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009). CONCLUSIONS The use of an additional drape reduced radiation exposure of both the first and second operator during routine radial procedures; a shield-attached curtain alone was only partially effective.Composite endpoints are commonly used in clinical trials, and time-to-first-event analysis has been the usual standard. Time-to-first-event analysis treats all components of the composite endpoint as having equal severity and is heavily influenced by short-term components. Over the last decade, novel statistical approaches have been introduced to overcome these limitations. We reviewed win ratio analysis, competing risk regression, negative binomial regression, Andersen-Gill regression, and weighted composite endpoint (WCE) analysis. Each method has both advantages and limitations. The advantage of win ratio and WCE analyses is that they take event severity into account by assigning weights to each component of the composite endpoint. These weights should be pre-specified, because they strongly influence treatment effect estimates. Negative binomial regression and Andersen-Gill analyses consider all events for each patient - rather than only the first event - and tend to have more statistical power than time-to-first-event analysis. Pre-specified novel statistical methods may enhance our understanding of novel therapy when components vary substantially in severity and timing. These methods consider the specific type of patients, drugs, devices, events, and follow-up duration.AIMS This study evaluated the optical frequency domain imaging (OFDI) artifact of tangential signal dropout (TSD), which mimics the appearance of lipid-rich plaque and macrophage (Mø) infiltration. METHODS AND RESULTS A total of 1,019 histological cross-sections from 23 autopsy hearts were matched with the corresponding OFDI images. Of those, 232 OFDI cross-sections that contained signal-poor regions with diffuse borders were classified as lipid-rich plaques. The angle θ was calculated between the OFDI beam that strikes the edge of the luminal surface of the low-intensity region and that which strikes the surface line of the low-intensity region. On histological evaluation, 182 (78%) cross-sections were classified as histologically lipidic/Mø infiltration, while the remaining 50 (22%) cross-sections as histologically non-lipidic/Mø infiltration. The angle θ was significantly smaller in the non-lipidic/Mø infiltration group than in the lipidic/Mø infiltration group (12±6° versus 37±14°, p less then 0.001). Receiver operating curve analysis revealed that the optimal cutoff value of the incident angle for predicting TSD was 23° with area under the curve 0.98. CONCLUSIONS When the OFDI imaging beam strikes the tissue at an angle q less then 23°, TSD artifact could occur. To eliminate image misinterpretation, our findings suggest that the OFDI catheter geometry should be considered for the accurate diagnosis of lipid-rich plaques and Mø infiltration.AIMS To assess, whether Culotte technique could be improved by an additional kissing dilation prior main branch (MB) stenting. METHODS AND RESULTS Double-kissing (DK) Culotte was compared to Culotte and DK-Crush techniques in bench model (n=24). Results were evaluated for stent apposition, for luminal opening and for flow dynamics. Total procedure duration of DK-Culotte was 18.3±3.4min, significantly lower than for DK-Crush (24.3±5.7min; p=0.015), however similar to Culotte (21.6±5.9min, p=0.104). In DK-Culotte overall rate of moderate (200-500mm) and significant (>500mm) malapposition was 2.1±1.9% and 0.4±0.2%; similar as compared to Culotte (3.7±3.8%, p=0.459 and 1.0±1.0%, p=0.517; respectively), and lower as compared to DK-Crush (8.1±2.5%, p less then 0.001 and 3.7±5.3%, p=0.002; respectively). Lower malapposition rate of DK-Culotte as compared to DK-Crush was due to less moderate and significant malapposition in proximal MB (0.0±0.0% vs. 14.0±7.6%, p less then 0.001 and 0.0±0.0% vs. 4.2±9.1%, p=0.026, respectively). Micro computed tomography did not show difference in luminal opening at proximal MB, distal MB or SB. There was no difference either in maximum shear rate or in areas of high shear or recirculation. CONCLUSIONS Bench tests data suggest that DK approach facilitates Culotte technique. selleck chemicals Clinical validity and relevance remains to be confirmed in larger in vivo population.The H2A.Z histone variant, a genome-wide hallmark of permissive chromatin, is enriched near transcription start sites in all eukaryotes. H2A.Z is deposited by the SWR1 chromatin remodeler and evicted by unclear mechanisms. We tracked H2A.Z in living yeast at single-molecule resolution, and found that H2A.Z eviction is dependent on RNA Polymerase II (Pol II) and the Kin28/Cdk7 kinase, which phosphorylates Serine 5 of heptapeptide repeats on the carboxy-terminal domain of the largest Pol II subunit Rpb1. These findings link H2A.Z eviction to transcription initiation, promoter escape and early elongation activities of Pol II. Because passage of Pol II through +1 nucleosomes genome-wide would obligate H2A.Z turnover, we propose that global transcription at yeast promoters is responsible for eviction of H2A.Z. Such usage of yeast Pol II suggests a general mechanism coupling eukaryotic transcription to erasure of the H2A.Z epigenetic signal.COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents. plain-language-summary The COVID-19 pandemic represents an unprecedented threat to global he of disease. This hypothesis is unproven, and more work is needed to see if it is clinically relevant. If that work provides a proof of concept, it means that existing treatments and registered drugs could potentially help patients with COVID-19, by preventing the need for mechanical ventilation and saving many lives. © 2020, van de Veerdonk et al.Recent studies indicate that many developing tissues modify glycolysis to favor lactate synthesis, but how this promotes development is unclear. Using forward and reverse genetics in zebrafish, we show that disrupting the glycolytic gene phosphoglycerate kinase-1 (pgk1) impairs Fgf-dependent development of hair cells and neurons in the otic vesicle and other neurons in the CNS/PNS. Fgf-MAPK signaling underperforms in pgk1-/- mutants even when Fgf is transiently overexpressed. Wild-type embryos treated with drugs that block synthesis or secretion of lactate mimic the pgk1-/- phenotype, whereas pgk1-/- mutants are rescued by treatment with exogenous lactate. Lactate treatment of wild-type embryos elevates expression of Etv5b/Erm even when Fgf signaling is blocked. However, lactate's ability to stimulate neurogenesis is reversed by blocking MAPK. Thus, lactate raises basal levels of MAPK and Etv5b (a critical effector of the Fgf pathway), rendering cells more responsive to dynamic changes in Fgf signaling required by many developing tissues. © 2020, Kantarci et al.piRNAs play a critical role in the regulation of transposons and other germline genes. In Caenorhabditis elegans, regulation of piRNA target genes is mediated by the mutator complex, which synthesizes high levels of siRNAs through the activity of an RNA-dependent RNA polymerase. However, the steps between mRNA recognition by the piRNA pathway and siRNA amplification by the mutator complex are unknown. Here, we identify the Tudor domain protein, SIMR-1, as acting downstream of piRNA production and upstream of mutator complex-dependent siRNA biogenesis. Interestingly, SIMR-1 also localizes to distinct subcellular foci adjacent to P granules and Mutator foci, two phase-separated condensates that are the sites of piRNA-dependent mRNA recognition and mutator complex-dependent siRNA amplification, respectively. Thus, our data suggests a role for multiple perinuclear condensates in organizing the piRNA pathway and promoting mRNA regulation by the mutator complex. © 2020, Manage et al.One of the fundamental gaps in our knowledge of how novel anatomical structures evolve is understanding the origins of the morphogenetic processes that form these features. Here, we traced the cellular development of a recently evolved morphological novelty, the posterior lobe of D. melanogaster. We found that this genital outgrowth forms through extreme increases in epithelial cell height. By examining the apical extracellular matrix (aECM), we also uncovered a vast matrix associated with the developing genitalia of lobed and non-lobed species. The aECM protein Dumpy is spatially expanded in lobe-forming species, connecting the posterior lobe to the ancestrally derived aECM network. Further analysis demonstrated that Dumpy attachments are necessary for cell height increases during posterior lobe development. We propose that the aECM presents a rich reservoir for generating morphological novelty and highlights a yet unseen role for aECM in regulating extreme cell height. © 2020, Smith et al.In the nucleus, the spatiotemporal regulation of the catalytic subunit of cAMP-dependent protein kinase A (PKA-C) is orchestrated by an intrinsically disordered protein kinase inhibitor, PKI, which recruits the CRM1/RanGTP nuclear exporting complex. How the PKA-C/PKI complex assembles and recognizes CRM1/RanGTP is not well understood. Using NMR, SAXS, fluorescence, metadynamics, and Markov model analysis, we determined the multi-state recognition pathway for PKI. After a fast binding step in which PKA-C selects PKI's most competent conformations, PKI folds upon binding through a slow conformational rearrangement within the enzyme's binding pocket. The high-affinity and pseudo-substrate regions of PKI become more structured and the transient interactions with the kinase augment the helical content of the nuclear export sequence, which is then poised to recruit the CRM1/RanGTP complex for nuclear translocation. The multistate binding mechanism featured by PKA-C/PKI complex represents a paradigm on how disordered, ancillary proteins (or protein domains) are able to operate multiple functions such as inhibiting the kinase while recruiting other regulatory proteins for nuclear export. © 2020, Olivieri et al.Minor and major spliceosomes control splicing of distinct intron types and are thought to act largely independent of one another. SR proteins are essential splicing regulators mostly connected to the major spliceosome. Here, we show that Srsf10 expression is controlled through an autoregulated minor intron, tightly correlating Srsf10 with minor spliceosome abundance across different tissues and differentiation stages in mammals. Surprisingly, all other SR proteins also correlate with the minor spliceosome and Srsf10, and abolishing Srsf10 autoregulation by Crispr/Cas9-mediated deletion of the autoregulatory exon induces expression of all SR proteins in a human cell line. Our data thus reveal extensive crosstalk and a global impact of the minor spliceosome on major intron splicing. © 2020, Meinke et al.