The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer, studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory, a versatile observatory designed to address the Hot and Energetic Universe science theme, selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), it aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over an hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR, browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters. Finally we briefly discuss on the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, and touch on communication and outreach activities, the consortium organisation, and finally on the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. (abridged).Comment: 48 pages, 29 figures, Accepted for publication in Experimental Astronomy with minor editin

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory. Athena is a versatile observatory designed to address the Hot and Energetic Universe science theme, as selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), X-IFU aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over a hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR (i.e. in the course of its preliminary definition phase, so-called B1), browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters, such as the instrument efficiency, spectral resolution, energy scale knowledge, count rate capability, non X-ray background and target of opportunity efficiency. Finally, we briefly discuss the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, touch on communication and outreach activities, the consortium organisation and the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. The X-IFU will be provided by an international consortium led by France, The Netherlands and Italy, with ESA member state contributions from Belgium, Czech Republic, Finland, Germany, Poland, Spain, Switzerland, with additional contributions from the United States and Japan.The French contribution to X-IFU is funded by CNES, CNRS and CEA. This work has been also supported by ASI (Italian Space Agency) through the Contract 2019-27-HH.0, and by the ESA (European Space Agency) Core Technology Program (CTP) Contract No. 4000114932/15/NL/BW and the AREMBES - ESA CTP No.4000116655/16/NL/BW. This publication is part of grant RTI2018-096686-B-C21 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”. This publication is part of grant RTI2018-096686-B-C21 and PID2020-115325GB-C31 funded by MCIN/AEI/10.13039/501100011033

Identification of a Novel Homozygous Nonsense Mutation Confirms the Implication of GNAT1 in Rod-Cone Dystrophy.

GNAT1, encoding the transducin subunit Gα, is an important element of the phototransduction cascade. Mutations in this gene have been associated with autosomal dominant and autosomal recessive congenital stationary night blindness. Recently, a homozygous truncating GNAT1 mutation was identified in a patient with late-onset rod-cone dystrophy. After exclusion of mutations in genes underlying progressive inherited retinal disorders, by targeted next generation sequencing, a 32 year-old male sporadic case with severe rod-cone dystrophy and his unaffected parents were investigated by whole exome sequencing. This led to the identification of a homozygous nonsense variant, c.963C>A p.(Cys321*) in GNAT1, which was confirmed by Sanger sequencing. The mother was heterozygous for this variant whereas the variant was absent in the father. c.963C>A p.(Cys321*) is predicted to produce a shorter protein that lacks critical sites for the phototransduction cascade. Our work confirms that the phenotype and the mode of inheritance associated with GNAT1 variants can vary from autosomal dominant, autosomal recessive congenital stationary night blindness to autosomal recessive rod-cone dystrophy

Clinical observations.

<p>(A) Color vision test with the Farnworth desaturated 15HUE shows a tritan axis defect. (B) Kinetic visual field tests demonstrate visual field constriction in both eyes. (C) Color fundus photographs reveal optic nerve pallor, narrowed retinal vessels, pigment clumping in retinal periphery some of which resembling more to coarse nummular pigments rather than classical bone spicules, as well as perifoveal atrophic changes. (D) Short-wavelength fundus autofluorescence shows hypo-autofluorescence in the periphery as well as in the perifoveal area. In (A, C, D), Ocula dextra (right eye; OD) is presented in the left part and ocular sinistra (left eye; OS) in the right part. (E) SD-OCT reveals thinning of the outer retinal layers. The two first SD-OCT correspond to OD results, the two next to OS results.</p

Validation and co-segregation of <i>GNAT1</i> variant in family F780.

<p>The pedigree and the respective electropherograms of each tested family member are depicted. Family F780 is composed of two unaffected parents (father: I.1, CIC01294; mother: I.2, CIC06690), one affected son (II.1; CIC01293) and one unaffected son (II.2). The nonsense variant c.963C>A p.(Cys321*) [M] in <i>GNAT1</i> (NM_144499.2; MIM *139330) was found homozygous in the affected boy (II.1, CIC01293), heterozygous in the unaffected mother (I.2, CIC06690) and absent in the unaffected father (I.1, CIC01294). Females and males are depicted by circles and squares, respectively. Filled and unfilled symbols indicate affected and unaffected status, respectively. The arrow indicates the nucleotide position 963 heterozygously and homozygously changed in the mother and index patient, respectively, and unchanged in the father.</p

Mutation and protein consequences in <i>GNAT1</i>.

<p>(A) Known and novel mutations leading to CSNB or RCD on the genomic structure of <i>GNAT1</i> (upper part) and the respective protein consequences (lower part). Different arrows indicate the mutation site and associated phenotype. C-terminal nonsense variants were associated with severe RCD (present study) or moderate RCD [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168271#pone.0168271.ref008" target="_blank">8</a>], while missense variants were associated with adCSNB and arCSNB affecting the nuclear localization signal (NLS) and/or GTP/GDP-binding site (GTP) (adCSNB) and an unknown domain of GNAT1 (arCSNB) (lower part) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168271#pone.0168271.ref002" target="_blank">2</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168271#pone.0168271.ref004" target="_blank">4</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168271#pone.0168271.ref009" target="_blank">9</a>]. (B) The protein is highly conserved in metazoa from human to hydra (data not shown), with 99% of identity between bovine and human GNAT1. Amino acid sequences of the human normal (huGNAT1) and two mutants, (Cys321* and Gln302*) GNAT1, of the bovine GNAT1 (boGNAT1) and the bovine GNAT1 sequence used for crystallization of the protein (1TND) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168271#pone.0168271.ref009" target="_blank">9</a>]. This last sequence corresponds to the bovine GNAT1 sequence lacking 25 amino acids at the N-terminus and the last phenylalanine amino acid residues, at position 350 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168271#pone.0168271.ref009" target="_blank">9</a>]. In addition, known CSNB causing mutations are depicted. Human and bovine amino acid sequences are highly conserved. α-helices are represented in black rectangles and β sheets in black arrows (below amino acid sequences) and named as previously reported [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168271#pone.0168271.ref009" target="_blank">9</a>] except for the α-helices G, 4 and 5 which became here 4, 5 and 6, respectively. Specific binding sites are present at following amino acid residues: βγ transducin binding at 1 to 23 (Gtβγ; black dotted and gray shaded box, [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168271#pone.0168271.ref009" target="_blank">9</a>]), NLS at 21–52 (NLS, gray unfilled box, predicted by a software, NLS Mapper), Magnesium binding sites at 43 and 177 (Mg, dark shaded box, predicted by Uniprot, GNAT1_HUMAN), GTP/GDP binding sites at 36–43, 171–177, 196–200, 265–268 and 321–323 (GTP, light grey shaded boxes, predicted by Uniprot, GNAT1_HUMAN and [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168271#pone.0168271.ref009" target="_blank">9</a>]), PDE6γ inhibitory binding site at 306–310 (PDEγ, black dotted unfilled boxes, [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168271#pone.0168271.ref009" target="_blank">9</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168271#pone.0168271.ref010" target="_blank">10</a>]) and activated-RHO binding sites at 311–328 and 340–350 (RHO, black filled boxes, [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168271#pone.0168271.ref009" target="_blank">9</a>]).</p

Poorly differentiated gastro-entero-pancreatic neuroendocrine carcinomas: Are they really heterogeneous? Insights from the FFCD-GTE national cohort

IF 6.029International audienceBackgroundDiagnosis and management of poorly differentiated gastro-entero-pancreatic (GEP) neuroendocrine carcinomas (NECs) remain challenging. Recent studies suggest prognostic heterogeneity. We designed within the French Group of Endocrine Tumours a prospective cohort to gain insight in the prognostic stratification and treatment of GEP-NEC.Patients and methodsAll patients with a diagnosis of GEP-NEC between 1st January 2010 and 31st December 2013 could be included in this national cohort. Adenoneuroendocrine tumours were excluded.Results253 patients from 49 centres were included. Median age was 66 years. Main primary locations were pancreas (21%), colorectal (27%), oesophagus-stomach (18%); primary location was unknown in 20%. Tumours were metastatic at diagnosis in 78% of cases. Performance status (PS) at diagnosis was 0–1 in 79% of patients. Among the 147 (58%) cases reviewed by an expert pathological network, 39% were classified as small cell NEC and 61% as large cell NEC. Median Ki67 index was 75% (range, 20–100). Median overall survival was 15.6 (13.6–17.0) months. Significant adverse prognostic factors in univariate analysis were PS > 1 (hazard ratio [HR] = 2.5), metastatic disease (HR = 1.6), NSE > 2 upper limit of normal [ULN]; HR = 3.2), CgA > 2 ULN (HR = 1.7) and lactate dehydrogenase >2 ULN (HR = 2.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (n = 152), objective response, progression-free survival and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (n = 72).ConclusionsWe report a large prospective series of GEP-NEC which show the predominance of large cell type and advanced stage at diagnosis. Prognosis was found more homogeneous than previously reported, mainly impacted by PS and tumour burden

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

48 pages, 29 figures, submitted for publication in Experimental AstronomyThe Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer, studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory, a versatile observatory designed to address the Hot and Energetic Universe science theme, selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), it aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over an hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR, browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters. Finally we briefly discuss on the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, and touch on communication and outreach activities, the consortium organisation, and finally on the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. It is expected that thanks to the studies conducted so far on X-IFU, along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained (abridged)

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

48 pages, 29 figures, submitted for publication in Experimental AstronomyThe Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer, studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory, a versatile observatory designed to address the Hot and Energetic Universe science theme, selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), it aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over an hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR, browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters. Finally we briefly discuss on the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, and touch on communication and outreach activities, the consortium organisation, and finally on the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. It is expected that thanks to the studies conducted so far on X-IFU, along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained (abridged)