Search

Extremely premature infants (EPIs) who are born before 30 weeks of gestation are susceptible to infection; however, the trajectory of their peripheral immunity is poorly understood. Here, we undertook longitudinal analyses of immune cells from 250 μl of whole blood at 1 week, 1 month, and 2 months from 10 EPIs and compared these with samples from healthy adults and with preterm and full-term cord blood samples. Single-cell suspensions from individual samples were split to perform single-cell RNA sequencing, T and B cell receptor sequencing, and phosphoprotein mass cytometry. The trajectories of circulating T, B, myeloid, and natural killer cells in EPIs over the first 2 months of life were distinct from those of full-term infants. In EPIs, peripheral T cell development rapidly progressed over the first month of life, with an increase in the proportion of naïve CD4+, regulatory, and cycling T cells, accompanied by greater STAT5 (signal transducer and activator of transcription 5) signaling. EPI memory CD4+ T cells showed a T helper 1 (TH1) predominance compared with TH2 skewing of central memory–like T cells in full-term infants, and B cells from 2-month-old EPIs exhibited increased signatures of activation and differentiation. Both B and T cells from 2-month-old EPIs displayed increased interferon signatures compared with cells from full-term infants. In conclusion, we demonstrated the feasibility of longitudinal multiomic analyses in EPIs using minute amounts of blood and developed a resource describing peripheral immune development in EPIs that suggested ongoing activation in early life. Editor's summary: Extremely premature infants are born before 30 weeks of gestation and complete development outside the uterus, where they are exposed to pathogens that may affect peripheral immune development. However, studies in these infants are limited by their very small circulating blood volumes. Here, Olaloye and colleagues performed multiomic analyses on immune cells isolated from 100 to 250 μl of blood to establish a single-cell atlas of peripheral immune cell development over the first 2 months of life in extremely premature infants. The trajectories of immune cell dynamics differed from those of full-term infants, and exposure to acute histologic chorioamnionitis before birth correlated with persistent T cell activation and impaired regulatory T cell function 1 month after birth, which may have relevance to complications seen in very premature infants. —Melissa L. Norton [ABSTRACT FROM AUTHOR]

Multistability is central to biological systems. It plays a crucial role in adaptation, evolvability, and differentiation. The presence of positive feedback loops can enable multistability. The simplest of such feedback loops are (a) a mutual inhibition (MI) loop, (b) a mutual activation (MA) loop, and (c) self-activation. While it is established that all three motifs can give rise to bistability, the characteristic differences in the bistability exhibited by each of these motifs is relatively less understood. Here, we use dynamical simulations across a large ensemble of parameter sets and initial conditions to study the bistability characteristics of these motifs. Furthermore, we investigate the utility of these motifs for achieving coordinated expression through cyclic and parallel coupling amongst them. Our analysis revealed that MI-based architectures offer discrete and robust control over gene expression, multistability, and coordinated expression among multiple genes, as compared to MA-based architectures. We then devised a combination of MI and MA architectures to improve coordination and multistability. Such designs help enhance our understanding of the control structures involved in robust cell-fate decisions and provide a way to achieve controlled decision-making in synthetic systems. [ABSTRACT FROM AUTHOR]