Biology subjects

Kao, A.

Publications and source records attributed to Kao, A..

5 recordsLinked to original sources

bioRxiv2026

Spatial Neuroimmune Crosstalk Driving Perineural Invasion in Head and Neck Squamous Cell Carcinoma

BackgroundPerineural invasion (PNI) is a clinically important feature of aggressive head and neck squamous cell carcinoma (HNSCC) and is associated with recurrence and poor survival. However, the spatial organization and molecular programs that characterize tumor-nerve interactions in HNSCC remain incompletely understood. MethodsSingle-cell-resolution Xenium spatial transcriptomic data from 10 HNSCC patients were analyzed to define nerve-associated regions, cell-type composition, tumor-nerve proximity, and perineural transcriptional programs. Complementary Visium spatial transcriptomic datasets were used to assess broader transcriptomic features of nerve-associated regions, including epithelial-mesenchymal transition and inferred ligand-receptor signaling. Clinical relevance was evaluated using bulk transcriptomic validation cohorts from TCGA-HNSC and GSE65858. ResultsSpatial mapping identified a distinct nerve-proximal microenvironment characterized by depletion of mature dendritic cells and altered immune and stromal composition, consistent with localized disruption of antigen-presenting support at the tumor-nerve interface. HPV- tumors exhibited closer tumor-nerve proximity and a higher exploratory PNI index compared with HPV+ tumors, suggesting subtype-specific differences in nerve-associated tumor behavior. Differential expression analysis of perineural versus distal tumor cells identified a spatially enriched gene program, including NFE2L2, MDM2, and PPARG, that demonstrated a nerve-proximal gradient most evident in HPV- disease. A composite three-gene score was associated with worse overall survival in HPV- patients in TCGA-HNSC and validated in GSE65858, while showing limited prognostic value in HPV+ disease. Visium analyses provided complementary evidence of EMT enrichment and inferred tumor-nerve signaling involving neural guidance and adhesion-associated pathways. ConclusionsThese findings support a model in which PNI in HNSCC reflects a spatially organized, transcriptionally distinct tumor-nerve microenvironment, particularly in HPV- disease. The NFE2L2/MDM2/PPARG signature may provide a candidate biomarker for risk stratification and nominates pathways for future mechanistic and therapeutic investigation.

cancer biology↗

bioRxiv2025

Integrative Genomic and Functional Analyses Reveal NINL as a Modulator of Tau Aggregation

IntroductionProteostasis dysfunction is a hallmark of frontotemporal dementia (FTD) and Alzheimers disease (AD), yet the genetic and molecular pathways that disrupt protein homeostasis remain poorly understood. MethodsWe integrated human genetics, transcriptomics, and functional studies to identify proteostasis network components involved in tauopathy. ResultsWe identified 18 proteostasis network genes harboring 75 rare, damaging variants enriched in FTD and/or AD. These genes, spanning multiple proteostasis pathways, were differentially expressed in MAPT mutant neurons and dysregulated in FTD and AD brains. NINL, which encodes Nlp, emerged as the only gene consistently upregulated across all datasets. NINL overexpression reduced tau seeding and enhanced lysosomal proteolytic activity, whereas two FTD-enriched NINL frameshift variants impaired Nlp expression and abolished these protective effects. DiscussionOur findings identify a set of proteostasis genes with genetic and transcriptional links to neurodegeneration and reveal NINL as a novel regulator of tau aggregation, potentially upregulated as an adaptive response to proteotoxic stress.

neuroscience↗

bioRxiv2023

Evolution of neuronal cell classes and types in the vertebrate retina

The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs (Baden et al., 2020). One might expect that retinal cell types evolved to accommodate these varied needs, but this has not been systematically studied. Here, we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a teleost fish, a bird, a reptile and a lamprey. Molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells [RGCs] and Muller glia) is striking, with transcriptomic differences across species correlated with evolutionary distance. Major subclasses are also conserved, whereas variation among types within classes or subclasses is more pronounced. However, an integrative analysis revealed that numerous types are shared across species based on conserved gene expression programs that likely trace back to the common ancestor of jawed vertebrates. The degree of variation among types increases from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified mammalian orthologs of midget RGCs, which comprise >80% of RGCs in the human retina, subserve high-acuity vision, and were believed to be primate-specific (Berson, 2008); in contrast, the mouse orthologs comprise <2% of mouse RGCs. Projections both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.

neuroscience↗

bioRxiv2018

Partitioning the genetic architecture of amyotrophic lateral sclerosis

The genetic basis of sporadic amyotrophic lateral sclerosis (ALS) is not well understood. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) associated with ALS conditional on genetic data from 65 different traits and diseases from >3 million people. We found strong genetic enrichment between ALS and a number of disparate traits including frontotemporal dementia, coronary artery disease, C-reactive protein, celiac disease and memory function. Beyond C9ORF72, we detected novel genetic signal within numerous loci including GIPC1, ELMO1 and COL16A and confirmed previously reported variants, such as ATXN2, KIF5A, UNC13A and MOBP. We found that ALS variants form a small-world co-expression network characterized by highly inter-connected hub genes. This network clustered into smaller sub-networks, each associated with a unique function. Altered gene expression of several sub-networks and hubs was over-represented in neuropathological samples from ALS patients and SOD1 G93A mice. Our collective findings indicate that the genetic architecture of ALS can be partitioned into distinct components where some genes are highly important for developing disease. These findings have implications for stratification and enrichment strategies for ALS clinical trials.

genetics↗

bioRxiv2017

Collective animal navigation and migratory culture: from theoretical models to empirical evidence

Animals often travel in groups, and their navigational decisions can be influenced by social interactions. Both theory and empirical observations suggest that such collective navigation can result in individuals improving their ability to find their way and could be one of the key benefits of sociality for these species. Here we provide an overview of the potential mechanisms underlying collective navigation and review the known, and supposed, empirical evidence for such behaviour, and highlight interesting directions for future research. We further explore how both social and collective learning during group navigation could lead to the accumulation of knowledge at the population level, resulting in the emergence of migratory culture.

ecology↗