Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter

A new mitochondrial uncoupler that forms membrane permeable dimers through interactions of remote acidic and anion receptor groups.</p

The structural basis of bacterial manganese import

Metal ions are essential for all forms of life. In prokaryotes, ATP-binding cassette (ABC) permeases serve as the primary import pathway for many micronutrients including the first-row transition metal manganese. However, the structural features of ionic metal transporting ABC permeases have remained undefined. Here, we present the crystal structure of the manganese transporter PsaBC from Streptococcus pneumoniae in an open-inward conformation. The type II transporter has a tightly closed transmembrane channel due to "extracellular gating" residues that prevent water permeation or ion reflux. Below these residues, the channel contains a hitherto unreported metal coordination site, which is essential for manganese translocation. Mutagenesis of the extracellular gate perturbs manganese uptake, while coordination site mutagenesis abolishes import. These structural features are highly conserved in metal-specific ABC transporters and are represented throughout the kingdoms of life. Collectively, our results define the structure of PsaBC and reveal the features required for divalent cation transport.Stephanie L. Neville, Jennie Sjöhamn, Jacinta A. Watts, Hugo MacDermott-Opeskin, Stephen J. Fairweather, Katherine Ganio, Alex Carey Hulyer, Aaron P. McGrath, Andrew J. Hayes, Tess R. Malcolm, Mark R. Davies, Norimichi Nomura, So Iwata, Megan L. O’Mara, Megan J. Maher, Christopher A. McDevit

A polycystic variant of a primary intracranial leptomeningeal astrocytoma: case report and literature review

<p>Abstract</p> <p>Background</p> <p>Primary leptomeningeal astrocytomas are rare intracranial tumors. These tumors are believed to originate from cellular nests which migrate by means of aberration, ultimately settling in the leptomeningeal structure. They may occur in both solitary and diffuse forms. The literature reports only fifteen cases of solitary primary intracranial leptomeningeal astrocytomas.</p> <p>Case presentation</p> <p>The authors report the case of a seventy-eight year-old woman with a polycystic variant of a solitary primary intracranial leptomeningeal astrocytoma. The first neurological signs were seizures and aphasia. CT and MRI scans demonstrated a fronto-parietal polycystic tumor adherent to the sub arachnoid space. A left fronto-temporo-parietal craniotomy revealed a tight coalescence between the tumor and the arachnoid layer which appeared to wrap the mass entirely. Removal of the deeper solid part of the tumor resulted difficult due to the presence of both a high vascularity and a tight adherence between the tumor and the ventricular wall.</p> <p>Conclusion</p> <p>A new case of a solitary primitive intracranial leptomeningeal astrocytoma of a rare polycystic variant is reported. Clinical, surgical, pathologic and therapeutic aspects of this tumor are discussed.</p

Vascular Endothelial Growth Factor Receptor-3 Directly Interacts with Phosphatidylinositol 3-Kinase to Regulate Lymphangiogenesis

Background Dysfunctional lymphatic vessel formation has been implicated in a number of pathological conditions including cancer metastasis, lymphedema, and impaired wound healing. The vascular endothelial growth factor (VEGF) family is a major regulator of lymphatic endothelial cell (LEC) function and lymphangiogenesis. Indeed, dissemination of malignant cells into the regional lymph nodes, a common occurrence in many cancers, is stimulated by VEGF family members. This effect is generally considered to be mediated via VEGFR-2 and VEGFR-3. However, the role of specific receptors and their downstream signaling pathways is not well understood. Methods and Results Here we delineate the VEGF-C/VEGF receptor (VEGFR)-3 signaling pathway in LECs and show that VEGF-C induces activation of PI3K/Akt and MEK/Erk. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCc1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in LECs was demonstrated both in vitro and in clinical cancer specimens. This interaction was strongly associated with the presence of lymph node metastases in primary small cell carcinoma of the lung in clinical specimens. Blocking PI3K activity abolished VEGF-C-stimulated LEC tube formation and migration. Conclusions Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for the inhibition of lymphatic metastasis

Community participation for malaria elimination in tafea province, vanuatu: part ii. social and cultural aspects of treatment-seeking behaviour

Background: Early diagnosis and prompt effective case management are important components of any malaria elimination strategy. Tafea Province, Vanuatu has a rich history of traditional practices and beliefs, which have been integrated with missionary efforts and the introduction of modern constructions of health. Gaining a detailed knowledge of community perceptions of malarial symptomatology and treatment-seeking behaviours is essential in guiding effective community participation strategies for malaria control and elimination

Integrated mutation, copy number and expression profiling in resectable non-small cell lung cancer

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to identify critical genes involved in non-small cell lung cancer (NSCLC) pathogenesis that may lead to a more complete understanding of this disease and identify novel molecular targets for use in the development of more effective therapies.</p> <p>Methods</p> <p>Both transcriptional and genomic profiling were performed on 69 resected NSCLC specimens and results correlated with mutational analyses and clinical data to identify genetic alterations associated with groups of interest.</p> <p>Results</p> <p>Combined analyses identified specific patterns of genetic alteration associated with adenocarcinoma vs. squamous differentiation; <it>KRAS </it>mutation; <it>TP53 </it>mutation, metastatic potential and disease recurrence and survival. Amplification of 3q was associated with mutations in <it>TP53 </it>in adenocarcinoma. A prognostic signature for disease recurrence, reflecting <it>KRAS </it>pathway activation, was validated in an independent test set.</p> <p>Conclusions</p> <p>These results may provide the first steps in identifying new predictive biomarkers and targets for novel therapies, thus improving outcomes for patients with this deadly disease.</p