Biology subjects

Thyagarajan, B.

Publications and source records attributed to Thyagarajan, B..

8 recordsLinked to original sources

bioRxiv2026

Erythrocyte Count and the Human Natural Lifespan Limit: Evidence from the Long Life Family Study

Erythropoiesis is the most replication-intensive process in the body. Its lifelong replicative demands may erode hematopoietic cells replicative capacity, leading to a decline in erythrocyte count (EC) in older adults and limiting their lifespan. We examined the relationship between EC and mortality among 1,620 participants aged [≥]70 years in the Long Life Family Study and found that lower EC further augmented the exponential, age-dependent rise in mortality. We identified an EC threshold (ECT) (3.8x1012/L) below which mortality was amplified (p=9.3x10-6). As EC declined with age (p=8.2x10-18), it fell below this threshold in many participants, sharply increasing their mortality risk. This mortality-based ECT emerged from modeling, independent of the World Health Organization anemia definition, which is based on statistical thresholds (5th centiles) of hemoglobin distribution in populations [≤] 65 years. Thus, declining EC may be one of the biological factors imposing a natural lifespan limit on many older adults.

physiology↗

bioRxiv2026

A Cross-Species Enhancer-AAV Toolkit for Cell Type-Specific Targeting Across the Basal Ganglia

The mammalian basal ganglia (BG) orchestrate motor, cognitive, and affective functions, yet cell type-specific genetic access remains limited, especially beyond rodents. Key structures implicated in movement and psychiatric disorders, including pallidum, subthalamic nucleus, and dopaminergic midbrain, lack scalable tools for cross-species targeting. Here, we present a comprehensive enhancer-AAV library enabling selective labeling and manipulation of major BG neuronal populations: striatal projection neuron subtypes, pallidal and subthalamic neurons, and midbrain dopaminergic and GABAergic populations. Using an evolutionarily informed discovery pipeline, we identified enhancers targeting canonical, non-canonical, and disease-relevant cell types, with validation demonstrating robust cross-species conservation of specificity between mouse and macaque. Computational modeling revealed sequence features predictive of in vivo performance, including motif grammar, chromatin accessibility, and evolutionary conservation, and identified distinct regulatory architectures across glial, projection, and interneuron lineages. This work establishes a comprehensive cross-species viral toolkit for the BG, unlocking previously inaccessible cell types for circuit dissection.

neuroscience↗

bioRxiv2026

A cross-sectional examination of immune adaptations during pregnancy in the ECHO Cohort

BackgroundPregnancy requires finely tuned immune changes that support implantation, placental development, maternal-fetal tolerance, and preparation for labor, yet the normative trajectories of circulating inflammatory proteins across gestation remain poorly defined. This cross-sectional study investigates how circulating inflammatory proteins vary with gestational age in pregnancy and examines the impacts of fundamental biological characteristics, such as gravidity and fetal sex. MethodsData were drawn from 1154 pregnant individuals from six study sites of the National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Cohort. We used Olink high-throughput proteomic profiling to map cross-sectional associations between protein expression levels and gestational age at blood draw using linear, spline-based, and generalized additive modeling approaches. ResultsGeneralized additive models provided the best fit, revealing that immune changes across pregnancy were predominantly nonlinear. Sixty-one proteins showed significant associations with gestational age, with many exhibiting shared inflection points that aligned with major physiological transitions. A small subset of proteins also showed evidence of modification by fetal and maternal characteristics. CD244 displayed different gestational patterns by fetal sex, while CST5 and SIRT2 showed varied gestational associations by maternal gravidity. ConclusionThe findings highlight pregnancy as a sequence of coordinated immune transitions rather than a simple linear shift and provide one of the most detailed characterizations to date of circulating inflammatory protein dynamics across human gestation. Establishing these normative trajectories offers a crucial reference for detecting early deviations that may signal risk for pregnancy complications and for identifying biomarkers in maternal and fetal health research.

immunology↗

bioRxiv2025

Construction of Multi-Modal Transcriptome-Small Molecule Interaction Networks from High-Throughput Measurements to Study Human Complex Traits

We present Gene-Embedded Multi-modal Networks (GEM-Net), a semi-supervised framework for constructing multi-modal networks centered on genes. GEM-Net uses gene-level modules and selectively incorporates heterogeneous omics profiles using a correlated meta-analysis strategy that accounts for scale imbalance, missingness, and intra-modular correlation. Prior to network inference, we developed a harmonized data processing protocol that adjusts each omic layer independently through a shared mathematical workflow involving transformation, dimensionality reduction, and regression-based covariate adjustment. GEM-Net modules were inferred and benchmarked against unsupervised methods using transcriptomic, metabolomic, and lipidomic data from the Long Life Family Study (LLFS), a unique cohort enriched for exceptional familial longevity and health. GEM-Net modules were more diverse and biologically interpretable, with stronger support from protein- protein interactions, transcriptional regulation, and metabolic annotations. Applying GEM-Net to metabolic health in LLFS revealed an axis between the microbiome-derived metabolite N-acetylglycine and immune genes (FCER1A, HDC, CPA3, MS4A2) associated with improved insulin sensitivity and reduced inflammation in healthy older individuals. GEM-Nets offer a reusable reference from a long-lived population and a generalizable framework for multi-omics discovery. https://doi.org/10.5281/zenodo.15003731.

systems biology↗

bioRxiv2024

Enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits

We present an enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct and indirect pathway MSNs, as well as Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, three different routes of virus delivery, and with diverse transgene cargos. Importantly, we provide detailed information necessary to achieve reliable cell type specific labeling under different experimental contexts. We demonstrate direct pathway circuit-selective optogenetic perturbation of behavior and multiplex labeling of striatal interneuron types for targeted analysis of cellular features. Lastly, we show conserved in vivo activity for exemplary MSN enhancers in rat and macaque. This collection of striatal enhancer AAVs offers greater versatility compared to available transgenic lines and can readily be applied for cell type and circuit studies in diverse mammalian species beyond the mouse model.

neuroscience↗

bioRxiv2024

Enhancer AAVs for targeting spinal motor neurons and descending motor pathways in rodents and macaque

Experimental access to cell types within the mammalian spinal cord is severely limited by the availability of genetic tools. To enable access to lower motor neurons (LMNs) and LMN subtypes, we generated single cell multiome datasets from mouse and macaque spinal cords and discovered putative enhancers for each neuronal population. We cloned these enhancers into adeno-associated viral vectors (AAVs) driving a reporter fluorophore and functionally screened them in mouse. We extensively characterized the most promising candidate enhancers in rat and macaque and developed an optimized pan LMN enhancer virus. Additionally, we generated derivative viruses expressing iCre297T recombinase or ChR2-EYFP for labeling and functional studies, and we created a single vector with combined enhancer elements to achieve simultaneous labeling of layer 5 extratelencephalic projecting (ET) neurons and LMNs. This unprecedented LMN toolkit will enable future investigations of cell type function across species and potential therapeutic interventions for human neurodegenerative diseases.

neuroscience↗

bioRxiv2024

A Paradigm For Calling Sequence In Families: The Long Life Family Study

Over Several years, we have developed a system for assuring the quality of whole genome sequence (WGS) data in the LLFS families. We have focused on providing data to identify germline genetic variants with the aim of releasing as many variants on as many individuals as possible. We aim to assure the quality of the individual calls. The availability of family data has enabled us to use and validate some filters not commonly used in population-based studies. We developed slightly different procedures for the autosomal, X, Y, and Mitochondrial (MT) chromosomes. Some of these filters are specific to family data, but some can be used with any WGS data set. We also describe the procedure we use to construct linkage markers from the SNP sequence data and how we compute IBD values for use in linkage analysis.

genetics↗

bioRxiv2022

Computational deconvolution of fifteen leukocyte subtypes from DNA methylation microarrays trained on flow cytometry data in the Health and Retirement Study

Adjusting for cell composition is critical in epigenome-wide association studies of whole blood samples. Using DNA methylation of whole blood samples (as opposed to purified cell types) and complete blood counts/flow cytometry data from 2530 participants in the Health and Retirement Study, we trained and tested a computational model that extends the number of estimated leukocyte subtypes to fifteen compared to established models with six or seven cell types. Our model, which can be applied to both Illumina 450k and EPIC microarrays, explained a larger proportion of the observed variance in whole blood DNA methylation levels than popular reference-based cell deconvolution approaches, and vastly reduced the number of false-positive findings in a reanalysis of an epigenome-wide association study of chronological age.

bioinformatics↗