Although adaptor protein complex 1 (AP-1) and Golgi-localized, γ ear-containing, ADP-ribosylation factor-binding proteins (GGAs) are both adaptors for clathrin-mediated intracellular trafficking, the ...pathways they mediate and their relationship to each other remain open questions 1. To tease apart the functions of AP-1 and GGAs, we rapidly inactivated each adaptor using the “knocksideways” system 2 and then compared the protein composition of clathrin-coated vesicle (CCV) fractions from control and knocksideways cells. The AP-1 knocksideways resulted in a dramatic and unexpected loss of GGA2 from CCVs. Over 30 other peripheral membrane proteins and over 30 transmembrane proteins were also depleted, including several mutated in genetic disorders, indicating that AP-1 acts as a linchpin for intracellular CCV formation. In contrast, the GGA2 knocksideways affected only lysosomal hydrolases and their receptors. We propose that there are at least two populations of intracellular CCVs: one containing both GGAs and AP-1 for anterograde trafficking and another containing AP-1 for retrograde trafficking. Our study shows that knocksideways and proteomics are a powerful combination for investigating protein function, which can potentially be used on many different types of proteins.
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► AP-1 knocksideways depletes ∼100 proteins from clathrin-coated vesicles (CCVs) ► GGA2 knocksideways mainly depletes hydrolases and their receptors ► GGA2 depends on AP-1 for incorporation into CCVs ► AP-1 acts as a linchpin for intracellular CCV formation and is bidirectional
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The incidence of head and neck cancer is on the rise. Most head and neck cancers are treated with surgery, radiotherapy, chemotherapy or a combination of these modalities. Patients undergoing ...radiotherapy can experience several unwanted oral side effects, which have both short and long term implications. Dental general practitioners should be aware of these implications and should liaise closely with the restorative consultants and the oncology team to establish the best oral care pathway. This two-part series is a review of the oral changes that occur during and after radiotherapy and the oral management of head and neck oncology before, during and after radiotherapy. This article deals with both immediate sequelae such as cellulitis, mucositis, dysphagia, dysguesia and weight loss as well as long term sequelae such as rampant caries, trismus, xerostomia and osteoradionecrosis. It also encompasses the importance and need for pre-radiotherapy assessment.
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CMK, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We report the first measurements of volcanic gases with an unmanned aerial vehicle (UAV). The data were collected at La Fossa crater, Vulcano, Italy, during April 2007, with a helicopter UAV of 3 kg ...payload, carrying an ultraviolet spectrometer for remotely sensing the SO2 flux (8.5 Mg d−1), and an infrared spectrometer, and electrochemical sensor assembly for measuring the plume CO2/SO2 ratio; by multiplying these data we compute a CO2 flux of 170 Mg d−1. Given the deeper exsolution of carbon dioxide from magma, and its lower solubility in hydrothermal systems, relative to SO2, the ability to remotely measure CO2 fluxes is significant, with promise to provide more profound geochemical insights, and earlier eruption forecasts, than possible with SO2 fluxes alone: the most ubiquitous current source of remotely sensed volcanic gas data.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The basal regions of continental ice sheets are gaps in our current understanding of the Earth's biosphere and biogeochemical cycles. We draw on existing and new chemical data sets for subglacial ...meltwaters to provide the first comprehensive assessment of sub‐ice sheet biogeochemical weathering. We show that size of the ice mass is a critical control on the balance of chemical weathering processes and that microbial activity is ubiquitous in driving dissolution. Carbonate dissolution fueled by sulfide oxidation and microbial CO2 dominate beneath small valley glaciers. Prolonged meltwater residence times and greater isolation characteristic of ice sheets lead to the development of anoxia and enhanced silicate dissolution due to calcite saturation. We show that sub‐ice sheet environments are highly geochemically reactive and should be considered in regional and global solute budgets. For example, calculated solute fluxes from Antarctica (72–130 t yr−1) are the same order of magnitude as those from some of the world's largest rivers and rates of chemical weathering (10–17 t km−2 yr−1) are high for the annual specific discharge (2.3–4.1 × 10−3 m). Our model of chemical weathering dynamics provides important information on subglacial biodiversity and global biogeochemical cycles and may be used to design strategies for the first sampling of Antarctic Subglacial Lakes and other sub‐ice sheet environments for the next decade.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Clathrin-mediated endocytosis is essential for a wide range of cellular functions. We used a multi-step siRNA-based screening strategy to identify regulators of the first step in clathrin-mediated ...endocytosis, formation of clathrin-coated vesicles (CCVs) at the plasma membrane. A primary genome-wide screen identified 334 hits that caused accumulation of CCV cargo on the cell surface. A secondary screen identified 92 hits that inhibited cargo uptake and/or altered the morphology of clathrin-coated structures. The hits include components of four functional complexes: coat proteins, V-ATPase subunits, spliceosome-associated proteins and acetyltransferase subunits. Electron microscopy revealed that V-ATPase depletion caused the cell to form aberrant non-constricted clathrin-coated structures at the plasma membrane. The V-ATPase-knockdown phenotype was rescued by addition of exogenous cholesterol, indicating that the knockdown blocks clathrin-mediated endocytosis by preventing cholesterol from recycling from endosomes back to the plasma membrane.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
Uncertainty surrounds estimates of microbial cell and organic detritus fluxes from glacier surfaces. Here, we present the first enumeration of biological particles draining from a ...supraglacial catchment, on Midtre Lovénbreen (Svalbard) over 36 days. A stream cell flux of 1.08 × 107 cells m−2 h−1 was found, with strong inverse, non‐linear associations between water discharge and biological particle concentrations. Over the study period, a significant decrease in cell‐like particles exhibiting 530 nm autofluorescence was noted. The observed total fluvial export of ∼ 7.5 × 1014 cells equates to 15.1–72.7 g C, and a large proportion of these cells were small (< 0.5 μm in diameter). Differences between the observed fluvial export and inputs from ice‐melt and aeolian deposition were marked: results indicate an apparent storage rate of 8.83 × 107 cells m−2 h−1. Analysis of surface ice cores revealed cell concentrations comparable to previous studies (6 × 104 cells ml−1) but, critically, showed no variation with depth in the uppermost 1 m. The physical retention and growth of particulates at glacier surfaces has two implications: to contribute to ice mass thinning through feedbacks altering surface albedo, and to potentially seed recently deglaciated terrain with cells, genes and labile organic matter. This highlights the merit of further study into glacier surface hydraulics and biological processes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Microplastics are widespread contaminants in terrestrial environments but comparatively little is known about interactions between microplastics and common terrestrial contaminants such as zinc (Zn). ...In adsorption experiments fragmented HDPE bags c. one mm2 in size showed similar sorption characteristics to soil. However, when present in combination with soil, concentrations of adsorbed Zn on a per mass basis were over an order of magnitude lower on microplastics. Desorption of the Zn was minimal from both microplastics and soil in synthetic soil solution (0.01 M CaCl2), but in synthetic earthworm guts desorption was higher from microplastics (40–60%) than soil (2–15%), suggesting microplastics could increase Zn bioavailability. Individual Lumbricus terrestris earthworms exposed for 28 days in mesocosms of 260 g moist soil containing 0.35 wt % of Zn-bearing microplastic (236–4505 mg kg–1) ingested the microplastics, but there was no evidence of Zn accumulation, mortality, or weight change. Digestion of the earthworms showed that they did not retain microplastics in their gut. These findings indicate that microplastics could act as vectors to increase metal exposure in earthworms, but that the associated risk is unlikely to be significant for essential metals such as Zn that are well regulated by metabolic processes.
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IJS, KILJ, NUK, PNG, UL, UM
We wished to examine treatment and outcome patterns in older diffuse large B-cell lymphoma (DLBCL) patients, with a focus on the effect of route-to-diagnosis to outcome.
Data were extracted from ...Public Health England's National Cancer Registration and Analysis Service between 2013 and 2015 included route-to-diagnosis, disease characteristics and survival for 9186 patients ≥65 years. Systemic Anti-Cancer Therapy data identified front-line regimens, cycles and doses.
Route-to-diagnosis were emergency (34%), NHS urgent cancer pathway (rapid haemato-oncologist review <2 weeks), (29%) and standard GP referral (25%). The most common regimen was R-CHOP (n = 4392). 313 patients received R-miniCHOP (7% of R-CHOP). For all patients, 3-year overall survival (OS) for 65-79 years was 57% and for ≥80 years was 32%. Three-year OS for R-CHOP-treated patients diagnosed via emergency presentation was 54% (adjusted hazard ratio (HR) 1.63, p < 0.01) and 75% (adjusted HR 0.81, p < 0.01) on the NHS urgent cancer pathway (reference HR:1.00: GP referrals). 3-year OS was 54% for both R-miniCHOP and R-CHOP in ≥80 years.
Our comprehensive population analysis is the first to show that the NHS urgent cancer pathway is associated with a superior survival after adjusting for multiple confounders. Equivalent survival for R-CHOP and R-mini-CHOP was demonstrated in those ≥80 years.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The incidence of head and neck cancer is on the rise. Radiation therapy is one of the major treatment modalities for the management of oral malignancies. As with any treatment modality, radiation ...therapy is associated with various complications. The second part of this series is a review of the oral changes that occur during and after radiotherapy and the oral management of head and neck oncology patients before, during and after radiotherapy. Dental practitioners will encounter patients who have been affected by cancer or who are current cancer patents. General dental practitioners (GDPs) have a vital and proactive role in supporting such patients. The aim of this article is to review the oral management of these patients during and after radiotherapy, and gives practical advice for GDPs and their teams in the long-term care of these patients.
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CMK, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Progressive glacier thinning, retreat and mass loss in the High-Arctic is increasingly exposing forefield sediments to processes of mobilisation and redistribution. In this paper, we quantify ...forefield sediment redistribution at Midtre Lovénbreen, Svalbard, using repeat light detection and ranging (lidar) surveys conducted in 2003 and 2005 in combination with field-based observations. Average surface lowering of the forefield over the observation period identified from lidar surveys is −0.05
ma
−1; and two primary areas of sediment reworking are identified: active fluvial incision of proglacial streams by ~
2
m and lateral moraine downwasting of similar magnitude. Multivariate analysis of fluvial and climatological field data indicates that observed forefield sediment mobilisation is driven primarily by discharge forcing, but with contributions from thermoerosive processes and stochastic, autogenic sediment supply. During the period of observation, disparity between sediment loss in forefield fluvial systems as calculated from lidar data (3000–4000
×
10
3
kg) and monitoring of fluvial sediment load (1600–3500
×
10
3
kg) suggests the likely presence of significant quantities of buried ice beneath a thick debris mantle, as evidenced by field observations. Relatively uniform lowering of the moraine crest identified from our repeat lidar surveys indicates thermoerosion of an ice core. However, simple debris layer thickness modelling indicates an increase in variation of debris layer thickness at lower elevations, providing support for the assertion that moraine disintegration is driven by complex combinations of both thermal and mechanical processes. This study demonstrates the viability of using lidar in conjunction with field monitoring to better understand sedimentary deglaciation dynamics and processes, and also highlights the significance of forefield areas in controlling the sediment yield from deglaciating catchments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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