Li+ alumino-silicate ion source development for the Neutralized Drift Compression Experiment (NDCX-II)

To heat targets to electron-volt temperatures for the study of warm dense matter with intense ion beams, low mass ions, such as lithium, have an energy loss peak (dE/dx) at a suitable kinetic energy. The Heavy Ion Fusion Sciences (HIFS) program at Lawrence Berkeley National Laboratory will carry out warm dense matter experiments using Li{sup +} ion beam with energy 1.2-4 MeV in order to achieve uniform heating up to 0.1-1 eV. The accelerator physics design of Neutralized Drift Compression Experiment (NDCX-II) has a pulse length at the ion source of about 0.5 {micro}s. Thus for producing 50 nC of beam charge, the required beam current is about 100 mA. Focusability requires a normalized (edge) emittance {approx}2 {pi}-mm-mrad. Here, lithium aluminosilicate ion sources, of {beta}-eucryptite, are being studied within the scope of NDCX-II construction. Several small (0.64 cm diameter) lithium aluminosilicate ion sources, on 70%-80% porous tungsten substrate, were operated in a pulsed mode. The distance between the source surface and the mid-plane of the extraction electrode (1 cm diameter aperture) was 1.48 cm. The source surface temperature was at 1220 C to 1300 C. A 5-6 {micro}s long beam pulsed was recorded by a Faraday cup (+300 V on the collector plate and -300 V on the suppressor ring). Figure 1 shows measured beam current density (J) vs. V{sup 3/2}. A space-charge limited beam density of {approx}1 mA/cm{sup 2} was measured at 1275 C temperature, after allowing a conditioning time of about {approx} 12 hours. Maximum emission limited beam current density of {ge} 1.8mA/cm{sup 2} was recorded at 1300 C with 10-kV extractions. Figure 2 shows the lifetime of two typical sources with space-charge limited beam current emission at a lower extraction voltage (1.75 kV) and at temperature of 1265 {+-} 7 C. These data demonstrate a constant, space-charge limited beam current for 20-50 hours. The lifetime of a source is determined by the loss of lithium from the alumino-silicate material either as ions or as neutral atoms. Our measurements suggest that for the low duty factor ({approx}10{sup -8}) required for NDCX-II, the lifetime of an emitter depends mostly on the duration that the emitter spends at elevated temperature, that is, at {ge} 1250 C. At this temperature, lithium loss is due mostly to neutral loss (not charged ion extraction). Extension of the lifetime of the source may be possible by lowering the temperature between beam pulses, when the idling time is sufficiently long between shots. The NDCX-II design seeks to operate the ion source at the maximum current density without running into heat management and lifetime problems. In preparation to fabricate a large (10.9 cm in diameter) source for the NDCXII experiment, recently a 7.6 cm diameter source has been fabricated. The method of fabrication of this larger source is similar to that of fabrication of a 6.3mm diameter source, except a longer furnace heating time was used due to mass differences. NDCX-II construction is in progress. Progress of lithium source study for NDCX-II is available in literature

Development of a Li + alumino-silicate ion source *

Abstract To uniformly heat targets to electron-volt temperatures for the study of warm dense matter, one strategy is to deposit most of the ion energy at the peak of energy loss (dE/dx) with a low (E <5 MeV) kinetic energy beam and a thin target. Lower mass ions, such as lithium, have a peak dE/dx at a lower kinetic energy. Alumino-silicates sources of K + and Cs + have been used extensively in beam experiments, but there are additional challenges for the production of a high current and high-quality Li + beam. There are tighter tolerances in preparing and sintering the Li aluminosilicate to the substrate to produce an emitter that gives uniform ion emission, sufficient current density and low beam emittance. Here we report recent progress on Li + source studies

"Now he walks and walks, as if he didn't have a home where he could eat": food, healing, and hunger in Quechua narratives of madness

In the Quechua-speaking peasant communities of southern Peru, mental disorder is understood less as individualized pathology and more as a disturbance in family and social relationships. For many Andeans, food and feeding are ontologically fundamental to such relationships. This paper uses data from interviews and participant observation in a rural province of Cuzco to explore the significance of food and hunger in local discussions of madness. Carers’ narratives, explanatory models, and theories of healing all draw heavily from idioms of food sharing and consumption in making sense of affliction, and these concepts structure understandings of madness that differ significantly from those assumed by formal mental health services. Greater awareness of the salience of these themes could strengthen the input of psychiatric and psychological care with this population and enhance knowledge of the alternative treatments that they use. Moreover, this case provides lessons for the global mental health movement on the importance of openness to the ways in which indigenous cultures may construct health, madness, and sociality. Such local meanings should be considered by mental health workers delivering services in order to provide care that can adjust to the alternative ontologies of sufferers and carers

Sequence- and Interactome-Based Prediction of Viral Protein Hotspots Targeting Host Proteins: A Case Study for HIV Nef

Virus proteins alter protein pathways of the host toward the synthesis of viral particles by breaking and making edges via binding to host proteins. In this study, we developed a computational approach to predict viral sequence hotspots for binding to host proteins based on sequences of viral and host proteins and literature-curated virus-host protein interactome data. We use a motif discovery algorithm repeatedly on collections of sequences of viral proteins and immediate binding partners of their host targets and choose only those motifs that are conserved on viral sequences and highly statistically enriched among binding partners of virus protein targeted host proteins. Our results match experimental data on binding sites of Nef to host proteins such as MAPK1, VAV1, LCK, HCK, HLA-A, CD4, FYN, and GNB2L1 with high statistical significance but is a poor predictor of Nef binding sites on highly flexible, hoop-like regions. Predicted hotspots recapture CD8 cell epitopes of HIV Nef highlighting their importance in modulating virus-host interactions. Host proteins potentially targeted or outcompeted by Nef appear crowding the T cell receptor, natural killer cell mediated cytotoxicity, and neurotrophin signaling pathways. Scanning of HIV Nef motifs on multiple alignments of hepatitis C protein NS5A produces results consistent with literature, indicating the potential value of the hotspot discovery in advancing our understanding of virus-host crosstalk

Tailoring pharmacotherapy to specific eating behaviours in obesity: Can recommendations for personalised therapy be made from the current data?

Pharmacotherapy provides an adjunct to behaviour modification in the management of obesity. There are a number of new drug therapies purportedly targeting appetite; liraglutide, and bupropion/naltrexone, which are European Medicines Agency and US Food and Drug Administration (FDA) approved, and lorcaserin and phentermine/topiramate, which have FDA approval only. Each of the six drugs, used singly or in combination, has distinct pharmacological, and presumably distinct behavioural, mechanisms of action, thus the potential to provide defined therapeutic options to personalise the management of obesity. Yet, with regard to pharmacotherapy for obesity, we are far from true personalised medicine. We review the limited mechanistic data with four mono and combination pharmacotherapies, to assess the potential for tailoring their use to target specific obesogenic behaviours. Potential treatment options are considered, but in the absence of adequate research in respect to effects of these drugs on eating behaviour, neural activity and psychological substrates that underlie poorly controlled eating, we are far from definitive therapeutic recommendations. Specific mechanistic studies and broader behavioural phenotyping, possibly in conjunction with pharmacogenetic research, are required to characterise responders for distinct pharmacotherapeutic options

A comparison of genomic copy number calls by Partek Genomics Suite, Genotyping Console and Birdsuite algorithms to quantitative PCR

<p>Abstract</p> <p>Background</p> <p>Copy number variants are >1 kb genomic amplifications or deletions that can be identified using array platforms. However, arrays produce substantial background noise that contributes to high false discovery rates of variants. We hypothesized that quantitative PCR could finitely determine copy number and assess the validity of calling algorithms.</p> <p>Results</p> <p>Using data from 29 Affymetrix SNP 6.0 arrays, we determined copy numbers using three programs: Partek Genomics Suite, Affymetrix Genotyping Console 2.0 and Birdsuite. We compared array calls at 25 chromosomal regions to those determined by qPCR and found nearly identical calls in regions of copy number 2. Conversely, agreement differed in regions called variant by at least one method. The highest overall agreement in calls, 91%, was between Birdsuite and quantitative PCR. Partek Genomics Suite calls agreed with quantitative PCR 76% of the time while the agreement of Affymetrix Genotyping Console 2.0 with quantitative PCR was 79%.</p> <p>Conclusions</p> <p>In 38 independent samples, 96% of Birdsuite calls agreed with quantitative PCR. Analysis of three copy number calling programs and quantitative PCR showed Birdsuite to have the greatest agreement with quantitative PCR.</p

Mechanisms of Loss of Functions of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

Background: Mutations in the coding region of angiogenin (ANG) gene have been found in patients suffering from Amyotrophic Lateral Sclerosis (ALS). Neurodegeneration results from the loss of angiogenic ability of ANG (protein coded by ANG). In this work, we performed extensive molecular dynamics (MD) simulations of wild-type ANG and disease associated ANG variants to elucidate the mechanism behind the loss of ribonucleolytic activity and nuclear translocation activity, functions needed for angiogenesis. Methodology/Principal Findings: MD simulations were carried out to study the structural and dynamic differences in the catalytic site and nuclear localization signal residues between WT-ANG (Wild-type ANG) and six mutants. Variants K17I, S28N, P112L and V113I have confirmed association with ALS, while T195C and A238G single nucleotide polymorphisms (SNPs) encoding L35P and K60E mutants respectively, have not been associated with ALS. Our results show that loss of ribonucleolytic activity in K17I is caused by conformational switching of the catalytic residue His114 by 99u. The loss of nuclear translocation activity of S28N and P112L is caused by changes in the folding of the residues 31 RRR 33 that result in the reduction in solvent accessible surface area (SASA). Consequently, we predict that V113I will exhibit loss of angiogenic properties by loss of nuclear translocation activity and L35P by loss of both ribonucleolytic activity and nuclear translocation activity. No functional loss was inferred for K60E. The MD simulation results were supported by hydrogen bond interactio

Leptin mediates the increase in blood pressure associated with obesity.

Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin's effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species

Angiogenin protects motoneurons against hypoxic injury.

Cells can adapt to hypoxia through the activation of hypoxia-inducible factor-1 (HIF-1), which in turn regulates the expression of hypoxia-responsive genes. Defects in hypoxic signaling have been suggested to underlie the degeneration of motoneurons in amyotrophic lateral sclerosis (ALS). We have recently identified mutations in the hypoxia-responsive gene, angiogenin (ANG), in ALS patients, and have shown that ANG is constitutively expressed in motoneurons. Here, we show that HIF-1alpha is sufficient and required to activate ANG in cultured motoneurons exposed to hypoxia, although ANG expression does not change in a transgenic ALS mouse model or in sporadic ALS patients. Administration of recombinant ANG or expression of wild-type ANG protected motoneurons against hypoxic injury, whereas gene silencing of ang1 significantly increased hypoxia-induced cell death. The previously reported ALS-associated ANG mutations (Q12L, K17I, R31K, C39W, K40I, I46V) all showed a reduced neuroprotective activity against hypoxic injury. Our data show that ANG plays an important role in endogenous protective pathways of motoneurons exposed to hypoxia, and suggest that loss of function rather than loss of expression of ANG is associated with ALS