Observing the onset of pressure-driven K-shell delocalization.

The gravitational pressure in many astrophysical objects exceeds one gigabar (one billion atmospheres)1-3, creating extreme conditions where the distance between nuclei approaches the size of the K shell. This close proximity modifies these tightly bound states and, above a certain pressure, drives them into a delocalized state4. Both processes substantially affect the equation of state and radiation transport and, therefore, the structure and evolution of these objects. Still, our understanding of this transition is far from satisfactory and experimental data are sparse. Here we report on experiments that create and diagnose matter at pressures exceeding three gigabars at the National Ignition Facility5 where 184 laser beams imploded a beryllium shell. Bright X-ray flashes enable precision radiography and X-ray Thomson scattering that reveal both the macroscopic conditions and the microscopic states. The data show clear signs of quantum-degenerate electrons in states reaching 30 times compression, and a temperature of around two million kelvins. At the most extreme conditions, we observe strongly reduced elastic scattering, which mainly originates from K-shell electrons. We attribute this reduction to the onset of delocalization of the remaining K-shell electron. With this interpretation, the ion charge inferred from the scattering data agrees well with ab initio simulations, but it is significantly higher than widely used analytical models predict6.

Adjudicating Mild Cognitive Impairment Due to Alzheimer's Disease as a Novel Endpoint Event in the TOMMORROW Prevention Clinical Trial.

BACKGROUND: The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer's disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. METHODS: The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant's clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages - independent review, collaborative review, and full committee review - requiring a unanimous decision and ratification by the chair. RESULTS: Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators' clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80-90% for the remainder of the study. CONCLUSIONS: The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.

Experimental Observations of Laser-Driven Tin Ejecta Microjet Interactions.

The study of high-velocity particle-laden flow interactions is of importance for the understanding of a wide range of natural phenomena, ranging from planetary formation to cloud interactions. Experimental observations of particle dynamics are sparse given the difficulty of generating high-velocity flows of many particles. Ejecta microjets are micron-scale jets formed by strong shocks interacting with imprinted surfaces to generate particle plumes traveling at several kilometers per second. As such, the interaction of two ejecta microjets provides a novel experimental methodology to study interacting particle streams. In this Letter, we report the first time sequences of x-ray radiography images of two interacting tin ejecta microjets taken on a platform designed for the OMEGA Extended Performance (OMEGA EP) laser. We observe that the microjets pass through each other unattenuated for the case of 11.7±3.2 GPa shock pressures and jet velocities of 2.2±0.5 km/s but show strong interaction dynamics for 116.0±6.1 GPa shock pressures and jet velocities of 6.5±0.5 km/s. We find that radiation-hydrodynamic simulations of the experiments are able to capture many aspects of the collisional behavior, such as the attenuation of jet velocity in the direction of propagation, but are unable to match the full spread of the strongly interacting cloud.

Measuring the structure and equation of state of polyethylene terephthalate at megabar pressures.

We present structure and equation of state (EOS) measurements of biaxially orientated polyethylene terephthalate (PET, [Formula: see text], also called mylar) shock-compressed to ([Formula: see text]) GPa and ([Formula: see text]) K using in situ X-ray diffraction, Doppler velocimetry, and optical pyrometry. Comparing to density functional theory molecular dynamics (DFT-MD) simulations, we find a highly correlated liquid at conditions differing from predictions by some equations of state tables, which underlines the influence of complex chemical interactions in this regime. EOS calculations from ab initio DFT-MD simulations and shock Hugoniot measurements of density, pressure and temperature confirm the discrepancy to these tables and present an experimentally benchmarked correction to the description of PET as an exemplary material to represent the mixture of light elements at planetary interior conditions.

Demonstration of X-ray Thomson scattering as diagnostics for miscibility in warm dense matter.

The gas and ice giants in our solar system can be seen as a natural laboratory for the physics of highly compressed matter at temperatures up to thousands of kelvins. In turn, our understanding of their structure and evolution depends critically on our ability to model such matter. One key aspect is the miscibility of the elements in their interiors. Here, we demonstrate the feasibility of X-ray Thomson scattering to quantify the degree of species separation in a 1:1 carbon-hydrogen mixture at a pressure of ~150 GPa and a temperature of ~5000 K. Our measurements provide absolute values of the structure factor that encodes the microscopic arrangement of the particles. From these data, we find a lower limit of [Formula: see text]% of the carbon atoms forming isolated carbon clusters. In principle, this procedure can be employed for investigating the miscibility behaviour of any binary mixture at the high-pressure environment of planetary interiors, in particular, for non-crystalline samples where it is difficult to obtain conclusive results from X-ray diffraction. Moreover, this method will enable unprecedented measurements of mixing/demixing kinetics in dense plasma environments, e.g., induced by chemistry or hydrodynamic instabilities.

Evidence for Crystalline Structure in Dynamically-Compressed Polyethylene up to 200 GPa.

We investigated the high-pressure behavior of polyethylene (CH2) by probing dynamically-compressed samples with X-ray diffraction. At pressures up to 200 GPa, comparable to those present inside icy giant planets (Uranus, Neptune), shock-compressed polyethylene retains a polymer crystal structure, from which we infer the presence of significant covalent bonding. The A2/m structure which we observe has previously been seen at significantly lower pressures, and the equation of state measured agrees with our findings. This result appears to contrast with recent data from shock-compressed polystyrene (CH) at higher temperatures, which demonstrated demixing and recrystallization into a diamond lattice, implying the breaking of the original chemical bonds. As such chemical processes have significant implications for the structure and energy transfer within ice giants, our results highlight the need for a deeper understanding of the chemistry of high pressure hydrocarbons, and the importance of better constraining planetary temperature profiles.

Using time-resolved penumbral imaging to measure low hot spot x-ray emission signals from capsule implosions at the National Ignition Facility.

We have developed and fielded a new x-ray pinhole-imaging snout that exploits time-resolved penumbral imaging of low-emission hot spots in capsule implosion experiments at the National Ignition Facility. We report results for a series of indirectly driven Be capsule implosions that aim at measuring x-ray Thomson scattering (XRTS) spectra at extreme density conditions near stagnation. In these implosions, x-ray emission at stagnation is reduced by 100-1000× compared to standard inertial confinement fusion (ICF) implosions to mitigate undesired continuum background in the XRTS spectra. Our snout design not only enables measurements of peak x-ray emission times, t o , where standard ICF diagnostics would not record any signal, but also allows for inference of hot spot shapes. Measurement of t o is crucial to account for shot-to-shot variations in implosion velocity and therefore to benchmark the achieved plasma conditions between shots and against radiation hydrodynamic simulations. Additionally, we used differential filtering to infer a hot spot temperature of 520 ± 80 eV, which is in good agreement with predictions from radiation hydrodynamic simulations. We find that, despite fluctuations of the x-ray flash intensity of up to 5×, the emission time history is similar from shot to shot and slightly asymmetric with respect to peak x-ray emission.

Developing a long-duration Zn K- α source for x-ray scattering experiments.

We are developing a long-duration K-α x-ray source at the Omega laser facility. Such sources are important for x-ray scattering measurements at small scattering angles where high spectral resolution is required. To date, He-α x-ray sources are the most common probes in scattering experiments, using ns-class lasers to heat foils to keV temperatures, resulting in K-shell emission from He-like charge states. The He-α spectrum can be broadened by emission from multiple charge states and lines (e.g., He-like, Li-like, Be-like). Here, we combine the long duration of He-α sources with the narrow spectral bandwidth of cold K-α emission. A Ge foil is irradiated by the Omega laser, producing principally Ge He-α emission, which pumps Zn K-α emission at 8.6 keV from a nearby Zn layer. Using this technique, we demonstrate a long-duration Zn K-α source suitable for scattering measurements. Our experimental results show a 60% reduction in spectral bandwidth compared to a standard Zn He-α source, significantly improving the measurement precision of scattering experiments with small inelastic shifts.

Liquid Structure of Shock-Compressed Hydrocarbons at Megabar Pressures.

We present results for the ionic structure in hydrocarbons (polystyrene, polyethylene) that were shock compressed to pressures of up to 190 GPa, inducing rapid melting of the samples. The structure of the resulting liquid is then probed using in situ diffraction by an x-ray free electron laser beam, demonstrating the capability to obtain reliable diffraction data in a single shot, even for low-Z samples without long range order. The data agree well with ab initio simulations, validating the ability of such approaches to model mixed samples in states where complex interparticle bonds remain, and showing that simpler models are not necessarily valid. While the results clearly exclude the possibility of complete carbon-hydrogen demixing at the conditions probed, they also, in contrast to previous predictions, indicate that diffraction is not always a sufficient diagnostic for this phenomenon.

Observation of Betatron X-Ray Radiation in a Self-Modulated Laser Wakefield Accelerator Driven with Picosecond Laser Pulses.

We investigate a new regime for betatron x-ray emission that utilizes kilojoule-class picosecond lasers to drive wakes in plasmas. When such laser pulses with intensities of ∼5×10^{18} W/cm^{2} are focused into plasmas with electron densities of ∼1×10^{19} cm^{-3}, they undergo self-modulation and channeling, which accelerates electrons up to 200 MeV energies and causes those electrons to emit x rays. The measured x-ray spectra are fit with a synchrotron spectrum with a critical energy of 10-20 keV, and 2D particle-in-cell simulations were used to model the acceleration and radiation of the electrons in our experimental conditions.

X-ray Thomson scattering measurements from hohlraum-driven spheres on the OMEGA laser.

X-ray Thomson scattering (XRTS) is a powerful diagnostic for probing warm and hot dense matter. We present the design and results of the first XRTS experiments with hohlraum-driven CH2 targets on the OMEGA laser facility at the Laboratory for Laser Energetics in Rochester, NY. X-rays seen directly from the XRTS x-ray source overshadow the elastic scattering signal from the target capsule but can be controlled in future experiments. From the inelastic scattering signal, an average plasma temperature is inferred that is in reasonable agreement with the temperatures predicted by simulations. Knowledge gained in this experiment shows a promising future for further XRTS measurements on indirectly driven OMEGA targets.

Improving a high-efficiency, gated spectrometer for x-ray Thomson scattering experiments at the National Ignition Facility.

We are developing x-ray Thomson scattering for applications in implosion experiments at the National Ignition Facility. In particular we have designed and fielded MACS, a high-efficiency, gated x-ray spectrometer at 7.5-10 keV [T. Döppner et al., Rev. Sci. Instrum. 85, 11D617 (2014)]. Here we report on two new Bragg crystals based on Highly Oriented Pyrolytic Graphite (HOPG), a flat crystal and a dual-section cylindrically curved crystal. We have performed in situ calibration measurements using a brass foil target, and we used the flat HOPG crystal to measure Mo K-shell emission at 18 keV in 2nd order diffraction. Such high photon energy line emission will be required to penetrate and probe ultra-high-density plasmas or plasmas of mid-Z elements.

Are APOE ɛ genotype and TOMM40 poly-T repeat length associations with cognitive ageing mediated by brain white matter tract integrity?

Genetic polymorphisms in the APOE ɛ and TOMM40 '523' poly-T repeat gene loci have been associated with significantly increased risk of Alzheimer's disease. This study investigated the independent effects of these polymorphisms on human cognitive ageing, and the extent to which nominally significant associations with cognitive ageing were mediated by previously reported genetic associations with brain white matter tract integrity in this sample. Most participants in the Lothian Birth Cohort 1936 completed a reasoning-type intelligence test at age 11 years, and detailed cognitive/physical assessments and structural diffusion tensor brain magnetic resonance imaging at a mean age of 72.70 years (s.d.=0.74). Participants were genotyped for APOE ɛ2/ɛ3/ɛ4 status and TOMM40 523 poly-T repeat length. Data were available from 758-814 subjects for cognitive analysis, and 522-543 for mediation analysis with brain imaging data. APOE genotype was significantly associated with performance on several different tests of cognitive ability, including general factors of intelligence, information processing speed and memory (raw P-values all<0.05), independently of childhood IQ and vascular disease history. Formal tests of mediation showed that several significant APOE-cognitive ageing associations--particularly those related to tests of information processing speed--were partially mediated by white matter tract integrity. TOMM40 523 genotype was not associated with cognitive ageing. A range of brain phenotypes are likely to form the anatomical basis for significant associations between APOE genotype and cognitive ageing, including white matter tract microstructural integrity.

Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms.

A polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-ß and other proteins into mitochondria, has been implicated in Alzheimer's disease and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms. Because of the similarities between Alzheimer's disease and sporadic inclusion body myositis (s-IBM), and the importance of amyloid-ß and mitochondrial changes in s-IBM, we investigated whether variation in poly-T repeat lengths in rs10524523 also influence susceptibility and age at onset in a cohort of 90 Caucasian s-IBM patients (55 males; age 69.1 ± 9.6). In carriers of APOE ε3/ε3 or ε3/ε4, genotypes with a very long (VL) poly-T repeat were under-represented in s-IBM compared to controls and were associated with a later age at symptom onset, suggesting that these genotypes may be protective. Our study is the first to suggest that polymorphisms in genes controlling mitochondrial function can influence susceptibility to s-IBM and have disease modifying effects. However, further studies in other s-IBM populations are needed to confirm these findings, as well as expression studies of different TOMM40 alleles in muscle tissue.

Comparison of nutrient-removing microbial communities in activated sludge from full-scale MBRs and conventional plants.

The composition of nutrient-removing microbial communities in five full-scale membrane bioreactors (MBRs) was investigated using fluorescence in situ hybridization and 16S rRNA pyrosequencing and compared to similar analyses of conventional activated sludge (CAS) communities. The communities were highly similar but some genera that are always present in enhanced biological phosphorus removal (EBPR) (core groups) were absent in the MBRs. The overall phylogenetic similarity of the communities indicated that these differences were primarily closely related groups. More research is needed to establish the operational significance of the observed differences between MBR and CAS sludge.

The Microbial Database for Danish wastewater treatment plants with nutrient removal (MiDas-DK) - a tool for understanding activated sludge population dynamics and community stability.

Since 2006 more than 50 Danish full-scale wastewater treatment plants with nutrient removal have been investigated in a project called 'The Microbial Database for Danish Activated Sludge Wastewater Treatment Plants with Nutrient Removal (MiDas-DK)'. Comprehensive sets of samples have been collected, analyzed and associated with extensive operational data from the plants. The community composition was analyzed by quantitative fluorescence in situ hybridization (FISH) supported by 16S rRNA amplicon sequencing and deep metagenomics. MiDas-DK has been a powerful tool to study the complex activated sludge ecosystems, and, besides many scientific articles on fundamental issues on mixed communities encompassing nitrifiers, denitrifiers, bacteria involved in P-removal, hydrolysis, fermentation, and foaming, the project has provided results that can be used to optimize the operation of full-scale plants and carry out trouble-shooting. A core microbial community has been defined comprising the majority of microorganisms present in the plants. Time series have been established, providing an overview of temporal variations in the different plants. Interestingly, although most microorganisms were present in all plants, there seemed to be plant-specific factors that controlled the population composition thereby keeping it unique in each plant over time. Statistical analyses of FISH and operational data revealed some correlations, but less than expected. MiDas-DK (www.midasdk.dk) will continue over the next years and we hope the approach can inspire others to make similar projects in other parts of the world to get a more comprehensive understanding of microbial communities in wastewater engineering.

Using genetics to enable studies on the prevention of Alzheimer's disease.

Curing Alzheimer's disease (AD) remains an elusive goal; indeed, it may even prove to be impossible, given the nature of the disease. Although modulating disease progression is an attractive target and will alleviate the burden of the most severe stages, this strategy will not reduce the prevalence of the disease itself. Preventing or (as described in this article) delaying the onset of cognitive impairment and AD will provide the greatest benefit to individuals and society by pushing the onset of disease into the later years of life. Because of the high variability in the age of onset of the disease, AD prevention studies that do not stratify participants by age-dependent disease risk will be operationally challenging, being large in size and of long duration. We present a composite genetic biomarker to stratify disease risk so as to facilitate clinical studies in high-risk populations. In addition, we discuss the rationale for the use of pioglitazone to delay the onset of AD in individuals at high risk.

Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies.

INTRODUCTION: Two phase 3 studies evaluated the efficacy and safety of rosiglitazone (RSG), a type 2 diabetes treatment, in an extended release (RSG XR) form as adjunctive therapy to ongoing acetylcholine esterase inhibitor (AChEI) treatment in AD (REFLECT-2, adjunctive to donepezil; REFLECT-3, to any AChEI). An open-label extension study (REFLECT-4) assessed RSG XR long-term safety. METHODS: In these two double-blind, placebo-controlled studies, subjects with mild-to-moderate probable AD were randomized within 2 apolipoprotein E (APOE) allelic strata (APOE ε4-positive, APOE ε4-negative) to once daily placebo, 2 mg RSG XR, or 8 mg RSG XR for 48 weeks (REFLECT-2, N=1,496; REFLECT-3, N=1,485). Co-primary efficacy endpoints were change from baseline in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) scores at week 48. Three populations were analyzed: APOE4-negative, all subjects except APOE ε4 homozygotes, and the full intent-to-treat population. RESULTS: No statistically or clinically relevant differences between treatment groups were observed on the a priori primary endpoints in REFLECT-2 or REFLECT-3. Edema was the most frequent adverse event with RSG in each study (14% and 19%, respectively, at 8 mg RSG XR). CONCLUSIONS: No evidence of statistically or clinically significant efficacy in cognition or global function was detected for 2 mg or 8 mg RSG XR as adjunctive therapy to ongoing AChEIs. There was no evidence of an interaction between treatment and APOE status. Safety and tolerability of RSG XR was consistent with the known profile of rosiglitazone.

A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease.

The ɛ4 allele of the apolipoprotein E (APOE) gene is currently the strongest and most highly replicated genetic factor for risk and age of onset of late-onset Alzheimer's disease (LOAD). Using phylogenetic analysis, we have identified a polymorphic poly-T variant, rs10524523, in the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene that provides greatly increased precision in the estimation of age of LOAD onset for APOE ɛ3 carriers. In two independent clinical cohorts, longer lengths of rs10524523 are associated with a higher risk for LOAD. For APOE ɛ3/4 patients who developed LOAD after 60 years of age, individuals with long poly-T repeats linked to APOE ɛ3 develop LOAD on an average of 7 years earlier than individuals with shorter poly-T repeats linked to APOE ɛ3 (70.5 ± 1.2 years versus 77.6 ± 2.1 years, P=0.02, n=34). Independent mutation events at rs10524523 that occurred during Caucasian evolution have given rise to multiple categories of poly-T length variants at this locus. On replication, these results will have clinical utility for predictive risk estimates for LOAD and for enabling clinical disease prevention studies. In addition, these results show the effective use of a phylogenetic approach for analysis of haplotypes of polymorphisms, including structural polymorphisms, which contribute to complex diseases.

Complex disease-associated pharmacogenetics: drug efficacy, drug safety, and confirmation of a pathogenetic hypothesis (Alzheimer's disease).

Safety and efficacy pharmacogenetics can be applied successfully to the drug discovery and development pipeline at multiple phases. We review drug-target screening using high throughput SNP associations with complex diseases testing more than 1,800 candidate targets with approximately 7,000 SNPs. Alzheimer's disease data are provided as an example. The supplementation of target-selected screening with genome-wide SNP association, to also define susceptibility genes and relevant disease pathways for human diseases, is discussed. Applications for determining predictive genetic or genomic profiles, or derived biomarkers, for drug efficacy and safety during clinical development are exemplified by several successful experiments at different phases of development. A Phase I-IIA study of side effects using an oral drug for the treatment of breast cancer is used as an example of early pipeline pharmacogenetics to predict side effects and allow optimization of dosing. References are provided for several other recently published genetic association studies of adverse events during drug development. We illustrate the early identification of gene variant candidates related to efficacy in a Phase IIA obesity drug trial to generate hypotheses for testing in subsequent development. How these genetic data generated in Phase IIA are subsequently incorporated as hypotheses into later Phase clinical protocols is discussed. A Phase IIB clinical trial for Alzheimer's disease is described that exemplifies the major pipeline decision between program attrition and further clinical development. In this case, there was no significant improvement in 511 intention-to-treat patients but, applying a confirmed prognostic biomarker (APOE4) to segment the clinical trial population, all three doses of rosiglitazone demonstrated improvement in patients who did not carry the APOE4 allele. The data for the APOE4 carriers demonstrated no significant improvement but suggested that there may be a need for higher doses. Thus, a development program that would have been terminated progressed to Phase III registration trials based on the results of prospective efficacy pharmacogenetic analyses. The implications of using APOE genotype as a biomarker to predict efficacy and possibly dose, as well as supporting the basic neurobiology and pharmacology that provided the original target validation, is discussed. Citations are provided that support a slow neurotoxic effect over many years of a specific fragment of apoE protein (over-produced by apoE4 substrate compared to apoE3) on mitochondria and the use of rosiglitazone to increase mitochondrial biogenesis and improve glucose utilization. Pharmacogenetics is currently being used across the pipeline to prevent attrition and to create safer and more effective medicines.