Brothers volcano, of the Kermadec intraoceanic arc, is host to a hydrothermal system unique among seafloor hydrothermal systems known anywhere in the world. It has two distinct vent fields, known as ...the NW Caldera and Cone sites, whose geology, permeability, vent fluid compositions, mineralogy, and ore-forming conditions are in stark contrast to each other. The NW Caldera site strikes for ∼600 m in a SW–NE direction with chimneys occurring over a ∼145-m depth interval, between ∼1,690 and 1,545 m. At least 100 dead and active sulfide chimney spires occur in this field and are typically 2–3 m in height, with some reaching 6–7 m. Their ages (at time of sampling) fall broadly into three groups: <4, 23, and 35 years old. The chimneys typically occur near the base of individual fault-controlled benches on the caldera wall, striking in lines orthogonal to the slopes. Rarer are massive sulfide crusts 2–3 m thick. Two main types of chimney predominate: Cu-rich (up to 28.5 wt.% Cu) and, more commonly, Zn-rich (up to 43.8 wt.% Zn). Geochemical results show that Mo, Bi, Co, Se, Sn, and Au (up to 91 ppm) are correlated with the Cu mineralization, whereas Cd, Hg, Sb, Ag, and As are associated with the dominant Zn-rich mineralization. The Cone site comprises the Upper Cone site atop the summit of the recent (main) dacite cone and the Lower Cone site that straddles the summit of an older, smaller, more degraded dacite cone on the NE flank of the main cone. Huge volumes of diffuse venting are seen at the Lower Cone site, in contrast to venting at both the Upper Cone and NW Caldera sites. Individual vents are marked by low-relief (≤0.5 m) mounds comprising predominately native sulfur with bacterial mats. Vent fluids of the NW Caldera field are focused, hot (≤300°C), acidic (pH ≥ 2.8), metal-rich, and gas-poor. Calculated end-member fluids from NW Caldera vents indicate that phase separation has occurred, with Cl values ranging from 93% to 137% of seawater values. By contrast, vent fluids at the Cone site are diffuse, noticeably cooler (≤122°C), more acidic (pH 1.9), metal-poor, and gas-rich. Higher-than-seawater values of SO
4
and Mg in the Cone vent fluids show that these ions are being added to the hydrothermal fluid and are not being depleted via normal water/rock interactions. Iron oxide crusts 3 years in age cover the main cone summit and appear to have formed from Fe-rich brines. Evidence for magmatic contributions to the hydrothermal system at Brothers includes: high concentrations of dissolved CO
2
(e.g., 206 mM/kg at the Cone site); high CO
2
/
3
He; negative δD and δ
18
O
H2O
for vent fluids; negative δ
34
S for sulfides (to −4.6‰), sulfur (to −10.2‰), and δ
15
N
2
(to −3.5‰); vent fluid pH values to 1.9; and mineral assemblages common to high-sulfidation systems. Changing physicochemical conditions at the Brothers hydrothermal system, and especially the Cone site, occur over periods of months to hundreds of years, as shown by interlayered Cu + Au- and Zn-rich zones in chimneys, variable fluid and isotopic compositions, similar shifts in
3
He/
4
He values for both Cone and NW Caldera sites, and overprinting of “magmatic” mineral assemblages by water/rock-dominated assemblages. Metals, especially Cu and possibly Au, may be entering the hydrothermal system via the dissolution of metal-rich glasses. They are then transported rapidly up into the system via magmatic volatiles utilizing vertical (∼2.5 km long), narrow (∼300-m diameter) “pipes,” consistent with evidence of vent fluids forming at relatively shallow depths. The NW Caldera and Cone sites are considered to represent stages along a continuum between water/rock- and magmatic/hydrothermal-dominated end-members.
In situ Rutherford backscattering spectrometry (RBS) and spectroscopic ellipsometry (SE) were applied to study the compositional and optical stability of a WAlSiN-based solar-selective coating (SSC) ...at high temperatures in vacuum. The samples were exposed to heating-cooling cycles between quasi room temperature and stepwise-increased high temperatures of 450 °C, 650 °C and 800 °C, respectively. In situ RBS revealed full compositional stability of the SSC during thermal cycling. In situ SE indicated full conservation of the optical response at 450 °C and 650 °C, and minimal changes at 800 °C. The analysis of the ex situ optical reflectance spectra after the complete thermal cycling gave an unchanged solar absorptance of 0.94 and a slightly higher calculated thermal emittance at 800 °C of 0.16 compared to 0.15 after deposition. Cross-sectional element distribution analysis performed in scanning transmission electron microscopy mode confirmed the conservation of the SSC microstructure after the heating – cooling cycles. The study demonstrates compositional, optical and structural stability of the WAlSiN-based solar-selective coating at temperatures targeted for the next generation of concentrated solar power plants.
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•In situ Rutherford backscattering spectrometry and spectroscopic ellipsometry measurements at 450 °C, 650 °C and 800 °C.•The superior compositional, structural stability and optical performance up to a temperature of 800 °C of WAlSiN SSC.•The coating has excellent high-temperature and oxidation stability.
AUTS2 syndrome is an 'intellectual disability (ID) syndrome' caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 ...syndrome have been described, but clinical data are limited and almost all cases involved young children.
We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist.
All patients have borderline to severe ID/developmental delay, 83-100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5' deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo.
The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.
variants (DNVs) are currently not routinely evaluated as part of diagnostic whole exome sequencing (WES) analysis in patients with suspected inborn errors of immunity (IEI).
This study explored the ...potential added value of systematic assessment of DNVs in a retrospective cohort of 123 patients with a suspected sporadic IEI that underwent patient-parent trio-based WES.
A (likely) molecular diagnosis for (part) of the immunological phenotype was achieved in 12 patients with the diagnostic
IEI WES gene panel. Systematic evaluation of rare, non-synonymous DNVs in coding or splice site regions led to the identification of 14 candidate DNVs in genes with an annotated immune function. DNVs were found in IEI genes (
and
) and in potentially novel candidate genes, including
,
,
and
. The
canonical splice site DNV was shown to lead to defective RNA splicing, increased NF-κB p65 signalling, and elevated IL-1β production in primary immune cells extracted from the patient with autoinflammatory disease.
Our findings in this retrospective cohort study advocate the implementation of trio-based sequencing in routine diagnostics of patients with sporadic IEI. Furthermore, we provide functional evidence supporting a causal role for
loss-of-function mutations in autoinflammatory disease.
This research was supported by grants from the European Union, ZonMW and the Radboud Institute for Molecular Life Sciences.
AUTS2 syndrome is characterized by low birth weight, feeding difficulties, intellectual disability, microcephaly and mild dysmorphic features. All affected individuals thus far were caused by ...chromosomal rearrangements, variants at the base pair level disrupting AUTS2 have not yet been described. Here we present the full clinical description of two affected men with intragenic AUTS2 variants (one two-base pair deletion in exon 7 and one deletion of exon 6). Both variants are de novo and are predicted to cause a frameshift of the full-length transcript but are unlikely to affect the shorter 3' transcript starting in exon 9. The similarities between the phenotypes of both men are striking and further support that AUTS2 syndrome is a single gene disorder.
Phospholipids play an important role in many signaling pathways in animal cells. Signaling cascades are triggered by the activation of phospholipid cleaving enzymes such as phospholipases C, D (PLD), ...and A2. Their activities result in the formation of second messengers and amplification of the initial signal. In this study, we provide experimental evidence that PLD is involved in the early events of dehydration in the resurrection plant Craterostigma plantagineum. The enzymatic activity of the PLD protein was activated within minutes after the onset of dehydration, and although it was not inducible by abscisic acid, PLD activity did increase in response to mastoparan, which suggests a role for heterotrimeric G proteins in PLD regulation. Two cDNA clones encoding PLDs, CpPLD-1 and CpPLD-2, were isolated. The CpPLD-1 transcript was constitutively expressed, whereas CpPLD-2 was induced by dehydration and abscisic acid. Immunological studies revealed changes in the subcellular localization of the PLD protein in response to dehydration. Taken together, the data on enzymatic activity as well as transcript and protein distributions allowed us to propose a role for PLD in the events leading to desiccation tolerance in C. plantagineum.
Summary
In mammalian cells, phospholipase D (PLD) and its product phosphatidic acid (PA) are involved in a number of signalling cascades, including cell proliferation, membrane trafficking and ...defence responses. In plant cells a signalling role for PLD and PA is also emerging. Plants have the extra ability to phosphorylate PA to produce diacylglycerol pyrophosphate (DGPP), a newly discovered phospholipid whose formation attenuates PA levels, but which could itself be a second messenger. Here we report that increases in PA and its conversion to DGPP are common stress responses to water deficit. Increases occur within minutes of treatment and are dependent on the level of stress. Part of the PA produced is due to PLD activity as measured by the in vivo transphosphatidylation of 1‐butanol, and part is due to diacylglycerol kinase activity as monitored via 32P‐PA formation in a differential labelling protocol. Increases in PA and DGPP are found not only in the green alga Chlamydomonas moewusii and cell‐suspension cultures of tomato and alfalfa when subjected to hyperosmotic stress, but also in dehydrated leaves of the resurrection plant Craterostigma plantagineum. These results provide further evidence that PLD and PA play a role in plant signalling, and provide the first demonstration that DGPP is formed during physiological conditions that evoke PA synthesis.
The HIV-1 subtype B epidemic amongst men who have sex with men (MSM) is resurgent in many countries despite the widespread use of effective combination antiretroviral therapy (cART). In this combined ...mathematical and phylogenetic study of observational data, we aimed to find out the extent to which the resurgent epidemic is the result of newly introduced strains or of growth of already circulating strains.
As of November 2011, the ATHENA observational HIV cohort of all patients in care in the Netherlands since 1996 included HIV-1 subtype B polymerase sequences from 5,852 patients. Patients who were diagnosed between 1981 and 1995 were included in the cohort if they were still alive in 1996. The ten most similar sequences to each ATHENA sequence were selected from the Los Alamos HIV Sequence Database, and a phylogenetic tree was created of a total of 8,320 sequences. Large transmission clusters that included ≥10 ATHENA sequences were selected, with a local support value ≥ 0.9 and median pairwise patristic distance below the fifth percentile of distances in the whole tree. Time-varying reproduction numbers of the large MSM-majority clusters were estimated through mathematical modeling. We identified 106 large transmission clusters, including 3,061 (52%) ATHENA and 652 Los Alamos sequences. Half of the HIV sequences from MSM registered in the cohort in the Netherlands (2,128 of 4,288) were included in 91 large MSM-majority clusters. Strikingly, at least 54 (59%) of these 91 MSM-majority clusters were already circulating before 1996, when cART was introduced, and have persisted to the present. Overall, 1,226 (35%) of the 3,460 diagnoses among MSM since 1996 were found in these 54 long-standing clusters. The reproduction numbers of all large MSM-majority clusters were around the epidemic threshold value of one over the whole study period. A tendency towards higher numbers was visible in recent years, especially in the more recently introduced clusters. The mean age of MSM at diagnosis increased by 0.45 years/year within clusters, but new clusters appeared with lower mean age. Major strengths of this study are the high proportion of HIV-positive MSM with a sequence in this study and the combined application of phylogenetic and modeling approaches. Main limitations are the assumption that the sampled population is representative of the overall HIV-positive population and the assumption that the diagnosis interval distribution is similar between clusters.
The resurgent HIV epidemic amongst MSM in the Netherlands is driven by several large, persistent, self-sustaining, and, in many cases, growing sub-epidemics shifting towards new generations of MSM. Many of the sub-epidemics have been present since the early epidemic, to which new sub-epidemics are being added.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar ...individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.
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