Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes

Life After Death in Lake Erie: Nutrient Controls Drive Fish Species Richness, Rehabilitation

We explored the recent (1969–1996) dynamics of fish communities within Lake Erie, a system formerly degraded by eutrophication and now undergoing oligotrophication owing to phosphorus abatement programs. By merging bottom trawl data from two lake basins of contrasting productivity with life-history information (i.e., tolerances to environmental degradation, diet and temperature preferences), we examined (1) the relationship between system productivity and species richness, (2) whether fish communities are resilient to eutrophication, and (3) whether oligotrophication necessarily leads to reduced sport and commercial fish production. Reduced phosphorus loading has led to fish community rehabilitation. In the productive west basin, six species tolerant of eutrophy (i.e., anoxia, turbidity) declined in abundance, whereas the abundance of three intolerant species increased through time. In the less productive central basin, although only one tolerant species declined, four species intolerant of eutrophic conditions recovered with oligotrophication. These differential responses appear to derive from dissimilar mechanisms by which reduced productivity alters habitat and resource availability for fishes. Specifically, enhanced bottom oxygen, combined with reduced biogenic turbidity and sedimentation, likely drove the loss of tolerant species in the west basin by reducing detrital mass or the ability of these species to compete with intolerant species under conditions of improved water clarity. In contrast, reduced bottom anoxia, which enhanced availability of cool- and cold-water habitat and benthic macroinvertebrate communities, appears important to the recovery of intolerant species in the central basin. Ultimately, these productivity-induced shifts caused species richness to decline in Lake Erie’s west basin and to increase in its central basin. Beyond confirming that unimodal models of productivity and species diversity can describe fish community change in a recovering system, our results provide optimism in an otherwise dismal state of affairs in fisheries management (e.g., overexploitation), given that many recovering intolerant species are desired sport or commercial fishes.Support for this work was provided by (1) Federal Aid in Sport Fish Restoration F-69-P (to R. A. Stein), administered jointly by the U.S. Fish and Wildlife Service and ODNR-ODW, (2) the Department of Evolution, Ecology, and Organismal Biology at The Ohio State University, and (3) a Presidential Fellowship awarded to S. A. Ludsin by The Ohio State University

Evidence of Walleye Spawning in Maumee Bay, Lake Erie

Author Institution: Department of Fisheries and Wildlife, Michigan State University ; Single Spin Guide Service ; Ohio Department of Natural Resources, Division of Wildlife, Sandusky Fisheries Research UnitDuring the mid-1990s, anglers reported large numbers of walleye (Stizostedion vitreum) in spawning condition concentrated on shallow points adjacent to the Maumee River channel during spring. These fish had flowing eggs and semen and were suspected to be actively spawning in Maumee Bay. To investigate the potential of walleye spawning, we used a benthic pump to sample for eggs at five sites adjacent to the Maumee River channel and one site near Turtle Island in Maumee Bay on 5 April 1998, a time when walleye were actively spawning in rivers and on mid-lake reefs. We found walleye eggs at each of the six sites sampled. Relative abundance of eggs ranged from 17 to 2,105 per 2-min sample, with a mean of 459 (±232). Egg viability ranged from 33 to 54% across the sites and 10% of the viable walleye eggs were observed to be in late stages of embryonic development indicating that egg survival to hatching is likely. These results are the first documentation of walleye spawning in Maumee Bay, indicating that Maumee Bay is a viable spawning location for walleye, possibly representing an important source of recruitment for the Lake Erie stock

Modeling sources of variation for growth and predatory demand of Lake Erie walleye (Stizostedion vitreum), 1986-1995

Abstract in English and FrenchGiven the variable nature of the Lake Erie ecosystem, we investigated biotic and abiotic sources of variation for walleye (Stizostedion vitreum) growth, consumption, and population-wide predatory demand. We determined how temperature, population structure, and age-specific consumption influenced walleye growth and consumption during 1986-1995. For each year, we used individual-based bioenergetics modeling to compare growth and consumption by walleye in Lake Erie's western or central basin with those of walleye moving seasonally between basins. Population structure strongly affected walleye growth and consumption but had little influence on interbasin growth rate comparisons. Based on water temperature alone, growth and consumption by western basin walleye were generally lower than for central basin or migratory populations and were more limited by summer water temperatures. In simulations combining effects of population structure, temperature, and age-specific consumption, migratory walleye grew most rapidly, taking advantage of temperature-related growth peaks in both basins. Estimates of walleye predatory demand declined with population size from 1988 through 1995. With natural feedbacks, predatory demand interacts with prey production, limiting walleye reproductive potential when prey availability is low. However, immediate impact on predatory inertia is limited, complicating our ability to predict how predatory demand and prey availability interact in Lake Erie.Support for this project was provided by a University Fellowship from the Graduate School of the Ohio State University (to M.W.K.) and by Federal Aid in Sportfish Restoration F-69-P, administered jointly by the U.S. Fish and Wildlife Service and the Ohio Division of Wildlife, and by the Department of Zoology, Ohio State University

Efficient one- and two-qubit pulsed gates for an oscillator stabilized Josephson qubit

We present theoretical schemes for performing high-fidelity one- and two-qubit pulsed gates for a superconducting flux qubit. The "IBM qubit" consists of three Josephson junctions, three loops, and a superconducting transmission line. Assuming a fixed inductive qubit-qubit coupling, we show that the effective qubit-qubit interaction is tunable by changing the applied fluxes, and can be made negligible, allowing one to perform high fidelity single qubit gates. Our schemes are tailored to alleviate errors due to 1/f noise; we find gates with only 1% loss of fidelity due to this source, for pulse times in the range of 20-30ns for one-qubit gates (Z rotations, Hadamard), and 60ns for a two-qubit gate (controlled-Z). Our relaxation and dephasing time estimates indicate a comparable loss of fidelity from this source. The control of leakage plays an important role in the design of our shaped pulses, preventing shorter pulse times. However, we have found that imprecision in the control of the quantum phase plays the major role in the limitation of the fidelity of our gates.Comment: Published version. Added references. Corrected minor typos. Added discussion on how the influence of 1/f noise is modeled. 36 pages, 11 figure

Detection of Crab Giant Pulses Using the Mileura Widefield Array Low Frequency Demonstrator Field Prototype System

We report on the detection of giant pulses from the Crab Nebula pulsar at a frequency of 200 MHz using the field deployment system designed for the Mileura Widefield Array's Low Frequency Demonstrator (MWA-LFD). Our observations are among the first high-quality detections at such low frequencies. The measured pulse shapes are deconvolved for interstellar pulse broadening, yielding a pulse-broadening time of 670$\pm$100 $\mu$s, and the implied strength of scattering (scattering measure) is the lowest that is estimated towards the Crab nebula from observations made so far. The sensitivity of the system is largely dictated by the sky background, and our simple equipment is capable of detecting pulses that are brighter than $\sim$9 kJy in amplitude. The brightest giant pulse detected in our data has a peak amplitude of $\sim$50 kJy, and the implied brightness temperature is $10^{31.6}$ K. We discuss the giant pulse detection prospects with the full MWA-LFD system. With a sensitivity over two orders of magnitude larger than the prototype equipment, the full system will be capable of detecting such bright giant pulses out to a wide range of Galactic distances; from $\sim$8 to $\sim$30 kpc depending on the frequency. The MWA-LFD will thus be a highly promising instrument for the studies of giant pulses and other fast radio transients at low frequencies.Comment: 10 pages, 6 figures, Accepted for publication in the Astrophysical Journa

International telemedicine consultations for neurodevelopmental disabilities

Background: A telemedicine program was developed between the Children\u27s National Medical Center (CNMC) in Washington, DC, and the Sheikh Khalifa Bin Zayed Foundation in the United Arab Emirates (UAE). A needs assessment and a curriculum of on-site training conferences were devised preparatory to an ongoing telemedicine consultation program for children with neurodevelopmental disabilities in the underserved eastern region of the UAE. Materials and Methods: Weekly telemedicine consultations are provided by a multidisciplinary faculty. Patients are presented in the UAE with their therapists and families. Real-time (video over Internet protocol; average connection, 768 kilobits/s) telemedicine conferences are held weekly following previews of medical records. A full consultation report follows each telemedicine session. Results: Between February 29, 2012 and June 26, 2013, 48 weekly 1-h live interactive telemedicine consultations were conducted on 48 patients (28 males, 20 females; age range, 8 months–22 years; median age, 5.4 years). The primary diagnoses were cerebral palsy, neurogenetic disorders, autism, neuromuscular disorders, congenital anomalies, global developmental delay, systemic disease, and epilepsy. Common comorbidities were cognitive impairment, communication disorders, and behavioral disorders. Specific recommendations included imaging and DNA studies, antiseizure management, spasticity management including botulinum toxin protocols, and specific therapy modalities including taping techniques, customized body vests, and speech/language and behavioral therapy. Improved outcomes reported were in clinician satisfaction, achievement of therapy goals for patients, and requests for ongoing sessions. Conclusions: Weekly telemedicine sessions coupled with triannual training conferences were successfully implemented in a clinical program dedicated to patients with neurodevelopmental disabilities by the Center for Neuroscience at CNMC and the UAE government. International consultations in neurodevelopmental disabilities utilizing telemedicine services offer a reliable and productive method for joint clinical programs

Detection of Crab Giant Pulses Using the Mileura Widefield Array Low Frequency Demonstrator Field Prototype System

We report on the detection of giant pulses from the Crab Nebula pulsar at a frequency of 200 MHz using the field deployment system designed for the Mileura Widefield Array's Low Frequency Demonstrator (MWA-LFD). Our observations are among the first high-quality detections at such low frequencies. The measured pulse shapes are deconvolved for interstellar pulse broadening, yielding a pulse-broadening time of 670 ± 100 μs, and the implied strength of scattering (scattering measure) is the lowest that is estimated toward the Crab Nebula from observations made so far. The sensitivity of the system is largely dictated by the sky background, and our simple equipment is capable of detecting pulses that are brighter than ∼9 kJy in amplitude. The brightest giant pulse detected in our data has a peak amplitude of ∼50 kJy, and the implied brightness temperature is 10 31.6 K. We discuss the giant pulse detection prospects with the full MWA-LFD system. With a sensitivity over 2 orders of magnitude larger than the prototype equipment, the full system will be capable of detecting such bright giant pulses out to a wide range of Galactic distances; from ∼ 15 to ∼30 kpc depending on the frequency. The MWA-LFD will thus be a highly promising instrument for the studies of giant pulses and other fast radio transients at low frequencies