HoxA cluster is haploinsufficient for activity of hematopoietic stem and progenitor cells

Functional compensation between homeodomain proteins has hindered the ability to unravel their role in hematopoiesis using single gene knockouts. Because HoxB genes are dispensable for hematopoiesis, and most HoxA genes are expressed an order of magnitude higher than other cluster genes in hematopoietic stem cell (HSC)-enriched populations, we hypothesize that maintenance of HoxA cluster expression is important for adult hematopoiesis and that global decrease of HoxA gene expression levels affects steady-state hematopoiesis.

Spatial patterns and autocorrelation in the response of microarthropods to soil pollutants: The example of oribatid mites in an abandoned mining and smelting area

Although exogenous factors such as pollutants can act on endogenous drivers (e.g. dispersion) of populations and create spatially autocorrelated distributions, most statistical techniques assume independence of error terms. As there are no studies on metal soil pollutants and microarthropods that explicitly analyse this key issue, we completed a field study of the correlation between Oribatida and metal concentrations in litter, organic matter and soil in an attempt to account for spatial patterns of both metals and mites. The 50-m wide study area had homogenous macroscopic features, steep Pb and Cu gradients and high levels of Zn and Cd. Spatial models failed to detect metal-oribatid relationships because the observed latitudinal and longitudinal gradients in oribatid assemblages were independent of the collinear gradients in the concentration of metals. It is therefore hypothesised that other spatially variable factors (e.g. fungi, reduced macrofauna) affect oribatid assemblages, which may be influenced by metals only indirectly. (C) 2009 Elsevier Ltd. All rights reserved.

Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells

The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34 + cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript andor exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicingprocessing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expressionsplicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34 + cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processespathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.

Therapeutic revascularisation of ischaemic tissue. The opportunities and challenges for therapy using vascular stem/ progenitor cells

Ischaemia-related diseases such as peripheral artery disease and coronary heart disease constitute a major issue in medicine as they affect millions of individuals each year and represent a considerable economic burden to healthcare systems. If the underlying ischaemia is not sufficiently resolved it can lead to tissue damage, with subsequent cell death. Treating such diseases remains difficult and several strategies have been used to stimulate the growth of blood vessels and promote regeneration of ischaemic tissues, such as the use of recombinant proteins and gene therapy. Although these approaches remain promising, they have limitations and results from clinical trials using these methods have had limited success. Recently, there has been growing interest in the therapeutic potential of using a cell-based approach to treat vasodegenerative disorders. In vascular medicine, various stem cells and adult progenitors have been highlighted as having a vasoreparative role in ischaemic tissues. This review will examine the clinical potential of several stem and progenitor cells that may be utilised to regenerate defunct or damaged vasculature and restore blood flow to the ischaemic tissue. In particular, we focus on the therapeutic potential of endothelial progenitor cells as an exciting new option for the treatment of ischaemic diseases. © 2012 BioMed Central Ltd

Estimation of the surface area and volume of the retinal capillary basement membrane using the stereologic method of vertical sections

The modern stereologic method of vertical sections was applied to the retina as a means of generating unbiased estimates of three-dimensional structure. The method is illustrated with real data on the volume and surface area of the capillary basement membrane from the central retina of the rat. Novel methods of estimating the volume of retina sampled and of creating accurate vertical sections are described. The advantages of using stereologic methods to generate quantitative information on the three-dimensional structure of the retina are discussed and compared to those of previous quantitative methods that provide data on two-dimensional structure only.

A review of patents relating to therapeutic angiogenesis using endothelial progenitors and other vasculogenesis-related cell types

Stem and progenitor cells have generated considerable scientific and commercial interest in recent years due to their potential for novel cell therapy for a variety of medical conditions. A highly active research area in the field of regenerative medicine is vascular biology. Blood vessel repair and angiogenesis are key processes with endothelial progenitor cells (EPCs) playing a central role. Clinical trials for ischemic conditions, such as myocardial infarction and peripheral arterial disease, have suggested cell therapies to be feasible, safe, and potentially beneficial. Development of efficient methodologies to deliver EPC-based cytotherapies offers new hope for millions of patients with ischemic conditions. Evidence indicates that EPCs, depending on the subtype, mediate angiogenesis through different mechanisms. Differentiation into endothelium and complete integration into damaged vasculature was the first EPC mechanism to be proposed. However, many studies have demonstrated that vasoregulatory paracrine factor secretion by transplanted cells is also important. Many EPC subsets enhance angiogenesis and promote tissue repair by cytokine release without incorporating into the damaged vasculature. Whatever the mechanism, vascular repair and therapeutic angiogenesis using EPCs represent a realistic treatment option and also provides many commercialization opportunities. This review discusses recent advances in the EPC field whilst recounting relevant patents.

Examination of the flow rheological and textural properties of polymer gels composed of poly(methylvinylether-co-maleic anhydride) and poly(vinylpyrrolidone): rheological and mathematical interpretation of textural parameters.

The purpose of this study was to mathematically characterize the effects of defined experimental parameters (probe speed and the ratio of the probe diameter to the diameter of sample container) on the textural/mechanical properties of model gel systems. In addition, this study examined the applicability of dimensional analysis for the rheological interpretation of textural data in terms of shear stress and rate of shear. Aqueous gels (pH 7) were prepared containing 15% w/w poly(methylvinylether-co-maleic anhydride) and poly(vinylpyrrolidone) (PVP) (0, 3, 6, or 9% w/w). Texture profile analysis (TPA) was performed using a Stable Micro Systems texture analyzer (model TA-XT 2; Surrey, UK) in which an analytical probe was twice compressed into each formulation to a defined depth (15 mm) and at defined rates (1, 3, 5, 8, and 10 mm s-1), allowing a delay period (15 s) between the end of the first and beginning of the second compressions. Flow rheograms were performed using a Carri-Med CSL2-100 rheometer (TA Instruments, Surrey, UK) with parallel plate geometry under controlled shearing stresses at 20.0°?±?0.1°C. All formulations exhibited pseudoplastic flow with no thixotropy. Increasing concentrations of PVP significantly increased formulation hardness, compressibility, adhesiveness, and consistency. Increased hardness, compressibility, and consistency were ascribed to enhanced polymeric entanglements, thereby increasing the resistance to deformation. Increasing probe speed increased formulation hardness in a linear manner, because of the effects of probe speed on probe displacement and surface area. The relationship between formulation hardness and probe displacement was linear and was dependent on probe speed. Furthermore, the proportionality constant (gel strength) increased as a function of PVP concentration. The relationship between formulation hardness and diameter ratio was biphasic and was statistically defined by two linear relationships relating to diameter ratios from 0 to 0.4 and from 0.4 to 0.563. The dramatically increased hardness, associated with diameter ratios in excess of 0.4, was accredited to boundary effects, that is, the effect of the container wall on product flow. Using dimensional analysis, the hardness and probe displacement in TPA were mathematically transformed into corresponding rheological parameters, namely shearing stress and rate of shear, thereby allowing the application of the power law (??=?k?n) to textural data. Importantly, the consistencies (k) of the formulations, calculated using transformed textural data, were statistically similar to those obtained using flow rheometry. In conclusion, this study has, firstly, characterized the relationships between textural data and two key instrumental parameters in TPA and, secondly, described a method by which rheological information may be derived using this technique. This will enable a greater application of TPA for the rheological characterization of pharmaceutical gels and, in addition, will enable efficient interpretation of textural data under different experimental parameters.

Predisposition to arrhythmia and autonomic dysfunction in Nhlh1-deficient mice.

Nhlh1 is a basic helix-loop-helix transcription factor whose expression is restricted to the nervous system and which may play a role in neuronal differentiation. To directly study Nhlh1 function, we generated null mice. Homozygous mutant mice were predisposed to premature, adult-onset, unexpected death. Electrocardiograms revealed decreased total heart rate variability, stress-induced arrhythmia, and impaired baroreceptor sensitivity. This predisposition to arrhythmia is a likely cause of the observed death in the mutant mice. Heterozygosity for the closely related transcription factor Nhlh2 increased the severity of the Nhlh1-null phenotype. No signs of primary cardiac structural or conduction abnormalities could be detected upon necropsy of the null mice. The pattern of altered heart rhythm observed in basal and experimental conditions (stress and pharmacologically induced) suggests that a deficient parasympathetic tone may contribute to the arrhythmia in the Nhlh1-null mouse. The expression of Nhlh1 in the developing brain stem and in the vagal nuclei in the wild-type mouse further supports this hypothesis. The Nhlh1 mutant mouse may thus provide a model to investigate the contribution of the autonomic nervous system to arrhythmogenesis.

A phase Ib trial of Docetaxel, Carboplatin and Erlotinib in ovarian, fallopian tube and primary peritoneal cancers.

The safety and maximum tolerated dose (MTD) of erlotinib with docetaxel/carboplatin were assessed in patients with ovarian cancer. Chemonaive patients received intravenous docetaxel (75 mg m(-2)) and carboplatin (area under the curve 5) on day 1 of a 3-week cycle, and oral erlotinib at 50 (cohort 1), 100 (cohort 2a) or 75 mg day(-1) (cohort 2b) for up to six cycles. Dose-limiting toxicities were determined in cycle 1. Forty-five patients (median age 59 years) received treatment. Dose-limiting toxicities occurred in 1/5/5 patients (cohorts 1/2a/2b). The MTD of erlotinib in this regimen was determined to be 75 mg day(-1) (cohort 2b; the erlotinib dose was escalated to 100 mg day(-1) in 11 out of 19 patients from cycle 2 onwards). Neutropaenia was the predominant grade 3/4 haematological toxicity (85/100/95% respectively). Common non-haematological toxicities were diarrhoea, fatigue, nausea and rash. There were five complete and seven partial responses in 23 evaluable patients (52% response rate). Docetaxel/carboplatin had no measurable effect on erlotinib pharmacokinetics. In subsequent single-agent maintenance, erlotinib was given at 100-150 mg day(-1), with manageable toxicity, until tumour progression. Further investigation of erlotinib in epithelial ovarian carcinoma may be warranted, particularly as maintenance therapy

Preparation and characterisation of supported L(a0.)8Sr(0.2)MnO(3+x)

Three supported La0.8Sr0.2MnO3+x catalysts were prepared, one supported on lanthanum-stabilised alumina and two supported on a NiAl2O4 spinel. The catalysts were characterised using X-ray diffraction, transmission electron microscopy and surface area measurements following heat-treatments at temperatures up to 1200 degreesC in air. In the alumina-supported catalyst, a reaction occurred between the active phase and the support at high temperatures, indicating that these materials would be unsuitable for high temperature catalytic combustion. Only in the NiAl2O4-supported catalysts were the supported perovskite phases found to be stable at high temperature. These catalysts showed good methane combustion activity. (C) 2001 Elsevier Science B.V. All rights reserved.

Identifying the influence of geology, land use, and anthropogenic activities on riverine sulfate on a watershed scale by combining hydrometric, chemical and isotopic approaches

Throughout the last few decades, sulfate concentrations in streamwater have received considerable attention due to their dominant role in anthropogenic acidification of surface waters. The objectives of this study conducted in the Oldman River Basin in Alberta (Canada) were to determine the influence of geology, land use and anthropogenic activities on sources, concentrations and fluxes of riverine sulfate on a watershed scale. This was achieved by combining hydrological, chemical and isotopic techniques. Surface water samples were collected from the main stem and tributaries of the Oldman River on a monthly basis between December 2000 and March 2003 and analyzed for chemical and isotopic compositions. At a given sampling site, sulfate sources were primarily dependent on geology and did not vary with time or flow condition. With increasing flow distance a gradual shift from ?34S values > 10 ‰ and ?18O values > 0 ‰ of riverine sulfate indicating evaporite dissolution and soil-derived sulfate in the predominantly forested headwaters, to negative ?34S and ?18O values suggested that sulfide oxidation was the predominant sulfate source in the agriculturally used downstream part of the watershed. Significant increases in sulfate concentrations and fluxes with downstream distance were observed, and were attributed to anthropogenically enhanced sulfide oxidation due to the presence of an extensive irrigation drainage network with seasonally varying water levels. Sulfate-S exports in an artificially drained subbasin (64 kg S/ha/yr) were found to exceed those in a naturally drained subbasin (4 kg S/ha/yr) by an order of magnitude. Our dataset suggests that the naturally occurring process of sulfide oxidation has been enhanced in the Oldman River Basin by the presence of an extensive network of drainage and irrigation canals.

Language and Power: A Resource Book for Students

Language and Power offers a comprehensive survey of the ways in which language intersects and connects with the social, cultural and political aspects of power; provides a comprehensive introduction to the history of the field, and covers all the major approaches, theoretical concepts and methods of analysis in this important and developing area of academic study; covers all the 'traditional' topics, such as race, gender and institutional power, but also incorporates newer material from forensic discourse analysis, the discourse of new capitalism and the study of humour as power; includes readings from works by seminal figures in the field, such as Roger Fowler, Deborah Cameron and Teun van Dijk; uses real texts and examples throughout, including advertisements from cosmetics companies; newspaper articles and headlines; websites and internet media; and spoken dialogues such as a transcription from the Obama and McCain presidential debate; and is accompanied by a supporting website that aims to challenge students at a more advanced level and features a complete four-unit chapter which includes activities, a reading and suggestions for further work.