Volcano dome dynamics at Mount St. Helens:Deformation and intermittent subsidence monitored by seismicity and camera imagery pixel offsets

The surface deformation field measured at volcanic domes provides insights into the effects of magmatic processes, gravity-and gas-driven processes, and the development and distribution of internal dome structures. Here we study short-term dome deformation associated with earthquakes at Mount St. Helens, recorded by a permanent optical camera and seismic monitoring network. We use Digital Image Correlation (DIC) to compute the displacement field between successive images and compare the results to the occurrence and characteristics of seismic events during a 6 week period of dome growth in 2006. The results reveal that dome growth at Mount St. Helens was repeatedly interrupted by short-term meter-scale downward displacements at the dome surface, which were associated in time with low-frequency, large-magnitude seismic events followed by a tremor-like signal. The tremor was only recorded by the seismic stations closest to the dome. We find a correlation between the magnitudes of the camera-derived displacements and the spectral amplitudes of the associated tremor. We use the DIC results from two cameras and a high-resolution topographic model to derive full 3-D displacement maps, which reveals internal dome structures and the effect of the seismic activity on daily surface velocities. We postulate that the tremor is recording the gravity-driven response of the upper dome due to mechanical collapse or depressurization and fault-controlled slumping. Our results highlight the different scales and structural expressions during growth and disintegration of lava domes and the relationships between seismic and deformation signals

The Second Transmembrane Domain of P2X7 Contributes to Dilated Pore Formation

Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors. © 2013 Sun et al

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

P2X7 is a transmembrane receptor expressed in multiple cell types including neurons, dendritic cells, macrophages, monocytes, B and T cells where it can drive a wide range of physiological responses from pain transduction to immune response. Upon activation by its main ligand, extracellular ATP, P2X7 can form a nonselective channel for cations to enter the cell. Prolonged activation of P2X7, via high levels of extracellular ATP over an extended time period can lead to the formation of a macropore, leading to depolarization of the plasma membrane and ultimately to cell death. Thus, dependent on its activation state, P2X7 can either drive cell survival and proliferation, or induce cell death. In cancer, P2X7 has been shown to have a broad range of functions, including playing key roles in the development and spread of tumor cells. It is therefore unsurprising that P2X7 has been reported to be upregulated in several malignancies. Critically, ATP is present at high extracellular concentrations in the tumor microenvironment (TME) compared to levels observed in normal tissues. These high levels of ATP should present a survival challenge for cancer cells, potentially leading to constitutive receptor activation, prolonged macropore formation and ultimately to cell death. Therefore, to deliver the proven advantages for P2X7 in driving tumor survival and metastatic potential, the P2X7 macropore must be tightly controlled while retaining other functions. Studies have shown that commonly expressed P2X7 splice variants, distinct SNPs and post-translational receptor modifications can impair the capacity of P2X7 to open the macropore. These receptor modifications and potentially others may ultimately protect cancer cells from the negative consequences associated with constitutive activation of P2X7. Significantly, the effects of both P2X7 agonists and antagonists in preclinical tumor models of cancer demonstrate the potential for agents modifying P2X7 function, to provide innovative cancer therapies. This review summarizes recent advances in understanding of the structure and functions of P2X7 and how these impact P2X7 roles in cancer progression. We also review potential therapeutic approaches directed against P2X7

The Missoula and Bonneville floods—A review of ice-age megafloods in the Columbia River basin

The Channeled Scabland of eastern Washington State, USA, brought megafloods to the scientific forefront. A 30,000-km2 landscape of coulees and cataracts carved into the region’s loess-covered basalt attests to overwhelming volumes of energetic water. The scarred landscape, garnished by huge boulder bars and far-travelled ice-rafted erratics, spurred J Harlen Bretz’s vigorously disputed flood hypothesis in the 1920s. First known as the Spokane flood, it was rebranded the Missoula flood once understood that the water came from glacial Lake Missoula, formed when the Purcell Trench lobe of the last-glacial Cordilleran ice sheet dammed the Clark Fork valley in northwestern Idaho with ice a kilometer thick. Bretz’s flood evidence in the once-remote Channeled Scabland, widely seen and elaborated by the 1950s, eventually swayed consensus for cataclysmic flooding. Missoula flood questions then turned to some that continue today: how many? when? how big? what routes? what processes? The Missoula floods passed through eastern Washington by a multitude of valleys, coulees and scabland tracts, some contemporaneously, some sequentially. Routings and their timing depended on the positions of various lobes of the multi-pronged Cordilleran ice sheet and the erosional development of the channels themselves. The first floods mostly followed the big bend of Columbia valley looping through north-central Washington. But the south-advancing Okanogan ice lobe soon blocked that path, forming long-lasting glacial Lake Columbia in the impounded Columbia valley. Missoula floods into this lake were diverted south out of the Columbia valley and into eastern Washington coulees and scabland tracts. At least four floods entered Moses Coulee, but then as the Okanogan lobe advanced over and blocked the head of that coulee, more eastern paths took the water, including Grand Coulee and the Telford-Crab-Creek and Cheney-Palouse scabland tracts. Flood routing also depended on the erosion of the coulees. At some point, headward erosion of upper Grand Coulee lowered the divide saddle between the west-running Columbia valley and the deep and wide Grand Coulee heading southwest. Still uncertain is when this happened and the consequences with respect to the stage and extent of glacial Lake Columbia and to flood access to the other, higher, flood routes. Downstream, all flood routes converged into Pasco Basin, flowed through Wallula Gap and the Columbia River Gorge into the Pacific Ocean, following submarine canyons and depositing sediment layers on abyssal plains. Stratigraphic studies indicate dozens—likely more than a hundred—separate Missoula floods during the last glacial period. Over the length of the flood route, backwater areas and depositional basins preserve multiple flood beds, many of which are separated by signs of time, including volcanic ash layers and soil development in subaerial environments; and varve-like beds and pelagic mud layers in lacustrine and marine settings. Evidence also comes from the glacial Lake Missoula basin, where stratigraphy indicates dozens of filling and emptying cycles. Varve counts in conjunction with radiocarbon dating and paleomagnetic secular variation show the repeated filling-and-release cycles of glacial Lake Missoula had intervals possibly as long as 100 years early in the lake’s history but diminished to just one or two years for the last few floods. This behavior accords with jökulhlaup-style floods released by subglacial drainage from a self-dumping ice-dammed lake. Not yet clear is whether such a mechanism applies to all the floods or if some emptied more cataclysmically as hypothesized by some. Radiocarbon dating of sparse organic materials remains key to defining flood chronology but has been lately bolstered by analyses of terrestrial cosmogenic nuclides and optically stimulated luminescence. Varve counts and paleomagnetic secular variation studies help to define durations and intervals represented by sequences of flood beds. The ~16 ka Mount St. Helens Set S tephra is commonly interbedded within flood deposits, enabling correlation of deposits among sites. Tephra from the 13.7–13.4 ka eruption of Glacier Peak overlies all glacial Lake Missoula and Missoula flood deposits, defining an end time. Overall conclusions are that glacial Lake Missoula was extant and producing floods for at least 3–4 ky during 20–14 ka. At least ~75 floods preceded Mount St Helens Set S, followed by 30 or more after the tephra fall. Most floods entered glacial Lake Columbia, impounded by the Okanogan lobe, for 2–5 ky between about 18.5 and 15 ka. Glacial Lake Columbia outlived Lake Missoula by >200–400 yr but may have been born later since at least one flood came down the Columbia valley before the Okanogan ice lobe blocked the Columbia valley at 18.5–18 ka. The maximum extent of the Okanogan and Purcell Trench lobes, many Missoula floods, substantial erosion of upper Grand Coulee, and the widespread tephra falls from Mount St. Helens eruptions all happened about 17–15 ka. People, in the area since 16.6–15.3 ka, almost certainly witnessed the last of the Missoula floods and later large floods from other ice-dammed lakes in the Columbia River basin. Quantitative flow analyses give peak discharge estimates and support understanding of erosional and depositional processes. The first flow assessments were simple cross-section calculations but recent assessments employ two-dimensional hydrodynamic models. The general finding is that emplacement of the maximum stage evidence requires about 20 million m3/s near the Lake Missoula outlet and about 5–15 million m3/s through Wallula Gap and downstream in the Columbia River Gorge. These hydraulic analyses raise still-unresolved questions regarding canyon erosion and possible additional water sources. The large Pleistocene Bonneville flood entered the Columbia River system from the southeast from pluvial Lake Bonneville, the Pleistocene predecessor to Great Salt Lake in the eastern Great Basin. During the last glacial, the lake basin filled, covering >50,000 km2 with 10,400 km3 of water before reaching its maximum possible stage governed by Red Rock Pass, the lowest divide separating the basin from the Snake River basin to the north. The overtopping lake rapidly incised 108–125 m into the Red Rock Pass outlet, spilling half of its total lake volume. G.K. Gilbert described the essential sequence in the 1870s, but the flood was mostly forgotten until the late 1950s when Harold Malde linked the spectacular scabland topography and bouldery “melon gravel” on the Snake River Plain to the Lake Bonneville overflow. The Bonneville flood appears to have been a singular event at about 18 ka. No evidence of multiple or pre-last-glacial spillovers has yet been found. Its total volume was about twice that of a maximum Lake Missoula flood yet its peak discharge was ~1 million m3/s, less than a tenth of the largest Missoula floods. Its comparatively simple flow path and much steadier flow make the Bonneville flood ideal for new studies of erosional and depositional processes. At least two floods seem to have passed down the Columbia valley after the last of the Missoula floods, including a large flood about ~14 ka likely from cataclysmic demise of the thinning Okanogan ice lobe dam impounding glacial Lake Columbia. Floods from earlier glacial ages left scant yet clear evidence in the Channeled Scabland and Columbia valley. But their source, timing, and magnitudes are little understood. Some deposits are paleomagnetically reversed, thus older than ~800 ka. Last-glacial floods and perhaps older ones affected the Snake River Plain, some likely sourced in lakes dammed by alpine glaciers in central Idaho

C-terminal Calmodulin-binding Motif Differentially Controls Human and Rat P2X7 Receptor Current Facilitation*

P2X7 receptors (P2X7R) are ATP-gated calcium-permeable cationic channels structurally unique among the P2X family by their much longer intracellular C-terminal tail. P2X7Rs show several unusual biophysical properties, in particular marked facilitation of currents and leftward shift in agonist affinity in response to repeated or prolonged agonist applications. We previously found the facilitation at rat P2X7R resulted from a Ca2+-calmodulin-dependent process and a distinct calcium-independent process. However, P2X7Rs show striking species differences; thus, this study compared the properties of ATP-evoked facilitation of currents in HEK293 cells transiently expressing the human or rat P2X7R as well as rat/human, human/rat chimeric, and mutated P2X7Rs. Facilitation at the human P2X7R was 5-fold slower than at the rat P2X7R. Facilitation did not resulting from an increase of receptor addressing the plasma membrane. We found the human P2X7R shows only calcium-independent facilitation with no evidence for calmodulin-dependent processes, nor does it contain the novel 1-5-16 calmodulin binding domain present in the C terminus of rat P2X7R. Replacement of three critical residues of this binding domain from the rat into the human P2X7R (T541I, C552S, and G559V) reconstituted the Ca2+-calmodulin-dependent facilitation, leaving the calcium-independent facilitation unaltered. The leftward shift in the ATP concentration-response curve with repeated agonist applications appears to be a property of the calcium-independent facilitation process because it was not altered in any of the chimeric or mutated P2X7Rs. The absence of Ca2+-dependent facilitation at the human P2X7R may represent a protective adaptation of the innate immune response in which P2X7R plays significant roles

Many ways to dilate the P2X7 receptor pore

The P2X7 receptor is associated with two different membrane permeabilities: a small cation conductance which opens within milliseconds, followed by the appearance of a second channel carrying higher molecular weight compounds (including organic dyes) after prolonged agonist stimulation. This activation profile has also been found in cells expressing P2X2 and P2X4 receptors; however, the P2X7 receptor-dependent pathway has the unique ability to activate pro-inflammatory signalling in macrophages. In this issue of the BJP, Marques-da-Silva et al. demonstrate that colchicine is a potent inhibitor of both P2X7 and P2X2 receptor-dependent dye uptake, without affecting the ion channels. Colchicine also blocked the pro-inflammatory signalling downstream of P2X7 receptor activation, both in vitro and in vivo. This report suggests that the dye uptake associated with activation of P2X7 receptors is distinct from the P2X7 receptor ion channel and could be a therapeutic target for the treatment of chronic inflammation