DLC2 modulates angiogenic responses in vascular endothelial cells by regulating cell attachment and migration.

Deleted in liver cancer 1 (DLC1) is a RhoGTPase activation protein-containing tumor suppressor that associates with various types of cancer. Although DLC2 shares a similar domain structure with that of DLC1, the function of DLC2 is not well characterized. Here, we describe the expression and ablation of DLC2 in mice using a reporter-knockout approach. DLC2 is expressed in several tissues and in endothelial cells (ECs) of blood vessels. Although ECs and blood vessels show no histological abnormalities and mice appear overall healthy, DLC2-mutant mice display enhanced angiogenic responses induced by matrigel and by tumor cells. Silencing of DLC2 in human ECs has reduced cell attachment, increased migration, and tube formation. These changes are rescued by silencing of RhoA, suggesting that the process is RhoA pathway dependent. These results indicate that DLC2 is not required for mouse development and normal vessel formation, but may protect mouse from unwanted angiogenesis induced by, for example, tumor cells

LSD1 is essential for oocyte meiotic progression by regulating CDC25B expression in mice

Mammalian oocytes are arrested at prophase I until puberty when hormonal signals induce the resumption of meiosis I and progression to meiosis II. Meiotic progression is controlled by CDK1 activity and is accompanied by dynamic epigenetic changes. Although the signalling pathways regulating CDK1 activity are well defined, the functional significance of epigenetic changes remains largely unknown. Here we show that LSD1, a lysine demethylase, regulates histone H3 lysine 4 di-methylation (H3K4me2) in mouse oocytes and is essential for meiotic progression. Conditional deletion of Lsd1 in growing oocytes results in precocious resumption of meiosis and spindle and chromosomal abnormalities. Consequently, most Lsd1-null oocytes fail to complete meiosis I and undergo apoptosis. Mechanistically, upregulation of CDC25B, a phosphatase that activates CDK1, is responsible for precocious meiotic resumption and also contributes to subsequent spindle and chromosomal defects. Our findings uncover a functional link between LSD1 and the major signalling pathway governing meiotic progression

Deletion within the Src homology domain 3 of Bruton's tyrosine kinase resulting in X-linked agammaglobulinemia (XLA).

The gene responsible for X-linked agammaglobulinemia (XLA) has been recently identified to code for a cytoplasmic tyrosine kinase (Bruton's agammaglobulinemia tyrosine kinase, BTK), required for normal B cell development. BTK, like many other cytoplasmic tyrosine kinases, contains Src homology domains (SH2 and SH3), and catalytic kinase domain. SH3 domains are important for the targeting of signaling molecules to specific subcellular locations. We have identified a family with XLA whose affected members have a point mutation (g-->a) at the 5' splice site of intron 8, resulting in the skipping of coding exon 8 and loss of 21 amino acids forming the COOH-terminal portion of the BTK SH3 domain. The study of three generations within this kinship, using restriction fragment length polymorphism and DNA analysis, allowed identification of the mutant X chromosome responsible for XLA and the carrier status in this family. BTK mRNA was present in normal amounts in Epstein-Barr virus-induced B lymphoblastoid cell lines established from affected family members. Although the SH3 deletion did not alter BTK protein stability and kinase activity of the truncated BTK protein was normal, the affected patients nevertheless have a severe B cell defect characteristic for XLA. The mutant protein was modeled using the normal BTK SH3 domain. The deletion results in loss of two COOH-terminal beta strands containing several residues critical for the formation of the putative SH3 ligand-binding pocket. We predict that, as a result, one or more crucial SH3 binding proteins fail to interact with BTK, interrupting the cytoplasmic signal transduction process required for B cell differentiation

Theory of STM Spectroscopy of Kondo Ions on Metal Surfaces

The conduction electron density of states nearby a single magnetic impurity, as measured recently by scanning tunneling microscopy (STM), is calculated. It is shown that the Kondo effect induces a narrow Fano resonance as an intrinsic feature in the conduction electron density of states. The line shape varies with the distance between STM tip and impurity, in qualitative agreement with experiments, and is sensitive to details of the band structure. For a Co impurity the experimentally observed width and shift of the Kondo resonance are in accordance with those obtained from a combination of band structure and strongly correlated calculations.Comment: 5 pages, 4 figures, presented at the NATO Advanced Research Workshop on "Size Dependent Magnetic Scattering", Pecs, Hungary, May 28 - June 1, 200

Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

GUT theories from Calabi-Yau 4-folds with SO(10) Singularities

We consider an SO(10) GUT model from F-theory compactified on an elliptically fibered Calabi-Yau with a D5 singularity. To obtain the matter curves and the Yukawa couplings, we use a global description to resolve the singularity. We identify the vector and spinor matter representations and their Yukawa couplings and we explicitly build the G-fluxes in the global model and check the agreement with the semi-local results. As our bundle is of type SU(2k), some extra conditions need to be applied to match the fluxes.Comment: 27 page

Conductivity of twin walls - surface junctions in ferroelastics: interplay of deformation potential, octahedral rotations, improper ferroelectricity and flexoelectric coupling

Electronic and structural phenomena at the twin domain wall-surface junctions in the ferroelastic materials are analyzed. Carriers accumulation caused by the strain-induced band structure changes originated via the deformation potential mechanism, structural order parameter gradient, rotostriction and flexoelectric coupling is explored. Approximate analytical results show that inhomogeneous elastic strains, which exist in the vicinity of the twin walls - surface junctions due to the rotostriction coupling, decrease the local band gap via the deformation potential and flexoelectric coupling mechanisms. This is the direct mechanism of the twin walls static conductivity in ferroelastics and, by extension, in multiferroics and ferroelectrics. On the other hand, flexoelectric and rotostriction coupling leads to the appearance of the improper polarization and electric fields proportional to the structural order parameter gradient in the vicinity of the twin walls - surface junctions. The "flexo-roto" fields leading to the carrier accumulation are considered as indirect mechanism of the twin walls conductivity. Comparison of the direct and indirect mechanisms illustrates complex range of phenomena directly responsible for domain walls static conductivity in materials with multiple order parameters.Comment: 35 pages, 11 figures, 3 table, 3 appendices Improved set of rotostriction coefficients are used in calculation

Inhibition decorrelates visual feature representations in the inner retina

The retina extracts visual features for transmission to the brain. Different types of bipolar cell split the photoreceptor input into parallel channels and provide the excitatory drive for downstream visual circuits. Mouse bipolar cell types have been described at great anatomical and genetic detail, but a similarly deep understanding of their functional diversity is lacking. Here, by imaging light-driven glutamate release from more than 13,000 bipolar cell axon terminals in the intact retina, we show that bipolar cell functional diversity is generated by the interplay of dendritic excitatory inputs and axonal inhibitory inputs. The resulting centre and surround components of bipolar cell receptive fields interact to decorrelate bipolar cell output in the spatial and temporal domains. Our findings highlight the importance of inhibitory circuits in generating functionally diverse excitatory pathways and suggest that decorrelation of parallel visual pathways begins as early as the second synapse of the mouse visual system

Rigidly Supersymmetric Gauge Theories on Curved Superspace

In this note we construct rigidly supersymmetric gauged sigma models and gauge theories on certain Einstein four-manifolds, and discuss constraints on these theories. In work elsewhere, it was recently shown that on some nontrivial Einstein four-manifolds such as AdS$_4$, N=1 rigidly supersymmetric sigma models are constrained to have target spaces with exact K\"ahler forms. Similarly, in gauged sigma models and gauge theories, we find that supersymmetry imposes constraints on Fayet-Iliopoulos parameters, which have the effect of enforcing that K\"ahler forms on quotient spaces be exact. We also discuss general aspects of universality classes of gauged sigma models, as encoded by stacks, and also discuss affine bundle structures implicit in these constructions.Comment: 23 pages; references added; more discussion added; v4: typos fixe

Chylous effusion presenting in a 37-year-old woman with severe hypothyroidism: a case report

<p>Abstract</p> <p>Introduction</p> <p>We report what is to the best of our knowledge the second adult case of chylothorax clearly associated with severe hypothyroidism in the English-language medical literature. To the best of our knowledge, this is the first case of its kind reported without a prior history of malignancy.</p> <p>Case presentation</p> <p>A 37-year-old Hispanic woman with no reported significant past medical history initially presented with shortness of breath and inability to lose weight. She was found to have a large chylous effusion requiring chest-tube drainage, as well as severe hypothyroidism. After several weeks of thyroid hormone-replacement therapy, the formation of chylous pleural fluid in the patient greatly diminished, and the chest tube was removed. Upon long-term follow-up her minimal residual effusion remains stable on serial chest radiographs.</p> <p>Conclusion</p> <p>Although the exact pathophysiologic relation between low thyroid hormone levels and chyle formation remains to be elucidated, hypothyroidism should be a diagnostic consideration in patients with chylous effusions, especially those refractory to conventional treatments.</p