Early warning and predicting of COVID-19 using zero-inflated negative binomial regression model and negative binomial regression model.

BACKGROUND: It is difficult to detect the outbreak of emergency infectious disease based on the exiting surveillance system. Here we investigate the utility of the Baidu Search Index, an indicator of how large of a keyword is in Baidu's search volume, in the early warning and predicting the epidemic trend of COVID-19. METHODS: The daily number of cases and the Baidu Search Index of 8 keywords (weighted by population) from December 1, 2019 to March 15, 2020 were collected and analyzed with times series and Spearman correlation with different time lag. To predict the daily number of COVID-19 cases using the Baidu Search Index, Zero-inflated negative binomial regression was used in phase 1 and negative binomial regression model was used in phase 2 and phase 3 based on the characteristic of independent variable. RESULTS: The Baidu Search Index of all keywords in Wuhan was significantly higher than Hubei (excluded Wuhan) and China (excluded Hubei). Before the causative pathogen was identified, the search volume of "Influenza" and "Pneumonia" in Wuhan increased with the number of new onset cases, their correlation coefficient was 0.69 and 0.59, respectively. After the pathogen was public but before COVID-19 was classified as a notifiable disease, the search volume of "SARS", "Pneumonia", "Coronavirus" in all study areas increased with the number of new onset cases with the correlation coefficient was 0.69 ~ 0.89, while "Influenza" changed to negative correlated (rs: -0.56 ~ -0.64). After COVID-19 was closely monitored, the Baidu Search Index of "COVID-19", "Pneumonia", "Coronavirus", "SARS" and "Mask" could predict the epidemic trend with 15 days, 5 days and 6 days lead time, respectively in Wuhan, Hubei (excluded Wuhan) and China (excluded Hubei). The predicted number of cases would increase 1.84 and 4.81 folds, respectively than the actual number of cases in Wuhan and Hubei (excluded Wuhan) from 21 January to 9 February. CONCLUSION: The Baidu Search Index could be used in the early warning and predicting the epidemic trend of COVID-19, but the search keywords changed in different period. Considering the time lag from onset to diagnosis, especially in the areas with medical resources shortage, internet search data can be a highly effective supplement of the existing surveillance system.

Structural insights into the specific recognition of mitochondrial ribosome-binding factor hsRBFA and 12 S rRNA by methyltransferase METTL15.

Mitochondrial rRNA modifications are essential for mitoribosome assembly and its proper function. The m4C methyltransferase METTL15 maintains mitochondrial homeostasis by catalyzing m4C839 located in 12 S rRNA helix 44 (h44). This modification is essential to fine-tuning the ribosomal decoding center and increasing decoding fidelity according to studies of a conserved site in Escherichia coli. Here, we reported a series of crystal structures of human METTL15-hsRBFA-h44-SAM analog, METTL15-hsRBFA-SAM, METTL15-SAM and apo METTL15. The structures presented specific interactions of METTL15 with different substrates and revealed that hsRBFA recruits METTL15 to mitochondrial small subunit for further modification instead of 12 S rRNA. Finally, we found that METTL15 deficiency caused increased reactive oxygen species, decreased membrane potential and altered cellular metabolic state. Knocking down METTL15 caused an elevated lactate secretion and increased levels of histone H4K12-lactylation and H3K9-lactylation. METTL15 might be a suitable model to study the regulation between mitochondrial metabolism and histone lactylation.

The lead time and geographical variations of Baidu Search Index in the early warning of COVID-19.

Internet search data was a useful tool in the pre-warning of COVID-19. However, the lead time and indicators may change over time and space with the new variants appear and massive nucleic acid testing. Since Omicron appeared in late 2021, we collected the daily number of cases and Baidu Search Index (BSI) of seven search terms from 1 January to 30 April, 2022 in 12 provinces/prefectures to explore the variation in China. Two search peaks of "COVID-19 epidemic", "Novel Coronavirus" and "COVID-19" can be observed. One in January, which showed 3 days lead time in Henan and Tianjin. Another on early March, which occurred 0-28 days ahead of the local epidemic but the lead time had spatial variation. It was 4 weeks in Shanghai, 2 weeks in Henan and 5-8 days in Jilin Province, Jilin and Changchun Prefecture. But it was only 1-3 days in Tianjin, Quanzhou Prefecture, Fujian Province and 0 day in Shenzhen, Shandong Province, Qingdao and Yanbian Prefecture. The BSI was high correlated (rs:0.70-0.93) to the number of cases with consistent epidemiological change trend. The lead time of BSI had spatial and temporal variation and was close related to the strength of nucleic acid testing. The case detection ability should be strengthened when perceiving BSI increase.

The recognition mode between hsRBFA and mitoribosome 12S rRNA during mitoribosomal biogenesis.

Eukaryotes contain two sets of genomes: the nuclear genome and the mitochondrial genome. The mitochondrial genome transcripts 13 mRNAs that encode 13 essential proteins for the oxidative phosphorylation complex, 2 rRNAs (12s rRNA and 16s rRNA), and 22 tRNAs. The proper assembly and maturation of the mitochondrial ribosome (mitoribosome) are critical for the translation of the 13 key proteins and the function of the mitochondrion. Human ribosome-binding factor A (hsRBFA) is a mitoribosome assembly factor that binds with helix 28, helix 44 and helix 45 of 12S rRNA and facilitates the transcriptional modification of 12S rRNA during the mitoribosomal biogenesis. Previous research mentioned that the malfunction of hsRBFA will induce the instability of mitoribosomes and affect the function of mitochondria, but the mechanisms underlying the interaction between hsRBFA and 12S rRNA and its influence on mitochondrial function are still unknown. In this study, we found that hsRBFA binds with double strain RNA (dsRNA) through its whole N-terminus (Nt) instead of the KH-like domain alone, which is different from the other homologous. Furthermore, we mapped the key residues that affected the RNA binding and maturation of mitoribosomes in vitro. Finally, we investigated how these residues affect mitochondrial functions in detail and systematically.

RNA-Targeting Carbon Dots for Live-Cell Imaging of Granule Dynamics.

It is significant to monitor the different RNA granules dynamics and phase separation process inside cells under various stresses, for example, oxidative stress. The current small-molecule RNA probes work well only in fixed cells and usually encounter problems such as insufficient stability and biocompatibility, and thus a specific RNA-targeting fluorescent nanoprobe that can be used in the living cells is urgently desired. Here, the de novo design and microwave-assisted synthesis of a novel RNA-targeting, red-emissive carbon dots (named as M-CDs) are reported by choosing neutral red and levofloxacin as precursors. The as-synthesized M-CDs is water-soluble with a high fluorescence quantum yield of 22.83% and can selectively bind to RNA resulting in an enhanced red fluorescence. More interestingly, such an RNA-targeting, red-emissive M-CDs can be fast internalized into cells within 5 s and thus used for real-time imaging the dynamic process of intracellular stress granules under oxidative stress, revealing some characteristics of granules that have not been identified by previously reported RNA and protein biomarkers. This research paves a new pathway for visualizing bulk RNA dynamics and studying phase-separation behaviors in living cells by rational design of the fluorescent carbon dots in terms of structure and functionality.

Huangqin Qingre Qubi Capsule inhibits RA pathology by binding FZD8 and further inhibiting the activity of Wnt/ß-catenin signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqin Qingre Qubi Capsule (HQC) is a Chinese herbal compound for the treatment of rheumatoid arthritis (RA), which is made from dry roots of Scutellaria baicalensis Georgi, dry mature seeds of Gardenia jasminoides J.Ellis, dry and mature seeds of Coix lacryma-jobi var. stenocarpa Oliv., dry mature seeds of Amygdalus persica L. and roots and rhizomes of Clematis chinensis Osbeck in the proportion of 10:9:30:5:10. HQC has a significant effect in clinical treatment of RA, which can inhibit RA inflammation, improve oxidative stress state, and effectively relieve symptoms of RA patients. AIM OF THE STUDY: The anti-arthritis effect of HQC and its mechanism, especially whether it improves RA through FZD8-Wnt/ß-catenin signal axis, were studied using adjuvant arthritis (AA) rats and FLS from RA patients. MATERIALS AND METHODS: Real time qPCR (RT-qPCR), Western blot (WB), confocal microscopy and other molecular biological methods were used to study the anti-RA effect of HQC and its mechanism. RESULTS: The expression of FZD8 was significantly up-regulated in synovium and FLS of AA rats and RA FLS. FZD8 significantly activated the Wnt/ß-catenin signaling pathway, promoted abnormal proliferation of FLS, increased the levels of inflammatory factors IL-1ß, IL-6 and IL-8, and significantly increased the expression of matrix metalloproteinase 3 (MMP3) and fibronectin. HQC has significant therapeutic effect on AA rats. Molecular docking and molecular dynamics showed that HQC had a good binding ability with FZD8. We also confirmed that HQC inhibited Wnt/ß-catenin signaling pathway by binding FZD8, and reduced the levels of the above inflammatory factors and pathological genes of RA. CONCLUSIONS: The expression of FZD8 is significantly increased in AA rats and FLS from RA patients. Clarify that HQC improves RA through the FZD8-Wnt/ß-catenin signal axis, provide a clear therapeutic mechanism for HQC to improve RA, and also provide a basis for clinical promotion of HQC.

Clematichinenoside AR inhibits the pathology of rheumatoid arthritis by blocking the circPTN/miR-145-5p/FZD4 signal axis.

BACKGROUNDS: Traditional Chinese medicine roots and rhizomes of Clematis chinensis Osbeck (CCO) has the effect of improving rheumatoid arthritis (RA), Clematichinenoside AR (CAR) is an effective monomer of CCO and a promising natural product for the treatment of RA. METHODS: In this work, we aim to systematically evaluate whether CAR can improve RA pathology, inhibit the fibroblast-like synoviocytes (FLS) proliferation and inflammatory response, and further investigate the mechanism of CAR inhibiting RA through molecular docking, molecular dynamics and molecular biology methods. RESULTS: Combined with the research results of CIA mice and FLS from RA patients, we found that CAR significantly improved the severity of CIA mice, and inhibited the proliferation and inflammatory response of FLS. Combined with bioinformatics prediction, we confirmed that circPTN promoted frizzled-4 (FZD4) expression through sponging miR-145-5p, then activating the Wnt/ß-catenin pathway. The circPTN/miR-145-5p/FZD4 signal axis was involved in the pathogenesis of RA. Furthermore, CAR blocked the circPTN/miR-145-5p/FZD4 signal axis by combining with FZD4 and improved RA pathology. CONCLUSIONS: The circPTN/miR-145-5p/FZD4 signal axis plays an important role in promoting the pathogenesis of RA, and CAR from CCO may inhibit RA pathology by combining the FZD4 and further blocking this signal axis.

The molecular structure and biological functions of RNA methylation, with special emphasis on the roles of RNA methylation in autoimmune diseases.

Autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic vasculitis are caused by the body's immune response to autoantigens. The pathogenesis of autoimmune diseases is complex. RNA methylation is known to play a key role in disease progression as it regulates almost all aspects of RNA processing, including RNA nuclear export, translation, splicing, and noncoding RNA processing. This review summarizes the mechanisms, molecular structures of RNA methylations and their roles in biological functions. Similar to the roles of RNA methylation in cancers, RNA methylation in RA and SLE involves "writers" that deposit methyl groups to form N6-methyladenosine (m6A) and 5-methylcytosine (m5C), "erasers" that remove these modifications, and "readers" that further affect mRNA splicing, export, translation, and degradation. Recent advances in detection methods have identified N1-methyladenosine (m1A), N6,2-O-dimethyladenosine (m6Am), and 7-methylguanosine (m7G) RNA modifications, and their roles in RA and SLE need to be further studied. The relationship between RNA methylation and other autoimmune diseases has not been reported, and the roles and mechanisms of RNA modifications in these diseases need to be explored in the future.

Exosomes as a New Delivery Vehicle in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a type of chronic relapsing inflammatory disease. The pathogenesis of IBD is still unclear, which may involve environmental factors, genetic factors, intestinal microbiota disorder, and abnormal immune responses. Exosomes (30-150 nm) are found in various body fluids, including blood, saliva, urine, and cerebrospinal fluid. Exosomes mediate intercellular communication and regulate cell biological activity by carrying non-coding RNAs, proteins, and lipids. There is evidence that exosomes are involved in the pathogenesis of IBD. In view of the important roles of exosomes in the pathogenesis of IBD, this work systematically reviews the latest research progress of exosomes in IBD, especially the roles of exosomes as non-coding RNA delivery systems in the pathogenesis of IBD, including a disordered immune response, barrier function, and intestinal microbiota. The review will help to clarify the pathogenesis of IBD and explore new diagnostic markers and therapeutic targets for patients with IBD.

RNA Methylations in Cardiovascular Diseases, Molecular Structure, Biological Functions and Regulatory Roles in Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in the world. Despite considerable progress in the diagnosis, treatment and prognosis of CVDs, new diagnostic biomarkers and new therapeutic measures are urgently needed to reduce the mortality of CVDs and improve the therapeutic effect. RNA methylations regulate almost all aspects of RNA processing, such as RNA nuclear export, translation, splicing and non-coding RNA processing. In view of the importance of RNA methylations in the pathogenesis of diseases, this work reviews the molecular structures, biological functions of five kinds of RNA methylations (m6A, m5C, m1a, m6am and m7G) and their effects on CVDs, including pulmonary hypertension, hypertension, vascular calcification, cardiac hypertrophy, heart failure. In CVDs, m6A "writers" catalyze the installation of m6A on RNAs, while "erasers" remove these modifications. Finally, the "readers" of m6A further influence the mRNA splicing, nuclear export, translation and degradation. M5C, m1A, m6Am and m7G are new types of RNA methylations, their roles in CVDs need to be further explored. RNA methylations have become a new research hotspot and the roles in CVDs is gradually emerging, the review of the molecular characteristics, biological functions and effects of RNA methylation on CVDs will contribute to the elucidation of the pathological mechanisms of CVDs and the discovery of new diagnostic markers and therapeutic targets of CVDs.

The Research Progress of Exosomes in Osteoarthritis, With Particular Emphasis on the Mediating Roles of miRNAs and lncRNAs.

Osteoarthritis (OA) is a kind of degenerative disease, which is caused by many factors such as aging, obesity, strain, trauma, congenital joint abnormalities, joint deformities. Exosomes are mainly derived from the invagination of intracellular lysosomes, which are released into the extracellular matrix after fusion of the outer membrane of multi vesicles with the cell membrane. Exosomes mediate intercellular communication and regulate the biological activity of receptor cells by carrying non-coding RNA, long noncoding RNAs (lncRNAs), microRNAs (miRNAs), proteins and lipids. Evidences show that exosomes are involved in the pathogenesis of OA. In view of the important roles of exosomes in OA, this paper systematically reviewed the roles of exosomes in the pathogenesis of OA, including the roles of exosomes in OA diagnosis, the regulatory mechanisms of exosomes in the pathogenesis, and the intervention roles of exosomes in the treatment of OA. Reviewing the roles of exosomes in OA will help to clarify the pathogenesis of OA and explore new diagnostic biomarkers and therapeutic targets.

The emerging roles of exosomes in autoimmune diseases, with special emphasis on microRNAs in exosomes.

Autoimmune diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic vasculitis, dermatomyositis, systemic sclerosis (SSc), mixed connective tissue disease, autoimmune hemolytic anemia, autoimmune thyroiditis (AITD) and ulcerative colitis. Exosomes exist in body fluids, including blood, saliva, urine, cerebrospinal fluid and milk. They are mainly derived from the invagination of intracellular lysosomal particles, which are released into the extracellular matrix after fusion of the outer membrane of the exosomes with the cell membrane. Exosomes mediate intercellular communication and regulate the biological activity of receptor cells by carrying proteins, nucleic acids and lipids. Evidences show that exosomes are involved in the pathogenesis of various autoimmune diseases. In view of the important roles of exosomes in autoimmune diseases, this work systematically reviewed the effects of exosomes on the pathogenesis of autoimmune diseases, especially the regulatory roles of exosome derived microRNAs (miRNAs) in the pathogenesis of RA, SLE, dermatomyositis, SSc, AITD and ulcerative colitis. The review of the roles of exosomes in autoimmune diseases will help to clarify the pathogenesis of these diseases and explore new diagnostic markers and therapeutic targets.