Safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster following three doses of CoronaVac: a multicentre, open-label, phase 4, randomised trial.

BACKGROUND: Aerosolised Ad5-nCoV is the first approved mucosal respiratory COVID-19 vaccine to be used as a booster after the primary immunisation with COVID-19 vaccines. This study aimed to evaluate the safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster. METHODS: This is an open-label, parallel-controlled, phase 4 randomised trial enrolling healthy adult participants (≥18 years) who had completed a two-dose primary immunisation and a booster immunisation with inactivated COVID-19 vaccines (CoronaVac only) at least 6 months before, in Lianshui and Donghai counties, Jiangsu Province, China. We recruited eligible participants from previous trials in China (NCT04892459, NCT04952727, and NCT05043259) as cohort 1 (with the serum before and after the first booster dose available), and from eligible volunteers in Lianshui and Donghai counties, Jiangsu Province, as cohort 2. Participants were randomly assigned at a ratio of 1:1:1, using a web-based interactive response randomisation system, to receive the fourth dose (second booster) of aerosolised Ad5-nCoV (0·1 mL of 1·0 × 1011 viral particles per mL), intramuscular Ad5-nCoV (0·5 mL of 1·0 × 1011 viral particles per mL), or inactivated COVID-19 vaccine CoronaVac (0·5 mL), respectively. The co-primary outcomes were safety and immunogenicity of geometric mean titres (GMTs) of serum neutralising antibodies against prototype live SARS-CoV-2 virus 28 days after the vaccination, assessed on a per-protocol basis. Non-inferiority or superiority was achieved when the lower limit of the 95% CI of the GMT ratio (heterologous group vs homologous group) exceeded 0·67 or 1·0, respectively. This study was registered with ClinicalTrials.gov, NCT05303584 and is ongoing. FINDINGS: Between April 23 and May 23, 2022, from 367 volunteers screened for eligibility, 356 participants met eligibility criteria and received a dose of aerosolised Ad5-nCoV (n=117), intramuscular Ad5-nCoV (n=120), or CoronaVac (n=119). Within 28 days of booster vaccination, participants in the intramuscular Ad5-nCoV group reported a significantly higher frequency of adverse reactions than those in the aerosolised Ad5-nCoV and intramuscular CoronaVac groups (30% vs 9% and 14%, respectively; p<0·0001). No serious adverse events related to the vaccination were reported. The heterologous boosting with aerosolised Ad5-nCoV triggered a GMT of 672·4 (95% CI 539·7-837·7) and intramuscular Ad5-nCoV triggered a serum neutralising antibody GMT of 582·6 (505·0-672·2) 28 days after the booster dose, both of which were significantly higher than the GMT in the CoronaVac group (58·5 [48·0-71·4]; p<0·0001). INTERPRETATION: A heterologous fourth dose (second booster) with either aerosolised Ad5-nCoV or intramuscular Ad5-nCoV was safe and highly immunogenic in healthy adults who had been immunised with three doses of CoronaVac. FUNDING: National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan.

Role of chemokine-like factor 1 as an inflammatory marker in diseases.

Immunoinflammatory mechanisms have been incrementally found to be involved in the pathogenesis of multiple diseases, with chemokines being the main drivers of immune cell infiltration in the inflammatory response. Chemokine-like factor 1 (CKLF1), a novel chemokine, is highly expressed in the human peripheral blood leukocytes and exerts broad-spectrum chemotactic and pro-proliferative effects by activating multiple downstream signaling pathways upon binding to its functional receptors. Furthermore, the relationship between CKLF1 overexpression and various systemic diseases has been demonstrated in both in vivo and in vitro experiments. In this context, it is promising that clarifying the downstream mechanism of CKLF1 and identifying its upstream regulatory sites can yield new strategies for targeted therapeutics of immunoinflammatory diseases.

Detection of myeloma cell-derived microvesicles: a tool to monitor multiple myeloma load.

The persistence of tumor load in multiple myeloma (MM) lead to relapse in patients achieving complete remission (CR). Appropriate and effective methods of myeloma tumor load monitoring are important for guiding clinical management. This study aimed to clarify the value of microvesicles in monitoring MM tumor load. Microvesicles in bone marrow and peripheral blood were isolated by differential ultracentrifugation and detected by flow cytometry. Western blotting was applied to assess myosin light chain phosphorylation levels. Flow cytometry to detect Ps+CD41a-, Ps+CD41a-CD138+, Ps+CD41a-BCMA+ microvesicles from bone marrow can be used to predict myeloma burden, furthermore, Ps+CD41a- microvesicles may as a potential index to MRD test. Mechanistically, the releasing of microvesicles from MM cell was regulated by Pim-2 Kinase via Phosphorylation of MLC-2 protein.

LTA4H extensively associates with mRNAs and lncRNAs indicative of its novel regulatory targets.

The RNA-binding metabolic enzyme LTA4H is a novel target for cancer chemoprevention and chemotherapy. Recent research shows that the increased expression of LTA4H in laryngeal squamous cell carcinoma (LSCC) promotes tumor proliferation, migration, and metastasis. However, its mechanism remains unclear. To investigate the potential role of LTA4H in LSCC, we employed the improved RNA immunoprecipitation and sequencing (iRIP-Seq) experiment to get the expression profile of LTA4H binding RNA in HeLa model cells, a cancer model cell that is frequently used in molecular mechanism research. We found that LTA4H extensively binds with mRNAs/pre-mRNAs and lncRNAs. In the LTA4H binding peak, the frequency of the AAGG motif reported to interact with TRA2ß4 was high in both replicates. More notably, LTA4H-binding genes were significantly enriched in the mitotic cell cycle, DNA repair, RNA splicing-related pathways, and RNA metabolism pathways, which means that LTA4H has tumor-related alternative splicing regulatory functions. QRT-PCR validation confirmed that LTA4H specifically binds to mRNAs of carcinogenesis-associated genes, including LTBP3, ROR2, EGFR, HSP90B1, and lncRNAs represented by NEAT1. These results suggest that LTA4H may combine with genes associated with LSCC as an RNA-binding protein to perform a cancer regulatory function. Our study further sheds light on the molecular mechanism of LTA4H as a clinical therapy target for LSCC.

Classification, diagnosis and clinical strategy of congenital coronary artery disease in children.

Some of the congenital coronary artery diseases in children have potential life-threatening complications. In addition to anatomical classification, the peadiatricians should pay more attention to the risk of adverse cardiac events classification; and then, they can eventrually make the personalized guidance suggestions and treatment decisions according to different diseases.

Toxic effects of cadmium exposure on intestinal histology, oxidative stress, microbial community, and transcriptome change in the mud crab (Scylla paramamosain).

Cadmium is one of hazardous pollutants that has a great threat to aquatic organisms and ecosystems. The intestine plays important roles in barrier function and immunity to defend against environmental stress. However, whether cadmium exposure caused the intestine injury is not well studied. Thus, the aim of this study was to explore the potential mechanisms of cadmium toxicity in the intestine of mud crab (Scylla paramamosain) via physiological, histological, microbial community, and transcriptional analyses. Mud crabs were exposed to 0, 0.01, and 0.125 mg/L cadmium. After a 21-day of cadmium exposure, 0.125 mg/L cadmium caused intestine damaged by decreasing superoxide dismutase and catalase activities, and increasing hydrogen peroxide and malondialdehyde levels. Integrated biological index analysis confirmed that the toxicity of cadmium exhibited a concentration-dependent manner. Comparative transcriptional analyses showed that the up-regulations of several genes associated with heat shock proteins, detoxification and anti-oxidant defense, and two key signaling pathways (PI3k-Akt and apoptosis) revealed an adaptive response mechanism against cadmium exposure. Transcriptomic analysis also suggested that cadmium exposure disturbed the expression of ion transport and immune-related genes, indicating that it has negative effects on the immune functions of the mud crab. Furthermore, the intestinal microbial diversity and composition were significantly influenced by cadmium exposure. The abundance of the dominant phyla Fusobacteria and Bacteroidetes significantly changed after cadmium exposure. KEGG pathway analysis demonstrated that cadmium exposure could change energy metabolism and environmental information processing. Overall, we concluded that excessive cadmium exposure could be potentially exerted adverse effects to the mud crab health by inducing oxidative damage, decreasing immune system, disrupting metabolic function, and altering intestinal microbial composition. These results provided a novel insight into the mechanism of cadmium toxicity on crustaceans.

Signaling pathway mechanisms of neurological diseases induced by G protein-coupled receptor 39.

BACKGROUND: G protein-coupled receptor 39 (GPR39) is a transmembrane zinc receptor with two splice variants, which belongs to the G-protein-coupled receptor growth hormone-releasing peptide family. Its expression is induced by zinc, which activates GPR39, and its activation mediates cell proliferation, ion homeostasis, and anti-inflammatory, antioxidant, and other pathophysiological effects via different signaling pathways. AIMS: The article reviews the latest literature in this field. In particular, the role of GPR39 in nervous system is discussed. MATERIALS AND METHODS: GPR39 can be a promising target in neurological diseases for targeted therapy, which will help doctors overcome the associated problems. DISCUSSION: GPR39 is expressed in vivo at several sites. Increasing evidence suggests that GPR39 plays an important role as a neuroprotective agent in vivo and regulates various neurological functions, including neurodegeneration, neuroelectrophysiology, and neurovascular homeostasis. CONCLUSION: This review aims to provide an overview of the functions, signal transduction pathways, and pathophysiological role of GPR39 in neurological diseases and summarize the GPR39 agonists that have been identified in the recent years.

Essential role of the Cytochrome P450 2 (CYP2) in the mud crab Scylla paramamosain antioxidant defense and immune responses.

Cytochrome P450 (CYPs) enzymes are one of the critical detoxification enzymes, playing a key role in antioxidant defense. However, the information of CYPs cDNA sequences and their functions are lacked in crustaceans. In this study, a novel full-length of CYP2 from the mud crab (designated as Sp-CYP2) was cloned and characterized. The coding sequence of Sp-CYP2 was 1479 bp in length and encoded a protein containing 492 amino acids. The amino acid sequence of Sp-CYP2 comprised a conserved heme binding site and chemical substrate binding site. Quantitative real-time PCR analysis revealed that Sp-CYP2 was ubiquitously expressed in various tissues, and it was highest in the heart followed by the hepatopancreas. Subcellular localization showed that Sp-CYP2 was prominently located in the cytoplasm and nucleus. The expression of Sp-CYP2 was induced by Vibrio parahaemolyticus infection and ammonia exposure. During ammonia exposure, ammonia exposure can induce oxidative stress and cause severely tissue damage. Knocking down Sp-CYP2 in vivo can increase malondialdehyde content and the mortality of mud crabs after ammonia exposure. All these results suggested that Sp-CYP2 played a crucial role in the defense against environmental stress and pathogen infection in crustaceans.

B cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis.

Hyperhomocysteinemia (HHcy) is a risk factor for chronic kidney diseases (CKDs) that affects about 85% CKD patients. HHcy stimulates B cells to secrete pathological antibodies, although it is unknown whether this pathway mediates kidney injury. In HHcy-treated 2-kidney, 1-clip (2K1C) hypertensive murine model, HHcy-activated B cells secreted anti-beta 2 glycoprotein I (ß2GPI) antibodies that deposited in glomerular endothelial cells (GECs), exacerbating glomerulosclerosis and reducing renal function. Mechanistically, HHcy 2K1C mice increased phosphatidylethanolamine (PE) (18:0/20:4, 18:0/22:6, 16:0/20:4) in kidney tissue, as determined by lipidomics. GECs oxidative lipidomics validated the increase of oxidized phospholipids upon Hcy-activated B cells culture medium (Hcy-B CM) treatment, including PE (18:0/20:4 + 3[O], PE (18:0a/22:4 + 1[O], PE (18:0/22:4 + 2[O] and PE (18:0/22:4 + 3[O]). PE synthases ethanolamine kinase 2 (etnk2) and ethanolamine-phosphate cytidylyltransferase 2 (pcyt2) were increased in the kidney GECs of HHcy 2K1C mice and facilitated polyunsaturated PE synthesis to act as lipid peroxidation substrates. In HHcy 2K1C mice and Hcy-B CM-treated GECs, the oxidative environment induced by iron accumulation and the insufficient clearance of lipid peroxides caused by transferrin receptor (TFR) elevation and down-regulation of SLC7A11/glutathione peroxidase 4 (GPX4) contributed to GECs ferroptosis of the kidneys. In vivo, pharmacological depletion of B cells or inhibition of ferroptosis mitigated the HHcy-aggravated hypertensive renal injury. Consequently, our findings uncovered a novel mechanism by which B cell-derived pathogenic anti-ß2GPI IgG generated by HHcy exacerbated hypertensive kidney damage by inducing GECs ferroptosis. Targeting B cells or ferroptosis may be viable therapeutic strategies for ameliorating lipid peroxidative renal injury in HHcy patients with hypertensive nephropathy.

Administration of macrolide antibiotics increases cardiovascular risk.

Background: The increased risk of cardiovascular events in patients prescribed macrolides has been subject to debate for decades. Methods: Medline, EMBASE databases and ClinicalTrials.gov were searched from inception until August 31, 2022 for studies investigating the link between macrolides and cardiovascular risk. A meta-analysis was performed using a random-effects model. Results: A total of 80 studies involving 39,374,874 patients were included. No association was found between macrolides and all-cause death. However, compared with the non-macrolide group, macrolides were associated with a significantly increased risk of ventricular arrhythmia or sudden cardiac death (VA or SCD) (azithromycin, relative ratio [RR]: 1.53; 95% confidence interval [CI]: 1.19 to 1.97; clarithromycin, RR: 1.52; 95% CI: 1.07 to 2.16). Besides, administration of macrolides was associated with a higher risk of cardiovascular disease (CVD) death (azithromycin, RR: 1.63; 95% CI: 1.17 to 2.27) and a slightly increased risk of myocardial infarction (MI) (azithromycin, RR: 1.08; 95% CI: 1.02 to 1.15). Interestingly, no association was observed between roxithromycin and adverse cardiac outcomes. Increased risk of VA or SCD was observed for recent or current use of macrolides, MI for former use, and CVD death for current use. Conclusion: Administration of macrolide antibiotics and timing of macrolide use are associated with increased risk for SCD or VTA and cardiovascular death, but not all-cause death.

North Atlantic oscillation controls multidecadal changes in the North Tropical Atlantic-Pacific connection.

By exciting subtropical teleconnections, sea surface temperature (SST) anomalies in the North Tropical Atlantic (NTA) during boreal spring can trigger El Niño-Southern Oscillation (ENSO) events in the following boreal winter, thereby providing a precursor for ENSO predictability. However, this NTA-ENSO connection is not stationary, and it varies considerably over multidecadal timescales, which cannot be directly explained by the Atlantic multidecadal oscillation or the global warming trend. Here we show that multidecadal changes in the NTA-ENSO connection are principally controlled by multidecadal variability associated with the North Atlantic Oscillation (NAO). During the positive phase of the NAO, the amplification of the NTA impact on ENSO mainly arises from strengthening of the boreal spring mean precipitation over the equatorial Atlantic and enhancement of the persistence of NTA SST anomalies, which enhance the NTA influence by exciting stronger and more persistent subtropical teleconnections. Our findings show that multidecadal variability of the NAO is key to understanding the impacts of the NTA SST on the tropical Pacific Ocean.

EDA-E7 Activated DCs Induces Cytotoxic T Lymphocyte Immune Responses against HPV Expressing Cervical Cancer in Human Setting.

Cervical cancer is a major cause of cancer death in women worldwide. Targeting human papillomavirus (HPV) viral oncoproteins E6 and E7 is a new strategy for cervical cancer immunotherapy and has been associated with resolution of HPV-induced lesions. How to efficiently induce T cell target killing of HPV infected cervical cancer is of great potential benefit for cervical cancer treatment. Fusion protein containing the extra domain A (EDA) from fibronectin, a natural ligand for Toll-like receptor 4 (TLR4), and HPVE7 (EDA-E7) has been shown to efficiently induce dendritic cells maturation and trigger specific antitumor CD8+ T cells response in mice. In this study, we constructed EDA-E7 fusion protein of human origin and tested its function in dendritic cell maturation as well as antitumor T cell response. We found that EDA-E7 could be efficiently captured by human PBMC derived dendritic cells (DCs) in vitro and induce DCs maturation. Importantly, this effect could work in synergy with the TLR ligand anti-CD40 agonist, polyinosinic-polycytidylic acid [poly (I:C)], R848, and CpG2216. EDA-E7 matured DCs could activate T cells and trigger an anti-tumor response in vitro. Single cell RNA sequencing and T cell targeted killing assay confirmed the activation of T cells by EDA-E7 matured DCs. Therefore, therapeutic vaccination with EDA-E7 fusion protein maybe effective for human cervical carcinoma treatment.

Exendin-4 and linagliptin attenuate neuroinflammation in a mouse model of Parkinson's disease.

Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus. Therefore, using these two treatments may help treat Parkinson's disease. To further investigate the mechanisms of action of these two compounds, we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin. We found that both exendin-4 and linagliptin reversed motor dysfunction, glial activation, and dopaminergic neuronal death in this model. In addition, both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion. Moreover, in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain- and leucine-rich-repeat- and pyrin-domain-containing 3/caspase-1/interleukin-1ß pathway and subsequent pyroptosis by decreasing the production of reactive oxygen species. These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotide-binding oligomerization domain- and leucine-rich-repeat- and pyrin-domain-containing 3/caspase-1/interleukin-1ß pathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Therefore, these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.

A SARS-CoV-2-Related Virus from Malayan Pangolin Causes Lung Infection without Severe Disease in Human ACE2-Transgenic Mice.

Coronavirus disease 2019 (COVID-19), which is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the most severe emerging infectious disease in the current century. The discovery of SARS-CoV-2-related coronaviruses (SARSr-CoV-2) in bats and pangolins in South Asian countries indicates that SARS-CoV-2 likely originated from wildlife. To date, two SARSr-CoV-2 strains have been isolated from pangolins seized in Guangxi and Guangdong by the customs agency of China, respectively. However, it remains unclear whether these viruses cause disease in animal models and whether they pose a transmission risk to humans. In this study, we investigated the biological features of a SARSr-CoV-2 strain isolated from a smuggled Malayan pangolin (Manis javanica) captured by the Guangxi customs agency, termed MpCoV-GX, in terms of receptor usage, cell tropism, and pathogenicity in wild-type BALB/c mice, human angiotensin-converting enzyme 2 (ACE2)-transgenic mice, and human ACE2 knock-in mice. We found that MpCoV-GX can utilize ACE2 from humans, pangolins, civets, bats, pigs, and mice for cell entry and infect cell lines derived from humans, monkeys, bats, minks, and pigs. The virus could infect three mouse models but showed limited pathogenicity, with mild peribronchial and perivascular inflammatory cell infiltration observed in lungs. Our results suggest that this SARSr-CoV-2 virus from pangolins has the potential for interspecies infection, but its pathogenicity is mild in mice. Future surveillance among these wildlife hosts of SARSr-CoV-2 is needed to monitor variants that may have higher pathogenicity and higher spillover risk. IMPORTANCE SARS-CoV-2, which likely spilled over from wildlife, is the third highly pathogenic human coronavirus. Being highly transmissible, it is perpetuating a pandemic and continuously posing a severe threat to global public health. Several SARS-CoV-2-related coronaviruses (SARSr-CoV-2) in bats and pangolins have been identified since the SARS-CoV-2 outbreak. It is therefore important to assess their potential of crossing species barriers for better understanding of their risk of future emergence. In this work, we investigated the biological features and pathogenicity of a SARSr-CoV-2 strain isolated from a smuggled Malayan pangolin, named MpCoV-GX. We found that MpCoV-GX can utilize ACE2 from 7 species for cell entry and infect cell lines derived from a variety of mammalian species. MpCoV-GX can infect mice expressing human ACE2 without causing severe disease. These findings suggest the potential of cross-species transmission of MpCoV-GX, and highlight the need of further surveillance of SARSr-CoV-2 in pangolins and other potential animal hosts.

Towards low carbon demand and highly efficient nutrient removal: Establishing denitrifying phosphorus removal in a biofilm-based system.

The combined denitrifying phosphorus removal (DPR) and Anammox process is expected to achieve advanced nutrient removal with low carbon consumption. However, exchanging ammonia/nitrate between them is one limitation. This study investigated the feasibility of conducting DPR in a biofilm reactor to solve that problem. After 46-day anaerobic/aerobic operation, high phosphorus removal efficiency (PRE, 83.15 %) was obtained in the activated sludge (AS) and biofilm co-existed system, in which the AS performed better. Phosphate-accumulating organisms might quickly adapt to the anoxic introduced nitrate, but the following aerobic stage ensured a low effluent orthophosphate (<1.03 mg/L). Because of waste sludge discharging and AS transforming to biofilm, the suspended solids dropped below 60 mg/L on Day 100, resulting in PRE decline (17.17 %) and effluent orthophosphate rise (4.23 mg/L). Metagenomes analysis revealed that Pseudomonas and Thiothrix had genes for denitrification and encoding Pit phosphate transporter, and Candidatus_Competibacter was necessary for biofilm formation.

A SARS-CoV-2-Related Virus from Malayan Pangolin Causes Lung Infection without Severe Disease in Human ACE2-Transgenic Mice.

Coronavirus disease 2019 (COVID-19), which is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the most severe emerging infectious disease in the current century. The discovery of SARS-CoV-2-related coronaviruses (SARSr-CoV-2) in bats and pangolins in South Asian countries indicates that SARS-CoV-2 likely originated from wildlife. To date, two SARSr-CoV-2 strains have been isolated from pangolins seized in Guangxi and Guangdong by the customs agency of China, respectively. However, it remains unclear whether these viruses cause disease in animal models and whether they pose a transmission risk to humans. In this study, we investigated the biological features of a SARSr-CoV-2 strain isolated from a smuggled Malayan pangolin (Manis javanica) captured by the Guangxi customs agency, termed MpCoV-GX, in terms of receptor usage, cell tropism, and pathogenicity in wild-type BALB/c mice, human angiotensin-converting enzyme 2 (ACE2)-transgenic mice, and human ACE2 knock-in mice. We found that MpCoV-GX can utilize ACE2 from humans, pangolins, civets, bats, pigs, and mice for cell entry and infect cell lines derived from humans, monkeys, bats, minks, and pigs. The virus could infect three mouse models but showed limited pathogenicity, with mild peribronchial and perivascular inflammatory cell infiltration observed in lungs. Our results suggest that this SARSr-CoV-2 virus from pangolins has the potential for interspecies infection, but its pathogenicity is mild in mice. Future surveillance among these wildlife hosts of SARSr-CoV-2 is needed to monitor variants that may have higher pathogenicity and higher spillover risk. IMPORTANCE SARS-CoV-2, which likely spilled over from wildlife, is the third highly pathogenic human coronavirus. Being highly transmissible, it is perpetuating a pandemic and continuously posing a severe threat to global public health. Several SARS-CoV-2-related coronaviruses (SARSr-CoV-2) in bats and pangolins have been identified since the SARS-CoV-2 outbreak. It is therefore important to assess their potential of crossing species barriers for better understanding of their risk of future emergence. In this work, we investigated the biological features and pathogenicity of a SARSr-CoV-2 strain isolated from a smuggled Malayan pangolin, named MpCoV-GX. We found that MpCoV-GX can utilize ACE2 from 7 species for cell entry and infect cell lines derived from a variety of mammalian species. MpCoV-GX can infect mice expressing human ACE2 without causing severe disease. These findings suggest the potential of cross-species transmission of MpCoV-GX, and highlight the need of further surveillance of SARSr-CoV-2 in pangolins and other potential animal hosts.

Emodin attenuates inflammation and demyelination in experimental autoimmune encephalomyelitis.

Emodin, a substance extracted from herbs such as rhubarb, has a protective effect on the central nervous system. However, the potential therapeutic effect of emodin in the context of multiple sclerosis remains unknown. In this study, a rat model of experimental autoimmune encephalomyelitis was established by immune induction to simulate multiple sclerosis, and the rats were intraperitoneally injected with emodin (20 mg/kg/d) from the day of immune induction until they were sacrificed. In this model, the nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and the microglia exacerbated neuroinflammation, playing an important role in the development of multiple sclerosis. In addition, silent information regulator of transcription 1 (SIRT1)/peroxisome proliferator-activated receptor-alpha coactivator (PGC-1α) was found to inhibit activation of the NLRP3 inflammasome, and SIRT1 activation reduced disease severity in experimental autoimmune encephalomyelitis. Furthermore, treatment with emodin decreased body weight loss and neurobehavioral deficits, alleviated inflammatory cell infiltration and demyelination, reduced the expression of inflammatory cytokines, inhibited microglial aggregation and activation, decreased the levels of NLRP3 signaling pathway molecules, and increased the expression of SIRT1 and PGC-1α. These findings suggest that emodin improves the symptoms of experimental autoimmune encephalomyelitis, possibly through regulating the SIRT1/PGC-1α/NLRP3 signaling pathway and inhibiting microglial inflammation. These findings provide experimental evidence for treatment of multiple sclerosis with emodin, enlarging the scope of clinical application for emodin.

Exosome-transported lncRNA H19 regulates insulin-like growth factor-1 via the H19/let-7a/insulin-like growth factor-1 receptor axis in ischemic stroke.

LncRNA (long non-coding RNA) H19 is a transcript of the H19 gene that is expressed during embryogenesis. We previously discovered a role for circular lncRNA H19 in the onset and prognosis of cerebral ischemic stroke. In this study, we used serum from patients with ischemic stroke, and mouse and cell culture models to elucidate the roles of plasma and neuronal exosomes in the regulatory effect of lncRNA H19 on insulin-like growth factor-1 and its mechanism in ischemic stroke, using western blotting, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assays. Plasma exosomal lncRNA H19 was negatively associated with blood levels of insulin-like growth factor-1 in samples from patients with cerebral ischemic stroke. In a mouse model, levels of exosomal lncRNA H19 were positively correlated with plasma and cerebral lncRNA H19. In a cell co-culture model, we confirmed that lncRNA H19 was transported from neurons to astrocytes by exosomes to induce downregulation of insulin-like growth factor-1 through the H19/let-7a/insulin-like growth factor-1 receptor axis. This study provides the first evidence for the transportation of lncRNA H19 by exosomes and the relationship between lncRNA H19 and insulin-like growth factor-1.

Association between Parkinson's Disease and Diabetes Mellitus: From Epidemiology, Pathophysiology and Prevention to Treatment.

Diabetes mellitus (DM) and Parkinson's disease (PD) are both age-related diseases of global concern being among the most common chronic metabolic and neurodegenerative diseases, respectively. While both diseases can be genetically inherited, environmental factors play a vital role in their pathogenesis. Moreover, DM and PD have common underlying molecular mechanisms, such as misfolded protein aggregation, mitochondrial dysfunction, oxidative stress, chronic inflammation, and microbial dysbiosis. Recently, epidemiological and experimental studies have reported that DM affects the incidence and progression of PD. Moreover, certain antidiabetic drugs have been proven to decrease the risk of PD and delay its progression. In this review, we elucidate the epidemiological and pathophysiological association between DM and PD and summarize the antidiabetic drugs used in animal models and clinical trials of PD, which may provide reference for the clinical translation of antidiabetic drugs in PD treatment.