Biology subjects

Arachchilage, K. H.

Publications and source records attributed to Arachchilage, K. H..

5 recordsLinked to original sources

bioRxiv2025

Dynamic landscapes of gene regulatory networks in early mammalian neurogenesis: Insights into brain evolution and disorder risk

Neurogenesis--the process of generating neurons--is governed by dynamic transcriptional programs that vary across time, brain regions, and cell types, forming regionally specialized neuronal circuits. To understand these dynamics, we constructed a comprehensive gene regulatory network (GRN) resource encompassing 22 neurogenic lineages from human, macaque, and mouse, enabling cross-species and cross-regional comparisons. Leveraging state-of-the-art trajectory analysis and GRN inference, we characterized temporal regulatory dynamics and introduced a "dynamic score" to identify key subnetworks with lineage-specific dynamics, including hundreds of regulons and co-regulatory modules. Our analysis uncovered both known and novel candidate regulators driving neuronal differentiation and regional identity, spanning the entire human brain, as well as evolutionary divergence in neurogenic GRNs distinguishing human brains. Mapping risk genes to the resource helped understand associated early gene regulatory dynamics with 35 neurodevelopmental disorders and traits including autism, schizophrenia, severe intellectual disability, and microcephaly. This resource is publicly available as an interactive online platform.

developmental biology↗

bioRxiv2025

Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex

Down syndrome is the most common genetic cause of intellectual disability and is characterized by early-onset delays in motor, cognitive, and language development. The molecular mechanisms underlying these neurodevelopmental impairments remain poorly understood. Here, we utilized single-nucleus multiomic sequencing to simultaneously profile gene expression and chromatin accessibility in the Down syndrome prefrontal cortex during early postnatal development, a critical period for synaptogenesis, neural maturation, and developmental neuroimmune interactions. Our findings reveal widespread dysregulation of chromatin accessibility and gene expression, with deficits spanning metabolic and synaptic pathways, oligodendrocyte lineage progression, and a pronounced neuroinflammatory signature. We present a molecular atlas of Down syndrome neuropathology at a critical stage of brain development, highlighting convergent neurodevelopmental and neurodegenerative pathways and informing potential targeted therapies for Down syndrome-associated neuroinflammation.

neuroscience↗

bioRxiv2025

Single-nucleus analysis reveals dysregulated oxidative phosphorylation in Down syndrome basal forebrain at birth

INTRODUCTIONBasal forebrain cholinergic neurons (BFCNs) are integral to learning, attention, and memory, and are prone to degeneration in Down syndrome (DS), Alzheimers disease, and other neurodegenerative diseases. However, the mechanisms that lead to the degeneration of these neurons are not known. METHODSSingle-nucleus gene expression and ATAC sequencing were performed on postmortem human basal forebrain from unaffected control and DS tissue samples at 0-2 years of age (n=4 each). RESULTSSequencing analysis of postmortem human basal forebrain identifies gene expression differences in DS early in life. Genes encoding proteins associated with energy metabolism pathways, specifically oxidative phosphorylation and glycolysis, and genes encoding antioxidant enzymes are upregulated in DS BFCNs. DISCUSSIONMultiomic analyses reveal that energy metabolism may be disrupted in DS BFCNs by birth. Increased oxidative phosphorylation and the accumulation of reactive oxygen species byproducts may be early contributors to DS BFCN neurodegeneration.

neuroscience↗

bioRxiv2023

Multimodal analysis of neuronal maturation in the developing primate prefrontal cortex

The prefrontal cortex (PFC) is critical for myriad high-cognitive functions and is associated with several neuropsychiatric disorders. Here, using Patch-seq and single-nucleus multiomic analyses, we identified genes and regulatory networks governing the maturation of distinct neuronal populations in the PFC of rhesus macaque. We discovered that specific electrophysiological properties exhibited distinct maturational kinetics and identified key genes underlying these properties. We unveiled that RAPGEF4 is important for the maturation of resting membrane potential and inward sodium current in both macaque and human. We demonstrated that knockdown of CHD8, a high-confidence autism risk gene, in human and macaque organotypic slices led to impaired maturation, via downregulation of key genes, including RAPGEF4. Restoring the expression of RAPGEF4 rescued the proper electrophysiological maturation of CHD8-deficient neurons. Our study revealed regulators of neuronal maturation during a critical period of PFC development in primates and implicated such regulators in molecular processes underlying autism.

neuroscience↗

bioRxiv2022

Exploring how ecological and epidemiological processes shape multi-host disease dynamics using global sensitivity analysis

We use global sensitivity analysis (specifically, Partial Rank Correlation Coefficients) to explore the roles of ecological and epidemiological processes in shaping the temporal dynamics of a parameterized SIR-type model of two host species and an environmentally transmitted pathogen. We compute the sensitivities of disease prevalence in each host species to model parameters. Sensitivity rankings and subsequent biological interpretations are calculated and contrasted for cases were the pathogen is introduced into a disease-free community and where a second host species is introduced into an endemic single-host community. In some cases the magnitudes and dynamics of the sensitivities can be predicted only by knowing the host species characteristics (i.e., their competitive abilities and disease competence) whereas in other cases they can be predicted by factors independent of the species characteristics (specifically, intraspecific versus interspecific processes or the species roles of invader versus resident). For example, when a pathogen is initially introduced into a disease-free community, disease prevalence in both hosts is more sensitive to the burst size of the first host than the second host. In comparison, disease prevalence in each host is more sensitive to its own infection rate than the infection rate of the other host species. In total, this study illustrates that global sensitivity analysis can provide useful insight into how ecological and epidemiological processes shape disease dynamics and how those effects vary across time and system conditions. Our results show that sensitivity analysis can provide quantification and direction when exploring biological hypotheses.

ecology↗