Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response.

The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases are key contributors to the maintenance of protein homeostasis with age. We previously reported that expression of granulin peptides, the cleavage products of the neurodegenerative disease protein progranulin, enhance the accumulation and toxicity of TAR DNA binding protein 43 (TDP-43) in Caenorhabditis elegans (C. elegans). In this study we show that C. elegans granulins are produced in an age- and stress-dependent manner. Granulins localize to the endolysosomal compartment where they impair lysosomal protease expression and activity. Consequently, protein homeostasis is disrupted, promoting the nuclear translocation of the lysosomal transcription factor HLH-30/TFEB, and prompting cells to activate a compensatory transcriptional program. The three C. elegans granulin peptides exhibited distinct but overlapping functional effects in our assays, which may be due to amino acid composition that results in distinct electrostatic and hydrophobicity profiles. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease

Eruption frequency patterns through time for the current (1999–2018) activity cycle at Volcán de Fuego derived from remote sensing data:Evidence for an accelerating cycle of explosive paroxysms and potential implications of eruptive activity

Volcán de Fuego is a stratovolcano in Guatemala that has produced over 50 VEI ≥ 2 eruptions since 1524. After two decades of quiescence, in 1999 Fuego entered a new period of eruptive activity that continues until the present day, characterized by persistent Strombolian activity interspersed with occasional “paroxysmal” eruptions of greater magnitude, the most recent of which occurred in 2018. The land surrounding Fuego accommodates tens of thousands of people, so greater understanding of its eruptive behaviour has important implications for hazard assessment. Nevertheless, there is relatively little literature that studies recent (since 1999) activity of Fuego in detail. Using time-series analysis of remote sensing thermal data during the period 2000–2018 combined with recent bulletin reports, we present evidence for a new eruptive regime beginning in 2015. We find that this regime is defined by a greater frequency of paroxysmal eruptions than in previous years and is characterized by the following sequence of events: (i) effusion of lava flows and increase in summit explosive activity, followed by (ii) an intense eruptive phase lasting 24–48 h, producing a sustained eruptive column, continuous explosions, and occasional pyroclastic flows, followed by (iii) decrease in explosive activity. We discuss various models that explain this increase in paroxysmal frequency, and consider its implications for hazard assessment at Fuego. We advocate the pairing of remote sensing data with monitoring reports for understanding long-term changes in behaviour of poorly-instrumented volcanoes. The results that we present here provide a standard for informed assessment of future episodes of unrest and paroxysmal eruptions of Fuego

Icy thermometers : quantifying the impact of volcanic heat on glacier elevation

ACKNOWLEDGEMENTS This project was supported by the NERC Global Partnerships Seedcorn grant NE/W003724/1 and the Leverhulme Trust Research Project RPG-2019-093. We thank Kevin A. Reath for support in analysing volcanic thermal anomalies. A.G.P. and M.E.P. were partly supported by the NASA Science Mission Directorate Earth Surface and Interior grant 80NSSC21K0842. J.J. was supported by the NERC Quadrat Doctoral Training Partnership. We express our gratitude to John Smellie and an anonymous reviewer for fruitful feedback which greatly improved the manuscript.Peer reviewedPostprin

Direct visualization of individual aromatic compound structures in low molecular weight marine dissolved organic carbon

Dissolved organic carbon (DOC) is the largest pool of exchangeable organic carbon in the ocean. However, less than 10% of DOC has been molecularly characterized in the deep ocean to understand DOC’s recalcitrance. Here we analyze the radiocarbon (14C) depleted, and presumably refractory, low molecular weight (LMW) DOC from the North Central Pacific using atomic force microscopy to produce the first atomic-resolution images of individual LMW DOC molecules. We evaluate surface and deep LMW DOC chemical structures in the context of their relative persistence and recalcitrance. Atomic force microscopy resolved planar structures with features similar to polycyclic aromatic compounds and carboxylic-rich alicyclic structures with less than five aromatic carbon rings. These compounds comprise 8% and 20% of the measurable molecules investigated in the surface and deep, respectively. Resolving the structures of individual DOC molecules represents a step forward in molecular characterization of DOC and in understanding its long-term stability

Icy thermometers: quantifying the impact of volcanic heat on glacier elevation

We present a continent-wide study of 600 glaciers located on and near 37 ice-clad volcanoes in South America, that demonstrates glacier sensitivity to volcanic heat. We distinguish between ‘volcanic-glaciers’ (≤1 km from volcanic centres; n=74), and ‘proximal glaciers’ (1-15 km; n=526) and calculate their equilibrium line altitudes (ELA). For each ice-clad volcano we compare the ELAs of its volcanic-glaciers to those of its proximal glaciers which shows that the ELAs of the former are higher than the ELAs of the latter. ΔELAmean, defined as the offset between the mean ELA of the volcanic-glaciers and that of the proximal glaciers, is calculated for each ice-clad volcano. ΔELAmean is positive for 92% of the 37 volcanoes, and a quantitative relationship between ΔELAmean and volcanic thermal anomaly is established. Results highlight the impact of volcanic heat on glacier elevation; emphasise the need to exclude glaciers on, or near, volcanoes from glacier-climate investigations; and demonstrate the first-order potential for glaciers as ‘volcanic thermometers’. Volcanic-glacier monitoring could contribute to our understanding of magmatic and thermal activity, with changes in glacier geometries potentially reflecting long-term fluctuations in volcanic heat and unrest

An assessment of particulate organic carbon to thorium-234 ratios in the ocean and their impact on the application of 234Th as a POC flux proxy

Author Posting. © The Authors, 2006. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Marine Chemistry 100 (2006): 213-233, doi:10.1016/j.marchem.2005.10.013.Thorium-234 is increasingly used as a tracer of ocean particle flux, primarily as a means to estimate particulate organic carbon export from the surface ocean. This requires determination of both the 234Th activity distribution (in order to calculate 234Th fluxes) and an estimate of the C/234Th ratio on sinking particles, to empirically derive C fluxes. In reviewing C/234Th variability, results obtained using a single sampling method show the most predictable behavior. For example, in most studies that employ in situ pumps to collect size fractionated particles, C/234Th either increases or is relatively invariant with increasing particle size (size classes >1 to 100’s μm). Observations also suggest that C/234Th decreases with depth and can vary significantly between regions (highest in blooms of large diatoms and highly productive coastal settings). Comparisons of C fluxes derived from 234Th show good agreement with independent estimates of C flux, including mass balances of C and nutrients over appropriate space and time scales (within factors of 2-3). We recommend sampling for C/234Th from a standard depth of 100 m, or at least one depth below the mixed layer using either large volume size fractionated filtration to capture the rarer large particles, or a sediment trap or other device to collect sinking particles. We also recommend collection of multiple 234Th profiles and C/234Th samples during the course of longer observation periods to better sample temporal variations in both 234Th flux and the characteristic of sinking particles. We are encouraged by new technologies which are optimized to more reliably sample truly settling particles, and expect the utility of this tracer to increase, not just for upper ocean C fluxes but for other elements and processes deeper in the water column.Individuals and science efforts discussed herein were supported by many national science programs, including the U.S. National Science Foundation and U.S. Department of Energy. S.F. and J.C.M. acknowledge the support provided to the International Atomic Energy Agency (IAEA) Marine Environment Laboratory by the Government of the Principality of Monaco. T.T. acknowledges support from the Australian Antarctic Science Program. K.B. was supported in part by a WHOI Ocean Life Institute Fellowship

Kinetics of Rab27a-dependent actions on vesicle docking and priming in pancreatic Β-cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65888/1/jphysiol.2008.158477.pd

The interplay between the Rab27A effectors Slp4-a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis.

Weibel-Palade body (WPB) exocytosis underlies hormone-evoked VWF secretion from endothelial cells (ECs). We identify new endogenous components of the WPB: Rab3B, Rab3D, and the Rab27A/Rab3 effector Slp4-a (granuphilin), and determine their role in WPB exocytosis. We show that Rab3B, Rab3D, and Rab27A contribute to Slp4-a localization to WPBs. siRNA knockdown of Slp4-a, MyRIP, Rab3B, Rab3D, Rab27A, or Rab3B/Rab27A, or overexpression of EGFP-Slp4-a or EGFP-MyRIP showed that Slp4-a is a positive and MyRIP a negative regulator of WPB exocytosis and that Rab27A alone mediates these effects. We found that ECs maintain a constant amount of cellular Rab27A irrespective of the WPB pool size and that Rab27A (and Rab3s) cycle between WPBs and a cytosolic pool. The dynamic redistribution of Rab proteins markedly decreased the Rab27A concentration on individual WPBs with increasing WPB number per cell. Despite this, the probability of WPB release was independent of WPB pool size showing that WPB exocytosis is not determined simply by the absolute amount of Rab27A and its effectors on WPBs. Instead, we propose that the probability of release is determined by the fractional occupancy of WPB-Rab27A by Slp4-a and MyRIP, with the balance favoring exocytosis