Citations

Abstract Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is a human cell surface protein expressed exclusively on eosinophils, mast cells, and basophils that, when engaged, induces eosinophil apoptosis and inhibits mast cell mediator release. This makes Siglec-8 a promising therapeutic target to treat diseases involving these cell types. However, preclinical studies of Siglec-8 targeting in vivo are lacking because this protein is only found in humans, apes, and some monkeys. Therefore, we have developed a mouse strain in which SIGLEC8 transcription is activated by Cre recombinase and have crossed this mouse with the eoCre mouse to achieve eosinophil-specific expression. We confirmed that Siglec-8 is expressed exclusively on the surface of mature eosinophils in multiple tissues at levels comparable to those on human blood eosinophils. Following ovalbumin sensitization and airway challenge, Siglec-8 knock-in mice generated a pattern of allergic lung inflammation indistinguishable from that of littermate controls, suggesting that Siglec-8 expression within the eosinophil compartment does not alter allergic eosinophilic inflammation. Using bone marrow from these mice, we demonstrated that, during maturation, Siglec-8 expression occurs well before the late eosinophil developmental marker C-C motif chemokine receptor 3, consistent with eoCre expression. Antibody ligation of the receptor induces Siglec-8 endocytosis and alters the phosphotyrosine profile of these cells, indicative of productive signaling. Finally, we demonstrated that mouse eosinophils expressing Siglec-8 undergo cell death when the receptor is engaged, further evidence that Siglec-8 is functional on these cells. These mice should prove useful to investigate Siglec-8 biology and targeting in vivo in a variety of eosinophilic disease models. We have developed a novel eosinophil-specific Siglec-8 knock-in mouse strain that facilitates the in vivo study of Siglec-8 targeting and biology.

Abstract Objective In recent years, electronic health record systems have been widely implemented in China, making clinical data available electronically. However, little effort has been devoted to making drug information exchangeable among these systems. This study aimed to build a Normalized Chinese Clinical Drug (NCCD) knowledge base, by applying and extending the information model of RxNorm to Chinese clinical drugs. Methods Chinese drugs were collected from 4 major resources—China Food and Drug Administration, China Health Insurance Systems, Hospital Pharmacy Systems, and China Pharmacopoeia—for integration and normalization in NCCD. Chemical drugs were normalized using the information model in RxNorm without much change. Chinese patent drugs (i.e., Chinese herbal extracts), however, were represented using an expanded RxNorm model to incorporate the unique characteristics of these drugs. A hybrid approach combining automated natural language processing technologies and manual review by domain experts was then applied to drug attribute extraction, normalization, and further generation of drug names at different specification levels. Lastly, we reported the statistics of NCCD, as well as the evaluation results using several sets of randomly selected Chinese drugs. Results The current version of NCCD contains 16 976 chemical drugs and 2663 Chinese patent medicines, resulting in 19 639 clinical drugs, 250 267 unique concepts, and 2 602 760 relations. By manual review of 1700 chemical drugs and 250 Chinese patent drugs randomly selected from NCCD (about 10%), we showed that the hybrid approach could achieve an accuracy of 98.60% for drug name extraction and normalization. Using a collection of 500 chemical drugs and 500 Chinese patent drugs from other resources, we showed that NCCD achieved coverages of 97.0% and 90.0% for chemical drugs and Chinese patent drugs, respectively. Conclusion Evaluation results demonstrated the potential to improve interoperability across various electronic drug systems in China.

The effect of chronic exogenous testosterone (T) treatment on neuromuscular transmission in the diaphragm (Dia) muscle of adult male rats was determined. The contribution of neuromuscular transmission failure (NTF) to Dia fatigue was evaluated by superimposing intermittent direct muscle stimulation on repetitive nerve stimulation of isometric contraction in vitro. T treatment significantly reduced the contribution of NTF to Dia fatigue by ∼20% ( P < 0.001). Fiber type-specific effects on NTF were determined by measuring Dia fiber glycogen levels subsequent to repetitive nerve or muscle stimulation. T treatment had no effect on glycogen depletion in Dia type I and IIa fibers regardless of stimulation route. In the control group, type IIx fibers demonstrated significantly less glycogen depletion after nerve stimulation compared with direct muscle stimulation ( P < 0.05), suggesting the presence of NTF. In contrast, T treatment increased glycogen depletion of type IIx fibers during nerve stimulation to levels similar to those after direct muscle stimulation. These data indicate that testosterone treatment substantially improves neuromuscular transmission in the Dia.

It has been found that maximum specific force (Fmax; force per cross-sectional area) of rat diaphragm muscle doubles from birth to 84 days (adult). We hypothesize that this developmental change in Fmax reflects an increase in myosin heavy chain (MHC) content per half-sarcomere (an estimate of the number of cross bridges in parallel) and/or a greater force per cross bridge in fibers expressing fast MHC isoforms compared with slow and neonatal MHC isoforms (MHCslow and MHCneo, respectively). Single Triton 100-X-permeabilized fibers were activated at a pCa of 4.0. MHC isoform expression was determined by SDS-PAGE. MHC content per half-sarcomere was determined by densitometric analysis and comparison to a standard curve of known MHC concentrations. MHC content per half-sarcomere progressively increased during early postnatal development. When normalized for MHC content per half-sarcomere, fibers expressing MHCslow and coexpressing MHCneoproduced less force than fibers expressing fast MHC isoforms. We conclude that lower force per cross bridge in fibers expressing MHCslow and MHCneo contributes to the lower Fmax seen in early postnatal development.