ALBERT

Beschreibung: Observations made near the Celtic Sea shelf edge are used to investigate the interaction between wind generated near-inertial oscillations and the semi-diurnal internal tide. Linear, baroclinic energy fluxes within the near-inertial ( f ) and semi-diurnal (M 2 ) wave bands are calculated from measurements of velocity and density structure at two moorings located 40 km from the internal tidal generation zone. Over the two week deployment period the semi-diurnal tide drove 28-48 W m -1 of energy directly on-shelf. Little spring-neap variability could be detected. Horizontal near-inertial energy fluxes were an order of magnitude weaker, but non-linear interaction between the vertical shear of inertial oscillations and the vertical velocity associated with the semi-diurnal internal tide led to a 25-43% increase in positive on-shelf energy flux. The phase relationship between f and M 2 determines whether this non-linear interaction enhances or dampens the linear tidal component of the flux, and introduces a 2-day counter clockwise beating to the energy transport. Two very clear contrasting regimes of (a) tidally and (b) inertially driven shear and energy flux are captured in the observations.

Beschreibung: Geodynamic models of mantle convection predict that Mexico and western North America share a history of dynamic support. We calculate admittance between gravity and topography, which indicates that the elastic thickness of the plate in Mexico is 11 km and in western North America it is 12 km. Admittance at wavelengths 〉 500 km in these regions suggests that topography is partly supported by sub-crustal processes. These results corroborate estimates of residual topography from isostatic calculations and suggest that the amount of North American topography supported by the mantle may exceed 1 km. The Cenozoic history of magmatism, sedimentary flux, thermochronometric denudation estimates and uplifted marine terraces imply that North American lithosphere was uplifted and eroded during the last 30 Ma. We jointly invert 533 Mexican and North American longitudinal river profiles to reconstruct a continent-scale rock uplift rate history. Uplift rate is permitted to vary in space and time. Erosional parameters are calibrated using incision rate data in southwest Mexico and the Colorado Plateau. Calculated rock uplift rates were 0.15–0.2 mm/yr between 25–10 Ma. Central Mexico experienced the highest uplift rates. Central and southern Mexico continued to uplift at 0.1 mm/yr until recent times. This uplift history is corroborated by independent constraints. We predict clastic flux to the Gulf of Mexico and compare it to independent estimates. We tentatively suggest that the loop between uplift, erosion and deposition can be closed here. Mexico's staged uplift history suggests that its dynamic support has changed during the last 30 Ma. This article is protected by copyright. All rights reserved.

Beschreibung: The potential for climate change mitigation by bioenergy crops and terrestrial carbon sinks has been the object of intensive research in the past decade. There has been much debate about whether energy crops used to offset fossil fuel use, or carbon sequestration in forests, would provide the best climate mitigation benefit. Most current food cropland is unlikely to be used for bioenergy, but in many regions of the world, a proportion of cropland is being abandoned, particularly marginal croplands, and some of this land is now being used for bioenergy. In this paper we assess the consequences of land use change on cropland. We first identify areas where cropland is so productive that it may never be converted, and assess the potential of the remaining cropland to mitigate climate change by identifying which alternative land use provides the best climate benefit: C 4 grass bioenergy crops, coppiced woody energy crops, or allowing forest regrowth to create a carbon sink. We do not present this as a scenario of land use change – we simply assess the best option in any given global location should a land use change occur. To do this we use global biomass potential studies based on food-crop productivity, forest inventory data, and Dynamic Global Vegetation Models to provide, for the first time, a global comparison of the climate change implications of either deploying bioenergy crops or allowing forest regeneration on current crop land, over a period of 20 years starting in the nominal year of 2000 AD. Globally, the extent of cropland on which conversion to energy crops or forest would result in a net carbon loss, and therefore likely always to remain as cropland, was estimated to be about 420.1 Mha, or 35.6% of the total cropland in Africa, 40.3% in Asia and Russia Federation, 30.8% in Europe-25, 48.4% in North America, 13.7% in South America, and 58.5% in Oceania. Fast growing C 4 Grasses such as Miscanthus and switch-grass cultivars are the bioenergy feedstock with the highest climate mitigation potential. Fast growing C 4 grasses such as Miscanthus and switch-grass cultivars provide the best climate mitigation option on ≈ 485 Mha of cropland worldwide with ~ 42% of this land characterized by a terrain slope equal or above 20%. If that land use change did occur, it would displace ≈ 58.1 Pg fossil fuel C equivalent (C eq oil). Woody energy crops such as poplar, willow, and Eucalyptus species would be the best option on only 2.4% (≈ 26.3 Mha) of current cropland, and if this land use change occurred it would displace ≈ 0.9 Pg C eq oil. Allowing cropland to revert to forest would be the best climate mitigation option on ≈ 17% of current cropland (≈ 184.5 Mha) and if this land use change occurred it would sequester ≈ 5.8 Pg C in biomass in the 20-year-old forest, and ≈ 2.7 Pg C in soil. This article is protected by copyright. All rights reserved.

Beschreibung: Ecology, Ahead of Print. Predation pressure can alter the morphology, physiology, life history and behavior of prey; this in turn can change how surviving prey interact with parasites. These trait-mediated indirect effects may change in direction or intensity during growth or, in sexually dimorphic species, between the sexes. The Trinidadian guppy Poecilia reticulata presents a unique opportunity to examine these interactions; its behavioral ecology has been intensively studied in wild populations with well-characterized predator faunas. Predation pressure is known to have driven the evolution of many guppy traits; for example, in high-predation sites, females (but not males) tend to shoal, and this anti-predator behavior facilitates parasite transmission. To test for evidence of predator-driven differences in infection in natural populations, we collected 4715 guppies from 62 sites across Trinidad between 2003 and 2009 and screened them for ectosymbionts including Gyrodactylus. A novel model-averaging analysis revealed that females were more likely to be infected with Gyrodactylus parasites than males, but only in populations with both high predation pressure and high infection incidence. We propose that the difference in shoaling tendency between the sexes could explain the observed difference in infection incidence between males and females in high-predation sites. The infection rate of juveniles did not vary with predation regime, probably because juveniles face constant predation pressure from conspecific adults and therefore tend to shoal both in high- and low-predation sites. This represents the first evidence for age- and sex-specific trait-mediated indirect effects of predators on the probability of infection in their prey.

Beschreibung: ABSTRACT A workshop was held at the University of the West Indies, Jamaica, in May 2012 to build capacity in climate data rescue and to enhance knowledge about climate change in the Caribbean region. Scientists brought their daily observational surface temperature and precipitation data from weather stations for an assessment of quality and homogeneity and for the calculation of climate indices helpful for studying climate change in their region. This study presents the trends in daily and extreme temperature and precipitation indices in the Caribbean region for records spanning the 1961–2010 and 1986–2010 intervals. Overall, the results show a warming of the surface air temperature at land stations. In general, the indices based on minimum temperature show stronger warming trends than indices calculated from maximum temperature. The frequency of warm days, warm nights and extreme high temperatures has increased while fewer cool days, cool nights and extreme low temperatures were found for both periods. Changes in precipitation indices are less consistent and the trends are generally weak. Small positive trends were found in annual total precipitation, daily intensity, maximum number of consecutive dry days and heavy rainfall events particularly during the period 1986–2010. Correlations between indices and the Atlantic multidecadal oscillation (AMO) index suggest that temperature variability and, to a lesser extent, precipitation extremes are related to the AMO signal of the North Atlantic surface sea temperatures: stronger associations are found in August and September for the temperature indices and in June and October for some of the precipitation indices.

Beschreibung: Introduction: Interphase FISH on CD138-selected bone marrow cells enables genetic risk stratification in newly diagnosed multiple myeloma (MM), however as MM remains incurable, most centres still treat newly diagnosed MM uniformly, utilising the most active regimens available. At relapse an increasing choice of regimens, coupled with co-morbidities and treatment-emergent toxicities, means no uniform approach is possible. Instead, therapy is tailored to disease and patient related risk factors. In this setting, FISH testing may be particularly useful if not done at diagnosis and to identify progression events that may alter prognosis. Aim: To evaluate the outcome of FISH analysis in consecutive patients with relapsed MM undertaken at our centre: success rate, frequency of abnormalities, incidence of progression events and correlation of FISH abnormalities with treatment outcomes. Methods: FISH analysis was performed on 192 samples from 154 relapsed patients (2012-13). Plasma cells were selected using magnetic CD138 MicroBeads and interphase FISH carried out using probes as recommended by the EMN (Ross et al, 2012). If patients had no prior results, a full FISH MM panel was performed, using probes for t(4;14), t(14;16), t(11;14), deletion 17p (17p-), Chr 1 abnormalities (1p-/1q+) and deletion 13q (13q-). If patients had been previously tested for an IgH translocation (Tx), a progression event panel was used: 1p-/1q+, 17p- and 13q-. Patients underwent FISH testing prior to starting the next line of therapy. Results: 79% of samples were successfully analysed, with analysis limited in 16% and failed in 5%. Common reasons for failure were poor quality/aged slides, insufficient material and poor hybridisation. 17% of patients had no cytogenetic abnormality. The most common abnormality was 13q- (43.1%), followed by 1q+ (41.4%), t(11;14) (18.3%), t(4;14) (12.4%), 17p- (12.0%) 1p- (8.9%), and t(14;16) (5.6%) Progression events were more common in t(14;16) and t(4;14) groups. All patients with t(14;16) and 82% with t(4;14) had an additional genetic lesion. Only 21% of patients with t(11;14) and 54% with no IgH Tx had an additional event. 80 patients (51.3%) had prior FISH results and 13 (16.3%) had developed a new abnormality on the later test. In 9 cases the progression event was 17p-, in 2 it was 1q+ and 2 cases developed 17p- and 1q+. The patients developing 1q+ were previously standard risk, so repeat testing altered risk group. Acquisition of 17p- indicates especially poor outcome, thus in all 13 cases repeat FISH analysis altered risk. Among patients with progression events none harboured t(11;14), 8 (64%) had no IgH Tx, 3 had t(14;16) and 2 had t(4;14). FISH results were correlated with clinical outcome. Patients were stratified as having high risk genetics [t(4;14), t(14,16), 17p- in ≥50% cells, 1p-/1q+] or standard risk [t(11;14), normal cytogenetics]. 63 (41%) patients were high risk, 83 (54%) standard risk, with no information available for 8 (5%). Both groups had received a median of 2 prior lines of therapy. Response rates (≥PR) to the next line of therapy were similar (60.4% standard risk vs 56.0% high risk). PFS from time of FISH was significantly longer in the standard risk group (9.8 months vs 5.9, p

Beschreibung: Background:Flow cytometric studies are useful in the diagnostic workup of patients with unexplained cytopenias and it has been demonstrated that bone marrow aspirates with immunophenotypic abnormalities by flow cytometry but not diagnostic morphologic or cytogenetic findings frequently evolve into myelodysplastic syndromes (MDS) (Kern 2013). Two flow cytometric scoring systems (FCSSs), the Wells FCSS and the Ogata FCSS, have diagnostic and prognostic utility. The Wells FCSS utilizes a difference from normal algorithm incorporating more than ten phenotypic parameters. The accumulation of these abnormalities is not only useful in diagnosis but is predictive of patient outcome (Wells 2003, Scott 2008, Alhan 2014). The recommended Ogata FCSS has evolved to include four cardinal parameters: (1) CD45 intensity on the myeloid progenitors, (2) frequency of lymphoblasts, (3) frequency of myeloid progenitors, and (4) granularity of the maturing myeloid cells. The Wells FCSS is more comprehensive as it uses more phenotypic characteristics, while the Ogata score is considered straightforward to implement in a routine setting (Della Porta 2012, Ogata 2009). This study compares the Wells FCSS and Ogata FCSS for sensitivity and specificity to detect clonal abnormalities documented by SNP/CGH microarray and conventional cytogenetics. Patients and Methods: The cohort included 99 patients with unexplained cytopenias whose bone marrow aspirates were submitted for SNP/CGH microarray and flow cytometry (HematoLogics). The immunophenotypic data were independently assigned a Wells FCSS (Cutler 2012) and an Ogata FCSS (Della Porta 2012). SNP/CGH microarray was assessed for MDS-associated genetic abnormalities. The findings were further correlated with conventional cytogenetic findings. Results: Of the 99 bone marrow aspirates, 20 exhibited clonal abnormalities associated with MDS. The Wells FCSS identified immunophenotypic abnormalities suggestive of MDS for 18 of 20 CGH positive specimens (sensitivity of 90%) and did not detect phenotypic abnormalities suggestive of MDS in 68 of 79 CGH negative specimens (specificity of 86%). In contrast the Ogata FCSS identified immunophenotypic abnormalities suggestive of MDS for 13 of 20 CGH positive specimens (sensitivity of 65%) and did not detect phenotypic abnormalities suggestive of MDS in 64 of 79 the CGH negative specimens (specificity of 81%). In an attempt to improve the sensitivity and specificity of the Ogata score, the granularity parameter was modified from side scatter channel mode of the granulocytes (compared to the side scatter mode of the lymphocytes) to the side scatter channel at the 15thpercentile of granulocytes (compared to the mean of lymphocytes). This modified parameter detected all specimens defined as hypogranular by the side scatter mode, and detected an additional 11 specimens as hypogranular. All of these specimens were detected as hypogranular by the Wells definition. This modified granularity method was then used along with the other three cardinal parameters to create a modified Ogata FCSS. The granularity modification resulted in improved sensitivity (70% versus 65%); specificity was unchanged. While the modified method outperformed the original, it did not match the performance of the Wells FCSS. Conclusions: In patients with unexplained cytopenias, the Wells FCSS demonstrates superior specificity and sensitivity than the Ogata FCSS for detecting myeloid immunophenotypic clones associated with SNP/CGH array and cytogenetic abnormalities. Modifying the Ogata granularity parameter marginally improves the sensitivity but does not improve the specificity. Implementation of the Wells FCSS requires a comprehensive understanding of phenotypic intensities and relationships in non-clonal hematopoiesis for patients with cytopenias. While the relative ease of implementing the Ogata FCSS is attractive, improvements are essential for diagnostic accuracy; improving the granularity parameter alone is not sufficient. Adding measurements for the maturing myeloid and erythroid compartments may increase the diagnostic utility of the Ogata FCSS but requires further study. Disclosures Brodersen: Hematologics Inc.: Employment. Menssen:Hematologics Inc.: Employment. Zehentner:HematoLogics Inc.: Employment, Equity Ownership. Stephenson:Hematologics Inc.: Employment. de Baca:Hematologics Inc.: Employment. Johnson:Hematologics Inc.: Employment. Singleton:Hematologics Inc.: Employment. Hartmann:Hematologics Inc.: Employment. Loken:Hematologics: Employment, Equity Ownership. Wells:HematoLogics Inc.: Employment, Equity Ownership.

Beschreibung: The concept of clonal diversity is becoming well accepted as a hallmark of cancer. As a tumor grows and progresses, the genetic landscape of the cell population can change. These changes are largely due to random errors occurring during each cell division or through mutational events stimulated by various exposures. When one of these random events occurs in the right locus it will result in a survival advantage for all of the subsequent offspring of that initial cell. Understanding the underpinnings of clonal diversity may prove to be an essential part of the treatment plan for patients, helping to guide drug selection and to determine the percentage of clones that may be responsive/resistant to specific treatments. Moreover, many of the therapies used to treat myeloma will likely induce mutations through their mechanisms of action or through unexpected secondary effects. Understanding the effects of individual therapies and specific combinations on the underlying mutation rates that drive the diversity of a tumor population will help to identify regimens that increase the underlying mutation rate and put the patient at an increased risk of developing an aggressive clone. These changes can be identified by next generation sequencing of the bulk tumor population compared to single cell clones that have been selected from that population. In order to identify the diversity of mutations found in the bulk tumor population, we propose that single cell cloning the parent population, and then sequencing and comparing across several individual clones will give a better idea of the random variety of mutations present in individual cells that originate from the same parent population. To identify the diversity present in a random population of myeloma cells we selected the human myeloma cell line KMS-18 as a model system. We sorted single cells from the KMS-18 parent population by FACS with the selection criteria based solely on the viable, single cells. These individually sorted cells expanded over a period of weeks until the population was large enough to be collected for analysis (target approximately 5E6 cells). Four of these single cell clones were selected (SCC_04, SCC_10, SCC_16, SCC_18) for analysis. We prepared whole genome libraries and captured a 3.2Mb region using the Agilent SureSelect Kinome capture kit. The final capture libraries were sequenced on the Illumina MiSeq platform to an average target region depth of 200X. Results were filtered to identify the number of mutations present exclusively in one subclone compared to another. Such events either existed in the original single cell or occurred early in the expansion of the single cell clone. To limit the analysis to events present in the original single cell or very early in the doubling process we identified the variants that were found at a frequency of 〉20%. Many of these events were present in multiple single cell clones that could define the clonal relationship of each original cell, however, 10% of these variants were unique to a single subclone. On average we observed 1.6 mutations per Mb of the target region. If this same mutation rate holds true across the entire genome, we would expect to see over 5000 unique mutations between any two random cells taken from a bulk tumor sample. Studies are currently ongoing to examine clonal diversity between generations of subclones. Further studies are also underway to look at changes in clonal diversity between different myeloma subtypes, with the hypothesis that more aggressive subtypes like t(4;14) and MAF may lead to a more diverse clonal population. If a more diverse clonal population correlates with more aggressive tumor subtype, then this returns full circle to the question of appropriate therapies, and if certain therapies may indeed increase diversity in the tumor population and result in a more aggressive relapse of the disease. Disclosures No relevant conflicts of interest to declare.

Beschreibung: Background: Single nucleotide polymorphism (SNP) and comparative genomic hybridization (CGH) microarray analysis is a powerful tool to assess myelodysplastic bone marrow specimens for the presence of genomic gains and losses as well as loss of heterozygosity (LOH) (reviewed by Nybakken & Bagg, JMD 2014). Its application can be a valuable addition to conventional cytogenetic analysis and may be superior to FISH testing for MDS assessment. Currently, microarray analysis does not have widespread use in an MDS work-up. Several groups have demonstrated that flow cytometric analysis can detect phenotypic aberrations in bone marrow aspirates with cytopenias with more abnormalities identified in patients with poor prognosis or with multiple genotypic abnormalities (Loken et al. 2008; Cutler et al. 2011; van de Loosdrecht et al. 2013). In this study SNP microarray results were compared with conventional cytogenetic and MDS panel FISH findings as well as phenotypic abnormalities detected by flow cytometry. Patients and Methods: 185 bone marrow aspirate specimens submitted to our laboratory for MDS work-up were analyzed by SNP/CGH studies. 36 of these (19.5%) were positive by SNP/CGH microarray analysis. 32 of the positive microarray cases (88.9%) were also analyzed by conventional cytogenetic studies, 35 (97.2%) by MDS FISH panel (5p, 7q, +8, -17p, -20q) and 31 (86.1%) were assessed by multidimensional flow cytometry (FCM) and were assigned an FCSS score (Wells et al. 2003). Results: Of the specimens in which the SNP/CGH array demonstrated genotypic abnormalities, 11/32 (34.4%) were negative by conventional cytogenetic analysis while 12/35 (34.3%) showed no abnormalities by MDS FISH panel analysis. SNP/CGH analysis revealed additional chromosomal gains and losses in 18/32 (56%) in comparison to cytogenetic analysis and in 22/35 (63%) in comparison to FISH analysis. Loss of Heterozygosity regions were detected in 28/36 cases (78%) with 96.4% (27/28) of these being larger than 2 Mb and 53% (19/28) spanning a significant chromosomal region (e.g. 1p, 5q, 7q and 17p) with known oncogenic and other MDS related genes. In 10/32 cases (31%), microarray analysis was able to characterize the origin of marker chromosome material, previously reported with unknown identity by conventional cytogenetic analysis. In an additional subset of 10 out of 32 cases (31%), cytogenetic analysis was able to either characterize balanced translocations or low level sub-clonal abnormalities not identified by microarray analysis alone. In 11/36 (31%) microarray analysis was able to detect clonal heterogeneity and evolution. In none of the specimens did FISH analysis detected abnormalities not revealed by microarray analysis. Flow cytometry performed on 31 of the array positive specimens revealed 6 to have 〉20% abnormal myeloid progenitor cells (classified as AML) while 23 the remaining 25 cases showed phenotypic abnormalities consistent with MDS (FCSS ranging from 1-6). In two specimens with a FCSS of 0, LOH regions on 16q or 1p and 21q were found, respectively, without the presence of numerical aberrations. A FCSS score of 1 with minimal phenotypic abnormalities (n=3), was comprised of one specimen with del(5q), one with LOH of 7q and one with trisomy 8, 1p loss and 1q gain. Specimens with an FCSS of 2 (n=7) showed only one specimen classified as complex (5 or more abnormalities). The two FCSS =3 specimens showed del(5q) with del(12p) and several LOH regions, not complex findings. One of the 4 specimen with FCSS = 4 was classified as complex while the other 3 specimens showed monosomy 7, LOH of 7q or LOH of 1p, respectively. Genotypic abnormalities were also related to phenotypic abnormalities in 4/7 (57%) specimens in the FCSS = 5/6 category which revealed complex microarray findings. Half (3/6) of the AML class had complex findings as well. Conclusions: These results emphasize the additional value that CGH/SNP microarray analysis adds to conventional cytogenetic analysis. Our dataset confirms that FISH studies do not provide additional information for MDS specimens positive by cytogenetic and/or microarray analysis. Most importantly, a high correlation between our phenotypic flow cytometric scoring system for myeloid abnormalities and microarray findings has been identified. Higher flow cytometric abnormality scores correlate with increasing complexity of genomic abnormalities. Disclosures Zehentner: HematoLogics Inc.: Employment, Equity Ownership. Brodersen:Hematologics Inc.: Employment. Stephenson:Hematologics Inc.: Employment. de Baca:Hematologics Inc.: Employment. Menssen:Hematologics Inc.: Employment. Hammock:Hematologics Inc.: Employment. Johnson:Hematologics Inc.: Employment. Hartmann:Hematologics Inc.: Employment. Loken:Hematologics Inc.: Employment, Equity Ownership. Wells:HematoLogics Inc.: Employment, Equity Ownership.