Building resilience in practice to support coral communities in the Western Indian Ocean

Global environmental change and other site specific pressures (e.g. over fishing and pollution) are threating coral reefs and the livelihoods of dependent coastal communities. Multiple strategies are used to build the resilience of both coral reefs and reef dependent communities but the effectiveness of these strategies is largely unknown. Using the Western Indian Ocean (WIO) as a case study, this paper combines published literature and expert opinion elicited through a multi-stakeholder workshop to assess the intended and realised social and ecological implications of strategies commonly applied in the region. Findings suggest that all strategies can contribute to building social and ecological resilience, but this varies with context and the overall strategy objectives. The ability of strategies to be successful in the future is questioned. To support effective resilience policy development more nuanced lesson learning requires effective monitoring and evaluation as well as a disaggregated understanding of resilience in terms of gender, agency and the interaction between ecological and social resilience. Opportunities for further lesson sharing between experts in the region are needed

Characterisation of GLUT4 trafficking in HeLa cells: Comparable kinetics and orthologous trafficking mechanisms to 3T3-L1 adipocytes

Insulin-stimulated glucose transport is a characteristic property of adipocytes and muscle cells and involves the regulated delivery of glucose transporter (GLUT4)- containing vesicles from intracellular stores to the cell surface. Fusion of these vesicles results in increased numbers of GLUT4 molecules at the cell surface. In an attempt to overcome some of the limitations associated with both primary and cultured adipocytes, we expressed an epitope- and GFP-tagged version of GLUT4 (HA–GLUT4–GFP) in HeLa cells. Here we report the characterisation of this system compared to 3T3-L1 adipocytes. We show that insulin promotes translocation of HA–GLUT4–GFP to the surface of both cell types with similar kinetics using orthologous trafficking machinery. While the magnitude of the insulin-stimulated translocation of GLUT4 is smaller than mouse 3T3-L1 adipocytes, HeLa cells offer a useful, experimentally tractable, human model system. Here, we exemplify their utility through a small-scale siRNA screen to identify GOSR1 and YKT6 as potential novel regulators of GLUT4 trafficking in human cells

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

Surgical resection for persistent seroma, following modified radical mastectomy

<p>Abstract</p> <p>Background</p> <p>Seroma formation following modified radical mastectomy with axillary lymph node dissection for breast cancer is a most common wound complication. In our experience seroma occurs in approximately 50% of patients undergoing mastectomy. Postmastectomy seromas usually vanishes within a few weeks after operation.</p> <p>Case presentation</p> <p>In this report we present the case of a 73 year old woman who had undergone mastectomy with axillary lymph node dissection for breast cancer, complicated by lymphorrhea and formation fibrous encapsulated seroma resistant to conservative treatment which required surgical resection.</p> <p>Conclusion</p> <p>We stand in opinion that in some cases of prolonged seromatous effusion with confirmed formation of thick walled reservoir the operation with resection and closure of supplying regional lymph vessels may be the best treatment, if possible preceded by arm lymphoscyntygraphy.</p

Combinatorial Clustering of Residue Position Subsets Predicts Inhibitor Affinity across the Human Kinome

The protein kinases are a large family of enzymes that play fundamental roles in propagating signals within the cell. Because of the high degree of binding site similarity shared among protein kinases, designing drug compounds with high specificity among the kinases has proven difficult. However, computational approaches to comparing the 3-dimensional geometry and physicochemical properties of key binding site residue positions have been shown to be informative of inhibitor selectivity. The Combinatorial Clustering Of Residue Position Subsets (CCORPS) method, introduced here, provides a semi-supervised learning approach for identifying structural features that are correlated with a given set of annotation labels. Here, CCORPS is applied to the problem of identifying structural features of the kinase ATP binding site that are informative of inhibitor binding. CCORPS is demonstrated to make perfect or near-perfect predictions for the binding affinity profile of 8 of the 38 kinase inhibitors studied, while only having overall poor predictive ability for 1 of the 38 compounds. Additionally, CCORPS is shown to identify shared structural features across phylogenetically diverse groups of kinases that are correlated with binding affinity for particular inhibitors; such instances of structural similarity among phylogenetically diverse kinases are also shown to not be rare among kinases. Finally, these function-specific structural features may serve as potential starting points for the development of highly specific kinase inhibitors

The Cysteine Protease α-Clostripain is Not Essential for the Pathogenesis of Clostridium perfringens-Mediated Myonecrosis

Clostridium perfringens is the causative agent of clostridial myonecrosis or gas gangrene and produces many different extracellular toxins and enzymes, including the cysteine protease α-clostripain. Mutation of the α-clostripain structural gene, ccp, alters the turnover of secreted extracellular proteins in C. perfringens, but the role of α-clostripain in disease pathogenesis is not known. We insertionally inactivated the ccp gene C. perfringens strain 13 using TargeTron technology, constructing a strain that was no longer proteolytic on skim milk agar. Quantitative protease assays confirmed the absence of extracellular protease activity, which was restored by complementation with the wild-type ccp gene. The role of α-clostripain in virulence was assessed by analysing the isogenic wild-type, mutant and complemented strains in a mouse myonecrosis model. The results showed that although α-clostripain was the major extracellular protease, mutation of the ccp gene did not alter either the progression or the development of disease. These results do not rule out the possibility that this extracellular enzyme may still have a role in the early stages of the disease process

Magnetic Resonance Water Proton Relaxation in Protein Solutions and Tissue: T1ρ Dispersion Characterization

BACKGROUND: Image contrast in clinical MRI is often determined by differences in tissue water proton relaxation behavior. However, many aspects of water proton relaxation in complex biological media, such as protein solutions and tissue are not well understood, perhaps due to the limited empirical data. PRINCIPAL FINDINGS: Water proton T(1), T(2), and T(1rho) of protein solutions and tissue were measured systematically under multiple conditions. Crosslinking or aggregation of protein decreased T(2) and T(1rho), but did not change high-field T(1). T(1rho) dispersion profiles were similar for crosslinked protein solutions, myocardial tissue, and cartilage, and exhibited power law behavior with T(1rho)(0) values that closely approximated T(2). The T(1rho) dispersion of mobile protein solutions was flat above 5 kHz, but showed a steep curve below 5 kHz that was sensitive to changes in pH. The T(1rho) dispersion of crosslinked BSA and cartilage in DMSO solvent closely resembled that of water solvent above 5 kHz but showed decreased dispersion below 5 kHz. CONCLUSIONS: Proton exchange is a minor pathway for tissue T(1) and T(1rho) relaxation above 5 kHz. Potential models for relaxation are discussed, however the same molecular mechanism appears to be responsible across 5 decades of frequencies from T(1rho) to T(1)

Small PARP inhibitor PJ-34 induces cell cycle arrest and apoptosis of adult T-cell leukemia cells

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author’s publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Background HTLV-I is associated with the development of an aggressive form of lymphocytic leukemia known as adult T-cell leukemia/lymphoma (ATLL). A major obstacle for effective treatment of ATLL resides in the genetic diversity of tumor cells and their ability to acquire resistance to chemotherapy regimens. As a result, most patients relapse and current therapeutic approaches still have limited long-term survival benefits. Hence, the development of novel approaches is greatly needed. Methods In this study, we found that a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), PJ-34, is very effective in activating S/G2M cell cycle checkpoints, resulting in permanent cell cycle arrest and reactivation of p53 transcription functions and caspase-3-dependent apoptosis of HTLV-I-transformed and patient-derived ATLL tumor cells. We also found that HTLV-I-transformed MT-2 cells are resistant to PJ-34 therapy associated with reduced cleaved caspase-3 activation and increased expression of RelA/p65. Conclusion Since PJ-34 has been tested in clinical trials for the treatment of solid tumors, our results suggest that some ATLL patients may be good candidates to benefit from PJ-34 therapy

Effect of crystalline disorder on quantum tunneling in the single-molecule magnet Mn12 benzoate

10 páginas, 9 figuras, 1 tabla.-- PACS number(s): 75.45.+j, 75.50.Xx, 75.60.Jk, 75.50.Kj.-- et al.We report a detailed study of the effects that crystalline disorder has on the magnetic relaxation and quantum tunneling of Mn12 benzoate clusters. Thanks to the absence of interstitial molecules in the crystal structure of this molecular compound, we have been able to isolate the influence of long-range crystalline disorder. For this, we compare results obtained under two extreme situations: a crystalline sample and a nearly amorphous material. The results show that crystalline disorder affects little the anisotropy, magnetic relaxation, and quantum tunneling of these materials. It follows that disorder is not a necessary ingredient for the existence of magnetic quantum tunneling. The results unveil, however, a subtle influence of crystallinity via the modification of the symmetry of dipole-dipole interactions. The faster tunneling rates measured for the amorphous material are accounted for by a narrower distribution of dipolar bias in this material, as compared with the crystalline sample.This work has been partly funded by Grants No. MAT2009-13977-C03, No. MAT2008-06542- C04, and No. CSD2007-00010 from the Spanish Ministerio de Ciencia e Innovación, and NABISUP from DGA. We acknowledge funding from Acción Integrada under Grant No. HA2006-0051 and the Network of Excellence MAGMANet. J.v.S and S.D. acknowledge the financial support of the Deutsche Forschungsgemeinschaft (DFG) and the DAAD. Ch.C. and I.I. acknowledge the Spanish Ministerio de Ciencia e Innovación.Peer reviewe