Biology subjects

Agrawal, A.

Publications and source records attributed to Agrawal, A..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Toll-like Receptor 4 Contributes to PCOS-like Metabolic and Reproductive Pathogenesis

Polycystic ovary syndrome (PCOS) is a reproductive disorder with heterogeneous symptoms and severity. Despite extensive research documenting chronic immune dysfunction as a hallmark of PCOS, the specific molecular mechanisms driving immune activation and its connection to the syndromes diverse symptoms remain poorly understood. Emerging evidence suggests that gut-derived bacterial endotoxins, particularly lipopolysaccharide (LPS), may breach the intestinal barriers in PCOS patients and trigger systemic inflammation through Toll-like receptor 4 (TLR4), a pattern recognition receptor of the innate immune system. This study investigated whether TLR4 serves as a critical mechanistic driver of PCOS pathogenesis by examining the effect of genetic TLR4 knockout (TLR4-/-) in a letrozole (LET)-induced mouse model of PCOS. Our results demonstrate that TLR4 deficiency reduces many PCOS-like symptoms, including elevated luteinizing hormone, anovulation, and metabolic dysfunction. TLR4 knockout also preserved estrous cycling and fertility, improved glucose tolerance, maintained gut barrier integrity, and reduced inflammatory markers in LET-treated females. These findings establish TLR4 as a key mediator orchestrating PCOSs multi-system pathology, positioning TLR4 as a critical convergence point rather than affecting individual symptoms in isolation. This novel work reveals that TLR4-mediated inflammation drives multiple PCOS pathologies, opening avenues for targeted anti-inflammatory treatments in women with this disorder. Significance StatementPolycystic ovary syndrome (PCOS) affects up to 15% of reproductive-age women worldwide. This study reveals that TLR4, an innate immune receptor, is key to the pathophysiology of PCOS-like symptoms in female mice. When TLR4 was genetically deleted, mice treated with letrozole to induce PCOS-like symptoms maintained normal weight, glucose regulation, estrous cycling, and fertility. The improvements coincided with preserved gut barrier breakdown and reduced inflammation. These findings identify TLR4 as a key mediator between gut health, immune activation, and PCOS pathophysiology, suggesting that targeting TLR4 could offer new therapeutic approaches for this common but poorly understood syndrome affecting millions of women.

immunology↗

bioRxiv2025

Molecular attributes of intrinsically disordered regions in secretomes influence fungal pathogenesis

Secretory proteins are crucial for establishing fungal infection through biomolecular interactions with the host. Accumulating evidence suggest that intrinsically disordered regions (IDRs) in proteins facilitate molecular interactions. How do IDRs of secretory proteins influence fungal pathogenesis? By analyzing 195,359 secretory proteins of 73 fungal species, we find that IDRs in plant pathogen extracellular non-effectors are enriched for weak polyampholytes and polyelectrolytes. These could adopt beads-on-string conformation effectively promoting assembly of diverse enzymes aiding swift degradation of host cell wall. Both animal pathogen secretory proteins and intracellular plant pathogen effectors show enrichment for strong polyampholytes, potentially aiding phase-separation and organizing intracellular biological matter to hijack or suppress host machinery. Importantly, IDRs of plant pathogen effectors which mimic host IDRs could have emerged through convergent evolution, while those of non-effectors might have evolved de novo. Thus, specific molecular attributes of fungal secretome IDRs can influence initiation, establishment and long-term persistence of infection.

systems biology↗

bioRxiv2025

T13F2.2 of C. elegans is Critical for Chromatin Organization, Autophagy, and Longevity

Intricately modulated by a spectrum of proteins, Chromatin structure governs gene expression and cellular homeostasis. In Caenorhabditis elegans, critical components like the TATA-binding protein tbp-1 play pivotal roles in orchestrating chromatin dynamics. While the function of many of the interacting partners of tbp-1 is well-understood, our study brings into focus a lesser-known entity, T13F2.2, an unexplored tbp-1 interacting protein and a putative RNA polymerase II transcriptional coactivator. Employing reverse genetics, we found that RNAi-induced depletion of T13F2.2 resulted in pronounced disruptions to nuclear architecture, evidenced by nuclear staining and transmission electron microscopy. Accompanying these structural anomalies, we observed increased autophagy, pointing to cellular stress and a hyperacetylation of the core histones, suggesting potential chromatin decompaction. Notably, multifaceted functional alterations, upon the partial knockdown of the T13F2.2, culminated in a substantial reduction in the worms lifespan. Intriguingly, interventions such as administering ROS scavengers and autophagy modulators offered a reprieve from this life-shortening effect. Transcriptomic analysis upon T13F2.2 knockdown revealed upregulation of genes related to autophagy and chromatin remodelling, alongside downregulation of genes involved in longevity pathways and oxidative stress response. This study, thus, not only puts forward the functional implication of an uncharacterized gene in C. elegans biology, but also further emphasizes the role of chromatin organization in aging at the organismal level.

genetics↗

bioRxiv2025

Profibrotic monocyte-derived alveolar macrophages as a biomarker and therapeutic target in systemic sclerosis-associated interstitial lung disease

Interstitial lung disease (ILD) is present in over 60% of patients with systemic sclerosis (SSc) and is the leading cause of SSc-related deaths. Profibrotic monocyte-derived alveolar macrophages (MoAM) play a causal role in the pathogenesis of pulmonary fibrosis in animal models where their persistence in the niche requires signaling through Colony Stimulating Factor 1 Receptor (CSF1R). We hypothesized that the presence and proportion of MoAM in bronchoalveolar lavage (BAL) fluid from patients with SSc-ILD may be a biomarker of ILD severity. To test this hypothesis, we analyzed BAL fluid from 9 prospectively enrolled patients with SSc-ILD and 13 healthy controls using flow cytometry and single-cell RNA sequencing. Patients with SSc-ILD had more MoAM and interstitial macrophages in BAL fluid than healthy controls, and their abundance was associated with lung fibrosis severity. We identified changes in the MoAM transcriptome as a function of treatment with mycophenolate, an effective therapy for SSc-ILD. In SSc-ILD lung explants, spatial transcriptomics identified an expanded population of interstitial macrophages spilling into the alveolar space. Our findings suggest that the proportion of profibrotic MoAM and interstitial macrophages in BAL fluid may serve as a biomarker of SSc-ILD and credential them as possible targets for therapy.

immunology↗

bioRxiv2025

Bounds on the computational complexity of neurons due to dendritic morphology

The simple linear threshold units used in many artificial neural networks have a limited computational capacity. Famously, a single unit cannot handle non-linearly separable problems like XOR. In contrast, real neurons exhibit complex morphologies as well as active dendritic integration, suggesting that their computational capacities outperform those of simple linear units. Considering specific families of Boolean functions, we empirically examine the computational limits of single units that incorporate more complex dendritic structures. For random Boolean functions, we show that there is a phase transition in learnability as a function of the input dimension, with most random functions below a certain critical dimension being learnable and those above not. This critical dimension is best predicted by the overall size of the dendritic arbor. This demonstrates that real neurons have a far higher computational complexity than is usually considered in neural models, whether in machine learning or computational neuroscience. Furthermore, using architectures that are, respectively, more "apical" or "basal" we show that there are non-trivially disjoint sets of learnable functions by each type of neuron. Importantly, these two types of architectures differ in the robustness and generality of the computations they can perform. The basal-like architecture shows a higher probability of function realization, while the apical-like architecture shows an advantage with fast retraining for different functions. Given the cell-type specificity of morphological characteristics, these results suggest both that different components of the dendritic arbor as well as distinct cell types may have distinct computational roles. Our analysis offers new directions for neuronlevel inductive biases in NeuroAI models using scalable models for neuronal cell-type specific computation.

neuroscience↗

bioRxiv2025

An immunobiliary single-cell atlas resolves crosstalk of type 2 cDCs and γδT cells in cholangitis

Background and aimsThe immunobiliary niche serves as a reservoir of tissue-resident immune cells, yet the role of unconventional T cells during cholangitis remains poorly understood. Here, we connect cell state dynamics of type 2 conventional dendritic cells (cDC2) in cholangitis with site-specific{gamma}{delta} T17 responses in liver and draining lymph nodes (LN). MethodsThe 0.1% Diethoxycarbonyl-1,4-Dihydrocollidine (DDC) diet was used to generate an immunobiliary DC- and{gamma}{delta} T-enriched mouse liver and LN single-cell RNA-sequencing (scRNA-seq) atlas covering temporal disease dynamics, resolution and cDC2B depletion. cDC2 trajectories were inferred using VarID2 and{gamma}{delta} T cell transcription factor (TF) regulon activity was predicted by SCENIC. The human biliary niche was resolved by integrating human liver scRNA-seq data with available spatial transcriptomics data. Functional studies were conducted using Tcrd knockout, Il17a/f knockout and Tcrd reporter mice. ResultsA disease trajectory of Mgl2+ cDC2B was identified connecting DC maturation, homing and the expression of Il17-inducing genes. Disease progression was associated with numeric exhaustion of mature cDC2B and recruitment of DC precursors.{gamma}{delta} T cells were the main Il17 producers and were subtyped into Il17ahigh Scart1+ V{gamma}6+ and Il17low Scart2+ V{gamma}4+ populations exhibiting cDC2-directed communication and divergent TF regulon activity. Spatial proximity and conserved molecular interactions of cDC2 and{gamma}{delta} T cells were confirmed in human cholangitis. Il17-deficiency resulted in reduced liver fibrosis in mice, while cDC2B depletion attenuated{gamma}{delta} T17 cell states. ConclusionsIn cholangitis, a profibrogenic function of{gamma}{delta} T cells is contingent on the induction by peribiliary cDC2B, thereby highlighting relevant disease determinants within the immunobiliary and liver-draining LN niche. Impact and ImplicationsThe immunobiliary niche contains rare immune cells such as conventional dendritic cells and unconventional T cells, however, the function of these cell types in liver inflammation remains poorly understood. Mirroring human biliary diseases such as primary sclerosing cholangitis, we induced experimental cholangitis in a mouse model to generate a site-specific single-cell sequencing atlas resource resolving underexplored cell populations. Our data capture a profibrotic hepatic disease state trajectory of Mgl2+ cDC2B inducing a{gamma}{delta} T cell-specific Il17-response, which is attenuated upon cDC2B depletion and in DC precursors, which are characterized by reduced genomic accessibility of{gamma}{delta} T cell-interacting genes. These results highlight the importance of portal niche residing underexplored immune cell populations and the necessity to further resolve immunobiliary niche responses and crosstalk in inflammatory settings such as in cholangitis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/664083v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1d21193org.highwire.dtl.DTLVardef@7ff3dcorg.highwire.dtl.DTLVardef@630c78org.highwire.dtl.DTLVardef@c79f9b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Klotho deficiency promotes skeletal muscle weakness and is associated with impaired motor unit connectivity

Muscle wasting and weakness are important clinical problems that impact quality of life and health span by restricting mobility and independence, and by increasing the risk for physical disability. The molecular basis for this has not been fully determined. Klotho expression is downregulated in conditions associated with muscle wasting, including aging, chronic kidney disease, and myopathy. The objective of this study was to investigate a mechanistic role for Klotho in regulating muscle wasting and weakness. Body weight, lean mass, muscle mass, and myofiber caliber were reduced in Klotho-deficient mice. In the tibialis anterior muscle of Klotho null mice, type IIa myofibers were resistant to changes in size, and muscle composition differed with a higher concentration of type IIb fibers to the detriment of type IIx fibers. Glycolytic enzymatic activity also increased. The composition of the soleus muscle was unaffected and myofiber caliber was reduced comparably in type I, IIa, and IIx fibers. Muscle contractile function declined in Klotho-deficient mice, as evidenced by reduced absolute twitch and torque, and decreased rates of contraction and relaxation. RNA-sequencing analysis identified increased transcriptional expression of synaptic and fetal sarcomeric genes, which prompted us to test effects on muscle innervation. Klotho-deficiency induced morphological remodeling of the neuromuscular junction, myofiber denervation, and a functional loss of motor units. Loss of motor units correlated with absolute torque. Collectively, our findings have uncovered a novel mechanism through which Klotho-deficiency leads to alterations to the muscle synapse affecting motor unit connectivity that likely influences muscle wasting and weakness. Key points summaryO_LIMaintaining skeletal muscle mass and function is critical to preserve physical capacity and independence. Clinical observations implicate longevity factor Klotho as a key regulator of muscle mass and weakness. Low Klotho levels are reported to correlate with muscle weakness and frailty. C_LIO_LIUsing Klotho null mice, our study shows that Klotho-deficiency promotes skeletal muscle weakness and impaired motor unit connectivity. C_LIO_LIRNA-sequencing analysis identified altered expression of sarcomeric and synaptic genes suggesting changes to the muscle synapse in Klotho-deficient mice. C_LIO_LIHistopathological analyses revealed Klotho-deficiency is associated with reduced myofiber caliber, altered muscle composition, and increased prevalence of NCAM+ denervated fibers. Imaging of the NMJ further showed morphological changes and reduced area of synaptic contact. C_LIO_LIOverall, our findings show that Klotho regulates the structure and function of the NMJ affecting motor unit connectivity which may have an important role in the pathogenesis of muscle wasting and weakness. C_LI

physiology↗

bioRxiv2025

Cellular profiling identifies an early profibrotic alveolar type 2 cell signature in lung fibrosis

RationaleIdiopathic pulmonary fibrosis (IPF) is a progressive, age-associated, lung disease characterized by short telomeres in alveolar type 2 (AT2) cells, epithelial remodeling, and fibrosis. ObjectivesThis study investigated how telomere dysfunction in AT2 cells lacking Telomere Repeat Binding Factor 1 (TRF1) drives lung remodeling in SPC-creTRF1flox/flox mice and its relevance to IPF. MethodsMouse model of telomere dysfunction was used to conditionally delete TRF1 in AT2 cells. SPC-creTRF1flox/flox mouse lung epithelial cells were used to perform single cell RNA sequencing. AT2 cells from IPF lungs were analyzed by single cell RNA sequencing in an organoid model. Measurements and Main ResultsSingle cell RNA-sequencing revealed distinct pathological AT2 cells enriched in DNA damage, senescence, oxidative stress, and pro-fibrotic genes, along with fewer "normal" AT2 cells and increased club cells in SPC-creTRF1flox/flox mice. Pathological AT2 cells showed different early and late-stage gene signatures, with a prominent p53 signature at both time-points. Genetic deletion of p53 in SPC-creTRF1flox/flox AT2 cells improved survival and prevented lung fibrosis. p53 deletion or inhibition improved organoid formation, surfactant protein C expression, and reduced pro-fibrotic gene expression in AT2 cells isolated from SPC-creTRF1flox/flox mice or IPF lungs. ConclusionsThese data suggest that the DNA damage response to AT2 cell telomere dysfunction, driven by enhanced p53 activity, mediates early AT2 cell transdifferentiation and senescence, leading to epithelial cell remodeling and fibrosis and that reversing this reprogramming is a potential therapeutic approach for managing IPF.

cell biology↗

bioRxiv2025

Immune Composition of the Mononuclear Cell Fraction of Human Umbilical Cord Blood

Despite its therapeutic potential and unique immunological properties, the immune composition of umbilical cord blood lacks consistent and comprehensive characterizations. Human umbilical cord blood (UCB) is often discarded after delivery and is difficult to obtain for research purposes. Furthermore, most research on UCB is focused on properties of CD34+ hematopoietic stem cells for transplantation. The Binns Program for Cord Blood Research at Stanford University has the unique advantage of regular collection and isolation of mononuclear cells (MNC) from UCB donors. This study provides a robust characterization of the immune subset compositions of the CD34-negative MNC fraction of UCB (n=50). The study also compares the UCB data to adult peripheral blood (PB) mononuclear cells to identify differences in immune maturity. Using flow cytometry and single-cell RNA sequencing (scRNA-Seq), we analyzed UCB and adult PB MNC samples to characterize the cell surface protein and transcriptomic profiles of different immune subsets. Our study findings bring a higher-definition understanding of the unique immunological properties of umbilical cord blood. Study findings reveal a distinct immune profile in UCB, such as a higher average percentage of CD19 B Lymphocytes, CD4 T Cells, CD4 Naive T Cells, CD4 Recent Thymic Emigrants, CD8 Naive T Cells, CD8 Recent Thymic Emigrants, and CD19 Naive B Cells compared to adult PB. Additionally, there were fewer CD19 Memory B Cells in UCB compared to PB. The scRNA-Seq showed concordance in the proportion of immune cell types but captured more differentiated subtypes of cells. Additionally, scRNA-Seq showed unique clustering patterns in UCB, which reflect cell types that converge in adulthood as the immune system matures. These analyses yield the intriguing possibility that the immune heterogeneity of individuals at birth gives way to more stereotyped immune subsets as the immune system is exposed to the external environment and undergoes maturation. Overall, our findings provide a robust characterization of MNC UCB immune subsets and insights into how immune function develops from birth to adulthood.

immunology↗

bioRxiv2025

Dissecting the cortical stages of invariant word recognition

Fluent reading requires the brain to precisely encode the positions of letters within words, distinguishing for instance FORM and FROM across variations in size, position, and font. While early visual areas are known to encode retinotopic positions, how these representations transform into invariant neural codes remains unclear. Building on a computational model of reading, we used 7T fMRI and MEG to reveal a cortical hierarchy in which early visual areas (V1-V4) predominantly encode retinotopic information, whereas higher-level regions, including the Visual Word Form Area (VWFA), transition to an ordinal letter-position code. MEG analyses confirm that retinotopic encoding emerges early (60-200 ms), followed by a shift toward ordinal representations in later time windows (220-450 ms). Despite this transition, word position remained a dominant factor across all time points, suggesting a concurrent coding of both retinotopic and abstract positional information. These findings uncover the spatiotemporal dynamics by which the human brain transforms visual input into structured linguistic representations, shedding light on the cortical stages of reading and their developmental and clinical implications.

neuroscience↗

bioRxiv2025

Amino acid repeat signatures underlying human-pathogen interactions

Emerging evidence suggests that amino acid homorepeats (HRs) in proteins (HRPs) contribute to protein interactability. What is the role of HRs in human-pathogen protein interactions? We find that pathogens engage physiologically important human HRPs, thereby affecting diverse host physiological processes. From the pathogen standpoint, (i) eukaryotic pathogens engage more HRPs but with host-sparse HRs, leading to disparate and discriminate interactions, (ii) prokaryotic pathogens engage less HRPs but with host-abundant non-polar HRs via host protein proxies bringing about discriminate or promiscuous interactions and (iii) viral pathogens engage more HRPs with host-abundant polar uncharged HRs affecting promiscuous interactions using host-partner HR tract mimicry. To propel further research, we introduce a resource Hi-PHI (http://hiphi.iisertirupati.ac.in/) cataloging critical information about human and pathogen HRPs and HRs. We propose mechanisms to (i) repurpose drugs targeting human HRPs engaged by pathogens for treating different infections and (ii) exploit HRs and their flanks as targets for pathogen-targeted anti-infectives.

systems biology↗

bioRxiv2025

Exploring vulnerable building blocks in protein-protein interaction networks of breast tumor and adjacent normal tissues

Tumor-adjacent normal tissues (TANTs) histologically and morphologically look normal and are commonly used as a control in patient-based cancer studies. Previous studies have revealed that TANTs present a unique transitional state between healthy normal and tumor tissues. However, there is little or no knowledge about the landscape of protein-protein interactions (PPIs) in TANTs and how they differ from the tumor tissues. Here, we integrate the PPI data mapped onto the differentially expressed genes in TANTs and tumor tissues compared to healthy normal tissues to comprehensively construct and analyze the PPI networks of TANTs and breast tumor tissues (viz., Luminal A, Luminal B, Her2, Basal, and Normal-Like). First, these PPI networks were analyzed using network influence and vulnerability analyses from the NetVA R package. Consequently, our study revealed 134 vulnerable proteins (VPs), 21 vulnerable protein pairs (VPPs), and 94 influential proteins (IPs) commonly shared across all six tissue networks. Further, we identified a set of 34 proteins as common hubs and another set of seven proteins as common bottlenecks across all six tissue networks. Next, these VPs, IPs, hubs, and bottlenecks were investigated for their associations with various diseases, including cancers, and found to share a significant number of well-known cancer-associated proteins, viz., AR, BRCA1, ERBB2, FN1, FOXA1, JUN, MKI67, and NRAS. Thus, by applying network vulnerability, influence, and gene-disease association-based analyses, we suggest lists of known and novel candidates along with their associated protein complexes potentially involved in breast cancer tumorigenesis and present across TANTs and different breast cancer subtypes.

bioinformatics↗

bioRxiv2025

Longitudinal Trajectories of Cognition and Neural Metrics as Predictors of Persistent Distressing Psychotic-Like Experiences Across Middle Childhood and Early Adolescence

ObjectivesPsychotic-like experiences (PLEs) may arise from genetic and environmental risk leading to worsening cognitive and neural metrics over time, which in turn lead to worsening PLEs. Persistence and distress are factors that distinguish more clinically significant PLEs. Analyses used three waves of unique longitudinal Adolescent Brain Cognitive Development Study data (ages 9-13) to test whether changes in cognition and structural neural metrics attenuate associations between genetic and environmental risk with persistent distressing PLEs. MethodsMultigroup univariate latent growth models examined three waves of cognitive metrics and global structural neural metrics separately for three PLE groups: persistent distressing PLEs (n=356), transient distressing PLEs (n=408), and low-level PLEs (n=7901). Models then examined whether changes in cognitive and structural neural metrics over time attenuated associations between genetic liability (i.e., schizophrenia polygenic risk scores/family history) or environmental risk scores (e.g., poverty) and PLE groups. ResultsPersistent distressing PLEs showed greater decreases (i.e., more negative slopes) of cognition and neural metrics over time compared to those in low-level PLE groups. Associations between environmental risk and persistent distressing PLEs were attenuated when accounting for lowered scores over time on cognitive (e.g., picture vocabulary) and to a lesser extent neural (e.g., cortical thickness, volume) metrics. ConclusionsAnalyses provide novel evidence for extant theories that worsening cognition and global structural metrics may partially account for associations between environmental risk with persistent distressing PLEs.

neuroscience↗

bioRxiv2024

Spatio-temporal dynamics of the fibrotic niche in cardiac repair

The heart is one of the least regenerative organs in humans, and ischemic heart disease is the leading cause of death worldwide. Understanding the cellular and molecular processes that occur during cardiac wound healing is an essential prerequisite to reducing health burden and improve cardiac function after myocardial tissue damage. By integrating single-cell RNA-sequencing with imaging-based spatial transcriptomics, we reconstructed the spatio-temporal dynamics of the fibrotic niche after ventricular injury in adult mice. Our analysis reveals dynamic regulation of local cell communication niches over time. We identified interactions that regulate cardiac repair, including fibroblast proliferation silencing by Trem2high macrophages that prevents excessive fibrosis. Moreover, we discovered a rare population of dedifferentiating cardiomyocytes during early post-lesion stages, which was sustained by signals from myeloid and lymphoid cells. Culturing non-regenerative mouse cardiomyocytes or human heart tissue with these niche factors reactivated progenitor gene expression and cell cycle activity. In summary, this spatio-temporal cell type atlas provides valuable insights into the heterocellular interactions that control cardiac repair. HighlightsO_LIscRNA-seq and in situ sequencing reveal spatio-temporal dynamics of heart repair C_LIO_LILocal heterocellular communication niches coordinate overall wound response C_LIO_LIFibroblast cell cycle silencing by Trem2high macrophages suppresses excessive fibrosis C_LIO_LICardiomyocyte plasticity is promoted by myeloid and lymphoid cells C_LI

systems biology↗

bioRxiv2024

NiCo Identifies Extrinsic Drivers of Cell State Modulation by Niche Covariation Analysis

Cell states are modulated by intrinsic driving forces such as gene expression noise and extrinsic signals from the tissue microenvironment. The distinction between intrinsic and extrinsic cell state determinants is essential for understanding the regulation of cell fate in tissues during development, homeostasis and disease. The rapidly growing availability of single-cell resolution spatial transcriptomics makes it possible to meet this challenge. However, available computational methods to infer topological tissue domains, spatially variable gene expression, or ligand-receptor interactions are limited in capturing cell state changes driven by crosstalk between individual cell types within the same niche. We present NiCo, a computational framework for integrating single-cell resolution spatial transcriptomics with matched single-cell RNA-sequencing reference data to infer the influence of the spatial niche on the cell state. By applying NiCo to mouse embryogenesis, adult small intestine and liver data, we demonstrate the capacity to predict novel niche interactions that govern cell state variation underlying tissue development and homeostasis. In particular, NiCo predicts a feedback mechanism between Kupffer cells and neighboring stellate cells limiting stellate cell activation in the normal liver. NiCo provides a powerful tool to elucidate tissue architecture and to identify drivers of cellular states in local niches.

bioinformatics↗

bioRxiv2024

Integrated Single-Cell Multiomic Profiling of Caudate Nucleus Suggests Key Mechanisms in Alcohol Use Disorder

Alcohol use disorder (AUD) induces complex transcriptional and regulatory changes across multiple brain regions including the caudate nucleus, which remains understudied. Using paired single-nucleus RNA-seq and ATAC-seq on caudate samples from 143 human postmortem brains, including 74 with AUD, we identified 17 distinct cell types. We found that a significant portion of the alcohol-induced changes in gene expression occurred through altered chromatin accessibility. Notably, we identified novel transcriptional and chromatin accessibility differences in medium spiny neurons, impacting pathways such as RNA metabolism and immune response. A small cluster of D1/D2 hybrid neurons showed distinct differences, suggesting a unique role in AUD. Microglia exhibited distinct activation states deviating from classical M1/M2 designations, and astrocytes entered a reactive state partially regulated by JUND, affecting glutamatergic synapse pathways. Oligodendrocyte dysregulation, driven in part by OLIG2, was linked to demyelination and increased TGF-{beta}1 signaling from microglia and astrocytes. We also observed increased microglia-astrocyte communication via the IL-1{beta} pathway. Leveraging our multiomic data, we performed cell type-specific expression quantitative trait loci analysis, integrating that with public genome-wide association studies to identify AUD risk genes such as ADAL and PPP2R3C, providing a direct link between genetic variants, chromatin accessibility, and gene expression in AUD. These findings not only provide new insights into the genetic and cellular mechanisms in the caudate related to AUD but also demonstrate the broader utility of large-scale multiomic studies in uncovering complex gene regulation across diverse cell types, which has implications beyond the substance use field.

neuroscience↗

bioRxiv2024

Biological changes, political ideology, and scientific communication shape human perceptions of pollen seasons

Climate change is changing the timing and intensity of pollen seasons, thereby increasing human exposure to allergenic pollen. Climate-driven changes in pollen seasons present a unique opportunity to craft messaging aimed at communicating climate change impacts on public health through changes in the biological systems. However, it is unclear how pollen seasons are experienced and understood by the public, including how well we detect pollen seasons or what factors we view as responsible for changes in pollen seasons. Here, we use social media data in the United States from 2012 to 2022 to assess public perceptions of pollen seasons at large spatiotemporal scales. We show that pollen seasons detected by social media (Twitter) users align well with natural pollen seasons. Attribution of changing pollen seasons, however, varies based on political ideology: liberal users, compared to conservative users, are more likely to attribute changing pollen seasons to climate change. Mass media and scientific experts play a key role in communicating how climate change drives changing pollen seasons. Our findings reveal how changes in biological systems, political ideology, and scientific communications collectively shape public perceptions of pollen seasons under climate change. Our findings constitute a step towards more effective climate change impact communication and public health intervention design.

scientific communication and education↗

bioRxiv2024

Hierarchical Bayesian inference to model continuous phenotypical progression in Alzheimer's Disease

Throughout an organisms life, a multitude of complex and interdependent biological systems transition through biophysical processes that serve as indicators of the underlying biological states. Inferring these latent, unobserved states is a goal of modern biology and neuroscience. However, in many experimental setups, we can at best obtain discrete snapshots of the system at different times and for different individuals. This challenge is particularly relevant in the study of Alzheimers Disease (AD) progression, where we observe the aggregation of pathology in brain donors, but the underlying disease state is unknown. This paper proposes a biophysically motivated Bayesian framework (B-BIND: Biophysical Bayesian Inference for Neurode-generative Dynamics), where the disease state is modeled and continuously inferred from observed quantifications of multiple AD pathological proteins. Inspired by biophysical models, we describe pathological burden as an exponential process. The progression of AD is modeled by assigning a latent score, termed pseudotime, to each pathological state, creating a pseudotemporal order of donors based on their pathological burden. We study the theoretical properties of the model using linearization to reveal convergence and identifiability properties. We provide Markov chain Monte Carlo estimation algorithms, illustrating the effectiveness of our approach with multiple simulation studies across various data conditions. Applying this methodology to data from the Seattle Alzheimers Disease Brain Cell Atlas, we infer the pseudotime ordering of donors. Finally, we analyze the information within each pathological feature to refine the model, focusing on the most informative pathologies. This framework lays the groundwork for continuous pseudotime modeling in the analysis of neurodegenerative diseases.

neuroscience↗