The spacetime structure of MOND with Tully-Fisher relation and Lorentz invariance violation

It is believed that the modification of Newtonian dynamics (MOND) is possible alternate for dark matter hypothesis. Although Bekenstein's TeVeS supplies a relativistic version of MOND, one may still wish a more concise covariant formulism of MOND. In this paper, within covariant geometrical framwork, we present another version of MOND. We show the spacetime structure of MOND with properties of Tully-Fisher relation and Lorentz invariance violation.Comment: 6 pages. arXiv admin note: substantial text overlap with arXiv:1111.1383 and arXiv:1108.344

Multiobjective optimization of water distribution systems accounting for economic cost, hydraulic reliability, and greenhouse gas emissions

In this paper, three objectives are considered for the optimization of water distribution systems (WDSs): the traditional objectives of minimizing economic cost and maximizing hydraulic reliability and the recently proposed objective of minimizing greenhouse gas (GHG) emissions. It is particularly important to include the GHG minimization objective for WDSs involving pumping into storages or water transmission systems (WTSs), as these systems are the main contributors of GHG emissions in the water industry. In order to better understand the nature of tradeoffs among these three objectives, the shape of the solution space and the location of the Pareto-optimal front in the solution space are investigated for WTSs and WDSs that include pumping into storages, and the implications of the interaction between the three objectives are explored from a practical design perspective. Through three case studies, it is found that the solution space is a U-shaped curve rather than a surface, as the tradeoffs among the three objectives are dominated by the hydraulic reliability objective. The Pareto-optimal front of real-world systems is often located at the "elbow" section and lower "arm" of the solution space (i.e., the U-shaped curve), indicating that it is more economic to increase the hydraulic reliability of these systems by increasing pipe capacity (i.e., pipe diameter) compared to increasing pumping power. Solutions having the same GHG emission level but different cost-reliability tradeoffs often exist. Therefore, the final decision needs to be made in conjunction with expert knowledge and the specific budget and reliability requirements of the system. © 2013. American Geophysical Union. All Rights Reserved.Wenyan Wu, Holger R. Maier, and Angus R. Simpso

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential

Expression of the RNA helicase DDX3 and the hypoxia response in breast cancer

<p>Aims: DDX3 is an RNA helicase that has antiapoptotic properties, and promotes proliferation and transformation. In addition, DDX3 was shown to be a direct downstream target of HIF-1α (the master regulatory of the hypoxia response) in breast cancer cell lines. However, the relation between DDX3 and hypoxia has not been addressed in human tumors. In this paper, we studied the relation between DDX3 and the hypoxic responsive proteins in human breast cancer.</p> <p>Methods and Results: DDX3 expression was investigated by immunohistochemistry in breast cancer in comparison with hypoxia related proteins HIF-1α, GLUT1, CAIX, EGFR, HER2, Akt1, FOXO4, p53, ERα, COMMD1, FER kinase, PIN1, E-cadherin, p21, p27, Transferrin receptor, FOXO3A, c-Met and Notch1. DDX3 was overexpressed in 127 of 366 breast cancer patients, and was correlated with overexpression of HIF-1α and its downstream genes CAIX and GLUT1. Moreover, DDX3 expression correlated with hypoxia-related proteins EGFR, HER2, FOXO4, ERα and c-Met in a HIF-1α dependent fashion, and with COMMD1, FER kinase, Akt1, E-cadherin, TfR and FOXO3A independent of HIF-1α.</p> <p>Conclusions: In invasive breast cancer, expression of DDX3 was correlated with overexpression of HIF-1α and many other hypoxia related proteins, pointing to a distinct role for DDX3 under hypoxic conditions and supporting the oncogenic role of DDX3 which could have clinical implication for current development of DDX3 inhibitors.</p&gt

The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin

Tissue-resident memory T cells (T(RM) cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103(+)CD8(+) T(RM) cells developed in the skin from epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-β (TGF-β) was required for the formation of these long-lived memory cells. Notably, differentiation into T(RM) cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues.Supported by National Health and Medical Research Council of Australia and Australian Research Council

Gravitational deflection of light in Rindler-type potential as a possible resolution to the observations of Bullet Cluster 1E0657-558

The surface density $\Sigma$-map and the convergence $\kappa$-map of Bullet Cluster 1E0657-558 show that the center of baryonic matters separates from the center of gravitational force, and the distribution of gravitational force do not possess spherical symmetry. This hints that a modified gravity with difference to Newtonian inverse-square law at large scale, and less symmetry is worth investigating. In this paper, we study the dynamics in Randers-Finsler spacetime. The Newtonian limit and gravitational deflection of light in a Rindler-type potential is focused in particular. It is shown that the convergence in Finsler spacetime could account for the observations of Bullet Cluster.Comment: 11 page

Molecular Structural Differences between Type-2-Diabetic and Healthy Glycogen

Glycogen is a highly branched glucose polymer functioning as a glucose buffer in animals. Multiple-detector size exclusion chromatography and fluorophore-assisted carbohydrate electrophoresis were used to examine the structure of undegraded native liver glycogen (both whole and enzymatically debranched) as a function of molecular size, isolated from the livers of healthy and db/db mice (the latter a type 2 diabetic model). Both the fully branched and debranched levels of glycogen structure showed fundamental differences between glycogen from healthy and db/db mice. Healthy glycogen had a greater population of large particles, with more α particles (tightly linked assemblages of smaller β particles) than glycogen from db/db mice. These structural differences suggest a new understanding of type 2 diabetes

Pharmacogenomics of GLP-1 Receptor Agonists:a genome-wide analysis of observational data and large randomised controlled trials

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged >= 18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G -> A (Gly168Ser) in the GLP1R (0.08% [95% CI 0.04-0.12] or 0.9 mmol/mol lower reduction in HbA1c per serine, p=6.0 x 10(-5)) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6.7 x 10(-8)), largely driven by rs140226575G -> A (Thr370Met; 0.25% [SE 0.06] or 2.7 mmol/mol [SE 0.7] greater HbA1c reduction per methionine, p=5.2 x 10(-6)). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6-11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists

The Tensor-Vector-Scalar theory and its cosmology

Over the last few decades, astronomers and cosmologists have accumulated vast amounts of data clearly demonstrating that our current theories of fundamental particles and of gravity are inadequate to explain the observed discrepancy between the dynamics and the distribution of the visible matter in the Universe. The Modified Newtonian Dynamics (MOND) proposal aims at solving the problem by postulating that Newton's second law of motion is modified for accelerations smaller than ~10^{-10}m/s^2. This simple amendment, has had tremendous success in explaining galactic rotation curves. However, being non-relativistic, it cannot make firm predictions for cosmology. A relativistic theory called Tensor-Vector-Scalar (TeVeS) has been proposed by Bekenstein building on earlier work of Sanders which has a MOND limit for non-relativistic systems. In this article I give a short introduction to TeVeS theory and focus on its predictions for cosmology as well as some non-cosmological studies.Comment: 44 pages, topical review for Classical and Quantum Gravit

The central dark matter content of early-type galaxies: scaling relations and connections with star formation histories

We examine correlations between the masses, sizes, and star formation histories for a large sample of low-redshift early-type galaxies, using a simple suite of dynamical and stellar populations models. We confirm an anti-correlation between size and stellar age, and survey for trends with the central content of dark matter (DM). An average relation between central DM density and galaxy size of ~ Reff^-2 provides the first clear indication of cuspy DM haloes in these galaxies -- akin to standard LCDM haloes that have undergone adiabatic contraction. The DM density scales with galaxy mass as expected, deviating from suggestions of a universal halo profile for dwarf and late-type galaxies. We introduce a new fundamental constraint on galaxy formation by finding that the central DM fraction decreases with stellar age. This result is only partially explained by the size-age dependencies, and the residual trend is in the opposite direction to basic DM halo expectations. Therefore we suggest that there may be a connection between age and halo contraction, and that galaxies forming earlier had stronger baryonic feedback which expanded their haloes, or else lumpier baryonic accretion that avoided halo contraction. An alternative explanation is a lighter initial mass function for older stellar populations.Comment: 24 pages, 23 figures. MNRAS, submitted with minor modifications following referee report