Non-physiological increase of AV conduction time in sinus disease patients programmed in AAIR-based pacing mode

Purpose The EVOCAVDS trial aimed to quantify the paradoxal atrioventricular (AV) conduction time lengthening in sinus node (SD) patients (pts) paced in AAIR-based pacing mode. Methods SD pts, implanted with dual-chamber pacemaker programmed in AAIR-based pacing mode, were randomized in two arms for a 1-month period: the low atrial pacing (LAP; basic rate at 60 bpm, dual sensor with minimal slope) and the high atrial pacing (HAP; basic rate at 70 bpm, dual sensor with optimized slope, overdrive pacing) arm. At 1 month, crossover was performed for an additional 1-month period. AV conduction time, AV block occurrence and AV conduction time adaptation during exercise were ascertained from device memories at each follow-up. Results Seventy-nine pts participated to the analysis (75 ± 8 years; 32 male; PR = 184 ± 38 ms; bundle branch block n = 12; AF history n = 36; antiarrhythmic treatment n = 53; beta-blockers n = 27; class III/Ic n = 18; both n = 8). The mean AV conduction time was significantly greater during the HAP (275 ± 51 ms) vs. LAP (263 ± 49 ms) period (p < 0.0001). Class III/Ic drugs were the only predictors of this abnormal behaviour. Degree II/III AV blocks occurred in 49 % of pts in the HAP vs. 19 % in the LAP period (p < 0.0001). Fifty-two patients (66 %) presented a lengthening of AV conduction time during exercise. Conclusion AAIR-based pacing in SD pts may induce a significant lengthening of pts’ AV conduction time, including frequent abnormal adaptation of AV conduction time during exercise

Crustal structure beneath the Strait of Juan de Fuca and southern Vancouver Island from seismic and gravity analyses

Wide-angle and vertical incidence seismic data from Seismic Hazards Investigations in Puget Sound (SHIPS), gravity modeling, and seismicity are used to derive two-dimensional crustal models beneath the Strait of Juan de Fuca. The Eocene volcanic Crescent-Siletz terrane is significantly thicker than previously recognized and extends from near the surface to depths of 22 km or greater. For the northern strait, a weak midcrustal reflector, dipping east from 12- to 22-km depth, is inferred from wide-angle reflections. A stronger deeper reflector, dipping eastward from 23- to 36-km depth, is associated with the top of ‘‘reflector band E,’’ a zone of high reflectivity on coincident Multichannel Seismic (MCS) data, interpreted as a shear zone. A high-velocity zone (7.60 ± 0.2 km s⁻¹) between these reflectors is interpreted as a localized slice of mantle accreted with the overlying Crescent-Siletz terrane. For the southern strait, no deep high-velocity layer is observed and the E-band reflectivity is weaker than to the north. A strong deep reflector, interpreted as the oceanic Moho dips eastward from 35 to 42 km. Seismicity within the subducting slab occurs mainly above the inferred oceanic Moho. Gravity modeling, constrained by the wide-angle seismic models and seismicity, is consistent with the inferred large thickness of Crescent-Siletz and high-density rocks (3030 kg m⁻³) in the lower crust.Keywords: crustal structure, wide-angle seismic, deep crustal reflectivity, Cascadia subduction zone, Vancouver Island, Juan de Fuca Strait, Crescent-Siletz terran

Deep structure of the Ionian Sea and Sicily Dionysus - Cruise No. M111, October 10 - November 1, 2014, Catania (Italy) – Catania (Italy)

Summary The origin of the Ionian Sea lithosphere and the deep structure of its margins remain a little investigated part of the Mediterranean Sea. To shed light on the plate tectonic setting in this central part of southern Europe, R/V METEOR cruise M111 set out to acquire deep penetrating seismic data in the Ionian Sea. M111 formed the core of an amphibious investigation covering the Ionian Sea and island of Sicily. A total of 153 OBS/OBH deployments using French and German instruments were successfully carried out, in addition to 12 land stations installed on Sicily, which recorded the offshore air gun shots. The aim of this onshore-offshore study is to quantify the deep geometry and architecture of the Calabria subduction zone and Ionian Sea lithosphere and to shed light on the nature of the Ionian Sea crust (oceanic crust vs. thinned continental crust). Investigating the structure of the Ionian crust and lithospheric mantle will contribute to unravel the unknown ocean-continent transition and Tethys margin. Analyzing the tectonic activity and active deformation zones is essential for understanding the subduction processes that underlie the neotectonics of the Calabrian subduction zone and earthquake hazard of the Calabria/Sicily region, especially in the vicinity of local decoupling zones

Ionian Abyssal Plain: a window into the Tethys oceanic lithosphere

The nature of the Ionian Sea crust has been the subject of scientific debate for more than 30 years, mainly because seismic imaging of the deep crust and upper mantle of the Ionian Abyssal Plain (IAP) has not been conclusive to date. The IAP is sandwiched between the Calabrian and Hellenic subduction zones in the central Mediterranean. A NNE–SSW-oriented 131&thinsp;km long seismic refraction and wide-angle reflection profile, consisting of eight ocean bottom seismometers and hydrophones, was acquired in 2014. The profile was designed to univocally confirm the proposed oceanic nature of the IAP crust as a remnant of the Tethys and to confute its interpretation as a strongly thinned part of the African continental crust. A P-wave velocity model developed from travel-time forward modelling is refined by gravimetric data and synthetic modelling of the seismic data. A roughly 6–7&thinsp;km thick crust with velocities ranging from 5.1 to 7.2&thinsp;km&thinsp;s−1, top to bottom, can be traced throughout the IAP. In the vicinity of the Medina seamounts at the southern IAP boundary, the crust thickens to about 9&thinsp;km and seismic velocities decrease to 6.8&thinsp;km&thinsp;s−1 at the crust–mantle boundary. The seismic velocity distribution and depth of the crust–mantle boundary in the IAP document its oceanic nature and support the interpretation of the IAP as a remnant of the Tethys lithosphere with the Malta Escarpment as a transform margin and a Tethys opening in the NNW–SSE direction.</p

Limits of the seismogenic zone in the epicentral region of the 26 December 2004 great Sumatra-Andaman earthquake: Results from seismic refraction and wide-angle reflection surveys and thermal modeling

The 26 December 2004 Sumatra earthquake (Mw = 9.1) initiated around 30 km depth and ruptured 1300 km of the Indo-Australian Sunda plate boundary. During the Sumatra OBS (ocean bottom seismometer) survey, a wide angle seismic profile was acquired across the epicentral region. A seismic velocity model was obtained from combined travel time tomography and forward modeling. Together with reflection seismic data from the SeaCause II cruise, the deep structure of the source region of the great earthquake is revealed. Four to five kilometers of sediments overlie the oceanic crust at the trench, and the subducting slab can be imaged down to a depth of 35 km. We find a crystalline backstop 120 km from the trench axis, below the fore arc basin. A high velocity zone at the lower landward limit of the raycovered domain, at 22 km depth, marks a shallow continental Moho, 170 km from the trench. The deep structure obtained from the seismic data was used to construct a thermal model of the fore arc in order to predict the limits of the seismogenic zone along the plate boundary fault. Assuming 100C-150C as its updip limit, the seismogenic zone is predicted to begin 530 km from the trench. The downdip limit of the 2004 rupture as inferred from aftershocks is within the 350C 450C temperature range, but this limit is 210-250 km from the trench axis and is much deeper than the fore arc Moho. The deeper part of the rupture occurred along the contact between the mantle wedge and the downgoing plate

Genetic Relations Between the Aves Ridge and the Grenada Back-Arc Basin, East Caribbean Sea

The Grenada Basin separates the active Lesser Antilles Arc from the Aves Ridge, described as a Cretaceous‐Paleocene remnant of the “Great Arc of the Caribbean.” Although various tectonic models have been proposed for the opening of the Grenada Basin, the data on which they rely are insufficient to reach definitive conclusions. This study presents, a large set of deep‐penetrating multichannel seismic reflection data and dredge samples acquired during the GARANTI cruise in 2017. By combining them with published data including seismic reflection data, wide‐angle seismic data, well data and dredges, we refine the understanding of the basement structure, depositional history, tectonic deformation and vertical motions of the Grenada Basin and its margins as follows: (1) rifting occurred during the late Paleocene‐early Eocene in a NW‐SE direction and led to seafloor spreading during the middle Eocene; (2) this newly formed oceanic crust now extends across the eastern Grenada Basin between the latitude of Grenada and Martinique; (3) asymmetrical pre‐Miocene depocenters support the hypothesis that the southern Grenada Basin originally extended beneath the present‐day southern Lesser Antilles Arc and probably partly into the present‐day forearc before the late Oligocene‐Miocene rise of the Lesser Antilles Arc; and (4) the Aves Ridge has subsided along with the Grenada Basin since at least the middle Eocene, with a general subsidence slowdown or even an uplift during the late Oligocene, and a sharp acceleration on its southeastern flank during the late Miocene. Until this acceleration of subsidence, several bathymetric highs remained shallow enough to develop carbonate platforms

Calmodulin-like proteins localized to the conoid regulate motility and cell invasion by Toxoplasma gondii

Toxoplasma gondii contains an expanded number of calmodulin (CaM)-like proteins whose functions are poorly understood. Using a combination of CRISPR/Cas9-mediated gene editing and a plant-like auxin-induced degron (AID) system, we examined the roles of three apically localized CaMs. CaM1 and CaM2 were individually dispensable, but loss of both resulted in a synthetic lethal phenotype. CaM3 was refractory to deletion, suggesting it is essential. Consistent with this prediction auxin-induced degradation of CaM3 blocked growth. Phenotypic analysis revealed that all three CaMs contribute to parasite motility, invasion, and egress from host cells, and that they act downstream of microneme and rhoptry secretion. Super-resolution microscopy localized all three CaMs to the conoid where they overlap with myosin H (MyoH), a motor protein that is required for invasion. Biotinylation using BirA fusions with the CaMs labeled a number of apical proteins including MyoH and its light chain MLC7, suggesting they may interact. Consistent with this hypothesis, disruption of MyoH led to degradation of CaM3, or redistribution of CaM1 and CaM2. Collectively, our findings suggest these CaMs may interact with MyoH to control motility and cell invasion

Alveolar proteins stabilize cortical microtubules in Toxoplasma gondii

Single-celled protists use elaborate cytoskeletal structures, including arrays of microtubules at the cell periphery, to maintain polarity and rigidity. The obligate intracellular parasite Toxoplasma gondii has unusually stable cortical microtubules beneath the alveoli, a network of flattened membrane vesicles that subtends the plasmalemma. However, anchoring of microtubules along alveolar membranes is not understood. Here, we show that GAPM1a, an integral membrane protein of the alveoli, plays a role in maintaining microtubule stability. Degradation of GAPM1a causes cortical microtubule disorganisation and subsequent depo-lymerisation. These changes in the cytoskeleton lead to parasites becoming shorter and rounder, which is accompanied by a decrease in cellular volume. Extended GAPM1a depletion leads to severe defects in division, reminiscent of the effect of disrupting other alveolar proteins. We suggest that GAPM proteins link the cortical microtubules to the alveoli and are required to maintain the shape and rigidity of apicomplexan zoites

Final Pre-40S Maturation Depends on the Functional Integrity of the 60S Subunit Ribosomal Protein L3

Ribosomal protein L3 is an evolutionarily conserved protein that participates in the assembly of early pre-60S particles. We report that the rpl3[W255C] allele, which affects the affinity and function of translation elongation factors, impairs cytoplasmic maturation of 20S pre-rRNA. This was not seen for other mutations in or depletion of L3 or other 60S ribosomal proteins. Surprisingly, pre-40S particles containing 20S pre-rRNA form translation-competent 80S ribosomes, and translation inhibition partially suppresses 20S pre-rRNA accumulation. The GTP-dependent translation initiation factor Fun12 (yeast eIF5B) shows similar in vivo binding to ribosomal particles from wild-type and rpl3[W255C] cells. However, the GTPase activity of eIF5B failed to stimulate processing of 20S pre-rRNA when assayed with ribosomal particles purified from rpl3[W255C] cells. We conclude that L3 plays an important role in the function of eIF5B in stimulating 3′ end processing of 18S rRNA in the context of 80S ribosomes that have not yet engaged in translation. These findings indicate that the correct conformation of the GTPase activation region is assessed in a quality control step during maturation of cytoplasmic pre-ribosomal particles

Systematic Analysis of Cis-Elements in Unstable mRNAs Demonstrates that CUGBP1 Is a Key Regulator of mRNA Decay in Muscle Cells

BACKGROUND: Dramatic changes in gene expression occur in response to extracellular stimuli and during differentiation. Although transcriptional effects are important, alterations in mRNA decay also play a major role in achieving rapid and massive changes in mRNA abundance. Moreover, just as transcription factor activity varies between different cell types, the factors influencing mRNA decay are also cell-type specific. PRINCIPAL FINDINGS: We have established the rates of decay for over 7000 transcripts expressed in mouse C2C12 myoblasts. We found that GU-rich (GRE) and AU-rich (ARE) elements are over-represented in the 3'UTRs of short-lived mRNAs and that these mRNAs tend to encode factors involved in cell cycle and transcription regulation. Stabilizing elements were also identified. By comparing mRNA decay rates in C2C12 cells with those previously measured for pluripotent and differentiating embryonic stem (ES) cells, we identified several groups of transcripts that exhibit cell-type specific decay rates. Further, whereas in C2C12 cells the impact of GREs on mRNA decay appears to be greater than that of AREs, AREs are more significant in ES cells, supporting the idea that cis elements make a cell-specific contribution to mRNA stability. GREs are recognized by CUGBP1, an RNA-binding protein and instability factor whose function is affected in several neuromuscular diseases. We therefore utilized RNA immunoprecipitation followed by microarray (RIP-Chip) to identify CUGBP1-associated transcripts. These mRNAs also showed dramatic enrichment of GREs in their 3'UTRs and encode proteins linked with cell cycle, and intracellular transport. Interestingly several CUGBP1 substrate mRNAs, including those encoding the myogenic transcription factors Myod1 and Myog, are also bound by the stabilizing factor HuR in C2C12 cells. Finally, we show that several CUGBP1-associated mRNAs containing 3'UTR GREs, including Myod1, are stabilized in cells depleted of CUGBP1, consistent with the role of CUGBP1 as a destabilizing factor. CONCLUSIONS: Taken together, our results systematically establish cis-acting determinants of mRNA decay rates in C2C12 myoblast cells and demonstrate that CUGBP1 associates with GREs to regulate decay of a wide range of mRNAs including several that are critical for muscle development