Publications

Parkinson’s Disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which is associated with changes in microglia function. While age remains the biggest risk factor, the underlying molecular cause of PD onset and its concurrent neuroinflammation are not well understood. Many identified PD risk genes have been directly linked to dopamine neuron impairment, while others are linked to immune cell function. In this study, we found that the PD risk gene FAM49B is critically expressed in microglia of the human SNpc and is downregulated with age and PD. We utilized human and murine microglia cells to demonstrate the role of FAM49B in regulating fundamental microglial functions such as cytoskeletal maintenance, migration, surface adherence, energy homeostasis, autophagy, and, importantly, inflammatory response. Downregulation of microglial FAM49B, as observed in the SNpc of aging individuals, led to significant alterations in these cellular functions, which are associated with increased microglial activation. Thus, our study highlights novel cell-type-specific roles of FAM49B and provides a potential mechanism for susceptibility to neuroinflammation, and reactive gliosis observed in both PD and normal aging.

Pose estimation is a general problem in computer vision with wide applications. The relative orientation of a 3D reference object can be determined from a 3D rotated version of that object, or from a projection of the rotated object to a 2D planar image. This projection can be a perspective projection (the PnP problem) or an orthographic projection (the OnP problem). We restrict our attention here to the OnP problem and the full 3D pose estimation task (the EnP problem). Here we solve the least squares systems for both the error-free EnP and OnP problems in terms of the determinant ratio matrix (DRaM) approach. The noisy-data case can be addressed with a straightforward rotation correction scheme. While the SVD and optimal quaternion eigensystem methods solve the noisy EnP 3D-3D alignment exactly, the noisy 3D-2D orthographic (OnP) task has no known comparable closed form, and can be solved by DRaM-class methods. We note that while previous similar work has been presented in the literature exploiting both the QR decomposition and the Moore-Penrose pseudoinverse transformations, here we place these methods in a larger context that has not previously been fully recognized in the absence of the corresponding DRaM solution. We term this class of solutions as the DRaM family, and conduct comparisons of the behavior of the families of solutions for the EnP and OnP rotation estimation problems. Overall, this work presents both a new solution to the 3D and 2D orthographic pose estimation problems and provides valuable insight into these classes of problems. With hindsight, we are able to show that our DRaM solutions to the exact EnP and OnP problems possess derivations that could have been discovered in the time of Gauss, and in fact generalize to all analogous N-dimensional Euclidean pose estimation problems.

3D chromatin structure is critical for the regulation of gene expression during development. Here we used Micro-C assays at 100-bp resolution to map genome organization in Drosophila melanogaster throughout the first half of embryogenesis. These high-resolution contact maps reveal fine-scale features such as loops and boundaries delineating topologically associating domains. Notably, we observe that 3D chromatin structures form prior to zygotic genome activation and persist during successive mitotic cycles. Integrative analysis with 149 public chromatin immunoprecipitation sequencing (ChIP-seq) datasets identifies four classes of chromatin structuring elements, including a distinct group enriched for GAGA-associated factor (GAF) and Zelda binding, associated with developmental-gene regulation. These elements are mitotically retained and exhibit sequence and structure similarity between D. melanogaster and D. virilis. We propose that 3D chromatin organization in the pre-cellular embryo facilitates deployment of developmentally regulated genes during Drosophila embryogenesis.

The formation and maintenance of the finite mammalian ovarian reserve are critical for fertility and species survival. Genetic and developmental studies have uncovered various mechanisms underlying oocyte development and maturation, revealing two curious features of the ovarian germline: (a) The establishment of the follicle reserve involves an initial massive overproduction of oocyte precursors, and (b) the total number of ovulated oocytes across an animal's fertile lifetime is a very small proportion of the initial ovarian reserve. Many have proposed that this indicates the existence of selective quality control to ensure gamete fitness. Here, we review the findings underlying the hypotheses for germline quality control during prepubertal development, homeostatic fertility, and reproductive aging. We evaluate whether the existing evidence base distinguishes the active selection of specific germ cell subsets from neutral dynamics. Throughout, we discuss strategies for applying statistical frameworks to evaluate selection in oogenesis and the implications of neutrality versus selection at various points in oocyte development.

Viral infections can induce prolonged changes in innate immunity. Here, we use blood samples from a human influenza H3N2 challenge study (NCT03883113) to perform comprehensive multi-omics analyses. We detect remodeling of immune programs in circulating innate immune cells that persist after resolution of the infection. We find changes associated with suppressed inflammation, including decreased cytokine and AP-1 gene expression as well as decreased accessibility at AP-1 targets and interleukin-related gene promoter regions. We also find decreased histone deacetylase gene expression, increased MAP kinase gene expression, and increased accessibility at interferon-related gene promoter regions. Genes involved in inflammation and methylation remodeling show modulation of gene-chromatin site regulatory circuit activity. These results reveal a coordinated rewiring of the molecular landscape in innate immune cells induced by mild influenza virus infection.

Large Language Models (LLMs) are increasingly being used across applications, ranging from content generation to decision-making, raising concerns about biases embedded in them. While biases related to gender, race, and culture have been studied extensively, understanding age-bias and stereotypes of aging in LLMs remain underexplored. This study analyzes LLM-generated responses to prompts related to aging, revealing stereotypical biases about aging pertaining to technology proficiency, cognitive and physical decline, and job roles. We noted that even responses without explicit age bias also had mentions of ageist stereotypes. We discuss considerations for involving older adults’ perspectives through human-in-the-loop methodologies yet exercising caution about aspects like internalized ageism.

IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and minimal change disease (MCD) account for the majority of idiopathic glomerulopathies (GN). However, there are no powered transcriptomic datasets coupled to genetic data to investigate the genetic mechanisms underlying gene regulation in the context of GN.

The segregation of the epiblast (EPI) and primitive endoderm (PE) cell types in the preimplantation mouse embryo is not only a crucial decision that sets aside the precursors of the embryo proper from extraembryonic cells, respectively, but also has served as a central model to study a key concept in mammalian development: how much of developmental patterning is predetermined vs. stochastically emergent. Here, we address this question by quantitative live imaging of multiple endogenously tagged transcription factors key to this fate decision and trace their dynamics at a single-cell resolution through the formation of EPI and PE cell fates. Strikingly, we reveal an initial symmetry breaking event, the formation of a primary EPI cell lineage, and show that this is linked to the dynamics of the prior inner cell mass/trophectoderm fate decision through the expression of SOX2. This primary EPI lineage, through fibroblast growth factor (FGF) signaling, induces an increase in the transcription factor GATA6 in other inner cell mass cells, setting them on the course toward PE differentiation. Interestingly, this trajectory can switch during a defined developmental window, leading to the emergence of secondary EPI cells. Finally, we show that early expression levels of NANOG, which are seemingly stochastic, can bias whether a cell’s trajectory switches to secondary EPI or continues as PE. Our data give unique insight into how fate patterning is initiated and propagated during unperturbed embryonic development through the interplay of lineage-history-biased and stochastic cell-intrinsic molecular features, unifying previous models of EPI/PE segregation.

The first cell fate bifurcation in mammalian development directs cells toward either the trophectoderm (TE) or inner cell mass (ICM) compartments in pre-implantation embryos. This decision is regulated by the subcellular localization of a transcriptional co-activator YAP and takes place over several progressively asynchronous cleavage divisions. As a result of this asynchrony and variable arrangement of blastomeres, reconstructing the dynamics of the TE/ICM cell specification from fixed embryos is extremely challenging. To address this, we developed a live-imaging approach and applied it to measure pairwise dynamics of nuclear YAP and its direct target genes, CDX2 and SOX2, which are key transcription factors of the TE and ICM, respectively. Using these datasets, we constructed a generative model of the first cell fate bifurcation, which reveals the time-dependent statistics of the TE and ICM cell allocation. In addition to making testable predictions for the joint dynamics of the full YAP/CDX2/SOX2 motif, the model revealed the stochastic nature of the induction timing of the key cell fate determinants and identified the features of YAP dynamics that are necessary or sufficient for this induction. Notably, temporal heterogeneity was particularly prominent for SOX2 expression among ICM cells. As heterogeneities within the ICM have been linked to the initiation of the second cell fate decision in the embryo, understanding the origins of this variability is of key significance. The presented approach reveals the dynamics of the first cell fate choice and lays the groundwork for dissecting the next cell fate decisions in mouse development.

A fundamental problem in computer system performance, as well as in the natural sciences, concerns inferring from observations an understanding of the behavior of stochastic processes of interacting system components whose dynamics are driven by an unknown underlying stochastic differential equation (SDE). The objective in solving this problem is to infer the underlying equations of the dynamics of the system from sets of system measurements, indexed over time. Given the stochastic nature of such systems, together with a lack of information on stochastic trajectories in many cases [1, 3], this represents a very challenging problem in general.