Molecular epidemiological study of Scrub Typhus in residence, farm and forest habitats from Yunnan Province, China.

The number of people suffering from scrub typhus, which is not of concern, is increasing year by year, especially in Yunnan Province, China. From June 1, 2021 to August 15, 2022, a total of 505 mammalian samples were collected from farm, forest, and residential habitats with high incidence of scrub typhus in Yunnan, China, for nPCR (nested PCR) and qPCR (quantitative real-time PCR) detection of Orientia tsutsugamushi. A total of 4 orders of murine-like animals, Rodentia (87.52%, n = 442), Insectivora (10.29%, n = 52), Lagomorpha (1.79%, n = 9) and Scandentia (0.40%, n = 2) were trapped. Comparing the qPCR infection rates in the three habitats, it was no significant difference that the infection rate of residential habitat (44.44%) and that of the farm habitat (45.05%, P>0.05), which is much larger than that of the forest habitat (3.08%) (P<0.001). Three genotypes (Karp-like, Kato-like and TA763-like) of O. tsutsugamushi were found from Yunnan, China in this study.

Metagenomic analysis of individual mosquito viromes reveals the geographical patterns and drivers of viral diversity.

Mosquito transmitted viruses are responsible for an increasing burden of human disease. Despite this, little is known about the diversity and ecology of viruses within individual mosquito hosts. Here, using a meta-transcriptomic approach, we determined the viromes of 2,438 individual mosquitoes (81 species), spanning ~4,000 km along latitudes and longitudes in China. From these data we identified 393 viral species associated with mosquitoes, including 7 (putative) species of arthropod-borne viruses (that is, arboviruses). We identified potential mosquito species and geographic hotspots of viral diversity and arbovirus occurrence, and demonstrated that the composition of individual mosquito viromes was strongly associated with host phylogeny. Our data revealed a large number of viruses shared among mosquito species or genera, enhancing our understanding of the host specificity of insect-associated viruses. We also detected multiple virus species that were widespread throughout the country, perhaps reflecting long-distance mosquito dispersal. Together, these results greatly expand the known mosquito virome, linked viral diversity at the scale of individual insects to that at a country-wide scale, and offered unique insights into the biogeography and diversity of viruses in insect vectors.

Metagenomic analysis of individual mosquitos reveals the ecology of insect viruses.

Mosquito transmitted viruses are responsible for an increasing burden of human disease. Despite this, little is known about the diversity and ecology of viruses within individual mosquito hosts. Using a meta-transcriptomic approach, we analysed the virome of 2,438 individual mosquitos (79 species), spanning ~4000 km along latitudes and longitudes in China. From these data we identified 393 core viral species associated with mosquitos, including seven (putative) arbovirus species. We identified potential species and geographic hotspots of viral richness and arbovirus occurrence, and demonstrated that host phylogeny had a strong impact on the composition of individual mosquito viromes. Our data revealed a large number of viruses shared among mosquito species or genera, expanding our knowledge of host specificity of insect-associated viruses. We also detected multiple virus species that were widespread throughout the country, possibly facilitated by long-distance mosquito migrations. Together, our results greatly expand the known mosquito virome, linked the viral diversity at the scale of individual insects to that at a country-wide scale, and offered unique insights into the ecology of viruses of insect vectors.

Individual bat virome analysis reveals co-infection and spillover among bats and virus zoonotic potential.

Bats are reservoir hosts for many zoonotic viruses. Despite this, relatively little is known about the diversity and abundance of viruses within individual bats, and hence the frequency of virus co-infection and spillover among them. We characterize the mammal-associated viruses in 149 individual bats sampled from Yunnan province, China, using an unbiased meta-transcriptomics approach. This reveals a high frequency of virus co-infection (simultaneous infection of bat individuals by multiple viral species) and spillover among the animals studied, which may in turn facilitate virus recombination and reassortment. Of note, we identify five viral species that are likely to be pathogenic to humans or livestock, based on phylogenetic relatedness to known pathogens or in vitro receptor binding assays. This includes a novel recombinant SARS-like coronavirus that is closely related to both SARS-CoV and SARS-CoV-2. In vitro assays indicate that this recombinant virus can utilize the human ACE2 receptor such that it is likely to be of increased emergence risk. Our study highlights the common occurrence of co-infection and spillover of bat viruses and their implications for virus emergence.

Sclerotherapy for congenital vascular malformations with mixing foam of polidocanol and liquid of bleomycin.

OBJECTIVE: To evaluate the efficacy of sclerotherapy for congenital vascular malformation (CVM) using a combination of polidocanol foam and bleomycin liquid. METHODS: A retrospective review of a prospectively collected data on patients who had sclerotherapy for CVM from May 2015 to July 2022 was performed. RESULTS: A total of 210 patients with a mean age of 24.8 ± 2.0 years were included. Venous malformation (VM) was the most common type of CVM, accounting for 81.9% (172/210) of all patients. At 6 months follow-up, the overall clinical effective rate was 93.3% (196/210), and 50% (105/210) of patients were clinically cured. The clinical effective rates in VM, lymphatic, and arteriovenous malformation group were 94.2%, 100%, and 100%. CONCLUSION: Sclerotherapy using a combination of polidocanol foam and bleomycin liquid is an effective and safe treatment for venous and lymphatic malformations. It is a promising treatment option with satisfactory clinical outcome in arteriovenous malformations.

[Mammalian DMRTs: Structure, function and relationship with cancer].

DMRT, a gene family related to sexual determination, encodes a large group of transcription factors (DMRTs) with the double-sex and mab-3 (DM) domain (except for DMRT8), which is able to bind to and regulate DNAs. Current studies have shown that the DMRT gene family plays a critical role in the development of sexual organs (such as gender differentiation, gonadal development, germ cell development, etc.) as well as extrasexual organs (such as musculocartilage development, nervous system development, etc.). Additionally, it has been suggested that DMRTs may be involved in the cancer development and progression (such as prostate cancer, breast cancer, lung cancer, etc.). This review summarizes the research progress about the mammalian DMRTs' structure, function and its critical role in cancer development, progression and therapy (mainly in human and mice), which suggests that DMRT gene could be a candidate gene in the study of tumor formation and therapeutic strategy.

Repressing IRS1/2 by NT157 inhibits the malignant behaviors of ovarian cancer through inactivating PI3K/AKT/mTOR pathway and inducing autophagy.

Insulin receptor substrate 1 and 2 (IRS1/2) have been found involved in many cancers development and their inhibitors exert significant tumor-suppressive effects. Here, we tried to explore the function of NT157, an IGF1R-IRS1/2 inhibitor, in ovarian cancer. We treated ovarian cancer cells with varying doses of NT157. The MTT assay was employed to evaluate cell proliferation and colony formation assay was used for detecting colony-forming ability. TUNEL assay was adopted to test cell apoptosis. Cell invasion was checked by the Transwell assay. The expression of apoptosis-related proteins, autophagy markers, IRS1/2, and PI3K/AKT/mTOR pathway was compared by Western blot, immunofluorescence, or qRT-PCR. As indicated by the data, NT157 abated the viability, proliferation, and induced autophagy of ovarian cancer cells. Overexpressing IRS1/2 attenuated the tumor-suppressive effect of NT157 and heightened the PI3K/AKT/mTOR pathway activation. Inhibition of the PI3K/AKT/mTOR pathway enhanced the tumor-suppressive effect of NT157 and facilitated NT157-mediated autophagy. However, the autophagy inhibitor 3-MA partly reversed NT-157-mediated antitumor effects. In conclusion, this study disclosed that NT157 suppressed the malignant phenotypes of ovarian cancer cells by inducing autophagy and hampering the expression of IRS1/2 and PI3K/AKT/mTOR pathway.

Individual bat viromes reveal the co-infection, spillover and emergence risk of potential zoonotic viruses.

Bats are reservoir hosts for many zoonotic viruses. Despite this, relatively little is known about the diversity and abundance of viruses within bats at the level of individual animals, and hence the frequency of virus co-infection and inter-species transmission. Using an unbiased meta-transcriptomics approach we characterised the mammalian associated viruses present in 149 individual bats sampled from Yunnan province, China. This revealed a high frequency of virus co-infection and species spillover among the animals studied, with 12 viruses shared among different bat species, which in turn facilitates virus recombination and reassortment. Of note, we identified five viral species that are likely to be pathogenic to humans or livestock, including a novel recombinant SARS-like coronavirus that is closely related to both SARS-CoV-2 and SARS-CoV, with only five amino acid differences between its receptor-binding domain sequence and that of the earliest sequences of SARS-CoV-2. Functional analysis predicts that this recombinant coronavirus can utilize the human ACE2 receptor such that it is likely to be of high zoonotic risk. Our study highlights the common occurrence of inter-species transmission and co-infection of bat viruses, as well as their implications for virus emergence.

A time-series meta-transcriptomic analysis reveals the seasonal, host, and gender structure of mosquito viromes.

Although metagenomic sequencing has revealed high numbers of viruses in mosquitoes sampled globally, our understanding of how their diversity and abundance varies in time and space as well as by host species and gender remains unclear. To address this, we collected 23,109 mosquitoes over the course of 12 months from a bat-dwelling cave and a nearby village in Yunnan province, China. These samples were organized by mosquito species, mosquito gender, and sampling time for meta-transcriptomic sequencing. A total of 162 eukaryotic virus species were identified, of which 101 were novel, including representatives of seventeen RNA virus multi-family supergroups and four species of DNA virus from the families Parvoviridae, Circoviridae, and Nudiviridae. In addition, two known vector-borne viruses-Japanese encephalitis virus and Banna virus-were found. Analyses of the entire virome revealed strikingly different viral compositions and abundance levels in warmer compared to colder months, a strong host structure at the level of mosquito species, and no substantial differences between those viruses harbored by male and female mosquitoes. At the scale of individual viruses, some were found to be ubiquitous throughout the year and across four mosquito species, while most of the other viruses were season and/or host specific. Collectively, this study reveals the diversity, dynamics, and evolution of the mosquito virome at a single location and sheds new lights on the ecology of these important vector animals.

Systematic review of comparing single-incision versus conventional laparoscopic right hemicolectomy for right colon cancer.

BACKGROUND: Single-incision laparoscopic right hemicolectomy (SILS) has long used in surgery for a long time. However, there is barely a systemic review related to the comparison between the SILS and the conventional laparoscopic right hemicolectomy (CLS) for the right colon cancer in the long term follow-up. Herein, we used the most recent articles to compare these two techniques by meta-analysis. METHODS: We searched PubMed, Web of Science, Cochrane Library and Wanfang databases to compare SILS with CLS for right colon cancer up to May 2019. The operative, postoperative, pathological and mid-term follow-up outcomes of nine studies were extracted and compared. RESULTS: A total of 1356 patients participated in 9 studies, while 653 patients were assigned to the SILS group and 703 patients were assigned to the CLS group. The patients' baselines in the SILS group were consistent with those in the CLS group. Compared to the CLS group, the SILS group had a shorter operation duration (SMD - 23.49, 95%CI - 36.71 to - 10.27, P < 0.001, chi-square = 24.11), shorter hospital stay (SMD - 0.76, 95% `CI - 1.07 to - 0.45, P < 0.001, chi-square = 9.85), less blood loss (SMD - 8.46, 95% CI - 14.59 to - 2.34; P < 0.05; chi-square = 2.26), smaller incision length (SMD - 1.60, 95% CI - 2.66 to - 0.55, P < 0.001; chi-square = 280.44), more lymph node harvested (SMD - 0.98, 95% CI - 1.79 to - 0.16, P < 0.05; chi-square = 4.61), and a longer proximal surgical edge (SMD - 0.51, 95% CI - 0.93 to - 0.09, P < 0.05; chi-square = 2.42). No significant difference was found in other indexes. After we removed a single large study, we performed another meta-analysis again. The operation duration in the SILS group was still better than that in the CLS group. CONCLUSION: SILS could be a faster and more reliable approach than CLS for the right colon cancer and could accelerate patient recovery, especially for patients with a low BMI.

Detection and genome characterization of two novel papillomaviruses and a novel polyomavirus in tree shrew (Tupaia belangeri chinensis) in China.

BACKGROUND: Papillomaviruses (PVs) and polyomaviruses (PyVs) infect diverse vertebrates including human and cause a broad spectrum of outcomes from asymptomatic infection to severe disease. There has been no PV and only one PyV detected in tree shrews, though the genomic properties of tree shrews are highly similar to those of the primates. METHODS: Swab and organ samples of tree shrews collected in the Yunnan Province of China, were tested by viral metagenomic analysis and random PCR to detect the presence of PVs and PyVs. By PCR amplification using specific primers, cloning, sequencing and assembling, genomes of two PVs and one PyV were identified in the samples. RESULTS: Two novel PVs and a novel PyV, named tree shrew papillomavirus 1 and 2 (TbelPV1 and TbelPV2) and polyomavirus 1 (TbelPyV1) were characterized in the Chinese tree shrew (Tupaia belangeri chinensis). The genomes of TbelPV1, TbelPV2, and TbelPyV1 are 7410 bp, 7526 bp, and 4982 bp in size, respectively. The TbelPV1 genome contains 7 putative open-reading frames (ORFs) coding for viral proteins E1, E2, E4, E6, E7, L1, and L2; the TbelPV2 genome contains 6 ORFs coding for viral proteins E1, E2, E6, E7, L1, and L2; and the TbelPyV1 genome codes for the typical small and large T antigens of PyV, as well as the VP1, VP2, and VP3 capsid proteins. Genomic comparison and phylogenetic analysis indicated that TbelPV1 and TbelPV2 represented 2 novel PV genera of Papillomaviridae, and TbelPyV1 represented a new species of genus Alphapolyomavirus. Our epidemiologic study indicated that TbelPV1 and TbelPV2 were both detected in oral swabs, while TbelPyV1 was detected in oral swabs and spleens. CONCLUSION: Two novel PVs (TbelPV1 and TbelPV2) and a novel PyV (TbelPyV) were discovered in tree shrews and their genomes were characterized. TbelPV1, TbelPV2, and TbelPyV1 have the highest similarity to Human papillomavirus type 63, Ursus maritimus papillomavirus 1, and Human polyomavirus 9, respectively. TbelPV1 and TbelPV2 only showed oral tropism, while TbelPyV1 showed oral and spleen tropism.

Drug Treatment of Hyperlipidemia in Chinese Patients: Focus on the Use of Simvastatin and Ezetimibe Alone and in Combination.

Elevated serum low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease (CHD). Many guidelines recommend LDL-C as a primary treatment target, and statins represent the cornerstone of treatment for lipid management. Recently revised guidelines recommend even more intense management of LDL-C, especially in patients at moderate and high risk. However, LDL-C levels in the Chinese population differ from those in Western populations, and the benefits and safety of the maximum allowable dose of statins have yet to be determined. Furthermore, in practice, many patients do not achieve the increasingly stringent LDL-C goals. Consequently, alternative approaches to lipid management are required. Combination therapy with ezetimibe and a statin, which have complementary mechanisms of action, is more effective than statin monotherapies, even at high doses. Several clinical studies have consistently shown that combination therapy with ezetimibe and simvastatin lowers LDL-C more potently than statin monotherapies. Moreover, the safety and tolerability profile of the combination therapy appears to be similar to that of low-dose statin monotherapies. This review discusses the role of simvastatin in combination with ezetimibe in controlling dyslipidemia in Chinese patients, particularly the efficacy and safety of combination therapy in light of recently published clinical data.

Chevrier's Field Mouse (Apodemus chevrieri) and Père David's Vole (Eothenomys melanogaster) in China Carry Orthohepeviruses that form Two Putative Novel Genotypes Within the Species Orthohepevirus C.

Hepatitis E virus (HEV) is the prototype of the family Hepeviridae and the causative agent of common acute viral hepatitis. Genetically diverse HEV-related viruses have been detected in a variety of mammals and some of them may have zoonotic potential. In this study, we tested 278 specimens collected from seven wild small mammal species in Yunnan province, China, for the presence and prevalence of orthohepevirus by broad-spectrum reverse transcription (RT)-PCR. HEV-related sequences were detected in two rodent species, including Chevrier's field mouse (Apodemus chevrieri, family Muridae) and Père David's vole (Eothenomys melanogaster, family Cricetidae), with the infection rates of 29.20% (59/202) and 7.27% (4/55), respectively. Further four representative full-length genomes were generated: two each from Chevrier's field mouse (named RdHEVAc14 and RdHEVAc86) and Père David's vole (RdHEVEm40 and RdHEVEm67). Phylogenetic analyses and pairwise distance comparisons of whole genome sequences and amino acid sequences of the gene coding regions showed that orthohepeviruses identified in Chinese Chevrier's field mouse and Père David's vole belonged to the species Orthohepevirus C but were highly divergent from the two assigned genotypes: HEV-C1 derived from rat and shrew, and HEV-C2 derived from ferret and possibly mink. Quantitative real-time RT-PCR demonstrated that these newly discovered orthohepeviruses had hepatic tropism. In summary, our work discovered two putative novel genotypes orthohepeviruses preliminarily named HEV-C3 and HEV-C4 within the species Orthohepevirus C, which expands our understanding of orthohepevirus infection in the order Rodentia and gives new insights into the origin, evolution, and host range of orthohepevirus.

Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis.

Sterile inflammation after tissue damage is a ubiquitous response, yet it has the highest amplitude in the liver. This has major clinical consequences, for alcoholic and non-alcoholic steatohepatitis (ASH and NASH) account for the majority of liver disease in industrialized countries and both lack therapy. Requirements for sustained sterile inflammation include increased oxidative stress and activation of the HIF-1α signaling pathway. We demonstrate the ability of digoxin, a cardiac glycoside, to protect from liver inflammation and damage in ASH and NASH. Digoxin was effective in maintaining cellular redox homeostasis and suppressing HIF-1α pathway activation. A proteomic screen revealed that digoxin binds pyruvate kinase M2 (PKM2), and independently of PKM2 kinase activity results in chromatin remodeling and downregulation of HIF-1α transactivation. These data identify PKM2 as a mediator and therapeutic target for regulating liver sterile inflammation, and demonstrate a novel role for digoxin that can effectively protect the liver from ASH and NASH.

Regulation of UGT1A expression by miR-298 in human livers from the Han Chinese population and in human cell lines.

AIM: This study aimed to investigate the role of miRNAs in UGT1A regulation. MATERIALS & METHODS: Based on bioinformatic prediction results, luciferase reporter assay and cell-transfection experiments were performed to study effects of miR-298 on UGT1A expression. Correlation study was conducted in human livers. RESULTS: miR-298 overexpression reduced mRNA level of UGT1A1 and UGT1A4 in HepG2 and LS174T cells, and that of UGT1A3 and UGT1A9 in LS174T cells. miR-298 repression increased mRNA level of UGT1A4 in HepG2 and LS174T cells, and that of UGT1A1 and UGT1A3 in LS174T cells. Inverse correlations between miR-298, as well as miR-491-3p, and UGT1A3 and 1A4 mRNA levels were observed in livers. CONCLUSION: The study demonstrates that miR-298 and miR-491-3p downregulates UGT1A expression.

Detection of alpha- and betacoronaviruses in rodents from Yunnan, China.

BACKGROUND: Rodents represent the most diverse mammals on the planet and are important reservoirs of human pathogens. Coronaviruses infect various animals, but to date, relatively few coronaviruses have been identified in rodents worldwide. The evolution and ecology of coronaviruses in rodent have not been fully investigated. RESULTS: In this study, we collected 177 intestinal samples from thress species of rodents in Jianchuan County, Yunnan Province, China. Alphacoronavirus and betacoronavirus were detected in 23 rodent samples from three species, namely Apodemus chevrieri (21/98), Eothenomys fidelis (1/62), and Apodemus ilex (1/17). We further characterized the full-length genome of an alphacoronavirus from the A. chevrieri rat and named it as AcCoV-JC34. The AcCoV-JC34 genome was 27,649 nucleotides long and showed a structure similar to the HKU2 bat coronavirus. Comparing the normal transcription regulatory sequence (TRS), 3 variant TRS sequences upstream the spike (S), ORF3, and ORF8 genes were found in the genome of AcCoV-JC34. In the conserved replicase domains, AcCoV-JC34 was most closely related to Rattus norvegicus coronavirus LNRV but diverged from other alphacoronaviruses, indicating that AcCoV-JC34 and LNRV may represent a novel alphacoronavirus species. However, the S and nucleocapsid proteins showed low similarity to those of LRNV, with 66.5 and 77.4% identities, respectively. Phylogenetic analysis revealed that the S genes of AcCoV-JC34, LRNV, and HKU2 formed a distinct lineage with all known coronaviruses. CONCLUSIONS: Both alphacoronaviruses and betacoronaviruses were detected in Apodemus chevrieri in the Yunnan Province of China, indicating that Apodemus chevrieri is an important host for coronavirus. Several new features were identified in the genome of an Apodemus chevrieri coronavirus. The phylogenetic distance to other coronaviruses suggests a variable origin and evolutionary route of the S genes of AcCoV-JC34, LRNV, and HKU2. These results indicate that the diversity of rodent coronaviruses is much higher than previously expected. Further surveillance and functional studies of these coronaviruses will help to better understand the importance of rodent as host for coronaviruses.

Developmental regulation of CYP3A4 and CYP3A7 in Chinese Han population.

CYP3A4 and CYP3A7 are generally served as the major adult and fetal liver forms, respectively, and exhibited a developmental switch during liver maturation. The objective of this study was to explore the potential mechanisms associated with the developmental switch of CYP3A4 and CYP3A7 in the Chinese Han population. We analyzed CYP3A4/7, nuclear receptors, and epigenetic modifications in human liver samples. We found that the expression levels of CYP3A4 mRNA in adults were significantly higher than the levels in fetus. In contrast, CYP3A7 mRNA expression reached a maximal level at an estimated gestational age of 25 weeks and then substantially decreased during the first year after birth. We also found that the expression level of hepatocyte nuclear factor 4 alpha (HNF4A) was most associated with CYP3A4 expression in adult liver; whereas the expression level of glucocorticoid receptor (GR) was intensively correlated with CYP3A7 expression in fetal liver. Furthermore, we illustrated the dynamic changes of H3K4me2 and H3K27me3 in the developmental switch of CYP3A7 and CYP3A4. In summary, our data suggested that HNF4A and GR, and epigenetic changes of H3K4me2 and H3K27me3 are associated with the ontogenic expressions of CYP3A4/3A7 in the livers of the Chinese Han population.

Fugong virus, a novel hantavirus harbored by the small oriental vole (Eothenomys eleusis) in China.

BACKGROUND: Rodents are natural reservoirs of hantaviruses, which cause two disease types: hemorrhagic fever with renal syndrome in Eurasia and hantavirus pulmonary syndrome in North America. Hantaviruses related human cases have been observed throughout Asia, Europe, Africa, and North America. To date, 23 distinct species of hantaviruses, hosted by reservoir, have been identified. However, the diversity and number of hantaviruses are likely underestimated in China, and hantavirus species that cause disease in many regions, including Yunnan province, are unknown. RESULTS: In August 2012, we collected tissue samples from 189 captured animals, including 15 species belonging to 10 genera, 5 families, and 4 orders in Fugong county, Yunnan province, China. Seven species were positive for hantavirus: Eothenomys eleusis (42/94), Apodemus peninsulae (3/25), Niviventer eha (3/27), Cryptotis montivaga (2/8), Anourosorex squamipes (1/1), Sorex araneus (1/1), and Mustela sibirica (1/2). We characterized one full-length genomic sequence of the virus (named fugong virus, FUGV) from a small oriental vole (Eothenomys eleusis). The full-length sequences of the small, medium, and large segments of FUGV were 1813, 3630, and 6531 nt, respectively. FUGV was most closely related to hantavirus LX309, a previously reported species detected in the red-backed vole in Luxi county, Yunnan province, China. However, the amino acid sequences of nucleocapsid (N), glycoprotein (G), and large protein (L) were highly divergent from those of Hantavirus LX309, with amino acid differences of 11.2, 15.3, and 12.7 %, respectively. In phylogenetic trees, FUGV clustered in the lineage corresponding to hantaviruses carried by rodents in the subfamily Arvicolinae. CONCLUSIONS: High prevalence of hantavirus infection in small mammals was found in Fugong county, Yunnan province, China. A novel hantavirus species FUGV was identified from the small oriental vole. This virus is phylogenetic clustering with another hantavirus LX309, but shows highly genomic divergence.