Investigating patterns of T cell differentiation in the blood and skin of patients with melanoma

Melanoma progression occurs despite evidence of melanoma-specific T cell activation. Chronic or repeated antigen stimulation can cause dysregulated T cell differentiation through upregulation of inhibitory receptors (immune exhaustion) or end-stage differentiation (immune senescence). This thesis therefore investigated the hypothesis that blood and skin derived T cells of melanoma patients are driven towards immune exhaustion and senescence. An increase in senescent CD8+ TEMRA cells was detected in the blood of old melanoma patients. These cells had high cytotoxic but low proliferative potential. Whilst it could not be determined whether they were melanoma specific, the TEMRA expansions occurred independently from persistent viral infections such as CMV, and their function could be boosted through p38 signalling blockade. Skin resident T cells of melanoma patients showed no increase in T cell differentiation but instead upregulation of exhaustion markers PD-1 and CTLA-4. Granzyme B and perforin, essential for granule mediated cell killing, remained low in these cells, suggesting insufficient cytotoxic function. Skin derived T cells from healthy individuals also expressed high levels of PD-1 and low levels of cytotoxic granule components. Exposure to IL-2, IL-15 and CD3/CD28 boosted perforin and granzyme expression in healthy skin cells. Conversely, PD-1 signalling blockade during CD3 stimulation increased granzyme B expression. In summary, melanoma associated immune dysfunctions were of a different nature in blood and skin T cells. Immunotherapies designed to boost immune function in patients might therefore have different efficacies in both organs

Robust Structured Low-Rank Approximation on the Grassmannian

Over the past years Robust PCA has been established as a standard tool for reliable low-rank approximation of matrices in the presence of outliers. Recently, the Robust PCA approach via nuclear norm minimization has been extended to matrices with linear structures which appear in applications such as system identification and data series analysis. At the same time it has been shown how to control the rank of a structured approximation via matrix factorization approaches. The drawbacks of these methods either lie in the lack of robustness against outliers or in their static nature of repeated batch-processing. We present a Robust Structured Low-Rank Approximation method on the Grassmannian that on the one hand allows for fast re-initialization in an online setting due to subspace identification with manifolds, and that is robust against outliers due to a smooth approximation of the $\ell_p$-norm cost function on the other hand. The method is evaluated in online time series forecasting tasks on simulated and real-world data

Quantum Bounds on Bell inequalities

We have determined the maximum quantum violation of 241 tight bipartite Bell inequalities with up to five two-outcome measurement settings per party by constructing the appropriate measurement operators in up to six-dimensional complex and eight-dimensional real component Hilbert spaces using numerical optimization. Out of these inequalities 129 has been introduced here. In 43 cases higher dimensional component spaces gave larger violation than qubits, and in 3 occasions the maximum was achieved with six-dimensional spaces. We have also calculated upper bounds on these Bell inequalities using a method proposed recently. For all but 20 inequalities the best solution found matched the upper bound. Surprisingly, the simplest inequality of the set examined, with only three measurement settings per party, was not among them, despite the high dimensionality of the Hilbert space considered. We also computed detection threshold efficiencies for the maximally entangled qubit pair. These could be lowered in several instances if degenerate measurements were also allowed.Comment: 12 pages, 4 tables; corrected Table I and modified Table III to comply with Table I; more detailed results are available at http://www.atomki.hu/atomki/TheorPhys/Bell_violation

The Characterization of Varicella Zoster Virus-Specific T Cells in Skin and Blood during Aging

Reactivation of the varicella zoster virus (VZV) increases during aging. Although the effects of VZV reactivation are observed in the skin (shingles), the number and functional capacity of cutaneous VZV-specific T cells have not been investigated. The numbers of circulating IFN-γ-secreting VZV-specific CD4+ T cells are significantly decreased in old subjects. However, other measures of VZV-specific CD4+ T cells, including proliferative capacity to VZV antigen stimulation and identification of VZV-specific CD4+ T cells with an major histocompatibility complex class II tetramer (epitope of IE-63 protein), were similar in both age groups. The majority of T cells in the skin of both age groups expressed CD69, a characteristic of skin-resident T cells. VZV-specific CD4+ T cells were significantly increased in the skin compared with the blood in young and old subjects, and their function was similar in both age groups. In contrast, the number of Foxp3+ regulatory T cells and expression of the inhibitory receptor programmed cell death -1 PD-1 on CD4+ T cells were significantly increased in the skin of older humans. Therefore, VZV-specific CD4+ T cells in the skin of older individuals are functionally competent. However, their activity may be restricted by multiple inhibitory influences in situ

The Atmosphere above Ny-Ålesund – Climate and global warming, ozone and surface UV radiation

The Arctic region is considered to be most sensitive to climate change, with warming in the Arctic occurring considerably faster than the global average due to several positive feedback mechanisms contributing to the “Arctic amplification”. Also the maritime and mountainous climate of Svalbard has undergone changes during the last decades. Here, the focus is set on the current atmospheric boundary conditions for the marine ecosystem in the Kongsfjorden area, discussed in the frame of long-term climatic observations in the larger regional and hemispheric context. During the last century, a general warming is found with temperature increases and precipitation changes varying in strength. During the last decades, a strong seasonality of the warming is observed in the Kongsfjorden area, with the strongest temperature increase occurring during the winter season. The winter warming is related to observed changes in the net longwave radiation. Moreover, changes in the net shortwave are observed during the summer period, attributed to the decrease in reflected radiation caused by the retreating snow cover. Another related aspect of radiation is the intensity of solar ultra-violet radiation that is closely coupled to the abundance of ozone in the column of air overhead. The long term evolution of ozone losses in the Arctic and their connection to climate change are discussed

Clinical Implication of Targeting of Cancer Stem Cells

The existence of cancer stem cells (CSCs) is receiving increasing interest particularly due to its potential ability to enter clinical routine. Rapid advances in the CSC field have provided evidence for the development of more reliable anticancer therapies in the future. CSCs typically only constitute a small fraction of the total tumor burden; however, they harbor self-renewal capacity and appear to be relatively resistant to conventional therapies. Recent therapeutic approaches aim to eliminate or differentiate CSCs or to disrupt the niches in which they reside. Better understanding of the biological characteristics of CSCs as well as improved preclinical and clinical trials targeting CSCs may revolutionize the treatment of many cancers. Copyright (c) 2012 S. Karger AG, Base

Breakup Temperature of Target Spectators in Au + Au Collisions at E/A = 1000 MeV

Breakup temperatures were deduced from double ratios of isotope yields for target spectators produced in the reaction Au + Au at 1000 MeV per nucleon. Pairs of $^{3,4}$He and $^{6,7}$Li isotopes and pairs of $^{3,4}$He and H isotopes (p, d and d, t) yield consistent temperatures after feeding corrections, based on the quantum statistical model, are applied. The temperatures rise with decreasing impact parameter from 4 MeV for peripheral to about 10 MeV for the most central collisions. The good agreement with the breakup temperatures measured previously for projectile spectators at an incident energy of 600 MeV per nucleon confirms the observed universality of the spectator decay at relativistic bombarding energies. The measured temperatures also agree with the breakup temperatures predicted by the statistical multifragmentation model. For these calculations a relation between the initial excitation energy and mass was derived which gives good simultaneous agreement for the fragment charge correlations. The energy spectra of light charged particles, measured at $\theta_{lab}$ = 150$^{\circ}$, exhibit Maxwellian shapes with inverse slope parameters much higher than the breakup temperatures. The statistical multifragmentation model, because Coulomb repulsion and sequential decay processes are included, yields light-particle spectra with inverse slope parameters higher than the breakup temperatures but considerably below the measured values. The systematic behavior of the differences suggests that they are caused by light-charged-particle emission prior to the final breakup stage. PACS numbers: 25.70.Mn, 25.70.Pq, 25.75.-qComment: 29 pages, TeX with 11 included figures; Revised version accepted for publication in Z. Phys. A Two additional figure

Dynamical Boson Stars

The idea of stable, localized bundles of energy has strong appeal as a model for particles. In the 1950s John Wheeler envisioned such bundles as smooth configurations of electromagnetic energy that he called {\em geons}, but none were found. Instead, particle-like solutions were found in the late 1960s with the addition of a scalar field, and these were given the name {\em boson stars}. Since then, boson stars find use in a wide variety of models as sources of dark matter, as black hole mimickers, in simple models of binary systems, and as a tool in finding black holes in higher dimensions with only a single killing vector. We discuss important varieties of boson stars, their dynamic properties, and some of their uses, concentrating on recent efforts.Comment: 79 pages, 25 figures, invited review for Living Reviews in Relativity; major revision in 201

Acclimatization of the crustose coralline alga Porolithon onkodes to variable pCO2

Ocean acidification (OA) has important implications for the persistence of coral reef ecosystems, due to potentially negative effects on biomineralization. Many coral reefs are dynamic with respect to carbonate chemistry, and experience fluctuations in pCO2 that exceed OA projections for the near future. To understand the influence of dynamic pCO2 on an important reef calcifier, we tested the response of the crustose coralline alga Porolithon onkodes to oscillating pCO2. Individuals were exposed to ambient (400 ??atm), high (660 ??atm), or variable pCO2 (oscillating between 400/660 ??atm) treatments for 14 days. To explore the potential for coralline acclimatization, we collected individuals from low and high pCO2 variability sites (upstream and downstream respectively) on a back reef characterized by unidirectional water flow in Moorea, French Polynesia. We quantified the effects of treatment on algal calcification by measuring the change in buoyant weight, and on algal metabolism by conducting sealed incubations to measure rates of photosynthesis and respiration. Net photosynthesis was higher in the ambient treatment than the variable treatment, regardless of habitat origin, and there was no effect on respiration or gross photosynthesis. Exposure to high pCO2 decreased P. onkodes calcification by >70%, regardless of the original habitat. In the variable treatment, corallines from the high variability habitat calcified 42% more than corallines from the low variability habitat. The significance of the original habitat for the coralline calcification response to variable, high pCO2 indicates that individuals existing in dynamic pCO2 habitats may be acclimatized to OA within the scope of in situ variability. These results highlight the importance of accounting for natural pCO2 variability in OA manipulations, and provide insight into the potential for plasticity in habitat and species-specific responses to changing ocean chemistry.Funding was provided by grants from the National Science Foundation (OCE-0417412, OCE-10-26852, OCE-1041270) and gifts from the Gordon and Betty Moore Foundation. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript