DNA nano-mechanics: how proteins deform the double helix

It is a standard exercise in mechanical engineering to infer the external forces and torques on a body from its static shape and known elastic properties. Here we apply this kind of analysis to distorted double-helical DNA in complexes with proteins. We extract the local mean forces and torques acting on each base-pair of bound DNA from high-resolution complex structures. Our method relies on known elastic potentials and a careful choice of coordinates of the well-established rigid base-pair model of DNA. The results are robust with respect to parameter and conformation uncertainty. They reveal the complex nano-mechanical patterns of interaction between proteins and DNA. Being non-trivially and non-locally related to observed DNA conformations, base-pair forces and torques provide a new view on DNA-protein binding that complements structural analysis.Comment: accepted for publication in JCP; some minor changes in response to review 18 pages, 5 figure + supplement: 4 pages, 3 figure

Magnetically warped discs in close binaries

We demonstrate that measurable vertical structure can be excited in the accretion disc of a close binary system by a dipolar magnetic field centred on the secondary star. We present the first high resolution hydrodynamic simulations to show the initial development of a uniform warp in a tidally truncated accretion disc. The warp precesses retrogradely with respect to the inertial frame. The amplitude depends on the phase of the warp with respect to the binary frame. A warped disc is the best available explanation for negative superhumps.Comment: 11 pages, 10 figures, MNRAS accepte

Molecular Imaging in Pancreatic Cancer - A Roadmap for Therapeutic Decisions

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer characterized by multiple molecular alterations, the presence of an intense stroma, poor perfusion, and resistance to therapy. In addition to standard imaging techniques, experimental imaging strategies, such as those utilizing molecular probes, nanoparticle-based agents, and tagged antibodies are actively being explored experimentally. It is hoped that advances in these technologies will allow for detecting PDAC at an early stage, and could serve to validate experimental therapies, rapidly identify non-responders, and assist in the design of novel therapeutic strategies tailored to the patient’s molecular profile

Meteor light curves: the relevant parameters

We investigate a uniform sample of 113 light curves (LCs) of meteors collected at the Wise Observatory in November 2002 while observing the Leonid meteor shower. We use previously defined descriptors such as the skewness F and a recently defined pointedness parameter along with a number of other measurable or derived quantities to explore the parameter space in search of meaningful LC descriptors. We make extensive use of statistical techniques to reveal links among the variables and to understand their relative importance. In particular, we show that meteors with long-duration trails rise slowly to their maximal brightness and also decay slowly from there while showing milder flaring than other meteors. Early skewed LCs show a fast rise to the peak. We show that the duration of te luminous phase of the meteor is th emost important variable differentiating among the 2002 LCs. The skewness parameter F appears only as the 2nd or 3rd in explaining the LC variance. We suggest that the pointedness parameter P could possibly be useful to discriminate among meteors from different showers, or to compare observations and model predictions.Comment: 10 pages (2 figures) in press with MNRA

Optogenetic Interrogation of Functional Synapse Formation by Corticospinal Tract Axons in the Injured Spinal Cord

To restore function after injury to the CNS, axons must be stimulated to extend into denervated territory and, critically, must form functional synapses with appropriate targets. We showed previously that forced overexpression of the transcription factor Sox11 increases axon growth by corticospinal tract (CST) neurons after spinal injury. However, behavioral outcomes were not improved, raising the question of whether the newly sprouted axons are able to form functional synapses. Here we developed an optogenetic strategy, paired with single-unit extracellular recordings, to assess the ability of Sox11-stimulated CST axons to functionally integrate in the circuitry of the cervical spinal cord. Initial time course experiments established the expression and function of virally expressed Channelrhodopsin (ChR2) in CST cell bodies and in axon terminals in cervical spinal cord. Pyramidotomies were performed in adult mice to deprive the left side of the spinal cord of CST input, and the right CST was treated with adeno-associated virus (AAV)–Sox11 or AAV–EBFP control, along with AAV–ChR2. As expected, Sox11 treatment caused robust midline crossing of CST axons into previously denervated left spinal cord. Clear postsynaptic responses resulted from optogenetic activation of CST terminals, demonstrating the ability of Sox11-stimulated axons to form functional synapses. Mapping of the distribution of CST-evoked spinal activity revealed overall similarity between intact and newly innervated spinal tissue. These data demonstrate the formation of functional synapses by Sox11-stimulated CST axons without significant behavioral benefit, suggesting that new synapses may be mistargeted or otherwise impaired in the ability to coordinate functional output. SIGNIFICANCE STATEMENT As continued progress is made in promoting the regeneration of CNS axons, questions of synaptic integration are increasingly prominent. Demonstrating direct synaptic integration by regenerated axons and distinguishing its function from indirect relay circuits and target field plasticity have presented technical challenges. Here we force the overexpression of Sox11 to stimulate the growth of corticospinal tract axons in the cervical spinal cord and then use specific optogenetic activation to assess their ability to directly drive postsynaptic activity in spinal cord neurons. By confirming successful synaptic integration, these data illustrate a novel optogenetic-based strategy to monitor and optimize functional reconnection by newly sprouted axons in the injured CNS

Local back pressure caused by a training roller during lunging with and without a Pessoa training aid

Ground schooling (especially lunging) is routinely performed in the rehabilitation and training of horses. Training rollers are commonly used to provide attachment for training aids. The objective of the study was to objectively measure pressures beneath a training roller during lunging exercise with and without a Pessoa training aid. To measure pressures underneath the roller; 10 nonlame horses (mean ± standard deviation [SD] age 12 ± 8.77 years, mean ± SD height 1.65 ± 0.94 m) were lunged on a 16-m circle wearing a training roller on top of a high withered dressage square and wool pad. A Pliance (Novel) pressure mat was positioned transversely over the spinous processes covering thoracic vertebrae 10 to 15. Data were collected in both trot and canter on the left and right reins, with and without a Pessoa training aid. For pelvic range of motion (ROM), horses were instrumented with five inertial measuring unit sensors (IMU). A paired t-test was used to determine differences in pressure and pelvic ROM with/without Pessoa training aid (P ≤ .05). In trot and canter, consistent high pressures on the spinous processes beneath the roller were greater than those thought to cause back discomfort. These pressures were consistent between horses. No significant differences were found in any IMU outcome parameters. An awareness of the increased local spinal pressure a training roller exerts on the back, especially in horses undergoing rehabilitation of back problems is needed

The Tumor Suppressor HHEX Inhibits Axon Growth when Prematurely Expressed in Developing Central Nervous System Neurons

Neurons in the embryonic and peripheral nervoussystem respond to injury by activating transcriptional programs supportive of axon growth, ultimately resulting in functional recovery. In contrast, neurons in the adult central nervous system (CNS) possess a limited capacity to regenerate axons after injury, fundamentally constraining repair. Activating pro-regenerative gene expression in CNS neurons is a promising therapeutic approach, but progress is hampered by incomplete knowledge of the relevant transcription factors. An emerging hypothesis is that factors implicated in cellular growth and motility outside the nervous system may also control axon growth in neurons. We therefore tested sixty-nine transcription factors, previously identified as possessing tumor suppressive or oncogenic properties in non-neuronal cells, in assays of neurite outgrowth. This screen identified YAP1 and E2F1 as enhancers of neurite outgrowth, and PITX1, RBM14, ZBTB16, and HHEX as inhibitors. Follow-up experiments are focused on the tumor suppressor HHEX, one of the strongest growth inhibitors. HHEX is widely expressed in adult CNS neurons, including corticospinal tract neurons after spinal injury, but is present only in trace amounts in immature cortical neurons and adult peripheral neurons. HHEX overexpression in early postnatal cortical neurons reduced both initial axonogenesis and the rate of axon elongation, and domain deletion analysis strongly implicated transcriptional repression as the underlying mechanism. These findings suggest a role for HHEX in restricting axon growth in the developing CNS, and substantiate the hypothesis that previously identified oncogenes and tumor suppressors can play conserved roles in axon extension

The relationship of systemic hemodynamics and oxygen consumption to early allograft failure after liver transplantation.

The early postoperative hemodynamic data of 88 patients who underwent primary liver transplantation between July 1989 and October 1990 at the University Health Center of Pittsburgh were analyzed to establish the relationship of systemic hemodynamics and oxygen consumption to perioperative allograft function. The 15 patients whose allografts failed within the 1st month following transplantation were designated as group 1, while 73 patients who retained adequate graft function constituted group 2. Although the cardiac index and oxygen delivery did not differ significantly between the groups, group 1 consistently demonstrated a lower mean arterial pressure, oxygen consumption, arteriovenous oxygen content difference, and arterial ketone body ratio. The etiology of reduced oxygen consumption in group 1 patients is speculative, but the data support the notion that oxygen consumption is a useful, predictive indicator for liver allograft function after transplantation

X-ray and Radio Timing of the Pulsar in 3C 58

We present timing data spanning 6.4 yr for the young and energetic PSR J0205+6449, in the supernova remnant 3C 58. Data were obtained with the Rossi X-ray Timing Explorer, the Jodrell Bank Observatory and the Green Bank Telescope. We present phase-coherent timing analyses showing timing noise and two spin-up glitches with fractional frequency increases of ~3.4E-7 near MJD 52555, and ~3.8E-6 between MJDs 52777 and 53062. These glitches are unusually large if the pulsar was created in the historical supernova in 1181 as has been suggested. For the X-ray timing we developed a new unbinned maximum-likelihood method for determining pulse arrival times which performs significantly better than the traditional binned techniques. In addition, we present an X-ray pulse profile analysis of four years of RXTE data showing that the pulsar is detected up to ~40 keV. We also present the first measurement of the phase offset between the radio and X-ray pulse for this source, showing that the radio pulse leads the X-ray pulse by phi=0.10+/-0.01 in phase. We compile all known measurements of the phase offsets between radio and X-ray and radio and gamma-ray pulses for X-ray and gamma-ray pulsars. We show that there is no relationship between pulse period and phase offset, supported by our measurement of the phase offset for PSR J0205+6449.Comment: 19 pages, 12 figures. Published in the Astrophysical Journal. Includes additional data analysis and two new figure

Ongoing monitoring of data clustering in multicenter studies

Background: Multicenter study designs have several advantages, but the possibility of non-random measurement error resulting from procedural differences between the centers is a special concern. While it is possible to address and correct for some measurement error through statistical analysis, proactive data monitoring is essential to ensure high-quality data collection. Methods: In this article, we describe quality assurance efforts aimed at reducing the effect of measurement error in a recent follow-up of a large cluster-randomized controlled trial through periodic evaluation of intraclass correlation coefficients (ICCs) for continuous measurements. An ICC of 0 indicates the variance in the data is not due to variation between the centers, and thus the data are not clustered by center. Results: Through our review of early data downloads, we identified several outcomes (including sitting height, waist circumference, and systolic blood pressure) with higher than expected ICC values. Further investigation revealed variations in the procedures used by pediatricians to measure these outcomes. We addressed these procedural inconsistencies through written clarification of the protocol and refresher training workshops with the pediatricians. Further data monitoring at subsequent downloads showed that these efforts had a beneficial effect on data quality (sitting height ICC decreased from 0.92 to 0.03, waist circumference from 0.10 to 0.07, and systolic blood pressure from 0.16 to 0.12). Conclusions: We describe a simple but formal mechanism for identifying ongoing problems during data collection. The calculation of the ICC can easily be programmed and the mechanism has wide applicability, not just to cluster randomized controlled trials but to any study with multiple centers or with multiple observers