Chronic myelogenous leukemia arises from the transformation of hematopoietic stem cells by the BCR-ABL oncogene. Though transformed cells are predominantly BCR-ABL-dependent and sensitive to tyrosine ...kinase inhibitor treatment, some BMPR1B+ leukemic stem cells are treatment-insensitive and rely, among others, on the bone morphogenetic protein (BMP) pathway for their survival via a BMP4 autocrine loop. Here, we further studied the involvement of BMP signaling in favoring residual leukemic stem cell persistence in the bone marrow of patients having achieved remission under treatment. We demonstrate by single-cell RNA-Seq analysis that a sub-fraction of surviving BMPR1B+ leukemic stem cells are co-enriched in BMP signaling, quiescence and stem cell signatures, without modulation of the canonical BMP target genes, but enrichment in actors of the Jak2/Stat3 signaling pathway. Indeed, based on a new model of persisting CD34+CD38- leukemic stem cells, we show that BMPR1B+ cells display co-activated Smad1/5/8 and Stat3 pathways. Interestingly, we reveal that only the BMPR1B+ cells adhering to stromal cells display a quiescent status. Surprisingly, this quiescence is induced by treatment, while non-adherent BMPR1B+ cells treated with tyrosine kinase inhibitors continued to proliferate. The subsequent targeting of BMPR1B and Jak2 pathways decreased quiescent leukemic stem cells by promoting their cell cycle re-entry and differentiation. Moreover, while Jak2-inhibitors alone increased BMP4 production by mesenchymal cells, the addition of the newly described BMPR1B inhibitor (E6201) impaired BMP4-mediated production by stromal cells. Altogether, our data demonstrate that targeting both BMPR1B and Jak2/Stat3 efficiently impacts persisting and dormant leukemic stem cells hidden in their bone marrow microenvironment.
The medullary niche is a complex ecosystem that is essential to maintain homeostasis for resident cells. Indeed, the bone marrow, which includes a complex extracellular matrix and various cell types, ...such as mesenchymal stem cells, osteoblasts, and endothelial cells, is deeply involved in hematopoietic stem cell regulation through direct cell-cell interactions, as well as cytokine production. To closely mimic this in vivo structure and conduct experiments reflecting the responses of the human bone marrow, several 3D models have been created based on biomaterials, relying primarily on primary stromal cells. Here, a protocol is described to obtain a minimal and standardized system that is easy to set up and provides features of bone marrow-like structure, which combines different cell populations including endothelial cells, and reflects the heterogeneity of in vivo bone marrow tissue. This 3D bone marrow-like structure-assembled using calcium phosphate-based particles and human cell lines, representative of the bone marrow microenvironment-allows the monitoring of a wide variety of biological processes by combining or replacing different primary cell populations within the system. The final 3D structures can then either be harvested for image analysis after fixation, paraffin-embedding, and histological/immunohistochemical staining for cell localization within the system, or dissociated to collect each cellular component for molecular or functional characterization.
Our research is a step toward ascertaining the need for personalization in XAI, and we do so in the context of investigating the value of explanations of AI-driven hints and feedback in Intelligent ...Tutoring Systems (ITS). We added an explanation functionality to the Adaptive CSP (ACSP) applet, an interactive simulation that helps students learn an algorithm for constraint satisfaction problems by providing AI-driven hints adapted to their predicted level of learning. We present the design of the explanation functionality and the results of a controlled study to evaluate its impact on students' learning and perception of the ACPS hints. The study includes an analysis of how these outcomes are modulated by several user characteristics such as personality traits and cognitive abilities, to asses if explanations should be personalized to these characteristics. Our results indicate that providing explanations increase students' trust in the ACPS hints, perceived usefulness of the hints, and intention to use them again. In addition, we show that students' access of the ACSP explanation and learning gains are modulated by three user characteristics, Need for Cognition, Contentiousness and Reading Proficiency, providing insights on how to personalize the ACSP explanations to these traits, as well as initial evidence on the potential value of personalized Explainable AI (XAI) for ITS.
Current treatment of cutaneous leishmaniasis includes pentavalent antimonials as first-line drugs, but this therapy has shown severe adverse effects. An alternative to minimize this issue is based on ...combination therapy scheme with other drugs. In this study we analyzed the potential of the association of meglumine antimoniate (MA) with the oxiranes epoxy-α-lapachone (LAP) or epoxymethyl-lawsone (LAW). Results demonstrated that association between these drugs enhanced leishmanicidal activity on Leishmania (Leishmania) amazonensis infection. The compounds were tested in monotherapy or in combinations (3:1; 1:1 and 1:3) and reduced intracellular parasite numbers, measured by the endocytic index, in all tested conditions. The most effective combination regimens were MA/LAP or MA/LAW in 3:1 ratio, which achieved a reduction of 98.3% and 93.6% in the endocytic index, respectively. BALB/c mice challenged with L. (L.) amazonensis showed significant reduction in lesion size and parasite load in both footpad and lymph nodes, after four weeks of treatment. Although, MA, LAP or LAW monotherapy were able to control the evolution of lesions when compared to untreated animals (30%, 40% and 40% of reduction, respectively), the combination of MA/LAP and LAW in 3:1 ratio showed better results reducing 61.7 and 54.4%, respectively. The results indicate that the association of meglumine antimoniate to oxiranes lead to an increment in the antileishmanial activity and represent a promising approach for the cutaneous leishmaniasis treatment.
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•Meglumine antimoniate with oxiranes enhanced effect against Leishmania infection.•The most effective treatment in vitro infection was observed in a 3:1 ratio.•Mice treatment with drugs caused reductions in lesion size and parasite load.•Antimony-based combination has the potential for leishmaniasis treatment.
Visceral leishmaniasis (VL) or Kala-azar is a serious protozoan infectious disease caused by an obligate intracellular parasite. Cytokines have a major role in determining progression and severity of ...clinical manifestations in VL. We investigated polymorphisms in the
TGFB1and
IL8 genes, which are cytokines known to have a role in onset and severity of the disease. Polymorphisms at
TGFB1 −509 C/T and +869 T/C, and
IL8 −251 A/T were analyzed by a PCR-RFLP technique, in 198 patients with VL, 98 individuals with asymptomatic infection positive for a delayed-type hypersensitivity test (DTH+) and in 101 individuals with no evidence of infection (DTH−). The presence of the T allele in position −509 of the
TGFB1 gene conferred a two-fold risk to develop infection both when including those with clinical symptoms (DTH+ and VL, grouped) or when considering DTH+ only, respectively
p
=
0.007, OR
=
1.9 1.19–3.02 and
p
=
0.012, OR
=
2.01 1.17–3.79, when compared with DTH− individuals. In addition, occurrence of hemorrhage was associated with
TGFB1 −509 T allele. We suggest that the −509 T allele of the
TGFB1 gene, a cytokine with a biologically relevant role in the natural history of the disease, may contribute to overall susceptibility to infection by
Leishmania and to severity of the clinical disease.
Cysteine proteinases are well-known virulence factors of Leishmania spp. with demonstrated actions in both experimental mouse infection and human infection. However, studies on these enzymes in ...canine leishmaniasis are scarce. Here, we show, for the first time, the reactivity of sera from dogs living in an endemic area to a recombinant protein from the COOH-terminal region of cysteine B protease. In this work, enzyme-linked immunosorbent assays were performed using a 14kDa rcyspep protein obtained through a pET28-a expression system in Escherichia coli. First, 96-well plates were coated with rcyspep (500ng/well) and incubated with sera from dogs (1:100). Subsequently, IgG antibody detection was performed using rabbit anti-dog IgG antibodies conjugated with peroxidase. Sera from dogs (n=114), including suspect (n=30) and positive (n=50) dogs from a leishmaniasis-endemic area and dogs from a nonendemic area, (n=34), negative for leishmaniasis, were assessed. The results showed that sera from the suspect (42%) and positive (68%) groups responded differently to the antigen titers tested above the cut-off (Optical Density=0.166). This finding suggests that the immune response detected against cyspep may be related to clinical disorders present in these animals. Collectively, the data gathered here suggest that cyspep can sensitize the immune systems of dogs from a leishmaniasis-endemic area to elicit a humoral response, an immunological parameter indicating the contribution of this protein in host-parasite interaction.
Drones, capteurs, satellites ou algorithmes, les outils numériques sont présentés comme autant de solutions technologiques qui doivent permettre d’adapter l’agriculture aux nouveaux défis climatiques ...et environnementaux. Mais ce récent emballement médiatique et politique ne tend-il pas à écraser l’histoire plus longue, plus erratique et plus critique de la diffusion de ces innovations dans les mondes agricoles ? Pour éclaircir cette question, ce dossier propose une série d’enquêtes empiriques en France, au Brésil et en Suisse, inscrites dans différentes approches disciplinaires croisant la sociologie des sciences et des techniques, la géographie politique de l’environnement et la sociologie économique. Des infrastructures satellitaires de gouvernance des activités agricoles aux politiques publiques ou paysannes d’innovation, en passant par la recomposition des modalités de prescription par les services numériques et les réseaux sociaux, les différentes contributions du dossier abordent la multiplicité des enjeux liés au développement des outils numériques dans les mondes agricoles.
Our research is a step toward ascertaining the need for personalization, in XAI, and we do so in the context of investigating the value of explanations of AI-driven hints and feedback are useful in ...Intelligent Tutoring Systems (ITS). We added an explanation functionality for the adaptive hints provided by the Adaptive CSP (ACSP) applet, an interactive simulation that helps students learn an algorithm for constraint satisfaction problems by providing AI-driven hints adapted to their predicted level of learning. We present the design of the explanation functionality and the results of a controlled study to evaluate its impact on students' learning and perception of the ACPS hints. The study includes an analysis of how these outcomes are modulated by several user characteristics such as personality traits and cognitive abilities, to asses if explanations should be personalized to these characteristics. Our results indicate that providing explanations increase students' trust in the ACPS hints, perceived usefulness of the hints, and intention to use them again. In addition, we show that students' access of the explanation and learning gains are modulated by user characteristics, providing insights toward designing personalized Explainable AI (XAI) for ITS.
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