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

MethOds and tools for comprehensive impact Assessment of the CCAM solutions for passengers and goods. D1.1: CCAM solutions review and gaps

Review of the state-of-the-art on Cooperative, Connected and Automated mobility use cases, scenarios, business models, Key Performance Indicators, impact evaluation methods, technologies, and user needs (for organisations & citizens)

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

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

SAS6-like protein in Plasmodium indicates that conoid-associated apical complex proteins persist in invasive stages within the mosquito vector

The SAS6-like (SAS6L) protein, a truncated paralogue of the ubiquitous basal body/centriole protein SAS6, has been characterised recently as a flagellum protein in trypanosomatids, but associated with the conoid in apicomplexan Toxoplasma. The conoid has been suggested to derive from flagella parts, but is thought to have been lost from some apicomplexans including the malaria-causing genus Plasmodium. Presence of SAS6L in Plasmodium, therefore, suggested a possible role in flagella assembly in male gametes, the only flagellated stage. Here, we have studied the expression and role of SAS6L throughout the Plasmodium life cycle using the rodent malaria model P. berghei. Contrary to a hypothesised role in flagella, SAS6L was absent during gamete flagellum formation. Instead, SAS6L was restricted to the apical complex in ookinetes and sporozoites, the extracellular invasive stages that develop within the mosquito vector. In these stages SAS6L forms an apical ring, as we show is also the case in Toxoplasma tachyzoites. The SAS6L ring was not apparent in blood-stage invasive merozoites, indicating that the apical complex is differentiated between the different invasive forms. Overall this study indicates that a conoid-associated apical complex protein and ring structure is persistent in Plasmodium in a stage-specific manner

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

Mechanism of eIF6 release from the nascent 60S ribosomal subunit.

SBDS protein (deficient in the inherited leukemia-predisposition disorder Shwachman-Diamond syndrome) and the GTPase EFL1 (an EF-G homolog) activate nascent 60S ribosomal subunits for translation by catalyzing eviction of the antiassociation factor eIF6 from nascent 60S ribosomal subunits. However, the mechanism is completely unknown. Here, we present cryo-EM structures of human SBDS and SBDS-EFL1 bound to Dictyostelium discoideum 60S ribosomal subunits with and without endogenous eIF6. SBDS assesses the integrity of the peptidyl (P) site, bridging uL16 (mutated in T-cell acute lymphoblastic leukemia) with uL11 at the P-stalk base and the sarcin-ricin loop. Upon EFL1 binding, SBDS is repositioned around helix 69, thus facilitating a conformational switch in EFL1 that displaces eIF6 by competing for an overlapping binding site on the 60S ribosomal subunit. Our data reveal the conserved mechanism of eIF6 release, which is corrupted in both inherited and sporadic leukemias.Supported by a Federation of European Biochemical Societies Long term Fellowship (to FW), Specialist Programme from Bloodwise [12048] (AJW), the Medical Research Council [MC_U105161083] (AJW) and [U105115237] (RRK), Wellcome Trust strategic award to the Cambridge Institute for Medal Research [100140], Tesni Parry Trust (AJW), Ted’s Gang (AJW) and the Cambridge NIHR Biomedical Research Centre.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nsmb.311

The Use of Nanoscale Visible Light-Responsive Photocatalyst TiO2-Pt for the Elimination of Soil-Borne Pathogens

Exposure to the soil-borne pathogens Burkholderia pseudomallei and Burkholderia cenocepacia can lead to severe infections and even mortality. These pathogens exhibit a high resistance to antibiotic treatments. In addition, no licensed vaccine is currently available. A nanoscale platinum-containing titania photocatalyst (TiO2-Pt) has been shown to have a superior visible light-responsive photocatalytic ability to degrade chemical contaminants like nitrogen oxides. The antibacterial activity of the catalyst and its potential use in soil pathogen control were evaluated. Using the plating method, we found that TiO2-Pt exerts superior antibacterial performance against Escherichia coli compared to other commercially available and laboratory prepared ultraviolet/visible light-responsive titania photocatalysts. TiO2-Pt-mediated photocatalysis also affectively eliminates the soil-borne bacteria B. pseudomallei and B. cenocepacia. An air pouch infection mouse model further revealed that TiO2-Pt-mediated photocatalysis could reduce the pathogenicity of both strains of bacteria. Unexpectedly, water containing up to 10% w/v dissolved soil particles did not reduce the antibacterial potency of TiO2-Pt, suggesting that the TiO2-Pt photocatalyst is suitable for use in soil-contaminated environments. The TiO2-Pt photocatalyst exerted superior antibacterial activity against a broad spectrum of human pathogens, including B. pseudomallei and B. cenocepacia. Soil particles (<10% w/v) did not significantly reduce the antibacterial activity of TiO2-Pt in water. These findings suggest that the TiO2-Pt photocatalyst may have potential applications in the development of bactericides for soil-borne pathogens