Actions for Vacuum Einstein's Equation with a Killing Symmetry

In a space-time $M$ with a Killing vector field $\xi^a$ which is either everywhere timelike or everywhere spacelike, the collection of all trajectories of $\xi^a$ gives a 3-dimension space $S$. Besides the symmetry-reduced action from that of Einstein-Hilbert, an alternative action of the fields on $S$ is also proposed, which gives the same fields equations as those reduced from the vacuum Einstein equation on $M$.Comment: 8 pages, the difference between the action we proposed and the symmetry-reduced action is clarifie

The fibroblast Tiam1-osteopontin pathway modulates breast cancer invasion and metastasis

Background The tumor microenvironment has complex effects in cancer pathophysiology that are not fully understood. Most cancer therapies are directed against malignant cells specifically, leaving pro-malignant signals from the microenvironment unaddressed. Defining specific mechanisms by which the tumor microenvironment contributes to breast cancer metastasis may lead to new therapeutic approaches against advanced breast cancer. Methods We use a novel method for manipulating three-dimensional mixed cell co-cultures, along with studies in mouse xenograft models of human breast cancer and a histologic study of human breast cancer samples, to investigate how breast cancer-associated fibroblasts affect the malignant behaviors of breast cancer cells. Results Altering fibroblast Tiam1 expression induces changes in invasion, migration, epithelial-mesenchymal transition, and cancer stem cell characteristics in associated breast cancer cells. These changes are both dependent on fibroblast secretion of osteopontin and also long-lasting even after cancer cell dissociation from the fibroblasts, indicating a novel Tiam1-osteopontin pathway in breast cancer-associated fibroblasts. Notably, inhibition of fibroblast osteopontin with low doses of a novel small molecule prevents lung metastasis in a mouse model of human breast cancer metastasis. Moreover, fibroblast expression patterns of Tiam1 and osteopontin in human breast cancers show converse changes correlating with invasion, supporting the hypothesis that this pathway in tumor-associated fibroblasts regulates breast cancer invasiveness in human disease and is thus clinically relevant. Conclusions These findings suggest a new therapeutic paradigm for preventing breast cancer metastasis. Pro-malignant signals from the tumor microenvironment with long-lasting effects on associated cancer cells may perpetuate the metastatic potential of developing cancers. Inhibition of these microenvironment signals represents a new therapeutic strategy against cancer metastasis that enables targeting of stromal cells with less genetic plasticity than associated cancer cells and opens new avenues for investigation of novel therapeutic targets and agents.National Institute of General Medical Sciences (U.S.) (GM074825

Intermediate filament–membrane attachments function synergistically with actin-dependent contacts to regulate intercellular adhesive strength

By tethering intermediate filaments (IFs) to sites of intercellular adhesion, desmosomes facilitate formation of a supercellular scaffold that imparts mechanical strength to a tissue. However, the role IF–membrane attachments play in strengthening adhesion has not been directly examined. To address this question, we generated Tet-On A431 cells inducibly expressing a desmoplakin (DP) mutant lacking the rod and IF-binding domains (DPNTP). DPNTP localized to the plasma membrane and led to dissociation of IFs from the junctional plaque, without altering total or cell surface distribution of adherens junction or desmosomal proteins. However, a specific decrease in the detergent-insoluble pool of desmoglein suggested a reduced association with the IF cytoskeleton. DPNTP-expressing cell aggregates in suspension or substrate-released cell sheets readily dissociated when subjected to mechanical stress whereas controls remained largely intact. Dissociation occurred without lactate dehydrogenase release, suggesting that loss of tissue integrity was due to reduced adhesion rather than increased cytolysis. JD-1 cells from a patient with a DP COOH-terminal truncation were also more weakly adherent compared with normal keratinocytes. When used in combination with DPNTP, latrunculin A, which disassembles actin filaments and disrupts adherens junctions, led to dissociation up to an order of magnitude greater than either treatment alone. These data provide direct in vitro evidence that IF–membrane attachments regulate adhesive strength and suggest furthermore that actin- and IF-based junctions act synergistically to strengthen adhesion

Efficient Derivation of Human Cardiac Precursors and Cardiomyocytes from Pluripotent Human Embryonic Stem Cells with Small Molecule Induction

To date, the lack of a suitable human cardiac cell source has been the major setback in regenerating the human myocardium, either by cell-based transplantation or by cardiac tissue engineering. Cardiomyocytes become terminally-differentiated soon after birth and lose their ability to proliferate. There is no evidence that stem/progenitor cells derived from other sources, such as the bone marrow or the cord blood, are able to give rise to the contractile heart muscle cells following transplantation into the heart. The need to regenerate or repair the damaged heart muscle has not been met by adult stem cell therapy, either endogenous or via cell delivery. The genetically stable human embryonic stem cells (hESCs) have unlimited expansion ability and unrestricted plasticity, proffering a pluripotent reservoir for in vitro derivation of large supplies of human somatic cells that are restricted to the lineage in need of repair and regeneration. Due to the prevalence of cardiovascular disease worldwide and acute shortage of donor organs, there is intense interest in developing hESC-based therapies as an alternative approach. However, how to channel the wide differentiation potential of pluripotent hESCs efficiently and predictably to a desired phenotype has been a major challenge for both developmental study and clinical translation. Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, resulting in inefficient and uncontrollable lineage-commitment that is often followed by phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity (see a schematic in Fig. 1A). In addition, undefined foreign/animal biological supplements and/or feeders that have typically been used for the isolation, expansion, and differentiation of hESCs may make direct use of such cell-specialized grafts in patients problematic. To overcome these obstacles, we have resolved the elements of a defined culture system necessary and sufficient for sustaining the epiblast pluripotence of hESCs, serving as a platform for de novo derivation of clinically-suitable hESCs and effectively directing such hESCs uniformly towards clinically-relevant lineages by small molecules (see a schematic in Fig. 1B). After screening a variety of small molecules and growth factors, we found that such defined conditions rendered nicotinamide (NAM) sufficient to induce the specification of cardiomesoderm direct from pluripotent hESCs that further progressed to cardioblasts that generated human beating cardiomyocytes with high efficiency (Fig. 2). We defined conditions for induction of cardioblasts direct from pluripotent hESCs without an intervening multi-lineage embryoid body stage, enabling well-controlled efficient derivation of a large supply of human cardiac cells across the spectrum of developmental stages for cell-based therapeutics

GPU-based Fast Low-dose Cone Beam CT Reconstruction via Total Variation

Cone-beam CT (CBCT) has been widely used in image guided radiation therapy (IGRT) to acquire updated volumetric anatomical information before treatment fractions for accurate patient alignment purpose. However, the excessive x-ray imaging dose from serial CBCT scans raises a clinical concern in most IGRT procedures. The excessive imaging dose can be effectively reduced by reducing the number of x-ray projections and/or lowering mAs levels in a CBCT scan. The goal of this work is to develop a fast GPU-based algorithm to reconstruct high quality CBCT images from undersampled and noisy projection data so as to lower the imaging dose. The CBCT is reconstructed by minimizing an energy functional consisting of a data fidelity term and a total variation regularization term. We developed a GPU-friendly version of the forward-backward splitting algorithm to solve this model. A multi-grid technique is also employed. We test our CBCT reconstruction algorithm on a digital NCAT phantom and a head-and-neck patient case. The performance under low mAs is also validated using a physical Catphan phantom and a head-and-neck Rando phantom. It is found that 40 x-ray projections are sufficient to reconstruct CBCT images with satisfactory quality for IGRT patient alignment purpose. Phantom experiments indicated that CBCT images can be successfully reconstructed with our algorithm under as low as 0.1 mAs/projection level. Comparing with currently widely used full-fan head-and-neck scanning protocol of about 360 projections with 0.4 mAs/projection, it is estimated that an overall 36 times dose reduction has been achieved with our algorithm. Moreover, the reconstruction time is about 130 sec on an NVIDIA Tesla C1060 GPU card, which is estimated ~100 times faster than similar iterative reconstruction approaches.Comment: 20 pages, 10 figures, Paper was revised and more testing cases were added

3D tumor localization through real-time volumetric x-ray imaging for lung cancer radiotherapy

Recently we have developed an algorithm for reconstructing volumetric images and extracting 3D tumor motion information from a single x-ray projection. We have demonstrated its feasibility using a digital respiratory phantom with regular breathing patterns. In this work, we present a detailed description and a comprehensive evaluation of the improved algorithm. The algorithm was improved by incorporating respiratory motion prediction. The accuracy and efficiency were then evaluated on 1) a digital respiratory phantom, 2) a physical respiratory phantom, and 3) five lung cancer patients. These evaluation cases include both regular and irregular breathing patterns that are different from the training dataset. For the digital respiratory phantom with regular and irregular breathing, the average 3D tumor localization error is less than 1 mm. On an NVIDIA Tesla C1060 GPU card, the average computation time for 3D tumor localization from each projection ranges between 0.19 and 0.26 seconds, for both regular and irregular breathing, which is about a 10% improvement over previously reported results. For the physical respiratory phantom, an average tumor localization error below 1 mm was achieved with an average computation time of 0.13 and 0.16 seconds on the same GPU card, for regular and irregular breathing, respectively. For the five lung cancer patients, the average tumor localization error is below 2 mm in both the axial and tangential directions. The average computation time on the same GPU card ranges between 0.26 and 0.34 seconds

Efficient Derivation of Human Neuronal Progenitors and Neurons from Pluripotent Human Embryonic Stem Cells with Small Molecule Induction

There is a large unfulfilled need for a clinically-suitable human neuronal cell source for repair or regeneration of the damaged central nervous system (CNS) structure and circuitry in today's healthcare industry. Cell-based therapies hold great promise to restore the lost nerve tissue and function for CNS disorders. However, cell therapies based on CNS-derived neural stem cells have encountered supply restriction and difficulty to use in the clinical setting due to their limited expansion ability in culture and failing plasticity after extensive passaging1-3. Despite some beneficial outcomes, the CNS-derived human neural stem cells (hNSCs) appear to exert their therapeutic effects primarily by their non-neuronal progenies through producing trophic and neuroprotective molecules to rescue the endogenous cells1-3. Alternatively, pluripotent human embryonic stem cells (hESCs) proffer cures for a wide range of neurological disorders by supplying the diversity of human neuronal cell types in the developing CNS for regeneration1,4-7. However, how to channel the wide differentiation potential of pluripotent hESCs efficiently and predictably to a desired phenotype has been a major challenge for both developmental study and clinical translation. Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, resulting in inefficient and uncontrollable lineage-commitment that is often followed by phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity7-10. In addition, undefined foreign/animal biological supplements and/or feeders that have typically been used for the isolation, expansion, and differentiation of hESCs may make direct use of such cell-specialized grafts in patients problematic11-13. To overcome these obstacles, we have resolved the elements of a defined culture system necessary and sufficient for sustaining the epiblast pluripotence of hESCs, serving as a platform for de novo derivation of clinically-suitable hESCs and effectively directing such hESCs uniformly towards clinically-relevant lineages by small molecules14 (please see a schematic in Fig. 1). Retinoic acid (RA) does not induce neuronal differentiation of undifferentiated hESCs maintained on feeders1, 14. And unlike mouse ESCs, treating hESC-differentiated embryoid bodies (EBs) only slightly increases the low yield of neurons1, 14, 15. However, after screening a variety of small molecules and growth factors, we found that such defined conditions rendered retinoic acid (RA) sufficient to induce the specification of neuroectoderm direct from pluripotent hESCs that further progressed to neuroblasts that generated human neuronal progenitors and neurons in the developing CNS with high efficiency (Fig. 2). We defined conditions for induction of neuroblasts direct from pluripotent hESCs without an intervening multi-lineage embryoid body stage, enabling well-controlled efficient derivation of a large supply of human neuronal cells across the spectrum of developmental stages for cell-based therapeutics

Laughlin liquid - Wigner solid transition at high density in wide quantum wells

Assuming that the phase transition between the Wigner solid and the Laughlin liquid is first-order, we compare ground-state energies to find features of the phase diagram at fixed $\nu$. Rather than use the Coulomb interaction, we calculate the effective interaction in a square quantum well, and fit the results to a model interaction with length parameter $\lambda$ roughly proportional to the width of the well. We find a transition to the Wigner solid phase at high density in very wide wells, driven by the softening of the interaction at short distances, as well as the more well-known transition to the Wigner solid at low density, driven by Landau-level mixing.Comment: RevTeX 3.0, 3 Postscript figures appended in uuencoded forma

Engineering Superfluidity in Electron-Hole Double Layers

We show that band-structure effects are likely to prevent superfluidity in semiconductor electron-hole double-layer systems. We suggest the possibility that superfluidity could be realized by the application of uniaxial pressure perpendicular to the electron and hole layers.Comment: 4 pages, includes 3 figure

Excitonic condensation in a symmetric electron-hole bilayer

Using Diffusion Monte Carlo simulations we have investigated the ground state of a symmetric electron-hole bilayer and determined its phase diagram at T=0. We find clear evidence of an excitonic condensate, whose stability however is affected by in-layer electronic correlation. This stabilizes the electron-hole plasma at large values of the density or inter-layer distance, and the Wigner crystal at low density and large distance. We have also estimated pair correlation functions and low order density matrices, to give a microscopic characterization of correlations, as well as to try and estimate the condensate fraction.Comment: 4 pages, 3 figures, 2 table