Highly homologous miR-135a and miR-135b converting non-small cell lung cancer from suppression to progression via enhancer switching.

microRNAs (miRNAs) are short non-coding RNAs that have been increasingly recognized for their significant roles in the progression of cancer. Distinct miRNAs exhibit diverse functions attributed to variations in their sequences. As a result of possessing highly homologous seed sequences, these miRNAs target overlapping or similar gene sets, thus performing analogous roles. However, different from this sight, our study discovered that miR-135a-5p and miR-135b-5p, despite differing by only one nucleotide, exhibit distinct functional roles. Using non-small cell lung cancer (NSCLC) as a paradigm, our findings unveiled the downregulation of miR-135a-5p and upregulation of miR-135b-5p within NSCLC through TCGA database. Consequently, we further investigated their functional differences in A549 cells. Overexpression of miR-135b-5p enhanced the proliferation and migration capabilities of A549 cells, whereas miR-135a-5p transfection exhibited the opposite effect. We demonstrated that the activation of specific enhancers serves as a crucial mechanism underlying the disparate functions exerted by miR-135a-5p and miR-135b-5p in the context of NSCLC, consequently instigating a shift from inhibition to activation in NSCLC progression. Finally, we validated through animal experiments that miR-135b-5p promoted tumor progression, while miR-135a-5p exerted inhibitory effects on NSCLC development. This study offers a novel perspective for researchers to elucidate functional disparities exhibited by highly homologous miRNAs (miR-135a-5p and miR-135b-5p) in the context of NSCLC, along with the transition from inhibitory to progressive states in NSCLC. This study provides a solid foundation for future investigations into the functional roles of highly homologous miRNAs in pathological situation.

miR-1246 promotes osteosarcoma cell migration via NamiRNA-enhancer network dependent on Argonaute 2.

High metastatic propensity of osteosarcoma leads to its therapeutic failure and poor prognosis. Although nuclear activation miRNAs (NamiRNAs) are reported to activate gene transcription via targeting enhancer and further promote tumor metastasis, it remains uncertain whether NamiRNAs regulate osteosarcoma metastasis and their exact mechanism. Here, we found that extracellular vesicles of the malignant osteosarcoma cells (143B) remarkably increased the migratory abilities of MNNG cells representing the benign osteosarcoma cells by two folds, which attributed to their high miR-1246 levels. Specially, miR-1246 located in nucleus could activate the migration gene expression (such as MMP1) to accelerate MNNG cell migration through elevating the enhancer activities via increasing H3K27ac enrichment. Instead, MMP1 expression was dramatically inhibited after Argonaute 2 (AGO2) knockdown. Notably, in vitro assays demonstrated that AGO2 recognized the hybrids of miR-1246 and its enhancer DNA via PAZ domains to prevent their degradation from RNase H and these protective roles of AGO2 may favor the gene activation by miR-1246 in vivo. Collectively, our findings suggest that miR-1246 could facilitate osteosarcoma metastasis through interacting with enhancer to activate gene expression dependent on AGO2, highlighting the nuclear AGO2 as a guardian for NamiRNA-targeted gene activation and the potential of miR-1246 for osteosarcoma metastasis therapy.

PCDHGB7 hypermethylation-based Cervical cancer Methylation (CerMe) detection for the triage of high-risk human papillomavirus-positive women: a prospective cohort study.

BACKGROUND: Implementation of high-risk human papillomavirus (hrHPV) screening has greatly reduced the incidence and mortality of cervical cancer. However, a triage strategy that is effective, noninvasive, and independent from the subjective interpretation of pathologists is urgently required to decrease unnecessary colposcopy referrals in hrHPV-positive women. METHODS: A total of 3251 hrHPV-positive women aged 30-82 years (median = 41 years) from International Peace Maternity and Child Health Hospital were included in the training set (n = 2116) and the validation set (n = 1135) to establish Cervical cancer Methylation (CerMe) detection. The performance of CerMe as a triage for hrHPV-positive women was evaluated. RESULTS: CerMe detection efficiently distinguished cervical intraepithelial neoplasia grade 2 or worse (CIN2 +) from cervical intraepithelial neoplasia grade 1 or normal (CIN1 -) women with excellent sensitivity of 82.4% (95% CI = 72.6 ~ 89.8%) and specificity of 91.1% (95% CI = 89.2 ~ 92.7%). Importantly, CerMe showed improved specificity (92.1% vs. 74.9%) in other 12 hrHPV type-positive women as well as superior sensitivity (80.8% vs. 61.5%) and specificity (88.9% vs. 75.3%) in HPV16/18 type-positive women compared with cytology testing. CerMe performed well in the triage of hrHPV-positive women with ASC-US (sensitivity = 74.4%, specificity = 87.5%) or LSIL cytology (sensitivity = 84.4%, specificity = 83.9%). CONCLUSIONS: PCDHGB7 hypermethylation-based CerMe detection can be used as a triage strategy for hrHPV-positive women to reduce unnecessary over-referrals. TRIAL REGISTRATION: ChiCTR2100048972. Registered on 19 July 2021.

Modelling the dynamic basic reproduction number of dengue based on MOI of Aedes albopictus derived from a multi-site field investigation in Guangzhou, a subtropical region.

BACKGROUND: More than half of the global population lives in areas at risk of dengue (DENV) transmission. Developing an efficient risk prediction system can help curb dengue outbreaks, but multiple variables, including mosquito-based surveillance indicators, still constrain our understanding. Mosquito or oviposition positive index (MOI) has been utilized in field surveillance to monitor the wild population density of Aedes albopictus in Guangzhou since 2005. METHODS: Based on the mosquito surveillance data using Mosq-ovitrap collection and human landing collection (HLC) launched at 12 sites in Guangzhou from 2015 to 2017, we established a MOI-based model of the basic dengue reproduction number (R0) using the classical Ross-Macdonald framework combined with a linear mixed-effects model. RESULTS: During the survey period, the mean MOI and adult mosquito density index (ADI) using HLC for Ae. albopictus were 12.96 ± 17.78 and 16.79 ± 55.92, respectively. The R0 estimated from the daily ADI (ADID) showed a significant seasonal variation. A 10-unit increase in MOI was associated with 1.08-fold (95% CI 1.05, 1.11) ADID and an increase of 0.14 (95% CI 0.05, 0.23) in the logarithmic transformation of R0. MOI-based R0 of dengue varied by month and average monthly temperature. During the active period of Ae. albopictus from April to November in Guangzhou region, a high risk of dengue outbreak was predicted by the MOI-based R0 model, especially from August to October, with the predicted R0 > 1. Meanwhile, from December to March, the estimates of MOI-based R0 were < 1. CONCLUSIONS: The present study enriched our knowledge about mosquito-based surveillance indicators and indicated that the MOI of Ae. albopictus could be valuable for application in estimating the R0 of dengue using a statistical model. The MOI-based R0 model prediction of the risk of dengue transmission varied by month and temperature in Guangzhou. Our findings lay a foundation for further development of a complex efficient dengue risk prediction system.

Activating transcription factor 3 is a new biomarker correlation with renal clear cell carcinoma progression.

Background: Clear cell renal cell carcinoma (ccRCC) is the most invasive type of cancer, with a high risk of metastasis and recurrence. Therefore, there is an urgent need to identify novel prognostic predictors and therapeutic targets of ccRCC. Activating transcription factor 3 (ATF3), a tumor oncogene or repressor, has rarely been examined in ccRCC. In the present study, we comprehensively elucidate the prognostic value and potential functions of ATF3 in ccRCC.Methods: Several TCGA-based online databases were used to analyze ATF3 expression in ccRCC and determine ccRCC prognosis. The upstream-binding micro (mi) RNAs of ATF3 and long non-coding (lnc)RNAs were predicted using the StarBase database.Results: Analysis of several TCGA-based online databases showed that ATF3 expression is decreased in ccRCC, suggesting a significant association with the prognosis of patients with ccRCC. Furthermore, we found hsa-miR-221-3p to be potential regulatory miRNA of ATF3 in ccRCC. Prediction and analysis of the upstream lncRNAs indicated that PAXIP1-AS2 and OIP5-AS1 were the most potent upstream lncRNAs of the hsa-miR-221-3p/ATF3 axis in ccRCC. The results of the GO and KEGG analyses implied that ATF3 is likely involved in the regulation of apoptotic signaling in response to endoplasmic reticulum (ER) stress in ccRCC. Correlation analysis revealed a positive relationship between ATF3 expression and ER stress.Conclusions: Our in silico findings highlighted that ATF3 expression was low in ccRCC and negatively correlated with poor prognosis. Furthermore, PAXIP1-AS2 and the OIP5-AS1/hsa-miR-221-3p/ATF3 axis were identified as significant potential regulators of ER stress-mediated apoptosis in ccRCC.

Down-regulation of interleukin-2 predicts poor prognosis and associated with immune escape in lung adenocarcinoma.

Background and Objective: Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and has a poor prognosis. Interleukin-2 (IL2) is a cytokine that stimulates lymphocyte proliferation. However, its role in LUAD remains unclear. Methods: The UALCAN, human protein atlas (HPA), and tumor immune estimation resource (TIMER) databases were used to investigate IL2 expression in samples from patients with LUAD. The HPA, PrognoScan, and Kaplan-Meier plotter databases were used to examine the prognostic value of IL2 in LUAD. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to analyze IL2-interacting genes identified through the GeneMANIA database. TIMER was used to analyze the correlation of IL2 expression with immune cell infiltration and immune checkpoint expression levels in LUAD. Results: Bioinformatic analysis using the TIMER, The University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), and HPA public databases showed that IL2 expression was lower in patients with LUAD than in the normal control group. Moreover, patients with low IL2 expression exhibited poor overall survival. Furthermore, IL2 expression was significantly positively correlated with various immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells, in patients with LUAD. Additionally, IL2 expression was markedly positively associated with the above-mentioned immune cells. Furthermore, IL2 expression was positively correlated with PD-1, PD-L1, and CTLA-4 expression. Conclusion: Our results indicate that down-regulation of IL2 predicts poor prognosis and is associated with immune escape in LUAD, and IL2 could serve as a potential novel prognostic biomarker of LUAD.

Characteristics of leptospirosis cases, prevention and control managements 1955-2020, Guangzhou, China.

Background: Leptospirosis, which is an easily overlooked zoonotic disease, was once widespread in Guangzhou, China. However, due to the implementation of control measures, the number of cases is decreasing. Based on the characteristics of leptospirosis cases in Guangzhou, China, between 1955 and 2020, we describe the changes and achievements in prevention and control management strategies over that period. Methods: The development of the leptospirosis control system in Guangzhou occurred over three periods: Period I: 1955-1978; Period II: 1979-2000; and Period III: 2001-2020. Data about leptospirosis cases were obtained from the Guangzhou Center for Disease Control and Prevention (CDC) and national health departments. The demographic characteristics of leptospirosis patients were analyzed using descriptive statistics. Results: During Period I, only the Guangzhou CDC and medical institutions at every level participated in the leptospirosis control system. During Period II, additional types of organizations, including local CDCs, countryside committees, community committees, and the Patriotic Health Movement Commission, were involved in the control system. Additionally, strong links were established between different organizations. After entering Period III, an increasing number of departments joined the cooperation, and the management of human patients was expanded to include the management of host animals, and thus, the prevalence of leptospirosis was monitored and controlled in various ways. The leptospirosis control system in Guangzhou has been further improved. From 1955 to 2020, a total of 2501 leptospirosis cases were recorded in Guangzhou, and the number of cases decreased significantly over time, from 1608 (Period I) to 744 (Period II) and then to 149 (Period III). Conclusion: The improvements of the leptospirosis control system in Guangzhou that occurred over decades were associated with a marked decrease in the number of leptospirosis cases. Guangzhou's experience can provide guidance for other countries or cities around the world facing similar challenges.

One Health responses to prevent the occurrence of rabies due to attacks by a rabid stray dog.

BACKGROUND: The number of human rabies cases caused by pet dogs in Guangzhou has been decreasing after years of comprehensive interventions. Consequently, attacks by stray dogs become a major issue in rabies control. OBJECTIVES: To share our experience of successfully dealing with rabies to provide some inspiration for prevention and control in countries and regions affected by it. METHODS: A multidisciplinary One Health response was initiated to control this outbreak. Rabies virus was detected by PCR in the brain tissue of the associated stray dog. The sequences were aligned with reference sequences downloaded from GenBank using ClustalX. The maximum likelihood method implemented in MEGA 5.0 software package was used in a phylogenetic analysis of the aligned sequences. RESULTS: Twelve patients with exposure to the stray dog were identified in the field investigation. Rabies vaccines and immunoglobulin were administered to all patients within 48 h. After 1 year of follow-up, no exposed patients showed symptoms. Maximum likelihood analysis of the nucleotide sequences obtained from the PCR products indicated that the rabies virus in the dog was closely related to isolates from neighbouring provinces of Guangdong as well as those from surrounding countries of China. CONCLUSIONS: Multidisciplinary One Health intervention is effective not only in the control of rabies but also in rapid emergency responses to attacks by rabid stray dogs.

Associations between greenspace surrounding schools and lipid levels in Chinese children and teenagers.

Little evidence exists concerning the associations of greenspace with childhood lipid profiles and dyslipidemias, especially in developing countries and regions. We aimed to investigate the associations of greenspace surrounding schools with lipid levels and dyslipidemia prevalence among Chinese children and teenagers. We obtained baseline information and health data of 10,408 children and teenagers (aged 6-18 years) who studied from 94 schools in China. We measured levels of four blood lipids: triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Dyslipidemias were defined using standard recommendations. Greenness surrounding schools were assessed using two satellite-based greenness indices, Normalized Difference Vegetation Index (NDVI) and Soil Adjusted Vegetation Index (SAVI) at 300-, 500-, and 1000-m circular buffers based on each school's latitude and longitude. We used random forest model combined with meteorological and remote sensing data to estimate air pollution levels surrounding each school. We used generalized linear mixed models to estimate the associations of greenness with lipid levels and dyslipidemias prevalence. We also performed sub-group and mediation analyses. An interquartile range (IQR) increase in NDVI500m was significantly associated with a 0.064 mmol/L (95% confidence interval [CI]: 0.083, -0.045) and 0.049 mmol/L (95% CI: 0.065, -0.033) decreased TC and LDL-C levels, respectively, as well as a 0.13-fold (95% CI: 0.01, 0.23) and 0.17-fold (95% CI: 0.01, 0.30) decreased odds of hypercholesterolemia and hyperbetalipoproteinemia, respectively. Associations were stronger in students aged ≤12 years and born to parents having lower education levels compared to their counterparts. Particle with aerodynamic diameter ≤2.5 µm (PM2.5) mediated 61.5% and 16.7% of the association of greenness with TG and LDL-C levels, respectively. In summary, higher school-based greenness exposure was beneficially associated with lipid levels among Chinese children and adolescents, and part of the association can be explained by lowed PM2.5 levels.

Serum amyloid A (SAA) and Interleukin-6 (IL-6) as the potential biomarkers for gastric cancer.

To explore serum amyloid A (SAA) and interleukin-6 (IL-6) as potential diagnostic biomarkers for gastric cancer (GCa) and the application value of the combined diagnosis of SAA, IL6, and Cancer embryonic antigen. Serum samples were collected before the initial surgery from 159 patients comprising samples from 122 patients with GCa and 37 patients with benign gastric disease. All patients were hospitalized at Beijing Aerospace General Hospital in China between 2018 and 2020. The IL-6 and SAA levels were assessed using standard laboratory protocols. The levels of SAA and IL-6 were significantly higher in patients with GCa than in controls. Compared with the healthy group, the concentration of SAA and IL-6 in FIGO III-IV group were significantly higher and the difference were statistically significant. In addition, significant differences were observed between the FIGO III-IV group and FIGO I-II groups. The Receiver operating characteristic (ROC) curve for the combined detection of SAA, IL-6, and Cancer embryonic antigen showed an area under the curve (AUC) of 0.948, sensitivity of 91.0%, and specificity of 89.2%. Spearman's correlation analysis indicated obvious correlations among the levels of serum SAA, IL-6, advanced FIGO stage, lymphatic invasion, and distant metastasis. AA and IL-6 may serve as useful biomarkers for poor prognosis of GCa. Clinical diagnosis combined with SAA and IL-6 may help assess therapeutic outcomes.

Waning of maternal antibody against measles virus in Shufu, China.

BACKGROUND: As measles vaccination coverage has increased, measles infection has shifted to the population of infants. We conducted a follow-up seroepidemiological study among mothers and their infants to evaluate measles seroprevalence and the persistence of maternal measles antibody in Shufu, Kashgar from 2018 to 2020. METHODS: Maternal venous blood and cord blood was obtained among mothers and their infants at 0, 3, 5, 8, 9, and 12 months of age. An enzyme-linked immunosorbent assay was used for quantitative measurement of measles antibodies. We analyzed the correlation between maternal and neonatal measles antibodies, and antibodies persistence after infants were born. RESULTS: The overall neonatal maternal ratio was 2.38 (95%CI: 2.05-2.71). The measles antibodies for mothers and newborns were 438.93 IU/mL (95%CI: 409.47-470.51 IU/mL) and 440.10 IU/mL (95%CI: 410.82-471.48 IU/mL), respectively. Neonatal measles antibodies were dropping after birth and then beginning to increase starting at 8 months of age. CONCLUSIONS: Infant measles antibody levels progressively declined after birth regardless of maternal measles antibody levels. Efforts should be carried out to eliminate measles.

A unified global genotyping framework of dengue virus serotype-1 for a stratified coordinated surveillance strategy of dengue epidemics.

BACKGROUND: Dengue is the fastest spreading arboviral disease, posing great challenges on global public health. A reproduceable and comparable global genotyping framework for contextualizing spatiotemporal epidemiological data of dengue virus (DENV) is essential for research studies and collaborative surveillance. METHODS: Targeting DENV-1 spreading prominently in recent decades, by reconciling all qualified complete E gene sequences of 5003 DENV-1 strains with epidemiological information from 78 epidemic countries/areas ranging from 1944 to 2018, we established and characterized a unified global high-resolution genotyping framework using phylogenetics, population genetics, phylogeography, and phylodynamics. RESULTS: The defined framework was discriminated with three hierarchical layers of genotype, subgenotype and clade with respective mean pairwise distances 2-6%, 0.8-2%, and ≤ 0.8%. The global epidemic patterns of DENV-1 showed strong geographic constraints representing stratified spatial-genetic epidemic pairs of Continent-Genotype, Region-Subgenotype and Nation-Clade, thereby identifying 12 epidemic regions which prospectively facilitates the region-based coordination. The increasing cross-transmission trends were also demonstrated. The traditional endemic countries such as Thailand, Vietnam and Indonesia displayed as persisting dominant source centers, while the emerging epidemic countries such as China, Australia, and the USA, where dengue outbreaks were frequently triggered by importation, showed a growing trend of DENV-1 diffusion. The probably hidden epidemics were found especially in Africa and India. Then, our framework can be utilized in an accurate stratified coordinated surveillance based on the defined viral population compositions. Thereby it is prospectively valuable for further hampering the ongoing transition process of epidemic to endemic, addressing the issue of inadequate monitoring, and warning us to be concerned about the cross-national, cross-regional, and cross-continental diffusions of dengue, which can potentially trigger large epidemics. CONCLUSIONS: The framework and its utilization in quantitatively assessing DENV-1 epidemics has laid a foundation and re-unveiled the urgency for establishing a stratified coordinated surveillance platform for blocking global spreading of dengue. This framework is also expected to bridge classical DENV-1 genotyping with genomic epidemiology and risk modeling. We will promote it to the public and update it periodically.

Clinical outcomes of doxycycline, azithromycin and chloramphenicol for the treatment of patients with severe scrub typhus.

BACKGROUND: Previous studies have evaluated treatment efficacy of various antibiotics for patients with mild-to-moderate scrub typhus (ST). However, the efficacy of different antibiotics for treating severe ST remains uncertain. METHODS: A retrospective study of patients with severe ST was undertaken in China. The treatment efficacy rates of doxycycline, azithromycin and chloramphenicol were compared, using treatment failure and time to defervescence as primary outcomes. RESULTS: In total, 876 patients with severe ST who initially received doxycycline, azithromycin or chloramphenicol were recruited. The treatment failure rate did not differ significantly between patients receiving doxycycline and patients receiving azithromycin (6.0% vs 11.4%; P=0.109). However, a higher treatment failure rate was observed for chloramphenicol compared with doxycycline (14.6% vs 6.0%; P=0.004). No significant difference in time to defervescence was observed between patients receiving doxycycline, azithromycin or chloramphenicol. Further subgroup analysis revealed a higher risk of treatment failure for chloramphenicol compared with doxycycline in patients with acute kidney injury, pneumonia and shock; and a higher risk of treatment failure for azithromycin compared with doxycycline in patients with meningitis. Significant correlation was found between azithromycin resistance and meningitis (P=0.009), and between chloramphenicol resistance and acute respiratory distress syndrome (ARDS) (P<0.001) using Cramer's V correlation coefficient. Multi-variate Cox regression analysis revealed significant associations between time to defervescence and presence of ARDS, shock, myocarditis, meningitis and acute kidney injury. CONCLUSION: Azithromycin and doxycycline were found to have significant therapeutic effects in patients with severe ST. In contast, chloramphenicol was less efficacious for the treatment of these patients.

Crucial control measures to contain China's first Delta variant outbreak.

The SARS-CoV-2 B.1.617.2 (Delta) variant flared up in late May in Guangzhou, China. Transmission characteristics of Delta variant were analysed for 153 confirmed cases and two complete transmission chains with seven generations were fully presented. A rapid transmission occurred in five generations within 10 days. The basic reproduction number (R0) was 3.60 (95% confidence interval: 2.50-5.30). After redefining the concept of close contact, the proportion of confirmed cases discovered from close contacts increased from 43% to 100%. With the usage of a yellow health code, the potential exposed individuals were self-motivated to take a nucleic acid test and regained public access with a negative testing result. Facing the massive requirement of screening, novel facilities like makeshift inflatable laboratories were promptly set up as a vital supplement and 17 cases were found, with 1 pre-symptomatic. The dynamic adjustment of these three interventions resulted in the decline of Rt from 5.00 to 1.00 within 9 days. By breaking the transmission chain and eliminating the transmission source through extending the scope of the close-contact tracing, health-code usage and mass testing, the Guangzhou Delta epidemic was effectively contained.

Clinical characteristics and risk factors for severe scrub typhus in pediatric and elderly patients.

BACKGROUND: Scrub typhus (ST) is a life-threatening infectious disease if appropriate treatment is unavailable. Large discrepancy of clinical severity of ST patients was reported among age groups, and the underlying risk factors for severe disease are unclear. METHODS: Clinical and epidemiological data of ST patients were collected in 55 surveillance hospitals located in Guangzhou City, China, from 2012 to 2018. Severe prognosis and related factors were determined and compared between pediatric and elderly patients. RESULTS: A total of 2,074 ST patients including 209 pediatric patients and 1,865 elderly patients were included, with a comparable disease severity rate of 11.0% (95% CI 7.1%-16.1%) and 10.3% (95% CI 9.0%-11.8%). Different frequencies of clinical characteristics including lymphadenopathy, skin rash, enlarged tonsils, etc. were observed between pediatric and elderly patients. Presence of peripheral edema and decreased hemoglobin were the most important predictors of severe illness in pediatric patients with adjusted ORs by 38.99 (9.96-152.67, p<0.001) and 13.22 (1.54-113.50, p = 0.019), respectively, while presence of dyspnea and increased total bilirubin were the potential determinants of severe disease in elderly patients with adjusted ORs by 11.69 (7.33-18.64, p<0.001) and 3.17 (1.97-5.11, p<0.001), respectively. Compared with pediatric patients, elderly patients were more likely to receive doxycycline (64.8% v.s 9.9%, p<0.001), while less likely to receive azithromycin therapy (5.0% v.s 41.1%, p<0.001). CONCLUSION: The disease severity rate is comparable between pediatric and elderly ST patients, while different clinical features and laboratory indicators were associated with development of severe complications for pediatric and elderly patients, which is helpful for diagnosis and progress assessment of disease for ST patients.

Hymecromone: a clinical prescription hyaluronan inhibitor for efficiently blocking COVID-19 progression.

Currently, there is no effective drugs for treating clinically COVID-19 except dexamethasone. We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluronic acid (HA). As the inhibitor of HA synthesis, hymecromone is an approved prescription drug used for treating biliary spasm. Here, we aimed to investigate the relation between HA and COVID-19, and evaluate the therapeutic effects of hymecromone on COVID-19. Firstly, HA was closely relevant to clinical parameters, including lymphocytes (n = 158; r = -0.50; P < 0.0001), C-reactive protein (n = 156; r = 0.55; P < 0.0001), D-dimer (n = 154; r = 0.38; P < 0.0001), and fibrinogen (n = 152; r = 0.37; P < 0.0001), as well as the mass (n = 78; r = 0.43; P < 0.0001) and volume (n = 78; r = 0.41; P = 0.0002) of ground-glass opacity, the mass (n = 78; r = 0.48; P < 0.0001) and volume (n = 78; r = 0.47; P < 0.0001) of consolidation in patient with low level of hyaluronan (HA < 48.43 ng/mL). Furthermore, hyaluronan could directly cause mouse pulmonary lesions. Besides, hymecromone remarkably reduced HA via downregulating HAS2/HAS3 expression. Moreover, 89% patients with hymecromone treatment had pulmonary lesion absorption while only 42% patients in control group had pulmonary lesion absorption (P < 0.0001). In addition, lymphocytes recovered more quickly in hymecromone-treated patients (n = 8) than control group (n = 5) (P < 0.05). These findings suggest that hymecromone is a promising drug for COVID-19 and deserves our further efforts to determine its effect in a larger cohort.

Circulation of genotypes of dengue virus serotype 2 in Guangzhou over a period of 20 years.

BACKGROUND: The dengue epidemic in Guangzhou has imposed a rising burden on society and health infrastructure. Here, we present the genotype data for dengue virus serotype 2 (DENV-2) to improve understanding of this dengue epidemic. METHODS: We sequenced the envelope gene of DENV-2 obtained from patient serum samples and subsequently performed maximum-likelihood phylogenetic analysis using PhyMLv3.1, maximum clade credibility analysis using BEAST v.1.10.4, and selection pressure analysis using Datamonkey 2.0. RESULTS: The prevalent DENV-2 strains identified in Guangzhou region are related to those in Southeast Asian countries. In particular, the Malaysia/Indian subcontinent genotype is prevailing in Guangzhou with no apparent genotype shift having occurred over the past 20 years. However, episodic positive selection was detected at one site. CONCLUSIONS: Local control of the DENV-2 epidemic in Guangzhou requires effective measures to prevent and monitor imported cases. Moreover, the shift between the Malaysia/Indian subcontinent genotype lineages, which originated at different time points, may account for the rise in DENV-2 cases in Guangzhou. Meanwhile, the low rate of dengue haemorrhagic fever in Guangzhou may be explained by the dominance of the less virulent Malaysia/Indian subcontinent genotype.

SARS-CoV-2 RNA elements share human sequence identity and upregulate hyaluronan via NamiRNA-enhancer network.

BACKGROUND: Since late 2019, SARS-CoV-2 infection has resulted in COVID-19 accompanied by diverse clinical manifestations. However, the underlying mechanism of how SARS-CoV-2 interacts with host and develops multiple symptoms is largely unexplored. METHODS: Bioinformatics analysis determined the sequence similarity between SARS-CoV-2 and human genomes. Diverse fragments of SARS-CoV-2 genome containing Human Identical Sequences (HIS) were cloned into the lentiviral vector. HEK293T, MRC5 and HUVEC were infected with laboratory-packaged lentivirus or transfected with plasmids or antagomirs for HIS. Quantitative RT-PCR and chromatin immunoprecipitation assay detected gene expression and H3K27ac enrichment, respectively. UV-Vis spectroscopy assessed the interaction between HIS and their target locus. Enzyme-linked immunosorbent assay evaluated the hyaluronan (HA) levels of culture supernatant and plasma of COVID-19 patients. FINDINGS: Five short sequences (24-27 nt length) sharing identity between SARS-CoV-2 and human genome were identified. These RNA elements were highly conserved in primates. The genomic fragments containing HIS were predicted to form hairpin structures in silico similar to miRNA precursors. HIS may function through direct genomic interaction leading to activation of host enhancers, and upregulation of adjacent and distant genes, including cytokine genes and hyaluronan synthase 2 (HAS2). HIS antagomirs and Cas13d-mediated HIS degradation reduced HAS2 expression. Severe COVID-19 patients displayed decreased lymphocytes and elevated D-dimer, and C-reactive proteins, as well as increased plasma hyaluronan. Hymecromone inhibited hyaluronan production in vitro, and thus could be further investigated as a therapeutic option for preventing severe outcome in COVID-19 patients. INTERPRETATION: HIS of SARS-CoV-2 could promote COVID-19 progression by upregulating hyaluronan, providing novel targets for treatment. FUNDING: The National Key R&D Program of China (2018YFC1005004), Major Special Projects of Basic Research of Shanghai Science and Technology Commission (18JC1411101), and the National Natural Science Foundation of China (31872814, 32000505).