Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2.

Poly(ADP-ribose) polymerase-1 (PARP-1) has become an important pharmacological target in the treatment of cancer due to its cellular role as a 'DNA-strand break sensor', which leads in part to resistance to some existing chemo- and radiological treatments. Inhibitors have now been developed which prevent PARP-1 from synthesizing poly(ADP-ribose) in response to DNA-breaks and potentiate the cytotoxicity of DNA damaging agents. However, with the recent discoveries of PARP-2, which has a similar DNA-damage dependent catalytic activity, and additional members containing the 'PARP catalytic' signature, the isoform selectivity and resultant pharmacological effects of existing inhibitors are brought into question. We present here the crystal structure of the catalytic fragment of murine PARP-2, at 2.8 A resolution, and compare this to the catalytic fragment of PARP-1, with an emphasis on providing a possible framework for rational drug design in order to develop future isoform-specific inhibitors

Evaluation of Euler Fluxes for Hypersonic Flow Computations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76462/1/AIAA-33735-324.pd

A genuinely multi-dimensional upwind cell-vertex scheme for the Euler equations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77007/1/AIAA-1989-95-623.pd

Twenty-year outcome of a longitudinal prospective evaluation of isolated endoscopic anterior cruciate ligament reconstruction with patellar tendon or hamstring autograft

Background: Long-term prospective follow-up studies of single-incision endoscopic anterior cruciate ligament (ACL) reconstruction are limited and may include confounding factors. Purpose: This longitudinal prospective study reports the outcomes of isolated ACL reconstruction using middle-third patellar tendon autografts in 90 patients over 20 years. Study Design: Case series; Level of evidence, 4. Methods: Between January 1993 and April 1994, a total of 90 patients met study inclusion criteria: evaluation at 1, 2, 3, 4, 5, 7, 10, 15, and 20 years after surgery. Exclusion criteria were associated ligamentous injuries requiring surgery, previous meniscectomy or meniscal injuries requiring more than one-third meniscectomy, chondral injuries, and an abnormal contralateral knee. Results: At 20 years, 32 (36%) patients had sustained another ACL injury: 8 (9%) to the index limb and 27 (30%) to the contralateral limb (3 injuring both knees). The mean International Knee Documentation Committee (IKDC) score was 86. Of the patients, 50% participated in strenuous/very strenuous activities, and kneeling pain was present in 63%. Radiographic degenerative change was found in 61%; 20% had IKDC grade C, and 0% had grade D. The IKDC clinical examination revealed that 95% had a normal/nearly normal knee. Significant sex differences existed: when compared with male patients, female patients were less likely to reinjure the reconstructed ACL (18% vs 2%, respectively; P = .01), reported poorer IKDC subjective scores (90 vs 83, respectively; P = .03), had more activity-related pain (20% vs 57%, respectively; P = .02), and were less likely to participate in strenuous activities (66% vs 35%, respectively; P = .009). ACL graft survival was not related to age. Patients \u3c18 years old had an increased odds ratio (3.2) for rupturing the contralateral ACL. A coronal graft angle \u3c17° increased the risk of failure compared with an angle \u3e17° (77% vs 96% survival, respectively) by a factor of 8.5. Conclusion: Injuries more commonly occurred in the contralateral ACL than in the reconstructed ACL graft, and the most significant predictor of a contralateral ACL injury was age \u3c18 years. The most significant predictor of an ACL graft rupture was a coronal graft angle \u3c17°. Female patients had lower rerupture rates, poorer subjective scores, and decreased participation in strenuous activities, putting the graft at a lower risk of failure. Kneeling pain remained persistent over 20 years. Radiographic osteoarthritis was evident in 61% of patients, but symptomatic osteoarthritic symptoms were rarely reported

Inference for bounded parameters

The estimation of signal frequency count in the presence of background noise has had much discussion in the recent physics literature, and Mandelkern [1] brings the central issues to the statistical community, leading in turn to extensive discussion by statisticians. The primary focus however in [1] and the accompanying discussion is on the construction of a confidence interval. We argue that the likelihood function and $p$-value function provide a comprehensive presentation of the information available from the model and the data. This is illustrated for Gaussian and Poisson models with lower bounds for the mean parameter

High Order Upwind Schemes for Multidimensional Magnetohydrodynamics

A general method for constructing high order upwind schemes for multidimensional magnetohydrodynamics (MHD), having as a main built-in condition the divergence-free constraint \divb=0 for the magnetic field vector \bb, is proposed. The suggested procedure is based on {\em consistency} arguments, by taking into account the specific operator structure of MHD equations with respect to the reference Euler equations of gas-dynamics. This approach leads in a natural way to a staggered representation of the \bb field numerical data where the divergence-free condition in the cell-averaged form, corresponding to second order accurate numerical derivatives, is exactly fulfilled. To extend this property to higher order schemes, we then give general prescriptions to satisfy a $(r+1)^{th}$ order accurate \divb=0 relation for any numerical \bb field having a $r^{th}$ order interpolation accuracy. Consistency arguments lead also to a proper formulation of the upwind procedures needed to integrate the induction equations, assuring the exact conservation in time of the divergence-free condition and the related continuity properties for the \bb vector components. As an application, a third order code to simulate multidimensional MHD flows of astrophysical interest is developed using ENO-based reconstruction algorithms. Several test problems to illustrate and validate the proposed approach are finally presented.Comment: 34 pages, including 14 figure

Improving interagency service integration of the Australian Nurse Family Partnership Program for First Nations women and babies: a qualitative study.

BackgroundThe Australian Nurse Family Partnership Program (ANFPP) is an evidence-based, home visiting program that offers health education, guidance, social and emotional support to first-time mothers having Aboriginal and/or Torres Strait Islander (First Nations) babies. The community-controlled sector identified the need for specialised support for first time mothers due to the inequalities in birthing and early childhood outcomes between First Nations' and other babies in Australia. The program is based on the United States' Nurse Family Partnership program which has improved long-term health outcomes and life trajectories for mothers and children. International implementation of the Nurse Family Partnership program has identified interagency service integration as key to program recruitment, retention, and efficacy. How the ANFPP integrates with other services in an Australian urban setting and how to improve this is not yet known. Our research explores the barriers and enablers to interagency service integration for the Australian Nurse Family Partnership Program ANFPP in an urban setting.MethodsA qualitative study using individual and group interviews. Purposive and snowball sampling was used to recruit clients, staff (internal and external to the program), Elders and family members. Interviews were conducted using a culturally appropriate 'yarning' method with clients, families and Elders and semi-structured interview guide for staff. Interviews were audio-recorded and transcribed prior to reflexive thematic analysis.ResultsSeventy-six participants were interviewed: 26 clients, 47 staff and 3 Elders/family members. Three themes were identified as barriers and three as enablers. Barriers: 1) confusion around program scope, 2) duplication of care, and 3) tensions over 'ownership' of clients. Enablers (existing and potential): 1) knowledge and promotion of the program; 2) cultural safety; and 3) case coordination, co-location and partnership forums.ConclusionEffective service integration is essential to maximise access and acceptability of the ANFPP; we provide practical recommendations to improve service integration in this context

The effects of charge transfer inefficiency (CTI) on galaxy shape measurements

(Abridged) We examine the effects of charge transfer inefficiency (CTI) during CCD readout on galaxy shape measurements required by studies of weak gravitational lensing. We simulate a CCD readout with CTI such as that caused by charged particle radiation damage. We verify our simulations on data from laboratory-irradiated CCDs. Only charge traps with time constants of the same order as the time between row transfers during readout affect galaxy shape measurements. We characterize the effects of CTI on various galaxy populations. We baseline our study around p-channel CCDs that have been shown to have charge transfer efficiency up to an order of magnitude better than several models of n-channel CCDs designed for space applications. We predict that for galaxies furthest from the readout registers, bias in the measurement of galaxy shapes, Delta(e), will increase at a rate of 2.65 +/- 0.02 x 10^(-4) per year at L2 for accumulated radiation exposure averaged over the solar cycle. If uncorrected, this will consume the entire shape measurement error budget of a dark energy mission within about 4 years. Software mitigation techniques demonstrated elsewhere can reduce this by a factor of ~10, bringing the effect well below mission requirements. CCDs with higher CTI than the ones we studeied may not meet the requirements of future dark energy missions. We discuss ways in which hardware could be designed to further minimize the impact of CTI.Comment: 11 pages, 6 figures, and 2 tables. Accepted for publication in PAS

The prismatic Sigma 3 (10-10) twin bounday in alpha-Al2O3 investigated by density functional theory and transmission electron microscopy

The microscopic structure of a prismatic $\Sigma 3$ $(10\bar{1}0)$ twin boundary in \aal2o3 is characterized theoretically by ab-initio local-density-functional theory, and experimentally by spatial-resolution electron energy-loss spectroscopy in a scanning transmission electron microscope (STEM), measuring energy-loss near-edge structures (ELNES) of the oxygen $K$-ionization edge. Theoretically, two distinct microscopic variants for this twin interface with low interface energies are derived and analysed. Experimentally, it is demonstrated that the spatial and energetical resolutions of present high-performance STEM instruments are insufficient to discriminate the subtle differences of the two proposed interface variants. It is predicted that for the currently developed next generation of analytical electron microscopes the prismatic twin interface will provide a promising benchmark case to demonstrate the achievement of ELNES with spatial resolution of individual atom columns

Evaluation of Euler Fluxes for Hypersonic Heating Computations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83575/1/AIAA-41605-439.pd