A sono-responsive antibacterial nanosystem co-loaded with metformin and bone morphogenetic protein-2 for mitigation of inflammation and bone loss in experimental peri-implantitis.

Background: Dental implants have become an increasingly popular option for replacing missing teeth, and the prevalence of peri-implantitis has also increased, which is expected to become a public health problem worldwide and cause high economic and health burdens. This scenario highlights the need for new therapeutic options to treat peri-implantitis. Methods: In this study, we proposed a novel sono-responsive antibacterial nanosystem co-loaded with metformin (Met) and bone morphogenetic protein-2 (BMP-2) to promote efficacy in treating peri-implantitis. We introduced the zeolitic imidazolate framework-8 (ZIF-8) as a carrier for hematoporphyrin monomethyl ether (HMME) to enhance the antibacterial effect of sonodynamic antibacterial therapy and tested its reactive oxygen species (ROS) production efficiency and bactericidal effect in vitro. Afterward, HMME-loaded ZIF-8, BMP-2-loaded polylactic acid-glycolic acid (PLGA), and Met were incorporated into gelatin methacryloyl (GelMA) hydrogels to form HMME@ZIF-8/Met/BMP-2@PLGA/GelMA composite hydrogels, and the biocompatibility of which was determined in vitro and in vivo. A bacterial-induced peri-implantitis model in the maxilla of rats was established to detect the effects of the composite hydrogels with adjunctive use of ultrasound on regulating inflammation and promoting bone tissue repair in vivo. Results: The results indicated that HMME@ZIF-8 with ultrasound stimulation demonstrated more better ROS production efficiency and antimicrobial efficacy. The composite hydrogels had good biocompatibility. Ultrasound-assisted application of the composite hydrogels reduced the release of the inflammatory factors IL-6 and TNF-α and reduced bone loss around the implant in rats with bacterial-induced peri-implantitis. Conclusion: Our observations suggest that HMME@ZIF-8 may be a new good sonosensitizer material for sonodynamic antibacterial therapy. The use of HMME@ZIF-8/Met/BMP-2@PLGA/GelMA composite hydrogels in combination with ultrasound can provide a novel option for treating peri-implantitis in the future.

The role of live transcripts in synchronous online L2 classrooms: Learning outcomes and learner perceptions.

This study explored the role of live transcripts in online synchronous academic English classrooms by focusing on how automatically generated live transcripts influence the learning outcomes of lower-proficiency and higher-proficiency learners and on their perceptions towards live transcripts. The study adop ted a 2 × 2 factorial design, with the two factors being learner proficiency (high vs. low) and availability of live transcription (presence and absence). The participants were 129 second-year Japanese university students from four synchronous classes taught on Zoom by the same teacher under an academic English reading course. Learning outcomes in this study were evaluated according to the course syllabus through grades and participation in class activities. A questionnaire consisting of nine Likert-scale questions and a comment box was administered to explore participants' perceived usefulness of, perceived ease of use of, and perceived reliance on live transcripts. Results showed that contrary to previous studies reporting the effectiveness of captioned audiovisual materials in L2 learning, live transcripts as a special type of captions were not effective in promoting the grades of learners of either proficiency. However, it significantly improved the activity participation of lower-proficiency learners, but not that of higher-proficiency learners. Questionnaire results showed that there were no significant differences between learners of two proficiencies in their perceptions towards live transcription, which contradicts previous findings that lower-proficiency learners tend to rely more on captions. Besides enhancement of lecture comprehension, participants reported innovative uses of live transcripts such as screenshots with transcripts for notetaking purposes and transcripts downloaded for later review.

Effect and mechanism of baicalin on the proliferation and migration of human periodontal ligament stem cells induced by lipopolysaccharide / 中国药房

OBJECTIVE To explore the regulatory effects of baicalin on the proliferation and migration of human periodontal ligament stem cells （hPDLSCs） induced by lipopolysaccharide （LPS） and Janus protein tyrosine kinase 2 （JAK2）/signal transduction and transcription activator 3 （STAT3） signaling pathways. METHODS hPDLSCs were divided into control group， LPS group， different concentration baicalin groups （0.1， 1 and 10 mg/L）. ELISA method and CCK-8 assay were used to determine the contents of cell inflammatory factors [interleukin 6 （IL-6）， IL-1β and tumor necrosis factor-α （TNF-α）] and cell viability， so as to screen the optimal concentration of baicalin for follow-up pathway validation experiments. The cells were then divided into control group， LPS group， optimal baicalin concentration group and inhibitor group （10 μg/mL LPS+1 mg/L baicalin +3 μmol/L JAK2/STAT3 pathway inhibitor AG490）. After treated for 24 h， the proliferation rate of hPDLSCs， apoptosis rate， migration rate， invasion cell number， mRNA and protein expressions of Cyclin D1 and caspase-3， the expression of JAK2/STAT3 pathway-related proteins were all detected. RESULTS According to cell inflammatory factors and cell viability， 1 mg/L was selected as the optimal concentration of baicalin. Compared with control group， cell proliferation rate， migration rate， invasion cell number， Cyclin D1 mRNA and protein expression were significantly decreased in LPS group， while cell apoptosis rate， caspase-3 mRNA and protein expression， p-JAK2 and p-STAT3 protein expression were significantly increased （P＜0.05）. After treated with 1 mg/L baicalin， the above indexes were reversed significantly （P＜0.05）. The improvement of above indexes in the inhibitor group was more obvious （P＜0.05）. CONCLUSIONS Baicalin can promote the proliferation， migration and invasion of LPS-induced hPDLSCs and inhibit their apoptosis and inflammation by blocking the JAK2/STAT3 pathway.

Anti-inflammatory material basis and mechanism of Artemisia stolonifera based on UPLC-Q-TOF-MS combined with network pharmacology and molecular docking / 中国中药杂志

This study aimed to explore the anti-inflammatory material basis and molecular mechanism of Artemisia stolonifera based on the analysis of the chemical components in different extracted fractions of A. stolonifera and their antioxidant and anti-inflammatory effects in combination with network pharmacology and molecular docking. Thirty-two chemical components were identified from A. stolonifera by ultra-performance liquid chromatography coupled to tandem quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS). Among them, there were 7, 21 and 22 compounds in water, n-butanol and ethyl acetate fractions, respectively. The antio-xidant capacity of different extracted fractions was evaluated by measuring their scavenging ability against 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl(DPPH) and 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonic acid)(ABTS) free radicals and total antioxidant capacity [ferric reducing antioxidant power(FRAP) assay]. The inflammatory model of RAW264.7 cells was induced by lipopolysaccharide(LPS), and the levels of nitrite oxide(NO), tumor necrosis factor-α(TNF-α), interleukin-6(IL-6) in the supernatant and the mRNA expression of related inflammatory factors in cells were used to evaluate the anti-inflammatory effects. The results revealed that ethyl acetate fraction of A. stolonifera was the optimal antioxidant and anti-inflammatory fraction. By network pharmacology, it was found that flavonoids such as rhamnazin, eupatilin, jaceosidin, luteolin and nepetin could act on key targets such as TNF, serine/threonine protein kinase 1(AKT1), tumor protein p53(TP53), caspase-3(CASP3) and epidermal growth factor receptor(EGFR), and regulate the phosphatidylinositol-3-kinase-protein kinase B(PI3K-AKT) and mitogen-activated protein kinase(MAPK) signaling pathways to exert the anti-inflammatory effects. Molecular docking further indicated excellent binding properties between the above core components and core targets. This study preliminarily clarified the anti-inflammatory material basis and mechanism of ethyl acetate fraction of A. stolonifera, providing a basis for the follow-up clinical application of A. stolonifera and drug development.

Component identification and analysis in vivo of Sanhan Huashi formula / 中国中药杂志

Sanhan Huashi formula(SHF) is the intermediate of a newly approved traditional Chinese medicine(TCM) Sanhan Huashi Granules for the treatment of COVID-19 infection. The chemical composition of SHF is complex since it contains 20 single herbal medicines. In this study, UHPLC-Orbitrap Exploris 240 was used to identify the chemical components in SHF and in rat plasma, lung and feces after oral administration of SHF, and heat map was plotted for characterizing the distribution of the chemical components. Chromatographic separation was conducted on a Waters ACQUITY UPLC BEH C_(18)(2.1 mm×100 mm, 1.7 μm) using 0.1% formic acid(A)-acetonitrile(B) as mobile phases in a gradient elution. Electrospray ionization(ESI) source was used to acquire data in positive and negative mode. By reference to quasi-molecular ions and MS/MS fragment ions and in combination with MS spectra of reference substances and compound information in literature reports, 80 components were identified in SHF, including 14 flavonoids, 13 coumarins, 5 lignans, 12 amino-compounds, 6 terpenes and 30 other compounds; 40 chemical components were identified in rat plasma, 27 in lung and 56 in feces. Component identification and characterization of SHF in vitro and in vivo lay foundations for disclosure of its pharmacodynamic substances and elucidation of the scientific connotation.

Fortuitous Somatic Mutations during Antibody Evolution Endow Broad Neutralization against SARS-CoV-2 Omicron Variants

Striking antibody evasion by emerging circulating SARS-CoV-2 variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identified a clonally-related antibody family from a convalescent individual. One of the members, XG005, exhibited potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members showed significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface revealed how crucial somatic mutations endowed XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality, exhibited a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provided a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.

A novel SERS substrate of MIL-100(Fe)/AgNFs for sensitive detection of ascorbic acid in cellular media.

A novel SERS substrate of MIL-100(Fe)/AgNFs was firstly prepared for sensitive and selective detection of ascorbic acid (L-AA), with a LOD of 10-11 M. A spectral decrease of MIL-100(Fe)/AgNFs towards L-AA solution thanks to the efficient capture and reduction of Fe3+ in MIL-100(Fe) constituted the assay, which was demonstrated to function well in food samples and in cellular media for L-AA sensing.

Complete plastome sequence of Lonicera gynochlamydea Hemsl. (Caprifoliaceae).

We report and characterize the complete plastome of Lonicera gynochlamydea Hemsl. L. gynochlamydea is a shrub, belonging to the family Caprifoliaceae. Our results show that the length of the complete plastome is 154,643 bp, including 131 genes consisting of 84 protein-coding genes, 39 tRNA genes, and eight rRNA genes. The plastome exhibits the typical quadripartite structure and gene content of angiosperms, composed of two inverted repeats (IRs) regions of 23,846 bp, a large single-copy (LSC) region of 88,298 bp, and a small single-copy (SSC) region of 18,653 bp. The total G/C content in L. gynochlamydea plastome is 38.4%. The complete plastome sequence of L. gynochlamydea will make contributions to the conservation genetics of this species as well as to phylogenetic studies in Caprifoliaceae.

Synchronous tele-ultrasonography is helpful for a naive operator to perform high-quality thyroid ultrasound examinations

Purpose@#This study investigated the value of synchronous tele-ultrasonography (TUS) for naive operators in thyroid ultrasonography (US) examinations. @*Methods@#Ninety-seven patients were included in this prospective, parallel-controlled trial. Thyroid scanning and diagnosis were completed by resident A independently, resident B with guidance from a US expert through synchronous TUS, and an on-site US expert. The on-site expert’s findings constituted the reference standard. Two other off-site US experts analyzed all data in a blind manner. Inter-operator consistency between the two residents and the on-site US expert for thyroid size measurements, nodule measurements, nodule features, American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) categories, and image quality was compared. Two questionnaires were completed to evaluate the clinical benefit. @*Results@#Resident B detected more nodules consistent with the on-site expert than resident A did (89.4% vs. 56.5%, P0.75), while resident A achieved lower consistency in ACR TI-RADS categories, composition, echogenicity, margin, echogenic foci, and vascularity (all ICCs 0.40-0.75). Residents A and B had excellent consistency in target nodule measurements (all ICCs >0.75). Resident B achieved better performance than resident A for gray values, time gain compensation, depth, color Doppler adjustment, and the visibility of key information (all P<0.05). Furthermore, 61.9% (60/97) of patients accepted synchronous TUS, and 59.8% (58/97) patients were willing to pay for it. @*Conclusion@#Synchronous TUS can help inexperienced residents achieve comparable thyroid diagnostic capability to a US expert.

A third dose of inactivated vaccine augments the potency, breadth, and duration of anamnestic responses against SARS-CoV-2

Emergence of variants of concern (VOC) with altered antigenic structures and waning humoral immunity to SARS-CoV-2 are harbingers of a long pandemic. Administration of a third dose of an inactivated virus vaccine can boost the immune response. Here, we have dissected the immunogenic profiles of antibodies from 3-dose vaccinees, 2-dose vaccinees and convalescents. Better neutralization breadth to VOCs, expeditious recall and long-lasting humoral response bolster 3-dose vaccinees in warding off COVID-19. Analysis of 171 complex structures of SARS-CoV-2 neutralizing antibodies identified structure-activity correlates, revealing ultrapotent, VOCs-resistant and broad-spectrum antigenic patches. Construction of immunogenic and mutational heat maps revealed a direct relationship between "hot" immunogenic sites and areas with high mutation frequencies. Ongoing antibody somatic mutation, memory B cell clonal turnover and antibody composition changes in B cell repertoire driven by prolonged and repeated antigen stimulation confer development of monoclonal antibodies with enhanced neutralizing potency and breadth. Our findings rationalize the use of 3-dose immunization regimens for inactivated vaccines. One sentence summaryA third booster dose of inactivated vaccine produces a highly sifted humoral immune response via a sustained evolution of antibodies capable of effectively neutralizing SARS-CoV-2 variants of concern.

Soil Physical and Chemical Properties， Microorganisms and Metabolites in Different Culture Environments of Gastrodia elata / 中国实验方剂学杂志

Objective:To study the soil physical and chemical properties， microorganisms， and metabolites in different culture environments of <italic>Gastrodia elata</italic>， so as to provide scientific basis for subsequent cultivation of <italic>G. elata</italic> in multiple environments. Method:The tubersphere soil of <italic>G. elata</italic> cultured in different environments was collected for analyzing the soil nutrients， microbial numbers， and metabolite differences using the agrochemical method， plate-count method， and gas chromatography-time-of-flight mass spectrometry （GC-TOF-MS）-based non-targeted metabonomic approach. Result:The analysis of soil physical and chemical properties revealed the highest soil moisture， pH， available potassium， and available phosphorus in the spinney and the highest electrical conductivity， total nitrogen， alkali-hydrolyzable nitrogen， and organic matter in the pinewood. As demonstrated by the quantitative analysis of soil microorganisms， the cultivable microorganisms were bacteria， actinomycetes， and fungi， with the bacterial population and total microbial biomass in the spinney and the number of fungi and actinomycetes in the barren slope detected to be the largest. The ratio of bacteria to fungi （B/F value） in the pinewood was the highest， while that in the barren slope was the lowest. The results of metabonomic research demonstrated that the compositions and quantities of soil metabolites in the spinney （Z group）， pinewood （S group）， and barren slope （HD group） varied. Through comparisons between S and Z groups， between HD and Z groups， as well as between HD and S groups by orthogonal partial least squares discriminant analysis （OPLS-DA）， 18， 35， and 24 differential metabolites were separately screened out， and the Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis yielded 5， 9， and 13 metabolic pathways. There existed a significant causal relationship of the soil physical and chemical properties and microbial numbers with the metabolites. Conclusion:The soil physical and chemical properties， microbial numbers， and metabolite changes differed significantly in different culture environments of <italic>G. elata</italic>， which were sorted by the suitability in a descending order as follows： spinney > pinewood >barren slope. The soil physical and chemical properties and microbial numbers are the crucial factors driving changes in soil metabolites， suggesting that regulating the soil physical and chemical characteristics and microbial characteristics in the culture environment is an important mechanism for maintaining the <italic>G. elata</italic>-soil-microbial symbiotic system.

Effects of Proprioceptive Neuromuscular Facilitation on Balance, Motor and Activities of Daily Living for Stroke Patients: A Meta-analysis / 中国康复理论与实践

Objective:To analyze the effects of proprioceptive neuromuscular facilitation (PNF) on balance, motor and activities of daily living (ADL) for stroke patients. Methods:The randomized controlled trials about the effects of PNF on motor, balance and ADL in stroke patients were retrieved from PubMed, Embase, CNKI, Wanfang data, and VIP, since establishment to December, 2019. The primary outcome measures were Berg Balance Scale (BBS), Fugl-Meyer Assessment (FMA) and modified Bathel Index (MBI). The secondary outcome measures were Functional Reach Test (FRT), Trunk Impairment Scale (TIS), and Timed 'Up and Go' Test (TUGT). The literatures were independently screened by two investigators, and the quality of the articles was evaluated using the Cochrane Library systematic review criteria, and meta-analysis was performed using RevMan 5.3. Results:A total of 13 articles were included with 786 stroke patients. PNF increased the score of BBS for sequelae patients (MD = 3.31, 95%CI 2.58 to 4.04, P < 0.001), FMA for recovery patients (MD = 8.31, 95%CI 5.68 to 10.97, P < 0.001); as well as MBI score (MD = 6.84, 95%CI 5.20 to 8.48, P < 0.001), FRT distance (MD = 1.11, 95%CI 0.39 to 1.84, P = 0.003) and TIS score (MD = 1.75, 95%CI 1.19 to 2.31, P < 0.001) for all the patients, and decreased TUGT time for sequelae patients (MD = -1.86, 95%CI -2.62 to -1.10, P < 0.001). Conclusion:PNF can significantly improve balance, motor and ADL for stroke patients. The effectiveness is various with the course of disease. More high-quality researches are needed.

Effect of Forsythionin A on Gastrointestinal Motility Disorders in Mice Treated with Chemotherapy / 中国实验方剂学杂志

Objective:To observe the effect of forsythiaside A on gastrointestinal motility disorder induced by chemotherapy in mice， and explore the mechanism of forsythiaside A regulating gastrointestinal motility. Method:The 60 KM mice were randomly divided into normal group， model group， metoclopramide group （5 mg·kg-1） and forsythiaside A low， medium and high-dose groups （30， 60， 120 mg·kg-1）， 10 for each group， which include half male and half female. The above dose was given once a day for 4 consecutive days， which the intragastric volume was 10 mL·kg-1. One hour after 1rd day administration， equal volume of saline was intraperitoneally injected to the normal group， 2 mg·kg-1 cisplatin was intraperitoneally injected to the other groups with daily for 4 consecutive days. Observing the effects of forsythiaside A on gastric emptying and small intestinal propulsion on mice models， serum gastrin （GAS） and somatostatin （SS）， motilin （MTL）， vasoactive intestinal peptide （VIP） levels were examined by enzyme-linked immunosorbent assay （ELISA）. Activities of acetylcholinesterase （AChE） and total nitric oxide synthase （tNOS） in gastric antrum and ileum were detected by ELISA. The expression of AChE and inducible nitric oxide synthase （iNOS） in gastric antrum and ileum were detected by Western blot. Result:Compared with normal group， the gastric retention rate and small intestinal propulsion rate of the model group were significantly increased （P<0.01）， serum levels of MTL， GAS， SS and VIP， the AChE activity in the homogenate of ileum in the model group were significantly reduced （P<0.05，P<0.01）， while the tNOS activities in gastric antrum and ileum were significantly increased （P<0.05，P<0.01）. Protein expression of AChE in gastric antrum and ileum were significantly decreased （P<0.05）， and the expression level of iNOS protein was significantly increased in the model group （P<0.05）. Compared with model group， different doses of forsythiaside A can reduce the gastric residual rate and small intestinal propulsion rate of mice to varying degrees. Meanwhile forsythiaside A can increase the serum levels of MTL， GAS， SS， and VIP， and the AChE activity and protein expression levels in gastric antrum and ileum tissues were also increased， while tNOS activity and iNOS protein expression were decreased in gastric antrum and ileum （P<0.05，P<0.01）. Conclusion:Forsythiaside A can significantly ameliorate the delayed gastric emptying and small intestine hyperfunction induced by cisplatin in mice. Its mechanism to ameliorate gastrointestinal dysfunction caused by chemotherapy is related to the regulation of gastrointestinal AChE and NOS activity in gastric antrum and ileum and the regulation of gastrointestinal hormone levels.

Effect and Involved Mechanism of RSL3-induced Ferroptosis in Acute Leukemia Cells MOLM13 and Drug-resistant Cell Lines / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect and involved mechanism of RSL3 on ferroptosis action in acute leukemia cells MOLM13 and its drug-resistant cells.@*METHODS@#After MOLM13 treated with RSL3, CCK-8 assay was performed to detect cell viability, flow cytometry was used to detect the reactive oxygen species (ROS) level of the cells, RT-qPCR and Western blot were used to detect the expression of glutathione peroxidase 4 (GPX4). After MOLM13/IDA and MOLM13/Ara-C, the drug-resistant cell lines were constructed, the ferroptosis induced by RSL3 was observed. Bone marrow samples were collected from patients with acute monocytic leukemia. RT-qPCR and Western blot were performed to detect the expression of related genes and proteins involved in ferroptosis pathway.@*RESULTS@#RSL3 significantly inhibited the cell viability of MOLM13 and increased the intracellular ROS level, which were partially reversed by ferrostatin-1. The mRNA and protein expression of GPX4 decreased in MOLM13 treated with RSL3. RSL3 inhibited the viability of MOLM13/IDA and MOLM13/Ara-C cells more strongly than that of non-drug resistant cells, also increased the intracellular ROS level . The cytotoxic effects were partially reversed by ferrostatin-1. The mRNA and protein expressions of GPX4 in MOLM13/IDA and MOLM13/Ara-C cells were higher than those in non-drug resistant cells. The mRNA and protein levels of GPX4 in bone marrow of relapsed/refractory acute mononuclear leukemia patients were higher than those of ordinary acute mononuclear leukemia patients.@*CONCLUSION@#RSL3 can induce non-drug resistant cells MOLM13 ferroptosis by inhibiting GPX4 activity. MOLM13/IDA and MOLM13/Ara-C are more sensitive to RSL3 compared with non-drug resistant cells MOLM13, which may be caused by the differences in GPX4 expression. The expressions of GPX4 mRNA and protein in relapsed/refractory acute mononuclear leukemia are higher than those in ordinary acute mononuclear leukemia.

Superiority of motor imagery acupuncture in improving muscle tension for patients with upper limb hemiplegia of stroke in early stage / 中国针灸

OBJECTIVE@#To verify the superiority of motor imagery acupuncture in improving muscle tension for patients with upper limb hemiplegia in early stroke.@*METHODS@#A total of 64 patients of stroke hemiplegia with upper limb flaccid paralysis were randomly divided into an observation group (32 cases, 1 case dropped off ) and a control group (32 cases, 4 cases dropped off ). The observation group was treated with motor imagery acupuncture (both acupuncture and motor imagery therapy at affected upper limb were performed).The control group was treated with acupuncture plus motor imagery therapy at affected lower limb, 2 h later after acupuncture, motor imagery therapy was applied to upper limb. Baihui (GV 20) to Taiyang (EX-HN 5) of healthy side, Fengchi (GB 20) and Jianyu (LI 15), Jianjing (GB 21), Quchi (LI 11), Waiguan (TE 5) on the affected side, ect. were selected in both groups, once a day, 5 times a week for 4 weeks. Before and after treatment, 4, 8 weeks after treatment, the modified Ashworth scale (MAS) grade and Brunnstrom stage were compared in the two groups.@*RESULTS@#Compared before treatment, the muscle tension of shoulder, elbow and wrist each time point after treatment was increased in the two groups (@*CONCLUSION@#Motor imagery acupuncture could promote hemiplegia upper limb muscle tension recovery in patients of stroke hemiplegia with upper limb flaccid paralysis, make the patients gradually shift to the separate fine movement mode, inhibit and relieve the appearance and development of spasm.

Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat due to the lack of effective drugs or vaccines against SARS-CoV-2. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a relatively new antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry into host cells, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and SARS-CoV-2-infected Ad-ACE2-transduced Tmprss2 knockout (Tmprss2-KO) and wild-type (WT) mice. TMPRSS2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cancer cells (LNCaP) but not in human lung cancer cells or patient-derived lung organoids. Although Tmprss2 knockout effectively blocked SARS-CoV-2 infection in ACE2-transduced mice, enzalutamide showed no antiviral activity due to the AR independence of TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19.

Transmission in Latent Period Causes A Large Number of Infected People in the United States

The cumulative number of confirmed cases in the United States exceeded one million on 29 April 2020, becoming the country of the most serious pandemic in the world. We proposed a model to analyze the real situation and follow-up trend of the epidemic in the US. The proposed model divides the epidemic period into two phases, and includes three different categories of transmitters: the latent population, the documented infectious population, and the undocumented infectious population. We use metapopulation network to simulate the spread of the COVID-19 in the US, and apply the Bayesian inference to estimate the key parameters of the model. We also perform component analysis and sensitivity analysis, researching the compositions of the people with COVID-19. The results show that the basic reproduction number in the early period of propagation is 4.06. As of April 13, 2020, only 45% (95% CI: 35% - 73%) of symptom onset cases in the United States were documented. The incubation period of COVID-19 is 10.69 days (95% CI: 10.02 - 11.74). If the current level of interventions is continued, the cumulative number of confirmed cases is expected to reach more than 1.7 million in July and continue to grow.

Assessing the Global Tendency of COVID-19 Outbreak

COVID-19 is now widely spreading around the world as a global pandemic. In this report, we estimated the global tendency of COVID-19 and analyzed the associated global epidemic risk, given that the status quo is continued without further measures being taken. Based on official data of confirmed and recovered cases until May 21, 2020, the results showed that the global R0, excluding China, was estimated to be 2.76 (95% CI: 2.57 - 2.95). The United States, Germany, Italy, and Spain have peak values over 100,000. Using dynamical model and cluster analysis, we partition the globe into four regional epicenters of the outbreak: Southeast Asia extending southward to Oceania, the Middle East, Western Europe, and North America. Among them, Western Europe would become the major center of the outbreak. The peak values in Germany, Italy, and Spain were estimated to be 228,000, 291,000, and 298,000, respectively. Based on the current control measures by May 21, 2020, the peak value in the United States will reach 2,114,000. The cumulative number of 51 mainly researched countries patients might finally attain 6,542,000 (95% CI: 4,772,000 - 40,735,000). We also estimated the diagnosis rate, recovery rate, and infection degree of each country or region, and used clustering algorithm to retrieve countries or regions with similar epidemic characteristics. Several suggestions have been proposed for countries or regions in different clusters.

Estimating the Efficacy of Traffic Blockage and Quarantine for the Epidemic Caused by 2019-nCoV (COVID-19)

BackgroundSince the 2019-nCoV (COVID-19) outbreaks in Wuhan, China, the cumulative number of confirmed cases is increasing every day, and a large number of populations all over the world are at risk. The quarantine and traffic blockage can alleviate the risk of the epidemic and the infections, henceforth evaluating the efficacy of such actions is essential to inform policy makers and raise the public awareness of the importance of self-isolation and quarantine. MethodWe collected confirmed case data and the migration data, and introduced the quarantine factor and traffic blockage factor to the Flow-SEIR model. By varying the quarantine factor and traffic blockage factor, we simulated the change of the peak number and arrival time of infections, then the efficacy of these two intervation measures can be analyzed in our simulation. In our study, the self-protection at home is also included in quarantine. ResultsIn the simulated results, the quarantine and traffic blockage are effective for epidemic control. For Hubei province, the current quarantine factor is estimaed to be 0.405, which means around 40.5% of suceptibles who are close contacting with are in quarantine, and the current traffic blockage factor is estimaed to be 0.66, which indicates around 34% of suceptibles who had flowed out from Hubei. For the other provinces outside Hubei, the current quarantine factor is estimated to be 0.285, and the current traffic blockage factor is estimated to be 0.26. With the quarantine and traffic blockage factor increasing, the number of infections decrease dramatically. We also simulated the start dates of quarantine and traffic blockage at four time points, the simulated results show that the early of warning is also effective for epidemic containing. However, provincial level traffic blockage can only alleviate 21.06% - 22.38% of the peak number of infections. In general, the quarantine is much more effective than the traffic blockage control. ConclusionBoth of quarantine and traffic blockage are effective ways to control the spread of COVID-19. However, the eff icacy of quarantine is found to be much stronger than that of traffic blockage. Considering traffic blockage may also cause huge losses of economy, we propose to gradually deregulate the traffic blockage, and improve quarantine instead. Also, there might be a large number of asymptomatic carriers of COVID-19, the quarantine should be continued for a long time until the epidemic is totally under control.

EPIDEMIC TRENDS ANALYSIS AND RISK ESTIMATION OF 2019-NCOV OUTBREAK

Since December 1, 2019, the spread of COVID-19 is increasing every day. It is particularly important to predict the trend of the epidemic for the timely adjustment of the economy and industries. We proposed a Flow-SEHIR model in this paper to perform the trends of 2019-nCoV (COVID-19) in China. The results show that the number of daily confirmed new cases reaches the inflection point on Feb. 6 - 10 outside Hubei. For the maximum of temporal infected cases number, the predicted peak value in China except Hubei was estimated to be 21721 (95% CI: 18764 - 24929). The peak arrival time is on March 3 - 9. The temporal number of patients in most areas of China outside Hubei will peak from March 12 to March 15. The peak values of more than 73.5% provinces or regions in China will be controlled within 1000. According to Flow-SEHIR model and estimations from the data of evacuation of nationals from Wuhan, the real peak cumulative number of patients in Hubei is estimated to be 403481 (95% CI: 143284 - 1166936).