VUV frequency combs from below-threshold harmonics

Recent demonstrations of high-harmonic generation (HHG) at very high repetition frequencies (~100 MHz) may allow for the revolutionary transfer of frequency combs to the vacuum ultraviolet (VUV). This advance necessitates unifying optical frequency comb technology with strong-field atomic physics. While strong-field studies of HHG have often focused on above-threshold harmonic generation (photon energy above the ionization potential), for VUV frequency combs an understanding of below-threshold harmonic orders and their generation process is crucial. Here we present a new and quantitative study of the harmonics 7-13 generated below and near the ionization threshold in xenon gas. We show multiple generation pathways for these harmonics that are manifested as on-axis interference in the harmonic yield. This discovery provides a new understanding of the strong-field, below-threshold dynamics under the influence of an atomic potential and allows us to quantitatively assess the achievable coherence of a VUV frequency comb generated through below threshold harmonics. We find that under reasonable experimental conditions temporal coherence is maintained. As evidence we present the first explicit VUV frequency comb structure beyond the 3rd harmonic.Comment: 16 pages, 4 figures, 1 tabl

Breast cancer in systemic lupus

OBJECTIVE: There is a decreased breast cancer risk in systemic lupus erythematosus (SLE) versus the general population. We assessed a large sample of SLE patients, evaluating demographic and clinical characteristics and breast cancer risk. METHODS: We performed case-cohort analyses within a multi-center international SLE sample. We calculated the breast cancer hazard ratio (HR) in female SLE patients, relative to demographics, reproductive history, family history of breast cancer, and time-dependent measures of anti-dsDNA positivity, cumulative disease activity, and drugs, adjusted for SLE duration. RESULTS: There were 86 SLE breast cancers and 4498 female SLE cancer-free controls. Patients were followed on average for 7.6 years. Versus controls, SLE breast cancer cases tended to be white and older. Breast cancer cases were similar to controls regarding anti-dsDNA positivity, disease activity, and most drug exposures over time. In univariate and multivariate models, the principal factor associated with breast cancers was older age at cohort entry. CONCLUSIONS: There was little evidence that breast cancer risk in this SLE sample was strongly driven by any of the clinical factors that we studied. Further search for factors that determine the lower risk of breast cancer in SLE may be warranted

Projected Range Contractions of European Protected Oceanic Montane Plant Communities: Focus on Climate Change Impacts Is Essential for Their Future Conservation

Global climate is rapidly changing and while many studies have investigated the potential impacts of this on the distribution of montane plant species and communities, few have focused on those with oceanic montane affinities. In Europe, highly sensitive bryophyte species reach their optimum occurrence, highest diversity and abundance in the northwest hyperoceanic regions, while a number of montane vascular plant species occur here at the edge of their range. This study evaluates the potential impact of climate change on the distribution of these species and assesses the implications for EU Habitats Directive-protected oceanic montane plant communities. We applied an ensemble of species distribution modelling techniques, using atlas data of 30 vascular plant and bryophyte species, to calculate range changes under projected future climate change. The future effectiveness of the protected area network to conserve these species was evaluated using gap analysis. We found that the majority of these montane species are projected to lose suitable climate space, primarily at lower altitudes, or that areas of suitable climate will principally shift northwards. In particular, rare oceanic montane bryophytes have poor dispersal capacity and are likely to be especially vulnerable to contractions in their current climate space. Significantly different projected range change responses were found between 1) oceanic montane bryophytes and vascular plants; 2) species belonging to different montane plant communities; 3) species categorised according to different biomes and eastern limit classifications. The inclusion of topographical variables in addition to climate, significantly improved the statistical and spatial performance of models. The current protected area network is projected to become less effective, especially for specialised arctic-montane species, posing a challenge to conserving oceanic montane plant communities. Conservation management plans need significantly greater focus on potential climate change impacts, including models with higher-resolution species distribution and environmental data, to aid these communities’ long-term survival

The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy.

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão's historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage

A Prominent Role for DC-SIGN+ Dendritic Cells in Initiation and Dissemination of Measles Virus Infection in Non-Human Primates

Measles virus (MV) is a highly contagious virus that is transmitted by aerosols. During systemic infection, CD150+T and B lymphocytes in blood and lymphoid tissues are the main cells infected by pathogenic MV. However, it is unclear which cell types are the primary targets for MV in the lungs and how the virus reaches the lymphoid tissues. In vitro studies have shown that dendritic cell (DC) C-type lectin DC-SIGN captures MV, leading to infection of DCs as well as transmission to lymphocytes. However, evidence of DC-SIGN-mediated transmission in vivo has not been established. Here we identified DC-SIGNhiDCs as first target cells in vivo and demonstrate that macaque DC-SIGN functions as an attachment receptor for MV. Notably, DC-SIGNhicells from macaque broncho-alveolar lavage and lymph nodes transmit MV to B lymphocytes, providing in vivo support for an important role for DCs in both initiation and dissemination of MV infection

Arginine Metabolism by Macrophages Promotes Cardiac and Muscle Fibrosis in mdx Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is the most common, lethal disease of childhood. One of 3500 new-born males suffers from this universally-lethal disease. Other than the use of corticosteroids, little is available to affect the relentless progress of the disease, leading many families to use dietary supplements in hopes of reducing the progression or severity of muscle wasting. Arginine is commonly used as a dietary supplement and its use has been reported to have beneficial effects following short-term administration to mdx mice, a genetic model of DMD. However, the long-term effects of arginine supplementation are unknown. This lack of knowledge about the long-term effects of increased arginine metabolism is important because elevated arginine metabolism can increase tissue fibrosis, and increased fibrosis of skeletal muscles and the heart is an important and potentially life-threatening feature of DMD.We use both genetic and nutritional manipulations to test whether changes in arginase metabolism promote fibrosis and increase pathology in mdx mice. Our findings show that fibrotic lesions in mdx muscle are enriched with arginase-2-expressing macrophages and that muscle macrophages stimulated with cytokines that activate the M2 phenotype show elevated arginase activity and expression. We generated a line of arginase-2-null mutant mdx mice and found that the mutation reduced fibrosis in muscles of 18-month-old mdx mice, and reduced kyphosis that is attributable to muscle fibrosis. We also observed that dietary supplementation with arginine for 17-months increased mdx muscle fibrosis. In contrast, arginine-2 mutation did not reduce cardiac fibrosis or affect cardiac function assessed by echocardiography, although 17-months of dietary supplementation with arginine increased cardiac fibrosis. Long-term arginine treatments did not decrease matrix metalloproteinase-2 or -9 or increase the expression of utrophin, which have been reported as beneficial effects of short-term treatments.Our findings demonstrate that arginine metabolism by arginase promotes fibrosis of muscle in muscular dystrophy and contributes to kyphosis. Our findings also show that long-term, dietary supplementation with arginine exacerbates fibrosis of dystrophic heart and muscles. Thus, commonly-practiced dietary supplementation with arginine by DMD patients has potential risk for increasing pathology when performed for long periods, despite reports of benefits acquired with short-term supplementation

Inter-rater agreement in glioma segmentations on longitudinal MRI

Background Tumor segmentation of glioma on MRI is a technique to monitor, quantify and report disease progression. Manual MRI segmentation is the gold standard but very labor intensive. At present the quality of this gold standard is not known for different stages of the disease, and prior work has mainly focused on treatment-naive glioblastoma. In this paper we studied the inter-rater agreement of manual MRI segmentation of glioblastoma and WHO grade II-III glioma for novices and experts at three stages of disease. We also studied the impact of inter-observer variation on extent of resection and growth rate. Methods In 20 patients with WHO grade IV glioblastoma and 20 patients with WHO grade II-III glioma (defined as non-glioblastoma) both the enhancing and non-enhancing tumor elements were segmented on MRI, using specialized software, by four novices and four experts before surgery, after surgery and at time of tumor progression. We used the generalized conformity index (GCI) and the intra-class correlation coefficient (ICC) of tumor volume as main outcome measures for inter-rater agreement. Results For glioblastoma, segmentations by experts and novices were comparable. The inter-rater agreement of enhancing tumor elements was excellent before surgery (GCI 0.79, ICC 0.99) poor after surgery (GCI 0.32, ICC 0.92), and good at progression (GCI 0.65, ICC 0.91). For non-glioblastoma, the inter-rater agreement was generally higher between experts than between novices. The inter-rater agreement was excellent between experts before surgery (GCI 0.77, ICC 0.92), was reasonable after surgery (GCI 0.48, ICC 0.84), and good at progression (GCI 0.60, ICC 0.80). The inter-rater agreement was good between novices before surgery (GCI 0.66, ICC 0.73), was poor after surgery (GCI 0.33, ICC 0.55), and poor at progression (GCI 0.36, ICC 0.73). Further analysis showed that the lower inter-rater agreement of segmentation on postoperative MRI could only partly be explained by the smaller volumes and fragmentation of residual tumor. The median interquartile range of extent of resection between raters was 8.3% and of growth rate was 0.22 mm/year. Conclusion Manual tumor segmentations on MRI have reasonable agreement for use in spatial and volumetric analysis. Agreement in spatial overlap is of concern with segmentation after surgery for glioblastoma and with segmentation of non-glioblastoma by non-experts