The Clinical and Pathological Profile of BRCA1 Gene Methylated Breast Cancer Women. A Meta-Analysis

Background: DNA aberrant hypermethylation is the major cause of transcriptional silencing of the breast cancer gene 1 (BRCA1) gene in sporadic breast cancer patients. The aim of the present meta-analysis was to analyze all available studies reporting clinical characteristics of BRCA1 gene hypermethylated breast cancer in women, and to pool the results to provide a unique clinical profile of this cancer population. Methods: On September 2020, a systematic literature search was performed. Data were retrieved from PubMed, MEDLINE, and Scopus by searching the terms: “BRCA*” AND “methyl*” AND “breast”. All studies evaluating the association between BRCA1 methylation status and breast cancer patients’ clinicopathological features were considered for inclusion. Results: 465 studies were retrieved. Thirty (6.4%) studies including 3985 patients met all selection criteria. The pooled analysis data revealed a significant correlation between BRCA1 gene hypermethylation and advanced breast cancer disease stage (OR = 0.75: 95% CI: 0.58–0.97; p = 0.03, fixed effects model), lymph nodes involvement (OR = 1.22: 95% CI: 1.01–1.48; p = 0.04, fixed effects model), and pre-menopausal status (OR = 1.34: 95% CI: 1.08–1.66; p = 0.008, fixed effects model). No association could be found between BRCA1 hypermethylation and tumor histology (OR = 0.78: 95% CI: 0.59–1.03; p = 0.08, fixed effects model), tumor grading (OR = 0.78: 95% CI: 0.46–1.32; p = 0.36, fixed effects model), and breast cancer molecular classification (OR = 1.59: 95% CI: 0.68–3.72; p = 0.29, random effects model). Conclusions: hypermethylation of the BRCA1 gene significantly correlates with advanced breast cancer disease, lymph nodes involvement, and pre-menopausal cancer onset

Natural cycle results in lower implantation failure than ovarian stimulation in advanced-age poor responders undergoing IVF. fertility outcomes from 585 patients

To compare pregnancy rate and implantation rate in poor responder women, aged over 40 years, who underwent natural cycle versus conventional ovarian stimulation. This is a retrospective single-center cohort study conducted at the GENERA IVF program, Rome, Italy, between September 2012 and December 2018, including only poor responder patients, according to Bologna criteria, of advanced age, who underwent IVF treatment through Natural Cycle or conventional ovarian stimulation. Between September 2012 and December 2018, 585 patients were included within the study. Two hundred thirty patients underwent natural cycle and 355 underwent conventional ovarian stimulation. In natural cycle group, both pregnancy rate per cycle (6.25 vs 12.89%, respectively, p = 0.0001) and pregnancy rate per patient101 with at least one embryo-transfer (18.85 vs 28.11% respectively, p = 0.025) resulted significant reduced. Pregnancy rate per patient managed with conventional ovarian stimulation resulted not significantly different compared with natural cycle (19.72 vs 15.65% respectively, p = 0.228), but embryo implantation rate was significantly higher in patients who underwent natural cycle rather than patient subjected to conventional ovarian stimulation (13 vs 8.28% respectively, p = 0.0468). No significant difference could be detected among the two groups in terms of abortion rate (p = 0.2915) or live birth pregnancy (p = 0.2281). Natural cycle seems to be a valid treatment in patients over 40 years and with a low ovarian reserve, as an alternative to conventional ovarian stimulation

Biological Impact of Unilateral Oophorectomy. Does the Number of Ovaries Really Matter? [Biologische auswirkungen der einseitigen ovarektomie: Kommt es wirklich auf die anzahl der eierstöcke an?]

Although unilateral oophorectomies are performed more often than bilateral ones in women of reproductive age, their clinical consequences have been less intensively investigated. Experimental models in animals have shown that compensa- tory mechanisms occur after a unilateral oophorectomy (UO). This review aims to summarize the available evidence on the biological effects of unilateral oophorectomy on wom- en. Evaluated outcomes include age at onset of menopause, risk of cardiovascular and neurological disease, risk of mortal- ity and fertility outcome after spontaneous conception or in vitro fertilization (IVF). Results were compared with findings reported after bilateral oophorectomy and/or ovarian excision and/or women with intact ovaries. An electronic database search was performed using PubMed and Scopus, followed by a manual search to identify controlled studies that com- pared women after UO with women with two intact ovaries. In particular, a systematic review of fertility outcomes after IVF was performed, and the data were summarized in a table. Women who underwent UO had a similar age at menopause and similar clinical pregnancy rate compared to women with two ovaries. However, decreased ovarian reserve affecting the quantity but not the quality of the ovarian pool after IVF was observed in the UO group. Furthermore, an increased risk of neurological disease and even an increased risk of mortality was observed in women with single ovary. These data need to be confirmed by further studies, and a plausible mecha- nism of action must be identified. At present, patients who undergo UO can be reassured with regard to their reproduc- tive potential and their age at onset of menopause

X Chromosome Inactivation and Differentiation Occur Readily in ES Cells Doubly-Deficient for MacroH2A1 and MacroH2A2

Macrohistones (mH2As) are unusual histone variants found exclusively in vertebrate chromatin. In mice, the H2afy gene encodes two splice variants, mH2A1.1 and mH2A1.2 and a second gene, H2afy2, encodes an additional mH2A2 protein. Both mH2A isoforms have been found enriched on the inactive X chromosome (Xi) in differentiated mammalian female cells, and are incorporated into the chromatin of developmentally-regulated genes. To investigate the functional significance of mH2A isoforms for X chromosome inactivation (XCI), we produced male and female embryonic stem cell (ESC) lines with stably-integrated shRNA constructs that simultaneously target both mH2A1 and mH2A2. Surprisingly, we find that female ESCs deficient for both mH2A1 and mH2A2 readily execute and maintain XCI upon differentiation. Furthermore, male and female mH2A-deficient ESCs proliferate normally under pluripotency culture conditions, and respond to several standard differentiation procedures efficiently. Our results show that XCI can readily proceed with substantially reduced total mH2A content

Axonal Odorant Receptors Mediate Axon Targeting

In mammals, odorant receptors not only detect odors but also define the target in the olfactory bulb, where sensory neurons project to give rise to the sensory map. The odorant receptor is expressed at the cilia, where it binds odorants, and at the axon terminal. The mechanism of activation and function of the odorant receptor at the axon terminal is, however, still unknown. Here, we identify phosphatidylethanolamine- binding protein 1 as a putative ligand that activates the odorant receptor at the axon terminal and affects the turning behavior of sensory axons.Genetic ablation of phosphatidylethanolamine-binding protein 1 in mice results in a strongly disturbed olfactory sensory map. Our data suggest that the odorant receptor at the axon terminal of olfactory neurons acts as an axon guidance cue that responds to molecules originating in the olfactory bulb. The dual function of the odorant receptor links specificity of odor perception and axon targeting

Broad-spectrum coronavirus 3C-like protease peptidomimetic inhibitors effectively block SARS-CoV-2 replication in cells: Design, synthesis, biological evaluation, and X-ray structure determination

Despite the approval of vaccines, monoclonal antibodies and restrictions during the pandemic, the demand for new efficacious and safe antivirals is compelling to boost the therapeutic arsenal against the COVID-19. The viral 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for replication with high homology in the active site across CoVs and variants showing an almost unique specificity for Leu-Gln as P2-P1 residues, allowing the development of broad-spectrum inhibitors.The design, synthesis, biological activity, and cocrystal structural information of newly conceived peptidomimetic covalent reversible inhibitors are herein described. The inhibitors display an aldehyde warhead, a Gln mimetic at P1 and modified P2-P3 residues. Particularly, functionalized proline residues were inserted at P2 to stabilize the beta-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CLpro of SARS-CoV-2 and MERS-CoV and inhibited viral replication of three human CoVs, i.e. SARS-CoV-2, MERS-CoV, and HCoV 229 in different cell lines. Particularly, derivative 12 exhibited nM-low mu M antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CLpro validating our design. Altogether, these results foster future work toward broad-spectrum 3CLpro inhibitors to challenge CoVs related pandemics

Design of a modular Autonomous Underwater Vehicle for archaeological investigations

MARTA (MARine Tool for Archaeology) is a modular AUV (Autonomous Underwater Vehicle) designed and developed by the University of Florence in the framework of the ARROWS (ARchaeological RObot systems for the World's Seas) FP7 European project. The ARROWS project challenge is to provide the underwater archaeologists with technological tools for cost affordable campaigns: i.e. ARROWS adapts and develops low cost AUV technologies to significantly reduce the cost of archaeological operations, covering the full extent of an archaeological campaign (underwater mapping, diagnosis and cleaning tasks). The tools and methodologies developed within ARROWS comply with the "Annex" of the 2001 UNESCO Convention for the protection of Underwater Cultural Heritage (UCH). The system effectiveness and MARTA performance will be demonstrated in two scenarios, different as regards the environment and the historical context, the Mediterranean Sea (Egadi Islands) and the Baltic Sea

Superclustering with the Atacama cosmology telescope and dark energy survey. I. Evidence for thermal energy anisotropy using oriented stacking

Lokken et al.The cosmic web contains filamentary structure on a wide range of scales. On the largest scales, superclustering aligns multiple galaxy clusters along intercluster bridges, visible through their thermal Sunyaev–Zel'dovich signal in the cosmic microwave background. We demonstrate a new, flexible method to analyze the hot gas signal from multiscale extended structures. We use a Compton y-map from the Atacama Cosmology Telescope (ACT) stacked on redMaPPer cluster positions from the optical Dark Energy Survey (DES). Cutout images from the y-map are oriented with large-scale structure information from DES galaxy data such that the superclustering signal is aligned before being overlaid. We find evidence of an extended quadrupole moment of the stacked y signal at the 3.5σ level, demonstrating that the large-scale thermal energy surrounding galaxy clusters is anisotropically distributed. We compare our ACT × DES results with the Buzzard simulations, finding broad agreement. Using simulations, we highlight the promise of this novel technique for constraining the evolution of anisotropic, non-Gaussian structure using future combinations of microwave and optical surveys.J.R.B. was funded by the Natural Sciences and Engineering Research Council of Canada Discovery Grant Program and a fellowship from the Canadian Institute for Advanced Research (CIFAR) Gravity and Extreme Universe program. A.D.H. acknowledges support from the Sutton Family Chair in Science, Christianity and Cultures. R.H. is a CIFAR Azrieli Global Scholar, Gravity and the Extreme Universe Program, 2019, and a 2020 Alfred P. Sloan Research Fellow. R.H. is supported by the Natural Sciences and Engineering Research Council of Canada Discovery Grant Program and the Connaught Fund. The Dunlap Institute is funded through an endowment established by the David Dunlap family and the University of Toronto. J.P.H. acknowledges funding for SZ cluster studies from NSF AAG No. AST-1615657. M.L. acknowledges the support of the National Sciences and Engineering Research Council of Canada (NSERC) [PGSD - 559296 - 2021] and the Queen Elizabeth II / Graduate Scholarships in Science and Technology (QEII-GSST). K.M. acknowledges support from the National Research Foundation of South Africa. This work was supported by the U.S. National Science Foundation through awards AST-0408698, AST-0965625, and AST-1440226 for the ACT project, as well as awards PHY-0355328, PHY-0855887, and PHY-1214379. Funding was also provided by Princeton University, the University of Pennsylvania, and a Canada Foundation for Innovation (CFI) award to UBC. ACT operates in the Parque Astronómico Atacama in northern Chile under the auspices of the Comisión Nacional de Investigación (CONICYT). The development of multichroic detectors and lenses was supported by NASA grants NNX13AE56G and NNX14AB58G. Detector research at NIST was supported by the NIST Innovations in Measurement Science program. Funding for the DES Projects has been provided by the U.S. Department of Energy, the U.S. National Science Foundation, the Ministry of Science and Education of Spain, the Science and Technology Facilities Council of the United Kingdom, the Higher Education Funding Council for England, the National Center for Supercomputing Applications at the University of Illinois at Urbana-Champaign, the Kavli Institute of Cosmological Physics at the University of Chicago, the Center for Cosmology and Astro-Particle Physics at the Ohio State University, the Mitchell Institute for Fundamental Physics and Astronomy at Texas A&M University, Financiadora de Estudos e Projetos, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Conselho Nacional de Desenvolvimento Científico e Tecnológico and the Ministério da Ciência, Tecnologia e Inovação, the Deutsche Forschungsgemeinschaft and the Collaborating Institutions in the Dark Energy Survey. The Collaborating Institutions are Argonne National Laboratory, the University of California at Santa Cruz, the University of Cambridge, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas-Madrid, the University of Chicago, University College London, the DES-Brazil Consortium, the University of Edinburgh, the Eidgenössische Technische Hochschule (ETH) Zürich, Fermi National Accelerator Laboratory, the University of Illinois at Urbana-Champaign, the Institut de Ciències de l'Espai (IEEC/CSIC), the Institut de Física d'Altes Energies, Lawrence Berkeley National Laboratory, the Ludwig-Maximilians Universität München and the associated Excellence Cluster Universe, the University of Michigan, NFS' NOIRLab, the University of Nottingham, The Ohio State University, the University of Pennsylvania, the University of Portsmouth, SLAC National Accelerator Laboratory, Stanford University, the University of Sussex, Texas A&M University, and the OzDES Membership Consortium. Based in part on observations at Cerro Tololo Inter-American Observatory at NSF's NOIRLab (NOIRLab Prop. ID 2012B-0001; PI: J. Frieman), which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation. The DES data management system is supported by the National Science Foundation under grant Nos. AST-1138766 and AST-1536171. The DES participants from Spanish institutions are partially supported by MICINN under grant Nos. ESP2017-89838, PGC2018-094773, PGC2018-102021, SEV-2016-0588, SEV-2016-0597, and MDM-2015-0509, some of which include ERDF funds from the European Union. IFAE is partially funded by the CERCA program of the Generalitat de Catalunya. Research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Program (FP7/2007-2013), including ERC grant agreements 240672, 291329, and 306478. We acknowledge support from the Brazilian Instituto Nacional de Ciência e Tecnologia (INCT) do e-Universo (CNPq grant 465376/2014-2). We thank the anonymous referee for providing valuable comments which improved the quality of the manuscript. This manuscript has been authored by Fermi Research Alliance, LLC under Contract No. DE-AC02-07CH11359 with the U.S. Department of Energy, Office of Science, Office of High Energy Physics. This work received support from the U.S. Department of Energy under contract No. DE-AC02-76SF00515 at SLAC National Accelerator Laboratory. This research used computing resources at SLAC National Accelerator Laboratory and at the National Energy Research Scientific Computing Center (NERSC), a U.S. Department of Energy Office of Science User Facility located at Lawrence Berkeley National Laboratory, operated under contract No. DE-AC02-05CH11231.Peer reviewe

The DES view of the Eridanus supervoid and the CMB cold spot

A. Kovács et al.The Cold Spot is a puzzling large-scale feature in the Cosmic Microwave Background temperature maps and its origin has been subject to active debate. As an important foreground structure at low redshift, the Eridanus supervoid was recently detected, but it was subsequently determined that, assuming the standard ΛCDM model, only about 10–20 per cent of the observed temperature depression can be accounted for via its Integrated Sachs–Wolfe imprint. However, R ≳ 100 h−1Mpc supervoids elsewhere in the sky have shown ISW imprints AISW ≈ 5.2 ± 1.6 times stronger than expected from ΛCDM (AISW = 1), which warrants further inspection. Using the Year-3 redMaGiC catalogue of luminous red galaxies from the Dark Energy Survey, here we confirm the detection of the Eridanus supervoid as a significant underdensity in the Cold Spot’s direction at z < 0.2. We also show, with S/N ≳ 5 significance, that the Eridanus supervoid appears as the most prominent large-scale underdensity in the dark matter mass maps that we reconstructed from DES Year-3 gravitational lensing data. While we report no significant anomalies, an interesting aspect is that the amplitude of the lensing signal from the Eridanus supervoid at the Cold Spot centre is about 30 per cent lower than expected from similar peaks found in N-body simulations based on the standard ΛCDM model with parameters Ωm = 0.279 and σ8 = 0.82. Overall, our results confirm the causal relation between these individually rare structures in the cosmic web and in the CMB, motivating more detailed future surveys in the Cold Spot region.AK has been supported by a Juan de la Cierva Incorporación fellowship with project number IJC2018-037730-I, and funding for this project was also available in part through SEV-2015-0548 and AYA2017-89891-P. Funding for the DES Projects has been provided by the U.S. Department of Energy, the U.S. National Science Foundation, the Ministry of Science and Education of Spain, the Science and Technology Facilities Council of the United Kingdom, the Higher Education Funding Council for England, the National Center for Supercomputing Applications at the University of Illinois at Urbana-Champaign, the Kavli Institute of Cosmological Physics at the University of Chicago, the Center for Cosmology and Astro-Particle Physics at the Ohio State University, the Mitchell Institute for Fundamental Physics and Astronomy at Texas A&M University, Financiadora de Estudos e Projetos, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Conselho Nacional de Desenvolvimento Científico e Tecnológico and the Ministério da Ciência, Tecnologia e Inovação, the Deutsche Forschungsgemeinschaft and the Collaborating Institutions in the Dark Energy Survey. The DES data management system is supported by the National Science Foundation under Grant Numbers AST-1138766 and AST-1536171. The DES participants from Spanish institutions are partially supported by MICINN under grants ESP2017-89838, PGC2018-094773, PGC2018-102021, SEV-2016-0588, SEV-2016-0597, and MDM-2015-0509, some of which include ERDF funds from the European Union. IFAE is partially funded by the CERCA program of the Generalitat de Catalunya. Research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Program (FP7/2007-2013) including ERC grant agreements 240672, 291329, and 306478. We acknowledge support from the Brazilian Instituto Nacional de Ciência e Tecnologia (INCT) do e-Universo (CNPq grant 465376/2014-2).Peer reviewe

The ARROWS project: Adapting and developing robotics technologies for underwater archaeology

ARchaeological RObot systems for the World's Seas (ARROWS) EU Project proposes to adapt and develop low-cost Autonomous Underwater Vehicle (AUV) technologies to significantly reduce the cost of archaeological operations, covering the full extent of archaeological campaign. ARROWS methodology is to identify the archaeologists requirements in all phases of the campaign and to propose related technological solutions. Starting from the necessities identified by archaeological project partners in collaboration with the Archaeology Advisory Group, a board composed of European archaeologists from outside ARROWS, the aim is the development of a heterogeneous team of cooperating AUVs capable of comply with a complete archaeological autonomous mission. Three new different AUVs have been designed in the framework of the project according to the archaeologists' indications: MARTA, characterized by a strong hardware modularity for ease of payload and propulsion systems configuration change; U-C AT, a turtle inspired bio-mimetic robot devoted to shipwreck penetration and A-Size AUV, a vehicle of small dimensions and weight easily deployable even by a single person. These three vehicles will cooperate within the project with AUVs already owned by ARROWS partners exploiting a distributed high-level control software based on the World Model Service (WMS), a storage system for the environment knowledge, updated in real-time through online payload data process, in the form of an ontology. The project includes also the development of a cleaning tool for well-known artifacts maintenance operations. The paper presents the current stage of the project that will lead to overall system final demonstrations, during Summer 2015, in two different scenarios, Sicily (Italy) and Baltic Sea (Estonia