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Permafrost is a key element of the cryosphere and an essential climate variable in the Global Climate Observing System. There is no remote-sensing method available to reliably monitor the permafrost thermal state. To estimate permafrost distribution at a hemispheric scale, we employ an equilibrium state model for the temperature at the top of the permafrost (TTOP model) for the 2000–2016 period, driven by remotely- sensed land surface temperatures, down-scaled ERA-Interim climate reanalysis data, tundra wetness classes and landcover map from the ESA Landcover Climate Change Initiative (CCI) project. Subgrid variability of ground temperatures due to snow and landcover variability is represented in the model using subpixel statistics. The results are validated against borehole measurements and reviewed regionally. The accuracy of the modelled mean annual ground temperature (MAGT) at the top of the permafrost is ±2 °C when compared to permafrost borehole data. The modelled permafrost area (MAGT 0) is around 21 × 106 km2 (22% of exposed land area), which is approximately 2 × 106 km2 less than estimated previously. Detailed comparisons at a regional scale show that the model performs well in sparsely vegetated tundra regions and mountains, but is less accurate in densely vegetated boreal spruce and larch forests.

Recently, FGFR1 was found to be overexpressed in osteosarcoma and represents an important target for precision medicine. However, because targeted cancer therapy based on FGFR inhibitors has so far been less efficient than expected, a detailed understanding of the target is important. We have here applied proximity-dependent biotin labeling combined with label-free quantitative mass spectrometry to identify determinants of FGFR1 activity in an osteosarcoma cell line. Many known FGFR interactors were identified (e.g. FRS2, PLCG1, RSK2, SRC), but the data also suggested novel determinants. A strong hit in our screen was the tyrosine phosphatase PTPRG. We show that PTPRG and FGFR1 interact and colocalize at the plasma membrane where PTPRG directly dephosphorylates activated FGFR1. We further show that osteosarcoma cell lines depleted for PTPRG display increased FGFR activity and are hypersensitive to stimulation by FGF1. In addition, PTPRG depletion elevated cell growth and negatively affected the efficacy of FGFR kinase inhibitors. Thus, PTPRG may have future clinical relevance by being a predictor of outcome after FGFR inhibitor treatment.

Summary Clathrin-coated vesicles form by rapid assembly of discrete coat constituents into a cargo-sorting lattice. How the sequential phases of coat construction are choreographed is unclear, but transient protein-protein interactions mediated by short interaction motifs are pivotal. We show that arrayed Asp-Pro-Phe (DPF) motifs within the early-arriving endocytic pioneers Eps15/R are differentially decoded by other endocytic pioneers Fcho1/2 and AP-2. The structure of an Eps15/R⋅Fcho1 μ-homology domain complex reveals a spacing-dependent DPF triad, bound in a mechanistically distinct way from the mode of single DPF binding to AP-2. Using cells lacking FCHO1/2 and with Eps15 sequestered from the plasma membrane, we establish that without these two endocytic pioneers, AP-2 assemblies are fleeting and endocytosis stalls. Thus, distinct DPF-based codes within the unstructured Eps15/R C terminus direct the assembly of temporary Fcho1/2⋅Eps15/R⋅AP-2 ternary complexes to facilitate conformational activation of AP-2 by the Fcho1/2 interdomain linker to promote AP-2 cargo engagement., Graphical Abstract, Highlights • The endocytic pioneer protein Eps15 engages AP-2 and Fcho1/2 noncompetitively • Structural analysis shows arrayed DPF motif triad in Eps15 for Fcho1/2 μHD binding • DPF-based codes direct transient Fcho1/2⋅Eps15/R⋅AP-2 ternary complex formation • In ternary complex, Fcho1 interdomain linker primes AP-2 for cargo capture, How clathrin-coated vesicles initiate at the plasma membrane is uncertain. Ma et al. show through structural and biochemical analyses that a three-way interaction between early-arriving endocytic factors Eps15/R and Fcho1/2, and the adaptor AP-2, promotes membrane deposition of AP-2 in open conformation for sustained clathrin-coat assembly and cargo loading.

Empirical–statistical methods were used to model mountain permafrost probability above and below treeline for five areas distributed across the southern half of the Yukon (60°–64°N). The modeling addressed a key issue by incorporating the effects of inverted or weak surface lapse rates below treeline, as well as the interfingering of lowland and mountain permafrost in the region. The variables used to predict the Basal Temperature of Snow (BTS) by linear regression included equivalent elevation, Potential Incoming Solar Radiation (PISR), slope and Normalized Difference Vegetation Index (NDVI). Topographic Position Index (TPI) was also examined as an explanatory variable but was not statistically significant in any of the areas. Predicted BTS temperatures were compared using logistic regression to late-summer physical verification of permafrost presence or absence. The resulting models indicate that permafrost underlies 19–24% of the Johnson's Crossing area, 30% of the Sa Dena Hes area, 63% of the Faro and Dawson study areas and 79% of the Keno area. In the most northerly study locations where surface lapse rates are inverted, predictions include high permafrost probabilities within valleys, and decreasing probabilities up to treeline. The methods should be transferable to other areas where they could be used as a tool for infrastructure route planning.

Fibroblast growth factor 1 (FGF1) has the property to become translocated from the extracellular space into the cell cytosol and nucleus. Membrane translocation of FGF1 occurs subsequent to endocytic uptake and is strictly FGF-receptor (FGFR) dependent. Here we have investigated the timing of FGF1 translocation in relation to FGFR1 signalling. We found that the translocation of FGF1 is a periodic event that occurs with 24h intervals. Serum-starved cells translocated the growth factor with peak occurrences ~6 h, ~30 h, and ~54 h after the addition of FGF1. The periodic FGF1 translocation was totally independent of the FGFR1 tyrosine kinase activity as it proceeded unchanged when the kinase activity was chemically inhibited or the kinase domain was deleted. Furthermore, FGF1 translocation was not restricted to a particular phase of the cell cycle or dependent on cell cycle progression. The results demonstrate that the FGF1/FGFR1 complex constitutes a signalling module that independently of the receptor tyrosine kinase can convey a signal that initiates a strictly timed and periodic release of endocytosed FGF1 into the cytosol/nucleus.

This study describes the origin and age of a body of massive ground ice exposed in the headwall of a thaw slump in the Red Creek valley, central Yukon, Canada. The site is located beyond the limits of Pleistocene glaciation in central Yukon and within the southern limit of the modern continuous permafrost zone. The origin of the massive ground ice, which is preserved under a fine-grained diamicton containing thin layers of tephra, was determined through ice petrography, stable O-H isotope composition of the ice, and gas composition of occluded air entrapped in the ice. The age of the massive ground ice was established by identifying the overlying tephra and radiocarbon dating of a ‘‘muck’’ deposit preserved within the ice. Collectively, the results indicate that the massive ground ice formed by snow densification with limited melting-refreezing and is interpreted as being a buried perennial snowbank. The muck deposit within the ice, which yielded an age of 30,720 � 340 14 C a BP, and the Dawson tephra (25,300 14 C a BP) overlying the perennial snowbank, indicates that the snowbank accumulated at roughly the transition between marine isotope stages 3 and 2. Dry climatic conditions at this time and possibly high winds enabled the snowbank to accumulate in the absence of extensive local valley glaciation as occurred in the mountains to the south. In addition to documenting the persistence of relict permafrost and ground ice to warming climate in regions where they are predicted to disappear by numerical models, this study presents evidence of an isotopic biosignature preserved in a body of massive ground ice.

Humus horizons associated with thirteen solifluction lobes on a single slope were radiocarbon dated at fixed distances behind the risers, as well as ahead of the lobes. The dated horizons, together with stratigraphic observations of planar discontinuities inside the lobes and shallow burial of vegetation ahead of the lobes, all suggest rapid advance of lobe fronts. We infer that lobe advance at this site results from slow accumulation of soliflucted material behind a relatively rigid riser, progressive steepening of the riser and build-up of stress, and finally rupture of the front and its collapse onto the slope. Rebuilding of the lobe usually then takes place. The time for a full cycle of development is estimated to be in the order of a few hundred years. Long-term frontal movement appears inversely related to lobe size, and is mainly controlled by soil moisture and sediment characteristics. These findings call into question the usefulness of solifluction lobe advance rates for paleoclimate reconstructions, at least at this site.

Fifty active-layer detachment failures triggered after forest fire in the discontinuous permafrost zone (central Mackenzie Valley, 65° N.) are compared to several hundred others caused by summer meteorological triggers in continuous permafrost (Fosheim Peninsula, Ellesmere Island, 80°N). Most failures fall into compact or elongated morphological categories. The compact type occur next to stream channels and have little internal disturbance of the displaced block, whereas the elongated types can develop on any part of the slope and exhibit greater internal deformation. Frequency distributions of length-to-width and length-to-depth ratios are similar at all sites. Positive pore pressures, expected theoretically, were measured in the field at the base of the thawing layer. Effective stress analysis could predict the instability of slopes in both areas, providing cohesion across the thaw plane was set to zero and/or residual strength parameters were employed. The location of the shear planes or zones in relation to the permafrost table and the degree of post-failure secondary movements (including headwall recession and thermokarst development within the failure track) differed between the localities, reflecting dissimilarity in the environmental triggers and in the degree of ground thermal disturbance.

Surface wash erosion was measured at runoff plots on low to moderate slopes in clayey and sandy silts underlain by continuous permafrost on the Fosheim Peninsula, Ellesmere Island. Due to snow redistribution in winter, total precipitation on the plots varied from 34 to 150 mm, with corresponding surface runoff values of 0 to 102 mm. Where runoff occurred, at least 80% of it was derived from snowmelt. Suspended sediment removal was Plot data (precipitation, vegetation and surface grain-size) from the Fosheim Peninsula and Banks Island were used to develop a statistical model of suspended sediment removal by surface wash on undisturbed slopes. For any given grain-size, the model predicts a rise in erosion from zero precipitation (because of an absence of runoff) to a peak at about 50 mm, a decline as precipitation increases to 300 mm and a further increase in erosion beyond this inflection point. This non-linear response is due to the complex interaction of moisture (primarily snow) and vegetation cover. Erosion at any given precipitation value varies through three orders of magnitude depending on surface grain-size. The maximum erosion predicted is 1 kg m−2 a−1 for a runoff plot with 1100 mm of precipitation, a corresponding vegetation cover of 77% and a median surface grain-size of 7 φ.

FGF-1 stimulated DNA synthesis and induced expression of IL-2 receptors in the murine fibrosarcoma cell line, F69-3. Concomitant treatment with IL-2 abolished the stimulation of DNA synthesis, but not binding of FGF-1 to the FGF-receptors or subsequent endocytosis of the bound growth factor. Also, it did not inhibit activation of the FGF-receptor tyrosine kinase or stimulation of the downstream effector, MAP kinase. Treatment with IL-2 prevented transport of FGF-1 to the nuclear fraction in a time- and dose-dependent manner that parallelled the inhibition of FGF-1 stimulated DNA synthesis. The data support our earlier finding that transport of FGF-1 to the nucleus is an important event in the mechanism of stimulation of DNA synthesis induced by the growth factor, and they demonstrate that treatment with a cytokine can modulate the cellular response to FGF-1.

In a previous study, we have isolated and characterized cDNA encoding a novel `short form' of heparin-binding EGF-like growth factor (SF HB-EGF) ( Loukianov et al., 1997 ). In the present work, we have found that cDNA for SF HB-EGF and for full-length HB-EGF are each represented by two variants, which we refer to as L and P forms. The L form is the previously known form of HB-EGF cDNA and encodes a leucine in position 33. The P form described in this report, encodes a proline in codon 33. The L33P substitution is predicted to cause a significant alteration in the proregion structure of SF HB-EGF and HB-EGF.

Producción Científica, Acidic fibroblast growth factor (aFGF) is a potent mitogen. It acts through activation of specific cell surface receptors leading to intracellular tyrosine phosphorylation cascades, but several reports also indicate that aFGF enters cells and that it has an intracellular function as well. The aFGF(K132E) mutant binds to and activates fibroblast growth factor receptors equally strongly as the wild-type, but it is a poor mitogen. We demonstrate that aFGF(K132E) enters NIH 3T3 cells and is transported to the nuclear fraction like wild-type aFGF. A fusion protein of aFGF(K132E) and diphtheria toxin A-fragment (aFGF(K132E)-DT-A) and a similar fusion protein containing wild-type aFGF (aFGF-DT-A) were reconstituted with diphtheria toxin B-fragment. Both fusion proteins were translocated to the cytosol by the diphtheria toxin pathway and subsequently recovered from the nuclear fraction. Whereas translocation of aFGF-DT-A stimulated DNA synthesis in U2OSDR1 cells lacking functional fibroblast growth factor receptors, aFGF(K132E)-DT-A did not. The mutation disrupts a protein kinase C phosphorylation site in the growth factor making it unable to be phosphorylated. The data indicate that a defect in the intracellular action of aFGF(K132E) is the reason for its strongly reduced mitogenicity, possibly due to inability to be phosphorylated.

Acidic fibroblast growth factor (aFGF), fused to diphtheria toxin and translocated into cells, stimulated DNA synthesis in toxin-resistant cells lacking functional aFGF receptors while having a high number of diphtheria toxin receptors. In NIH 3T3 cells that lack diphtheria toxin receptors, but have receptors for aFGF, both aFGF and the fusion protein induced tyrosine phosphorylation, but only aFGF as such entered the nuclei and stimulated DNA synthesis. The results indicate that signaling occurs partly through cell surface receptors and partly by transport of the growth factor into the cell.

Active diphtheria toxin consists of two parts, fragments A and B. Fragment A has enzymatic activity and inhibits protein synthesis. Fragment B binds to cellular receptors, and upon exposure to low pH it inserts into the membrane and facilitates translocation of the A fragment into the cytosol, concomitantly with formation of cation-selective channels. Reduction of the interfragment disulfide bridge is required for release of fragment A and intoxication. In cells treated with N-ethylmaleimide (NEM), which inhibits reduction of the disulfide bridge, fragment A was translocated to the cytosol but not released from fragment B. In the presence of NEM a peptide larger than fragment A was protected against extracellularly added Pronase. This peptide (M(r) approximately 24,000) was released to the supernatant fraction of saponin-treated cells. This indicates that fragment A, which is 21 kDa, is covalently attached via a disulfide bond to an N-terminal (M(r) approximately 3,000) piece of fragment B. The 24-kDa fragment disappeared upon reduction, and the 21-kDa fragment A appeared instead. NEM did not prevent channel activity by fragment B in the context of full-length toxin, demonstrating that channel formation occurs in spite of inhibited reduction of the disulfide bond. Thus, channel formation is not dependent on release of fragment A from the toxin-receptor complex.

Summary Using a preembedding electron microscopic technique, the binding and internalization of gold labelled mistletoe lectin I ( MLI · Au ), its 2 A subunits ( MLI-A · Au ) and of the B subunit ( MLI-B · Au ) in murine L 1210V leukemia cells was analysed. Furthermore, the endocytosis of a gold marked immunotoxin ( MoAb-16-MLI-A · Au ), consisting of a monoclonal antibody ( MoAb-16 ) reacting with L 1210V cells and the cytotoxic A subunits ( MLI-A ) was detected. The cells were incubated with MLI · Au, MLI-A · Au, MLI-B · Au, or MoAb-16-MLI-A · Au at 37°C for 1, 3, 5, 10, 20 or 30 min, respectively. Remarkable differences were found in the endocytotic pathway and internalization kinetics. The endocytosis of MLI, its subunits and of the immunotoxin has been compared to that of other ligands in various systems.