We synthesize estimates of the contemporary net air‐sea CO2 flux on the basis of an inversion of interior ocean carbon observations using a suite of 10 ocean general circulation models (Mikaloff ...Fletcher et al., 2006, 2007) and compare them to estimates based on a new climatology of the air‐sea difference of the partial pressure of CO2 (pCO2) (Takahashi et al., 2008). These two independent flux estimates reveal a consistent description of the regional distribution of annual mean sources and sinks of atmospheric CO2 for the decade of the 1990s and the early 2000s with differences at the regional level of generally less than 0.1 Pg C a−1. This distribution is characterized by outgassing in the tropics, uptake in midlatitudes, and comparatively small fluxes in thehigh latitudes. Both estimates point toward a small (∼ −0.3 Pg C a−1) contemporary CO2 sink in the Southern Ocean (south of 44°S), a result of the near cancellation between a substantial outgassing of natural CO2 and a strong uptake of anthropogenic CO2. A notable exception in the generally good agreement between the two estimates exists within the Southern Ocean: the ocean inversion suggests a relatively uniform uptake, while the pCO2‐based estimate suggests strong uptake in the region between 58°S and 44°S, and a source in the region south of 58°S. Globally and for a nominal period between 1995 and 2000, the contemporary net air‐sea flux of CO2 is estimated to be −1.7 ± 0.4 Pg C a−1 (inversion) and −1.4 ± 0.7 Pg C a−1 (pCO2‐climatology), respectively, consisting of an outgassing flux of river‐derived carbon of ∼+0.5 Pg C a−1, and an uptake flux of anthropogenic carbon of −2.2 ± 0.3 Pg C a−1 (inversion) and −1.9 ± 0.7 Pg C a−1 (pCO2‐climatology). The two flux estimates also imply a consistent description of the contemporary meridional transport of carbon with southward ocean transport throughout most of the Atlantic basin, and strong equatorward convergence in the Indo‐Pacific basins. Both transport estimates suggest a small hemispheric asymmetry with a southward transport of between −0.2 and −0.3 Pg C a−1 across the equator. While the convergence of these two independent estimates is encouraging and suggests that it is now possible to provide relatively tight constraints for the net air‐sea CO2 fluxes at the regional basis, both studies are limited by their lack of consideration of long‐term changes in the ocean carbon cycle, such as the recent possible stalling in the expected growth of the Southern Ocean carbon sink.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The last 6000
years are of particular interest to the understanding of the Earth System because the boundary conditions of the climate system did not change dramatically (in comparison to larger ...glacial–interglacial changes), and because abundant, detailed regional palaeoclimatic proxy records cover this period. We use selected proxy-based reconstructions of different climate variables, together with state-of-the-art time series of natural forcings (orbital variations, solar activity variations, large tropical volcanic eruptions, land cover and greenhouse gases), underpinned by results from General Circulation Models (GCMs) and Earth System Models of Intermediate Complexity (EMICs), to establish a comprehensive explanatory framework for climate changes from the Mid-Holocene (MH) to pre-industrial time. The redistribution of solar energy, due to orbital forcing on a millennial timescale, was the cause of a progressive southward shift of the Northern Hemisphere (NH) summer position of the Intertropical Convergence Zone (ITCZ). This was accompanied by a pronounced weakening of the monsoon systems in Africa and Asia and increasing dryness and desertification on both continents. The associated summertime cooling of the NH, combined with changing temperature gradients in the world oceans, likely led to an increasing amplitude of the El Niño Southern Oscillation (ENSO) and, possibly, increasingly negative North Atlantic Oscillation (NAO) indices up to the beginning of the last millennium. On decadal to multi-century timescales, a worldwide coincidence between solar irradiance minima, tropical volcanic eruptions and decadal to multi-century scale cooling events was not found. However, reconstructions show that widespread decadal to multi-century scale cooling events, accompanied by advances of mountain glaciers, occurred in the NH (e.g., in Scandinavia and the European Alps). This occurred namely during the Little Ice Age (LIA) between AD ∼1350 and 1850, when the lower summer insolation in the NH, due to orbital forcing, coincided with solar activity minima and several strong tropical volcanic eruptions. The role of orbital forcing in the NH cooling, the southward ITCZ shift and the desertification of the Sahara are supported by numerous model simulations. Other simulations have suggested that the fingerprint of solar activity variations should be strongest in the tropics, but there is also evidence that changes in the ocean heat transport took place during the LIA at high northern latitudes, with possible additional implications for climates of the Southern Hemisphere (SH).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Endocrine treatment is the most preferable systemic treatment in metastatic breast cancer patients that have had an estrogen receptor (ER) positive primary tumor or metastatic lesions, however, ...approximately 20% of these patients do not benefit from the therapy and demonstrate further metastatic progress. One reason for failure of endocrine therapy might be the heterogeneity of ER expression in tumor cells spreading from the primary tumor to distant sites which is reflected in detectable circulating tumor cells (CTCs).
A sensitive and specific staining protocol for ER, keratin 8/18/19, CD45 was established. Peripheral blood from 35 metastatic breast cancer patients with ER-positive primary tumors was tested for the presence of CTCs. Keratin 8/18/19 and DAPI positive but CD45 negative cells were classified as CTCs and evaluated for ER staining. Subsequently, eight individual CTCs from four index patients (2 CTCs per patient) were isolated and underwent whole genome amplification and ESR1 gene mutation analysis.
CTCs were detected in blood of 16 from 35 analyzed patients (46%), with a median of 3 CTCs/7.5 ml. In total, ER-negative CTCs were detected in 11/16 (69%) of the CTC positive cases, including blood samples with only ER-negative CTCs (19%) and samples with both ER-positive and ER-negative CTCs (50%). No correlation was found between the intensity and/or percentage of ER staining in the primary tumor with the number and ER status of CTCs of the same patient. ESR1 gene mutations were not found.
CTCs frequently lack ER expression in metastatic breast cancer patients with ER-positive primary tumors and show a considerable intra-patient heterogeneity, which may reflect a mechanism to escape endocrine therapy. Provided single cell analysis did not support a role of ESR1 mutations in this process.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Water mass ventilation provides an important link between the atmosphere and the global ocean circulation. In this study, we present a newly developed, probabilistic tool for offline water mass ...tracking. In particular, NEMOTAM, the tangent-linear and adjoint counterpart to the NEMO ocean general circulation model, is modified to allow passive-tracer transport. By terminating dynamic feedbacks in NEMOTAM, tagged water can be tracked forward and backward in time as a passive dye, producing a probability distribution of pathways and origins, respectively. To represent surface (re-)ventilation, we optionally decrease the tracer concentration in the surface layer and track this concentration removal to produce a ventilation record. Two test cases are detailed, examining the creation and fate of North Atlantic Subtropical Mode Water (NASMW) and North Atlantic Deep Water (NADW) in a 2∘ configuration of NEMO run with repeated annual forcing for up to 400 years. Model NASMW is shown to have an expected age of 4.5 years and is predominantly eradicated by internal processes. A bed of more persistent NASMW is detected below the mixed layer with an expected age of 8.7 years. It is shown that while model NADW has two distinct outcrops (in the Arctic and North Atlantic), its formation primarily takes place in the subpolar Labrador and Irminger seas. Its expected age is 112 years.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Owing to late diagnosis in advanced disease stages, prognosis of patients with epithelial ovarian cancer (EOC) is poor. The quantification of deregulated levels of microRNAs could facilitate earlier ...diagnosis and improve prognosis of EOC.
Seven microRNAs (miR-7, miR-16, miR-25, miR-93, miR-182, miR-376a and miR-429) were quantified in the serum of 180 EOC patients and 66 healthy women by TaqMan PCR microRNA assays. Median follow-up time was 21 months. The effects of miR-7 and miR-429 on apoptosis, cell proliferation, migration and invasion were investigated in two (EOC) cell lines.
Serum levels of miR-25 (P=0.0001) and miR-93 (P=0.0001) were downregulated, whereas those of miR-7 (P=0.001) and miR-429 (P=0.0001) were upregulated in EOC patients compared with healthy women. The four microRNAs discriminated EOC patients from healthy women with a sensitivity of 93% and a specificity of 92%. The levels of miR-429 positively correlated with CA125 values (P=0.0001) and differed between FIGO I-II and III-IV stages (P=0.001). MiR-429 was an independent predictor of overall survival (P=0.011). Overexpressed miR-429 in SKOV3 cells led to suppression of cell migration (P=0.037) and invasion (P=0.011). Increased levels of miR-7 were associated with lymph node metastases (P=0.0001) and FIGO stages III-IV (P=0.0001). Overexpressed miR-7 in SKOV3 cells resulted in increased cell migration (P=0.001) and invasion (P=0.011). Additionally, the increased levels of miR-376a correlated with FIGO stages III-IV (P=0.02).
Our data indicate the diagnostic potential of miR-7, miR-25, miR-93 and miR-429 in EOC and the prognostic potential of miR-429. This microRNA panel may be promising molecules to be targeted in the treatment of EOC.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In polymer nanocomposites, mechanical properties essentially depend on the alignment of nanoparticles and polymers. In this work, we investigate an entangled polymer melt in a confinement ...computationally, in order to get an insight into the mobility behavior of the polymer chains. The confinement consists of nanotubes, arranged in a hexagonal array. We use dissipative particle dynamics, a fast, soft-core simulation method, and reintroduce entanglement dynamics via slip-springs. We observe a distinct influence of the confinement as diffusion is increased in the direction parallel to the nanotubes. Furthermore, we observe that an orientation of the polymers parallel to the nanotubes and chains are compressed in the direction orthogonal to their primitive path. The diffusion parallel to the nanotubes increases further as we increase the nanotube volume fraction in our systems. Moreover, we investigate the slip-spring distribution in the proximity of the nanotube surfaces of our fast and simple slip-spring model, which we find to coincide with results reported for more sophisticated and expensive methods. Our DPD model shows potential applicability to a wide range of polymer nanocomposites while preserving reptation behavior, which is typically lost due to the use of soft-core models.
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IJS, KILJ, NUK, PNG, UL, UM
Circulating tumor cells (CTC) might function as early markers for breast cancer metastasis or monitoring therapy efficacy. Enrichment and identification of CTCs are based on epithelial markers that ...might be modulated during epithelial-mesenchymal transition. Little is known about the expression of keratins in CTCs and whether all CTCs can be detected with antibodies directed against a limited panel of keratins.
Protein expression of keratin 2, 4-10, 13-16, 18, and 19 were assessed by a cocktail of antibodies (C11, AE1, AE3, and K7) and keratin antibodies C11 and A45-B/B3 alone in 11 breast cancer cell lines and 50 primary breast carcinomas and their lymph node metastases. Furthermore, CTCs were assessed in blood of 70 metastatic breast cancer patients.
Claudin-low cell lines did not show expression of normal breast epithelial keratins but were positive for K14 and K16, detected by the cocktail only. Primary breast carcinomas showed changes in keratin expression during metastatic progression to the lymph nodes. In 35 of 70 patients CTCs were identified, of which 83%, 40%, and 57% were identified by the cocktail, C11 and A45-B/B3, respectively. Identification of CTCs by the cocktail was associated with shorter survival (P < 0.01). In silico analyses revealed association between KRT16 expression and shorter relapse-free survival in metastatic breast cancer.
Breast cancer cells show a complex pattern of keratin expression with potential biologic relevance. Individual keratin antibodies recognizing only a limited set of keratins inherit the risk to miss biologically relevant CTCs in cancer patients, and antibody cocktails including these keratins are therefore recommended.
The incidence of brain metastases in breast cancer (BCBM) patients is increasing. These patients have a very poor prognosis, and therefore, identification of blood-based biomarkers, such as ...circulating tumor cells (CTCs), and understanding the genomic heterogeneity could help to personalize treatment options.
Both EpCAM-dependent (CellSearch® System) and EpCAM-independent Ficoll-based density centrifugation methods were used to detect CTCs from 57 BCBM patients. DNA from individual CTCs and corresponding primary tumors and brain metastases were analyzed by next-generation sequencing (NGS) in order to evaluate copy number aberrations and single nucleotide variations (SNVs).
CTCs were detected after EpCAM-dependent enrichment in 47.7% of the patients (≥ 5 CTCs/7.5 ml blood in 20.5%). The CTC count was associated with ERBB2 status (p = 0.029) of the primary tumor as well as with the prevalence of bone metastases (p = 0.021). EpCAM-independent enrichment revealed CTCs in 32.6% of the patients, especially among triple-negative breast cancer (TNBC) patients (70.0%). A positive CTC status after enrichment of either method was significantly associated with decreased overall survival time (p < 0.05). Combining the results of both enrichment methods, 63.6% of the patients were classified as CTC positive. In three patients, the matched tumor tissue and single CTCs were analyzed by NGS showing chromosomal aberrations with a high genomic clonality and mutations in pathways potentially important in brain metastasis formation.
The detection of CTCs, regardless of the enrichment method, is of prognostic relevance in BCBM patients and in combination with molecular analysis of CTCs can help defining patients with higher risk of early relapse and suitability for targeted treatment.
Up to 40% of advance lung, melanoma and breast cancer patients suffer from brain metastases (BM) with increasing incidence. Here, we assessed whether circulating tumor cells (CTCs) in peripheral ...blood can serve as a disease surrogate, focusing on CD44 and CD74 expression as prognostic markers for BM. We show that a size-based microfluidic approach in combination with a semi-automated cell recognition system are well suited for CTC detection in BM patients and allow further characterization of tumor cells potentially derived from BM. CTCs were found in 50% (7/14) of breast cancer, 50% (9/18) of non-small cell lung cancer (NSCLC) and 36% (4/11) of melanoma patients. The next-generation sequencing (NGS) analysis of nine single CTCs from one breast cancer patient revealed three different CNV profile groups as well as a resistance causing ERS1 mutation. CD44 and CD74 were expressed on most CTCs and their expression was strongly correlated, whereas matched breast cancer BM tissues were much less frequently expressing CD44 and CD74 (negative in 46% and 54%, respectively). Thus, plasticity of CD44 and CD74 expression during trafficking of CTCs in the circulation might be the result of adaptation strategies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Identification of the causes of past climate change requires detailed knowledge of one of the most important natural factors—solar forcing. Prior to the period of direct solar observations, ...radionuclide abundances in natural archives provide the best-known proxies for changes in solar activity. Here we present two independent reconstructions of changes in solar activity during the last 1000
yr, which are inferred from
10Be and
14C records. We analyse the tree-ring
14C data (SHCal, IntCal04 from 1000 to 1510 AD and annual data from 1511 to 1950 AD) and four
10Be records from Greenland ice cores (Camp Century, GRIP, Milcent and Dye3) together with two
10Be records from Antarctic ice cores (Dome Concordia and South Pole). In general, the
10Be and
14C records exhibit good agreement that allows us to obtain reliable estimates of past solar magnetic modulation of the radionuclide production rates. Differences between
10Be records from Antarctica and Greenland indicate that climatic changes have influenced the deposition of
10Be during some periods of the last 1000
yr. The radionuclide-based reconstructions of past changes in solar activity do not always agree with the sunspot record, which indicates that the coupling between those proxies is not as close as has been sometimes assumed. The tree-ring
14C record and
10Be from Antarctica indicate that recent solar activity is high but not exceptional with respect to the last 1000
yr.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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