Rab proteins and Rab-associated proteins: major actors in the mechanism of protein-trafficking disorders

Ras-associated binding (Rab) proteins and Rab-associated proteins are key regulators of vesicle transport, which is essential for the delivery of proteins to specific intracellular locations. More than 60 human Rab proteins have been identified, and their function has been shown to depend on their interaction with different Rab-associated proteins regulating Rab activation, post-translational modification and intracellular localization. The number of known inherited disorders of vesicle trafficking due to Rab cycle defects has increased substantially during the past decade. This review describes the important role played by Rab proteins in a number of rare monogenic diseases as well as common multifactorial human ones. Although the clinical phenotype in these monogenic inherited diseases is highly variable and dependent on the type of tissue in which the defective Rab or its associated protein is expressed, frequent features are hypopigmentation (Griscelli syndrome), eye defects (Choroideremia, Warburg Micro syndrome and Martsolf syndrome), disturbed immune function (Griscelli syndrome and Charcot–Marie–Tooth disease) and neurological dysfunction (X-linked non-specific mental retardation, Charcot–Marie–Tooth disease, Warburg Micro syndrome and Martsolf syndrome). There is also evidence that alterations in Rab function play an important role in the progression of multifactorial human diseases, such as infectious diseases and type 2 diabetes. Rab proteins must not only be bound to GTP, but they need also to be ‘prenylated’—i.e. bound to the cell membranes by isoprenes, which are intermediaries in the synthesis of cholesterol (e.g. geranyl geranyl or farnesyl compounds). This means that isoprenylation can be influenced by drugs such as statins, which inhibit isoprenylation, or biphosphonates, which inhibit that farnesyl pyrophosphate synthase necessary for Rab GTPase activity. Conclusion: Although protein-trafficking disorders are clinically heterogeneous and represented in almost every subspeciality of pediatrics, the identification of common pathogenic mechanisms may provide a better diagnosis and management of patients with still unknown Rab cycle defects and stimulate the development of therapeutic agents

Potential climatic transitions with profound impact on Europe

We discuss potential transitions of six climatic subsystems with large-scale impact on Europe, sometimes denoted as tipping elements. These are the ice sheets on Greenland and West Antarctica, the Atlantic thermohaline circulation, Arctic sea ice, Alpine glaciers and northern hemisphere stratospheric ozone. Each system is represented by co-authors actively publishing in the corresponding field. For each subsystem we summarize the mechanism of a potential transition in a warmer climate along with its impact on Europe and assess the likelihood for such a transition based on published scientific literature. As a summary, the ‘tipping’ potential for each system is provided as a function of global mean temperature increase which required some subjective interpretation of scientific facts by the authors and should be considered as a snapshot of our current understanding. <br/

An integrated 1D–2D hydraulic modelling approach to assess the sensitivity of a coastal region to compound flooding hazard under climate change

Coastal regions are dynamic areas that often lie at the junction of different natural hazards. Extreme events such as storm surges and high precipitation are significant sources of concern for flood management. As climatic changes and sea-level rise put further pressure on these vulnerable systems, there is a need for a better understanding of the implications of compounding hazards. Recent computational advances in hydraulic modelling offer new opportunities to support decision-making and adaptation. Our research makes use of recently released features in the HEC-RAS version 5.0 software to develop an integrated 1D–2D hydrodynamic model. Using extreme value analysis with the Peaks-Over-Threshold method to define extreme scenarios, the model was applied to the eastern coast of the UK. The sensitivity of the protected wetland known as the Broads to a combination of fluvial, tidal and coastal sources of flooding was assessed, accounting for different rates of twenty-first century sea-level rise up to the year 2100. The 1D–2D approach led to a more detailed representation of inundation in coastal urban areas, while allowing for interactions with more fluvially dominated inland areas to be captured. While flooding was primarily driven by increased sea levels, combined events exacerbated flooded area by 5–40% and average depth by 10–32%, affecting different locations depending on the scenario. The results emphasise the importance of catchment-scale strategies that account for potentially interacting sources of flooding

Evidence of marine ice-cliff instability in Pine Island Bay from iceberg-keel plough marks.

Marine ice-cliff instability (MICI) processes could accelerate future retreat of the Antarctic Ice Sheet if ice shelves that buttress grounding lines more than 800 metres below sea level are lost. The present-day grounding zones of the Pine Island and Thwaites glaciers in West Antarctica need to retreat only short distances before they reach extensive retrograde slopes. When grounding zones of glaciers retreat onto such slopes, theoretical considerations and modelling results indicate that the retreat becomes unstable (marine ice-sheet instability) and thus accelerates. It is thought that MICI is triggered when this retreat produces ice cliffs above the water line with heights approaching about 90 metres. However, observational evidence confirming the action of MICI has not previously been reported. Here we present observational evidence that rapid deglacial ice-sheet retreat into Pine Island Bay proceeded in a similar manner to that simulated in a recent modelling study, driven by MICI. Iceberg-keel plough marks on the sea-floor provide geological evidence of past and present iceberg morphology, keel depth and drift direction. From the planform shape and cross-sectional morphologies of iceberg-keel plough marks, we find that iceberg calving during the most recent deglaciation was not characterized by small numbers of large, tabular icebergs as is observed today, which would produce wide, flat-based plough marks or toothcomb-like multi-keeled plough marks. Instead, it was characterized by large numbers of smaller icebergs with V-shaped keels. Geological evidence of the form and water-depth distribution of the plough marks indicates calving-margin thicknesses equivalent to the threshold that is predicted to trigger ice-cliff structural collapse as a result of MICI. We infer rapid and sustained ice-sheet retreat driven by MICI, commencing around 12,300 years ago and terminating before about 11,200 years ago, which produced large numbers of icebergs smaller than the typical tabular icebergs produced today. Our findings demonstrate the effective operation of MICI in the past, and highlight its potential contribution to accelerated future retreat of the Antarctic Ice Sheet

Quantification and analysis of icebergs in a tidewater glacier fjord using an object-based approach

Tidewater glaciers are glaciers that terminate in, and calve icebergs into, the ocean. In addition to the influence that tidewater glaciers have on physical and chemical oceanography, floating icebergs serve as habitat for marine animals such as harbor seals (Phoca vitulina richardii). The availability and spatial distribution of glacier ice in the fjords is likely a key environmental variable that influences the abundance and distribution of selected marine mammals; however, the amount of ice and the fine-scale characteristics of ice in fjords have not been systematically quantified. Given the predicted changes in glacier habitat, there is a need for the development of methods that could be broadly applied to quantify changes in available ice habitat in tidewater glacier fjords. We present a case study to describe a novel method that uses object-based image analysis (OBIA) to classify floating glacier ice in a tidewater glacier fjord from high-resolution aerial digital imagery. Our objectives were to (i) develop workflows and rule sets to classify high spatial resolution airborne imagery of floating glacier ice; (ii) quantify the amount and fine-scale characteristics of floating glacier ice; (iii) and develop processes for automating the object-based analysis of floating glacier ice for large number of images from a representative survey day during June 2007 in Johns Hopkins Inlet (JHI), a tidewater glacier fjord in Glacier Bay National Park, southeastern Alaska. On 18 June 2007, JHI was comprised of brash ice ([Formula: see text] = 45.2%, SD = 41.5%), water ([Formula: see text] = 52.7%, SD = 42.3%), and icebergs ([Formula: see text] = 2.1%, SD = 1.4%). Average iceberg size per scene was 5.7 m2 (SD = 2.6 m2). We estimate the total area (± uncertainty) of iceberg habitat in the fjord to be 455,400 ± 123,000 m2. The method works well for classifying icebergs across scenes (classification accuracy of 75.6%); the largest classification errors occur in areas with densely-packed ice, low contrast between neighboring ice cover, or dark or sediment-covered ice, where icebergs may be misclassified as brash ice about 20% of the time. OBIA is a powerful image classification tool, and the method we present could be adapted and applied to other ice habitats, such as sea ice, to assess changes in ice characteristics and availability

Ice-sheet collapse and sea-level rise at the Bølling warming 14,600 years ago

Past sea-level records provide invaluable information about the response of ice sheets to climate forcing. Some such records suggest that the last deglaciation was punctuated by a dramatic period of sea-level rise, of about 20 metres, in less than 500 years. Controversy about the amplitude and timing of this meltwater pulse (MWP-1A) has, however, led to uncertainty about the source of the melt water and its temporal and causal relationships with the abrupt climate changes of the deglaciation. Here we show that MWP-1A started no earlier than 14,650 years ago and ended before 14,310 years ago, making it coeval with the Bolling warming. Our results, based on corals drilled offshore from Tahiti during Integrated Ocean Drilling Project Expedition 310, reveal that the increase in sea level at Tahiti was between 12 and 22 metres, with a most probable value between 14 and 18 metres, establishing a significant meltwater contribution from the Southern Hemisphere. This implies that the rate of eustatic sea-level rise exceeded 40 millimetres per year during MWP-1A

Twenty-first century glacier slowdown driven by mass loss in High Mountain Asia

International audienc

Paleoclimate Implications for Human-Made Climate Change

Paleoclimate data help us assess climate sensitivity and potential human-made climate effects. We conclude that Earth in the warmest interglacial periods of the past million years was less than 1{\deg}C warmer than in the Holocene. Polar warmth in these interglacials and in the Pliocene does not imply that a substantial cushion remains between today's climate and dangerous warming, but rather that Earth is poised to experience strong amplifying polar feedbacks in response to moderate global warming. Thus goals to limit human-made warming to 2{\deg}C are not sufficient - they are prescriptions for disaster. Ice sheet disintegration is nonlinear, spurred by amplifying feedbacks. We suggest that ice sheet mass loss, if warming continues unabated, will be characterized better by a doubling time for mass loss rate than by a linear trend. Satellite gravity data, though too brief to be conclusive, are consistent with a doubling time of 10 years or less, implying the possibility of multi-meter sea level rise this century. Observed accelerating ice sheet mass loss supports our conclusion that Earth's temperature now exceeds the mean Holocene value. Rapid reduction of fossil fuel emissions is required for humanity to succeed in preserving a planet resembling the one on which civilization developed.Comment: 32 pages, 9 figures; final version accepted for publication in "Climate Change at the Eve of the Second Decade of the Century: Inferences from Paleoclimate and Regional Aspects: Proceedings of Milutin Milankovitch 130th Anniversary Symposium" (eds. Berger, Mesinger and Sijaci

Recent Advances in Our Understanding of the Role of Meltwater in the Greenland Ice Sheet System

Nienow, Sole and Cowton’s Greenland research has been supported by a number of UK NERC research grants (NER/O/S/2003/00620; NE/F021399/1; NE/H024964/1; NE/K015249/1; NE/K014609/1) and Slater has been supported by a NERC PhD studentshipPurpose of the review:  This review discusses the role that meltwater plays within the Greenland ice sheet system. The ice sheet’s hydrology is important because it affects mass balance through its impact on meltwater runoff processes and ice dynamics. The review considers recent advances in our understanding of the storage and routing of water through the supraglacial, englacial, and subglacial components of the system and their implications for the ice sheet Recent findings:   There have been dramatic increases in surface meltwater generation and runoff since the early 1990s, both due to increased air temperatures and decreasing surface albedo. Processes in the subglacial drainage system have similarities to valley glaciers and in a warming climate, the efficiency of meltwater routing to the ice sheet margin is likely to increase. The behaviour of the subglacial drainage system appears to limit the impact of increased surface melt on annual rates of ice motion, in sections of the ice sheet that terminate on land, while the large volumes of meltwater routed subglacially deliver significant volumes of sediment and nutrients to downstream ecosystems. Summary:  Considerable advances have been made recently in our understanding of Greenland ice sheet hydrology and its wider influences. Nevertheless, critical gaps persist both in our understanding of hydrology-dynamics coupling, notably at tidewater glaciers, and in runoff processes which ensure that projecting Greenland’s future mass balance remains challenging.Publisher PDFPeer reviewe