Biology subjects

Ryan, N.

Publications and source records attributed to Ryan, N..

7 recordsLinked to original sources

bioRxiv2026

Early and current environments exert distinct effects on immune function in the Orang Asli

Humans evolved in environments characterized by subsistence foraging and hunting, high levels of physical activity, and regular and diverse pathogen exposure. Industrialization has rapidly altered these environments, leading to increased metabolic and inflammatory disease risk. These observations have motivated studies of how industrialization shapes immune function, but whether industrialization alters immune biology through developmental embedding of early-life environments or ongoing plastic responses to current conditions remains poorly understood. To address this gap, we worked with the Orang Asli--the Indigenous peoples of Peninsular Malaysia--who currently span a gradient from subsistence horticulture, foraging, and hunting to industrialized, urban environments with substantial inter-individual variation in life course experiences. Leveraging continuous measures of both early-life and current lifestyle, we found that current lifestyle exerts stronger effects on adult immune gene expression than early-life conditions, impacting 1,428 as compared to 223 genes, respectively. Early-life associated genes were enriched for pathways regulating adaptive immunity, particularly T cell development and differentiation, consistent with higher predicted T cell abundance and circulating IL-8 in urban-born individuals. In contrast, current exposure to urban, industrialized conditions was linked to innate immune and inflammatory activation, including dendritic cell abundance, metabolic pathway upregulation, and elevated CRP. Finally, consistent with lower rates of immune disorders in non-industrial settings, current exposure to this lifestyle was associated with up-regulation of genes involved in Th1/Th2 differentiation. Together, these results emphasize that industrialized immune profiles reflect both early-life developmental embedding and ongoing environmental responses, highlighting the importance of considering exposures across the life course. Significance statementHumans evolved in environments with high levels of physical activity, subsistence-based diets, and constant pathogen exposure. Rapid industrialization has dramatically changed these conditions, coinciding with rising rates of non-communicable diseases with inflammatory underpinnings. Our study with the Orang Asli, the Indigenous peoples of Peninsular Malaysia, tests how exposure to industrialization across the life course shapes immune variation. We find that early-life environments leave lasting marks on adaptive immune function particularly T cells, while industrialized adult lifestyle influences innate immune activity and inflammation. These results clarify how different stages of life contribute to immune remodeling and point to a mechanistic link between industrialization and disease risk, highlighting the importance of both early-life and current environments in shaping later life health.

genetics↗

bioRxiv2025

Age and early life adversity shape heterogeneity of the epigenome across tissues in macaques

Age and early life adversity (ELA) are both key determinants of health, but whether they target similar physiological mechanisms across the body is unknown due to limited multi-tissue datasets from well-characterized cohorts. We generated DNA methylation (DNAm) profiles across 14 tissues in 237 semi-free ranging rhesus macaques, with records of naturally occurring ELA. We show that age-associated DNAm variation is predominantly tissue-dependent, yet tissue-specific epigenetic clocks reveal that the pace of epigenetic aging is relatively consistent within individuals. ELA effects on loci are adversity-dependent, but a given ELA has a coordinated impact across tissues. Finally, ELA targeted many of the same loci as age, but the direction of these effects varied, indicating that ELA does not uniformly contribute to accelerated age in the epigenome. ELA thus imprints a coordinated, tissue-spanning epigenetic signature that is both distinct from and intertwined with age-related change, advancing our understanding of how early environments sculpt the molecular foundations of aging and disease.

genomics↗

bioRxiv2024

Public RNA-seq data are not representative of global human diversity

The field of human genetics has reached a consensus that it is important to work with diverse and globally representative participant groups. This diverse sampling is required to build a robust understanding of the genomic basis of complex traits and diseases as well as human evolution, and to ensure that all people benefit from downstream scientific discoveries. While previous work has characterized compositional biases and disparities for public genome-wide association (GWAS), microbiome, and epigenomic studies, we currently lack a comprehensive understanding of the degree of bias for transcriptomic studies. To address this gap, we analyzed the metadata for RNA-seq studies from two public databases--the Sequence Read Archive (SRA), representing 795,071 samples from 21,209 studies, and the Database of Genotypes and Phenotypes (dbGaP), representing 167,389 samples from 649 studies. We also randomly selected 620 studies from SRA for detailed, manual evaluation. We found that 3% of samples in SRA and 21% of individuals described in the literature had population descriptors (race, ethnicity, or ancestry); 28% of samples in dbGaP had paired genotype data that was used to empirically infer ancestry. In SRA, dbGaP, and the literature, race, ethnicity, and ancestry terms were frequently conflated and difficult to disambiguate. After standardizing population descriptors, we observed many clear biases: for example, among samples in SRA that were coded using US Census terms, 69.0% came from white donors, corresponding to an 1.2x overrepresentation of this group relative to the US population. Among samples in SRA coded using continental ancestry labels, 55.6% came from European ancestry donors--an 4.1x overrepresentation of this group relative to the global population. These biases were generally similar across datasets (SRA, dbGaP, literature review), and were comparable to previous reports for other omics data types. However, we note that, relative to other omics data subsets like GWAS, there is considerably less information, of arguably worse quality, about who is participating in RNA-seq studies. Together, these results demonstrate a critical need to improve our thoughtfulness, consistency, and effort around reporting population descriptors in RNA-seq studies, and to more generally strive for greater diversity in this important data type.

genomics↗

bioRxiv2024

Chemical imaging signatures delineate heterogeneous amyloid plaque populations across the Alzheimers disease spectrum

Amyloid plaque deposition is recognized as the primary pathological hallmark of Alzheimers disease(AD) that precedes other pathological events and cognitive symptoms. Plaque pathology represents itself with an immense polymorphic variety comprising plaques with different stages of amyloid fibrillization ranging from diffuse to fibrillar, mature plaques. The association of polymorphic A{beta} plaque pathology with AD pathogenesis, clinical symptoms and disease progression remains unclear. Advanced chemical imaging tools, such as functional amyloid microscopy combined with MALDI mass spectrometry imaging (MSI), are now enhanced by deep learning algorithms. This integration allows for precise delineation of polymorphic plaque structures and detailed identification of their associated A{beta} compositions. We here set out to make use of these tools to interrogate heterogenic plaque types and their associated biochemical architecture. Our findings reveal distinct A{beta} signatures that differentiate diffuse plaques from fibrilized ones, with the latter showing substantially higher levels of A{beta}x-40. Notably, within the fibrilized category, we identified a distinct subtype known as coarse-grain plaques. Both in sAD and fAD brain tissue, coarse grain plaques contained more A{beta}x-40 and less A{beta}x-42 compared with cored plaques. The coarse grain plaques in both sAD and fAD also showed higher levels of neuritic content including paired helical filaments (PHF-1)/phosphorylated phospho Tau-immunopositive neurites. Finally, the A{beta} peptide content in coarse grain plaques resembled that of vascular A{beta} deposits (CAA) though with relatively higher levels of A{beta}1-42 and pyroglutamated A{beta}x-40 and A{beta}x-42 species in coarse grain plaques. This is the first of its kind study on spatial in situ biochemical characterization of different plaque morphotypes demonstrating the potential of the correlative imaging techniques used that further increase the understanding of heterogeneous AD pathology. Linking the biochemical characteristics of amyloid plaque polymorphisms with various AD etiologies and toxicity mechanisms is crucial. Understanding the connection between plaque structure and disease pathogenesis can enhance our insights. This knowledge is particularly valuable for developing and advancing novel, amyloid-targeting therapeutics.

neuroscience↗

bioRxiv2022

Peroxisomal β-oxidation enzyme, DECR2, regulates lipid metabolism and promotes treatment resistance in advanced prostate cancer

Peroxisomes are central metabolic organelles that have key roles in fatty acid homeostasis, including {beta}-oxidation, and emerging evidence has linked aberrant peroxisome metabolism to cancer development and progression. While targeting mitochondrial {beta}-oxidation in prostate cancer (PCa) has gained significant attention in recent years, the contribution of peroxisomal {beta}-oxidation (perFAO) to PCa tumorigenesis is comparatively unexplored. Herein, we explored the therapeutic efficacy of targeting perFAO in PCa cells and clinical prostate tumours, and subsequently identified peroxisomal 2,4-dienoyl CoA reductase 2 (DECR2), as a key therapeutic target. DECR2 is markedly upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa. Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and enzalutamide-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. Using transcriptomic and lipidomic analyses, we determined that DECR2 influences cell cycle progression and lipid metabolism to enable tumour cell proliferation. We further demonstrated a novel role for perFAO in driving resistance to standard-of-care androgen receptor pathway inhibition, using genetic and pharmacological approaches to alter DECR2/perFAO in treatment-resistant PCa cells. Our findings highlight a need to focus on peroxisomes to suppress tumour cell proliferation and reveal new therapeutic targets for advanced, treatment-resistant PCa.

cancer biology↗

bioRxiv2022

Lamellar Thickness Measurements in Normal and Osteogenesis Imperfecta Human Bone, with development of a method of automated thickness averaging to simplify quantitation.

PurposeLamellar bone that forms in moderate and severe osteogenesis imperfecta (OI) is often composed of structurally irregular lamellae compared to those in normal bone. Polarization light microscopy (PLM) demonstrates lamellar bone well but has rarely been used for quantitative studies; information available on normal bone lamellae tends to be variable and studies specifically assessing OI bone lamellae have not been done. We report on PLM histomorphometry quantifying bright and dark lamellar thicknesses in normal and OI bone. Manual measurements of individual lamellar thicknesses have been made on histologic sections using the cellSens image analysis system; in an effort to augment the number of measurements we also developed a method of automated thickness averaging in quantifying regions of lamellae. MethodsFemoral and tibial cortical bone fragments from 5 individuals 5 - 26 years old (without molecular bone disorders) and 8 individuals 5 - 16 years old with progressively deforming (Sillence III) OI were obtained. The fragments were decalcified, infiltrated in JB4 solution, embedded in JB4 plastic, sectioned at 5 thickness and stained with 1% toluidine blue for light and polarizing microscopy. Manual measurements: Strict criteria for measurement, primarily to eliminate oblique lamellae, included accumulations of 16-20 bright and dark lamellae under PLM with a relatively narrow range of thicknesses, flattened elliptical osteocytes along the longitudinal axis of the lamellae and canaliculi passing from the walls of the osteocyte lacunae at right angles to the lamellae. Histomorphometric measurements of bright and dark lamellae by PLM were made at 20X magnification. Automated measurements: A script for automated measurement of average lamellar thicknesses from PLM images was developed in MATLAB (Mathworks, Natick, MA) to make measurement faster and less subjective. The script isolates a region from an image for measurement and marks each pixel as either bright or dark based on a local average intensity threshold. It then takes multiple pixel measurements along the length of the lamellae in the image and returns the average thickness of each in m. Results1. OI bone mean lamellar thickness values are always less than those in normal bone. The mean value for all OI bright and dark lamellae combined is 1.80 {+/-} 0.72 m and the value in normal bone is 2.54 {+/-} 0.92 m. 2. Mean value for the bright lamellae is less than that for the dark lamellae in both normal and OI bone. The mean value for bright lamellae in OI is 1.47 {+/-} 0.53 m and for dark lamellae 2.18 {+/-} 0.72 m; in normal bone the mean value for bright lamellae is 2.06 {+/-} 0.54 m and for dark lamellae 3.07 {+/-} 0.96 m. The differences are statistically significant: between groups of normal and OI lamellae (p<0.001), normal and OI light bands (p<0.001), and normal and OI dark bands (p<0.001). 3. Ratio of mean values for bright/dark lamellar thicknesses is the same in OI and normal bone. The ratio in OI bone is 0.67 (range: 0.54 - 0.83) and in normal bone 0.67 (range: 0.60 - 0.88). 4. Validation of automated vs. manual datasets: For each lamella in the validation dataset, the percent difference between the automated and manual measurements was calculated. The mean of the absolute values of these percent differences was 18.9%, a statistically non-significant difference (p = 0.0518). Discussion and conclusionsLamellar bone that forms in moderate and severe OI is composed of thinner and less regular lamellae than those in normal bone. i) PLM histomorphometry shows mean lamellar thicknesses (bright and dark merged) are statistically significantly decreased in OI compared to normal bone as are bright and dark lamellar thicknesses measured independently. ii) The automated method can be adapted readily to the assessment process for lamellar thicknesses and is, most likely, more accurate since it averages a greatly increased number of measurements per individual lamella. iii) Lamellar thickness measurements can be helpful in assessing the effect of specific collagen mutations on OI bone synthesis and warrant inclusion in both research and clinical histomorphometric assessments.

bioengineering↗

bioRxiv2020

Molecular and cellular pathology of monogenic Alzheimer's disease at single cell resolution

Cell and molecular biology analyses of sporadic Alzheimers disease brain are confounded by clinical variability, ageing and genetic heterogeneity. Therefore, we used single-nucleus RNA sequencing to characterize cell composition and gene expression in the cerebral cortex in early-onset, monogenic Alzheimers disease. Constructing a cellular atlas of frontal cortex from 8 monogenic AD individuals and 8 matched controls, provided insights into which neurons degenerate in AD and responses of different cell types to AD at the cellular and systems level. Such responses are a combination of positively adaptive and deleterious changes, including large-scale changes in synaptic transmission and marked metabolic reprogramming in neurons. The nature and scale of the transcriptional changes in AD emphasizes the global impact of the disease across all brain cell types. One Sentence SummaryAlzheimers disease brain atlas provides insights into disease mechanisms

neuroscience↗