ORFEUS-II Far-Ultraviolet Observations of 3C273: 1. Interstellar and Intergalactic Absorption Lines

We present the first intermediate-resolution (lambda / 3000) spectrum of the bright quasi-stellar object 3C273 at wavelengths between 900 and 1200 A. Observations were performed with the Berkeley spectrograph aboard the ORFEUS-SPAS II mission. We detect Lyman beta counterparts to previously-identified intergalactic Lyman-alpha features at cz = 19900, 1600, and 1000 km/s; counterparts to other putative Lyman-alpha clouds along the sight line are below our detection limit. The strengths of the two very low redshift Lyman-beta features, which are believed to arise in Virgo intracluster gas, exceed preflight expectations, suggesting that the previous determination of the cloud parameters may underestimate the true column densities. A curve-of-growth analysis sets a minimum H I column density of 4 E14/cm^2 for the 1600 km/s cloud. We find marginally significant evidence for Galactic H_2 along the sight line, with a total column density of about 1 E15/cm^2. We detect the stronger interstellar O VI doublet member unambiguously; the weaker member is blended with other features. If the Doppler b value for O VI is comparable to that determined for N V then the O VI column density is 7 +/- 2 E14/cm^2, significantly above the only previous estimate. The O VI / N V ratio is about 10, consistent with the low end of the range observed in the disk. Additional interstellar species detected for the first time toward 3C273 (at modest statistical significance) include P II, Fe III, Ar I, and S III.Comment: LaTeX file, 11 pages, 4 encapsulated PostScript figures. Uses aaspp4.sty and astrobib.sty. (Astrobib is available from http://www.stsci.edu/software/TeX.html .) The ORFEUS telescope is described at http://sag-www.ssl.berkeley.edu/orfeus/ . To appear in ApJ (Letters

A Single-Photon Server with Just One Atom

Neutral atoms are ideal objects for the deterministic processing of quantum information. Entanglement operations have been performed by photon exchange or controlled collisions. Atom-photon interfaces were realized with single atoms in free space or strongly coupled to an optical cavity. A long standing challenge with neutral atoms, however, is to overcome the limited observation time. Without exception, quantum effects appeared only after ensemble averaging. Here we report on a single-photon source with one-and-only-one atom quasi permanently coupled to a high-finesse cavity. Quasi permanent refers to our ability to keep the atom long enough to, first, quantify the photon-emission statistics and, second, guarantee the subsequent performance as a single-photon server delivering up to 300,000 photons for up to 30 seconds. This is achieved by a unique combination of single-photon generation and atom cooling. Our scheme brings truly deterministic protocols of quantum information science with light and matter within reach.Comment: 4 pages, 3 figure

Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease

In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi-allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA-synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring VARS2 mutations. All patients except one, who manifested with a less severe disease course, presented at birth exhibiting severe encephalomyopathy and cardiomyopathy. Features included hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal cranial MRI, and elevated lactate. The biochemical phenotype comprised a combined Complex I and Complex IV OXPHOS defect in muscle, with patient fibroblasts displaying normal OXPHOS activity. Homology modeling supported the pathogenicity of VARS2 missense variants. The detailed description of this cohort further delineates our understanding of the clinical presentation associated with pathogenic VARS2 variants and we recommend that this gene should be considered in early-onset mitochondrial encephalomyopathies or encephalocardiomyopathies.Peer reviewe

Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction

Background: Protein synthesis is a tightly controlled process, involving a host of translation-initiation factors and microRNA-associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental-delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability. Objective: We sought to characterize the role of EIF4A2 variants in dystonic conditions. Methods: We undertook an unbiased search for likely deleterious variants in mutation-constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for EIF4A2 variants. Western blotting and immunocytochemical studies were performed in patient-derived fibroblasts. Results: We report the discovery of a novel heterozygous EIF4A2 frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence- to adulthood-onset dystonia with tremor. In patient-derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4-Not, the complex that interacts with eIF4A2 to mediate microRNA-dependent translational repression. By complementing the analyses with fibroblasts bearing EIF4A2 biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4-Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified EIF4A2 deletion variants (c.470_472del, c.1144_1145del) in another two dystonia-affected pedigrees. Conclusions: Our findings demonstrate that EIF4A2 haploinsufficiency underlies a previously unrecognized dominant dystonia-tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later-onset dystonic conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AIMS Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, main causes are viral infections (12-16%) and inherited metabolic diseases (14-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. METHODS With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF (RALF). WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (46%), and in children with RALF (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8) and DGUOK (n=7) were the most frequent findings. When categorizing, most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%) and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplants. CONCLUSION This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics

Genetic landscape of pediatric acute liver failure of indeterminate origin

BACKGROUND AND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. APPROACH AND RESULTS: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation. CONCLUSIONS: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics

Large Binocular Telescope - Teilprojekt Lucifer

An Lucifer arbeiten die Mannheimer Fachhochschule für Technik und Gestaltung und die Landessternwarte Heidelberg eng zusammen. Das Projekt ist der deutsche Beitrag für ein neues Riesenteleskop in Arizona, USA. Es handelt sich um einen Spektrographen für den nahen Infrarotbereich, der auch als Kamera genutzt werden kann. Seine Besonderheit: Er kann das ferne Weltall erforschen, denn dort haben sich durch den Urknall viele uralte Spektren im Infrarotbereich ergeben, denen Lucifer auf die Spur kommen will. Die Landessternwarte Heidelberg lieferte ihr Know-how bei den Anforderungen an einen solchen Spektrographen. Das LBT (Large Binocular Telescope) steht auf dem Mt. Graham in der Nähe von Tucson in Arizona in einer Höhe von etwa 3200 m