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The anterior visceral endoderm (AVE) differs from the surrounding visceral endoderm (VE) in its migratory behavior and ability to restrict primitive streak formation to the opposite side of the mouse embryo. To characterize the molecular bases for the unique properties of the AVE, we combined single-cell RNA sequencing of the VE prior to and during AVE migration with phosphoproteomics, high-resolution live-imaging, and short-term lineage labeling and intervention. This identified the transient nature of the AVE with attenuation of "anteriorizing" gene expression as cells migrate and the emergence of heterogeneities in transcriptional states relative to the AVE's position. Using cell communication analysis, we identified the requirement of semaphorin signaling for normal AVE migration. Lattice light-sheet microscopy showed that Sema6D mutants have abnormalities in basal projections and migration speed. These findings point to a tight coupling between transcriptional state and position of the AVE and identify molecular controllers of AVE migration., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This paper examines the Chicago sociologist William F. Ogburn's (1886-1959) views about technological unemployment, which were intimately connected to his analysis of the social impacts of technological developments and resulting social problems due to cultural lag. We trace the development of his views as seen through his well-known 1922 book, Social Change with Respect to Culture and Original Nature, his important contributions to the President's Research Committee on Social Trends (1933), and his lesser-known pamphlets designed for a broader audience-Living with Machines (1933), You and Machines (1934), and Machines and Tomorrow's World (1938). He used these pamphlets to educate the public about the dangers of new machines and technological unemployment. In doing so, he drew upon sociological analysis in his professional scholarly writings and his long-standing personal interests in social betterment and social reform. Our analysis also calls into question the adequacy of existing scholarship on Ogburn that has emphasized his commitment to a statistical, dispassionate, and "objectivist" approach to social science research. We call for a revised, richer, and more complex view of Ogburn's work and legacy as one of the nation's leading social scientists during the first half of the 20th century., (© 2022 Wiley Periodicals LLC.)

Background: Acute leukemias represent deadly malignancies that require better treatment. As a challenge, treatment is counteracted by a microenvironment protecting dormant leukemia stem cells., Methods: To identify responsible surface proteins, we performed deep proteome profiling on minute numbers of dormant patient-derived xenograft (PDX) leukemia stem cells isolated from mice. Candidates were functionally screened by establishing a comprehensive CRISPR‒Cas9 pipeline in PDX models in vivo., Results: A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as an essential vulnerability required for the survival and growth of different types of acute leukemias in vivo, and reconstitution assays in PDX models confirmed the relevance of its sheddase activity. Of translational importance, molecular or pharmacological targeting of ADAM10 reduced PDX leukemia burden, cell homing to the murine bone marrow and stem cell frequency, and increased leukemia response to conventional chemotherapy in vivo., Conclusions: These findings identify ADAM10 as an attractive therapeutic target for the future treatment of acute leukemias., (© 2023. The Author(s).)

Innate-like T cell populations expressing conserved TCRs play critical roles in immunity through diverse developmentally acquired effector functions. Focusing on the prototypical lineage of invariant natural killer T (iNKT) cells, we sought to dissect the mechanisms and timing of fate decisions and functional effector differentiation. Utilizing induced expression of the semi-invariant NKT cell TCR on double positive thymocytes, an initially highly synchronous wave of iNKT cell development was triggered by brief homogeneous TCR signaling. After reaching a uniform progenitor state characterized by IL-4 production potential and proliferation, effector subsets emerged simultaneously, but then diverged toward different fates. While NKT17 specification was quickly completed, NKT1 cells slowly differentiated and expanded. NKT2 cells resembled maturing progenitors, which gradually diminished in numbers. Thus, iNKT subset diversification occurs in dividing progenitor cells without acute TCR input but utilizes multiple active cytokine signaling pathways. These data imply a two-step model of iNKT effector differentiation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of healthy hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease who were undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variant allele frequencies [VAFs] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF, 1% to 2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%), and ASXL1 (3.5%). CHIP is significantly associated with lower hemoglobin, higher mean corpuscular volume, previous or present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AIDs; multivariable adjusted odds ratio, 6.6; 95% confidence interval, 1.7-30; P = .0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for managing patients with OA and AIDs or mild anemia and question the use of hip bone-derived cells as healthy experimental controls., (© 2021 by The American Society of Hematology.)

Motivation: Intercellular communication plays an essential role in multicellular organisms and several algorithms to analyze it from single-cell transcriptional data have been recently published, but the results are often hard to visualize and interpret., Results: We developed Cell cOmmunication exploration with MUltiplex NETworks (COMUNET), a tool that streamlines the interpretation of the results from cell-cell communication analyses. COMUNET uses multiplex networks to represent and cluster all potential communication patterns between cell types. The algorithm also enables the search for specific patterns of communication and can perform comparative analysis between two biological conditions. To exemplify its use, here we apply COMUNET to investigate cell communication patterns in single-cell transcriptomic datasets from mouse embryos and from an acute myeloid leukemia patient at diagnosis and after treatment., Availability and Implementation: Our algorithm is implemented in an R package available from https://github.com/ScialdoneLab/COMUNET, along with all the code to perform the analyses reported here., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press.)

Background: Acute myeloid leukemia (AML) patients with a high allelic burden of an internal tandem duplication (ITD)-mutated FMS-like Tyrosine Kinase-3 (FLT3) have a dismal outcome. FLT3 ITD triggers the proliferation of the quiescent hematopoietic stem cell (HSC) pool but fails to directly transform HSCs. While the inflammatory transcription factor nuclear factor of activated T-cells 2 (NFAT2, NFATC1) is overexpressed in AML, it is unknown whether it plays a role in FLT3 ITD -induced HSC transformation., Methods: We generated a triple transgenic mouse model, in which tamoxifen-inducible Cre-recombinase targets expression of a constitutively nuclear transcription factor NFATC1 to FLT3 ITD positive HSC. Emerging genotypes were phenotypically, biochemically, and also transcriptionally characterized using RNA sequencing. We also retrospectively analyzed the overall survival of AML patients with different NFATC1 expression status., Results: We find that NFATC1 governs FLT3 ITD -driven precursor cell expansion and transformation, causing a fully penetrant lethal AML. FLT3 ITD /NFATC1-AML is re-transplantable in secondary recipients and shows primary resistance to the FLT3 ITD -kinase inhibitor quizartinib. Mechanistically, NFATC1 rewires FLT3 ITD -dependent signaling output in HSC, involving augmented K-RAS signaling and a selective de novo recruitment of key HSC-transforming signaling pathways such as the Hedgehog- and WNT/B-Catenin signaling pathways. In human AML, NFATC1 overexpression is associated with poor overall survival., Conclusions: NFATC1 expression causes FLT3 ITD -induced transcriptome changes, which are associated with HSC transformation, quizartinib resistance, and a poor prognosis in AML.

Nodamura Virus (NoV) is a nodavirus originally isolated from insects that can replicate in a wide variety of hosts, including mammals. Because of their simplicity and ability to replicate in many diverse hosts, NoV, and the Nodaviridae in general, provide a unique window into the evolution of viruses and host-virus interactions. Here we show that the C-terminus of the viral polymerase exhibits extreme structural and evolutionary flexibility. Indeed, fewer than 10 positively charged residues from the 110 amino acid-long C-terminal region of protein A are required to support RNA1 replication. Strikingly, this region can be replaced by completely unrelated protein sequences, yet still produce a functional replicase. Structure predictions, as well as evolutionary and mutational analyses, indicate that the C-terminal region is structurally disordered and evolves faster than the rest of the viral proteome. Thus, the function of an intrinsically unstructured protein region can be independent of most of its primary sequence, conferring both functional robustness and sequence plasticity on the protein. Our results provide an experimental explanation for rapid evolution of unstructured regions, which enables an effective exploration of the sequence space, and likely function space, available to the virus.

During the 1960s, a growing contingent of left-leaning voices claimed that the social sciences suffered mistreatment and undue constraints within the natural science-dominated federal science establishment. According to these critics, the entrenched scientific pecking order in Washington had an unreasonable commitment to the unity of the sciences, which reinforced unacceptable inequalities between the social and the natural sciences. The most important political figure who advanced this critique, together with a substantial legislative proposal for reform, was the Oklahoma Democratic Senator Fred Harris. Yet histories of science and social science have told us surprisingly little about Harris. Moreover, existing accounts of his effort to create a National Social Science Foundation have misunderstood crucial features of this story. This essay argues that Harris's NSSF proposal developed into a robust, historically unique, and increasingly critical liberal challenge to the post-World War II federal science establishment's treatment of the social sciences as "second-class citizens."

This article proposes that the postwar National Science Foundation (NSF) debate constituted a critical, transitional episode in American social science and partisan politics. I show that by responding to powerful conservative critics in the scientific and political communities, the Social Science Research Council's (SSRC's) leading scholars (re)asserted a contested scientistic strategy-to advance the social sciences by following the natural sciences. Further, I reconstruct a wider and longer framework of analysis in order to recover central challenges to the scientistic strategy raised by prominent liberal scholars who rejected the associated commitments to value neutrality and disinterested professionalism. In developing this framework for understanding the contrasting fortunes of each strategy, this article argues that the NSF debate has a deep historical significance-for the social sciences, for American liberalism, and for the nation., (Copyright 2004 Wiley Periodicals, Inc.)