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Imaging Mass Cytometry (IMC) is an emerging multiplexed imaging technology for analyzing complex microenvironments using more than 40 molecularly-specific channels. However, this modality has unique data processing requirements, particularly for patient tissue specimens where signal-to-noise ratios for markers can be low, despite optimization, and pixel intensity artifacts can deteriorate image quality and downstream analysis. Here we demonstrate an automated content-aware pipeline, IMC-Denoise, to restore IMC images deploying a differential intensity map-based restoration (DIMR) algorithm for removing hot pixels and a self-supervised deep learning algorithm for shot noise image filtering (DeepSNiF). IMC-Denoise outperforms existing methods for adaptive hot pixel and background noise removal, with significant image quality improvement in modeled data and datasets from multiple pathologies. This includes in technically challenging human bone marrow; we achieve noise level reduction of 87% for a 5.6-fold higher contrast-to-noise ratio, and more accurate background noise removal with approximately 2 × improved F1 score. Our approach enhances manual gating and automated phenotyping with cell-scale downstream analyses. Verified by manual annotations, spatial and density analysis for targeted cell groups reveal subtle but significant differences of cell populations in diseased bone marrow. We anticipate that IMC-Denoise will provide similar benefits across mass cytometric applications to more deeply characterize complex tissue microenvironments. Multiplexed imaging technologies can reveal the complex cellular and molecular profiles of tissue. Here, the authors develop and implement a denoising pipeline to significantly enhance imaging mass cytometry quality and improve single-cell analyses.

Tooth replacement rate can be calculated in extinct animals by counting incremental lines of deposition in tooth dentin. Calculating this rate in several taxa allows for the study of the evolution of tooth replacement rate. Sauropod dinosaurs, the largest terrestrial animals that ever evolved, exhibited a diversity of tooth sizes and shapes, but little is known about their tooth replacement rates. We present tooth replacement rate, formation time, crown volume, total dentition volume, and enamel thickness for two coexisting but distantly related and morphologically disparate sauropod dinosaurs Camarasaurus and Diplodocus. Individual tooth formation time was determined by counting daily incremental lines in dentin. Tooth replacement rate is calculated as the difference between the number of days recorded in successive replacement teeth. Each tooth family in Camarasaurus has a maximum of three replacement teeth, whereas each Diplodocus tooth family has up to five. Tooth formation times are about 1.7 times longer in Camarasaurus than in Diplodocus (315 vs. 185 days). Average tooth replacement rate in Camarasaurus is about one tooth every 62 days versus about one tooth every 35 days in Diplodocus. Despite slower tooth replacement rates in Camarasaurus, the volumetric rate of Camarasaurus tooth replacement is 10 times faster than in Diplodocus because of its substantially greater tooth volumes. A novel method to estimate replacement rate was developed and applied to several other sauropodomorphs that we were not able to thin section. Differences in tooth replacement rate among sauropodomorphs likely reflect disparate feeding strategies and/or food choices, which would have facilitated the coexistence of these gigantic herbivores in one ecosystem. Early neosauropods are characterized by high tooth replacement rates (despite their large tooth size), and derived titanosaurs and diplodocoids independently evolved the highest known tooth replacement rates among archosaurs.

Introduction Myeloid malignancies, including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN), exhibit overlapping pathophysiology. Chronic MPNs can transform into secondary AML (sAML), which is associated with poor prognosis and limited treatment options. However, the process and prognostic significance of leukemic transformation remain incompletely understood. Method Through a two-sample bidirectional Mendelian randomization (MR) analysis, we showed that genetic liability to MPN significantly predicts the risk of developing AML, establishing MPN as the precursor to leukemia. To identify mediators of this risk, we integrated population-level plasma proteomics data, identifying 55 proteins associated with MPN. Upon integrative analysis with the BEAT-AML cohort, we developed a prognostic proteogenomic gene signature, showing that higher expression of CDCP1, CRISP3, and DCXR, alongside lower MPO levels, correlates with worse AML outcomes. We further performed pharmacogenomic analysis to identify vulnerability to PI3K/AKT/mTOR signaling pathway inhibition in high-risk AML. In vitro and in vivo experiments validated the efficacy of mTOR inhibition in myeloid malignancies. Results This gene signature effectively stratified patients by risk, with significant survival differences across the BEAT-AML and TCGA-LAML cohorts, and revealed immune alterations in high-risk groups, including elevated monocyte prevalence and cytokine signaling activity. Single-cell RNA sequencing (scRNA-seq) further suggested enrichment of these genes in progenitor cells and AML blasts. Drug sensitivity predictions suggested that high-risk AML patients may be particularly responsive to PI3K/AKT/mTOR signaling pathway inhibitors. Consistently, we observed upregulation of the genes in cell line models harboring MPN and AML mutations, which was suppressible via dual PI3K/mTOR inhibitor omipalisib. The efficiency of PI3K/mTOR inhibition in myeloid malignancies was further corroborated by results from multiple in vivo models. Conclusion Together, our findings revealed shared molecular features across MPN and AML, identified a prognostic gene signature for risk stratification, and provided rationale for PI3K/mTOR inhibition as a promising therapeutic strategy in myeloid malignancies.

Above-ground thermonuclear weapons testing from 1952 through 1962 nearly doubled the concentration of radiocarbon (¹⁴C) in the atmosphere. As a result, organic material formed during or after this period may be radiocarbon-dated using the abrupt rise and steady fall of the atmospheric ¹⁴C concentration known as the bomb-curve. We test the accuracy of accelerator mass spectrometry radiocarbon dating of 29 herbivore and plant tissues collected on known dates between 1905 and 2008 in East Africa. Herbivore samples include teeth, tusks, soft tissue, hair, and horn. Tissues formed after 1955 are dated to within 0.3–1.3 y of formation, depending on the tissue type, whereas tissues older than ca. 1955 have high age uncertainties (>17 y) due to the Suess effect. ¹⁴C dating of tissues has applications to stable isotope (paleo)ecology and wildlife forensics. We use data from 41 additional samples to determine growth rates of tusks, molars, and hair, which improve interpretations of serial stable isotope data for (paleo)ecological studies. ¹⁴C dating can also be used to calculate the time interval represented in periodic histological structures in dental tissues (i.e., perikymata), which in turn may be used as chronometers in fossil teeth. Bomb-curve ¹⁴C dating of confiscated animal tissues (e.g., ivory statues) can be used to determine whether trade of the item is legal, because many Convention of International Trade of Endangered Species restrictions are based on the age of the tissue, and thus can serve as a powerful forensic tool to combat illegal trade in animal parts.

Pleistocene glacial-interglacial cycles are correlated with dramatic temperature oscillations. Examining how species responded to these natural fluctuations can provide valuable insights into the impacts of present-day anthropogenic climate change. Here we present a phylogeographic study of the extinct American mastodon ( Mammut americanum ), based on 35 complete mitochondrial genomes. These data reveal the presence of multiple lineages within this species, including two distinct clades from eastern Beringia. Our molecular date estimates suggest that these clades arose at different times, supporting a pattern of repeated northern expansion and local extirpation in response to glacial cycling. Consistent with this hypothesis, we also note lower levels of genetic diversity among northern mastodons than in endemic clades south of the continental ice sheets. The results of our study highlight the complex relationships between population dispersals and climate change, and can provide testable hypotheses for extant species expected to experience substantial biogeographic impacts from rising temperatures. Pleistocene population dynamics can inform the consequences of current climate change. This phylogeography of 35 complete American mastodon mitochondrial genomes suggests distinct lineages in this species repeatedly expanded northwards and then went locally extinct in response to glacial cycles.

Myeloid malignancies are heterogenous disorders characterized by distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. Here, we establish a comprehensive transcriptional atlas across the spectrum of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing of 158 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes. Supported by mass cytometry (CyTOF) profiling, we reveal aberrant networks of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation. Combining ATAC-Seq, CUT&Tag, RNA-seq, and CyTOF, we demonstrate that targeting of ribosomal protein S6 kinase A1 (RSK1) suppresses NFκB activation and diminishes pro-inflammatory mediators including tumor necrosis factor (TNF) associated with MPN disease severity and transformation. We further evaluate a therapeutic approach utilizing a first-in-class RSK inhibitor, PMD-026, currently in Phase 2 development for breast cancer, for use in myeloid malignancies. Treatment with PMD-026 suppressed disease burden across seven syngeneic and patient-derived xenograft leukemia mouse models spanning the spectrum of driver and disease-modifying mutations. These findings uncover a therapeutic avenue for a conserved dependency across MPN and sAML. Secondary acute myeloid leukemias (sAMLs) evolving from myeloproliferative neoplasms (MPNs) associate with poor prognosis. Here authors identify RSK1 as a vulnerability for MPN and sAML and show the efficacy of a first-in-class RSK inhibitor, PMD-026, against these types of myeloid malignancies.

Under harsh Pleistocene climates, migration and other forms of seasonally patterned landscape use were likely critical for reproductive success of mastodons (Mammut americanum) and other megafauna. However, little is known about how their geographic ranges and mobility fluctuated seasonally or changed with sexual maturity. We used a spatially explicit movement model that coupled strontium and oxygen isotopes from two serially sampled intervals (5+ adolescent years and 3+ adult years) in a male mastodon tusk to test for changes in landscape use associated with maturation and reproductive phenology. The mastodon’s early adolescent home range was geographically restricted, with no evidence of seasonal preferences. Following inferred separation from the matriarchal herd (starting age 12 y), the adolescent male’s mobility increased as landscape use expanded away from his natal home range (likely central Indiana). As an adult, the mastodon’s monthly movements increased further. Landscape use also became seasonally structured, with some areas, including northeast Indiana, used only during the inferred mastodon mating season (spring/summer). The mastodon died in this area (>150 km from his core, nonsummer range) after sustaining a craniofacial injury consistent with a fatal blow from a competing male’s tusk during a battle over access to mates. Northeast Indiana was likely a preferred mating area for this individual and may have been regionally significant for late Pleistocene mastodons. Similarities between mammutids and elephantids in herd structure, tusk dimorphism, tusk function, and the geographic component of male maturation indicate that these traits were likely inherited from a common ancestor.

Evidence of mastodon bone modifications for marrow extraction and/or tool production, found in the presence of hammerstones and anvils that showed use-wear and impact marks, suggest the presence of Homo in North America around 130 thousand years ago. America's oldest human activity Around 130,000 years ago, a mastodon died near what is now San Diego, California. Although this seems uncontroversial, Thomas Deméré and colleagues present evidence that the carcass had been modified by human beings. Stone hammers and anvils were found alongside mammoth bones and teeth that show signs of having been broken by percussion, presumably to extract bone marrow. Dating the site has been problematic because the bones preserved too little collagen for radiocarbon dating, and optically stimulated luminescence dating put the age at over 60,000–70,000 years. Dates based on the decay of uranium, constrained by the movement of uranium between the environment and the bone, now give an age of around 130,000 years. If confirmed, this would extend tenfold the time that human beings are known to have been present in the Americas and predate the time that modern humans are thought to have first left Africa. The identity of the hominin species—if any—remains unknown. The earliest dispersal of humans into North America is a contentious subject, and proposed early sites are required to meet the following criteria for acceptance: (1) archaeological evidence is found in a clearly defined and undisturbed geologic context; (2) age is determined by reliable radiometric dating; (3) multiple lines of evidence from interdisciplinary studies provide consistent results; and (4) unquestionable artefacts are found in primary context 1 , 2 . Here we describe the Cerutti Mastodon (CM) site, an archaeological site from the early late Pleistocene epoch, where in situ hammerstones and stone anvils occur in spatio-temporal association with fragmentary remains of a single mastodon ( Mammut americanum ). The CM site contains spiral-fractured bone and molar fragments, indicating that breakage occured while fresh. Several of these fragments also preserve evidence of percussion. The occurrence and distribution of bone, molar and stone refits suggest that breakage occurred at the site of burial. Five large cobbles (hammerstones and anvils) in the CM bone bed display use-wear and impact marks, and are hydraulically anomalous relative to the low-energy context of the enclosing sandy silt stratum. 230 Th/U radiometric analysis of multiple bone specimens using diffusion–adsorption–decay dating models indicates a burial date of 130.7 ± 9.4 thousand years ago. These findings confirm the presence of an unidentified species of Homo at the CM site during the last interglacial period (MIS 5e; early late Pleistocene), indicating that humans with manual dexterity and the experiential knowledge to use hammerstones and anvils processed mastodon limb bones for marrow extraction and/or raw material for tool production. Systematic proboscidean bone reduction, evident at the CM site, fits within a broader pattern of Palaeolithic bone percussion technology in Africa 3 , 4 , 5 , 6 , Eurasia 7 , 8 , 9 and North America 10 , 11 , 12 . The CM site is, to our knowledge, the oldest in situ , well-documented archaeological site in North America and, as such, substantially revises the timing of arrival of Homo into the Americas.

Myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed single-cell RNA sequencing on serial MPN and sAML patient stem and progenitor cells, identifying aberrantly increased expression of DUSP6 underlying disease transformation. Pharmacologic dual-specificity phosphatase (DUSP)6 targeting led to inhibition of S6 and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling while also reducing inflammatory cytokine production. DUSP6 perturbation further inhibited ribosomal S6 kinase (RSK)1, which we identified as a second indispensable candidate associated with poor clinical outcome. Ectopic expression of DUSP6 mediated JAK2-inhibitor resistance and exacerbated disease severity in patient-derived xenograft (PDX) models. Contrastingly, DUSP6 inhibition potently suppressed disease development across Jak2 and MPL MPN mouse models and sAML PDXs without inducing toxicity in healthy controls. These findings underscore DUSP6 in driving disease transformation and highlight the DUSP6-RSK1 axis as a vulnerable, druggable pathway in myeloid malignancies.

Probabilistic approaches to phylogenetic inference have recently gained traction in paleontological studies. Because they directly model processes of evolutionary change, probabilistic methods facilitate a deeper assessment of variability in evolutionary patterns by weighing evidence for competing models. Although phylogenetic methods used in paleontological studies have generally assumed that evolution proceeds by splitting cladogenesis, extensions to previous models help explore the potential for morphological and temporal data to provide differential support for contrasting modes of evolutionary divergence. Recent methodological developments have integrated ancestral relationships into probabilistic phylogenetic methods. These new approaches rely on parameter-rich models and sophisticated inferential methods, potentially obscuring the respective contributions of data and models. In this study, we describe a simple likelihoodist approach that combines probabilistic models of morphological evolution and fossil preservation to reconstruct both cladogenetic and anagenetic relationships. By applying this approach to a data set of fossil hominins, we demonstrate the capability of existing models to unveil evidence for anagenesis presented by morphological and temporal data. This evidence was previously recognized by qualitative assessments, but largely ignored by quantitative phylogenetic analyses. For example, we find support for directly ancestral relationships in multiple lineages: Sahelanthropus is ancestral to later hominins; Australopithecus anamensis is ancestral to Australopithecus afarensis; Australopithecus garhi is ancestral to Homo; Homo antecessor is ancestral to Homo heidelbergensis, which in turn is ancestral to both Homo sapiens and Homo neanderthalensis. By accommodating direct ancestry in phylogenetics, quantitative results align more closely with previous qualitative expectations.