Sigma-model soliton intersections from exceptional calibrations

A first-order `BPS' equation is obtained for 1/8 supersymmetric intersections of soliton-membranes (lumps) of supersymmetric (4+1)-dimensional massless sigma models, and a special non-singular solution is found that preserves 1/4 supersymmetry. For 4-dimensional hyper-K\"ahler target spaces ($HK_4$) the BPS equation is shown to be the low-energy limit of the equation for a Cayley-calibrated 4-surface in \bE^4\times HK_4. Similar first-order equations are found for stationary intersections of Q-lump-membranes of the massive sigma model, but now generic solutions preserve either 1/8 supersymmetry or no supersymmetry, depending on the time orientation.Comment: 21 pages. Version 3: Minor corrections and one further reference: version published in JHE

A comparison of age-standardised event rates for acute and chronic coronary heart disease in metropolitan and regional/remote Victoria: a retrospective cohort study

Abstract Background Acute and chronic coronary heart disease (CHD) pose different burdens on health-care services and require different prevention and treatment strategies. Trends in acute and chronic CHD event rates can guide service implementation. This study evaluated changes in acute and chronic CHD event rates in metropolitan and regional/remote Victoria. Methods Victorian hospital admitted episodes with a principal diagnosis of acute CHD or chronic CHD were identified from 2005 to 2012. Acute and chronic CHD age-standardised event rates were calculated in metropolitan and regional/remote Victoria. Poisson log-link linear regression was used to estimate annual change in acute and chronic CHD event rates. Results Acute CHD age-standardised event rates decreased annually by 2.9 % (95 % CI, −4.3 to −1.4 %) in metropolitan Victoria and 1.7 % (95 % CI, −3.2 to −0.1 %) in regional/remote Victoria. In comparison, chronic CHD age-standardised event rates increased annually by 4.8 % (95 % CI, +3.0 to +6.5 %) in metropolitan Victoria and 3.1 % (95 % CI, +1.3 to +4.9 %) in regional/remote Victoria. On average, age-standardised event rates for regional/remote Victoria were 30.3 % (95 % CI, 23.5 to 37.2 %) higher for acute CHD and 55.3 % (95 % CI, 47.1 to 63.5 %) higher for chronic CHD compared to metropolitan Victoria from 2005 to 2012. Conclusion Annual decreases in acute CHD age-standardised event rates might reflect improvements in primary prevention, while annual increases in chronic CHD age-standardised event rates suggest a need to improve secondary prevention strategies. Consistently higher acute and chronic CHD age-standardised event rates were evident in regional/remote Victoria compared to metropolitan Victoria from 2005 to 2012

Sox6 Directly Silences Epsilon Globin Expression in Definitive Erythropoiesis

Sox6 is a member of the Sox transcription factor family that is defined by the conserved high mobility group (HMG) DNA binding domain, first described in the testis determining gene, Sry. Previous studies have suggested that Sox6 plays a role in the development of the central nervous system, cartilage, and muscle. In the Sox6-deficient mouse, p(100H), ɛy globin is persistently expressed, and increased numbers of nucleated red cells are present in the fetal circulation. Transfection assays in GM979 (erythroleukemic) cells define a 36–base pair region of the ɛy proximal promoter that is critical for Sox6 mediated repression. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrate that Sox6 acts as a repressor by directly binding to the ɛy promoter. The normal expression of Sox6 in wild-type fetal liver and the ectopic expression of ɛy in p(100H) homozygous fetal liver demonstrate that Sox6 functions in definitive erythropoiesis. The present study shows that Sox6 is required for silencing of ɛy globin in definitive erythropoiesis and suggests a role for Sox6 in erythroid cell maturation. Thus, Sox6 regulation of ɛy globin might provide a novel therapeutical target in the treatment of hemoglobinopathies such as sickle cell anemia and thalassemia

Discovery of Genes Essential for Heme Biosynthesis through Large-Scale Gene Expression Analysis

SummaryHeme biosynthesis consists of a series of eight enzymatic reactions that originate in mitochondria and continue in the cytosol before returning to mitochondria. Although these core enzymes are well studied, additional mitochondrial transporters and regulatory factors are predicted to be required. To discover such unknown components, we utilized a large-scale computational screen to identify mitochondrial proteins whose transcripts consistently coexpress with the core machinery of heme biosynthesis. We identified SLC25A39, SLC22A4, and TMEM14C, which are putative mitochondrial transporters, as well as C1orf69 and ISCA1, which are iron-sulfur cluster proteins. Targeted knockdowns of all five genes in zebrafish resulted in profound anemia without impacting erythroid lineage specification. Moreover, silencing of Slc25a39 in murine erythroleukemia cells impaired iron incorporation into protoporphyrin IX, and vertebrate Slc25a39 complemented an iron homeostasis defect in the orthologous yeast mtm1Δ deletion mutant. Our results advance the molecular understanding of heme biosynthesis and offer promising candidate genes for inherited anemias

Twisting the arm: structural constraints in bicyclic expanded-ring N-heterocyclic carbenes

A series of diaryl, mono-aryl/alkyl and dialkyl mono- and bicyclic expanded-ring N-heterocyclic carbenes (ER-NHCs) have been prepared and their complexation to Au(I) investigated through the structural analysis of fifteen Au(NHC)X and/or [Au(NHC)2]X complexes. The substituted diaryl 7-NHCs are the most sterically encumbered with large buried volume (%VB) values of 40–50% with the less flexible six-membered analogues having %VB values at least 5% smaller. Although the bicyclic systems containing fused 6- and 7-membered rings (6,7-NHCs) are constrained with relatively acute NCN bond angles, they have the largest %VB values of the dialkyl derivatives reported here, a feature related to the fixed conformation of the heterocyclic rings and the compressional effect of a pre-set methyl substituent

Contagion or Confusion? Why Conflicts Cluster in Space

Civil wars cluster in space as well as time. In this study, we develop and evaluate empirically alternative explanations for this observed clustering. We consider whether the spatial pattern of intrastate conflict simply stems from a similar distribution of relevant country attributes or whether conflicts indeed constitute a threat to other proximate states. Our results strongly suggest that there is a genuine neighborhood effect of armed conflict, over and beyond what individual country characteristics can account for. We then examine whether the risk of contagion depends on the degree of exposure to proximate conflicts. Contrary to common expectations, this appears not to be the case. Rather, we find that conflict is more likely when there are ethnic ties to groups in a neighboring conflict and that contagion is primarily a feature of separatist conflicts. This suggests that transnational ethnic linkages constitute a central mechanism of conflict contagion. © 2008 International Studies Association

Buruli Ulcer (M. ulcerans Infection): New Insights, New Hope for Disease Control

Buruli ulcer is a disease of skin and soft tissue caused by Mycobacterium ulcerans. It can leave affected people scarred and disabled. What are the prospects for disease control

Snx3 Regulates Recycling of the Transferrin Receptor and Iron Assimilation

Sorting of endocytic ligands and receptors is critical for diverse cellular processes. The physiological significance of endosomal sorting proteins in vertebrates, however, remains largely unknown. Here we report that sorting nexin 3 (Snx3) facilitates the recycling of transferrin receptor (Tfrc) and thus is required for the proper delivery of iron to erythroid progenitors. Snx3 is highly expressed in vertebrate hematopoietic tissues. Silencing of Snx3 results in anemia and hemoglobin defects in vertebrates due to impaired transferrin (Tf)-mediated iron uptake and its accumulation in early endosomes. This impaired iron assimilation can be complemented with non-Tf iron chelates. We show that Snx3 and Vps35, a component of the retromer, interact with Tfrc to sort it to the recycling endosomes. Our findings uncover a role of Snx3 in regulating Tfrc recycling, iron homeostasis, and erythropoiesis. Thus, the identification of Snx3 provides a genetic tool for exploring erythropoiesis and disorders of iron metabolism.National Institutes of Health (U.S.) (P01 HL032262

Facilitated Monocyte-Macrophage Uptake and Tissue Distribution of Superparmagnetic Iron-Oxide Nanoparticles

BACKGROUND: We posit that the same mononuclear phagocytes (MP) that serve as target cells and vehicles for a host of microbial infections can be used to improve diagnostics and drug delivery. We also theorize that physical and biological processes such as particle shape, size, coating and opsonization that affect MP clearance of debris and microbes can be harnessed to facilitate uptake of nanoparticles (NP) and tissue delivery. METHODS: Monocytes and monocyte-derived macrophages (MDM) were used as vehicles of superparamagnetic iron oxide (SPIO) NP and immunoglobulin (IgG) or albumin coated SPIO for studies of uptake and distribution. IgG coated SPIO was synthesized by covalent linkage and uptake into monocytes and MDM investigated related to size, time, temperature, concentration, and coatings. SPIO and IgG SPIO were infused intravenously into naïve mice. T(2) measures using magnetic resonance imaging (MRI) were used to monitor tissue distribution in animals. RESULTS: Oxidation of dextran on the SPIO surface generated reactive aldehyde groups and permitted covalent linkage to amino groups of murine and human IgG and F(ab')(2) fragments and for Alexa Fluor(R) 488 hydroxylamine to form a Schiff base. This labile intermediate was immediately reduced with sodium cyanoborohydride in order to stabilize the NP conjugate. Optical density measurements of the oxidized IgG, F(ab')(2), and/or Alexa Fluor(R) 488 SPIO demonstrated approximately 50% coupling yield. IgG-SPIO was found stable at 4 degrees C for a period of 1 month during which size and polydispersity index varied little from 175 nm and 200 nm, respectively. In vitro, NP accumulated readily within monocyte and MDM cytoplasm after IgG-SPIO exposure; whereas, the uptake of native SPIO in monocytes and MDM was 10-fold less. No changes in cell viability were noted for the SPIO-containing monocytes and MDM. Cell morphology was not changed as observed by transmission electron microscopy. Compared to unconjugated SPIO, intravenous injection of IgG-SPIO afforded enhanced and sustained lymphoid tissue distribution over 24 hours as demonstrated by MRI. CONCLUSIONS: Facilitated uptake of coated SPIO in monocytes and MDM was achieved. Uptake was linked to particle size and was time and concentration dependent. The ability of SPIO to be rapidly taken up and distributed into lymphoid tissues also demonstrates feasibility of macrophage-targeted nanoformulations for diagnostic and drug therapy