In comparison to severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2 appears to be more contagious 1, and coronavirus disease 2019 (COVID-19) patients demonstrate varied clinical ...manifestations distinct from those seen in patients with SARS-CoV and Middle East respiratory syndrome coronavirus infections 2. Collective results from the clinical and epidemiological observations suggest a distinct viral–host interaction in COVID-19 patients. Profiling of the antibody response during SARS-CoV-2 infection may help improve our understanding of the viral–host interaction and the immunopathological mechanisms of the disease.
Humoral immune response to SARS-CoV-2 showed an early response of IgA, instead of IgM, in COVID-19 patients. As highlighted by this study, enhanced IgA responses observed in severe COVID-19 might confer damaging effects in severe COVID-19.
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Zika virus (ZIKV) has evolved into a global health threat because of its unexpected causal link to microcephaly. Phylogenetic analysis reveals that contemporary epidemic strains have accumulated ...multiple substitutions from their Asian ancestor. Here we show that a single serine-to-asparagine substitution Ser139→Asn139 (S139N) in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs) and led to more severe microcephaly in the mouse fetus, as well as higher mortality rates in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics.
Background and Purpose
The anthelmintic drug nitazoxanide has a mitochondrial uncoupling effect. Mitochondrial uncouplers have been proven to inhibit smooth muscle cell proliferation and migration, ...inhibit NLRP3 inflammasome activation of macrophages and improve dyslipidaemia. Therefore, we aimed to demonstrate that nitazoxanide would protect against atherosclerosis.
Experimental Approach
The mitochondrial oxygen consumption of cells was measured by using the high‐resolution respirometry system, Oxygraph‐2K. The proliferation and migration of A10 cells were measured by using Edu immunofluorescence staining, wound‐induced migration and the Boyden chamber assay. Protein levels were measured by using the western blot technique. ApoE (−/−) mice were fed with a Western diet to establish an atherosclerotic model in vivo.
Key Results
The in vitro experiments showed that nitazoxanide and tizoxanide had a mitochondrial uncoupling effect and activated cellular AMPK. Nitazoxanide and tizoxanide inhibited serum‐ and PDGF‐induced proliferation and migration of A10 cells. Nitazoxanide and tizoxanide inhibited NLRP3 inflammasome activation in RAW264.7 macrophages, the mechanism by which involved the AMPK/IκBα/NF‐κB pathway. Nitazoxanide and tizoxanide also induced autophagy in A10 cells and RAW264.7 macrophages. The in vivo experiments demonstrated that oral administration of nitazoxanide reduced the increase in serum IL‐1β and IL‐6 levels and suppressed atherosclerosis in Western diet‐fed ApoE (−/−) mice.
Conclusion and Implications
Nitazoxanide inhibits the formation of atherosclerotic plaques in ApoE (−/−) mice fed on a Western diet. In view of nitazoxanide being an antiprotozoal drug already approved by the FDA, we propose it as a novel anti‐atherosclerotic drug with clinical translational potential.
Restricted by the poor ability of polymers to dissociate lithium salts and transport ions, solid‐state polymer electrolytes (SPEs) show extremely low ionic conductivities (≈10−7–10−5 S cm−1) and ...transference number of lithium ions (tLi+ ≈0.2–0.4) at 25 °C. Here, a novel polymer matrix of SPEs that simultaneously promotes lithium salt dissociation and ion transportation based on a high dielectric poly(vinylidene fluoride‐trifluoroethylene‐chlorotrifluoroethylene) (TerP) and an all‐trans conformational poly(vinylidene fluoride‐trifluoroethylene) (CoP), is developed. The high dielectric constant increases the polarity of CH2CF2 polar groups; then, brings a strong electronegative end that dissociates Li+ from lithium salts. The all‐trans conformation assures all fluorine atoms locate on one side of the chain, constructing ion hopping highways. As a result, the TerP/CoP (TC) SPE exhibits a high ionic conductivity (2.37 × 10−4 S cm−1) and a quite large tLi+ of 0.61 at 25 °C. The Li/TC SPE/Li symmetric cells cycle stably for more than half a year (>4500 h) and the LiNi0.8Co0.1Mn0.1O2/TC SPE/Li cell cycles steadily for 1000 and 600 cycles at 1 C and 2 C at 25 °C, respectively. This work paves a new way to prepare high‐performance SPEs by simultaneously modulating dielectric constants and conformation of polymers.
Through conformational regulation of the high dielectric P(VDF‐TrFE‐CTFE), an all‐trans conformation with all F atoms located on one side of the chain is achieved, which constructs ion hopping highways and results in a high lithium‐ion transference number of 0.61. Both the Li//Li symmetric cells and the high‐voltage NCM811//Li cells show long‐term cycling stability at 25 °C.
Abstract
Background
The R1441G mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in late-onset Parkinson’s disease (PD). Peripheral inflammation and gut microbiota are closely ...associated with the pathogenesis of PD. Chronic periodontitis is a common type of peripheral inflammation, which is associated with PD.
Porphyromonas gingivalis
(Pg), the most common bacterium causing chronic periodontitis, can cause alteration of gut microbiota. It is not known whether Pg-induced dysbiosis plays a role in the pathophysiology of PD.
Methods
In this study, live Pg were orally administrated to animals, three times a week for 1 month. Pg-derived lipopolysaccharide (LPS) was used to stimulate mononuclear cells in vitro. The effects of oral Pg administration on the gut and brain were evaluated through behaviors, morphology, and cytokine expression.
Results
Dopaminergic neurons in the substantia nigra were reduced, and activated microglial cells were increased in R1441G mice given oral Pg. In addition, an increase in mRNA expression of tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) as well as protein level of α-synuclein together with a decrease in zonula occludens-1 (Zo-1) was detected in the colon in Pg-treated R1441G mice. Furthermore, serum interleukin-17A (IL-17A) and brain IL-17 receptor A (IL-17RA) were increased in Pg-treated R1441G mice.
Conclusions
These findings suggest that oral Pg-induced inflammation may play an important role in the pathophysiology of LRRK2-associated PD.
Atherosclerosis is a progressive, chronic inflammation in arterial walls. Long noncoding RNAs (lncRNAs) participate in inflammation, but the exact mechanism in atherosclerosis is unclear. Our ...microarray analyses revealed that the levels of lncRNA-FA2H-2 were significantly decreased by oxidized low-density lipoprotein (OX-LDL). Bioinformatics analyses indicated that mixed lineage kinase domain-like protein (MLKL) might be regulated by lncRNA-FA2H-2. In vitro experiments showed that lncRNA-FA2H-2 interacted with the promoter of the MLKL gene, downregulated MLKL expression, and the binding sites between -750 and 471 were necessary for lncRNA-FA2H-2 responsiveness to MLKL. Silencing lncRNA-FA2H-2 and overexpression of MLKL could activate inflammation and inhibited autophagy flux. Both lncRNA-FA2H-2 knockdown and overexpression of MLKL could significantly aggravate inflammatory responses induced by OX-LDL. We found that the 3-methyladenine (3-MA) and Atg7-shRNA enhanced inflammatory responses induced by knockdown of lncRNA-FA2H-2 and overexpression of MLKL. We demonstrated that the effects of MLKL on autophagy might be associated with a mechanistic target of rapamycin (mTOR)-dependent signaling pathways. In vivo experiments with apoE knockout mice fed a western diet demonstrated that LncRNA-FA2H-2 knockdown decreased microtubule-associated expression of microtubule-associated protein 1 light chain 3 II and lysosome-associated membrane protein 1, but increased expression of sequestosome 1 (p62), MLKL, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and interleukin-6 in atherosclerotic lesions. Our findings indicated that the lncRNA-FA2H-2-MLKL pathway is essential for regulation of autophagy and inflammation, and suggested that lncRNA-FA2H-2 and MLKL could act as potential therapeutic targets to ameliorate atherosclerosis-related diseases.
WRKY transcription factors play a key role in the tolerance of biotic and abiotic stresses across various crop species, but the function of some WRKY genes, particularly in tomato, remains ...unexplored. Here, we characterize the roles of a previously unstudied WRKY gene, SlWRKY8, in the resistance to pathogen infection and the tolerance to drought and salt stresses. Expression of SlWRKY8 was up‐regulated upon Pseudomonas syringae pv. tomato DC3000 (Pst. DC3000), abiotic stresses such as drought, salt and cold, as well as ABA and SA treatments. The SlWRKY8 protein was localized to the nucleus with no transcription activation in yeast, but it could activate W‐box‐dependent transcription in plants. The overexpression of SlWRKY8 in tomato conferred a greater resistance to the pathogen Pst. DC3000 and resulted in the increased transcription levels of two pathogen‐related genes SlPR1a1 and SlPR7. Moreover, transgenic plants displayed the alleviated wilting or chlorosis phenotype under drought and salt stresses, with higher levels of stress‐induced osmotic substances like proline and higher transcript levels of the stress‐responsive genes SlAREB, SlDREB2A and SlRD29. Stomatal aperature was smaller under drought stress in transgenic plants, maintaining higher water content in leaves compared with wild‐type plants. The oxidative pressure, indicated by the concentration of hydrogen peroxide (H2O2) and malondialdehyde (MDA), was also reduced in transgenic plants, where we also observed higher levels of antioxidant enzyme activities under stress. Overall, our results suggest that SlWRKY8 functions as a positive regulator in plant immunity against pathogen infection as well as in plant responses to drought and salt stresses.
The ongoing coronavirus disease 2019 (COVID-19) pandemic has prioritized the development of small-animal models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We adapted a clinical ...isolate of SARS-CoV-2 by serial passaging in the respiratory tract of aged BALB/c mice. The resulting mouse-adapted strain at passage 6 (called MASCp6) showed increased infectivity in mouse lung and led to interstitial pneumonia and inflammatory responses in both young and aged mice after intranasal inoculation. Deep sequencing revealed a panel of adaptive mutations potentially associated with the increased virulence. In particular, the N501Y mutation is located at the receptor binding domain (RBD) of the spike protein. The protective efficacy of a recombinant RBD vaccine candidate was validated by using this model. Thus, this mouse-adapted strain and associated challenge model should be of value in evaluating vaccines and antivirals against SARS-CoV-2.
This study aimed to determine the levels of health-related behaviours (physical activity, screen exposure and sleep status) among Chinese students from primary, secondary and high schools during the ...pandemic of COVID-19, as well as their changes compared with their status before the pandemic. A cross-sectional online survey of 10,933 students was conducted among 10 schools in Guangzhou, China, between 8th and 15th March, 2020. After getting the informed consent from student's caregivers, an online questionnaire was designed and used to obtain time spending on health-related behaviours during the pandemic of COVID-19, as well as the changes compared with 3 months before the pandemic, which was completed by students themselves or their caregivers. Students were stratified by regions (urban, suburban, exurban), gender (boys and girls), and grades (lower grades of primary school, higher grades of primary schools, secondary schools and high schools). Data were expressed as number and percentages and Chi-square test was used to analyse difference between groups. Overall, the response rate of questionnaire was 95.3% (10,416/10,933). The median age of included students was 13.0 (10.0, 16.0) years and 50.1% (n = 5,219) were boys. 41.4%, 53.6% and 53.7% of total students reported less than 15 min per day in light, moderate and vigorous activities and 58.7% (n = 6,113) reported decreased participation in physical activity compared with the time before pandemic. Over 5 h of screen time spending on online study was reported by 44.6% (n = 4,649) of respondents, particular among high school students (81.0%). 76.9% of students reported increased screen time compared with the time before pandemic. Inadequate sleep was identified among 38.5% of students and the proportion was highest in high school students (56.9%). Our study indicated that, during the COVID-19 pandemic, the school closure exerted tremendous negative effects on school-aged children's health habits, including less physical activity, longer screen exposure and irregular sleeping pattern.
Osteolysis induced by chronic Gram-negative bacterial infection underlies many bone diseases such as osteomyelitis, septic arthritis, and periodontitis. Drugs that inhibit lipopolysaccharide ...(LPS)-induced osteolysis are critically needed for the prevention of bone destruction in infective bone diseases. In this study, we assessed the effect of puerarin, a natural isoflavone isolated from Pueraria lobata OHWI root, on LPS-induced osteoclastogenesis and bone loss. Our in vitro study showed that puerarin significantly inhibited LPS-induced osteoclast differentiation from osteoclast precursor RAW264.7 cells. The inhibition occurred through suppressing the production of osteoclast activating factor tumor necrosis factor (TNF)-α, interleukin (IL)-1β and prostaglandin E2 (PGE2), which led to down-regulating mRNA expression of osteoclastogenic genes including tartrate-resistant acid phosphatase (TRAP), cathepsin K and matrix metalloprotein 9 (MMP-9). Furthermore, LPS triggered activation of Akt in osteoclast precursor RAW264.7 cells, which was inhibited by puerarin treatment. In vivo, puerarin attenuated LPS-induced bone loss in a murine calvarial osteolysis model. Collectively, puerarin prevents LPS-induced osteoclast formation, function and bone loss, where the inhibition of Akt activation plays an important role. These findings provide evidences that puerarin might be beneficial as a promising candidate drug for the prevention and treatment of bacteria-induced bone destruction disease, and give new insights for understanding its possible mechanism.
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