genotype restriction is heavily demanded. Here, a heat-shock protocol, independent of Japan Tobacco had been established. Transgenic plants can be obtained from immature embryo within only 60 days by this protocol. Morphogenic regulators Baby boom and Wuschel (BBM-WUS) was proved to promote transformation efficiency for five to six times in wheat when co-infiltrated with agrobacterium containing target construct. Notably, half of the transformants are BBM-WUS free and moreover, the BBM-WUS containing plants could be picked by florescent marker that was co-expressed with BBM-WUS. In conclusion, we managed to establish a new wheat transformation protocol with shorter duration than published protocol.

plant biology↗

Cilia regulate meiotic recombination in zebrafish

Meiosis is essential for evolution and genetic diversity in almost all sexual eukaryotic organisms. The mechanisms of meiotic recombination, such as synapsis, have been extensively investigated. However, it is still unclear whether signals from the cytoplasm or even outside of the cell can regulate the meiosis process. Cilia are microtubule-based structures that protrude from cell surface and function as signaling hubs to sense extracellular signals. Here, we reported an unexpected and critical role of cilia during meiotic recombination. During gametogenesis of zebrafish, cilia were specifically present in the prophase stages of both spermatocytes and primary oocytes. By developing a novel germ cell-specific CRISPR/Cas9 system, we demonstrated that germ cell-specific depletion of ciliary genes resulted in compromised double strand break repair, reduced crossover formation, and increased germ cell apoptosis. Our study reveals a previously undiscovered role for cilia during meiosis and suggests that extracellular signals may regulate meiotic recombination via this particular organelle.

developmental biology↗

Transcranial photobiomodulation enhances visual working memory capacity in humans

Transcranial photobiomodulation (tPBM) is a novel and noninvasive intervention, which has shown promise for improving cognitive performances. Whether tPBM can modulate brain activity and thereby enhance working memory (WM) capacity in humans remains unclear. In this study, we delivered double-blind and sham-control tPBM with different wavelengths to the prefrontal cortex (PFC) in 90 healthy participants and conducted four electroencephalography (EEG) experiments to investigate whether individual visual working memory capacity and related neural response could be modulated. We found that 1064 nm tPBM applied to the right PFC has both a substantial impact on visual working memory capacity and occipitoparietal contralateral delay activity (CDA), no matter orientation or color feature of the memorized objects. Importantly, the CDA set-size effect during the retention mediated the effect between 1064 nm tPBM and subsequent WM performance. However, these behavioral benefits and the corresponding changes of CDA set-size effect were absent with tPBM at 852 nm wavelength or with the stimulation on the left PFC. Our findings provide converging evidence that 1064 nm tPBM applied on the right PFC can improve visual working memory capacity, as well as explain the individuals electrophysiological changes about behavioral benefits.

neuroscience↗

An Improved Linear Mixed Model for Multivariate Genome-Wide Association Studies

Current methods of multivariate analysis require complete multivariate phenotypes from each individual and have a computational time complexity of O(n2) per SNP, where n is the sample size. We develop an efficient genomic multivariate analysis tool (GMAT) for genome-wide association studies of multiple correlated traits. The new method can handle incomplete multivariate data with missing records and reduce the time complexity to O(n) per SNP. Simulation studies based on known genotypes and phenotypes of actual populations show that GMAT has increased the statistical power with a proper control of false positivity for association studies compared to the conventional linear mixed model (LMM) that removes individuals with incomplete records. Applications to a balanced donkey data and an unbalanced yeast data show that the computational efficiency of the new method has been increased about tens of times faster than the conventional LMM analysis. The GMAT package can be downloaded at https://github.com/chaoning/GMAT.

bioinformatics↗

The brassinosteroid biosynthesis gene TaD11-2A controls grain size and its elite haplotype improves wheat grain yields

Brassinosteroids (BRs) control many important agronomic traits, therefore the manipulation of BR components could improve crop productivity and performance. However, the potential effects of BR-related genes on yield-related traits and stress tolerance in wheat (Triticum aestivum L.) remain poorly understood. Here, we identified TaD11 genes in wheat (rice D11 orthologs) that encoded enzymes involved in BR biosynthesis. TaD11 genes were highly expressed in roots (Zadoks scale: Z11) and grains (Z75), while expression was significantly suppressed by exogenous BR (24-epiBL). Ectopic expression of TaD11-2A rescued the abnormal panicle structure and plant height (PH) of the cpb1 mutant, and also increased endogenous BR levels, resulting in improved grain yields and grain quality in rice. Natural variations in TaD11-2A were associated with significant differences in yield-related traits, including PH, grain width (GW), 1000-grain weight (TGW), and grain yield per plant (GYPP), and its favorable haplotype, TaD11-2A-HapI was subjected to positive selection during wheat breeding. Additionally, TaD11-2A influenced root length and salt tolerance in rice and wheat at seedling stages. These results indicated the important role of BR TaD11 biosynthetic genes in controlling grain size and root length, and also highlighted their potential in the molecular biological analysis of wheat. HighlightThe brassinosteroid biosynthesis gene TaD11-2A regulates grain size and root length and its haplotype favorably improves grain yields and salt tolerance in wheat.

plant biology↗

Isocitrate dehydrogenase 3b is required for spermiogenesis but dispensable for retinal degeneration

Isocitrate dehydrogenase 3 (IDH3), a key enzyme in mitochondrial tricarboxylic acid (TCA) cycle, catalyzes the decarboxylation of isocitrate into -ketoglutarate (KG), converting NAD+ into NADH. We have found that IDH3 {beta} subunit (IDH3B) is essential for IDH3 activity in multiple tissues. Loss of Idh3b in mice causes substantial accumulation of the isocitrate and its precursors in the TCA cycle, particularly in the testes, whereas the levels of the downstream metabolites remain unchanged or slightly increased. The Idh3b-knockout (KO) mice have normal visual function without retinal degeneration. However, the male KO mice are infertile. Loss of Idh3b causes energetic deficit and disrupts the biogenesis of acrosome and flagellum, resulting in spermiogenesis arrestment in sperm cells. Together, we demonstrate IDH3B controls its substrate levels in the TCA cycle and it is required for sperm mitochondrial metabolism and spermiogenesis, highlighting the importance of the tissue-specific function of the ubiquitous TCA cycle.

biochemistry↗

Hedgehogs are the major amplifying hosts of severe fever with thrombocytopenia syndrome virus

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne bandavirus mainly transmitted by Haemaphysalis longicornis in East Asia, mostly in rural areas. To date, the amplifying host involved in the natural transmission of SFTSV remains unidentified. Our epidemiological field survey conducted in endemic areas in China showed that hedgehogs were widely distributed, had heavy tick infestations, and had high SFTSV seroprevalence and RNA prevalence. After experimental infection of Erinaceus amurensis and Atelerix albiventris hedgehogs with SFTSV, robust but transitory viremias were detected, which lasted for around nine to eleven days. The infected hedgehogs experienced light weight loss and histopathology of the spleen showed hemorrhagic necrosis and lymphopenia, with infected hedgehogs recovering after viral clearance. Remarkably, SFTSV transmission cycle between hedgehogs and nymph/adult H. longicornis was easily accomplished under laboratory condition with 100% efficiency. Furthermore, naive H. longicornis ticks could be infected by SFTSV-positive ticks co-feeding on naive hedgehogs, with transstadial transmission of SFTSV also confirmed. We also found that SFTSV viremia remained high in hedgehogs during hibernation, suggesting that this mechanism might contribute to the persistence of SFTSV from one year to the next. Of concern, we recently found evidence of the natural circulation of SFTSV in the urban area of Beijing City in China involving H. longicornis ticks and E. amurensis hedgehogs. Our study suggests that the hedgehogs are the major wildlife amplifying hosts of SFTSV and that urban outbreaks of SFTSV might occur in the future.

microbiology↗