ABSTRACT
COVID-19 is now causing a global pandemic, there is a demand to explain the different clinical patterns between children and adults. To clarify the organs/cell types vulnerable to COVID-19 infection and the potential age-depended expression patterns of five factors (ACE2, TMPRSS2, MTHFD1, CTSL, CTSB) associated with clinical symptoms. In this study, we analyzed expression levels of five COVID-19 host dependency factors in multiple adult and fetal human organs. The results allowed us to grade organs at risk and also pointed towards the target cell types in each organ mentioned above. Based on these results we constructed an organ- and cell type-specific vulnerability map of the expression levels of the five COVID-19 factors in the human body, providing insight into the mechanisms behind the symptoms, including the non-respiratory symptoms of COVID-19 infection and injury. Also, the different expression patterns of the COVID-19 factors well demonstrate an explanation that the different clinical patterns between adult and children/infants.
ABSTRACT
The delta-protocadherins (δ-Pcdhs) play key roles in neural development, and expression studies suggest they are expressed in combination within neurons. The extent of this combinatorial diversity, and how these combinations influence cell adhesion, is poorly understood. We show that individual mouse olfactory sensory neurons express 0-7 δ-Pcdhs. Despite this apparent combinatorial complexity, K562 cell aggregation assays revealed simple principles that mediate tuning of δ-Pcdh adhesion. Cells can vary the number of δ-Pcdhs expressed, the level of surface expression, and which δ-Pcdhs are expressed, as different members possess distinct apparent adhesive affinities. These principles contrast with those identified previously for the clustered protocadherins (cPcdhs), where the particular combination of cPcdhs expressed does not appear to be a critical factor. Despite these differences, we show δ-Pcdhs can modify cPcdh adhesion. Our studies show how intra- and interfamily interactions can greatly amplify the impact of this small subfamily on neuronal function.
Subject(s)
Cadherins/genetics , Gene Expression Profiling , Olfactory Receptor Neurons/metabolism , Protein Precursors/genetics , Animals , Cadherins/metabolism , Cell Adhesion/genetics , Cells, Cultured , Female , Humans , K562 Cells , Male , Mice, Inbred C57BL , Mutation , Olfactory Receptor Neurons/cytology , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Precursors/metabolism , Single-Cell Analysis/methodsABSTRACT
Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance.
