Degradation of MEPE, DMP1, and Release of SIBLING ASARM-Peptides (Minhibins): ASARM-Peptide(s) Are Directly Responsible for Defective Mineralization in HYP

Mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) and DMP1 (dentin matrix protein 1) result in X-linked hypophosphatemic rickets (HYP) and autosomal-recessive hypophosphatemic-rickets (ARHR), respectively. Specific binding of PHEX to matrix extracellular phosphoglycoprotein (MEPE) regulates the release of small protease-resistant MEPE peptides [acidic serine- and aspartate-rich MEPE-associated motif (ASARM) peptides]. ASARM peptides are potent inhibitors of mineralization (minhibins) that also occur in DMP1 [MEPE-related small integrin-binding ligand, N-linked glycoprotein (SIBLING) protein]. It is not known whether these peptides are directly responsible for the mineralization defect. We therefore used a bone marrow stromal cell (BMSC) coculture model, ASARM peptides, anti-ASARM antibodies, and a small synthetic PHEX peptide (SPR4; 4.2 kDa) to examine this. Surface plasmon resonance (SPR) and two-dimensional 1H/15N nuclear magnetic resonance demonstrated specific binding of SPR4 peptide to ASARM peptide. When cultured individually for 21 d, HYP BMSCs displayed reduced mineralization compared with wild type (WT) (−87%, P < 0.05). When cocultured, both HYP and WT cells failed to mineralize. However, cocultures (HYP and WT) or monocultures of HYP BMSCs treated with SPR4 peptide or anti-ASARM neutralizing antibodies mineralized normally. WT BMSCs treated with ASARM peptide also failed to mineralize properly without SPR4 peptide or anti-ASARM neutralizing antibodies. ASARM peptide treatment decreased PHEX mRNA and protein (−80%, P < 0.05) and SPR4 peptide cotreatment reversed this by binding ASARM peptide. SPR4 peptide also reversed ASARM peptide-mediated changes in expression of key osteoclast and osteoblast differentiation genes. Western blots of HYP calvariae and BMSCs revealed massive degradation of both MEPE and DMP1 protein compared with the WT. We conclude that degradation of MEPE and DMP-1 and release of ASARM peptides are chiefly responsible for the HYP mineralization defect and changes in osteoblast-osteoclast differentiation.We acknowledge the very kind gift of pure sPHEX by Dr. Philippe Crine (Department of Biochemistry, University of Montreal, and Enobia Pharma). Also, we acknowledge the anti-DMP1 antibodies generously donated by Dr. Larry Fisher, National Institute of Dental and Craniofacial Research, Bethesda, MD. Address all correspondence and requests for reprints to: Peter S. N. Rowe, Department of Internal Medicine, Division of Nephrology and Hypertension, The Kidney Institute, MS 3018, 3901 Rainbow Boulevard, Kansas City, Kansas 66160. E-mail: [email protected]. We acknowledge the generous financial support from the National Institutes of Health to P.S.N.R. (RO-1 AR51598-01; National Institute of Arthritis and Musculoskeletal Diseases). Also, the SPR experiments were performed in the UTHSCSA Center for Macromolecular Interactions, which is supported by grants from the National Cancer Institute (CA54174) and UTHSCSA Executive Research Committee Research fund

Degradation of a quantum directional reference frame as a random walk

We investigate if the degradation of a quantum directional reference frame through repeated use can be modeled as a classical direction undergoing a random walk on a sphere. We demonstrate that the behaviour of the fidelity for a degrading quantum directional reference frame, defined as the average probability of correctly determining the orientation of a test system, can be fit precisely using such a model. Physically, the mechanism for the random walk is the uncontrollable back-action on the reference frame due to its use in a measurement of the direction of another system. However, we find that the magnitude of the step size of this random walk is not given by our classical model and must be determined from the full quantum description.Comment: 5 pages, no figures. Comments are welcome. v2: several changes to clarify the key results. v3: journal reference added, acknowledgements and references update

Lake Michigan’s suitability for bigheaded carp: The importance of diet flexibility and subsurface habitat

As bighead (Hypophthalmichthys nobilis) and silver carp (Hypophthalmichthys molitrix)—collectively bigheaded carp (BHC)—arrive at Lake Michigan’s doorstep, questions remain as to whether there is sufficient food to support these invasive filter‐feeding fishes in the upper Laurentian Great Lakes. Previous studies suggest that suitable BHC habitat is limited to a few productive, nearshore areas. However, those studies did not consider the influence of BHC’s diet plasticity or the presence of spatially‐discrete subsurface prey resources. This study aimed to characterise Lake Michigan’s suitability for BHC and evaluate the importance of these considerations in habitat suitability assessments.We used simulated outputs of prey biomass (phytoplankton, zooplankton, and detritus) and water temperature from a three‐dimensional biophysical model of Lake Michigan to evaluate growth rate potential (GRP, quantitative index of habitat suitability) of adult BHC throughout the entire volume of the lake. Our GRP model applied a foraging model and a bioenergetics model to translate prey concentrations and water temperatures into habitat quality indexed by individual fish growth rate. We defined suitable habitat as habitats that can support GRP ≥ 0 g g−1 day−1. We developed six feeding scenarios to evaluate the impact of diet flexibility and subsurface prey resources on suitable habitat quantity. Scenarios were defined by the number of prey types the fish could consume and the depths at which they could feed (surface or whole water column).Consistent with previous studies, we found that habitats with the highest quality were concentrated near river mouths and in eutrophic areas of Green Bay. However, in contrast to previous studies, we found suitable offshore habitat for bighead carp owing to our added considerations of diet plasticity and subsurface prey resources. For silver carp, these considerations extended suitable habitat within Green Bay and in some tributary‐influenced nearshore areas, but offshore areas remained predominantly unsuitable in all feeding scenarios. Differences in simulated habitat suitability between these two species probably reflect differences in energy density and mass of the specific fishes we used in our model. However, reports of these two species in environments where they coexist indicate that bighead carp grow at faster rates than silver carp, as our model simulated.Our vertical analysis at Muskegon, MI, U.S.A. indicates that subsurface temperature and prey biomass are not only sufficient to support bighead carp growth but provide maximum habitat quality during late summer stratification.Overall, our study demonstrates that BHC are capable of surviving and growing in much larger areas of Lake Michigan than predicted by previous studies, and thus suggests that the risk of establishment is not sufficiently reduced by low plankton concentrations. Maps generated by our model identified the potential for cross‐lake migration corridors that may facilitate and accelerate lake‐wide movements. We believe these maps could be used to prioritise surveillance protocols by identifying areas to which BHC might spread upon entering the lake. More broadly, this research demonstrates how the physiology and trophic ecology of BHC contributes to their high invasive capacity and can permit their survival in novel environments.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151968/1/fwb13382_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151968/2/fwb13382.pd

Single- and double-beta decay Fermi-transitions in an exactly solvable model

An exactly solvable model suitable for the description of single and double-beta decay processes of the Fermi-type is introduced. The model is equivalent to the exact shell-model treatment of protons and neutrons in a single j-shell. Exact eigenvalues and eigenvectors are compared to those corresponding to the hamiltonian in the quasiparticle basis (qp) and with the results of both the standard quasiparticle random phase approximation (QRPA) and the renormalized one (RQRPA). The role of the scattering term of the quasiparticle hamiltonian is analyzed. The presence of an exact eigenstate with zero energy is shown to be related to the collapse of the QRPA. The RQRPA and the qp solutions do not include this zero-energy eigenvalue in their spectra, probably due to spurious correlations. The meaning of this result in terms of symmetries is presented.Comment: 29 pages, 9 figures included in a Postsript file. Submitted to Physcal Review

The Inflaton and Time in the Matter-Gravity System

The emergence of time in the matter-gravity system is addressed within the context of the inflationary paradigm. A quantum minisuperspace-homogeneous minimally coupled inflaton system is studied with suitable initial conditions leading to inflation and the system is approximately solved in the limit for large scale factor. Subsequently normal matter (either non homogeneous inflaton modes or lighter matter) is introduced as a perturbation and it is seen that its presence requires the coarse averaging of a gravitational wave function (which oscillates at trans-Planckian frequencies) having suitable initial conditions. Such a wave function, which is common for all types of normal matter, is associated with a ``time density'' in the sense that its modulus is related to the amount of time spent in a given interval (or the rate of flow of time). One is then finally led to an effective evolution equation (Schroedinger Schwinger-Tomonaga) for ``normal'' matter. An analogy with the emergence of a temperature in statistical mechanics is also pointed out.Comment: 14 pages, late

MEPE/OF45 protects cells from DNA damage induced killing via stabilizing CHK1

Matrix extracellular phosphoglycoprotein/osteoblast factor 45 (MEPE/OF45) was cloned in 2000 with functions related to bone metabolism. We identified MEPE/OF45 for the first time as a new co-factor of CHK1 in mammalian cells to protect cells from DNA damage induced killing. We demonstrate here that MEPE/OF45 directly interacts with CHK1. Knocking down MEPE/OF45 decreases CHK1 levels and sensitizes the cells to DNA damage inducers such as ionizing radiation (IR) or camptothicin (CPT)-induced killing. Over-expressing wild-type MEPE/OF45, but not the mutant MEPE/OF45 (depleted the key domain to interact with CHK1) increases CHK1 levels in the cells and increases the resistance of the cells to IR or CPT. MEPE/OF45, interacting with CHK1, increases CHK1 half-life and decreases CHK1 degradation through the ubiquitine-mediated pathway. In addition, the interaction of MEPE/OF45 with CHK1 decreases CHK1 levels in the ubiquitin E3 ligases (Cul1 and Cul4A) complex, which suggests that MEPE/OF45 competes with the ubiquitin E3 ligases binding to CHK1 and thus decreases CHK1 from ubiquitin-mediated proteolysis. These findings reveal an important role of MEPE/OF45 in protecting cells from DNA damage induced killing through stabilizing CHK1, which would provide MEPE/OF45 as a new target for sensitizing tumor cells to radiotherapy or chemotherapy

A Spectroscopic Survey of a Sample of Active M Dwarfs

A moderate resolution spectroscopic survey of Fleming's sample of 54 X-ray selected M dwarfs with photometric distances less than 25 pc is presented. Radial and rotation velocities have been measured by fits to the H-alpha profiles. Radial velocities have been measured by cross correlation. Artificial broadening of an observed spectrum has produced a relationship between H-alpha FWHM and rotation speed, which we use to infer rotation speeds for the entire sample by measurement of the H-alpha emission line. We find 3 ultra-fast rotators (UFRs, vsini > 100km/s), and 8 stars with 30 < vsini < 100 km/s. The UFRs have variable emission. Cross-correlation velocities measured for ultra-fast rotators (UFRs) are shown to depend on rotation speed and the filtering used. The radial velocity dispersion of the sample is 17 km/s. A new double emission line spectroscopic binary with a period of 3.55 days has been discovered, and another known one is in the sample. Three other objects are suspected spectroscopic binaries, and at least six are visual doubles. The only star in the sample observed to have significant lithium is a known TW Hya Association member, TWA 8A. These results show that there are a number of young (< 10^8 yr) and very young (< 10^7 yr) low mass stars in the immediate solar neighbourhood. The H-alpha activity strength does not depend on rotation speed. Our fast rotators are less luminous than similarly fast rotators in the Pleiades. They are either younger than the Pleiades, or gained angular momentum in a different way.Comment: 38 pages incl. 14 figures and 4 tables, plus 12 pages of table for electronic journal only; LaTeX, aastex.cls. Accepted 07/18/02 for publication in The Astronomical Journa

Aesthetics and literature : a problematic relation?

The paper argues that there is a proper place for literature within aesthetics but that care must be taken in identifying just what the relation is. In characterising aesthetic pleasure associated with literature it is all too easy to fall into reductive accounts, for example, of literature as merely "fine writing". Belleslettrist or formalistic accounts of literature are rejected, as are two other kinds of reduction, to pure meaning properties and to a kind of narrative realism. The idea is developed that literature-both poetry and prose fiction-invites its own distinctive kind of aesthetic appreciation which far from being at odds with critical practice, in fact chimes well with it