Combining laser interferometry and plasma spectroscopy for spatially resolved high-sensitivity plasma density measurements in discharge capillaries.

Precise characterization and tailoring of the spatial and temporal evolution of plasma density within plasma sources are critical for realizing high-quality accelerated beams in plasma wakefield accelerators. The simultaneous use of two independent diagnostics allowed the temporally and spatially resolved detection of plasma density with unprecedented sensitivity and enabled the characterization of the plasma temperature in discharge capillaries for times later than 0.5 µs after the initiation of the discharge, at which point the plasma is at local thermodynamic equilibrium. A common-path two-color laser interferometer for obtaining the average plasma density with a sensitivity of 2 × 1015 cm-2 was developed together with a plasma emission spectrometer for analyzing spectral line broadening profiles with a resolution of 5 × 1015 cm-3. Both diagnostics show good agreement when applying the spectral line broadening analysis methodology of Gigosos and Cardeñoso in the temperature range of 0.5 eV-5.0 eV. For plasma with densities of 0.5-2.5 × 1017 cm-3, temperatures of 1 eV-7 eV were indirectly measured by combining the diagnostic information. Measured longitudinally resolved plasma density profiles exhibit a clear temporal evolution from an initial flat-top to a Gaussian-like shape in the first microseconds as material is ejected out from the capillary. These measurements pave the way for highly detailed parameter tuning in plasma sources for particle accelerators and beam optics.

FLASHForward: plasma wakefield accelerator science for high-average-power applications.

The FLASHForward experimental facility is a high-performance test-bed for precision plasma wakefield research, aiming to accelerate high-quality electron beams to GeV-levels in a few centimetres of ionized gas. The plasma is created by ionizing gas in a gas cell either by a high-voltage discharge or a high-intensity laser pulse. The electrons to be accelerated will either be injected internally from the plasma background or externally from the FLASH superconducting RF front end. In both cases, the wakefield will be driven by electron beams provided by the FLASH gun and linac modules operating with a 10 Hz macro-pulse structure, generating 1.25 GeV, 1 nC electron bunches at up to 3 MHz micro-pulse repetition rates. At full capacity, this FLASH bunch-train structure corresponds to 30 kW of average power, orders of magnitude higher than drivers available to other state-of-the-art LWFA and PWFA experiments. This high-power functionality means FLASHForward is the only plasma wakefield facility in the world with the immediate capability to develop, explore and benchmark high-average-power plasma wakefield research essential for next-generation facilities. The operational parameters and technical highlights of the experiment are discussed, as well as the scientific goals and high-average-power outlook. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.

Aboriginal community understandings of dementia and responses to dementia care.

OBJECTIVE: Aboriginal people and Torres Strait Islanders are impacted by dementia at higher rates and at a younger age of onset than the broader Australia population. Public health strategies to support this population require a thorough understanding of how Aboriginal people perceive dementia and dementia care support needs. The aim of this study was to investigate Aboriginal community understandings of dementia and their responses to dementia care. STUDY DESIGN: This study is a community participatory action research partnership. METHODS: The mixed method study was undertaken in 2017 with members of a discrete Aboriginal community from rural Tasmania, Australia. Participants were older than 18 years, self-identified as an Aboriginal person and were living or had lived in the community studied. Data were derived from 50 participants who completed the 27-item Dementia Knowledge Assessment Scale (DKAS). Twelve of these participants also shared their dementia care experiences in individual interviews. RESULTS: The DKAS results showed a low overall level of dementia knowledge, with a total mean score of 27.73 (scoring 51% on average) of a possible score of 54. The salient interview theme was the cultural obligation to care for family members living with dementia. Dementia care metaphors represented ways to protect family members living with dementia and maintain their ongoing connections to home and community. However, limited understandings of dementia affected their capacity to provide quality care. CONCLUSION: The findings contribute to public health scholarship involving Aboriginal community responses to dementia care. The study has resulted in important initiatives including a community-based dementia education program to ensure Aboriginal people impacted by dementia are provided with effective and culturally appropriate care.

Tunable Plasma-Based Energy Dechirper.

A tunable plasma-based energy dechirper has been developed at FLASHForward to remove the correlated energy spread of a 681 MeV electron bunch. Through the interaction of the bunch with wakefields excited in plasma the projected energy spread was reduced from a FWHM of 1.31% to 0.33% without reducing the stability of the incoming beam. The experimental results for variable plasma density are in good agreement with analytic predictions and three-dimensional simulations. The proof-of-principle dechirping strength of 1.8 GeV/mm/m significantly exceeds those demonstrated for competing state-of-the-art techniques and may be key to future plasma wakefield-based free-electron lasers and high energy physics facilities, where large intrinsic chirps need to be removed.

Casein kinase 1-epsilon deletion increases mu opioid receptor-dependent behaviors and binge eating1.

Genetic and pharmacological studies indicate that casein kinase 1 epsilon (Csnk1e) contributes to psychostimulant, opioid, and ethanol motivated behaviors. We previously used pharmacological inhibition to demonstrate that Csnk1e negatively regulates the locomotor stimulant properties of opioids and psychostimulants. Here, we tested the hypothesis that Csnk1e negatively regulates opioid and psychostimulant reward using genetic inhibition and the conditioned place preference assay in Csnk1e knockout mice. Similar to pharmacological inhibition, Csnk1e knockout mice showed enhanced opioid-induced locomotor activity with the mu opioid receptor agonist fentanyl (0.2 mg/kg i.p.) as well as enhanced sensitivity to low-dose fentanyl reward (0.05 mg/kg). Interestingly, female knockout mice also showed a markedly greater escalation in consumption of sweetened palatable food - a behavioral pattern consistent with binge eating that also depends on mu opioid receptor activation. No difference was observed in fentanyl analgesia in the 52.5°C hot plate assay (0-0.4 mg/kg), naloxone conditioned place aversion (4 mg/kg), or methamphetamine conditioned place preference (0-4 mg/kg). To identify molecular adaptations associated with increased drug and food behaviors in knockout mice, we completed transcriptome analysis via mRNA sequencing of the striatum. Enrichment analysis identified terms associated with myelination and axon guidance and pathway analysis identified a differentially expressed gene set predicted to be regulated by the Wnt signaling transcription factor, Tcf7l2. To summarize, Csnk1e deletion increased mu opioid receptor-dependent behaviors, supporting previous studies indicating an endogenous negative regulatory role of Csnk1e in opioid behavior.

A revisionist history of adult marrow stem cell biology or 'they forgot about the discard'.

The adult marrow hematopoietic stem cell biology has largely been based on studies of highly purified stem cells. This is unfortunate because during the stem cell purification the great bulk of stem cells are discarded. These cells are actively proliferating. The final purified stem cell is dormant and not representative of the whole stem cell compartment. Thus, a large number of studies on the cellular characteristics, regulators and molecular details of stem cells have been carried on out of non-represented cells. Niche studies have largely pursued using these purified stem cells and these are largely un-interpretable. Other considerations include the distinction between baseline and transplant stem cells and the modulation of stem cell phenotype by extracellular vesicles, to cite a non-inclusive list. Work needs to proceed on characterizing the true stem cell population.

Hematopoietic Stem Cells: Uncomfortable Considerations.

PURPOSE: This report defines new concepts of hematopoietic stem cell biology. RECENT FINDINGS: We have utilized 3 different approaches which show that long-term repopulating hematopoietic stem cells are actively cycling and always changing phenotype. In addition this is reversible. This indicates that the stem cell cannot be purified by current epitope selection approaches. The vast bulk of hematopoietic stem cells are discarded in different populations when stem cells are purified to lineage negative c-kit positive and Sca-1 positive cells. Studies to define the hematopoietic niche have been largely carried out on these irrelevant purified cells and thus are not definitive. Studies have indicated the presence of baseline stem cells which function during the normal lifetime of mice. Baseline hematopoiesis appears to be run by thousands of relatively short lived clones with limited differentiation capacity. Thus there appear to be two basic hematopoietic stem cell modes; emergency and baseline.

Mesenchymal stromal cell-derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells.

Mesenchymal stromal cells (MSCs) have been shown to reverse radiation damage to marrow stem cells. We have evaluated the capacity of MSC-derived extracellular vesicles (MSC-EVs) to mitigate radiation injury to marrow stem cells at 4 h to 7 days after irradiation. Significant restoration of marrow stem cell engraftment at 4, 24 and 168 h post irradiation by exposure to MSC-EVs was observed at 3 weeks to 9 months after transplant and further confirmed by secondary engraftment. Intravenous injection of MSC-EVs to 500cGy exposed mice led to partial recovery of peripheral blood counts and restoration of the engraftment of marrow. The murine hematopoietic cell line, FDC-P1 exposed to 500cGy, showed reversal of growth inhibition, DNA damage and apoptosis on exposure to murine or human MSC-EVs. Both murine and human MSC-EVs reverse radiation damage to murine marrow cells and stimulate normal murine marrow stem cell/progenitors to proliferate. A preparation with both exosomes and microvesicles was found to be superior to either microvesicles or exosomes alone. Biologic activity was seen in freshly isolated vesicles and in vesicles stored for up to 6 months in 10% dimethyl sulfoxide at -80 °C. These studies indicate that MSC-EVs can reverse radiation damage to bone marrow stem cells.

The sociodemographic patterning of opposition to raising taxes on tobacco and restricting tobacco advertisements in Argentina.

BACKGROUND: Argentina has enacted important tobacco control initiatives in recent years. Yet little is known about the social patterning of attitudes toward tobacco control. Research is needed to explore what predicts opposition to tobacco control initiatives such as higher taxes on tobacco and the prohibition of tobacco advertising. STUDY DESIGN: Secondary analysis of Argentina's Global Adult Tobacco Survey (N = 6645). METHODS: Binary logistic regression analysis examining opposition to raising tobacco taxes and banning tobacco publicity. Models were stratified by smoking status. RESULTS: Respondents generally indicated very little opposition to either tobacco control measure, with only 15.6% of respondents opposed to increasing taxes on tobacco products and 9.6% opposed to banning tobacco advertisements. Smoking status is the most important predictor of opposition to increasing taxes (OR = 7.85, 95% CI = 6.60-9.34) and banning advertisements (OR = 1.72, 95% CI = 1.39-2.11). Opposition to these measures is most likely among young respondents (aged 15-24) and least likely among older age groups (55-64 and 65 or over), compared to the 25-34 age group. Stratified models suggest that the effect of age may be different for smokers and non-smokers. Low income is a significant predictor of opposition, but only in stratified models for smokers. CONCLUSION: There is general support for stronger tobacco control measures in Argentina. Opposition to raising taxes on tobacco products and banning tobacco advertisement appears to be concentrated among young smokers with low and medium levels of household income.

Overexpression of ERG in cord blood progenitors promotes expansion and recapitulates molecular signatures of high ERG leukemias.

High expression of the ETS family transcription factor ERG is associated with poor clinical outcome in acute myeloid leukemia (AML) and acute T-cell lymphoblastic leukemia (T-ALL). In murine models, high ERG expression induces both T-ALL and AML. However, no study to date has defined the effect of high ERG expression on primary human hematopoietic cells. In the present study, human CD34+ cells were transduced with retroviral vectors to elevate ERG gene expression to levels detected in high ERG AML. RNA sequencing was performed on purified populations of transduced cells to define the effects of high ERG on gene expression in human CD34+ cells. Integration of the genome-wide expression data with other data sets revealed that high ERG drives an expression signature that shares features of normal hematopoietic stem cells, high ERG AMLs, early T-cell precursor-ALLs and leukemic stem cell signatures associated with poor clinical outcome. Functional assays linked this gene expression profile to enhanced progenitor cell expansion. These results support a model whereby a stem cell gene expression network driven by high ERG in human cells enhances the expansion of the progenitor pool, providing opportunity for the acquisition and propagation of mutations and the development of leukemia.

Sex-stratified and age-adjusted social gradients in tobacco in Argentina and Uruguay: evidence from the Global Adult Tobacco Survey (GATS).

OBJECTIVE: To examine social gradients in tobacco use in Argentina and Uruguay, using newly available directly comparable data sets. METHODS: Secondary analysis of Global Adult Tobacco Survey data from Argentina (N=6645) and Uruguay (N=5581). Social gradients in current tobacco use, exposure to secondhand smoke, and cessation attempt were examined with sex-stratified and age-adjusted logistic regression. RESULTS: Among men, there is evidence of higher odds of being a current smoker among respondents with lower levels of education, but the association is only statistically significant for respondents with less than primary education in Uruguay (OR=2.15, 95% CI 1.22 to 3.77). Similarly, women with lower levels of education have higher odds of being a current smoker in Uruguay. The association between education and exposure to secondhand smoke is broadly similar for both sexes in both countries, with generally higher odds among groups with low education, though the relationship is only statistically significant among men in Uruguay (OR=1.77, 95% CI 1.08 to 2.92). In both countries, respondents with lower levels of education in general have higher odds of having attempted to quit smoking in the past year, although these associations did not attain statistical significance. CONCLUSIONS: Social gradients in tobacco use, exposure to secondhand smoke and cessation attempts are broadly similar in both countries. Efforts to evaluate the long-term effects of tobacco control efforts in these countries should monitor how policies affect national averages, and the social gradients that are embedded in aggregate data.

The murine long-term multi-lineage renewal marrow stem cell is a cycling cell.

Prevailing wisdom holds that hematopoietic stem cells (HSCs) are predominantly quiescent. Although HSC cycle status has long been the subject of scrutiny, virtually all marrow stem cell research has been based on studies of highly purified HSCs. Here we explored the cell cycle status of marrow stem cells in un-separated whole bone marrow (WBM). We show that a large number of long-term multi-lineage engraftable stem cells within WBM are in S/G2/M phase. Using bromodeoxyuridine, we show rapid transit through the cell cycle of a previously defined relatively dormant purified stem cell, the long-term HSC (LT-HSC; Lineage(-)/c-kit(+)/Sca-1(+)/Flk-2(-)). Actively cycling marrow stem cells have continually changing phenotype with cell cycle transit, likely rendering them difficult to purify to homogeneity. Indeed, as WBM contains actively cycling stem cells, and highly purified stem cells engraft predominantly while quiescent, it follows that the population of cycling marrow stem cells within WBM are lost during purification. Our studies indicate that both the discarded lineage-positive and lineage-negative marrow cells in a stem cell separation contain cycling stem cells. We propose that future work should encompass this larger population of cycling stem cells that is poorly represented in current studies solely focused on purified stem cell populations.

Economic benefit of the PHLAME wellness programme on firefighter injury.

BACKGROUND: Work-related injuries and illness are prevalent and costly. Firefighting is especially hazardous and many firefighters sustain work-related injuries. Workplace health promotion programmes have shown positive return on investment (ROI). Little is known about how similar programmes would impact injury and cost among firefighters. AIMS: To evaluate the impact of a workplace health promotion intervention on workers' compensation (WC) claims and medical costs among Oregon fire departments participating in the PHLAME (Promoting Healthy Lifestyles: Alternative Models' Effects) health promotion programme compared with Oregon fire departments not participating in PHLAME. METHODS: Data from firefighters from four large urban fire departments in Oregon were evaluated using a retrospective quasi-experimental study design. Outcomes were (i) total annual firefighter WC claims, (ii) total annual incurred medical costs prior to and after implementation of the PHLAME firefighter worksite health promotion programme (iii) and an ROI analysis. RESULTS: Data were obtained from 1369 firefighters (mean age of 42 years, 91% white, 93% male). WC claims (P < 0.001) and medical costs (P < 0.01) were significantly lower among PHLAME fire departments compared with Oregon fire departments not participating in the programme. Fire departments participating in the PHLAME TEAM programme demonstrated a positive ROI of 4.61-1.00 (TEAM is used to indicate the 12-session peer-led health promotion programme). CONCLUSIONS: Fire department WC claims and medical costs were reduced after implementation of the PHLAME workplace health promotion programme. This is a low cost, team-based, peer-led, wellness programme that may provide a feasible, cost-effective means to reduce firefighter injury and illness rates.

Pagetoid reticulosis in a prepubescent boy successfully treated with photodynamic therapy.

Pagetoid reticulosis or Woringer-Kolopp disease (WKD) is a rare variant of mycosis fungoides, consisting of localized patches or plaques containing intraepidermal proliferations of neoplastic T cells in a pagetoid distribution (similar to that of the adenocarcinomatous cells found in Paget disease of the nipple), which typically affects middle-aged and elderly men. We report a trial of photodynamic therapy (PDT) with topical aminolaevulinic acid (ALA), carried out on a 10-year-old boy with a solitary lesion of WKD on his foot, to avoid the long-term problems associated with the typical treatments for WKD of surgery and/or local irradiation. The plaque progressively flattened during treatment, and after nine PDT sessions over 13 months, the patient was clinically free of disease. PDT may be a viable alternative to surgery and local irradiation for localized cutaneous T-cell lymphoma, including WKD, especially in younger patients.

FTS and 2-DG induce pancreatic cancer cell death and tumor shrinkage in mice.

The Ras inhibitor S-trans-trans farnesylthiosalicylic acid (FTS) inhibits active Ras, which controls cell proliferation, differentiation, survival, and metabolism. FTS also inhibits HIF1α expression in cancer cells, leading to an energy crisis. The synthetic glucose analog 2-deoxy-D-glucose (2-DG), which inhibits glycolysis, is selectively directed to tumor cells that exhibit increased glucose consumption. The 2-DG enters tumor cells, where it competes with glucose for glycolytic enzymes. In cancer models, as well as in human phase 1 trials, 2-DG inhibits tumor growth without toxicity. We postulated that under normoxic conditions, tumor cells treated with FTS would be more sensitive than normal cells to 2-DG. We show here that combined treatment with FTS and 2-DG inhibited cancer cell proliferation additively, yet induced apoptotic cell death synergistically both in vitro and in vivo. The induced apoptosis was inferred from QVD-OPH inhibition, an increase in cleaved caspase 3, and loss of survivin. FTS and 2-DG when combined, but not separately, also induced an increase in fibrosis of the tumor tissue, chronic inflammation, and tumor shrinkage. Overall, these results suggest a possible new treatment of pancreatic tumors by the combined administration of FTS and 2-DG, which together induce pancreatic tumor cell death and tumor shrinkage under non-toxic conditions.