Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11

Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in HCCS (which encodes an important mitochondrially targeted protein) and COX7B, which, like NDUFB11, encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that NDUFB11 variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related)

Ventricular Tachyarrhythmias after Cardiac Arrest in Public versus at Home

Background The incidence of ventricular fibrillation or pulseless ventricular tachycardia as the first recorded rhythm after out-of-hospital cardiac arrest has unexpectedly declined. The success of bystander-deployed automated external defibrillators (AEDs) in public settings suggests that this may be the more common initial rhythm when outof-hospital cardiac arrest occurs in public. We conducted a study to determine whether the location of the arrest, the type of arrhythmia, and the probability of survival are associated. Methods Between 2005 and 2007, we conducted a prospective cohort study of out-of-hospital cardiac arrest in adults in 10 North American communities. We assessed the frequencies of ventricular fibrillation or pulseless ventricular tachycardia and of survival to hospital discharge for arrests at home as compared with arrests in public. Results Of 12,930 evaluated out-of-hospital cardiac arrests, 2042 occurred in public and 9564 at home. For cardiac arrests at home, the incidence of ventricular fibrillation or pulseless ventricular tachycardia was 25% when the arrest was witnessed by emergency-medical-services (EMS) personnel, 35% when it was witnessed by a bystander, and 36% when a bystander applied an AED. For cardiac arrests in public, the corresponding rates were 38%, 60%, and 79%. The adjusted odds ratio for initial ventricular fibrillation or pulseless ventricular tachycardia in public versus at home was 2.28 (95% confidence interval [CI], 1.96 to 2.66; P\u3c0.001) for bystanderwitnessed arrests and 4.48 (95% CI, 2.23 to 8.97; P\u3c0.001) for arrests in which bystanders applied AEDs. The rate of survival to hospital discharge was 34% for arrests in public settings with AEDs applied by bystanders versus 12% for arrests at home (adjusted odds ratio, 2.49; 95% CI, 1.03 to 5.99; P=0.04). Conclusions Regardless of whether out-of-hospital cardiac arrests are witnessed by EMS personnel or bystanders and whether AEDs are applied by bystanders, the proportion of arrests with initial ventricular fibrillation or pulseless ventricular tachycardia is much greater in public settings than at home. The incremental value of resuscitation strategies, such as the ready availability of an AED, may be related to the place where the arrest occurs. (Funded by the National Heart, Lung, and Blood Institute and others.

The deglacial history of 79N glacier and the Northeast Greenland Ice Stream

The Northeast Greenland Ice Stream (NEGIS) is the main artery for ice discharge from the northeast sector of the Greenland Ice Sheet (GrIS) to the North Atlantic. Understanding the past, present and future stability of the NEGIS with respect to atmospheric and oceanic forcing is of global importance as it drains around 17% of the GrIS and has a sea-level equivalent of 1.6 m. This paper reconstructs the deglacial and Holocene history of Nioghalvfjerdsbræ (or 79N Glacier); a major outlet of the NEGIS.At high elevation (>900 m asl) autochthonous blockfield, a lack of glacially moulded bedrock and pre LGM exposure ages point to a complex exposure/burial history extending back over half a million years. However, post Marine Isotope Stage 12, enhanced glacial erosion led to fjord incision and plateaux abandonment. Between 900 and 600 m asl the terrain is largely unmodified by glacial scour but post LGM erratics indicate the advection of cold-based ice through the fjord. In contrast, below ∼600 m asl Nioghalvfjerdsfjorden exhibits a geomorphological signal indicative of a warm-based ice stream operating during the last glacial cycle. Dated ice marginal landforms and terrain along the fjord walls show initial thinning rates were slow between ∼23 and 10 ka, but post-10 ka it is evident that Nioghalvfjerdsfjorden deglaciated extremely quickly with complete fjord deglaciation below ∼500 m asl between 10.0 and 8.5 ka.Both increasing air and ocean temperatures were pivotal in driving surface lowering and submarine melt during deglaciation, but the final withdrawal of ice through Nioghalvfjerdsfjorden was facilitated by the action of marine ice sheet instability. Our estimates show that thinning and retreat rates reached a maximum of 5.29 ma−1 and 613 ma−1, respectively, as the ice margin withdrew westwards. This would place the Early Holocene disintegration of this outlet of the NEGIS at the upper bounds of contemporary thinning and retreat rates seen both in Greenland and Antarctica. Combined with recent evidence of ice stream shutdown during the Holocene, as well as predictions of changing ice flow dynamics within downstream sections of the NEGIS catchment, this suggests that significant re-organisation of the terminal zone of the ice stream is imminent over the next century

The deglacial history of 79N glacier and the Northeast Greenland Ice Stream

Acknowledgements This work was funded by NERC Standard Grant NE/N011228/1. We thank the Alfred Wegner Institute, and particularly Hicham Rafiq and Daniel Steinhage, for their significant logistic support through the iGRIFF project. Additional support was provided from Station Nord (Jørgen Skafte), Nordland Air, Air Greenland, the Joint Arctic Command and the Department of Geography, Durham University. Naalakkersuisut, Government of Greenland, provided Scientific Survey (VU-00121) and Export (046/2017) licences for this work. We would also like to thank our Field Ranger Isak (Nanu-Travel) and dog Ooni for keeping us safe in the field. TCN Sample preparation was carried out at the National Environmental Isotope Facility, Scottish Universities Environmental Research Centre under grant allocation 9185.0814. Chris Orton in the Cartographic Unit, Geography, Durham University edited several figures. This paper is dedicated to Mr Arnold Jones – a true Quaternarist.Peer reviewe

Herpes Virus Infection Is Associated with Vascular Remodeling and Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis

Peer reviewe

Subduction controls of Hf and Nd isotopes in lavas of the Aleutian island arc

The Hf and Nd isotopic compositions of 71 Quaternary lavas collected from locations along the full length of the Aleutian island arc are used to constrain the sources of Aleutian magmas and to provide insight into the geochemical behavior of Nd and Hf and related elements in the Aleutian subduction-magmatic system. Isotopic compositions of Aleutian lavas fall approximately at the center of, and form a trend parallel to, the terrestrial Hf-Nd isotopic array with {var_epsilon}{sub Hf} of +12.0 to +15.5 and {var_epsilon}{sub Nd} of +6.5 to +10.5. Basalts, andesites, and dacites within volcanic centers or in nearby volcanoes generally all have similar isotopic compositions, indicating that there is little measurable effect of crustal or other lithospheric assimilation within the volcanic plumbing systems of Aleutian volcanoes. Hafnium isotopic compositions have a clear pattern of along-arc increase that is continuous from the eastern-most locations near Cold Bay to Piip Seamount in the western-most part of the arc. This pattern is interpreted to reflect a westward decrease in the subducted sediment component present in Aleutian lavas, reflecting progressively lower rates of subduction westward as well as decreasing availability of trench sediment. Binary bulk mixing models (sediment + peridotite) demonstrate that 1-2% of the Hf in Aleutian lavas is derived from subducted sediment, indicating that Hf is mobilized out of the subducted sediment with an efficiency that is similar to that of Sr, Pb and Nd. Low published solubility for Hf and Nd in aqueous subduction fluids lead us to conclude that these elements are mobilized out of the subducted component and transferred to the mantle wedge as bulk sediment or as a silicate melt. Neodymium isotopes also generally increase from east to west, but the pattern is absent in the eastern third of the arc, where the sediment flux is high and increases from east to west, due to the presence of abundant terrigenous sediment in the trench east of the Amlia Fracture Zone, which is being subducting beneath the arc at Seguam Island. Mixing trends between mantle wedge and sediment end members become flatter in Hf-Nd isotope space at locations further west along the arc, indicating that the sediment end member in the west has either higher Nd/Hf or is more radiogenic in Hf compared to Nd. This pattern is interpreted to reflect an increase in pelagic clay relative to the terrigenous subducted sedimentary component westward along the arc. Results of this study imply that Hf does not behave as a conservative element in the Aleutian subduction system, as has been proposed for some other arcs

The Drosophila G9a gene encodes a multi-catalytic histone methyltransferase required for normal development

Mammalian G9a is a histone H3 Lys-9 (H3–K9) methyltransferase localized in euchromatin and acts as a co-regulator for specific transcription factors. G9a is required for proper development in mammals as g9a(−)/g9a(−) mice show growth retardation and early lethality. Here we describe the cloning, the biochemical and genetical analyses of the Drosophila homolog dG9a. We show that dG9a shares the structural organization of mammalian G9a, and that it is a multi-catalytic histone methyltransferase with specificity not only for lysines 9 and 27 on H3 but also for H4. Surprisingly, it is not the H4–K20 residue that is the target for this methylation. Spatiotemporal expression analyses reveal that dG9a is abundantly expressed in the gonads of both sexes, with no detectable expression in gonadectomized adults. In addition we find a low but clearly observable level of dG9a transcript in developing embryos, larvae and pupae. Genetic and RNAi experiments reveal that dG9a is involved in ecdysone regulatory pathways

Supernova kicks and dynamics of compact remnants in the Galactic Centre

The Galactic Centre (GC) is a unique place to study the extreme dynamical processes occurring near a supermassive black hole (SMBH). Here, we investigate the role of supernova (SN) explosions occurring in massive binary systems lying in a disc-like structure within the innermost parsec. We use a regularized algorithm to simulate 3 7 104 isolated three-body systems composed of a stellar binary orbiting the SMBH. We start the integration when the primary member undergoes an SN explosion and analyse the impact of SN kicks on the orbits of stars and compact remnants.We find that SN explosions scatter the lighter stars in the pair on completely different orbits, with higher eccentricity and inclination. In contrast, stellar-mass black holes (BHs) and massive stars retain memory of the orbit of their progenitor star. Our results suggest that SN kicks are not sufficient to eject BHs from the GC. We thus predict that all BHs that form in situ in the central parsec of our Galaxy remain in the GC, building up a cluster of dark remnants. In addition, the change of neutron star (NS) orbits induced by SNe may partially account for the observed dearth of NSs in the GC. About 40 per cent of remnants stay bound to the stellar companion after the kick; we expect up to 70 per cent of them might become X-ray binaries through Roche lobe filling. Finally, the eccentricity of some light stars becomes > 0.7 as an effect of the SN kick, producing orbits similar to those of the G1 and G2 dusty objects

The deglacial history of 79N glacier and the Northeast Greenland Ice Stream

The Northeast Greenland Ice Stream (NEGIS) is the main artery for ice discharge from the northeast sector of the Greenland Ice Sheet (GrIS) to the North Atlantic. Understanding the past, present and future stability of the NEGIS with respect to atmospheric and oceanic forcing is of global importance as it drains around 17% of the GrIS and has a sea-level equivalent of 1.6 m. This paper reconstructs the deglacial and Holocene history of Nioghalvfjerdsbræ (or 79N Glacier); a major outlet of the NEGIS. At high elevation (>900 m asl) autochthonous blockfield, a lack of glacially moulded bedrock and pre LGM exposure ages point to a complex exposure/burial history extending back over half a million years. However, post Marine Isotope Stage 12, enhanced glacial erosion led to fjord incision and plateaux abandonment. Between 900 and 600 m asl the terrain is largely unmodified by glacial scour but post LGM erratics indicate the advection of cold-based ice through the fjord. In contrast, below ∼600 m asl Nioghalvfjerdsfjorden exhibits a geomorphological signal indicative of a warm-based ice stream operating during the last glacial cycle. Dated ice marginal landforms and terrain along the fjord walls show initial thinning rates were slow between ∼23 and 10 ka, but post-10 ka it is evident that Nioghalvfjerdsfjorden deglaciated extremely quickly with complete fjord deglaciation below ∼500 m asl between 10.0 and 8.5 ka. Both increasing air and ocean temperatures were pivotal in driving surface lowering and submarine melt during deglaciation, but the final withdrawal of ice through Nioghalvfjerdsfjorden was facilitated by the action of marine ice sheet instability. Our estimates show that thinning and retreat rates reached a maximum of 5.29 ma−1 and 613 ma−1, respectively, as the ice margin withdrew westwards. This would place the Early Holocene disintegration of this outlet of the NEGIS at the upper bounds of contemporary thinning and retreat rates seen both in Greenland and Antarctica. Combined with recent evidence of ice stream shutdown during the Holocene, as well as predictions of changing ice flow dynamics within downstream sections of the NEGIS catchment, this suggests that significant re-organisation of the terminal zone of the ice stream is imminent over the next century