Chromium vI induced cytoskeletal damage and cell death in isolated hepatocytes

Cr(VI) is a known human carcinogen. Although it has been investigated widely, the mechanism(s) of its action is/are not fully understood. The aim of this study was to evaluate Cr(VI)-induced damage to the cell cytoskeleton and the mode of cell death in primary cultures of hepatocytes. Exposure of the cultured cells (10(5)/cm(2)) to 1 and 5 microM Cr(VI) for 24 h resulted in loss of the cell cytoskeleton, and this was accompanied by membrane blebbing and shrinking of the cell. Staining of the cells with annexin V and propidium iodide showed that Cr(VI) induces apoptosis at low concentrations (5 microM), whereas at higher concentrations (25 microM) it induces necrosis. This study shows that Cr(VI) causes damage to the cell cytoskeleton, and induces apoptosis at low concentrations. However, the importance of necrosis and apoptosis in vivo, and the effects of longer exposure times, which simulate environmental and occupational exposure to Cr(VI), remain to be investigated

Can the quality of social research on ethnicity be improved through the introduction of guidance? Findings from a research commissioning pilot exercise

As the volume of UK social research addressing ethnicity grows, so too do concerns regarding the ethical and scientific rigour of this research domain and its potential to do more harm than good. The establishment of standards and principles and the introduction of guidance documents at critical points within the research cycle might be one way to enhance the quality of such research. This article reports the findings from the piloting of a guidance document within the research commissioning process of a major funder of UK social research. The guidance document was positively received by researchers, the majority of whom reported it to be comprehensible, relevant and potentially useful in improving the quality of research proposals. However, a review of the submitted proposals suggested the guidance had had little impact on practice. While guidance may have a role to play, it will need to be strongly promoted by commissioners and other gatekeepers. Findings also suggest the possibility that guidance may discourage some researchers from engaging with ethnicity if it raises problems without solutions; highlighting the need for complementary investments in research capacity development in this area

Optimization of anti-proliferative activity using a screening approach with a series of bis-heterocyclic G-quadruplex ligands

Using a phenotypic screening and SAR optimization approach, a phenyl-bis-oxazole derivative has been identified with anti-proliferative activity, optimized with the use of a panel of cancer cell lines. The lead compound was synthesized by means of a short and effective two-step synthesis using Pd-catalyzed direct arylation. The compound stabilizes several quadruplex DNA sequences including a human telomeric DNA and one from the promoter of the HSP90 gene, although the structure–activity relationships of the series are not obviously related to the quadruplex binding

The Nitrogen Dynamics of Newly Developed Lignite-Based Controlled-Release Fertilisers in the Soil-Plant Cycle

(c) The Author/sThe effect of newly developed controlled-release fertilisers (CRFs); Epox5 and Ver-1 and two levels of Fe2+ applications (478 and 239 kg-FeSO4 ha−1) on controlling nitrogen (N) losses, were tested on ryegrass, in a climate-controlled lysimeter system. The Epox5 and Ver-1 effectively decreased the total N losses by 37 and 47%, respectively, compared to urea. Nitrous oxide (N2O) emissions by Ver-1 were comparable to urea. However, Epox5 showed significantly higher (p < 0.05) N2O emissions (0.5 kg-N ha−1), compared to other treatments, possibly due to the lock-off nitrogen in Epox5. The application of Fe2+ did not show a significant effect in controlling the N leaching loss and N2O emission. Therefore, a dissimilatory nitrate reduction and chemodenitrification pathways were not pronounced in this study. The total dry matter yield, N accumulation, N use efficiency and soil residual N were not significantly different among any N treatments. Nevertheless, the N accumulation of CRFs was lower in the first month, possibly due to the slow release of urea. The total root biomass was significantly (p < 0.05) lower for Epox5 (35%), compared to urea. The hierarchical clustering of all treatments revealed that Ver-1 outperformed other treatments, followed by Epox5. Further studies are merited to identify the potential of Fe2+ as a controlling agent for N losses.fals

Learning To Be Affected: Social suffering and total pain at life’s borders.

The practice of Live Sociology in situations of pain and suffering is the author’s focus. An outline of the challenges of understanding pain is followed by a discussion of Bourdieu’s ‘social suffering’ (1999) and the palliative care philosophy of ‘total pain’. Using examples from qualitative research on disadvantaged dying migrants in the UK, attention is given to the methods that are improvised by dying people and care practitioners in attempts to bridge intersubjective divides, where the causes and routes of pain can be ontologically and temporally indeterminate and/or withdrawn. The paper contends that these latter phenomena are the incitement for the inventive bridging and performative work of care and Live Sociological methods, both of which are concerned with opposing suffering. Drawing from the ontology of total pain, I highlight the importance of (i) an engagement with a range of materials out of which attempts at intersubjective bridging can be produced, and which exceed the social, the material, and the temporally linear; and (ii) an empirical sensibility that is hospitable to the inaccessible and non-relational

A naphthalene diimide G-quadruplex ligand inhibits cell growth and down-regulates BCL-2 expression in an imatinib-resistant gastrointestinal cancer cell line

Gastro-intestinal tumours (GISTs) are driven by aberrant expression of the c-KIT oncoprotein. They can be effectively treated by the kinase inhibitor imatinib, which locks the c-KIT kinase domain into an inactive conformation. However resistance to imatinib, driven by active-site mutations, is a recurrent clinical challenge, which has been only partly met by the subsequent development of second and third-generation c-KIT inhibitors. It is reported here that a tetra-substituted naphthalene diimide derivative, which is a micromolar inhibitor of cell growth in a wild-type patient-derived GIST cell line, has a sub-micromolar activity in two distinct patient-derived imatinib-resistant cell lines. The compound has been previously shown to down-regulate expression of the c-KIT protein in a wild-type GIST cell line. It does not affect c-KIT protein expression in a resistant cell line to the same extent, whereas it profoundly down-regulates the expression of the anti-apoptopic protein BCL-2. It is proposed that the mechanism of action involves targeting quadruplex nucleic acid structures, and in particular those in the BCL-2 gene and its RNA transcript. The BCL-2 protein is up-regulated in the GIST-resistant cell line, and is strongly down-regulated after treatment. The compound strongly stabilises a range of G-quadruplexes including a DNA one from the BCL-2 promoter and an RNA quadruplex from its 5′-UTR region. A reporter assay construct incorporating the 5′-UTR quadruplex sequence demonstrates down-regulation of BCL-2 expression

Lung involvement at presentation predicts disease activity and permanent organ damage at 6, 12 and 24 months follow - up in ANCA - associated vasculitis.

BACKGROUND: Antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may present with pulmonary involvement ranging from mild to life-threatening disease such as diffuse alveolar hemorrhage. There is a paucity of information regarding morbidity outcomes for AAV subjects presenting with lung involvement. This study determines the relationship between disease activity and damage in these subjects using the Birmingham Vasculitis Activity Score v 3 (BVAS 3) and Vasculitis Damage Index (VDI) respectively. RESULTS: 151 patients with AAV were included with 59 presenting initially with pulmonary involvement. The initial BVAS scores recorded at time of diagnosis were positively correlated with the final VDI scores at 24 months (p \u3c 0.0001, rs = 0.5871). No differences between BVAS and VDI scores were seen for both groups, however in the lung-involvement group only, BVAS scores were significantly higher at 6, 12 and 24 months whilst the VDI scores were significantly higher at 12 and 24 months. Subjects presenting with pulmonary involvement had an increased likelihood for cardiovascular (OR 1.31, 95% CI 0.89, 1.54; p = 0.032) and renal (OR 1.32, 95% CI 1.22, 1.39; p = 0.005) involvement. Subjects presenting with lung involvement with granulomatosis with polyangiitis and microscopic polyangiitis had 24-month VDI scores that were significantly higher (p = 0.027, p = 0.045), and more likely to develop pulmonary fibrosis (OR 1.79, 95% CI 1.48, 2.12; p \u3c 0.001). CONCLUSION: AAV subjects with lung involvement at presentation had a higher disease activity and damage scores at 6, 12 and 24 months follow-up representing a considerable burden of disease despite improvement in overall survival due to the introduction of immunosuppressive therapy

Formulation and characterization of polyester-lignite composite coated slow-release fertilizers

CAUL read and publish agreement 2022Two polyester-lignite composite coated urea slow-release fertilizers (SRFs; Poly3 and Poly5) were developed and their physicochemical properties were studied. Both these SRFs significantly (p < 0.05) extended the urea release compared to uncoated urea; Poly3 and Poly5 by 117 and 172 h, respectively. The urea release characteristics of Poly5 were further enhanced by linseed oil application (Poly5-linseed). The SEM images demonstrated the coatings were in contact with the urea and encase urea particles completely with the average coating thickness of 167.2 ± 15 µm. The new interactions between polyester and lignite in the composite coating were confirmed by the FTIR analysis. Polyester-calcium carbonate (Polyester-CaCO3) coated SRFs (Calc3 and Calc5) were developed using CaCO3 as a filler in place of lignite and the urea dissolution rate was compared with Poly3 and Poly5. The urea release times for the polyester-CaCO3 formulations, 48 and 72 h, were significantly (P < 0.05) lower than the polyester-lignite formulation, showing that lignite imparted greater control over release time than CaCO3. Findings from this work showed that polyester-lignite composites can be used as a coating material for SRFs.fals

Negotiating professional and social voices in research principles and practice

This paper draws on work conducted for a qualitative interview based study which explores the gendered racialised and professional identifications of health and social care professionals. Participants for the project were drawn from the professional executive committees of recently formed Primary Care Trusts. The paper discusses how the feminist psychosocial methodological approach developed for the project is theoretically, practically and ethically useful in exploring the voices of those in positions of relative power in relation to both health and social care services and the social relations of gender and ethnicity. The approach draws on psychodynamic accounts of (defended) subjectivity and the feminist work of Carol Gilligan on a voice-centred relational methodology. Coupling the feminist with the psychosocial facilitates an emphasis on voice and dialogic communication between participant and researcher not always captured in psychosocial approaches which tend towards favouring the interviewer as ‘good listener’. This emphasis on dialogue is important in research contexts where prior and ongoing relationships with professional participants make it difficult and indeed undesirable for researchers to maintain silence

A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer

We report here that a tetra-substituted naphthalene-diimide derivative (MM41) has significant in vivo anti-tumour activity against the MIA PaCa-2 pancreatic cancer xenograft model. IV administration with a twice-weekly 15 mg/kg dose produces ca 80% tumour growth decrease in a group of tumour-bearing animals. Two animals survived tumour-free after 279 days. High levels of MM41 are rapidly transported into cell nuclei and were found to accumulate in the tumour. MM41 is a quadruplex-interactive compound which binds strongly to the quadruplexes encoded in the promoter sequences of the BCL-2 and k-RAS genes, both of which are dis-regulated in many human pancreatic cancers. Levels of BCL-2 were reduced by ca 40% in tumours from MM41-treated animals relative to controls, consistent with BCL-2 being a target for MM41. Molecular modelling suggests that MM41 binds to a BCL-2 quadruplex in a manner resembling that previously observed in co-crystal structures with human telomeric quadruplexes. This supports the concept that MM41 (and by implication other quadruplex-targeting small molecules) can bind to quadruplex-forming promoter regions in a number of genes and down-regulate their transcription. We suggest that quadruplexes within those master genes that are up-regulated drivers for particular cancers, may be selective targets for compounds such as MM41