A critical evaluation of secondary cancer risk models applied to Monte Carlo dose distributions of 2-dimensional, 3-dimensional conformal and hybrid intensity-modulated radiation therapy for breast cancer

The comparison of radiotherapy techniques regarding secondary cancer risk has yielded contradictory results possibly stemming from the many different approaches used to estimate risk. The purpose of this study was to make a comprehensive evaluation of different available risk models applied to detailed whole-body dose distributions computed by Monte Carlo for various breast radiotherapy techniques including conventional open tangents, 3D conformal wedged tangents and hybrid intensity modulated radiation therapy (IMRT). First, organ-specific linear risk models developed by the International Commission on Radiological Protection (ICRP) and the Biological Effects of Ionizing Radiation (BEIR) VII committee were applied to mean doses for remote organs only and all solid organs. Then, different general non-linear risk models were applied to the whole body dose distribution. Finally, organ-specific non-linear risk models for the lung and breast were used to assess the secondary cancer risk for these two specific organs. A total of 32 different calculated absolute risks resulted in a broad range of values (between 0.1% and 48.5%) underlying the large uncertainties in absolute risk calculation. The ratio of risk between two techniques has often been proposed as a more robust assessment of risk than the absolute risk. We found that the ratio of risk between two techniques could also vary substantially considering the different approaches to risk estimation. Sometimes the ratio of risk between two techniques would range between values smaller and larger than one, which then translates into inconsistent results on the potential higher risk of one technique compared to another. We found however that the hybrid IMRT technique resulted in a systematic reduction of risk compared to the other techniques investigated even though the magnitude of this reduction varied substantially with the different approaches investigated. Based on the epidemiological data available, a reasonable approach to risk estimation would be to use organ-specific non-linear risk models applied to the dose distributions of organs within or near the treatment fields (lungs and contralateral breast in the case of breast radiotherapy) as the majority of radiation-induced secondary cancers are found in the beam-bordering regions.

Quaternary uplift rates of the Central Anatolian Plateau, Turkey: insights from cosmogenic isochron-burial nuclide dating of the Kızılırmak River terraces

The Central Anatolian Plateau (CAP) in Turkey is a relatively small plateau (300 × 400 km) with moderate average elevations of ∼1 km situated between the Pontide and Tauride orogenic mountain belts. Kızılırmak, which is the longest river (1355 km) within the borders of Turkey, flows within the CAP and slowly incises into lacustrine and volcaniclastic units before finally reaching the Black Sea. We dated the Cappadocia section of the Kızılırmak terraces in the CAP by using cosmogenic burial and isochron-burial dating methods with 10Be and 26Al as their absolute dating can provide insight into long-term incision rates, uplift and climatic changes. Terraces at 13, 20, 75 and 100 m above the current river indicate an average incision rate of 0.051 ± 0.01 mm/yr (51 ± 1 m/Ma) since ∼1.9 Ma. Using the base of a basalt fill above the modern course of the Kızılırmak, we also calculated 0.05–0.06 mm/yr mean incision and hence rock uplift rate for the last 2 Ma. Although this rate might be underestimated due to normal faulting along the valley sides, it perfectly matches our results obtained from the Kızılırmak terraces. Although up to 5–10 times slower, the Quaternary uplift of the CAP is closely related to the uplift of the northern and southern plateau margins respectively.

Constraining age distributions of groundwater from public supply wells in diverse hydrogeological settings in Scania, Sweden

Twenty-five public supply wells throughout the hydrogeologically diverse region of Scania, southern Sweden are subjected to environmental tracer analysis (³H–³He,⁴He, CFCs, SF₆ and for one well only also ⁸⁵Kr and ³⁹Ar) to study well and aquifer vulnerability and evaluate possibilities of groundwater age distribution assessment. We find CFC and SF₆ concentrations well above solubility equilibrium with modern atmosphere, indicating local contamination, as well as indications of CFC degradation. The tracer-specific complications considerably constrain possibilities for sound quantitative regional ground- water age distribution assessment and demonstrate the importance of initial qualitative assessment of tracer-specific reliability, as well a need for additional, complementary tracers (e.g. ⁸⁵Kr,³⁹Ar and potentially also ¹⁴C). Lumped parameter modelling yields credible age distribution assessments for representative wells in four type aquifers. Pollution vulnerability of the aquifer types was based on the selected LPM models and qualitative age characterisation. Most vulnerable are unconfined dual porosity and fractured bedrock aquifers, due to a large component of very young groundwater. Unconfined sedimentary aquifers are vulnerable due to young groundwater and a small pre-modern component. Less vulnerable are semi-confined sedimentary or dual-porosity aquifers, due to older age of the modern component and a larger pre-modern component. Confined aquifers appear least vulnerable, due an entirely pre-modern groundwater age distribution (recharged before 1963). Tracer complications aside, environmental tracer analyses and lumped parameter modelling aid in vulnerability assessment and protection of regional groundwater resources.

Insolation, erosion, and morphology of comet 67P/Churyumov-Gerasimenko

Context. The complex shape of comet 67P and its oblique rotation axis cause pronounced seasonal effects. Irradiation and hence activity vary strongly. Aims. We investigate the insolation of the cometary surface in order to predict the sublimation of water ice. The strongly varying erosion levels are correlated with the topography and morphology of the present cometary surface and its evolution. Methods. The insolation as a function of heliocentric distance and diurnal (spin dependent) variation is calculated using >10(5) facets of a detailed digital terrain model. Shading, but also illumination and thermal radiation by facets in the field of view of a specific facet are iteratively taken into account. We use a two-layer model of a thin porous dust cover above an icy surface to calculate the water sublimation, presuming steady state and a uniform surface. Our second model, which includes the history of warming and cooling due to thermal inertia, is restricted to a much simpler shape model but allows us to test various distributions of active areas. Results. Sublimation from a dirty ice surface yields maximum erosion. A thin dust cover of 50 pm yields similar rates at perihelion. Only about 6% of the surface needs to be active to match the observed water production rates at perihelion. A dust layer of 1 mm thickness suppresses the activity by a factor of 4 to 5. Erosion on the south side can reach more than 10 m per orbit at active spots. The energy input to the concave neck area (Hapi) during northern summer is enhanced by about 50% owing to self-illumination. Here surface temperatures reach maximum values along the foot of the Hathor wall. Integrated over the whole orbit this area receives the least energy input. Based on the detailed shape model, the simulations identify "hot spots" in depressions and larger pits in good correlation with observed dust activity. Three-quarters of the total sublimation is produced while the sub-solar latitude is south, resulting in a distinct dichotomy in activity and morphology. Conclusions. The northern areas display a much rougher morphology than what is seen on Imhotep, an area at the equator that will be fully illuminated when 67P is closer to the Sun. Self-illumination in concave regions enhance the energy input and hence erosion. This explains the early activity observed at Hapi. Cliffs are more prone to erosion than horizontal, often dust covered, areas, which leads to surface planation. Local activity can only persist if the forming cliff walls are eroding. Comet 67P has two lobes and also two distinct sides. Transport of material from the south to the north is probable. The morphology of the Imhotep plain should be typical for the terrains of the yet unseen southern hemisphere.

Long-term Responses of Mountain Ecosystems to Environmental Changes: Resilience, Adjustment, and Vulnerability

The steep environmental gradients of mountain ecosystems over short distances reflect large gradients of several climatic parameters and hence provide excellent possibilities for ecological research on the effects of environmental change. To gain a better understanding of the dynamics of abiotic and biotic parameters of mountain ecosystems, long-term records are required since permanent plots in mountain regions cover in the best case about 50 - 70 years. In order to extend investigations of ecological dynamics beyond these temporal limitations of permanent plots, paleoecological approaches can be used if the sampling resolution can be adapted to ecological research questions, e.g. a sample every 10 years. Paleoecological studies in mountain ecosystems can provide new ecological insights through the combination of different spatial and temporal scales. [f we thus improve our understanding of processes across both steep environmental gradients and different time scales, we may be able to better estimate ecosystem responses to current and future environmental change (Ammann et al. 1993; Lotter et al. 1997). The complexity of ecological interactions in mountain regions forces us to concentrate on a number of sub-systems - without losing sight of the wider context. Here, we summarize a few case studies on the effects of Holocene climate change and disturbance on the vegetation of the Western Alps. To categorize the main response modes of vegetation to climatic change and disturbance in the Alps we use three classes of ecological behaviour: "resilience", "adjustment", and "vulnerability", We assume a resilient (or elastic) behaviour if vegetation is able to recover to its former state, regaining important ecosystem characteristics, such as floristic composition, biodiversity, species abundances, and biomass (e.g. Küttel 1990; Aber and Melillo 199 1). Conversely, vegetation displacements may occur in response to climatic change and/or disturbance. In some cases, this may culminate in irreversible large-scale processes such as species and/or community extinctions. Such drastic developments indicate high ecosystem vulnerability (or inelasticity or instability, for detailed definitions see Küttel 1990; Aber and Melillo 199 1) to climatic change and/or disturbance. In this sense, the "vulnerability" (or instability) of an ecosystem is expressed by the degree of failure to recover to the original state before disturbance and/or climatic change. Between these two extremes (resilience vs. vulnerability), ecosystem adjustments to climatic change and/or disturbance may occur, including the appearance of new and/or the disappearance of old species. The term "adjustment" is hence used to indicate the response of vegetational communities, which adapted to new environmental conditions without losing their main character. For forest ecosystems, we assume vegetational adjustments (rather than vulnerability) if the dominant (or co-dominant) tree species are not outnumbered or replaced by formerly unimportant plant species or new invaders. Adaptation as a genetic process is not discussed here and will require additional pbylogeographical studies (that incorporate the analysis of ancient DNA) in order to fully understand the distributions of ecotypes.

Cleavage of IgG1 and IgG3 by gingipain K from Porphyromonas gingivalis may compromise host defense in progressive periodontitis

Degradation of immunoglobulins is an effective strategy of bacteria to evade the immune system. We have tested whether human IgG is a substrate for gingipain K of Porphyromonas gingivalis and found that the enzyme can hydrolyze subclass 1 and 3 of human IgG. The heavy chain of IgG(1) was cleaved at a single site within the hinge region, generating Fab and Fc fragments. IgG(3) was also cleaved within the heavy chain, but at several sites around the CH2 region. Investigation of the enzyme kinetics of IgG proteolysis by gingipain K, using FPLC- and isothermal titration calorimetry-based assays followed by Hill plots, revealed non-Michaelis-Menten kinetics involving a mechanism of positive cooperativity. In ex vivo studies, it was shown that gingipain K retained its IgG hydrolyzing activity in human plasma despite the high content of natural protease inhibitors; that IgG(1) cleavage products were detected in gingival crevicular fluid samples from patients with severe periodontitis; and that gingipain K treatment of serum samples from patients with high antibody titers against P. gingivalis significantly hindered opsonin-dependent phagocytosis of clinical isolates of P. gingivalis by neutrophils. Altogether, these findings underline a biological function of gingipain K as an IgG protease of pathophysiological importance.

Validation of the Swiss Monte Carlo Plan for a static and dynamic 6 MV photon beam

Monte Carlo (MC) based dose calculations can compute dose distributions with an accuracy surpassing that of conventional algorithms used in radiotherapy, especially in regions of tissue inhomogeneities and surface discontinuities. The Swiss Monte Carlo Plan (SMCP) is a GUI-based framework for photon MC treatment planning (MCTP) interfaced to the Eclipse treatment planning system (TPS). As for any dose calculation algorithm, also the MCTP needs to be commissioned and validated before using the algorithm for clinical cases. Aim of this study is the investigation of a 6 MV beam for clinical situations within the framework of the SMCP. In this respect, all parts i.e. open fields and all the clinically available beam modifiers have to be configured so that the calculated dose distributions match the corresponding measurements. Dose distributions for the 6 MV beam were simulated in a water phantom using a phase space source above the beam modifiers. The VMC++ code was used for the radiation transport through the beam modifiers (jaws, wedges, block and multileaf collimator (MLC)) as well as for the calculation of the dose distributions within the phantom. The voxel size of the dose distributions was 2mm in all directions. The statistical uncertainty of the calculated dose distributions was below 0.4%. Simulated depth dose curves and dose profiles in terms of [Gy/MU] for static and dynamic fields were compared with the corresponding measurements using dose difference and γ analysis. For the dose difference criterion of ±1% of D(max) and the distance to agreement criterion of ±1 mm, the γ analysis showed an excellent agreement between measurements and simulations for all static open and MLC fields. The tuning of the density and the thickness for all hard wedges lead to an agreement with the corresponding measurements within 1% or 1mm. Similar results have been achieved for the block. For the validation of the tuned hard wedges, a very good agreement between calculated and measured dose distributions was achieved using a 1%/1mm criteria for the γ analysis. The calculated dose distributions of the enhanced dynamic wedges (10°, 15°, 20°, 25°, 30°, 45° and 60°) met the criteria of 1%/1mm when compared with the measurements for all situations considered. For the IMRT fields all compared measured dose values agreed with the calculated dose values within a 2% dose difference or within 1 mm distance. The SMCP has been successfully validated for a static and dynamic 6 MV photon beam, thus resulting in accurate dose calculations suitable for applications in clinical cases.

Variations of the Atlantic meridional overturning circulation in control and transient simulations of the last millennium

The variability of the Atlantic meridional overturing circulation (AMOC) strength is investigated in control experiments and in transient simulations of up to the last millennium using the low-resolution Community Climate System Model version 3. In the transient simulations the AMOC exhibits enhanced low-frequency variability that is mainly caused by infrequent transitions between two semi-stable circulation states which amount to a 10 percent change of the maximum overturning. One transition is also found in a control experiment, but the time-varying external forcing significantly increases the probability of the occurrence of such events though not having a direct, linear impact on the AMOC. The transition from a high to a low AMOC state starts with a reduction of the convection in the Labrador and Irminger Seas and goes along with a changed barotropic circulation of both gyres in the North Atlantic and a gradual strengthening of the convection in the Greenland-Iceland-Norwegian (GIN) Seas. In contrast, the transition from a weak to a strong overturning is induced by decreased mixing in the GIN Seas. As a consequence of the transition, regional sea surface temperature (SST) anomalies are found in the midlatitude North Atlantic and in the convection regions with an amplitude of up to 3 K. The atmospheric response to the SST forcing associated with the transition indicates a significant impact on the Scandinavian surface air temperature (SAT) in the order of 1 K. Thus, the changes of the ocean circulation make a major contribution to the Scandinavian SAT variability in the last millennium.

Sensitivity of pelagic calcification to ocean acidification

Ocean acidification might reduce the ability of calcifying plankton to produce and maintain their shells of calcite, or of aragonite, the more soluble form of CaCO3. In addition to possibly large biological impacts, reduced CaCO3 production corresponds to a negative feedback on atmospheric CO2. In order to explore the sensitivity of the ocean carbon cycle to increasing concentrations of atmospheric CO2, we use the new biogeochemical Bern3D/PISCES model. The model reproduces the large scale distributions of biogeochemical tracers. With a range of sensitivity studies, we explore the effect of (i) using different parameterizations of CaCO3 production fitted to available laboratory and field experiments, of (ii) letting calcite and aragonite be produced by auto- and heterotrophic plankton groups, and of (iii) using carbon emissions from the range of the most recent IPCC Representative Concentration Pathways (RCP). Under a high-emission scenario, the CaCO3 production of all the model versions decreases from ~1 Pg C yr−1 to between 0.36 and 0.82 Pg C yr−1 by the year 2100. The changes in CaCO3 production and dissolution resulting from ocean acidification provide only a small feedback on atmospheric CO2 of −1 to −11 ppm by the year 2100, despite the wide range of parameterizations, model versions and scenarios included in our study. A potential upper limit of the CO2-calcification/dissolution feedback of −30 ppm by the year 2100 is computed by setting calcification to zero after 2000 in a high 21st century emission scenario. The similarity of feedback estimates yielded by the model version with calcite produced by nanophytoplankton and the one with calcite, respectively aragonite produced by mesozooplankton suggests that expending biogeochemical models to calcifying zooplankton might not be needed to simulate biogeochemical impacts on the marine carbonate cycle. The changes in saturation state confirm previous studies indicating that future anthropogenic CO2 emissions may lead to irreversible changes in ΩA for several centuries. Furthermore, due to the long-term changes in the deep ocean, the ratio of open water CaCO3 dissolution to production stabilizes by the year 2500 at a value that is 30–50% higher than at pre-industrial times when carbon emissions are set to zero after 2100.

Axis I diagnoses and transition to psychosis in clinical high-risk patients EPOS project: prospective follow-up of 245 clinical high-risk outpatients in four countries

In selected samples, a considerable number of patients at clinical high risk of psychosis (CHR) are found to meet criteria for co-morbid clinical psychiatric disorders. It is not known how clinical diagnoses correspond to or even predict transitions to psychosis (TTP). Our aim was to examine distributions of life-time and current Axis I diagnoses, and their association with TTP in CHR patients.

Multiple time scales of temporal response in pyramidal and fast spiking cortical neurons

Neural dynamic processes correlated over several time scales are found in vivo, in stimulus-evoked as well as spontaneous activity, and are thought to affect the way sensory stimulation is processed. Despite their potential computational consequences, a systematic description of the presence of multiple time scales in single cortical neurons is lacking. In this study, we injected fast spiking and pyramidal (PYR) neurons in vitro with long-lasting episodes of step-like and noisy, in-vivo-like current. Several processes shaped the time course of the instantaneous spike frequency, which could be reduced to a small number (1-4) of phenomenological mechanisms, either reducing (adapting) or increasing (facilitating) the neuron's firing rate over time. The different adaptation/facilitation processes cover a wide range of time scales, ranging from initial adaptation (<10 ms, PYR neurons only), to fast adaptation (<300 ms), early facilitation (0.5-1 s, PYR only), and slow (or late) adaptation (order of seconds). These processes are characterized by broad distributions of their magnitudes and time constants across cells, showing that multiple time scales are at play in cortical neurons, even in response to stationary stimuli and in the presence of input fluctuations. These processes might be part of a cascade of processes responsible for the power-law behavior of adaptation observed in several preparations, and may have far-reaching computational consequences that have been recently described.

Provenance discrimination of Lower Cretaceous synrift sandstones (eastern Iberian Chain Spain) Constraints from detrital modes heavy minerals and geochemistry

Petrography, geochemical whole-rock composition, and chemical analyses of tourmaline were performed in order to determine the source areas of Lower Cretaceous Mora, El Castellar, and uppermost Camarillas Formation sandstones from the Iberian Chain, Spain. Sandstones were deposited in intraplate subbasins, which are bound by plutonic and volcanic rocks of Permian, Triassic, and Jurassic age, Paleozoic metamorphic rocks, and Triassic sedimentary rocks. Modal analyses together with petrographic and cathodoluminescence observations allowed us to define three quartz-feldspathic petrofacies and recognize diagenetic processes that modified the original framework composition. Results from average restored petrofacies are: Mora petrofacies = P/F >1 and Q(r)70 F(r)22 R(r)9; El Castellar petrofacies = P/F >1 and Q(r)57 F(r)25 R(r)18; and Camarillas petrofacies = P/F ∼ zero and Q(r)64 F(r)28 R(r)7 (P—plagioclase; F—feldspar; Q—quartz; R—rock fragments; r—restored composition). Trace-element and rare earth element abundances of whole-rock analyses discriminate well between the three petrofacies based on: (1) the Rb concentration, which is indicative of the K content and reflects the amount of K-feldspar modal abundance, and (2) the relative modal abundance of heavy minerals (tourmaline, zircon, titanite, and apatite), which is reproduced by the elements hosted in the observed heavy mineral assemblage (i.e., B and Li for tourmaline; Zr, Hf, and Ta for zircon; Ti, Ta, Nb, and their rare earth elements for titanite; and P, Y, and their rare earth elements for apatite). Tourmaline chemical composition for the three petrofacies ranges from Fe-tourmaline of granitic to Mg-tourmaline of metamorphic origin. The three defined petrofacies suggest a mixed provenance from plutonic and metamorphic source rocks. However, a progressively major influence of granitic source rocks was detected from the lowermost Mora petrofacies toward the uppermost Camarillas petrofacies. This provenance trend is consistent with the uplift and erosion of the Iberian Massif, which coincided with the development of the latest Berriasian synrift regional unconformity and affected all of the Iberian intraplate basins. The uplifting stage of Iberian Massif pluton caused a significant dilution of Paleozoic metamorphic source areas, which were dominant during the sedimentation of the lowermost Mora and El Castellar petrofacies. The association of petrographic data with whole-rock geochemical compositions and tourmaline chemical analysis has proved to be useful for determining source area characteristics, their predominance, and the evolution of source rock types during the deposition of quartz-feldspathic sandstones in intraplate basins. This approach ensures that provenance interpretation is consistent with the geological context.

Retrospective analysis of a nonforecasted rain-on-snow flood in the Alps – a matter of model limitations or unpredictable nature?

A rain-on-snow flood occurred in the Bernese Alps, Switzerland, on 10 October 2011, and caused significant damage. As the flood peak was unpredicted by the flood forecast system, questions were raised concerning the causes and the predictability of the event. Here, we aimed to reconstruct the anatomy of this rain-on-snow flood in the Lötschen Valley (160 km2) by analyzing meteorological data from the synoptic to the local scale and by reproducing the flood peak with the hydrological model WaSiM-ETH (Water Flow and Balance Simulation Model). This in order to gain process understanding and to evaluate the predictability. The atmospheric drivers of this rain-on-snow flood were (i) sustained snowfall followed by (ii) the passage of an atmospheric river bringing warm and moist air towards the Alps. As a result, intensive rainfall (average of 100 mm day-1) was accompanied by a temperature increase that shifted the 0° line from 1500 to 3200 m a.s.l. (meters above sea level) in 24 h with a maximum increase of 9 K in 9 h. The south-facing slope of the valley received significantly more precipitation than the north-facing slope, leading to flooding only in tributaries along the south-facing slope. We hypothesized that the reason for this very local rainfall distribution was a cavity circulation combined with a seeder-feeder-cloud system enhancing local rainfall and snowmelt along the south-facing slope. By applying and considerably recalibrating the standard hydrological model setup, we proved that both latent and sensible heat fluxes were needed to reconstruct the snow cover dynamic, and that locally high-precipitation sums (160 mm in 12 h) were required to produce the estimated flood peak. However, to reproduce the rapid runoff responses during the event, we conceptually represent likely lateral flow dynamics within the snow cover causing the model to react "oversensitively" to meltwater. Driving the optimized model with COSMO (Consortium for Small-scale Modeling)-2 forecast data, we still failed to simulate the flood because COSMO-2 forecast data underestimated both the local precipitation peak and the temperature increase. Thus we conclude that this rain-on-snow flood was, in general, predictable, but requires a special hydrological model setup and extensive and locally precise meteorological input data. Although, this data quality may not be achieved with forecast data, an additional model with a specific rain-on-snow configuration can provide useful information when rain-on-snow events are likely to occur.