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Given that terrestrial ecosystems globally are facing the loss of biodiversity from land use conversion, invasive species, and climate change, effective management requires a better understanding of the drivers and correlates of biodiversity. Increasingly, biodiversity is co-managed with aboveground carbon storage because high biodiversity in animal species is observed to correlate with high aboveground carbon storage. Most previous investigations into the relationship of biodiversity and carbon co-management do not focus on the biodiversity of the species rich plant kingdom, which may have tradeoffs with carbon storage. To examine the relationships of plant species richness with aboveground tree biomass carbon storage, we used a series of generalized linear models with understory plant species richness and diversity data from the USDA Forest Service Forest Inventory and Analysis dataset and high-resolution modeled carbon maps for the Tongass National Forest. Functional trait data from the TRY database was used to understand the potential mechanisms that drive the response of understory plants. Understory species richness and community weighted mean leaf dry matter content decreased along an increasing gradient of tree biomass carbon storage, but understory diversity, community weighted mean specific leaf area, and plant height at maturity did not. Leaf dry matter content had little variance at the community level. The decline of understory plant species richness but not diversity to increases in aboveground biomass carbon storage suggests that rare species are excluded in aboveground biomass carbon dense areas. These decreases in understory species richness reflect a tradeoff between the understory plant community and aboveground carbon storage. The mechanisms that are associated with observed plant communities along a gradient of biomass carbon storage in this forest suggest that slower-growing plant strategies are less effective in the presence of high biomass carbon dense trees in the overstory., Competing Interests: The authors declare that there are no competing interests regarding the publication of this article., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

The human endogenous retrovirus type-H (HERVH) family is expressed in the preimplantation embryo. A subset of these elements are specifically transcribed in pluripotent stem cells where they appear to exert regulatory activities promoting self-renewal and pluripotency. How HERVH elements achieve such transcriptional specificity remains poorly understood. To uncover the sequence features underlying HERVH transcriptional activity, we performed a phyloregulatory analysis of the long terminal repeats (LTR7) of the HERVH family, which harbor its promoter, using a wealth of regulatory genomics data. We found that the family includes at least eight previously unrecognized subfamilies that have been active at different timepoints in primate evolution and display distinct expression patterns during human embryonic development. Notably, nearly all HERVH elements transcribed in ESCs belong to one of the youngest subfamilies we dubbed LTR7up. LTR7 sequence evolution was driven by a mixture of mutational processes, including point mutations, duplications, and multiple recombination events between subfamilies, that led to transcription factor binding motif modules characteristic of each subfamily. Using a reporter assay, we show that one such motif, a predicted SOX2/3 binding site unique to LTR7up, is essential for robust promoter activity in induced pluripotent stem cells. Together these findings illuminate the mechanisms by which HERVH diversified its expression pattern during evolution to colonize distinct cellular niches within the human embryo., Competing Interests: TC, MS, GD, JC, JR, CF No competing interests declared, (© 2022, Carter et al.)

While the aurora has attracted attention for millennia, important questions remain unanswered. Foremost is how auroral electrons are accelerated before colliding with the ionosphere and producing auroral light. Powerful Alfvén waves are often found traveling Earthward above auroras with sufficient energy to generate auroras, but there has been no direct measurement of the processes by which Alfvén waves transfer their energy to auroral electrons. Here, we show laboratory measurements of the resonant transfer of energy from Alfvén waves to electrons under conditions relevant to the auroral zone. Experiments are performed by launching Alfvén waves and simultaneously recording the electron velocity distribution. Numerical simulations and analytical theory support that the measured energy transfer process produces accelerated electrons capable of reaching auroral energies. The experiments, theory, and simulations demonstrate a clear causal relationship between Alfvén waves and accelerated electrons that directly cause auroras.

Fast-ion driven Alfvén waves with frequency close to the ion cyclotron frequency (f=0.58f_{ci}) excited by energetic ions from a neutral beam are stabilized via a controlled energetic ion density ramp for the first time in a fusion research plasma. The scaling of wave amplitude with injection rate is consistent with theory for single mode collisional saturation near marginal stability. The wave is identified as a shear-polarized global Alfvén eigenmode excited by Doppler-shifted cyclotron resonance with fast ions with sub-Alfvénic energetic ions, a first in fusion research plasmas.

Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and re-routes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This corrects the article DOI: 10.1038/nature22991.

The genome sequence of the obligate chemolithoautotroph Hydrogenovibrio crunogenus paradoxically predicts a complete oxidative citric acid cycle (CAC). This prediction was tested by multiple approaches including whole cell carbon assimilation to verify obligate autotrophy, phylogenetic analysis of CAC enzyme sequences and enzyme assays. Hydrogenovibrio crunogenus did not assimilate any of the organic compounds provided (acetate, succinate, glucose, yeast extract, tryptone). Enzyme activities confirmed that its CAC is mostly uncoupled from the NADH pool. 2-Oxoglutarate:ferredoxin oxidoreductase activity is absent, though pyruvate:ferredoxin oxidoreductase is present, indicating that sequence-based predictions of substrate for this oxidoreductase were incorrect, and that H. crunogenus may have an incomplete CAC. Though the H. crunogenus CAC genes encode uncommon enzymes, the taxonomic distribution of their top matches suggests that they were not horizontally acquired. Comparison of H. crunogenus CAC genes to those present in other 'Proteobacteria' reveals that H. crunogenus and other obligate autotrophs lack the functional redundancy for the steps of the CAC typical for facultative autotrophs and heterotrophs, providing another possible mechanism for obligate autotrophy., (© FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4 + and CD8 + T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.

Mucin-1 kidney disease, previously described as medullary cystic kidney disease type 1 (MCKD1, OMIM 174000), is an autosomal dominant tubulointerstitial kidney disease recently shown to be caused by a single-base insertion within the variable number tandem repeat region of the MUC1 gene. Because of variable age of disease onset and often subtle signs and symptoms, clinical diagnosis of mucin-1 kidney disease and differentiation from other forms of hereditary kidney disease have been difficult. The causal insertion resides in a variable number tandem repeat region with high GC content, which has made detection by standard next-generation sequencing impossible to date. The inherently difficult nature of this mutation required an alternative method for routine detection and clinical diagnosis of the disease. We therefore developed and validated a mass spectrometry-based probe extension assay with a series of internal controls to detect the insertion event using 24 previously characterized positive samples from patients with mucin-1 kidney disease and 24 control samples known to be wild type for the variant. Validation results indicate an accurate and reliable test for clinically establishing the molecular diagnosis of mucin-1 kidney disease with 100% sensitivity and specificity across 275 tests called., (Copyright © 2016 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

We report the first observation of localized modulation of turbulent density fluctuations n[over ˜] (via beam emission spectroscopy) by neoclassical tearing modes (NTMs) in the core of the DIII-D tokamak. NTMs are important as they often lead to severe degradation of plasma confinement and disruptions in high-confinement fusion experiments. Magnetic islands associated with NTMs significantly modify the profiles and turbulence drives. In this experiment n[over ˜] was found to be modulated by 14% across the island. Gyrokinetic simulations suggest that n[over ˜] could be dominantly driven by the ion temperature gradient instability.

A shear Alfvén wave parametric instability is observed for the first time in the laboratory. When a single finite ω/Ω_{i} kinetic Alfvén wave (KAW) is launched in the Large Plasma Device above a threshold amplitude, three daughter modes are produced. These daughter modes have frequencies and parallel wave numbers that are consistent with copropagating KAW sidebands and a low frequency nonresonant mode. The observed process is parametric in nature, with the frequency of the daughter modes varying as a function of pump wave amplitude. The daughter modes are spatially localized on a gradient of the pump wave magnetic field amplitude in the plane perpendicular to the background field, suggesting that perpendicular nonlinear forces (and therefore k_{⊥} of the pump wave) play an important role in the instability process. Despite this, modulational instability theory with k_{⊥}=0 has several features in common with the observed nonresonant mode and Alfvén wave sidebands.

In 1991 a manuscript describing an instrument for studying magnetized plasmas was published in this journal. The Large Plasma Device (LAPD) was upgraded in 2001 and has become a national user facility for the study of basic plasma physics. The upgrade as well as diagnostics introduced since then has significantly changed the capabilities of the device. All references to the machine still quote the original RSI paper, which at this time is not appropriate. In this work, the properties of the updated LAPD are presented. The strategy of the machine construction, the available diagnostics, the parameters available for experiments, as well as illustrations of several experiments are presented here.

Proneurogenic compounds have recently shown promise in some mouse models of Alzheimer's pathology. Antagonists at Group II metabotropic glutamate receptors (Group II mGluR: mGlu2, mGlu3) are reported to stimulate neurogenesis. Agonists at those receptors trigger γ-secretase-inhibitor-sensitive biogenesis of Aβ42 peptides from isolated synaptic terminals, which is selectively suppressed by antagonist pretreatment. We have assessed the therapeutic potential of chronic pharmacological inhibition of Group II mGluR in Dutch APP (Alzheimer's amyloid precursor protein E693Q) transgenic mice that accumulate Dutch amyloid-β (Aβ) oligomers but never develop Aβ plaques. BCI-838 is a clinically well-tolerated, orally bioavailable, investigational prodrug that delivers to the brain BCI-632, the active Group II mGluR antagonist metabolite. Dutch Aβ-oligomer-forming APP transgenic mice (APP E693Q) were dosed with BCI-838 for 3 months. Chronic treatment with BCI-838 was associated with reversal of transgene-related amnestic behavior, reduction in anxiety, reduction in levels of brain Aβ monomers and oligomers, and stimulation of hippocampal neurogenesis. Group II mGluR inhibition may offer a unique package of relevant properties as an Alzheimer's disease therapeutic or prophylactic by providing both attenuation of neuropathology and stimulation of repair.

In nonlinear dynamical systems with highly nonorthogonal linear eigenvectors, linear nonmodal analysis is more useful than normal mode analysis in predicting turbulent properties. However, the nontrivial time evolution of nonmodal structures makes quantitative understanding and prediction difficult. We present a technique to overcome this difficulty by modeling the effect that the advective nonlinearities have on spatial turbulent structures. The nonlinearities are taken as a periodic randomizing force with time scale consistent with critical balance arguments. We apply this technique to a model of drift wave turbulence in the Large Plasma Device [W. Gekelman et al., Rev. Sci. Instrum. 62, 2875 (1991)], where nonmodal effects dominate the turbulence. We compare the resulting growth rate spectra to the spectra obtained from a nonlinear simulation, showing good qualitative agreement, especially in comparison to the eigenmode growth rate spectra.

Skeletal muscle aging results in a gradual loss of skeletal muscle mass, skeletal muscle function and regenerative capacity, which can lead to sarcopenia and increased mortality. Although the mechanisms underlying sarcopenia remain unclear, the skeletal muscle stem cell, or satellite cell, is required for muscle regeneration. Therefore, identification of signaling pathways affecting satellite cell function during aging may provide insights into therapeutic targets for combating sarcopenia. Here, we show that a cell-autonomous loss in self-renewal occurs via alterations in fibroblast growth factor receptor-1, p38α and p38β mitogen-activated protein kinase signaling in satellite cells from aged mice. We further demonstrate that pharmacological manipulation of these pathways can ameliorate age-associated self-renewal defects. Thus, our data highlight an age-associated deregulation of a satellite cell homeostatic network and reveal potential therapeutic opportunities for the treatment of progressive muscle wasting.

Despite years of preclinical efforts and hundreds of clinical studies, therapeutic cancer vaccines with the routine ability to limit or eliminate tumor growth in humans have been elusive. With advances in genome sequencing, it is now possible to identify a new class of tumor-specific antigens derived from mutated proteins that are present only in the tumor. These "neoantigens" should provide highly specific targets for antitumor immunity. Although many challenges remain in producing and testing neoantigen-based vaccines customized for each patient, a neoantigen vaccine offers a promising new approach to induce highly focused antitumor T cells aimed at eradicating cancer cells., (©2013 AACR.)

The nonlinear three-wave interaction process at the heart of the parametric decay process is studied by launching counterpropagating Alfvén waves from antennas placed at either end of the Large Plasma Device. A resonance in the beat wave response produced by the two launched Alfvén waves is observed and is identified as a damped ion acoustic mode based on the measured dispersion relation. Other properties of the interaction including the spatial profile of the beat mode and response amplitude are also consistent with theoretical predictions for a three-wave interaction driven by a nonlinear ponderomotive force.

A critical gradient threshold has been observed for the first time in a systematic, controlled experiment for a locally measured turbulent quantity in the core of a confined high-temperature plasma. In an experiment in the DIII-D tokamak where L(T(e))(-1) = |∇T(e)|/T(e) and toroidal rotation were varied, long wavelength (k(θ)ρ(s) ≲ 0.4) electron temperature fluctuations exhibit a threshold in L(T(e))(-1): below, they change little; above, they steadily increase. The increase in δT(e)/T(e) is concurrent with increased electron heat flux and transport stiffness. Observations were insensitive to rotation. Accumulated evidence strongly enforces the identification of the experimentally observed threshold with ∇T(e)-driven trapped electron mode turbulence.

Turbulence is a ubiquitous phenomenon in space and astrophysical plasmas, driving a cascade of energy from large to small scales and strongly influencing the plasma heating resulting from the dissipation of the turbulence. Modern theories of plasma turbulence are based on the fundamental concept that the turbulent cascade of energy is caused by the nonlinear interaction between counterpropagating Alfvén waves, yet this interaction has never been observationally or experimentally verified. We present here the first experimental measurement in a laboratory plasma of the nonlinear interaction between counterpropagating Alfvén waves, the fundamental building block of astrophysical plasma turbulence. This measurement establishes a firm basis for the application of theoretical ideas developed in idealized models to turbulence in realistic space and astrophysical plasma systems.

We used in vitro neurogenesis-based human neural stem cell (hNSCs) assays and rodent in vivo behavioral assays to identify potential novel antidepressants. A combination of buspirone and melatonin displayed antidepressant activity in these assays whereas neither buspirone nor melatonin alone showed any antidepressant-like profile. After evaluating numerous combination ratios, we determined that low dose buspirone 15 mg combined with melatonin-SR 3 mg yielded optimal antidepressant efficacy in our pre-clinical platform. The low dose of buspirone suggested that antidepressant efficacy might be achieved with only minimal adverse event liability. Based on these data, we conducted an exploratory 6-week, multi-center, double-blind, randomized, placebo- and comparator-controlled study of the combination of buspirone and melatonin in subjects with acute Major Depressive Disorder (MDD). The combination treatment revealed a significant antidepressant response in subjects with MDD on several measures (Clinical Global Impression of Severity and Improvement, Inventory of Depressive Symptomatology) compared to either placebo or buspirone 15 mg monotherapy. These preliminary findings have clinical implications and suggest that a platform of pre-clinical neurogenesis matched with confirmatory behavioral assays may be useful as a drug discovery strategy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Polarimetry is a powerful diagnostic technique to probe plasma equilibria and magnetic fluctuations in fusion plasmas. In a high beta plasma such as the National Spherical Torus eXperiment (NSTX), these measurements are important to understand plasma stability and anomalous transport. A 288 GHz polarimeter operating along a major radial chord in retroreflection geometry has been developed and is being tested on the DIII-D tokamak to prepare for future implementation on NSTX-Upgrade. The system launches a rotating linearly polarized beam and detects the phase shift directly related to the polarization change caused by the plasma. To accomplish this, a pair of orthogonal linearly polarized beams with a stable difference frequency is generated using a single sideband modulation technique, then combined and transformed to be counter-rotating circularly polarized. To improve phase resolution, quasi-optical isolation, using Faraday rotators and polarizers, is utilized to eliminate a multi-path feedback effect, which is found to be the primary source of phase error. The bench tests in the laboratory and DIII-D power supply test discharges indicate ≤1° phase resolution.

Doppler backscattering (DBS) is a plasma diagnostic used in tokamaks and other magnetic confinement devices to measure the fluctuation level of intermediate wavenumber (k(θ)ρ(s) ~ 1) density fluctuations and the lab frame propagation velocity of turbulence. Here, a synthetic DBS diagnostic is described, which has been used for comparisons between measurements in the DIII-D tokamak and predictions from nonlinear gyrokinetic simulations. To estimate the wavenumber range to which a Gaussian beam would be sensitive, a ray tracing code and a 2D finite difference, time domain full wave code are used. Experimental density profiles and magnetic geometry are used along with the experimental antenna and beam characteristics. An example of the effect of the synthetic diagnostic on the output of a nonlinear gyrokinetic simulation is presented.

Continuous control over azimuthal flow and shear in the edge of the Large Plasma Device (LAPD) has been achieved using a biasable limiter which has allowed a careful study of the effect of flow shear on pressure-gradient-driven turbulence and transport in the LAPD. The LAPD rotates spontaneously in the ion diamagnetic direction; positive limiter bias first reduces, then minimizes (producing a near-zero shear state), and finally reverses the flow into the electron diamagnetic direction. Degradation of particle confinement is observed in the minimum shearing state and a reduction in the turbulent particle flux is observed with increasing shearing in both flow directions. Near-complete suppression of the turbulent particle flux is observed for shearing rates comparable to the turbulent autocorrelation rate measured in the minimum shear state. Turbulent flux suppression is dominated by amplitude reduction in low-frequency (<10 kHz) density fluctuations. An increase in fluctuations for the highest shearing states is observed with the emergence of a coherent mode which does not lead to net particle transport. The variations of density fluctuations are fit well with power laws and compare favorably to simple models of shear suppression of transport.

Three-wave nonlinear coupling among spatial Fourier modes of density and magnetic fluctuations is directly measured in a magnetically confined toroidal plasma. Density fluctuations are observed to gain (lose) energy from (to) either equilibrium or fluctuating fields depending on the mode number. Experiments indicate that nonlinear interactions alter the phase relation between density and magnetic fluctuations, leading to strong particle transport.

The evolution of electromagnetic wave polarization is modeled for propagation in the major radial direction in the National Spherical Torus Experiment with retroreflection from the center stack of the vacuum vessel. This modeling illustrates that the Cotton-Mouton effect-elliptization due to the magnetic field perpendicular to the propagation direction-is shown to be strongly weighted to the high-field region of the plasma. An interaction between the Faraday rotation and Cotton-Mouton effects is also clearly identified. Elliptization occurs when the wave polarization direction is neither parallel nor perpendicular to the local transverse magnetic field. Since Faraday rotation modifies the polarization direction during propagation, it must also affect the resultant elliptization. The Cotton-Mouton effect also intrinsically results in rotation of the polarization direction, but this effect is less significant in the plasma conditions modeled. The interaction increases at longer wavelength and complicates interpretation of polarimetry measurements.

A novel multichannel, tunable Doppler backscattering (DBS)/reflectometry system has recently been developed and applied to a variety of DIII-D plasmas. Either DBS or reflectometry can be easily configured for use in a wide range of plasma conditions using a flexible quasi-optical antenna system. The multiple closely spaced channels, when combined with other fluctuation diagnostic systems, have opened up new measurements of plasma properties. For example, the toroidal and fine-scale radial structure of coherent plasma oscillations, such as geodesic acoustic modes, have been probed simultaneously in the core of high temperature plasmas by applying correlation analysis between two toroidally separated DBS systems, as well as within the multichannel array. When configured as a reflectometer, cross-correlation with electron cyclotron emission radiometry has uncovered detailed information regarding the crossphase relationship between density and temperature fluctuations. The density-temperature crossphase measurement yields insight into the physics of tokamak turbulence at a fundamental level that can be directly compared with predictions from nonlinear gyrokinetic simulations.

A new technique for manipulation and control of gradient-driven instabilities through nonlinear interaction with Alfvén waves in a laboratory plasma is presented. A narrow, field-aligned density depletion is created in the Large Plasma Device, resulting in coherent, unstable fluctuations on the periphery of the depletion. Two independent shear Alfvén waves are launched along the depletion at separate frequencies, creating a nonlinear beat-wave response at or near the frequency of the original instability. When the beat wave has sufficient amplitude, the original unstable mode is suppressed, leaving only the beat-wave response, generally at lower amplitude.

Treatment of AML patients with small molecule inhibitors of FLT3 kinase has been explored as a viable therapy. However, these agents are found to be less than optimal for the treatment of AML because of lack of sufficient potency or suboptimal oral pharmacokinetics (PK) or lack of adequate tolerability at efficacious doses. We have developed a series of extremely potent and highly selective FLT3 inhibitors with good oral PK properties. The first series of compounds represented by 1 (AB530) was found to be a potent and selective FLT3 kinase inhibitor with good PK properties. The aqueous solubility and oral PK properties at higher doses in rodents were found to be less than optimal for clinical development. A novel series of compounds were designed lacking the carboxamide group of 1 with an added water solubilizing group. Compound 7 (AC220) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. Compound 7 has demonstrated a desirable safety and PK profile in humans and is currently in phase II clinical trials.

A series of diaryl ureas with an amide substitution at the 4-position was prepared and found to be potent and selective FLT3 inhibitors with good oral bioavailability and efficacy in a tumor xenograft model.

A novel multichannel Doppler backscattering system has been designed and tested for application on the DIII-D [J. L. Luxon, Fusion Sci. Technol. 48, 828 (2005)] and National Spherical Torus Experiment (NSTX) [M. Ono et al., Nucl. Fusion 40, 557 (2000)] fusion plasma devices. Doppler backscattering measures localized intermediate wavenumber (k(perpendicular)rho(i) approximately 1-4,k(perpendicular) approximately 2-15 cm(-1)) density fluctuations and the propagation velocity of turbulent structures. Microwave radiation is launched at a frequency that approaches a cutoff layer in the plasma and at an angle that is oblique to the cutoff layer. Bragg backscattering occurs near the cutoff layer for fluctuations with k(perpendicular) approximately -2k(i), where k(i) is the incident probe wave vector at the scattering location. The turbulence propagation velocity can be determined from the Doppler shift in the return signal together with knowledge of the scattering wavenumber. Ray tracing simulations are used to determine k(perpendicular) and the scattering location. Frequency modulation of a voltage-controlled solid state microwave source followed by frequency multiplication is used to create an array of finely spaced (Delta f=350 MHz) frequencies spanning 1.4 GHz. The center of the array bandwidth is tunable within the range of approximately 53-78 GHz. This article details the system design, laboratory tests, and presents initial data from DIII-D plasmas.

Fluctuations are expected to play an important role in anomalous particle, momentum, and energy transport for magnetic confinement devices. Magnetic and density fluctuations are simultaneously measured using a high-speed laser-based Faraday rotation-interferometry system with a bandwidth of 500 kHz and 8 cm chord spacing. Density fluctuation and magnetic fluctuation profiles are obtained by using a newly developed fitting procedure.

Doppler backscattering (DBS) has been successfully used to measure the E x B flow velocity and local intermediate wavenumber density fluctuation levels in the DIII-D tokamak. Depending on the launch angle and the frequency of the probing beam, the signal backscattered from the plasma cut-off layer is sensitive to density fluctuations at a specific perpendicular wavenumber (1 < or = k(perpendicular rho(s)) < or = 4). Due to the localization and high time resolution for poloidal flow measurements, DBS is well suited to detect stationary and time-dependent shear flows [zonal flows (ZFs)]. We present a novel scheme to measure ZF spectra using a dual-channel DBS system capable of simultaneously probing two minor radii separated by a distance of 0.2 cm < Delta r < 3 cm. Frequency spectra of geodesic acoustic modes and low frequency ZFs (f or = 10 kHz) have been obtained for 0.6 < r/a < 0.95.

A correlation electron cyclotron emission (CECE) diagnostic has been used to measure local, turbulent fluctuations of the electron temperature in the core of DIII-D plasmas. This paper describes the hardware and testing of the CECE diagnostic and highlights the importance of measurements of multifield fluctuation profiles for the testing and validation of nonlinear gyrokinetic codes. The process of testing and validating such codes is critical for extrapolation to next-step fusion devices. For the first time, the radial profiles of electron temperature and density fluctuations are compared to nonlinear gyrokinetic simulations. The CECE diagnostic at DIII-D uses correlation radiometry to measure the rms amplitude and spectrum of the electron temperature fluctuations. Gaussian optics are used to produce a poloidal spot size with w(o) approximately 1.75 cm in the plasma. The intermediate frequency filters and the natural linewidth of the EC emission determine the radial resolution of the CECE diagnostic, which can be less than 1 cm. Wavenumbers resolved by the CECE diagnostic are k(theta) < or = 1.8 cm(-1) and k(r) < or = 4 cm(-1), relevant for studies of long-wavelength turbulence associated with the trapped electron mode and the ion temperature gradient mode. In neutral beam heated L-mode plasmas, core electron temperature fluctuations in the region 0.5 < r/a < 0.9, increase with radius from approximately 0.5% to approximately 2%, similar to density fluctuations that are measured simultaneously with beam emission spectroscopy. After incorporating "synthetic diagnostics" to effectively filter the code output, the simulations reproduce the characteristics of the turbulence and transport at one radial location r/a = 0.5, but not at a second location, r/a = 0.75. These results illustrate that measurements of the profiles of multiple fluctuating fields can provide a significant constraint on the turbulence models employed by the code.

Measurements of a magnetized plasma with a controlled electron temperature gradient show the development of a broadband spectrum of density and temperature fluctuations having an exponential frequency dependence at frequencies below the ion cyclotron frequency. The origin of the exponential frequency behavior is traced to temporal pulses of Lorentzian shape. Similar exponential frequency spectra are also found in limiter-edge plasma turbulence associated with blob transport. This finding suggests a universal feature of magnetized plasma turbulence leading to nondiffusive, cross-field transport, namely, the presence of Lorentzian shaped pulses.

Coherent temperature oscillations corresponding to thermal (diffusion) waves are observed to be spontaneously excited in a narrow temperature filament embedded in a large, but colder, magnetized plasma. The parallel and transverse propagation properties of the waves satisfy the predictions of the classical transport theory based on Coulomb collisions. The frequency of the oscillations meets the conditions for a quarter-wave thermal resonator. This is the plasma version of thermal resonators used in the study of other states of matter.

Core electron-temperature fluctuations [0.5%< or =T[over ]&#95;(e)/T&#95;(e)< or =2%, k&#95;(theta)rho&#95;(s)< or =0.3 in neutral-beam-heated low confinement-mode (L-mode) plasmas] are observed to decrease by at least a factor of 4 in standard and quiescent high-confinement-mode (H-mode and QH-mode) regimes in the DIII-D tokamak (r/a=0.7). These fluctuations are attributed to ion temperature gradient (ITG) modes stabilized by rotational shear at the H-mode transition. The simultaneous reduction in electron heat diffusivity (chi&#95;(e)(QH)/chi&#95;(e)(L)<0.25) suggests that T[over ]&#95;(e) fluctuations can contribute significantly to L-mode electron heat transport.

An experimental investigation of nonlinear interactions between shear Alfvén waves in a laboratory plasma is presented. Two Alfvén waves, generated by a resonant cavity, are observed to beat together, driving a pseudomode at the beat frequency. The pseudomode then scatters the Alfvén waves, generating a series of sidebands. The observed interaction is very strong, with the normalized amplitude of the driven pseudomode comparable to the normalized magnetic field amplitude (deltaB/B) of the interacting Alfvén waves.

Three experiments, which included 4 broiler flocks, were conducted to examine the usefulness of a novel bedding material for rearing broilers. The control bedding was pine shavings. The novel bedding, aGroChips (AC), was a chopped material made from cotton lint waste, gypsum, and old newsprint using a proprietary paper manufacturing process (Novovita, Inc., Raleigh, NC). All birds were fed the same feeding program: starter from 0 to 3 wk, grower from 3 to 5 or 6 wk, and finisher during the last week. Birds were marketed at either 6 or 7 wk of age. Feed consumption by pen and individual bird BW were measured at 3 and 6 or 7 wk. Mean BW and feed conversion, adjusted to include weight of mortality, were calculated. A sample of birds (n = 10) from each pen was evaluated for hock and foot pad condition. Each pen was evaluated at the end of the trial for litter cake index in 3 of the 4 flocks. Litter cake index scores were generally higher for birds reared on AC litters. There were no other differences in bird performance for any of the flocks. In conclusion, broilers reared on AC bedding perform as well as those reared on pine shavings.

To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved "gatekeeper" threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib- and BMS-354825-resistant ABL(T315I) kinase. The KIT/FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D/T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitinib- and erlotinib-resistant EGFR(L858R/T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib/erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of next-generation drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy.

Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.

Background: Progressive neurological dysfunction is a key aspect of human aging. Because of underlying differences in the aging of mice and humans, useful mouse models have been difficult to obtain and study. We have used gene-expression analysis and polymorphism screening to study molecular senescence of the retina and hippocampus in two rare inbred mouse models of accelerated neurological senescence (SAMP8 and SAMP10) that closely mimic human neurological aging, and in a related normal strain (SAMR1) and an unrelated normal strain (C57BL/6J)., Results: The majority of age-related gene expression changes were strain-specific, with only a few common pathways found for normal and accelerated neurological aging. Polymorphism screening led to the identification of mutations that could have a direct impact on important disease processes, including a mutation in a fibroblast growth factor gene, Fgf1, and a mutation in and ectopic expression of the gene for the chemokine CCL19, which is involved in the inflammatory response., Conclusion: We show that combining the study of inbred mouse strains with interesting traits and gene-expression profiling can lead to the discovery of genes important for complex phenotypes. Furthermore, full-genome polymorphism detection, sequencing and gene-expression profiling of inbred mouse strains with interesting phenotypic differences may provide unique insights into the molecular genetics of late-manifesting complex diseases.

Mutations in a large number of retinal and retinal pigment epithelium (RPE) expressed genes can lead to the degeneration of photoreceptors and consequently the loss of vision. The genetic and phenotypic heterogeneity of retinal dystrophies poses a complex problem with respect to rational development of therapeutic strategies. Delineation of physiological functions of disease genes and identification of pathways that lead to disease pathogenesis represent essential goals towards developing a systematic and global approach to gene-based treatments. We are interested in identifying cellular pathways that are involved in photoreceptor differentiation, function and degeneration. We are, therefore, generating comprehensive gene expression profiles of retina and RPE of humans and mice using both cDNA- and oligonucleotide-based (Affymetrix) microarrays. Because of the under-representation of retinal/RPE genes in the public databases, we have constructed several unamplified cDNA libraries and produced almost twenty thousand expressed sequence tags (ESTs) that are being printed onto glass slides ('I-Gene' microarrays). In this presentation, we will report the microarray analysis of the rodless (and cone-enhanced) retina from the Nrl-knockout mouse as a paradigm to initiate the identification of cellular pathways involved in photoreceptor differentiation and function.

A common method for generating mice with subtle genetic manipulations uses homologous recombination (HR) in embryonic stem (ES) cells to replace a wild-type gene with a slightly modified one. Generally, a drug resistance gene is inserted with the modified gene to select correctly targeted clones. Often, however, the presence of this drug resistance gene interferes with the normal locus and creates a null or hypomorphic allele. Flanking of the selectable marker by loxP sites followed by Cre-mediated deletion after drug selection can overcome this problem. The simplest method used to remove a loxP-flanked selectable marker is to breed an animal carrying a loxP-flanked drug resistance gene to an animal that expresses Cre recombinase in the germline. To date only outbred transgenic mice are available for this purpose. This can be problematic for phenotypic analysis in many organ systems, including the brain, and for the analysis of behavior. While attempting to make 129S6/SvEvTac inbred background (isogenic to our ES cells) mice that express Cre under the control of several tissue-specific promoters, we serendipitously generated a line that excises loxP-flanked drug resistance genes in all tissues, including the germline. This reagent allows deletion of loxP-flanked sequences while maintaining the mutation on an inbred background.

We present a detailed study of fluctuations in a laboratory current sheet undergoing magnetic reconnection. The measurements reveal the presence of lower-hybrid-frequency-range fluctuations on the edge of current sheets produced in the magnetic reconnection experiment (MRX). The measured fluctuation characteristics are consistent with theoretical predictions for the lower-hybrid drift instability (LHDI). Our observations suggest that the LHDI turbulence alone cannot explain the observed fast reconnection rate in MRX.

Highly parallel gene expression profiling has the potential to provide new insight into the molecular mechanisms of complex brain diseases and behavioral traits. We review how gene expression profiling in various brain regions of inbred mouse strains has been used to identify genes that may contribute to strain-specific phenotypes. New data, which demonstrate the use of gene expression profiling in combination with behavioral testing to identify candidate genes involved in mediating variation in running wheel activity, are also presented. These and other studies suggest that a combination of gene expression profiling and more traditional genetic approaches, such as quantitative trait locus analysis, can be used to identify genes responsible for specific neurobehavioral phenotypes.

Ataxia telangiectasia (A-T) is an autosomal recessive disease characterized by normal brain development followed by progressive neurodegeneration. The gene mutated in A-T (ATM) is a serine protein kinase implicated in cell cycle regulation and DNA repair. The role of ATM in the brain and the consequences of its loss on neuronal survival remain unclear. We studied the role of ATM in adult neural progenitor cells in vivo and in vitro to define the role of ATM in dividing and postmitotic neural cells from Atm-deficient (Atm(-/-)) mice in a physiologic context. We demonstrate that ATM is an abundant protein in dividing neural progenitor cells but is markedly down-regulated as cells differentiate. In the absence of ATM, neural progenitor cells of the dentate gyrus show abnormally high rates of proliferation and genomic instability. Atm(-/-) cells in vivo, and in cell culture, show a blunted response to environmental stimuli that promote neural progenitor cell proliferation, survival, and differentiation along a neuronal lineage. This study defines a role for ATM during the process of neurogenesis, demonstrates that ATM is required for normal cell fate determination and neuronal survival both in vitro and in vivo, and points to a mechanism for neuronal cell loss in progressive neurodegenerative diseases.

Patients with mutations in the thyroid hormone receptor beta (TRbeta) gene manifest resistance to thyroid hormone (RTH), resulting in a constellation of variable phenotypic abnormalities. To understand the molecular basis underlying the action of mutant TRbeta in vivo, we generated mice with a targeted mutation in the TRbeta gene (TRbetaPV; PV, mutant thyroid hormone receptor kindred PV) by using homologous recombination and the Cre/loxP system. Mice expressing a single PV allele showed the typical abnormalities of thyroid function found in heterozygous humans with RTH. Homozygous PV mice exhibit severe dysfunction of the pituitary-thyroid axis, impaired weight gains, and abnormal bone development. This phenotype is distinct from that seen in mice with a null mutation in the TRbeta gene. Importantly, we identified abnormal expression patterns of several genes in tissues of TRbetaPV mice, demonstrating the interference of the mutant TR with the gene regulatory functions of the wild-type TR in vivo. These results show that the actions of mutant and wild-type TRbeta in vivo are distinct. This model allows further study of the molecular action of mutant TR in vivo, which could lead to better treatment for RTH patients.

To determine the genetic causes and molecular mechanisms responsible for neurobehavioral differences in mice, we used highly parallel gene expression profiling to detect genes that are differentially expressed between the 129SvEv and C57BL/6 mouse strains at baseline and in response to seizure. In addition, we identified genes that are differentially expressed in specific brain regions. We found that approximately 1% of expressed genes are differentially expressed between strains in at least one region of the brain and that the gene expression response to seizure is significantly different between the two inbred strains. The results lead to the identification of differences in gene expression that may account for distinct phenotypes in inbred strains and the unique functions of specific brain regions.

Local ion temperature and flows are measured directly in the well-characterized reconnection layer of a laboratory plasma. The measurements indicate strongly that ions are heated due to reconnection and that more than half of the reconnected field energy is converted to ion thermal energy. Neither classical viscous damping of the observed sub-Alfvenic ion flows nor classical energy exchange with electrons is sufficient to account for the ion heating, suggesting the importance of nonclassical dissipation mechanisms in the reconnection layer.

Spinal muscular atrophy (SMA) is a motor neuron disease presenting with a wide spectrum of phenotypic variations. The primary cause of most, if not all, forms of childhood-onset spinal muscular atrophy appears to be the homozygous loss of the telomeric copy of the survival motor neuron (SMNT) gene. It is interesting that approximately half of all affected patients are likewise homozygous nulls for the neuronal apoptosis inhibitory protein (NAIP) gene and a somewhat lesser fraction for the basal transcription factor, p44 subunit (BTF2p44) gene. It has been proposed that homozygous loss of SMNT is the primary cause of spinal muscular atrophy while the loss of NAIP and perhaps other genes primarily affects the severity of disease manifestation. We explored this hypothesis by evaluating the extent of gene deletions in three multigenerational families with spinal muscular atrophy exhibiting dramatic intrafamilial phenotypic variation. Using somatic cell hybrid lines to sequester individual spinal muscular atrophy homologues, we show that homologues missing several contiguous genes correlate with "severe" disease alleles and homologues missing only SMNT correlate with "mild" disease alleles. These observations support the hypothesis that phenotypic severity among the childhood-onset spinal muscular atrophies is directly correlated with the extent of disease-specific deletions.