Infection with SARS-CoV-2 can cause pancreatic impairment.

Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes. Herein, we retrospectively analyzed pancreatic lesions in autopsy tissues from 67 SARS-CoV-2 infected non-human primates (NHPs) models and 121 vaccinated and infected NHPs from 2020 to 2023 and COVID-19 patients. Multi-label immunofluorescence revealed direct infection of both exocrine and endocrine pancreatic cells by the virus in NHPs and humans. Minor and limited phenotypic and histopathological changes were observed in adult models. Systemic proteomics and metabolomics results indicated metabolic disorders, mainly enriched in insulin resistance pathways, in infected adult NHPs, along with elevated fasting C-peptide and C-peptide/glucose ratio levels. Furthermore, in elder COVID-19 NHPs, SARS-CoV-2 infection causes loss of beta (ß) cells and lower expressed-insulin in situ characterized by islet amyloidosis and necrosis, activation of α-SMA and aggravated fibrosis consisting of lower collagen in serum, an increase of pancreatic inflammation and stress markers, ICAM-1 and G3BP1, along with more severe glycometabolic dysfunction. In contrast, vaccination maintained glucose homeostasis by activating insulin receptor α and insulin receptor ß. Overall, the cumulative risk of diabetes post-COVID-19 is closely tied to age, suggesting more attention should be paid to blood sugar management in elderly COVID-19 patients.

Effects of solution chemistry on dielectric barrier atmospheric non-thermal plasma for operative degradation of antiretroviral drug nevirapine.

The global prevalence of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has been an environmental menace. Tons of drug wastes from antiretroviral therapy are released into the environment annually. We, for the first time, employed the novel dielectric barrier atmospheric non-thermal plasma (DBANP) discharge, to mitigate the inadvertent pollution arising from the antiretroviral therapy. A 40-min treatment of nevirapine achieved >94 % (0.075 min-1) removal efficiency at discharge power of 63.5 W and plasma working gas of atmospheric air. Chemical probes confirmed •OH, ONOO- and eaq- as the dominant reactive species whilst further revealing the reaction acceleration role of NaNO3 and CCl4 which are known reaction terminators. The commonly coexisting inorganic anions potentiated nevirapine removal with over 98 % efficiency, achieving the highest rate constant of 0.148 min-1 in this study. Moreover, the initial solution pH (1.5-11.1) was no limiting factor either. The insensitivity of the DBANP discharge to actual water matrices was an eminent inference of its potential applicability in practical conditions. With reference to data obtained from the liquid chromatography-mass spectrometer analysis, nevirapine degradation pathway was proposed. A nucleophilic attack by ONOO- at the cyclopropyl group and •OH attack at the carbonyl carbon of the amide group, respectively, initiated nevirapine degradation process. It is anticipated that the findings herein, will provide new insights into antiretroviral drug waste management in environmental waters using the innovative and green non-thermal plasma process.

Efficacy and Safety of Spesolimab in Patients with Generalized Pustular Psoriasis: A Subgroup Analysis of Chinese Patients in the Effisayil 1 Trial.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening skin disease. The global Effisayil 1 study investigated the efficacy and safety of spesolimab, a humanized monoclonal antibody targeting the IL-36 receptor, in patients experiencing GPP flare. This analysis aimed to explore the efficacy and safety of spesolimab in the Chinese subgroup of Effisayil 1. METHODS: Effisayil 1 was a multicenter, randomized, double-blind, placebo-controlled phase II study. Eligible patients with a GPP flare were randomly assigned (2:1) to receive a single intravenous dose of spesolimab (900 mg) or placebo on day 1. On day 8, patients who had persistent symptoms that met a predefined criterion could receive open-label spesolimab. After day 8, patients with recurrent flares following clinical response could receive rescue treatment with open-label spesolimab. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation sub-score of 0 at week 1. The key secondary end point was a GPPGA total score of 0 or 1 at week 1. RESULTS: Eleven Chinese patients were randomized, with five patients receiving spesolimab and six receiving placebo. At week 1, 60.0% (3/5) of patients in the spesolimab group and 16.7% (1/6) of patients in the placebo group achieved a GPPGA pustulation sub-score of 0 (risk difference 43.3%; 95% CI -22.6, 86.2); 60.0% and 16.7% of patients in the spesolimab and placebo group, respectively, achieved a GPPGA total score 0 or 1 (risk difference 43.3%; 95% CI -22.6, 86.2). Overall, four patients in each group of the spesolimab and the placebo groups reported at least one adverse event (AE) by week 1, with two and three reporting drug-related AEs, respectively. One patient reported a serious AE that was not considered to be drug related. No death occurred during the study period. CONCLUSION: In the Chinese subgroup of the Effisayil 1 study, more patients receiving spesolimab experienced lesion clearance than those on placebo at week 1, with an acceptable safety profile that was consistent with the global study population. TRIAL REGISTRATION: NCT03782792.

Size transformation of Au nanoclusters for enhanced photocatalytic hydrogen generation: Interaction behavior at nanocluster/semiconductor interface.

Recently, atomically precise metal nanoclusters (NCs) become a new class of photosensitizer for light energy conversion in metal-cluster-sensitized semiconductor (MCSS) system. However, fundamental understanding for the suitable combination of NCs and semiconductor is still unclear. Aside from aspects of light harvesting, energy level alignment and catalytic activity, interfacial interaction behavior at NCs/semiconductor interface is also crucial due to its important influence in charge transportation. In this work, the interface interaction between Au NCs and TiO2 is examined by precise transformation of Au NCs from Au22(SG)18 to Au18(SG)14, as well as its effect on photocatalytic hydrogen production activity. From the optical, charge transport and solid-states spectroscopy analyses, it is able to display that precisely tuning the number of core atoms from Au22(SG)18 to Au18(SG)14 results in the strong interface interaction between Au NCs and TiO2, reflecting in high difference of work function and modified surface band bending of TiO2, therefore promoting the injection of electrons from NCs to TiO2 and reducing interfacial charges recombination. As a result, Au18(SG)14/TiO2 shows higher hydrogen generation rate than Au22(SG)18/TiO2 under light irradiation. This work would provide new insights into rational combination of metal NCs with semiconductor and highlights the overlooked effect of interfacial interaction behavior on light energy conversion.

TRPA1 promotes UVB-induced skin pigmentation by regulating melanosome luminal pH.

Melanocytes stimulated by ultraviolet radiation (UVR) produce melanin and melanosomes, which causes skin pigmentation and acts as an important physiological defence process for photoprotection. Neutral luminal pH of melanosomes is critical for providing optimal conditions for the rate-limiting, pH-sensitive melanin synthesizing enzyme tyrosinase (TYR). As a major component of extraocular phototransduction pathway, transient receptor potential ankyrin1 (TRPA1) can be activated by ultraviolet B (UVB) and reported to be expressed in melanocytes. However, whether TRPA1 is involved in the regulation of melanogenesis remains unclear. Melanogenic activity of TRPA1 was evaluated in primary normal human epidermal melanocytes (HEMs) and murine B16-F10 cell cultures, and the effects of topical applications of TRPA1 specific agonist and antagonist on UVB-induced skin pigmentation were confirmed on in vivo guinea pig models. Calcium (Ca2+ ) imaging and pH imaging were performed to analyse the effects of TRPA1 on intracellular Ca2+ concentration ([Ca2+ ]ic ) and melanosome luminal pH. TRPA1 regulated melanin synthesis, UVB-induced Ca2+ influx and melanosome luminal pH in HEMs and B16-F10 cells. Topical treatment of TRPA1 specific agonist JT010 increased UVB-induced skin pigmentation in guinea pigs, while topical using of TRPA1 selective antagonist HC-030031 mitigated such pigmentation. Our results indicated that TRPA1 activated by UVB enhanced the skin pigmentation, most likely by regulating the [Ca2+ ]ic and the melanosomal pH, consequently influencing the enzymatic activity of TYR. Therefore, the results suggest TRPA1 as a potential therapeutic target in the treatment of skin pigmented disorders that are at high risk under UVB irradiation.

Correlation analysis between gut microbiota characteristics and melasma.

In recent years, many studies have shown that the gut microbiota can affect the occurrence and development of a variety of human diseases. A variety of skin diseases are related to the regulation of the gut-skin axis, such as psoriasis, atopic dermatitis, and acne. Gut microbial dysbiosis can promote the development of these diseases. The gut microbiota can affect estrogen metabolism, ß-glucuronidase secreted by the gut microbiota can promote the reabsorption of estrogen by the gut, and estrogen is transported to other parts of the body through the circulatory system. The occurrence and development of melasma are closely related to abnormal metabolism of estrogen. The relationship between the structure of the gut microbiota and melasma remains unclear. Epidemiological surveys were conducted in patients with melasma and healthy subjects (control group) in this study. The feces were collected for 16S rRNA sequencing analysis of the gut microbiota. To compare the similarities and differences in species diversity of the gut microbiota between these two groups, we calculated the α-diversity and ß-diversity indices and analyzed the differences between them. We found that the abundance of Collinsella spp., Actinomyces spp. (belonging to Actinobacteria), Parabacteroides spp., Bacteroides spp., Paraprevotella spp. (belonging to Bacteroidetes), Blautia spp., and Roseburia spp. (belonging to Firmicutes) in the melasma group were significantly different compared with that in the healthy group. The largest difference was found in Actinobacteria (p < 0.05), and there were also significant differences in the abundance of Coriobacteriia, Actinobacteria, Coriobacteriales, Coriobacteriaceae, and Collinsella spp. between the two groups (all p < 0.05). Many of these differences in the microbiota were closely related to the production of ß-glucuronidase and the regulation of estrogen synthesis or metabolism. Changes in the gut microbiota structure and the biological effects of Collinsella spp. in the microbiota in patients with melasma can play an important role in the occurrence and development of melasma by affecting the body's estrogen metabolism. This study provides a theoretical basis and experimental data reference for future studies on the relationship between the gut microbiota and melasma, and may be helpful for the prevention and treatment of melasma.

A novel conversion strategy for organic compounds in waste liquid crystal displays based on the near/supercritical methanol process.

Waste liquid crystal displays (LCD) contain a large number of organic compounds such as cellulose triacetate (CTA), poly(vinyl alcohol) (PVA), triphenyl phosphate (TPP), and liquid crystal (LC). It is important to recover organic compounds from waste LCD due to their value and environmental toxicity. However, it is challenging to recover organic compounds from waste LCD because of the heterogeneous mixture of glass, organics and metals contained therein. In this study, an environment-friendly near/supercritical methanol (NSCM) process was developed as a closed cycle technology for the conversion of organic compounds from waste LCD. The acid-base catalytic activity and nonpolar property of the NSCM could efficiently promote the conversion of organic compounds from waste LCD. TPP could be extracted below 200 °C in the NSCM process. Below 250 °C, the conversion ratio of organic compounds from waste LCD ranged from 5 % to 68 % due to the extraction or decomposition of TPP, LC, and PVA. The main products obtained at 250 °C included long-chain alcohols and alkanes with a similar composition to industrial liquid paraffin, which could be widely used in other industrial processes. Under the optimal operation parameters (300 °C, 30 min, and 1:20 g/ml), the conversion ratio of organic compounds could reach 98 % due to the efficient decomposition of CTA. The main products obtained included ketones and esters chemicals, which could be further used as a chemical feedstock. No secondary pollutant was generated in the whole process. The low-boiling methanol could easily be recycled, which could make the NSCM a clean process for the production of high value-added organic products from waste LCD.

UVR Promotes Keratinocyte Phagocytosis and Skin Pigmentation Through TRPA1 Channels.

Purpose: Ultraviolet radiation (UVR) enhances skin pigmentation, which involves the production of melanin by melanocytes and subsequent transfer to keratinocytes. In the epidermis, keratinocyte phagocytosis plays a pivotal role in the process of melanosome transfer to protect DNA of epidermal cells against damage from UVR. Previous research suggested that transient receptor potential channels ankyrin 1 (TRPA1) was required for UVR-induced early melanin synthesis in melanocytes. Currently, there is no evidence that supports the detailed mechanism of TRPA1 for UVR-induced phagocytosis by keratinocytes. Here, we investigated the effect and the possible mechanisms of TRPA1 on keratinocyte phagocytosis and skin pigmentation after UVR exposure. Methods: Flow cytometry was applied to investigate the effect of TRPA1 on intracellular calcium concentration ([Ca2+]ic) and fluorescent microspheres uptake was carried out to analyze phagocytosis in HaCaT cells (human immortalized keratinocytes). Western blotting was applied to measure the protein expression of calcium/calmodulin-dependent protein kinase II (CaMKII), phosphorylated CaMKII and ß-catenin after UVA/UVB exposure. Masson-Fontana staining was applied to observe the effect of XAV-939 (decreasing the expression of ß-catenin) on UVB-induced skin pigmentation in guinea pigs. Results: TRPA1 channels activated by UVR increased the [ca2+]ic and phosphorylation of CaMKII in HaCaT cells. The UVR-induced phagocytosis was regulated by TRPA1 in HaCaT cells. TRPA1 promoted the protein expression of ß-catenin after UVR exposure in HaCaT cells. XAV-939, inhibiting ß-catenin expression, decreased the UVB-induced skin pigmentation on in vivo guinea pig models. Conclusion: Taken together, TRPA1 activated by UVR led to the increase of intracellular calcium, which promoted the phosphorylation of CaMKII, enhancing keratinocyte phagocytosis. Moreover, TRPA1 regulated the protein expression of ß-catenin to exert a lightening effect on skin pigmentation. Our findings suggest that TRPA1 may be a potential therapeutic target for UVR-induced skin pigmentary diseases.

TRPA1 promotes melanosome phagocytosis in keratinocytes via PAR-2/CYLD axis.

BACKGROUND: Keratinocytes are recipients of melanosomes. Although the chemical basis of melanogenesis is well documented, the molecular mechanism of melanosome transfer must be elucidated. TRPA1 is a member of the transient receptor potential A subfamily. Previous studies have shown that inhibition of TRPA1 activity reduces melanin synthesis in human epidermal melanocytes; however, the mechanism remains unknown. OBJECTIVE: This study aimed to investigate the roles and mechanism(s) of action of TRPA1 in keratinocytes. METHODS: The correlation between TRPA1 expression levels and the ability of keratinocytes to phagocytize melanosomes was examined using melanin silver staining. TRPA1 depleted human epidermal keratinocytes and keratinocyte cell lines HaCaT were established using adenovirus-expressing shRNAs against TRPA1. The effects of TRPA1 on keratinocytes and HaCaT cells were determined using cell-based analyses, including light stimulation, calcium imaging, melanin phagocytosis, immunoblotting, and co-immunoprecipitation assays. The degree of epidermal pigmentation was determined in a guinea pig model. RESULTS: TRPA1 mediated the phagocytic activity of keratinocytes. TRPA1 knockdown markedly suppressed melanosome transport to keratinocytes. Mechanistically, TRPA1 was required for PAR-2-induced melanosome phagocytosis in keratinocytes. Furthermore, TRPA1 activation indirectly stabilized microtubules by promoting the competitive binding of CYLD and acetylated α-tubulin. In addition, bortezomib (PS-341), a proteasome inhibitor, increased TRPA1 and CYLD expression and promoted phagocytic activity both in vitro and in vivo. CONCLUSIONS: Our findings firstly suggest that TRPA1 promotes melanosome transport in keratinocytes and reveal that TRPA1 is a regulator of PAR-2 activation and microtubule stability via the PAR-2/CYLD axis.

Sequential immunizations confer cross-protection against variants of SARS-CoV-2, including Omicron in Rhesus macaques.

Variants of concern (VOCs) like Delta and Omicron, harbor a high number of mutations, which aid these viruses in escaping a majority of known SARS-CoV-2 neutralizing antibodies (NAbs). In this study, Rhesus macaques immunized with 2-dose inactivated vaccines (Coronavac) were boosted with an additional dose of homologous vaccine or an RBD-subunit vaccine, or a bivalent inactivated vaccine (Beta and Delta) to determine the effectiveness of sequential immunization. The booster vaccination significantly enhanced the duration and levels of neutralizing antibody titers against wild-type, Beta, Delta, and Omicron. Animals administered with an indicated booster dose and subsequently challenged with Delta or Omicron variants showed markedly reduced viral loads and improved histopathological profiles compared to control animals, indicating that sequential immunization could protect primates against Omicron. These results suggest that sequential immunization of inactivated vaccines or polyvalent vaccines could be a potentially effective countermeasure against newly emerging variants.

Peroxisome proliferator-activator receptor γ and psoriasis, molecular and cellular biochemistry.

The pathophysiology of psoriasis is complex and has not been completely elucidated. Better understanding of the pathogenesis may contribute to further improvement of our therapeutic strategies controlling psoriasis. Emerging evidence points to a causative relationship between altered activity of peroxisome proliferator-activated receptor γ (PPARγ) and psoriasis. The present review focuses on deeper understanding of the possible role of PPARγ in the pathogenesis of psoriasis and the potential of PPARγ agonist to improve the treatment of psoriasis. PPARγ is decreased in psoriasis. PPARγ possibly has effects on the multiple aspects of the pathogenesis of psoriasis, including abnormal lipid metabolism, insulin resistance, immune cells, pro-inflammatory cytokines, keratinocytes, angiogenesis, oxidative stress, microRNAs and nuclear factor kappa B. As defective activation of PPARγ is involved in psoriasis development, PPARγ agonists may be promising agents for treatment of psoriasis. Pioglitazone appears an effective and safe option in the treatment of patients with psoriasis, but there are still concerns about its potential side effects. Research effort has recently been undertaken to explore the PPARγ-activating potential of natural products. Among them some have been studied clinically or preclinically for treatment of psoriasis with promising results.

Integrated histopathological, lipidomic, and metabolomic profiles reveal mink is a useful animal model to mimic the pathogenicity of severe COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted on mink farms between minks and humans in many countries. However, the systemic pathological features of SARS-CoV-2-infected minks are mostly unknown. Here, we demonstrated that minks were largely permissive to SARS-CoV-2, characterized by severe and diffuse alveolar damage, and lasted at least 14 days post inoculation (dpi). We first reported that infected minks displayed multiple organ-system lesions accompanied by an increased inflammatory response and widespread viral distribution in the cardiovascular, hepatobiliary, urinary, endocrine, digestive, and immune systems. The viral protein partially co-localized with activated Mac-2+ macrophages throughout the body. Moreover, we first found that the alterations in lipids and metabolites were correlated with the histological lesions in infected minks, especially at 6 dpi, and were similar to that of patients with severe and fatal COVID-19. Particularly, altered metabolic pathways, abnormal digestion, and absorption of vitamins, lipids, cholesterol, steroids, amino acids, and proteins, consistent with hepatic dysfunction, highlight metabolic and immune dysregulation. Enriched kynurenine in infected minks contributed to significant activation of the kynurenine pathway and was related to macrophage activation. Melatonin, which has significant anti-inflammatory and immunomodulating effects, was significantly downregulated at 6 dpi and displayed potential as a targeted medicine. Our data first illustrate systematic analyses of infected minks to recapitulate those observations in severe and fetal COVID-19 patients, delineating a useful animal model to mimic SARS-CoV-2-induced systematic and severe pathophysiological features and provide a reliable tool for the development of effective and targeted treatment strategies, vaccine research, and potential biomarkers.

Efficacy and Safety of HLX03, an Adalimumab Biosimilar, in Patients with Moderate-to-Severe Plaque Psoriasis: A Randomized, Double-Blind, Phase III Study.

INTRODUCTION: Adalimumab has been used successfully in the treatment of psoriasis. The objective of the study is to compare the efficacy, safety, and immunogenicity between HLX03, an adalimumab biosimilar, and adalimumab in Chinese patients with moderate-to-severe plaque psoriasis. METHODS: In this double-blind, active-controlled, parallel-group study, 262 patients with moderate-to-severe plaque psoriasis were randomized (1:1) to receive HLX03 or adalimumab (80 mg at week 1, 40 mg at week 2, and then 40 mg every 2 weeks) for 48 weeks. The primary endpoint was improvement in Psoriasis Area and Severity Index (PASI) score at week 16 comparing to baseline. Equivalence was demonstrated if 95% confidence interval (CI) of the between group difference fell within the equivalence margins of ± 15%. Other efficacy endpoints, safety and immunogenicity were also evaluated. RESULTS: In the full analysis set, PASI improvements at week 16 was 83.5% (n = 131) in the HLX03 group and 82.0% (n = 130) in the adalimumab group, with a least-square-mean difference of 1.5% (95% CI - 3.9% to 6.8%). There were no significant between-group differences in all secondary efficacy analyses including proportion of patients achieving ≥ 75% improvement from baseline PASI (PASI 75), physician global assessment (PGA) 0/1 (clear or almost clear) and change in dermatology life quality index (DLQI) score. The incidences of adverse events and the proportion of patients with antidrug antibodies were also comparable between the two treatment groups. CONCLUSION: HLX03 demonstrated equivalent efficacy, similar safety and immunogenicity to reference adalimumab, supporting its development as an alternative treatment for patients with plaque psoriasis in China. CLINICAL TRIAL REGISTRATION: Chinadrugtrials.org.cn, CTR20171123 (November 27, 2017); ClinicalTrials.gov, NCT03316781 (October 20, 2017).

Plaque psoriasis is a chronic, autoimmune, inflammatory skin disease associated with significant morbidity and reduced quality of life. In China, the prevalence of plaque psoriasis increased four-fold between 1987 and 2012. Adalimumab is a biologic antibody used to treat plaque psoriasis globally. However, high treatment costs remain as a significant barrier to adalimumab therapy. Therefore, HLX03 has been developed as an adalimumab (Humira^®) biosimilar, which is almost identical to the licensed reference adalimumab, but less expensive and more accessible to patients. In this randomized clinical trial, the efficacy (ability of a drug to produce the desired treatment effects), safety, and immunogenicity (ability of a drug to induce immune response which would affect its efficacy and safety) of HLX03 were compared with the reference adalimumab in Chinese patients with moderate-to-severe plaque psoriasis. Efficacy was evaluated by comparing the changes in severity and extent of disease using Psoriasis Area and Severity Index score between treatment initiation and week 16. Safety was monitored by adverse events, laboratory tests and vital signs. Immunogenicity was assessed by the incidence of antidrug antibodies. Among the 262 randomized patients, 131 received HLX03 and 130 received adalimumab. Both groups reported similar improvements in Psoriasis Area and Severity Index scores (between-group difference fell within the prespecified equivalence margins), and also in other efficacy evaluations. Additionally, the two treatment groups showed similar safety and immunogenicity profiles. In summary, HLX03 demonstrated equivalent efficacy to adalimumab, validating it as an alternative treatment for patients with plaque psoriasis in China.

Degradation and partial oxidation of waste plastic express packaging bags in supercritical water: Resources transformation and pollutants removal.

Millions of waste plastic express packaging bags (PEPBs) were generated with the rapid development of the express delivery industry due to the boom of electronic commerce. Waste PEPBs contain polyethylene (PE) material and large number of pollutants such as plasticizers and flame retardants. In this study, two effective and environmental-friendly methods were proposed to produce valuable products and remove pollutants from waste PEPBs by supercritical water degradation (SCWD) and supercritical water partial oxidation (SCWPO) treatments. Both SCWD and SCWPO treatments could effectively obtain valuable products (wax, liquid oil, CaCO3) and remove bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) from waste PEPBs. No obvious difference about the conversion could be found between SCWD and SCWPO treatments. 425 °C, 60 min, solid-to-liquid ratio of 1:20 g/mL, and V(H2O2):V(H2O) ratio of 1:3 mL/mL were the optimal conditions for the conversion of waste PEPBs by SCWD and SCWPO treatments. The maximum conversion could reach 98.13%. The produced wax and liquid oil were easily separated from each other. The produced wax mainly included long-chain olefins or long-chain alkanes, and a small amount of alcohols, ethers and aldehydes. SCWD treatment was favorable for obtaining long-chain alkenes, while SCWPO treatment was favorable for obtaining long-chain alkanes. The main chemical compounds contained in the produced liquid oil were decomposed from DEHP and BPA. DEHP was decomposed to produce 2-ethyl-1-hexanol and acetophenone. BPA was decomposed to produce 4-tert-butylphenol and other alkylated derivatives of benzene and phenol. In comparison with SCWD treatment, DEHP and BPA could be decomposed more thoroughly by SCWPO treatment.

SARS-CoV-2 crosses the blood-brain barrier accompanied with basement membrane disruption without tight junctions alteration.

SARS-CoV-2 has been reported to show a capacity for invading the brains of humans and model animals. However, it remains unclear whether and how SARS-CoV-2 crosses the blood-brain barrier (BBB). Herein, SARS-CoV-2 RNA was occasionally detected in the vascular wall and perivascular space, as well as in brain microvascular endothelial cells (BMECs) in the infected K18-hACE2 transgenic mice. Moreover, the permeability of the infected vessel was increased. Furthermore, disintegrity of BBB was discovered in the infected hamsters by administration of Evans blue. Interestingly, the expression of claudin5, ZO-1, occludin and the ultrastructure of tight junctions (TJs) showed unchanged, whereas, the basement membrane was disrupted in the infected animals. Using an in vitro BBB model that comprises primary BMECs with astrocytes, SARS-CoV-2 was found to infect and cross through the BMECs. Consistent with in vivo experiments, the expression of MMP9 was increased and collagen IV was decreased while the markers for TJs were not altered in the SARS-CoV-2-infected BMECs. Besides, inflammatory responses including vasculitis, glial activation, and upregulated inflammatory factors occurred after SARS-CoV-2 infection. Overall, our results provide evidence supporting that SARS-CoV-2 can cross the BBB in a transcellular pathway accompanied with basement membrane disrupted without obvious alteration of TJs.

Microarray microRNA profiling of urinary exosomes in a 5XFAD mouse model of Alzheimer's disease.

Background: Alzheimer's disease (AD) is an incurable and irreversible neurodegenerative disease, without a clear pathogenesis. Therefore, identification of candidates before amyloid-ß plaque (Aß) deposition proceeds is of major significance for earlier intervention in AD. Methods: To explore the potential noninvasive earlier biomarkers of AD in a 5XFAD mouse model, microRNAs (miRNAs) from urinary exosomes in 1-month-old pre-Aß accumulation 5XFAD mice models and their littermate controls were profiled by microarray analysis. The differentially expressed miRNAs were further analyzed via droplet digital PCR (ddPCR). Results: Microarray analysis demonstrated that 48 differentially expressed miRNAs (18 upregulated and 30 downregulated), of which six miRNAs - miR-196b-5p, miR-339-3p, miR-34a-5p, miR-376b-3p, miR-677-5p, and miR-721 - were predicted to display gene targets and important signaling pathways closely associated with AD pathogenesis and verified by ddPCR. Conclusions: Urinary exosomal miRNAs showing differences in expression prior to Aß-plaque deposition were identified. These exosomal miRNAs represent potential noninvasive biomarkers that may be used to prevent AD in clinical applications.

Novel spontaneous myelodysplastic syndrome mouse model.

Background: Myelodysplastic syndrome (MDS) is a group of disorders involving hemopoietic dysfunction leading to leukemia. Although recently progress has been made in identifying underlying genetic mutations, many questions still remain. Animal models of MDS have been produced by introduction of specific mutations. However, there is no spontaneous mouse model of MDS, and an animal model to simulate natural MDS pathogenesis is urgently needed. Methods: In characterizing the genetically diverse mouse strains of the Collaborative Cross (CC) we observed that one, designated JUN, had abnormal hematological traits. This strain was thus further analyzed for phenotypic and pathological identification, comparing the changes in each cell population in peripheral blood and in bone marrow. Results: In a specific-pathogen free environment, mice of the JUN strain are relatively thin, with healthy appearance. However, in a conventional environment, they become lethargic, develop wrinkled yellow hair, have loose and light stools, and are prone to infections. We found that the mice were cytopenic, which was due to abnormal differentiation of multipotent bone marrow progenitor cells. These are common characteristics of MDS. Conclusions: A mouse strain, JUN, was found displaying spontaneous myelodysplastic syndrome. This strain has the advantage over existing models in that it develops MDS spontaneously and is more similar to human MDS than genetically modified mouse models. JUN mice will be an important tool for pathogenesis research of MDS and for evaluation of new drugs and treatments.

Sequential infection with H1N1 and SARS-CoV-2 aggravated COVID-19 pathogenesis in a mammalian model, and co-vaccination as an effective method of prevention of COVID-19 and influenza.

Influenza A virus may circulate simultaneously with the SARS-CoV-2 virus, leading to more serious respiratory diseases during this winter. However, the influence of these viruses on disease outcome when both influenza A and SARS-CoV-2 are present in the host remains unclear. Using a mammalian model, sequential infection was performed in ferrets and in K18-hACE2 mice, with SARS-CoV-2 infection following H1N1. We found that co-infection with H1N1 and SARS-CoV-2 extended the duration of clinical manifestation of COVID-19, and enhanced pulmonary damage, but reduced viral shedding of throat swabs and viral loads in the lungs of ferrets. Moreover, mortality was increased in sequentially infected mice compared with single-infection mice. Compared with single-vaccine inoculation, co-inoculation of PiCoVacc (a SARS-CoV-2 vaccine) and the flu vaccine showed no significant differences in neutralizing antibody titers or virus-specific immune responses. Combined immunization effectively protected K18-hACE2 mice against both H1N1 and SARS-CoV-2 infection. Our findings indicated the development of systematic models of co-infection of H1N1 and SARS-CoV-2, which together notably enhanced pneumonia in ferrets and mice, as well as demonstrated that simultaneous vaccination against H1N1 and SARS-CoV-2 may be an effective prevention strategy for the coming winter.

Susceptibility and Attenuated Transmissibility of SARS-CoV-2 in Domestic Cats.

Domestic cats, an important companion animal, can be infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This has aroused concern regarding the ability of domestic cats to spread the virus that causes coronavirus disease 2019. We systematically demonstrated the pathogenesis and transmissibility of SARS-CoV-2 in cats. Serial passaging of the virus between cats dramatically attenuated the viral transmissibility, likely owing to variations of the amino acids in the receptor-binding domain sites of angiotensin-converting enzyme 2 between humans and cats. These findings provide insight into the transmissibility of SARS-CoV-2 in cats and information for protecting the health of humans and cats.