Hyper- and hypo- nutrition studies of the hepatic transcriptome and epigenome suggest that PPARα regulates anaerobic glycolysis

Diet plays a crucial role in shaping human health and disease. Diets promoting obesity and insulin resistance can lead to severe metabolic diseases, while calorie-restricted (CR) diets can improve health and extend lifespan. In this work, we fed mice either a chow diet (CD), a 16 week high-fat diet (HFD), or a CR diet to compare and contrast the effects of these diets on mouse liver biology. We collected transcriptomic and epigenomic datasets from these mice using RNA-Seq and DNase-Seq. We found that both CR and HFD induce extensive transcriptional changes, in some cases altering the same genes in the same direction. We used our epigenomic data to infer transcriptional regulatory proteins bound near these genes that likely influence their expression levels. In particular, we found evidence for critical roles played by PPARα and RXRα. We used ChIP-Seq to profile the binding locations for these factors in HFD and CR livers. We found extensive binding of PPARα near genes involved in glycolysis/gluconeogenesis and uncovered a role for this factor in regulating anaerobic glycolysis. Overall, we generated extensive transcriptional and epigenomic datasets from livers of mice fed these diets and uncovered new functions and gene targets for PPARα

Status of the QCDSP project

We describe the completed 8,192-node, 0.4Tflops machine at Columbia as well as the 12,288-node, 0.6Tflops machine assembled at the RIKEN Brookhaven Research Center. Present performance as well as our experience in commissioning these large machines is presented. We outline our on-going physics program and explain how the configuration of the machine is varied to support a wide range of lattice QCD problems, requiring a variety of machine sizes. Finally a brief discussion is given of future prospects for large-scale lattice QCD machines.Comment: LATTICE98(machines), 3 pages, 1 picture, 1 figur

The Molecular Basis of Vitamin D Receptor and β-Catenin Crossregulation

The signaling/oncogenic activity of β-catenin can be repressed by activation of the vitamin D receptor (VDR). Conversely, high levels of β-catenin can potentiate the transcriptional activity of 1,25-dihydroxyvitamin D3 (1,25D). We show here that the effects of β-catenin on VDR activity are due to interaction between the activator function-2 (AF-2) domain of the VDR and C terminus of β-catenin. Acetylation of the β-catenin C terminus differentially regulates its ability to activate TCF or VDR-regulated promoters. Mutation of a specific residue in the AF-2 domain, which renders the VDR trancriptionally inactive in the context of classical coactivators, still allows interaction with β-catenin and ligand-dependent activation of VDRE-containing promoters. VDR antagonists, which block the VDRE-directed activity of the VDR and recruitment of classical coactivators, do allow VDR to interact with β-catenin, which suggests that these and perhaps other ligands would permit those functions of the VDR that involve β-catenin interaction.The authors wish to acknowledge the support of National Institutes of Health grants DK058196 and U54 CA100971 (S.W.B.), the AACR-Bristol Myers Squibb Translational Fellowship in Colon Cancer (S.S.), and the following LCCC Core Facilities: macromolecular analysis, microscopy, and tissue culture

Linked Markov sources: Modeling outcome-dependent social processes

Many social processes are adaptive in the sense that the process changes as a result of previous outcomes. Data on such processes may come in the form of categorical time series. First, the authors propose a class of Markov Source models that embody such adaptation. Second, the authors discuss new methods to evaluate the fit of such models. Third, the authors apply these models and methods to data on a social process that is a preeminent example of an adaptive process: (encoded) conversation as arises in structured interviews. © 2007 Sage Publications

Beyond words: Aesthetic knowledge and knowing in design

Aesthetic knowledge comes from practitioners understanding the look, feel, smell, taste and sound of things. It is vital to work in many organizational contexts. In this paper, we explore aesthetic knowledge and knowing in organizations through detailed observation of design work in the architectural practice Edward Cullinan Architects. Through our research, we explore aesthetic knowledge in the context of architectural work, we unpack what it is, how it is generated, and how it is applied in design projects, shared between practitioners and developed at the level of the organization. Our analysis suggests that aesthetic knowledge plays an important part in organizational practice, not only as the symbolic context for work, but as an integral part of the work that people do. It suggests that aesthetic reflexivity, which involves an opening up and questioning of what is known, is experienced as part of practice as well as a `time out' from practice

Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications

Objective: Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation.Methods: A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance.Results: We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs.Significance: This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale

Heterodyne mixing of millimetre electromagnetic waves and sub-THz sound in a semiconductor device

We demonstrate heterodyne mixing of a 94 GHz millimetre wave photonic signal, supplied by a Gunn diode oscillator, with coherent acoustic waves of frequency ~ 100 GHz, generated by pulsed laser excitation of a semiconductor surface. The mixing takes place in a millimetre wave Schottky diode, and the intermediate frequency electrical signal is in the 1 – 12 GHz range. The mixing process preserves all the spectral content in the acoustic signal that falls within the intermediate frequency bandwidth. Therefore this technique may find application in high-frequency acoustic spectroscopy measurements, exploiting the nanometre wavelength of sub-THz sound. The result also points the way to exploiting acoustoelectric effects in photonic devices working at sub-THz and THz frequencies, which could provide functionalities at these frequencies, e.g. acoustic wave filtering, that are currently in widespread use at lower (GHz) frequencies

Measurement of the Total Active 8B Solar Neutrino Flux at the Sudbury Neutrino Observatory with Enhanced Neutral Current Sensitivity

The Sudbury Neutrino Observatory (SNO) has precisely determined the total active (nu_x) 8B solar neutrino flux without assumptions about the energy dependence of the nu_e survival probability. The measurements were made with dissolved NaCl in the heavy water to enhance the sensitivity and signature for neutral-current interactions. The flux is found to be 5.21 +/- 0.27 (stat) +/- 0.38 (syst) x10^6 cm^{-2}s^{-1}, in agreement with previous measurements and standard solar models. A global analysis of these and other solar and reactor neutrino results yields Delta m^{2} = 7.1^{+1.2}_{-0.6}x10^{-5} ev^2 and theta = 32.5^{+2.4}_{-2.3} degrees. Maximal mixing is rejected at the equivalent of 5.4 standard deviations.Comment: Submitted to Phys. Rev. Let

A Search for Neutrinos from the Solar hep Reaction and the Diffuse Supernova Neutrino Background with the Sudbury Neutrino Observatory

A search has been made for neutrinos from the hep reaction in the Sun and from the diffus