Mammalian models of extended healthy lifespan

Over the last two centuries, there has been a significant increase in average lifespan expectancy in the developed world. One unambiguous clinical implication of getting older is the risk of experiencing age-related diseases including various cancers, dementia, type-2 diabetes, cataracts and osteoporosis. Historically, the ageing process and its consequences were thought to be intractable. However, over the last two decades or so, a wealth of empirical data has been generated which demonstrates that longevity in model organisms can be extended through the manipulation of individual genes. In particular, many pathological conditions associated with the ageing process in model organisms, and importantly conserved from nematodes to humans, are attenuated in long-lived genetic mutants. For example, several long-lived genetic mouse models show attenuation in age-related cognitive decline, adiposity, cancer and glucose intolerance. Therefore, these long-lived mice enjoy a longer period without suffering the various sequelae of ageing. The greatest challenge in the biology of ageing is to now identify the mechanisms underlying increased healthy lifespan in these model organisms. Given that the elderly are making up an increasingly greater proportion of society, this focused approach in model organisms should help identify tractable interventions that can ultimately be translated to humans

Quantification Method of P2X3 Receptors in Rat DRG Neurons: Western Blotting

Skeletal muscle contractions are known to evoke pressor and cardioaccelerator responses in part by stimulating P2X3 receptors found on the peripheral endings of afferents. In diabetic patients, this pressor response is exaggerated. What is currently not known is whether P2X3 receptors play a role in evoking this exaggerated response. PURPOSE: The purpose of this project was to quantify P2X3 receptors in the L4 and L5 dorsal root ganglia (DRG) neurons in both healthy and type 1 diabetic rats using western blot analysis. METHODS: We injected 50 mg/kg streptozotocin (STZ) or the vehicle (CTL) i.p in fasted female and male Sprague Dawley rats and then waited at least 7 days for the rats to become diabetic. We then performed a laminectomy in the anesthetized rats to expose the spinal cord and roots. Using a dissecting microscope, we removed the L4 and L5 DRG from the spinal column. The DRG are the cell bodies of the peripheral afferents found in the hindlimb musculature. The DRG were placed in HBSS (is this buffer?) and stored at -80°C until analysis. For quantification, samples were lysed and proteins were isolated using the NucleoSpin RNA/Protein Kit (Macherey-Nagel, Bethlehem, PA, USA). A Qubit 3.0 Fluorometer was used to quantify the protein concentration of each sample so that equal protein concentrations could then be loaded onto a Bolt Bis-Tris (4-12%) gel. Following electrophoresis, the proteins were transferred to a membrane before being probed with a rabbit polyclonal P2X3 antibody (Alomone Labs), followed by an anti-rabbit secondary antibody conjugated to alkaline phosphatase (Life Technologies). The membrane was then exposed using a ChemiDoc XRS and the results analyzed using BioRad’s Quantity One imaging software. RESULTS: We were able to detect P2X3 receptor proteins. When compared with a molecular weight ladder, P2X3 receptor proteins were 54kDa, which is similar to the molecular weight of P2X3 receptors quantified in other studies. CONCLUSION: This method of quantifying P2X3 receptors in DRG neurons allows for a comparison between non-diabetic and diabetic rats. Further analyses are required to determine whether the quantity of P2X3 receptors in L4 and L5 DRG neurons is different in diabetic rats compared to non-diabetic rats

A Random Matrix Model of Adiabatic Quantum Computing

We present an analysis of the quantum adiabatic algorithm for solving hard instances of 3-SAT (an NP-complete problem) in terms of Random Matrix Theory (RMT). We determine the global regularity of the spectral fluctuations of the instantaneous Hamiltonians encountered during the interpolation between the starting Hamiltonians and the ones whose ground states encode the solutions to the computational problems of interest. At each interpolation point, we quantify the degree of regularity of the average spectral distribution via its Brody parameter, a measure that distinguishes regular (i.e., Poissonian) from chaotic (i.e., Wigner-type) distributions of normalized nearest-neighbor spacings. We find that for hard problem instances, i.e., those having a critical ratio of clauses to variables, the spectral fluctuations typically become irregular across a contiguous region of the interpolation parameter, while the spectrum is regular for easy instances. Within the hard region, RMT may be applied to obtain a mathematical model of the probability of avoided level crossings and concomitant failure rate of the adiabatic algorithm due to non-adiabatic Landau-Zener type transitions. Our model predicts that if the interpolation is performed at a uniform rate, the average failure rate of the quantum adiabatic algorithm, when averaged over hard problem instances, scales exponentially with increasing problem size.Comment: 9 pages, 7 figure

An Optical and X-ray Examination of Two Radio Supernova Remnant Candidates in 30 Doradus

The giant HII region 30 Doradus is known for its violent internal motions and bright diffuse X-ray emission, suggesting the existence of supernova remnants (SNRs), but no nonthermal radio emission has been detected. Recently, Lazendic et al. compared the H-alpha/H-beta and radio/H-alpha ratios and suggested two small radio sources to be nonthermal and thus SNR candidates; however, no optical or X-ray counterparts were detected. We have used high-resolution optical images and high-dispersion spectra to examine the morphological, spectral, and kinematic properties of these two SNR candidates, and still find no optical evidence supporting their identification as SNRs. We have also determined the X-ray luminosities of these SNR candidates, and find them 1-3 orders of magnitude lower than those commonly seen in young SNRs. High extinction can obscure optical and X-ray signatures of an SNR, but would prohibit the use of a high radio/H-alpha ratio to identify nonthermal radio emission. We suggest that the SNR candidate MCRX J053831.8-690620 is associated with a young star forming region; while the radio emission originates from the obscured star forming region, the observed optical emission is dominated by the foreground. We suggest that the SNR candidate MCRX J053838.8-690730 is associated with a dust/molecular cloud, which obscures some optical emission but not the radio emission.Comment: 13 pages, 2 figures, accepted for publication in the ApJ, Nov 10, 200

Optimal Location of Sources in Transportation Networks

We consider the problem of optimizing the locations of source nodes in transportation networks. A reduction of the fraction of surplus nodes induces a glassy transition. In contrast to most constraint satisfaction problems involving discrete variables, our problem involves continuous variables which lead to cavity fields in the form of functions. The one-step replica symmetry breaking (1RSB) solution involves solving a stable distribution of functionals, which is in general infeasible. In this paper, we obtain small closed sets of functional cavity fields and demonstrate how functional recursions are converted to simple recursions of probabilities, which make the 1RSB solution feasible. The physical results in the replica symmetric (RS) and the 1RSB frameworks are thus derived and the stability of the RS and 1RSB solutions are examined.Comment: 38 pages, 18 figure

Hiding solutions in random satisfiability problems: A statistical mechanics approach

A major problem in evaluating stochastic local search algorithms for NP-complete problems is the need for a systematic generation of hard test instances having previously known properties of the optimal solutions. On the basis of statistical mechanics results, we propose random generators of hard and satisfiable instances for the 3-satisfiability problem (3SAT). The design of the hardest problem instances is based on the existence of a first order ferromagnetic phase transition and the glassy nature of excited states. The analytical predictions are corroborated by numerical results obtained from complete as well as stochastic local algorithms.Comment: 5 pages, 4 figures, revised version to app. in PR

Confronting the Superbubble Model with X-ray Observations of 30 Dor C

We present an analysis of XMM-Newton observations of the superbubble 30 Dor C and compare the results with the predictions from the standard wind-blown bubble model. We find that the observed X-ray spectra cannot be fitted satisfactorily with the model alone and that there is evidence for nonthermal X-ray emission, which is particularly important at > 4 keV. The total unabsorbed 0.1-10 keV luminosities of the eastern and western parts of the bubble are ~3 10^36 erg/s and ~5 10^36 erg/s, respectively. The unabsorbed 0.1-10 keV luminosity of the bubble model is 4 10^36 erg/s and so the power-law component contributes between 1/3 and 1/2 to the total unabsorbed luminosity in this energy band. The nature of the hard nonthermal emission is not clear, although recent supernovae in the bubble may be responsible. We expect that about one or two core-collapse supernovae could have occured and are required to explain the enrichment of the hot gas, as evidenced by the overabundance of alpha-elements by a factor of 3, compared to the mean value of 0.5 solar for the interstellar medium in the Large Magellanic Cloud. As in previous studies of various superbubbles, the amount of energy currently present in 30 Dor C is significantly less than the expected energy input from the enclosed massive stars over their lifetime. We speculate that a substantial fraction of the input energy may be radiated in far-infrared by dust grains, which are mixed with the hot gas because of the thermal conduction and/or dynamic mixing.Comment: 25 pages, 4 figures. To appear in The Astrophysical Journal, August 20, 2004 issu

Modeling a high mass turn down in the stellar initial mass function

Statistical sampling from the stellar initial mass function (IMF) for all star-forming regions in the Galaxy would lead to the prediction of ~1000 Msun stars unless there is a rapid turn-down in the IMF beyond several hundred solar masses. Such a turndown is not necessary for dense clusters because the number of stars sampled is always too small. Here we explore several mechanisms for an upper mass cutoff, including an exponential decline of the star formation probability after a turbulent crossing time. The results are in good agreement with the observed IMF over the entire stellar mass range, and they give a gradual turn down compared to the Salpeter function above ~100 Msun for normal thermal Jeans mass, M_J. The upper mass turn down should scale with M_J in different environments. A problem with the models is that they cannot give both the observed power-law IMF out to the high-mass sampling limit in dense clusters, as well as the observed lack of supermassive stars in whole galaxy disks. Either there is a sharper upper-mass cutoff in the IMF, perhaps from self-limitation, or the IMF is different for dense clusters than for the majority of star formation that occurs at lower density. Dense clusters seem to have an overabundance of massive stars relative to the average IMF in a galaxy.Comment: 19 pages, 2 figures, Astrophysical Journal, Vol 539, August 10, 200

Regulation of Transforming Growth Factor-β1–driven Lung Fibrosis by Galectin-3

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a beta-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. Objectives: To examine the role of galectin-3 in pulmonary fibrosis. Methods: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis. Further mechanistic studies were performed in vitro and on samples from patients with IPF. Measurements and Main Results: Transforming growth factor (TGF)-beta and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-beta 1 induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of beta-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin -3, TD139, blocked TGF-beta-induced beta-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung fibrosis after bleomycin. There was increased expression of galectin-3 in the bronchoalveolar lavage fluid and serum from patients with stable IPF compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that. galectin-3 may be a marker of active fibrosis in IPF and that strategies that block galectin-3 may be effective in treating acute fibrotic exacerbations of IPF. Conclusions: This study identifies galectin-3 as an important regulator of lung fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF