144 research outputs found
Res Medica, April 1967, Special Issue – Lauder Brunton Centenary Symposium on Angina Pectoris
WelcomeHistorical SessionOpening AddressLauder BruntonHistory of Angina Pathophysiological SessionThe Pathology of AnginaExperimental Studies on the Myocardial Collateral CirculationFirst DiscussionCoronary Blood Flow and Myocardial Metabolism in Angina PectorisCardiac Function in Patients with AnginaSecond Discussion Therapeutic SessionThe Modern EpidemicIs Angina Preventable?Third DiscussionChest Pain, Exercise Electrocardiography and Coronary Arteriography(Correlative Studies in Angina PectorisPrognosis of Angina PectorisPanel DiscussionSumming U
Anomaly Equations and Intersection Theory
Six-dimensional supergravity theories with N=(1,0) supersymmetry must satisfy
anomaly equations. These equations come from demanding the cancellation of
gravitational, gauge and mixed anomalies. The anomaly equations have
implications for the geometrical data of Calabi-Yau threefolds, since F-theory
compactified on an elliptically fibered Calabi-Yau threefold with a section
generates a consistent six-dimensional N=(1,0) supergravity theory. In this
paper, we show that the anomaly equations can be summarized by three
intersection theory identities. In the process we also identify the geometric
counterpart of the anomaly coefficients---in particular, those of the abelian
gauge groups---that govern the low-energy dynamics of the theory. We discuss
the results in the context of investigating string universality in six
dimensions.Comment: 29 pages + appendices, 8 figures; v2: minor corrections, references
added; v3: minor corrections, reference adde
Explicit de Sitter Flux Vacua for Global String Models with Chiral Matter
We address the open question of performing an explicit stabilisation of all
closed string moduli (including dilaton, complex structure and Kaehler moduli)
in fluxed type IIB Calabi-Yau compactifications with chiral matter. Using toric
geometry we construct Calabi-Yau manifolds with del Pezzo singularities.
D-branes located at such singularities can support the Standard Model gauge
group and matter content. In order to control complex structure moduli
stabilisation we consider Calabi-Yau manifolds which exhibit a discrete
symmetry that reduces the effective number of complex structure moduli. We
calculate the corresponding periods in the symplectic basis of invariant
three-cycles and find explicit flux vacua for concrete examples. We compute the
values of the flux superpotential and the string coupling at these vacua.
Starting from these explicit complex structure solutions, we obtain AdS and dS
minima where the Kaehler moduli are stabilised by a mixture of D-terms,
non-perturbative and perturbative alpha'-corrections as in the LARGE Volume
Scenario. In the considered example the visible sector lives at a dP_6
singularity which can be higgsed to the phenomenologically interesting class of
models at the dP_3 singularity.Comment: 49 pages, 5 figures; v2: references adde
Kuhnian revolutions in neuroscience: the role of tool development.
The terms "paradigm" and "paradigm shift" originated in "The Structure of Scientific Revolutions" by Thomas Kuhn. A paradigm can be defined as the generally accepted concepts and practices of a field, and a paradigm shift its replacement in a scientific revolution. A paradigm shift results from a crisis caused by anomalies in a paradigm that reduce its usefulness to a field. Claims of paradigm shifts and revolutions are made frequently in the neurosciences. In this article I will consider neuroscience paradigms, and the claim that new tools and techniques rather than crises have driven paradigm shifts. I will argue that tool development has played a minor role in neuroscience revolutions.The work received no fundin
Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer
Drugs that inhibit estrogen receptor-α (ER) activity have been highly successful in treating and reducing breast cancer progression in ER-positive disease. However, resistance to these therapies presents a major clinical problem. Recent genetic studies have shown that mutations in the ER gene are found in >20% of tumours that progress on endocrine therapies. Remarkably, the great majority of these mutations localize to just a few amino acids within or near the critical helix 12 region of the ER hormone binding domain, where they are likely to be single allele mutations. Understanding how these mutations impact on ER function is a prerequisite for identifying methods to treat breast cancer patients featuring such mutations. Towards this end, we used CRISPR-Cas9 genome editing to make a single allele knock-in of the most commonly mutated amino acid residue, tyrosine 537, in the estrogen-responsive MCF7 breast cancer cell line. Genomic analyses using RNA-seq and ER ChIP-seq demonstrated that the Y537S mutation promotes constitutive ER activity globally, resulting in estrogen-independent growth. MCF7-Y537S cells were resistant to the anti-estrogen tamoxifen and fulvestrant. Further, we show that the basal transcription factor TFIIH is constitutively recruited by ER-Y537S, resulting in ligand-independent phosphorylation of Serine 118 (Ser118) by the TFIIH kinase, cyclin-dependent kinase (CDK)7. The CDK7 inhibitor, THZ1 prevented Ser118 phosphorylation and inhibited growth of MCF7-Y537S cells. These studies confirm the functional importance of ER mutations in endocrine resistance, demonstrate the utility of knock-in mutational models for investigating alternative therapeutic approaches and highlight CDK7 inhibition as a potential therapy for endocrine-resistant breast cancer mediated by ER mutations
Quiver gauge theories: beyond reflexivity
Reflexive polygons have been extensively studied in a variety of contexts in mathematics and physics. We generalize this programme by looking at the 45 different lattice polygons with two interior points up to SL(2,ℤ) equivalence. Each corresponds to some affine toric 3-fold as a cone over a Sasaki-Einstein 5-fold. We study the quiver gauge theories of D3-branes probing these cones, which coincide with the mesonic moduli space. The minimum of the volume function of the Sasaki-Einstein base manifold plays an important role in computing the R-charges. We analyze these minimized volumes with respect to the topological quantities of the compact surfaces constructed from the polygons. Unlike reflexive polytopes, one can have two fans from the two interior points, and hence give rise to two smooth varieties after complete resolutions, leading to an interesting pair of closely related geometries and gauge theories
On the structure of quadrilateral brane tilings
Brane tilings provide the most general framework in string and M-theory for
matching toric Calabi-Yau singularities probed by branes with superconformal
fixed points of quiver gauge theories. The brane tiling data consists of a
bipartite tiling of the torus which encodes both the classical superpotential
and gauge-matter couplings for the quiver gauge theory. We consider the class
of tilings which contain only tiles bounded by exactly four edges and present a
method for generating any tiling within this class by iterating combinations of
certain graph-theoretic moves. In the context of D3-branes in IIB string
theory, we consider the effect of these generating moves within the
corresponding class of supersymmetric quiver gauge theories in four dimensions.
Of particular interest are their effect on the superpotential, the vacuum
moduli space and the conditions necessary for the theory to reach a
superconformal fixed point in the infrared. We discuss the general structure of
physically admissible quadrilateral brane tilings and Seiberg duality in terms
of certain composite moves within this class.Comment: 57 pages, 22 figure
FKBP12 Activates the Cardiac Ryanodine Receptor Ca2+-Release Channel and Is Antagonised by FKBP12.6
Changes in FKBP12.6 binding to cardiac ryanodine receptors (RyR2) are implicated in mediating disturbances in Ca2+-homeostasis in heart failure but there is controversy over the functional effects of FKBP12.6 on RyR2 channel gating. We have therefore investigated the effects of FKBP12.6 and another structurally similar molecule, FKBP12, which is far more abundant in heart, on the gating of single sheep RyR2 channels incorporated into planar phospholipid bilayers and on spontaneous waves of Ca2+-induced Ca2+-release in rat isolated permeabilised cardiac cells. We demonstrate that FKBP12 is a high affinity activator of RyR2, sensitising the channel to cytosolic Ca2+, whereas FKBP12.6 has very low efficacy, but can antagonise the effects of FKBP12. Mathematical modelling of the data shows the importance of the relative concentrations of FKBP12 and FKBP12.6 in determining RyR2 activity. Consistent with the single-channel results, physiological concentrations of FKBP12 (3 µM) increased Ca2+-wave frequency and decreased the SR Ca2+-content in cardiac cells. FKBP12.6, itself, had no effect on wave frequency but antagonised the effects of FKBP12
NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration
<p>Abstract</p> <p>Background</p> <p>Activation of microglia causes the production of proinflammatory factors and upregulation of NADPH oxidase (NOX) that form reactive oxygen species (ROS) that lead to neurodegeneration. Previously, we reported that 10 daily doses of ethanol treatment induced innate immune genes in brain. In the present study, we investigate the effects of chronic ethanol on activation of NOX and release of ROS, and their contribution to ethanol neurotoxicity.</p> <p>Methods</p> <p>Male C57BL/6 and NF-κB enhanced GFP mice were treated intragastrically with water or ethanol (5 g/kg, i.g., 25% ethanol w/v) daily for 10 days. The effects of chronic ethanol on cell death markers (activated caspase-3 and Fluoro-Jade B), microglial morphology, NOX, ROS and NF-κB were examined using real-time PCR, immunohistochemistry and hydroethidine histochemistry. Also, Fluoro-Jade B staining and NOX gp91<sup>phox </sup>immunohistochemistry were performed in the orbitofrontal cortex (OFC) of human postmortem alcoholic brain and human moderate drinking control brain.</p> <p>Results</p> <p>Ethanol treatment of C57BL/6 mice showed increased markers of neuronal death: activated caspase-3 and Fluoro-Jade B positive staining with Neu-N (a neuronal marker) labeling in cortex and dentate gyrus. The OFC of human post-mortem alcoholic brain also showed significantly more Fluoro-Jade B positive cells colocalized with Neu-N, a neuronal marker, compared to the OFC of human moderate drinking control brain, suggesting increased neuronal death in the OFC of human alcoholic brain. Iba1 and GFAP immunohistochemistry showed activated morphology of microglia and astrocytes in ethanol-treated mouse brain. Ethanol treatment increased NF-κB transcription and increased NOX gp91<sup>phox </sup>at 24 hr after the last ethanol treatment that remained elevated at 1 week. The OFC of human postmortem alcoholic brain also had significant increases in the number of gp91<sup>phox </sup>+ immunoreactive (IR) cells that are colocalized with neuronal, microglial and astrocyte markers. In mouse brain ethanol increased gp91<sup>phox </sup>expression coincided with increased production of O<sub>2</sub><sup>- </sup>and O<sub>2</sub><sup>- </sup>- derived oxidants. Diphenyleneiodonium (DPI), a NOX inhibitor, reduced markers of neurodegeneration, ROS and microglial activation.</p> <p>Conclusions</p> <p>Ethanol activation of microglia and astrocytes, induction of NOX and production of ROS contribute to chronic ethanol-induced neurotoxicity. NOX-ROS and NF-κB signaling pathways play important roles in chronic ethanol-induced neuroinflammation and neurodegeneration.</p
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