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Atom probe tomography and correlative microscopy: Key techniques for future planetary science studies
Our Galaxy is vast and awe-inspiring. The stars, planets, and our sun capture our imagination as children. For many of us, that wonder never ceases. It continues to inspire us throughout our careers and prompts us to question the evolution of our Solar System, to question what our place is within it, and how we may maintain longevity in a relatively volatile environment. To answer these questions planetary scientists turn to the study of extraterrestrial material. They analyze meteorites, impact craters, and materials returned by sample return missions for the evidence of events that are known to induce crystallographic and/or elemental changes, or for evidence of extraterrestrial isotopic abundances that point to the age and the original source of the material. Through these studies, we can constrain timelines of events that have occurred throughout the Solar Systemâs extensive history. Recently, atom probe tomography (APT) has been applied to the study of these materials. APT in correlation with larger-scale analysis techniques has provided insights into isotopic ratios or nanoscale distribution of elements, enriching our knowledge, and minimizing uncertainties in the time frame of critical cosmic events. The continued use of correlative microscopy with APT for the study of planetary science, including studies of small amounts of pristine materials delivered to the Earth by exciting sample return missions, promises to provide key information into the history of our Solar System. Here, we highlight the implications of correlative microscopy with APT for the future pursuits of planetary science, we reflect on the groundbreaking research already achieved, the challenges that have been overcome to achieve these outcomes and the challenges yet to come
In-situ metallic coating of atom probe specimen for enhanced yield, performance, and increased field-of-view
Atom probe tomography requires needle-shaped specimens with a diameter
typically below 100 nm, making them both very fragile and reactive, and defects
(notches at grain boundaries or precipitates) are known to affect the yield and
data quality. The use of a conformal coating directly on the sharpened specimen
has been proposed to increase yield and reduce background. However, to date,
these coatings have been applied ex-situ and mostly are not uniformly. Here, we
report on the controlled focused ion beam in-situ deposition of a thin metal
film on specimens immediately after specimen preparation. Different metallic
targets e.g. Cr were attached to a micromanipulator via a conventional lift-out
method and sputtered using the Ga or Xe ions. We showcase the many advantages
of coating specimens from metallic to non-metallic materials. We have
identified an increase in data quality and yield, an improvement of the mass
resolution, as well as an increase in the effective field-of-view enabling
visualization of the entire original specimen, including the complete surface
oxide layer. The ease of implementation of the approach makes it very
attractive for generalizing its use across a very wide range of atom probe
analyses
Chemical and structural characterization of the native oxide scale on a Mg-based alloy
In this study, the structure and composition of the native oxide forming on
the basal plane (0001) of Mg-2Al-0.1Ca is investigated by a correlative
approach, combining scanning transmission electron microscopy (STEM) and atom
probe tomography (APT). Atom probe specimens were prepared conventionally in a
Ga focused ion beam (FIB) as well as a Xe plasma FIB in a cryogenic setup and
subsequently cleaned in the atom probe to remove surface contamination before
oxidation. While thermal energy input from the laser and longer atmospheric
exposure time increased the measured hydrogen content in the specimen's apex
region, cryo preparation revealed, that the hydrogen uptake in magnesium is
independent of the employment of conventional or cryogenic FIB preparation. TEM
measurements demonstrated the growth of a (111) MgO oxide layer with 3-4 nm
thickness on the basal (0001) plane of the Mg atom probe specimen. APT data
further revealed the formation of an aluminum-rich region between bulk Mg and
the native oxide. The aluminum enrichment of up to ~20 at.% at the interface is
consistent with an inward growth of the oxide scale
New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes
Polymorphisms near EXOC4 and LRGUK on chromosome 7q32 are associated with Type 2 Diabetes and fasting glucose; The NHLBI Family Heart Study
This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens
Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects
Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7Ă10â15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 Ă10â6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 Ă10â11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 Ă10â5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination
No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study
It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (ÎČ = 16.1, CI(ÎČ) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (ÎČ = 4.86,CI(ÎČ) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest
Age at first birth in women is genetically associated with increased risk of schizophrenia
Prof. Paunio on PGC:n jÀsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe
Genetic correlation between amyotrophic lateral sclerosis and schizophrenia
A. Palotie on työryhmÀn Schizophrenia Working Grp Psychiat jÀsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe
Mapping genomic loci implicates genes and synaptic biology in schizophrenia
Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies
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