A simple contact mapping algorithm for identifying potential peptide mimetics in protein–protein interaction partners

A simple, static contact mapping algorithm has been developed as a first step at identifying potential peptide biomimetics from protein interaction partner structure files. This rapid and simple mapping algorithm, “OpenContact” provides screened or parsed protein interaction files based on specified criteria for interatomic separation distances and interatomic potential interactions. The algorithm, which uses all-atom Amber03 force field models, was blindly tested on several unrelated cases from the literature where potential peptide mimetics have been experimentally developed to varying degrees of success. In all cases, the screening algorithm efficiently predicted proposed or potential peptide biomimetics, or close variations thereof, and provided complete atom-atom interaction data necessary for further detailed analysis and drug development. In addition, we used the static parsing/mapping method to develop a peptide mimetic to the cancer protein target, epidermal growth factor receptor. In this case, secondary, loop structure for the peptide was indicated from the intra-protein mapping, and the peptide was subsequently synthesized and shown to exhibit successful binding to the target protein. The case studies, which all involved experimental peptide drug advancement, illustrate many of the challenges associated with the development of peptide biomimetics, in general

Exploiting Laboratory and Heliophysics Plasma Synergies

Recent advances in space-based heliospheric observations, laboratory experimentation, and plasma simulation codes are creating an exciting new cross-disciplinary opportunity for understanding fast energy release and transport mechanisms in heliophysics and laboratory plasma dynamics, which had not been previously accessible. This article provides an overview of some new observational, experimental, and computational assets, and discusses current and near-term activities towards exploitation of synergies involving those assets. This overview does not claim to be comprehensive, but instead covers mainly activities closely associated with the authors’ interests and reearch. Heliospheric observations reviewed include the Sun Earth Connection Coronal and Heliospheric Investigation (SECCHI) on the National Aeronautics and Space Administration (NASA) Solar Terrestrial Relations Observatory (STEREO) mission, the first instrument to provide remote sensing imagery observations with spatial continuity extending from the Sun to the Earth, and the Extreme-ultraviolet Imaging Spectrometer (EIS) on the Japanese Hinode spacecraft that is measuring spectroscopically physical parameters of the solar atmosphere towards obtaining plasma temperatures, densities, and mass motions. The Solar Dynamics Observatory (SDO) and the upcoming Solar Orbiter with the Heliospheric Imager (SoloHI) on-board will also be discussed. Laboratory plasma experiments surveyed include the line-tied magnetic reconnection experiments at University of Wisconsin (relevant to coronal heating magnetic flux tube observations and simulations), and a dynamo facility under construction there; the Space Plasma Simulation Chamber at the Naval Research Laboratory that currently produces plasmas scalable to ionospheric and magnetospheric conditions and in the future also will be suited to study the physics of the solar corona; the Versatile Toroidal Facility at the Massachusetts Institute of Technology that provides direct experimental observation of reconnection dynamics; and the Swarthmore Spheromak Experiment, which provides well-diagnosed data on three-dimensional (3D) null-point magnetic reconnection that is also applicable to solar active regions embedded in pre-existing coronal fields. New computer capabilities highlighted include: HYPERION, a fully compressible 3D magnetohydrodynamics (MHD) code with radiation transport and thermal conduction; ORBIT-RF, a 4D Monte-Carlo code for the study of wave interactions with fast ions embedded in background MHD plasmas; the 3D implicit multi-fluid MHD spectral element code, HiFi; and, the 3D Hall MHD code VooDoo. Research synergies for these new tools are primarily in the areas of magnetic reconnection, plasma charged particle acceleration, plasma wave propagation and turbulence in a diverging magnetic field, plasma atomic processes, and magnetic dynamo behavior.United States. Office of Naval ResearchNaval Research Laboratory (U.S.

Climatic history of the northeastern United States during the past 3000 years

Many ecosystem processes that influence Earth system feedbacks – vegetation growth, water and nutrient cycling, disturbance regimes – are strongly influenced by multidecadal- to millennial-scale climate variations that cannot be directly observed. Paleoclimate records provide information about these variations, forming the basis of our understanding and modeling of them. Fossil pollen records are abundant in the NE US, but cannot simultaneously provide information about paleoclimate and past vegetation in a modeling context because this leads to circular logic. If pollen data are used to constrain past vegetation changes, then the remaining paleoclimate archives in the northeastern US (NE US) are quite limited. Nonetheless, a growing number of diverse reconstructions have been developed but have not yet been examined together. Here we conduct a systematic review, assessment, and comparison of paleotemperature and paleohydrological proxies from the NE US for the last 3000 years. Regional temperature reconstructions (primarily summer) show a long-term cooling trend (1000 BCE–1700 CE) consistent with hemispheric-scale reconstructions, while hydroclimate data show gradually wetter conditions through the present day. Multiple proxies suggest that a prolonged, widespread drought occurred between 550 and 750 CE. Dry conditions are also evident during the Medieval Climate Anomaly, which was warmer and drier than the Little Ice Age and drier than today. There is some evidence for an acceleration of the longer-term wetting trend in the NE US during the past century; coupled with an abrupt shift from decreasing to increasing temperatures in the past century, these changes could have wide-ranging implications for species distributions, ecosystem dynamics, and extreme weather events. More work is needed to gather paleoclimate data in the NE US to make inter-proxy comparisons and to improve estimates of uncertainty in reconstructions

How the Ionosphere-Thermosphere System Shapes the Quiet-Time Plasmasphere

The NRL SAMI3 ionosphere/plasmasphere code[1] has shown that the plasmasphere undergoes diurnal oscillations[2]. We find that those oscillations are consistent with variations found in in situ IMAGE/RPI density measurements during a quiet-time refilling event, 2001 February 01-05 and that the nature of the oscillations is strongly affected by thermospheric winds. The SAMI3 ionosphere code includes 7 ion species (H+, He+, O+, N+, O2+, N2+, NO+), each treated as a separate fluid, with temperature equations being solved for H+, He+, O+ and e-. We include a Weimer potential at high latitudes, driven by the solar wind, and the self-consistent dynamo potential at midto- low latitudes, driven by specified winds, such as the HWM07 or HWM93 empirical models or the TIMEGCM thermosphere model. During this quiet-time event, we find that the shape of the plasmasphere at any given time varies significantly with the wind model. In all cases, however, the diurnal oscillations persist and a similar degree of model-data agreement is found. [1] Huba, J. and J. Krall, 2013, ``Modeling the plasmasphere with SAMI3\u27\u27, Geophys. Res. Lett. 40, 6-10, doi:10.1029/2012GL054300 [2] Krall, J., and J. D. Huba, 2013, ``SAMI3 simulation of plasmasphere refilling\u27\u27, Geophys. Res. Lett., 40, 2484-2488, doi:10.1002/GRL.50458 Research supported by NRL base funds and the NASA LWS program

Shared Endo-phenotypes of Default Mode Dysfunction in Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder

International audienceCategorica ldiagnoses from the DSM or ICD manuals are increasingly found to be incongruent with emerging neuroscientific evidence that points towards shared neurobiological dysfunction underlying attention deficit/hyperactivity disorderand autism spectrum disorder. Using resting-state functional magnetic resonance imaging data, functional connectivity of the default mode network, the dorsal attention and salience network was studied in 1,305 typically developing and diagnosed participants. A transdiagnostic hierarchical Bayesian modeling framework combining Indian Buffet Processes and Latent Dirichlet Allocation was proposed to address the urgent need for objective brain-derived measures that can acknowledge shared brain network dysfunction in both disorders. We identified three main variation factors characterized by distinct coupling patterns of the temporoparietal cortices in the default mode network with the dorsal attention and salience network. The brain-derived factors were demonstrated to effectively capture the underlying neural dysfunction shared in both disorders more accurately, and to enable more reliable diagnoses of neurobiological dysfunction. The brain-derived phenotypes alone allowed fora classification accuracy reflecting underlying neuropathology of 67.33%(+/-3.07) in new individuals, which significantly out performed 46.73% (+/-3.97) accuracy of categorical diagnoses. Our results provide initial evidence that shared neural dysfunction in ADHD and ASD can be derived from conventional brain recordings in a data-led fashion. Our work is encouraging to pursue a translational endeavor to find and further study brain-derived phenotypes which could potentially be used to improve clinical decision-making and optimize treatment in the future