Increase in Tau Pathology in P290S Mapt Knock-In Mice Crossed with AppNL-G-F Mice

Alzheimer's Disease (AD) is characterized by the pathological assembly of Aβ peptide, which deposits into extracellular plaques, and tau, which accumulates in intraneuronal inclusions. To investigate the link between Aβ and tau pathologies, experimental models featuring both pathologies are needed. We developed a mouse model featuring both tau and Aβ pathologies by knocking the P290S mutation into murine Mapt and crossing these MaptP290S KI mice with the AppNL-G-F KI line. MaptP290S KI mice developed a small number of tau inclusions, which increased with age. The amount of tau pathology was significantly larger in AppNL-G-FxMaptP290S KI mice from 18-months of age onwards. Tau pathology was higher in limbic areas, including hippocampus, amygdala and piriform/entorhinal cortex. We also observed AT100-and Gallyas-Braak-silver-positive dystrophic neurites containing assembled filamentous tau, as visualized by in situ EM. Using a cell-based tau seeding assay, we showed that sarkosyl-insoluble brain extracts from both 18-month-old MaptP290S KI and AppNL-G-FxMaptP290S KI mice were seed-competent, with brain extracts from double KI mice seeding significantly more than those from the MaptP290S KI mice. Finally, we showed that AppNL-G-FxMaptP290S KI mice had neurodegeneration in the piriform cortex from 18-months of age. We suggest that AppNL-G-F x MaptP290S KI mice provide a good model for studying the interactions of aggregation-prone tau, Aβ, neuritic plaques, neurodegeneration and aging

Laser-plasma interactions in long-scale-length plasmas under direct-drive National Ignition Facility conditions

Laser-plasma interaction experiments have been carried out on the OMEGA laser system [T. R. Boehly et al., Opt. Commun. 133, 495 (1997)] under plasma conditions representative of the peak of a 1.5 MJ direct-drive laser pulse proposed for the National Ignition Facility (NIF). Plasmas have been formed by exploding 18–20 μm thick CH foils and by irradiating solid CH targets from one side, using up to 20 kJ of laser energy with phase plates installed on all beams. These plasmas and the NIF plasmas are predicted to have electron temperatures of 4 keV and density scale lengths close to 0.75 mm at the peak of the laser pulse. The electron temperature and density of the exploding-foil plasmas have been diagnosed using time-resolved x-ray spectroscopy and stimulated Raman scattering, respectively, and are consistent with predictions of the two-dimensional Eulerian hydrodynamics code SAGE [R. S. Craxton and R. L. McCrory, J. Appl. Phys. 56, 108 (1984)]. When the solid-target or exploding-foil plasmas were irradiated with an f/6f/6 interaction beam at 1.5×1015 W/cm2,1.5×1015W/cm2, well above the NIF f/8f/8 cluster intensity of ∼ 2×1014 W/cm2,∼2×1014W/cm2, stimulated Brillouin backscattering (SBS) was found to be completely inhibited. A conservative upper limit of direct-backscattered SRS was found to be ∼5% from the solid targets. SRS and SBS are thus unlikely to have a significant impact on target performance at the peak of the NIF direct-drive laser pulse. © 1999 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/70094/2/PHPAEN-6-5-2072-1.pd

Opportunities for advances in climate change economics

There have been dramatic advances in understanding the physical science of climate change, facilitated by substantial and reliable research support. The social value of these advances depends on understanding their implications for society, an arena where research support has been more modest and research progress slower. Some advances have been made in understanding and formalizing climate-economy linkages, but knowledge gaps remain [e.g., as discussed in (1, 2)]. We outline three areas where we believe research progress on climate economics is both sorely needed, in light of policy relevance, and possible within the next few years given appropriate funding: (i) refining the social cost of carbon (SCC), (ii) improving understanding of the consequences of particular policies, and (iii) better understanding of the economic impacts and policy choices in developing economies

Saturation of the Two-Plasmon Decay Instability in Long-Scale-Length Plasmas Relevant to Direct-Drive Inertial Confinement Fusion

Measurements of the hot-electron generation by the two-plasmon-decay instability are made in plasmas relevant to direct-drive inertial confinement fusion. Density-scale lengths of 400 {micro}m at n{sub cr}/4 in planar CH targets allowed the two-plasmon-decay instability to be driven to saturation for vacuum intensities above ~3.5 x 10{sup 14} W cm{sup -2}. In the saturated regime, ~1% of the laser energy is converted to hot electrons. The hot-electron temperature is measured to increase rapidly from 25 to 90 keV as the laser beam intensity is increased from 2 to 7 x 10{sup 14} W cm{sup -2}. This increase in the hot-electron temperature is compared with predictions from nonlinear Zakharov models

Promiscuous drugs compared to selective drugs (promiscuity can be a virtue)

BACKGROUND: The word selectivity describes a drug's ability to affect a particular cell population in preference to others. As part of the current state of art in the search for new therapeutic agents, the property of selectivity is a mode of action thought to have a high degree of desirability. Consequently there is a growing activity in this area of research. Selectivity is generally a worthy property in a drug because a drug having high selectivity may have a dramatic effect when there is a single agent that can be targeted against the appropriate molecular-driver involved in the pathogenesis of a disease. An example is chronic myeloid leukemia (CML). CML has a specific chromosomal abnormality, the Philadelphia chromosome, that results in a single gene that produces an abnormal protein DISCUSSION: There is a burgeoning understanding of the cellular mechanisms that control the etiology and pathogeneses of diseases. This understanding both enables and motivates the development of drugs that induce a specific action in a selected cell population; i.e., a targeted treatment. Consequently, drugs that can target distinct molecular targets involved in pathologic/pathogenetic processes, or signal-transduction pathways, are being developed. However, in most cases, diseases involve multiple abnormalities. A disease may be associated with more than one dysfunctional protein and these may be out-of-balance with each other. Likewise a drug might strongly target a protein that shares a similar active domain with other proteins. A drug may also target pleiotropic cytokines, or other proteins that have multi-physiological functions. In this way multiple normal cellular pathways can be simultaneously influenced. Long term experience with drugs supposedly designed for only a single target, but which unavoidably involve other functional effects, is uncovering the fact that molecular targeting is not medically flawless. SUMMARY: We contend that an ideal drug may be one whose efficacy is based not on the inhibition of a single target, but rather on the rebalancing of the several proteins or events, that contribute to the etiology, pathogeneses, and progression of diseases, i.e., in effect a promiscuous drug. Ideally, if this could be done at minimum drug concentration, side effects could be minimized. Corollaries to this argument are that the growing fervor for researching truly selective drugs may be imprudent when considering the totality of responses; and that the expensive screening techniques used to discover these, may be both medically and financially inefficient

Demonstration of Fuel Hot-Spot Pressure in Excess of 50 Gbar for Direct-Drive, Layered Deuterium-Tritium Implosions on OMEGA

A record fuel hot-spot pressure P[subscript hs] = 56±7  Gbar was inferred from x-ray and nuclear diagnostics for direct-drive inertial confinement fusion cryogenic, layered deuterium–tritium implosions on the 60-beam, 30-kJ, 351-nm OMEGA Laser System. When hydrodynamically scaled to the energy of the National Ignition Facility, these implosions achieved a Lawson parameter ∼60% of the value required for ignition [A. Bose et al., Phys. Rev. E 93, LM15119ER (2016)], similar to indirect-drive implosions [R. Betti et al., Phys. Rev. Lett. 114, 255003 (2015)], and nearly half of the direct-drive ignition-threshold pressure. Relative to symmetric, one-dimensional simulations, the inferred hot-spot pressure is approximately 40% lower. Three-dimensional simulations suggest that low-mode distortion of the hot spot seeded by laser-drive nonuniformity and target-positioning error reduces target performance.United States. Department of Energy (DE-NA0001944

B Cell Activating Factor (BAFF) and T Cells Cooperate to Breach B Cell Tolerance in Lupus-Prone New Zealand Black (NZB) Mice

The presence of autoantibodies in New Zealand Black (NZB) mice suggests a B cell tolerance defect however the nature of this defect is unknown. To determine whether defects in B cell anergy contribute to the autoimmune phenotype in NZB mice, soluble hen egg lysozyme (sHEL) and anti-HEL Ig transgenes were bred onto the NZB background to generate double transgenic (dTg) mice. NZB dTg mice had elevated levels of anti-HEL antibodies, despite apparently normal B cell functional anergy in-vitro. NZB dTg B cells also demonstrated increased survival and abnormal entry into the follicular compartment following transfer into sHEL mice. Since this process is dependent on BAFF, BAFF serum and mRNA levels were assessed and were found to be significantly elevated in NZB dTg mice. Treatment of NZB sHEL recipient mice with TACI-Ig reduced NZB dTg B cell survival following adoptive transfer, confirming the role of BAFF in this process. Although NZB mice had modestly elevated BAFF, the enhanced NZB B cell survival response appeared to result from an altered response to BAFF. In contrast, T cell blockade had a minimal effect on B cell survival, but inhibited anti-HEL antibody production. The findings suggest that the modest BAFF elevations in NZB mice are sufficient to perturb B cell tolerance, particularly when acting in concert with B cell functional abnormalities and T cell help