Precision care in the treatment of pediatric asthma.

PURPOSE OF REVIEW: Precision medicine in pediatric asthma involves identification of asthma phenotypes, genetic markers, biomarkers, and biologics that target specific pathways. This review includes a discussion of the efficacy of currently approved biologics for pediatric asthma and most recent advances in biomarker/phenotype identification and genetic associations that affect asthma care. RECENT FINDINGS: Biologics targeting type-2 mediated pathways have shown success in the treatment of moderate to severe asthma in pediatric and adult patients. In comparative studies, dupilumab, an interleukin-4 (IL-4) alpha receptor inhibitor, and mepolizumab, an IL-5 inhibitor, have shown more improvement in asthma exacerbation rates and lung function compared to other biologics such as tezepelumab, omalizumab and benralizumab. Other methods used to categorize asthma treatment response have been investigated and include use of biomarkers such as fractional exhaled nitric oxide (FeNO). Genomic studies are also emerging in precision care for pediatric asthma. SUMMARY: An understanding of underlying immunologic and genetic mechanisms affecting the development of asthma in pediatric patients has resulted in the production of numerous targeted therapies that have led to improvement in lung function and reduced exacerbation burden.

Stochastic gene expression and environmental stressors trigger variable somite segmentation phenotypes.

Mutations of several genes cause incomplete penetrance and variable expressivity of phenotypes, which are usually attributed to modifier genes or gene-environment interactions. Here, we show stochastic gene expression underlies the variability of somite segmentation defects in embryos mutant for segmentation clock genes her1 or her7. Phenotypic strength is further augmented by low temperature and hypoxia. By performing live imaging of the segmentation clock reporters, we further show that groups of cells with higher oscillation amplitudes successfully form somites while those with lower amplitudes fail to do so. In unfavorable environments, the number of cycles with high amplitude oscillations and the number of successful segmentations proportionally decrease. These results suggest that individual oscillation cycles stochastically fail to pass a threshold amplitude, resulting in segmentation defects in mutants. Our quantitative methodology is adaptable to investigate variable phenotypes of mutant genes in different tissues.

Regulatory Network of the Scoliosis-Associated Genes Establishes Rostrocaudal Patterning of Somites in Zebrafish.

Gene regulatory networks govern pattern formation and differentiation during embryonic development. Segmentation of somites, precursors of the vertebral column among other tissues, is jointly controlled by temporal signals from the segmentation clock and spatial signals from morphogen gradients. To explore how these temporal and spatial signals are integrated, we combined time-controlled genetic perturbation experiments with computational modeling to reconstruct the core segmentation network in zebrafish. We found that Mesp family transcription factors link the temporal information of the segmentation clock with the spatial action of the fibroblast growth factor signaling gradient to establish rostrocaudal (head to tail) polarity of segmented somites. We further showed that cells gradually commit to patterning by the action of different genes at different spatiotemporal positions. Our study provides a blueprint of the zebrafish segmentation network, which includes evolutionarily conserved genes that are associated with the birth defect congenital scoliosis in humans.

Noise in the Vertebrate Segmentation Clock Is Boosted by Time Delays but Tamed by Notch Signaling.

Taming cell-to-cell variability in gene expression is critical for precise pattern formation during embryonic development. To investigate the source and buffering mechanism of expression variability, we studied a biological clock, the vertebrate segmentation clock, controlling the precise spatiotemporal patterning of the vertebral column. By counting single transcripts of segmentation clock genes in zebrafish, we show that clock genes have low RNA amplitudes and expression variability is primarily driven by gene extrinsic sources, which is suppressed by Notch signaling. We further show that expression noise surprisingly increases from the posterior progenitor zone to the anterior segmentation and differentiation zone. Our computational model reproduces the spatial noise profile by incorporating spatially increasing time delays in gene expression. Our results, suggesting that expression variability is controlled by the balance of time delays and cell signaling in a vertebrate tissue, will shed light on the accuracy of natural clocks in multi-cellular systems and inspire engineering of robust synthetic oscillators.