Flattening the Curve after the Initial Outbreak of Coronavirus Disease 2019: A Data-Driven Modeling Analysis for the Omicron Pandemic in China.

China is relaxing COVID-19 measures from the "dynamic zero tolerance" (DZT) level. The "flatten-the-curve" (FTC) strategy, which decreases and maintains the low rate of infection to avoid overwhelming the healthcare system by adopting relaxed nonpharmaceutical interventions (NPIs) after the outbreak, has been perceived as the most appropriate and effective method in preventing the spread of the Omicron variant. Hence, we established an improved data-driven model of Omicron transmission based on the age-structured stochastic compartmental susceptible-latent-infectious-removed-susceptible model constructed by Cai to deduce the overall prevention effect throughout China. At the current level of immunity without the application of any NPIs, more than 1.27 billion (including asymptomatic individuals) were infected within 90 days. Moreover, the Omicron outbreak would result in 1.49 million deaths within 180 days. The application of FTC could decrease the number of deaths by 36.91% within 360 days. The strict implementation of FTC policy combined with completed vaccination and drug use, which only resulted in 0.19 million deaths in an age-stratified model, will help end the pandemic within about 240 days. The pandemic would be successfully controlled within a shorter period of time without a high fatality rate; therefore, the FTC policy could be strictly implemented through enhancement of immunity and drug use.

Synthesis and Antitumor Activities of Novel Mitochondria-Targeted Dihydroartemisinin Ether Derivatives.

Ten novel mitochondria-targeted dihydroartemisinin ether derivatives were designed, synthesized, and evaluated for antitumor activity against five cancer cell lines in vitro. Profoundly, compound D8-T (IC50 = 56.9 nM) showed the most potent antiproliferative activity against the T24 cells with low cytotoxicity in normal human umbilical vein endothelial cells. High-performance liquid chromatography analysis confirmed that D8-T targeted mitochondria 6.3-fold higher than DHA. ATP content assay demonstrated that D8-T decreased the ATP level of bladder cancer cells. The effect of D8-T on cell apoptosis was determined by flow cytometry and western blot of Bax and Bcl-2. Surprisingly, the results indicated that D8-T did not induce bladder cancer cell apoptosis. In contrast, the cell cycle analysis and western blot of CDK4, CDK6, cyclin D1, and p21 demonstrated that the cancer cell cycle was arrested at the G1 phase after D8-T treatment. Furthermore, the consistent results were received by RNA-seq assay. These promising findings implied that D8-T could serve as a great candidate against bladder cancer for further investigation.

Novel dihydroartemisinin derivative Mito-DHA5 induces apoptosis associated with mitochondrial pathway in bladder cancer cells.

BACKGROUND: Bladder cancer is the second most common genitourinary malignancy and the eleventh most common cancer worldwide. Dihydroartemisinin (DHA), a first-line antimalarial drug, has been found to have potent antitumor activity. In our previous study, a novel dihydroartemisinin derivative Mito-DHA5 synthesized in our laboratory has a stronger anti-tumor activity than DHA. In this study, we investigated the apoptotic effect of Mito-DHA5 on bladder cancer T24 cells and molecular mechanisms underlying. METHODS: Antitumor activity in vitro was evaluated by MTT, wound healing and cloning formation assays. Mitochondrial membrane potential (MMP) was detected by JC-1 probe and ROS levels were measured by specific kit. The expression of caspase-3, cleaved-caspase3, mitochondrial Cyt-C, Bcl-2, Bax and PARP in T24 cells was evaluated by Western blotting. RESULTS: The results showed that Mito-DHA5 reduced cell viability with an IC50 value of 3.2 µM and induced T24 cell apoptosis in a dose-dependent manner, increased the production of ROS and decreased MMP. Mito-DHA5 could down-regulate the expression of Bcl-2, mitochondrial Cyt-C, Caspase-3, PARP and up-regulate the expression of Bax and cleaved Caspase-3. CONCLUSIONS: These data suggested that Mito-DHA5 had a potent inhibitory effect on T24 bladder cancer cell growth and induced these cells apoptosis associated with mitochondrial pathway.

Synthesis and biological activities of novel mitochondria-targeted artemisinin ester derivatives.

A series of novel artemisinin ester derivatives were designed and synthesized for targeting mitochondria. Cytotoxicity against SMMC-7721, HepG2, OVCAR3, A549 and J82 cancer cell lines was evaluated. Compound 2c (IC50 = 3.0 µM) was the most potent anti-proliferative molecule against the OVCAR3 cells with low cytotoxicity in normal HUVEC cells. The mechanism of action of compound 2c was further investigated by analyzing cell apoptosis, mitochondrial membrane potential (Δψm) and intracellular ROS generation. The results indicated that compound 2c targeted mitochondria and induced cell apoptosis. ROS and heme attributed to the cytotoxicity and cell apoptosis of compound 2c. These promising findings indicated the compound 2c could serve as a great candidate against ovarian cancer for further investigation.

Recent research status of Bactrocera dorsalis: Insights from resistance mechanisms and population structure.

Bactrocera dorsalis (Hendel) is considered to be a highly invasive and destructive agricultural pest due to its strong dispersal and adaptive capacity. Rapid development of insecticide resistance poses a serious threat to the sustainable control of this pest. Here, the resistance mechanisms and invasion pathways of this fly are outlined for a better understanding of the resistance-gene flow pattern and invasion routes. We believe this microreview will provide a glimpse of the native regions, spread and management of resistance, and guide future work on these important topics.

Drug Synergy Slows Aging and Improves Healthspan through IGF and SREBP Lipid Signaling.

There is growing interest in pharmacological interventions directly targeting the aging process. Pharmacological interventions against aging should be efficacious when started in adults and, ideally, repurpose existing drugs. We show that dramatic lifespan extension can be achieved by targeting multiple, evolutionarily conserved aging pathways and mechanisms using drug combinations. Using this approach in C. elegans, we were able to slow aging and significantly extend healthy lifespan. To identify the mechanism of these drug synergies, we applied transcriptomics and lipidomics analysis. We found that drug interactions involved the TGF-ß pathway and recruited genes related with IGF signaling. daf-2, daf-7, and sbp-1 interact upstream of changes in lipid metabolism, resulting in increased monounsaturated fatty acid content and this is required for healthy lifespan extension. These data suggest that combinations of drugs targeting distinct subsets of the aging gene regulatory network can be leveraged to cause synergistic lifespan benefits.

A novel vibration-induced exercise paradigm improves fitness and lipid metabolism of Caenorhabditis elegans.

Exercise has been known to reduce the risk of obesity and metabolic syndrome, but the mechanisms underlying many exercise benefits remain unclear. This is, in part, due to a lack of exercise paradigms in invertebrate model organisms that would allow rapid mechanistic studies to be conducted. Here we report a novel exercise paradigm in Caenorhabditis elegans (C. elegans) that can be implemented under standard laboratory conditions. Mechanical stimulus in the form of vibration was transduced to C. elegans grown on solid agar media using an acoustic actuator. One day post-exercise, the exercised animals showed greater physical fitness compared to the un-exercised controls. Despite having higher mitochondrial reactive oxygen species levels, no mitohormetic adaptations and lifespan extension were observed in the exercised animals. Nonetheless, exercised animals showed lower triacylglycerides (TAG) accumulation than the controls. Among the individual TAG species, the most significant changes were found in mono- and polyunsaturated fatty acid residues. Such alteration resulted in an overall lower double bond index and peroxidation index which measure susceptibility towards lipid peroxidation. These observations are consistent with findings from mammalian exercise literature, suggesting that exercise benefits are largely conserved across different animal models.

Genome-wide identification, phylogenetic analysis, and expression profiles of ATP-binding cassette transporter genes in the oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae).

The ATP-binding cassette (ABC) is the largest transporter gene family and the genes play key roles in xenobiotic resistance, metabolism, and development of all phyla. However, the specific functions of ABC gene families in insects is unclear. We report a genome-wide identification, phylogenetic, and transcriptional analysis of the ABC genes in the oriental fruit fly, Bactrocera dorsalis (Hendel). We identified a total of 47 ABC genes (BdABCs) from the transcriptomic and genomic databases of B. dorsalis and classified these genes into eight subfamilies (A-H), including 7 ABCAs, 7 ABCBs, 9 ABCCs, 2 ABCDs, 1 ABCE, 3 ABCFs, 15 ABCGs, and 3 ABCHs. Comparative phylogenetic analysis of the ABCs suggests an orthologous relationship between B. dorsalis and other insect species in which these genes have been related to pesticide resistance and essential biological processes. Comparison of transcriptome and relative expression patterns of BdABCs indicated diverse multifunctions within different B. dorsalis tissues. The expression of 4, 10, and 14 BdABCs from 18 BdABCs was significantly upregulated after exposure to LD50s of malathion, avermectin, and beta-cypermethrin, respectively. The maximum expression level of most BdABCs (including BdABCFs, BdABCGs, and BdABCHs) occurred at 48h post exposures, whereas BdABCEs peaked at 24h after treatment. Furthermore, RNA interference-mediated suppression of BdABCB7 resulted in increased toxicity of malathion against B. dorsalis. These data suggest that ABC transporter genes might play key roles in xenobiotic metabolism and biosynthesis in B. dorsalis.

Functional characterization of NADPH-cytochrome P450 reductase from Bactrocera dorsalis: Possible involvement in susceptibility to malathion.

NADPH cytochrome P450 reductase (CPR) is essential for cytochrome P450 catalysis, which is important in the detoxification and activation of xenobiotics. In this study, two transcripts of Bactrocera dorsalis CPR (BdCPR) were cloned, and the deduced amino-acid sequence had an N-terminus membrane anchor for BdCPR-X1 and three conserved binding domains (FMN, FAD, and NADP), as well as an FAD binding motif and catalytic residues for both BdCPR-X1 and BdCPR-X2. BdCPR-X1 was detected to have the high expression levels in adults and in Malpighian tubules, fat bodies, and midguts of adults, but BdCPR-X2 expressed lowly in B. dorsalis. The levels of BdCPRs were similar in malathion-resistant strain compared to susceptible strain. However, injecting adults with double-stranded RNA against BdCPR significantly reduced the transcript levels of the mRNA, and knockdown of BdCPR increased adult susceptibility to malathion. Expressing complete BdCPR-X1 cDNA in Sf9 cells resulted in high activity determined by cytochrome c reduction and these cells had higher viability after exposure to malathion than control. The results suggest that BdCPR could affect the susceptibility of B. dorsalis to malathion and eukaryotic expression of BdCPR would lay a solid foundation for further investigation of P450 in B. dorsalis.