Publications

Identification of neural oscillations and epileptiform changes in human brain organoids

Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network-level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from induced pluripotent stem cells from individuals with Rett syndrome, accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, pifithrin-$α$. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

TLR9 expression in Chronic Lymphocytic Leukemia identifies a pro-migratory subpopulation and novel therapeutic target

Neuronal Network Topology Indicates Distinct Recovery Processes after Stroke

Dissecting the Regulatory Strategies of NF-κB RelA Target Genes in the Inflammatory Response Reveals Differential Transactivation Logics

An incoherent feedforward loop interprets NF$ąppa$B/RelA dynamics to determine TNF-induced necroptosis decisions

Substrate complex competition is a regulatory motif that allows NFκB RelA to license but not amplify NFκB RelB

An NFκB activity calculator to delineate signaling crosstalk: type I and II interferons enhance NFκB via distinct mechanisms

Polypyrimidine tract-binding protein blocks miRNA-124 biogenesis to enforce its neuronal-specific expression in the mouse

Nongenetic origins of cell-to-cell variability in B lymphocyte proliferation

Rapid antibody production in response to invading pathogens requires the dramatic expansion of pathogen-derived antigen-specific B lymphocyte populations. Whether B cell population dynamics are based on stochastic competition between competing cell fates, as in the development of competence by the bacterium Bacillus subtilis, or on deterministic cell fate decisions that execute a predictable program, as during the development of the worm Caenorhabditis elegans, remains unclear. Here, we developed long-term live-cell microscopy of B cell population expansion and multiscale mechanistic computational modeling to characterize the role of molecular noise in determining phenotype heterogeneity. We show that the cell lineage trees underlying B cell population dynamics are mediated by a largely predictable decision-making process where the heterogeneity of cell proliferation and death decisions at any given timepoint largely derives from nongenetic heterogeneity in the founder cells. This means that contrary to previous models, only a minority of genetically identical founder cells contribute the majority to the population response. We computationally predict and experimentally confirm nongenetic molecular determinants that are predictive of founder cells’ proliferative capacity. While founder cell heterogeneity may arise from different exposure histories, we show that it may also be due to the gradual accumulation of small amounts of intrinsic noise during the lineage differentiation process of hematopoietic stem cells to mature B cells. Our finding of the largely deterministic nature of B lymphocyte responses may provide opportunities for diagnostic and therapeutic development.

Deriving Quantitative Cell Biological Information from Dye-Dilution Lymphocyte Proliferation Experiments

COMPUTATIONAL MODELLING OF IRON TRANSPORT BETWEEN BLOOD CIRCULATION, BRAIN, AND DOPAMINERGIC NEURONS OF THE SUBSTANTIA NIGRA

Signaling via the NF$ąppa$B system

Training the 21st century immunologist

Studying NF-$ąppa$B signaling with mathematical models

A computational model of liver iron metabolism