Differential Hox expression in murine embryonic stem cell models of normal and malignant hematopoiesis

The Hox family are master transcriptional regulators of developmental processes, including hematopoiesis. The Hox regulators, caudal homeobox factors (Cdx1-4), and Meis1, along with several individual Hox proteins, are implicated in stem cell expansion during embryonic development, with gene dosage playing a significant role in the overall function of the integrated Hox network. To investigate the role of this network in normal and aberrant, early hematopoiesis, we employed an in vitro embryonic stem cell differentiation system, which recapitulates mouse developmental hematopoiesis. Expression profiles of Hox, Pbx1, and Meis1 genes were quantified at distinct stages during the hematopoietic differentiation process and compared with the effects of expressing the leukemic oncogene Tel/PDGFR;2. During normal differentiation the Hoxa cluster, Pbx1 and Meis1 predominated, with a marked reduction in the majority of Hox genes (27/39) and Meis1 occurring during hematopoietic commitment. Only the posterior Hoxa cluster genes (a9, a10, a11, and a13) maintained or increased expression at the hematopoietic colony stage. Cdx4, Meis1, and a subset of Hox genes, including a7 and a9, were differentially expressed after short-term oncogenic (Tel/PDGFR;2) induction. Whereas Hoxa4-10, b1, b2, b4, and b9 were upregulated during oncogenic driven myelomonocytic differentiation. Heterodimers between Hoxa7/Hoxa9, Meis1, and Pbx have previously been implicated in regulating target genes involved in hematopoietic stem cell (HSC) expansion and leukemic progression. These results provide direct evidence that transcriptional flux through the Hox network occurs at very early stages during hematopoietic differentiation and validates embryonic stem cell models for gaining insights into the genetic regulation of normal and malignant hematopoiesis

Reflection Seismic Imaging for Mineral Exploration in the Sotiel-Coronada Area, Southwest Spain

Near Surface Geoscience Conference & Exhibition Online 2020This work explores the first results of the seismic data acquired in the Sotiel-Coronada mine as part of the SIT4ME (Seismic Imaging Techniques for Mineral Exploration) project. In this experiment, a multi-source seismic data-set was acquired at the end of 2018 in the Sotiel- Coronada area of the Iberian Pyrite Belt (IPB) (southwest Spain). In the seismic experiment presented, 653 seismic receivers were deployed distributed in a pseudo 3D grid and six crooked lines across the study area. The sensors recorded c. 900 vibration points produced by a 32 Tn vibrotruck. Here, we present the stack results of the 2D seismic sections. Data from over 100 wells have been incorporating to aid in the structural interpretation. The preliminary interpretation reveals the complexity of this highly faulted ore-bearing area. Correlations between well log data information and 2D seismic profiles, suggest the location of a potentially mineralized area. The SIT4ME project has been funded by EIT Raw Materials (17024)

Mathematical and Statistical Techniques for Systems Medicine: The Wnt Signaling Pathway as a Case Study

The last decade has seen an explosion in models that describe phenomena in systems medicine. Such models are especially useful for studying signaling pathways, such as the Wnt pathway. In this chapter we use the Wnt pathway to showcase current mathematical and statistical techniques that enable modelers to gain insight into (models of) gene regulation, and generate testable predictions. We introduce a range of modeling frameworks, but focus on ordinary differential equation (ODE) models since they remain the most widely used approach in systems biology and medicine and continue to offer great potential. We present methods for the analysis of a single model, comprising applications of standard dynamical systems approaches such as nondimensionalization, steady state, asymptotic and sensitivity analysis, and more recent statistical and algebraic approaches to compare models with data. We present parameter estimation and model comparison techniques, focusing on Bayesian analysis and coplanarity via algebraic geometry. Our intention is that this (non exhaustive) review may serve as a useful starting point for the analysis of models in systems medicine.Comment: Submitted to 'Systems Medicine' as a book chapte

Lymphocyte subsets and the role of Th1/Th2 balance in stressed chronic pain patients

Background: The complex regional pain syndrome (CRPS) and fibromyalgia (FM) are chronic pain syndromes occurring in highly stressed individuals. Despite the known connection between the nervous system and immune cells, information on distribution of lymphocyte subsets under stress and pain conditions is limited. Methods: We performed a comparative study in 15 patients with CRPS type I, 22 patients with FM and 37 age- and sex-matched healthy controls and investigated the influence of pain and stress on lymphocyte number, subpopulations and the Th1/Th2 cytokine ratio in T lymphocytes. Results: Lymphocyte numbers did not differ between groups. Quantitative analyses of lymphocyte subpopulations showed a significant reduction of cytotoxic CD8+ lymphocytes in both CRPS (p < 0.01) and FM (p < 0.05) patients as compared with healthy controls. Additionally, CRPS patients were characterized by a lower percentage of IL-2-producing T cell subpopulations reflecting a diminished Th1 response in contrast to no changes in the Th2 cytokine profile. Conclusions: Future studies are warranted to answer whether such immunological changes play a pathogenetic role in CRPS and FM or merely reflect the consequences of a pain-induced neurohumoral stress response, and whether they contribute to immunosuppression in stressed chronic pain patients. Copyright (c) 2008 S. Karger AG, Basel

Acetylated histone variant H2A.Z is involved in the activation of neo-enhancers in prostate cancer.

Acetylation of the histone variant H2A.Z (H2A.Zac) occurs at active promoters and is associated with oncogene activation in prostate cancer, but its role in enhancer function is still poorly understood. Here we show that H2A.Zac containing nucleosomes are commonly redistributed to neo-enhancers in cancer resulting in a concomitant gain of chromatin accessibility and ectopic gene expression. Notably incorporation of acetylated H2A.Z nucleosomes is a pre-requisite for activation of Androgen receptor (AR) associated enhancers. H2A.Zac nucleosome occupancy is rapidly remodeled to flank the AR sites to initiate the formation of nucleosome-free regions and the production of AR-enhancer RNAs upon androgen treatment. Remarkably higher levels of global H2A.Zac correlate with poorer prognosis. Altogether these data demonstrate the novel contribution of H2A.Zac in activation of newly formed enhancers in prostate cancer

A Multicellular Model of Intestinal Crypt Buckling and Fission

Crypt fission is an in vivo tissue deformation process that is involved in both intestinal homeostasis and colorectal tumourigenesis. Despite its importance, the mechanics underlying crypt fission are currently poorly understood. Recent experimental development of organoids, organ-like buds cultured from crypt stem cells in vitro, has shown promise in shedding light on crypt fission. Drawing inspiration from observations of organoid growth and fission in vivo, we develop a computational model of a deformable epithelial tissue layer. Results from in silico experiments show the stiffness of cells and the proportions of cell subpopulations affect the nature of deformation in the epithelial layer. In particular, we find that increasing the proportion of stiffer cells in the layer increases the likelihood of crypt fission occurring. This is in agreement with and helps explain recent experimental work

Reflection seismic imaging to unravel subsurface geological structures of the Zinkgruvan mining area, central Sweden

The Zinkgruvan mining area is located on the south-eastern part of the Bergslagen district, one of the three major mineral producing regions in Sweden. In this study, we present the results from three (P1, P2 and P8) reflection seismic profiles each approximately 3000 m-long crossing the Zinkgruvan Zn-Pb-Ag-(Cu) mining area. P1 was acquired using cabled geophones with 10 m receiver and source interval and crossed major geological features. The other two profiles (P2 and P8) were acquired by wireless recorders with 20 m receiver and 10 m source interval and ran perpendicular to P1. Through a special data processing workflow adapted to this dataset, good quality seismic sections were obtained along these profiles, although a high noise level due to high voltage electric power lines was present. The interpretations were constrained by (1) seismic P-wave velocity and density data from a series of downhole logging measurements, (2) 3D forward reflection traveltime modelling in both pre- and post-stack domains, and (3) other geophysical and geological observations available from the site. Despite the notably complex geology, the processed seismic sections clearly reveal a series of horizontal to gently dipping reflections associated with known geological formations. Results indicate that most structures and lithological contacts dip or plunge to the northeast, including the targeted Zinkgruvan Formation. The results from this seismic survey are encouraging regarding the potential of the seismic method for base-metal exploration in Sweden and in particular in the Bergslagen district. It shows the high resolving power of the reflection seismic methods for imaging complex geological structures in a cost-effective and environmentally-friendly way.EIT-RawMaterials is gratefully thanked for funding this up-scaling project 17024.Peer reviewe