Biology subjects

Bansal, S.

Publications and source records attributed to Bansal, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Estimating spatially adjusted temperature-dependent time-varying reproduction numbers for vector-borne diseases

Estimating the effective reproduction number is crucial for understanding and managing infectious disease outbreaks. For vector-borne diseases like dengue, transmission depends on environmental and spatial conditions: temperature affects the extrinsic incubation period in mosquitoes, altering transmission timing, while spatial proximity can lead to clusters of transmission. We integrated a temperature-dependent (TD) generation time (GT) distribution and a spatial decay function weighting transmission likelihood by distance into the Wallinga & Teunis estimation framework. Simulations compared scenarios where the true generation time for spatially adjusted disease cases were TD or temperature independent (TI), versus their corresponding model assumptions. Daily reproduction numbers (Rt) estimated were evaluated via percent error against true values. We found error to be predominantly driven by variance rather than bias, indicating that stochastic uncertainty in infector assignment was the primary driver of inaccuracies rather than systematic model miscalibration. Assuming a spatial weighting function assigning higher probabilities of transmission to geographically close infector-infectee pairs (Gaussian spatial decay) percent errors measuring deviation between estimated and true Rt outperformed those of alternative spatial kernels. Mis-specifying temperature-dependence under a Gaussian spatial kernel yielded higher errors when the ground truth was TD (16-38% vs 36-58% deviation), and similar errors when it was TI (32-52% vs 35-56% deviation), indicating limited sensitivity to temperature dependence when it was not present in the underlying transmission process. Application to dengue case data in Singapore showed that spatially adjusted models produced more variable Rt trajectories than time-series smoothing approaches, with Gaussian decay yielding more stable estimates than exponential decay and the TD model producing modest refinements, suggesting that explicitly modeling spatial heterogeneity and TD transmission dynamics increases responsiveness to even fluctuations in case counts. Our framework is robust across climates, shown by simulations using a broader temperature range, and suggests a useful application in retrospective analyses.

ecology↗

bioRxiv2026

Targeting CD73-A2aR-Mediated Adenosine Signaling at the Tumor-Immune Interface Overcomes Radioresistance

BackgroundRadiotherapy efficacy is constrained by an immunosuppressive tumor microenvironment (TME) enriched in extracellular adenosine and suppressive myeloid populations that attenuate cytotoxic T-cell responses. The CD73-adenosine-A2a/A2b receptor axis represents a key metabolic immune checkpoint; however, the relative contributions of tumor cell-intrinsic versus host-derived adenosine signaling to radiotherapy response remain incompletely defined. MethodsUsing orthotopic murine breast carcinoma models, we interrogated radiation-induced adenosine dynamics and downstream immune remodeling through quantitative adenosine measurements, bulk RNA sequencing, and multiparameter flow cytometry. Genetically engineered models were employed to dissect the roles of tumor-derived CD73 and host A2a/A2b receptors in regulating radiosensitivity. Therapeutic studies evaluated combinatorial targeting of CD73 and A2a/A2b receptors with radiotherapy and anti-PD-1, followed by comprehensive immune profiling in breast carcinomas. ResultsTumor cell-intrinsic CD73 and host A2A receptor signaling cooperatively drive radioresistance and tumor progression. Radiotherapy induces a rapid surge in intratumoral adenosine, triggering transcriptional and cellular programs consistent with myeloid-mediated immunosuppression and lymphocyte dysfunction. Although T-cell infiltration increases at later time point post-irradiation, effector function remains constrained. Pharmacologic inhibition of CD73 and A2a/A2b receptors partially restores T-cell functionality but is insufficient for durable tumor control as monotherapy. In contrast, concurrent blockade of adenosine signaling during radiotherapy, followed by adjuvant PD-1 inhibition, amplifies adaptive antitumor immunity and significantly enhances tumor control. ConclusionsThese findings define a mechanistic link between radiation-induced adenosine signaling and immune dysfunction in the TME. Targeting the CD73-A2a/A2b axis in combination with radiotherapy and checkpoint blockade represents a rational strategy to overcome radioresistance and improve antitumor immunity. STATEMENT OF SIGNIFICANCEThe tumor and immune cell contributions to adenosine signaling play a central role in shaping the therapeutic outcomes of tumor irradiation. Therapeutic targeting of the adenosine signaling axis improves radiosensitivity and efficacy of checkpoint blockade.

cancer biology↗

bioRxiv2025

Fragmented social networks promote complex behavioural contagions over infectious disease spread

Group living and social interactions among animals provide key benefits, such as the exchange of beneficial social information and novel behaviours, but also pose the risk of spreading costly infectious diseases, presenting a social trade-off. While both information and infections spread across social networks, they typically have distinct mechanisms of transmission. Here, we model social information and behaviour spread as a complex contagion governed by a conformist learning rule, while pathogen transmission follows a simple contagion mechanism. Building on theoretical foundations, our study applies computational models to examine how subgroup structure (modularity) influences the spread of these contagions across diverse animal social structures sourced from the Animal Social Network Repository (ASNR). Our findings reveal that high modularity and subgroup structure slow simple contagion spread, whereas complex contagions are less impeded by this fragmentation. Consequently, our results suggest that social networks divided into small groups or subgroups can help balance the competing pressures of acquiring social information and avoiding infectious disease in real-world networks.

ecology↗

bioRxiv2025

Machine Learning Enables Rapid Assessment of Disease Vulnerability in a Threatened Cetacean Population

Cetaceans (whales and dolphins) are important ecosystem sentinels but face growing threats from major disease-related mortality events expected to intensify under climate change. Because both environmental factors (temperature, salinity) and demographics (age, sex) influence health and disease risk, understanding these relationships is essential for effective management. Direct health assessments are challenging in cetaceans, but skin lesions can indicate active infection and tooth-rake marks reflect social stressors that increase transmission risk. Yet, traditional photographic analysis of these indicators is inefficient, creating processing bottlenecks that limit timely evaluation of population health. To address this gap, we applied machine learning to rapidly assess lesions and rake marks in Tamanends bottlenose dolphins (Tursiops erebennus) photographed in the Chesapeake Bay, a known hotspot for disease-related die-offs. This represents the first analysis of environmental and demographic contributions to dolphin health in this region. We found significant negative relationships between lesion prevalence and both temperature and salinity for some lesion types. Adult males also showed higher rake mark coverage than adult females and calves. These patterns suggest dolphins in colder, fresher waters may face elevated disease risk, while adult males may be particularly vulnerable to behavioral stress and related health consequences. Our findings are consistent with prior studies, lending validity to our machine learning models, while also revealing novel patterns of calf and male vulnerability in this threatened population. More broadly, our approach demonstrates the potential of automated image analysis to enable timely, non-invasive health assessments across cetacean populations in an era of rapid global change.

ecology↗

bioRxiv2025

A Biosynthetic Thumb Prosthesis

In cases of severe damage to the extremities, the function and structure of compromised biological tissues must be replaced. If biological reconstruction using autologous tissue is not feasible, amputation and replacement with a synthetic prosthesis is often the next best option. Currently, the synthetic materials available for prostheses are limited, especially in their ability to restore skin sensation. Here we show a biosynthetic prosthesis that combines the versatility of titanium with the rich sensory capabilities of biological skin, to both increase movement and restore sensation to an amputated thumb. The prosthesis recreates opposition pinch by linking motion of the prosthetic joint to that of the residual biological joint. The device is enclosed in neurotized skin from the patients own body, providing natural sensation. We validated the biosynthetic thumbs ability to reproduce opposition pinch on the benchtop and in a cadaver, and showed in vivo viability of the skin interface in an animal model. These results provide a framework for functional reconstruction of amputated digits using a combination of synthetic materials and biological tissues. One Sentence SummaryA prosthetic thumb made up of a titanium mechanism and living skin can restore opposition pinch and touch sensation following thumb amputation.

bioengineering↗

bioRxiv2025

Stress Granules Underlie Acute Myeloid Leukemia Stem Cell Survival and Stress Adaptation

The link between cancer maintenance and an ability to sustain continued growth through stresses conferred by the cancer state itself is growing. However, there are significant gaps in our understanding of how this stress is managed, particularly at the level of cancer initiating cells. Here, we identify proteins comprising the dynamic, stress-adaptive ribonucleoprotein complexes known as stress granules (SG) to be enriched among the factors essential for leukemic stem cell (LSC)-driven leukemic propagation. Focusing on core SG nucleator G3BP1, we dissect the role of SGs in human acute myeloid leukemia (AML), their targetability, and the mechanisms they govern to uncover a novel propensity for AML, and in particular LSC-enriched fractions, to prime the expression of SG components, form SGs with greater fidelity and to be reliant on their establishment and continued integrity for LSC maintenance. We further unveil the transcript and protein interactome of G3BP1 in the AML context and show that consolidated control of innate immune signaling, and apoptosis repression is executed through regional binding specificity of G3BP1 to highly structured 3UTRs and cooperation with the RNA helicase UPF1 to mediate transcript decay in SGs. Altogether our findings advance novel fundamental principles of stress adaptation exploited in AML and LSCs that may extend to other cancers and uncover SGs as a novel axis for therapy development.

cancer biology↗

bioRxiv2024

The extent and drivers of gender and race/ethnicity imbalance in infectious disease dynamics research

Publication practices accumulate to affect credibility and career advancement. Understanding authorship and citation practices is critical to addressing inequities. While citation bias has been demonstrated in several fields, it remains uncharacterized in infectious disease dynamics (IDD), a quantitative, interdisciplinary domain highly visible during the COVID-19 pandemic. We analyze IDD articles and their bibliographies from 2000-2019 using machine-learning algorithms to infer the gender and race/ethnicity of each articles lead and senior author. We examine authorship and citation patterns by gender and racial group across geographic scales, including characterizing the author composition of each articles bibliography relative to the field. Our analysis reveals persistent gender and race imbalances in IDD research. Man-authored and White-authored publications dominate the field, with little progress in racial diversification of US and UK publications over the last two decades. Woman-authored articles have the most representative citation practices but are undercited, especially when women are senior authors. In the US and UK, most citations feature White lead and senior authors, even when citing articles have lead or senior authors of color. These findings underscore the urgent need for more inclusive IDD research practices. We discuss possible mechanisms and solutions to create opportunities for researchers from underrepresented groups.

scientific communication and education↗

bioRxiv2024

Seasonal contact and migration structure mass epidemics and inform outbreak preparedness in bottlenose dolphins

Infectious respiratory diseases have detrimental impacts across wildlife taxa, particularly in marine species. Despite this vulnerability, we lack information on the complex spatial and contact structures of marine populations which reduces our ability to understand disease spread and our preparedness for epidemic response. We leveraged a collated dataset to establish the first data-driven epidemiological model on a cetacean species, the Tamanends bottlenose dolphin (Tursiops erebennus), whose populations are periodically impacted by deadly respiratory disease in the northwest Atlantic. We found their spatial distribution and contact is heterogeneous along the coastline and varies by ecotype, which explains differences in infection burdens observed in past outbreaks. We also determined that outbreaks beginning in northern parts of their habitat during migratory seasons have the highest epidemic risk and that dolphins in North Carolina estuaries would be the best sentinels for disease surveillance. Our mathematical model provides a generalizable, non-invasive tool that takes advantage of routinely collected marine mammal data to mechanistically understand disease transmission and inform disease surveillance tactics for marine sentinels. Our findings highlight the heterogeneities that play a crucial role in shaping the impacts of infectious diseases in wildlife, and how a data-driven understanding of these mechanisms can enhance epidemic preparedness.

ecology↗

bioRxiv2024

Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In our mouse model, hematopoietic Tet2 mutation enhanced immune checkpoint blockade (ICB) response. Enhanced ICB response with Tet2 mutation required phagocytes, CD4 and CD8 T cells. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially induced anti-tumor states and restricted cell states linked to tumor progression. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, lesser exhaustion and decreased regulatory phenotype. Our murine data was clinically relevant, since we found that melanomas from patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, T cell activation, and T cell memory programs. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, our data establishes that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

cancer biology↗

bioRxiv2024

Automated Skin Lesion Detection and Prevalence Estimation in Tamanend's Bottlenose Dolphins

Anthropogenic global change is occurring at alarming rates, leading to increased urgency in the ability to monitor wildlife health in real time. Monitoring sentinel marine species, such as bottlenose dolphins, is particularly important due to extensive anthropogenic modifications to their habitats. The most common non-invasive method of monitoring cetacean health is documentation of skin lesions, often associated with poor health or disease, but the current methodology is inefficient and imprecise. Recent advancements in technology, such as machine learning, can provide researchers with more efficient ecological monitoring methods to address health questions at both the population and the individual levels. Our work develops a machine learning model to classify skin lesions on the understudied Tamanends bottlenose dolphins (Tursiops erebennus) of the Chesapeake Bay, using manual estimates of lesion presence in photographs. We assess the models performance and find that our best model performs with a high mean average precision (65.6%-86.8%), and generally increased accuracy with improved photo quality. We also demonstrate the models ability to address ecological questions across scales by generating model-based estimates of lesion prevalence and testing the effect of gregariousness on health status. At the population level, our model accurately estimates a prevalence of 72.1% spot and 27.3% fringe ring lesions, with a slight underprediction compared to manual estimates (82.2% and 32.1%). On the other hand, we find that individual-level analyses from the model predictions may be more sensitive to data quality, and thus, some individual scale questions may not be feasible to address if data quality is inconsistent. Manually, we do find that lesion presence in individuals suggests a positive relationship between lesion presence and gregariousness. This work demonstrates that object detection models on photographic data are reasonably successful, highly efficient, and provide initial estimates on the health status of understudied populations of bottlenose dolphins.

ecology↗

bioRxiv2024

Hypoxia-Inducible Factor-1 activated by PIM1 assembles a non-canonical transcription complex and resultant regulon that drives progression of JAK2V617F myeloproliferative neoplasms

Hypoxia-inducible factors (HIFs) are master transcriptional regulators, central to cellular survival under limited oxygen (hypoxia) and frequently activated within malignancy. Malignant context affects the role of HIFs within oncogenesis; however, the mechanisms regulating HIF context-specificities are not well characterised. Applying the JAK2V617F (JVF) model of myeloproliferative neoplasms (MPNs), in which HIF-1 is active in normoxia (20% O2), we sought to determine whether the modality of HIF-1 activation directs its function. We identify that HIF-1 is stabilised in JVF cells downstream of STAT1/5 signalling and upregulation of PIM1: PIM1 mediates phosphorylation of HIF-1 (Thr498/Ser500) in JVF cells that inhibits proteasomal degradation. PIM1 inhibition eradicates HIF-1 from JVF cells. Applying a single-input dual-omics output chromatin interactome methodology (DOCIA), we define JVF-specific transcription cofactors and genomic redistribution of HIF-1, and a JVF-HIF-1 regulon in primary haematopoietic stem/progenitor cells. In a cohort of 172 JVF-MPN patients, we observe significant association of the JVF-HIF-1 regulon (but strikingly, not canonical HIF-1 genes) with disease severity, progression, and patient survival. Finally, we identify a core set of JVF-HIF-1 targets significantly associated with spontaneous transformation of MPNs to AML. Our findings identify that HIF-1 activation by the JVF-PIM1 axis substantially alters its function, and that this reprogramming drives MPN disease progression, restoring the potential for targeted therapies that delineate HIF-1 activity co-opted by malignancy from essential roles within physiological oxygen homeostasis. Key PointsO_LIHIF-1 activation via PIM1 in JAK2V617F-MPNs drives non-canonical transcription complex formation/function. C_LIO_LIThe JAK2V617F-HIF-1 regulon drives MPN disease progression, transformation to AML and worse patient outcomes. C_LI

cancer biology↗

bioRxiv2024

Wolbachia incompatible insect technique program optimization over large spatial scales using a process-based model of mosquito metapopulation dynamics

BackgroundWolbachia incompatible insect technique (IIT) programs have been shown in field trials to be highly effective in suppressing populations of mosquitoes that carry diseases such as dengue, chikungunya and Zika. However, the frequent and repeated release of Wolbachia-infected male mosquitoes makes such programs resource-intensive. While the need for optimization is recognized, potential strategies to optimize releases and reduce resource utilization have not been fully explored. MethodsWe developed a process-based model to study the spatial-temporal metapopulation dynamics of mosquitoes in a Wolbachia IIT program, which explicitly incorporates climatic influence in mosquito life-history traits. We then used the model to simulate various scale-down and redistribution strategies to optimize the existing program in Singapore. Specifically, the model was used to study the trade-offs between the intervention efficacy outcomes and resource requirements of various release program strategies, such as the total number of release events and the number of mosquitoes released. ResultsWe found that scaling down releases in existing sites from twice a week to only once a week yielded minimal changes in suppression efficacy (from 91% to 85%), while requiring 45% fewer mosquitoes and release events. Additionally, redistributing mosquitoes from already suppressed areas and releasing them in new areas once a week led to a greater total suppressive efficacy (88% compared to 65%) while also yielding a 16% and 14% reduction in the number of mosquitoes and release events required respectively. ConclusionsBoth scale-down and redistribution strategies can be implemented to significantly reduce program resource requirements without compromising the suppressive efficacy of IIT. These findings will inform planners on ways to optimize existing and future IIT programs, potentially allowing for the wider adoption of this method for mosquito-borne disease control.

ecology↗

bioRxiv2024

FLT3 is genetically essential for ITD-mutated leukemic stem cells but dispensable for human hematopoietic stem cells

Leukemic stem cells (LSCs) fuel acute myeloid leukemia (AML) growth and relapse, but therapies tailored towards eradicating LSCs without harming healthy hematopoietic stem cells (HSCs) are lacking. FLT3 is considered an important therapeutic target due to frequent mutation in AML and association with relapse. However, there has been limited clinical success with FLT3 targeting, suggesting either that FLT3 is not a vulnerability in LSC, or that more potent inhibition is required, a scenario where HSC toxicity could become limiting. We tested these possibilities by ablating FLT3 using CRISPR/Cas9-mediated FLT3 knock-out (FLT3-KO) in human LSCs and HSCs followed by functional xenograft assays. FLT3-KO in LSCs from FLT3-ITD mutated, but not FLT3-WT AMLs, resulted in short-term leukemic grafts of FLT-3-KO edited cells that disappeared by 12 weeks. By contrast, FLT3-KO in HSCs from fetal liver, cord blood and adult bone marrow did not impair multilineage hematopoiesis in primary and secondary xenografts. Our study establishes FLT3 as an ideal therapeutic target where ITD+ LSC are eradicated upon FLT3 deletion, while HSCs are spared. These findings support the development of more potent FLT3-targeting drugs or gene-editing approaches for LSC eradication to improve clinical outcomes. KEY POINTSThe FLT3 gene is essential for ITD-mutated leukemic stem cells (LSCs) to establish and propagate leukemia. Normal human hematopoietic stem cells (HSCs) do not require FLT3 to engraft and sustain hematopoiesis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/601363v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@b77f56org.highwire.dtl.DTLVardef@109011dorg.highwire.dtl.DTLVardef@282e04org.highwire.dtl.DTLVardef@1e51e3b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

White adipose tissue remodeling in Little Brown Myotis (Myotis lucifugus) with white-nose syndrome

White-nose syndrome (WNS) is a fungal wildlife disease of bats that has caused precipitous declines in certain Nearctic bat species. A key driver of mortality is premature exhaustion of fat reserves, primarily white adipose tissue (WAT), that bats rely on to meet their metabolic needs during winter. However, the pathophysiological and metabolic effects of WNS have remained ill-defined. To elucidate metabolic mechanisms associated with WNS mortality, we infected a WNS susceptible species, the Little Brown Myotis (Myotis lucifugus), with Pseudogymnoascus destructans (Pd) and collected WAT biopsies for histology and targeted lipidomics. These results were compared to the WNS-resistant Big Brown Bat (Eptesicus fuscus). A similar distribution in broad lipid class was observed in both species, with [~]60% of total WAT consisting of triacylglycerides (TAGs). We found several baseline differences in WAT chemical composition between species. M. lucifugus WAT had significantly higher levels of measured TAGs ([~]30%). Higher lipid levels in E. fuscus WAT were primarily sphingomyelins and glycerophosphoethanolamines (PEs), along with glycerophospholipids (GPs) dominated by unsaturated or monounsaturated moieties and n-6 (18:2, 20:2, 20:3, 20:4) fatty acids. These differences between M. lucifugus and E. fuscus may indicate dietary differences that lead to differential "fuel" reserves that are available during torpor. Following Pd-infection, we found that perturbation to WAT reserves occurs in M. lucifugus, but not in the resistant E. fuscus. A total of 36 GPs (primarily PEs) were higher in Pd-infected M. lucifugus, indicating perturbation to the WAT structural component. In addition to changes in lipid chemistry, smaller adipocyte sizes and increased extracellular matrix deposition was observed in Pd-infected M. lucifugus. This is the first study to describe WAT lipidomic composition of bats with different susceptibilities to WNS and highlights that recovery from WNS may require repair from adipose remodeling in addition to replenishing depot fat during spring emergence.

biochemistry↗

bioRxiv2024

Human adherent cortical organoids in a multiwell format

In the growing diversity of human iPSC-derived models of brain development, we present here a novel method that exhibits 3D cortical layer formation in a highly reproducible topography of minimal dimensions. The resulting adherent cortical organoids develop by self-organization after seeding frontal cortex patterned iPSC-derived neural progenitor cells in 384-well plates during eight weeks of differentiation. The organoids have stereotypical dimensions of 3 x 3 x 0.2 mm, contain multiple subtypes of neurons, astrocytes and oligodendrocyte lineage cells, and are amenable to extended culture for at least 10 months. Longitudinal imaging revealed morphologically mature dendritic spines, axonal myelination, and robust neuronal activity. Moreover, adherent cortical organoids compare favorably to existing free-floating brain organoid models on the basis of robust reproducibility in obtaining topographically-standardized radial cortical structures and circumventing internal necrosis. Adherent human cortical organoids hold considerable potential for high-throughput drug discovery applications, neurotoxicological screening, and mechanistic pathophysiological studies of brain disorders.

neuroscience↗

bioRxiv2024

Metabolic interactions underpinning high methane fluxes across terrestrial freshwater wetlands

Current estimates of wetland contributions to the global methane budget carry high uncertainty, particularly in accurately predicting emissions from high methane-emitting wetlands. Microorganisms mediate methane cycling, yet knowledge of their conservation across wetlands remains scarce. To address this, we integrated 1,118 16S rRNA amplicon datasets (116 new), 305 metagenomes (20 new) that yielded 4,745 medium and high-quality metagenome assembled genomes (MAGs; 617 new), 133 metatranscriptomes, and annual methane flux data across 9 wetlands to create the Multi-Omics for Understanding Climate Change (MUCC) v2.0.0 database. This new resource was leveraged to link microbiome compositional profiles to encoded functions and emissions, with specific focus on methane-cycling populations and the microbial carbon decomposition networks that fuel them. We identified eight methane-cycling genera that were conserved across wetlands, and deciphered wetland specific metabolic interactions across marshes, revealing low methanogen-methanotroph connectivity in high-emitting wetlands. Methanoregula emerged as a hub methanogen across networks and was a strong predictor of methane flux, demonstrating the potential broad relevance of methylotrophic methanogenesis in these ecosystems. Collectively, our findings illuminate trends between microbial decomposition networks and methane flux and provide an extensive publicly available database to advance future wetland research.

microbiology↗

bioRxiv2023

Precise single-cell transcriptomic mapping of normal and leukemic cell states reveals unconventional lineage priming in acute myeloid leukemia

In acute myeloid leukemia (AML), genetic mutations distort hematopoietic differentiation, resulting in the accumulation of leukemic blasts. Yet, it remains unclear how these mutations intersect with cellular origins and whether they converge upon similar differentiation patterns. Single-cell RNA sequencing (scRNA-seq) has enabled high-resolution mapping of the relationship between leukemia and normal cell states, yet this application is hampered by imprecise reference maps of normal hematopoiesis and small sample sizes among patient cohorts. As a first step we constructed a reference atlas of human bone marrow hematopoiesis from 263,519 single-cell transcriptomes spanning 55 cellular states, that was benchmarked against independent datasets of immunophenotypically pure hematopoietic stem and progenitor cells. Using this reference atlas, we mapped over 1.2 million single-cell transcriptomes spanning 318 AML, mixed phenotype acute leukemia (MPAL), and acute erythroid leukemia (AEL) samples. This large-scale analysis, together with systematic mapping of genotype-to-phenotype associations between driver mutations and differentiation landscapes, revealed convergence of diverse genetic alterations on twelve recurrent patterns of aberrant differentiation in AML. This included unconventional lymphoid and erythroid priming linked to RUNX1 and TP53 mutations, respectively. We also identified non-genetic determinants of AML differentiation such as two subgroups of KMT2A-rearranged AML that differ in the identity of their leukemic stem cells (LSCs), likely reflecting distinct cellular origins. Furthermore, distinct LSC-driven hierarchies can co-exist within individual patients, providing insights into AML evolution. Together, precise mapping of normal and malignant cell states provides a framework for advancing the study and disease classification of hematologic malignancies thereby informing therapy development.

cancer biology↗

bioRxiv2023

Breathing in sync: how a social behavior structures respiratory epidemic risk in bottlenose dolphins

Dolphin morbillivirus has caused mass mortalities in dolphin populations globally. Given their role as ecosystem sentinels, mass mortalities among these populations can be detrimental. Morbillivirus is transmitted through respiratory droplets and occurs when dolphins breathe synchronously, a variable social behavior. To assess the role of variable social behavior on disease risk empirically, we collected behavioral data from two wild bottlenose dolphins populations (Tursiops spp.), developed network models that synthesize transmission contacts, and used an epidemiological model to predict disease consequences. We find that juveniles have more contacts than adults, adult males have more contacts than adult females, and that individuals preferentially contact others in their own demographic group. These patterns translate to higher infection risk for juveniles and adult males, which we support using data from a morbillivirus outbreak. Our work characterizes the impact of bottlenose dolphin social dynamics on infectious disease risk and informs the structure of vulnerability for future epizootics.

ecology↗