Recent Zoonotic Spillover and Tropism Shift of a Canine Coronavirus Is Associated with Relaxed Selection and Putative Loss of Function in NTD Subdomain of Spike Protein

A canine coronavirus (CCoV) has now been reported from two independent human samples from Malaysia (respiratory, collected in 2017–2018; CCoV-HuPn-2018) and Haiti (urine, collected in 2017); these two viruses were nearly genetically identical. In an effort to identify any novel adaptations associated with this apparent shift in tropism we carried out detailed evolutionary analyses of the spike gene of this virus in the context of related Alphacoronavirus 1 species. The spike 0-domain retains homology to CCoV2b (enteric infections) and Transmissible Gastroenteritis Virus (TGEV; enteric and respiratory). This domain is subject to relaxed selection pressure and an increased rate of molecular evolution. It contains unique amino acid substitutions, including within a region important for sialic acid binding and pathogenesis in TGEV. Overall, the spike gene is extensively recombinant, with a feline coronavirus type II strain serving a prominent role in the recombinant history of the virus. Molecular divergence time for a segment of the gene where temporal signal could be determined, was estimated at around 60 years ago. We hypothesize that the virus had an enteric origin, but that it may be losing that particular tropism, possibly because of mutations in the sialic acid binding region of the spike 0-domain.     

中药玉竹有效成分研究

自江苏海门产百合科植物玉竹[Polygonatum odoratum(Mill.)Druce]根茎的乙醇提取物中分得六个单体化合物,根据化学性质和光谱解析,鉴定其化学结构分别为β-谷甾醇(S-A)),β-谷甾醇-3-O-β-D-吡喃葡萄糖甙(S-B),25(R,S)螺甾-5-烯-3β-醇-3-O-β-D-吡喃葡萄糖基-(1→2)-[β-D-吡喃木糖基-(1→3)]-β-D-吡喃葡萄糖基(1→4)-β-吡喃半乳糖甙(POD-I),25(R)螺甾-5-烯-3β,14a-二醇-3-0-β-D-吡喃葡萄糖基-(1→2)-[β-D-吡喃木糖基-(1→3)]-β-D-吡喃葡萄糖基-(1→4)-β-D-吡喃半乳糖甙(POD-II),25(R,S)螺甾-5-烯-3β,14a-二醇-3-O-β-D-吡喃葡萄糖基-(1→2)-[β-D-吡喃葡萄糖基-(1→3)]-β-D-吡喃葡萄糖基(1→4)-β-D-吡喃半乳糖甙(POD-III)和25(R,S)螺甾-5-烯-3β-醇-3-O-β-D-吡喃葡萄糖基-(1-2)-[β-D-吡喃葡萄糖基-(1→3)]-β-D-吡喃哺葡萄糖基(1→4)-β-D-吡喃半乳糖甙(POD-IV)。POD-II为首次分离得到的25(R)构型的纯品,POD-III和POD-IV为首次从玉竹中得到。经初步药理实验显示,POD-II有诱生集落刺激因子(CSF)的作用,POD-III能协同ConA和Lps对淋巴细胞转化有促进作用。     

Paradoxical effects of tissue inhibitor of metalloproteinases 1 gene transfer in collagen‐induced arthritis

Objective

The imbalance between matrix metalloproteinases (MMPs) 1, 3, and 9 and their specific inhibitor, tissue inhibitor of metalloproteinases 1 (TIMP‐1), is a critical step in cartilage injury and angiogenesis in arthritis. To explore the therapeutic potential of TIMP‐1 gene transfer in erosive arthritis, the effects of an adenoviral vector (Ad‐TIMP‐1) were assessed in DBA/1 mice with collagen‐induced arthritis (CIA).

Methods

DBA/1 mice with CIA received an intravenous injection of replication‐deficient adenovirus containing the human TIMP‐1 gene or a control LacZ gene on day 28 postimmunization. The efficiency of gene transfer was determined by serum TIMP‐1 detection, measurements of paw swelling, as well as radiologic and histologic examination of the paws.

Results

A single administration of Ad‐TIMP‐1 resulted in detectable serum levels of the exogenous protein for at least 13 days. The incidence and onset of arthritis were not statistically modified after human TIMP‐1 gene transfer in DBA/1 mice compared with control mice. However, the severity of inflammation was statistically significantly increased in Ad‐TIMP‐1–treated mice and a similar trend was observed in the histologic and radiologic scores. With regard to the mechanisms of the worsened effect in the Ad‐TIMP‐1–treated mice, we observed 1) higher serum levels of anti–type II collagen IgG2a, 2) a significant increase in endogenous soluble tumor necrosis factor receptor I (TNFRI) in sera, and 3) increased labeling of mouse tumor necrosis factor α and TNFRI within arthritic joints.

Conclusion

These findings show that overexpression of TIMP‐1 does not prevent osteochondral injury in a mouse model of arthritis. Since MMPs have overlapping properties in terms of their roles in extracellular matrix degradation, angiogenesis, and shedding of cell surface adhesion molecules, cytokines, and cytokine receptors, the paradoxical results obtained suggest that TIMP‐1 is probably not the main inhibitor to target.

     

The vitamin B5/coenzyme A axis: A target for immunomodulation?

Coenzyme A (CoA) serves as a vital cofactor in numerous enzymatic reactions involved in energy production, lipid metabolism, and synthesis of essential molecules. Dysregulation of CoA-dependent metabolic pathways can contribute to chronic diseases, such as inflammatory diseases, obesity, diabetes, cancer, and cardiovascular disorders. Additionally, CoA influences immune cell activation by modulating the metabolism of these cells, thereby affecting their proliferation, differentiation, and effector functions. Targeting CoA metabolism presents a promising avenue for therapeutic intervention, as it can potentially restore metabolic balance, mitigate chronic inflammation, and enhance immune cell function. This might ultimately improve the management and outcomes for these diseases. This review will more specifically focus on the contribution of pathways regulating the availability of the CoA precursor Vitamin B5/pantothenate in vivo and modulating the development of Th17-mediated inflammation, CD8-dependent anti-tumor immunity but also tissue repair processes in chronic inflammatory or degenerative diseases.     

How we dealt with the double whammy! Acute pulmonary embolism with abdominal aortic clot and renal infarcts

Pulmonary embolism (PE) is the third most common cause of cardiovascular mortality in the United States, and the submassive PE accounts for 20%-25% of all acute PE. In the last decade, endovascular therapy with catheter-directed thrombolysis (CDT) intervention has shown great success in the treatment of submassive PE. There is limited data regarding using these devices to treat patients with concomitant abdominal aortic and renal vessel clots. Herein, we present a case of a 23-year-old male who presented with submassive PE associated with abdominal aortic thrombosis and renal infarcts. The patient was successfully treated with CDT with complete resolution of pulmonary and bilateral renal artery clots.