Humanized hemato-lymphoid system mice Theocharides, Alexandre P A; Rongvaux, Anthony; Fritsch, Kristin ...
Haematologica
101, Številka:
1
Journal Article
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Over the last decades, incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system, have been developed and now represent an important ...research tool in the field. The most significant contributions made by means of humanized mice are the identification of normal and leukemic hematopoietic stem cells, the characterization of the human hematopoietic hierarchy, and their use as preclinical therapy models for malignant hematopoietic disorders. Successful xenotransplantation depends on three major factors: tolerance by the mouse host, correct spatial location, and appropriately cross-reactive support and interaction factors such as cytokines and major histocompatibility complex molecules. Each of these can be modified. Experimental approaches include the genetic modification of mice to faithfully express human support factors as non-cross-reactive cytokines, to create free niche space, the co-transplantation of human mesenchymal stem cells, the implantation of humanized ossicles or other stroma, and the implantation of human thymic tissue. Besides the source of hematopoietic cells, the conditioning regimen and the route of transplantation also significantly affect human hematopoietic development in vivo. We review here the achievements, most recent developments, and the remaining challenges in the generation of pre-clinically-predictive systems for human hematology and immunology, closely resembling the human situation in a xenogeneic mouse environment.
This article studies routes to chaos occurring within a resonance wedge for a 3-parametric family of differential equations acting on a 3-sphere. Our starting point is an autonomous vector field ...whose flow exhibits an attracting heteroclinic network made by two 1-dimensional connections and a 2-dimensional separatrix between two equilibria with different Morse indices. After changing the parameters, while keeping the 1-dimensional connections unaltered, we concentrate our study in the case where the 2-dimensional invariant manifolds of the equilibria do not intersect. We derive the first return map near the network and we reduce the analysis of the system to a 2-dimensional map on the cylinder. Complex dynamical features arise from a discrete-time Bogdanov–Takens singularity, which may be seen as the organizing center by which one can obtain infinitely many attracting tori, strange attractors, infinitely many sinks and non-trivial contracting wandering domains. These dynamical phenomena occur within a structure that we call
resonance wedge
. As an application, we may see the “classical” Arnold tongue as a projection of a resonance wedge. The results are general, extend to other contexts and lead to a fine-tuning of the theory.
Chains of quantum dots coupled to superconductors are promising for the realization of the Kitaev model of a topological superconductor. While individual superconducting quantum dots have been ...explored, control of longer chains requires understanding of interdot coupling. Here, double quantum dots are defined by gate voltages in indium antimonide nanowires. High transparency superconducting niobium titanium nitride contacts are made to each of the dots in order to induce superconductivity, as well as probe electron transport. Andreev bound states induced on each of dots hybridize to define Andreev molecular states. The evolution of these states is studied as a function of charge parity on the dots, and in magnetic field. The experiments are found in agreement with a numerical model.Quantum dots in a nanowire are one possible approach to creating a solid-state quantum simulator. Here, the authors demonstrate the coupling of electronic states in a double quantum dot to form Andreev molecule states; a potential building block for longer chains suitable for quantum simulation.
Provision of feed is a major determinant of overall profitability in beef production systems, accounting for up to 75% of the variable costs. Thus, improving cattle feed efficiency, by way of ...determining the underlying genomic control and subsequently selecting for feed efficient cattle, provides a method through which feed input costs may be reduced. The objective of this study was to undertake gene co-expression network analysis using RNA-Sequence data generated from Longissimus dorsi and liver tissue samples collected from steers of two contrasting breeds (Charolais and Holstein-Friesian) divergent for residual feed intake (RFI), across two consecutive distinct dietary phases (zero-grazed grass and high-concentrate). Categories including differentially expressed genes (DEGs) based on the contrasts of RFI phenotype, breed and dietary source, as well as key transcription factors and proteins secreted in plasma were utilised as nodes of the gene co-expression network.
Of the 2,929 DEGs within the network analysis, 1,604 were reported to have statistically significant correlations (≥ 0.80), resulting in a total of 43,876 significant connections between genes. Pathway analysis of clusters of co-expressed genes revealed enrichment of processes related to lipid metabolism (fatty acid biosynthesis, fatty acid β-oxidation, cholesterol biosynthesis), immune function, (complement cascade, coagulation system, acute phase response signalling), and energy production (oxidative phosphorylation, mitochondrial L-carnitine shuttle pathway) based on genes related to RFI, breed and dietary source contrasts.
Although similar biological processes were evident across the three factors examined, no one gene node was evident across RFI, breed and diet contrasts in both liver and muscle tissues. However within the liver tissue, the IRX4, NR1H3, HOXA13 and ZNF648 gene nodes, which all encode transcription factors displayed significant connections across the RFI, diet and breed comparisons, indicating a role for these transcription factors towards the RFI phenotype irrespective of diet and breed. Moreover, the NR1H3 gene encodes a protein secreted into plasma from the hepatocytes of the liver, highlighting the potential for this gene to be explored as a robust biomarker for the RFI trait in beef cattle.
Neutrophils are the most abundant innate immune cells and the first line of defense against many pathogenic microbes, including the human fungal pathogen
. Among the neutrophils' arsenal of effector ...functions, neutrophil extracellular traps (NETs) are thought to be of particular importance for trapping and killing the large fungal filaments by means of their web-like structures that consist of chromatin fibers decorated with proteolytic enzymes and host defense proteins. Peptidylarginine deiminase 4 (PAD4)-mediated citrullination of histones in activated neutrophils correlates with chromatin decondensation and extrusion and is widely accepted to act as an integral process of NET induction (NETosis). However, the requirement of PAD4-mediated histone citrullination for NET release during
infection remains unclear. In this study, we show that although PAD4-dependent neutrophil histone citrullination is readily induced by
, PAD4 is dispensable for NETosis in response to the fungus and other common NET-inducing stimuli. Moreover, PAD4 is not required for antifungal immunity during mucosal and systemic
infection. Our results demonstrate that PAD4 is dispensable for
-induced NETosis, and they highlight the limitations of using histone citrullination as a marker for NETs and PAD4
mice as a model of NET-deficiency.
Human activities, such as research, innovation and industry, concentrate disproportionately in large cities. The ten most innovative cities in the United States account for 23% of the national ...population, but for 48% of its patents and 33% of its gross domestic product. But why has human activity become increasingly concentrated? Here we use data on scientific papers, patents, employment and gross domestic product, for 353 metropolitan areas in the United States, to show that the spatial concentration of productive activities increases with their complexity. Complex economic activities, such as biotechnology, neurobiology and semiconductors, concentrate disproportionately in a few large cities compared to less--complex activities, such as apparel or paper manufacturing. We use multiple proxies to measure the complexity of activities, finding that complexity explains from 40% to 80% of the variance in urban concentration of occupations, industries, scientific fields and technologies. Using historical patent data, we show that the spatial concentration of cutting-edge technologies has increased since 1850, suggesting a reinforcing cycle between the increase in the complexity of activities and urbanization. These findings suggest that the growth of spatial inequality may be connected to the increasing complexity of the economy.
Abstract
Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either
JAK2
or Calreticulin (
...CALR
) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First,
CALR
mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous
CALR
mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment.
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