The ChIP-seq-defined networks of Bcl-3 gene binding support its required role in skeletal muscle atrophy

NF-kappaB transcriptional activation is required for skeletal muscle disuse atrophy. We are continuing to study how the activation of NF-kB regulates the genes that encode the protein products that cause atrophy. Using ChIP-sequencing we found that Bcl-3, an NF-kB transcriptional activator required for atrophy, binds to the promoters of a number of genes whose collective function describes two major aspects of muscle wasting. By means of bioinformatics analysis of ChIP-sequencing data we found Bcl-3 to be directing transcription networks of proteolysis and energy metabolism. The proteolytic arm of the Bcl-3 networks includes many E3 ligases associated with proteasomal protein degradation, including that of the N-end rule pathway. The metabolic arm appears to be involved in organizing the change from oxidative phosphorylation to glycolysis in atrophying muscle. For one gene, MuRF1, ChIP-sequencing data identified the location of Bcl-3 and p50 binding in the promoter region which directed the creation of deletant and base-substitution mutations of MuRF1 promoter constructs to determine the effect on gene transcription. The results provide the first direct confirmation that the NF-kB binding site is involved in the muscle unloading regulation of MuRF1. Finally, we have combined the ChIP-sequencing results with gene expression microarray data from unloaded muscle to map several direct targets of Bcl-3 that are transcription factors whose own targets describe a set of indirect targets for NF-kB in atrophy. ChIP-sequencing provides the first molecular explanation for the finding that Bcl3 knockout mice are resistant to disuse muscle atrophy. Mapping the transcriptional regulation of muscle atrophy requires an unbiased analysis of the whole genome, which we show is now possible with ChIP-sequencing.R01 AR041705 - NIAMS NIH HHS; R01 AR060217 - NIAMS NIH HHS; AR041705 - NIAMS NIH HHS; AR060217 - NIAMS NIH HH

Effect of unitary impurities in non-STM-types of tunneling in high-T_c superconductors

Based on an extended Hubbard model, we present calculations of both the local (i.e., single-site) and spatially-averaged differential tunneling conductance in d-wave superconductors containing nonmagnetic impurities in the unitary limit. Our results show that a random distribution of unitary impurities of any concentration can at most give rise to a finite zero-bias conductance (with no peak there) in spatially-averaged non-STM type of tunneling, in spite of the fact that local tunneling in the immediate vicinity of an isolated impurity does show a conductance peak at zero bias, whereas to give rise to even a small zero-bias conductance peak in the former type of tunneling the impurities must form dimers, trimers, etc. along the [110] directions. In addition, we find that the most-recently-observed novel pattern of the tunneling conductance around a single impurity by Pan et al. [Nature (London) 403,746 (2000)] can be explained in terms of a realistic model of the tunneling configuration which gives rise to the experimental results reported there. The key feature in this model is the blocking effect of the BiO and SrO layers which exist between the tunneling tip and the CuO_2 layer being probed.Comment: 9 pages, 7 ps-figures, to appear in Phys. Rev. B (Sep. 1, 2000); typos corrected, references added, figure 6 changed to expand the explanation on recent experimental measurements by S.H. Pan et al. [Nature (London) 403, 746 (2000)

Medical Savings Accounts in Singapore: How much is adequate?

While many studies have examined the cost-containment aspect of Medical savings accounts (MSA), few have investigated the adequacy of MSA to finance the health care expenditure. This paper estimates the present value of lifetime healthcare expenses (PVHE) of the Singaporean male and female elderly upon retirement at age 62. The estimation involves calibrating the stream of future healthcare expenditure; stochastic forecasting of cohort survival probabilities; and discounting the projected lifetime healthcare expenditure. Estimated values of the PVHE under various scenarios are used to assess the adequacy of the government-decreed minimum saving to be maintained in the MSA.medical savings accounts, present value of lifetime health care expense, cohort survival probabilities

Monetizing Housing Equity to Generate Retirement Incomes

The public housing program and the unique way of financing housing through the mandatory savings system in Singapore have created a class of homeowners. This paper compares the instruments available to different flat owners to monetize their assets, including the Lease Buyback Scheme (LBS), subletting, downsizing and reverse mortgage. We estimate the present value of retirement incomes derived from these options by incorporating the survival probability which is forecasted using the Lee-Carter demographic model. We compare the monthly payouts that can be unlocked and discuss the tradeoffs of adequate retirement with the elderly preference for leaving a bequest and ageing in place. Our results show that LBS is the most attractive option. It allows the elderly to age-inplace while generating a steady stream of monthly drawdown and possibility of leaving a bequest. Subletting releases housing equity while retaining the asset. This helps the elderly to fulfill their bequest motive. Reverse mortgage is the least attractive option, yielding the lowest retirement income due to high loading factors.

Avalanche noise characteristics of single Al/sub x/Ga/sub 1-x/As(0.3

Avalanche multiplication and excess noise have been measured on a series of Al/sub x/Ga/sub 1-x/As-GaAs and GaAs-Al/sub x/Ga/sub 1-x/As (x=0.3,0.45, and 0.6) single heterojunction p/sup +/-i-n/sup +/ diodes. In some devices excess noise is lower than in equivalent homojunction devices with avalanche regions composed of either of the constituent materials, the heterojunction with x=0.3 showing the greatest improvement. Excess noise deteriorates with higher values of x because of the associated increase in hole ionization in the Al/sub x/Ga/sub 1-x/As layer. It also depends critically upon the carrier injection conditions and Monte Carlo simulations show that this dependence results from the variation in the degree of noisy feedback processes on the position of the injected carriers

Star formation and molecular hydrogen in dwarf galaxies: a non-equilibrium view

We study the connection of star formation to atomic (HI) and molecular hydrogen (H$_2$) in isolated, low metallicity dwarf galaxies with high-resolution ($m_{\rm gas}$ = 4 M$_\odot$, $N_{\rm ngb}$ = 100) SPH simulations. The model includes self-gravity, non-equilibrium cooling, shielding from an interstellar radiation field, the chemistry of H$_2$ formation, H$_2$-independent star formation, supernova feedback and metal enrichment. We find that the H$_2$ mass fraction is sensitive to the adopted dust-to-gas ratio and the strength of the interstellar radiation field, while the star formation rate is not. Star formation is regulated by stellar feedback, keeping the gas out of thermal equilibrium for densities $n <$ 1 cm$^{-3}$. Because of the long chemical timescales, the H$_2$ mass remains out of chemical equilibrium throughout the simulation. Star formation is well-correlated with cold ( T $\leqslant$ 100 K ) gas, but this dense and cold gas - the reservoir for star formation - is dominated by HI, not H$_2$. In addition, a significant fraction of H$_2$ resides in a diffuse, warm phase, which is not star-forming. The ISM is dominated by warm gas (100 K $<$ T $\leqslant 3\times 10^4$ K) both in mass and in volume. The scale height of the gaseous disc increases with radius while the cold gas is always confined to a thin layer in the mid-plane. The cold gas fraction is regulated by feedback at small radii and by the assumed radiation field at large radii. The decreasing cold gas fractions result in a rapid increase in depletion time (up to 100 Gyrs) for total gas surface densities $\Sigma_{\rm HI+H_2} \lesssim$ 10 M$_\odot$pc$^{-2}$, in agreement with observations of dwarf galaxies in the Kennicutt-Schmidt plane.Comment: Accepted for publication in MNRAS. Changes (including a pamameter study in Appendix C) highlighte

A study of earth radar returns from Alouette satellite

Ground radar reflection coefficient analysis on Alouette sounder ionogram