Phosphorylation-dependent inhibition of Cdc42 GEF Gef1 by 14-3-3 protein Rad24 spatially regulates Cdc42 GTPase activity and oscillatory dynamics during cell morphogenesis

© The Author(s), 2015. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Molecular Biology of the Cell 26 (2015): 3520-3534, doi:10.1091/mbc.E15-02-0095.Active Cdc42 GTPase, a key regulator of cell polarity, displays oscillatory dynamics that are anticorrelated at the two cell tips in fission yeast. Anticorrelation suggests competition for active Cdc42 or for its effectors. Here we show how 14-3-3 protein Rad24 associates with Cdc42 guanine exchange factor (GEF) Gef1, limiting Gef1 availability to promote Cdc42 activation. Phosphorylation of Gef1 by conserved NDR kinase Orb6 promotes Gef1 binding to Rad24. Loss of Rad24–Gef1 interaction increases Gef1 protein localization and Cdc42 activation at the cell tips and reduces the anticorrelation of active Cdc42 oscillations. Increased Cdc42 activation promotes precocious bipolar growth activation, bypassing the normal requirement for an intact microtubule cytoskeleton and for microtubule-dependent polarity landmark Tea4-PP1. Further, increased Cdc42 activation by Gef1 widens cell diameter and alters tip curvature, countering the effects of Cdc42 GTPase-activating protein Rga4. The respective levels of Gef1 and Rga4 proteins at the membrane define dynamically the growing area at each cell tip. Our findings show how the 14-3-3 protein Rad24 modulates the availability of Cdc42 GEF Gef1, a homologue of mammalian Cdc42 GEF DNMBP/TUBA, to spatially control Cdc42 GTPase activity and promote cell polarization and cell shape emergence.Work in F.V.’s laboratory is supported by National Institutes of Health R01 Grant GM095867. Part of this work was also supported by National Science Foundation Grant 0745129. J.R.Y. is supported by National Institutes of Health Grants P41 GM103533 and R01 MH 067880

Clinical actionability of comprehensive genomic profiling for management of rare or refractory cancers

Background. The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. Methods. A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Results. Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0–10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. Conclusion. Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. Implications for Practice: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents

Genome sequencing unveils a regulatory landscape of platelet reactivity

Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes

Acceptance towards Monkeypox Vaccination: A Systematic Review and Meta-Analysis

Vaccination it is considered a vital strategy in order to mitigate monkeypox by protecting from severe disease and helping in reduction of hospitalisations. In this sense, this study aims to estimate the global prevalence of vaccination acceptance against monkeypox. We conducted a systematic review with a comprehensive search strategy for the following databases: PubMed, Scopus and Web of Science. A random-effect model meta-analysis was carried out using observational studies assessing the intention of vaccines against monkeypox from multiple continents. The quality assessment was developed using the Newcastle-Ottawa Scale adapted for cross-sectional studies. In addition, a subgroup analysis by study location and population and a sensitivity analysis was developed.Eleven cross-sectional studies were included. A total of 8045 participants were included. The pooled prevalence of monkeypox vaccination acceptance in all participants was 56.0% (95%CI: 42.0–70.0%). In the subgroup analysis of monkeypox vaccine acceptance according to continents, the prevalence of vaccine acceptance was 50.0% (95%CI: 24.0–76.0%) in Asian countries and 70.0% (95%CI: 55.0–84.0%) in European countries. The prevalence of vaccine acceptance was 43.0% (95%CI: 35.0–50.0%) in the general population, 63.0% (95%CI: 42.0–70.0%) in healthcare workers, and 84.0% (95%CI: 83.0–86.0%) in the LGBTI community. Despite the high prevalence of monkeypox vaccination acceptance in the LGBTI community found in our study, vaccination acceptance from healthcare workers and the general population are lower. Governments could use these results for planning, developing or promoting vaccination strategies and public health policies focused on these populations.Revisión por pare

Quantum Correlation in One-dimensional Extend Quantum Compass Model

We study the correlations in the one-dimensional extended quantum compass model in a transverse magnetic field. By exactly solving the Hamiltonian, we find that the quantum correlation of the ground state of one-dimensional quantum compass model is vanishing. We show that quantum discord can not only locate the quantum critical points, but also discern the orders of phase transitions. Furthermore, entanglement quantified by concurrence is also compared.Comment: 8 pages, 14 figures, to appear in Eur. Phys. J.

Curated and harmonized gut microbiome 16S rRNA amplicon data from dietary fiber intervention studies in humans

Next generation amplicon sequencing has created a plethora of data from human microbiomes. The accessibility to this scientific data and its corresponding metadata is important for its reuse, to allow for new discoveries, verification of published results, and serving as path for reproducibility. Dietary fiber consumption has been associated with a variety of health benefits that are thought to be mediated by gut microbiota. To enable direct comparisons of the response of the gut microbiome to fiber, we obtained 16S rRNA sequencing data and its corresponding metadata from 11 fiber intervention studies for a total of 2,368 samples. We provide curated and pre-processed genetic data and common metadata for comparison across the different studies

Curated and Harmonized Gut Microbiome 16S rRNA Amplicon Data From Dietary Fiber Intervention Studies in Humans

Next generation amplicon sequencing has created a plethora of data from human microbiomes. The accessibility to this scientific data and its corresponding metadata is important for its reuse, to allow for new discoveries, verification of published results, and serving as path for reproducibility. Dietary fiber consumption has been associated with a variety of health benefits that are thought to be mediated by gut microbiota. To enable direct comparisons of the response of the gut microbiome to fiber, we obtained 16S rRNA sequencing data and its corresponding metadata from 11 fiber intervention studies for a total of 2,368 samples. We provide curated and pre-processed genetic data and common metadata for comparison across the different studies

Mid-Holocene, coral-based sea surface temperatures in the western tropical Atlantic

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial‐NoDerivs License. The definitive version was published in Rodriguez, L. G., Cohen, A. L., Ramirez, W., Oppo, D. W., Pourmand, A., Edwards, R. L., Alpert, A. E., & Mollica, N. Mid-Holocene, coral-based sea surface temperatures in the western tropical Atlantic. Paleoceanography and Paleoclimatology, 34(7), (2019): 1234-1245, doi:10.1029/2019PA003571.The Holocene is considered a period of relative climatic stability, but significant proxy data‐model discrepancies exist that preclude consensus regarding the postglacial global temperature trajectory. In particular, a mid‐Holocene Climatic Optimum, ~9,000 to ~5,000 years BP, is evident in Northern Hemisphere marine sediment records, but its absence from model simulations raises key questions about the ability of the models to accurately simulate climate and seasonal biases that may be present in the proxy records. Here we present new mid‐Holocene sea surface temperature (SST) data from the western tropical Atlantic, where twentieth‐century temperature variability and amplitude of warming track the twentieth‐century global ocean. Using a new coral thermometer Sr‐U, we first developed a temporal Sr‐U SST calibration from three modern Atlantic corals and validated the calibration against Sr‐U time series from a fourth modern coral. Two fossil corals from the Enriquillo Valley, Dominican Republic, were screened for diagenesis, U‐series dated to 5,199 ± 26 and 6,427 ± 81 years BP, respectively, and analyzed for Sr/Ca and U/Ca, generating two annually resolved Sr‐U SST records, 27 and 17 years long, respectively. Average SSTs from both corals were significantly cooler than in early instrumental (1870–1920) and late instrumental (1965–2016) periods at this site, by ~0.5 and ~0.75 °C, respectively, a result inconsistent with the extended mid‐Holocene warm period inferred from sediment records. A more complete sampling of Atlantic Holocene corals can resolve this issue with confidence and address questions related to multidecadal and longer‐term variability in Holocene Atlantic climate.This study was supported by NSF OCE 1747746 to Anne Cohen and by NSF OCE 1805618 to Anne Cohen and Delia Oppo. Eric Loss and his crew on Pangaea Exploration's Sea Dragon enabled fieldwork in Martinique, and George P. Lohman, Thomas DeCarlo, and Hanny Rivera assisted with coral coring. Kathryn Pietro and Julia Middleton assisted in the laboratory, and Louis Kerr provided technical support on the SEM at MBL. Gretchen Swarr provided technical support on the Element and iCap ICPMS at WHOI. We also thank Edwin Hernandez, Jose Morales, and Amos Winter for discussion. All data generated in this study will be made publicly available at http://www.ncdc.noaa.gov/data‐ access/paleoclimatology‐data/dataset