In addition, we observed a phenotypic, transcriptomic, and functional skewing towards a M1-like phenotype.Overall, we introduce CD137 as a positive immune checkpoint on human monocytes/macrophages, which can have therapeutic implications especially in view of synergistic effects when combining CD137 agonists with tumor-targeting antibodies.Hematopoiesis is hierarchical, and it has been postulated that acute myeloid leukemia (AML) is organized similarly with leukemia stem cells (LSCs) residing at the apex. Limited cells acquired by fluorescence activated cell sorting in tandem with targeted amplicon-based sequencing (LC-FACSeq) enables identification of mutations in small subpopulations of cells, such as LSCs. Leveraging this, we studied clonal compositions of immunophenotypically-defined compartments in AML through genomic and functional analyses at diagnosis, remission and relapse in 88 AML patients. Mutations involving DNA methylation pathways, transcription factors and spliceosomal machinery did not differ across compartments, while signaling pathway mutations were less frequent in putative LSCs. We also provide insights into TP53-mutated AML by demonstrating stepwise acquisition of mutations beginning from the preleukemic hematopoietic stem cell stage. In 10 analyzed cases, acquisition of additional mutations and del(17p) led to genetic and functional heterogeneity within the LSC pool with subclones harboring varying degrees of clonogenic potential. Finally, we use LC-FACSeq to track clonal evolution in serial samples, which can also be a powerful tool to direct targeted therapy against measurable residual disease. Therefore, studying clinically significant small subpopulations of cells can improve our understanding of AML biology and offers advantages over bulk sequencing to monitor the evolution of disease.Earthworm activity modifies soil structure and promotes important hydrological ecosystem functions for agricultural systems. Earthworms use their flexible hydroskeleton to burrow and expand biopores. Hence, their activity is constrained by soil hydromechanical conditions that permit deformation at earthworm’s maximal hydroskeletal pressure (≈200kPa). selleck chemicals A mechanistic biophysical model is developed here to link the biomechanical limits of earthworm burrowing with soil moisture and texture to predict soil conditions that permit bioturbation across biomes. We include additional constraints that exclude earthworm activity such as freezing temperatures, low soil pH, and high sand content to develop the first predictive global map of earthworm habitats in good agreement with observed earthworm occurrence patterns. Earthworm activity is strongly constrained by seasonal dynamics that vary across latitudes largely due to soil hydromechanical status. The mechanistic model delineates the potential for earthworm migration via connectivity of hospitable sites and highlights regions sensitive to climate.Social discrimination in rats requires activation of the intrinsic bulbar vasopressin system, but it is unclear how this system comes into operation, as olfactory nerve stimulation primarily inhibits bulbar vasopressin cells (VPCs). Here we show that stimulation with a conspecific can activate bulbar VPCs, indicating that VPC activation depends on more than olfactory cues during social interaction. A series of in vitro electrophysiology, pharmacology and immunohistochemistry experiments implies that acetylcholine, probably originating from centrifugal projections, can enable olfactory nerve-evoked action potentials in VPCs. Finally, cholinergic activation of the vasopressin system contributes to vasopressin-dependent social discrimination, since recognition of a known rat was blocked by bulbar infusion of the muscarinic acetylcholine receptor antagonist atropine and rescued by additional bulbar application of vasopressin. Thus, our results implicate that top-down cholinergic modulation of bulbar VPC activity is involved in social discrimination in rats.Understanding and treating heterogeneous brain disorders requires specialized techniques spanning genetics, proteomics, and neuroimaging. Designed to meet this need, NeuroPM-box is a user-friendly, open-access, multi-tool cross-platform software capable of characterizing multiscale and multifactorial neuropathological mechanisms. Using advanced analytical modeling for molecular, histopathological, brain-imaging and/or clinical evaluations, this framework has multiple applications, validated here with synthetic (N > 2900), in-vivo (N = 911) and post-mortem (N = 736) neurodegenerative data, and including the ability to characterize (i) the series of sequential states (genetic, histopathological, imaging or clinical alterations) covering decades of disease progression, (ii) concurrent intra-brain spreading of pathological factors (e.g., amyloid, tau and alpha-synuclein proteins), (iii) synergistic interactions between multiple biological factors (e.g., toxic tau effects on brain atrophy), and (iv) biologically-defined patient stratification based on disease heterogeneity and/or therapeutic needs. This freely available toolbox ( neuropm-lab.com/neuropm-box.html ) could contribute significantly to a better understanding of complex brain processes and accelerating the implementation of Precision Medicine in Neurology.It is unclear why medulloblastoma patients receiving similar treatments experience different outcomes. Transcriptomic profiling identified subgroups with different prognoses, but in each subgroup, individuals remain at risk of incurable recurrence. To investigate why similar-appearing tumors produce variable outcomes, we analyzed medulloblastomas triggered in transgenic mice by a common driver mutation expressed at different points in brain development. We genetically engineered mice to express oncogenic SmoM2, starting in multipotent glio-neuronal stem cells, or committed neural progenitors. Both groups developed medulloblastomas with similar transcriptomic profiles. We compared medulloblastoma progression, radiosensitivity, and cellular heterogeneity, determined by single-cell transcriptomic analysis (scRNA-seq). Stem cell-triggered medulloblastomas progressed faster, contained more OLIG2-expressing stem-like cells, and consistently showed radioresistance. In contrast, progenitor-triggered MBs progressed slower, down-regulated stem-like cells and were curable with radiation.