The Mars Science Laboratory Curiosity rover conducted a reconnaissance traverse across the Pahrump Hills outcrop within Gale crater from Sols 780–797. During the traverse, the Mars Descent Imager ...(MARDI) acquired a continuous imaging record of primary and secondary sedimentary features throughout the outcrop. The characteristics of the features (laminae, resistant features, fractures, gray clasts) and their spatial distribution provide insight into the processes that contributed to the formation of Pahrump Hills. Thin, regular laminae (mm-scale) are ubiquitous in the bedrock, implying that depositional processes at that scale did not change appreciably during deposition of the mudstone succession at Pahrump Hills. Higher bedrock slopes correlate with undulatory bedrock surfaces, bedrock with elevated Mg contents, and fractures exhibiting wide, raised edges. These collective features are consistent with increased erosional resistance caused by greater quantities of erosionally-resistant, Mg-bearing cement within the bedrock permitted by coarser grain sizes. Resistant features exhibit a range of morphologies, elevated Mg contents, and do not deflect laminae within the bedrock. Their characteristics implicate the involvement of Mg-enriched fluids in a late diagenetic overprint affecting the bedrock. The variations of fracture fill and edge morphologies and chemistries further suggest repeated fracturing and fluid interaction events within the strata exposed at Pahrump Hills. Gray clasts strongly resemble fragments eroded from sandstone horizons interspersed throughout the Pahrump Hills outcrop.
•A MARDI sidewalk mosaic was used to systematically map the Pahrump Hills outcrop.•MARDI identified primary and secondary sedimentary features throughout the outcrop.•MARDI determined the spatial distribution of the sedimentary features.•The features record the depositional and diagenetic history of Pahrump Hills.
Tuberous sclerosis is an autosomal dominant trait characterized by the development of hamartomatous growths in many organs. Renal cysts are also a frequent manifestation. Major genes for tuberous ...sclerosis and autosomal dominant polycystic kidney disease,
TSC2 and
PKD1, respectively, lie adjacent to each other at chromosome 16p13.3, suggesting a role for
PKD1 in the etiology of renal cystic disease in tuberous sclerosis. We studied 27 unrelated patients with tuberous sclerosis and renal cystic disease. Clinical histories and radiographic features were reviewed, and renal function was assessed. We sought mutations at the
TSC2 and
PKD1 loci, using pulsed field- and conventional-gel electrophoresis and FISH. Twenty-two patients had contiguous deletions of
TSC2 and
PKD1. In 17 patients with constitutional deletions, cystic disease was severe, with early renal insufficiency. One patient with deletion of
TSC2 and of only the 3′ UTR of
PKD1 had few cysts. Four patients were somatic mosaics; the severity of their cystic disease varied considerably. Mosaicism and mild cystic disease also were demonstrated in parents of 3 of the constitutionally deleted patients. Five patients without contiguous deletions had relatively mild cystic disease, 3 of whom had gross rearrangements of
TSC2 and 2 in whom no mutation was identified. Significant renal cystic disease in tuberous sclerosis usually reflects mutational involvement of the
PKD1 gene, and mosaicism for large deletions of
TSC2 and
PKD1 is a frequent phenomenon.
Although ultrasound is commonly used for screening subjects at risk of polycystic kidney disease 1 (PKD1), there has been no evaluation of ultrasonographic diagnostic criteria. We used DNA linkage ...among subjects from 128 sibships within 18 PKD1 families as the basis for an assessment of ultrasound sensitivity. Positive and negative predictive values were calculated to allow assessment of different diagnostic cut-off points in previously undiagnosed cases. Currently used criteria (bilateral cysts with at least two in one kidney) provided good sensitivity (88·5% at age 15-29 years and 100% at 30 years and above) but performance could be improved by less stringent criteria in subjects aged 15-29 years and more stringent criteria in older family members, in whom simple renal cysts are frequent. The presence of at least two renal cysts (unilateral or bilateral) in individuals at risk and younger than 30 years may be regarded as sufficient to establish a diagnosis; among those aged 30-59 years, the presence of at least two cysts in each kidney may be required, and among those aged 60 years and above, at least four cysts in each kidney should be required.
The successful 2020 launch and 2021 landing of the National Aeronautics and Space Administration’s (NASA) Perseverance Mars rover initiated the first phase of the NASA and European Space Agency (ESA) ...Mars Sample Return (MSR) campaign. The goal of the MSR campaign is to collect scientifically interesting samples from the Martian surface and return them to Earth for further study in terrestrial laboratories. The MSR campaign consists of three major spacecraft components to accomplish this objective: the Perseverance Mars rover, the Sample Retrieval Lander (SRL) and the Earth Return Orbiter (ERO). Onboard the ERO spacecraft is the Capture, Containment and Return System (CCRS). CCRS will capture, process and return to Earth the samples that have been collected after they are launched into Mars orbit by the Mars Ascent Vehicle (MAV), which is delivered to Mars onboard the SRL. To facilitate the processing of the orbiting sample (OS) via the CCRS, we have designed and developed a vision system to determine the OS capture orientation. The vision system is composed of two cameras sensitive to the visible portion of the electromagnetic spectrum and two illumination modules constructed from broadband light emitting diodes (LED). Vision system laboratory tests and physics-based optical simulations predict CCRS ground processing will be able to correctly identify the OS post-capture orientation using only a single vision system image that is transmitted to Earth from Mars orbit.
Sharing genomic variant interpretations across laboratories promotes consistency in variant assertions. A landscape analysis of Australian clinical genetic-testing laboratories in 2017 identified ...that, despite the national-accreditation-body recommendations encouraging laboratories to submit genotypic data to clinical databases, fewer than 300 variants had been shared to the ClinVar public database. Consultations with Australian laboratories identified resource constraints limiting routine application of manual processes, consent issues, and differences in interpretation systems as barriers to sharing. This information was used to define key needs and solutions required to enable national sharing of variant interpretations. The Shariant platform, using both the GRCh37 and GRCh38 genome builds, was developed to enable ongoing sharing of variant interpretations and associated evidence between Australian clinical genetic-testing laboratories. Where possible, two-way automated sharing was implemented so that disruption to laboratory workflows would be minimized. Terms of use were developed through consultation and currently restrict access to Australian clinical genetic-testing laboratories. Shariant was designed to store and compare structured evidence, to promote and record resolution of inter-laboratory classification discrepancies, and to streamline the submission of variant assertions to ClinVar. As of December 2021, more than 14,000 largely prospectively curated variant records from 11 participating laboratories have been shared. Discrepant classifications have been identified for 11% (28/260) of variants submitted by more than one laboratory. We have demonstrated that co-design with clinical laboratories is vital to developing and implementing a national variant-interpretation sharing effort. This approach has improved inter-laboratory concordance and enabled opportunities to standardize interpretation practices.
Sharing genomic variant interpretations across laboratories promotes consistency. The Shariant platform was developed to enable ongoing sharing of variant interpretations and associated evidence, resolution of inter-laboratory discrepancies, and streamlined submission of variant assertions to ClinVar. This approach has improved concordance and enabled opportunities for standardization of practices between Australian laboratories.
MECP2 mutations mainly occur in females with Rett syndrome. Mutations have been described in 11 boys with progressive encephalopathy: seven of nine with affected sisters and two de novo. The authors ...report four de novo occurrences: three pathogenic and one potentially pathogenic. Common features include failure to thrive, respiratory insufficiency, microcephaly, and abnormal motor control. MECP2 mutations should be assessed in boys with progressive encephalopathy and one or more of respiratory insufficiency, abnormal movements or tone, and intractable seizures.
OBJECTIVE To investigate whether citrus fruit, noncitrus fruit, and other dietary factors act as environmental modifiers of iron status in the absence or presence of hemochromatotic HFE gene ...mutations. PARTICIPANTS AND METHODS Iron studies, HFE genotypic analyses, and dietary data from a survey conducted from March 21, 1994, through December 15, 1995, were analyzed for a group of 2232 residents (1105 men, 1127 women) aged 20 to 79 years recruited from the community electoral roll of Busselton in Western Australia. Data were analyzed by linear regression analysis and analysis of covariance. RESULTS Higher levels of fresh fruit intake (excluding citrus fruits and citrus juices) had a significant protective effect ( P =.002) against high body iron status as gauged by ferritin levels in men, irrespective of HFE genotype. Consumption of 2 or more pieces of fruit per day on average reduced mean serum ferritin levels by 20% compared with average consumption of less than 1 piece of fruit per day. This effect was not observed in women. Consumption of citrus fruits and citrus juices had no significant effects in either sex. No protective effects were observed for tea consumption or any other dietary factors studied. Red meat and alcohol consumption correlated with high body iron stores ( P <.05), consistent with previous studies, but did not interact with fruit with regard to effects on serum ferritin ( P >.05). CONCLUSION Noncitrus fruits are environmental modifiers of iron status independent of HFE genotype. This could have important implications for the provision of evidence-based dietary advice to patients with other iron-storage disorders.
People with genetic haemochromatosis (GH) accumulate iron from excessive dietary absorption. In populations of northern European origin, over 90% of patients are homozygous for the C282Y mutation of ...the HFE gene. While about 1 in 200 people in the general population have this genotype the proportion who develop clinical haemochromatosis is not known. The influence of HFE genotype on iron status was investigated in 10 556 blood donors. The allele frequencies of the C282Y and H63D mutations were 8·23% and 15·3% respectively. Heterozygosity for C282Y occurred in 1 in 7·9 donors, for H63D in 1 in 4·2 donors, and 1 in 42 were compound heterozygotes. Homozygosity for H63D occurred in 1 in 42 donors and 1 in 147 (72) were homozygous for C282Y. Mean values increased for transferrin saturation (TS) and serum ferritin (sFn), and decreased for unsaturated iron binding capacity (UIBC) in the order: donors lacking the mutations, H63D heterozygotes, C282Y heterozygotes, H63D homozygotes, compound heterozygotes and C282Y homozygotes, but serum ferritin (sFn) concentrations were no higher in H63D heterozygotes and C282Y heterozygous women than in donors lacking mutations. The percentage of donors failing the screening test for anaemia or of those with sFn < 15 µg/l did not differ among the genotype groups. C282Y and H63D heterozygotes and donors homozygous for H63D were at no greater risk of iron accumulation than donors lacking mutations, of whom 1 in 1200 had both a raised TS and sFn. The risk was higher for compound heterozygotes (1 in 80, P = 0·003) and for C282Y homozygotes (1 in 5, P < 0·0001). There was no correlation between sFn and either age or donation frequency in C282Y homozygotes. None of the 63 C282Y homozygous donors interviewed showed physical signs of overload or were aware of relatives with haemochromatosis. The Welsh Blood Service collects blood from about 140 000 people each year including an estimated 950 who are homozygous for HFE C282Y. They are probably healthy and unaware of any family history of iron overload.
Introduction: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that is usually associated with mutations in the MECP2 gene. The most common mutations in the gene are p.R168X ...and p.T158M. The influence of X-chromosome inactivation (XCI) on clinical severity in patients with RTT with these mutations was investigated, taking into account the extent and direction of skewing. Methods: Female patients and their parents were recruited from the UK and Australia. Clinical severity was measured by the Pineda Severity and Kerr profile scores. The degree of XCI and its direction relative to the X chromosome parent of origin were measured in DNA prepared from peripheral blood leucocytes, and allele-specific polymerase chain reaction was used to determine the parental origin of mutation. Combining these, the percentage of cells expected to express the mutant allele was calculated. Results: Linear regression analysis was undertaken for fully informative cases with p.R168X (n = 23) and p.T158M (n = 20) mutations. A statistically significant increase in clinical severity with increase in the proportion of active mutated allele was shown for both the p.R168X and p.T158M mutations. Conclusions: XCI may vary in neurological and haematological tissues. However, these data are the first to show a relationship between the degree and direction of XCI in leucocytes and clinical severity in RTT, although the clinical utility of this in giving a prognosis for individual patients is unclear.
Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Mutations of two genes, PKD1 and PKD2, account for the disease in ...approximately 80 to 85% and 10 to 15% of the cases, respectively. Significant interfamilial and intrafamilial renal disease variability in ADPKD has been well documented. Locus heterogeneity is a major determinant for interfamilial disease variability (i.e., patients from PKD1-linked families have a significantly earlier onset of ESRD compared with patients from PKD2-linked families). More recently, two studies have suggested that allelic heterogeneity might influence renal disease severity. The current study examined the genotype-renal function correlation in 461 affected individuals from 71 ADPKD families with known PKD2 mutations. Fifty different mutations were identified in these families, spanning between exon 1 and 14 of PKD2. Most (94%) of these mutations were predicted to be inactivating. The renal outcomes of these patients, including the age of onset of end-stage renal disease (ESRD) and chronic renal failure (CRF; defined as creatinine clearance < or = 50 ml/min, calculated using the Cockroft and Gault formula), were analyzed. Of all the affected individuals clinically assessed, 117 (25.4%) had ESRD, 47 (10.2%) died without ESRD, 65 (14.0%) had CRF, and 232 (50.3%) had neither CRF nor ESRD at the last follow-up. Female patients, compared with male patients, had a later mean age of onset of ESRD (76.0 95% CI, 73.8 to 78.1 versus 68.1 95% CI, 66.0 to 70.2 yr) and CRF (72.5 95% CI, 70.1 to 74.9 versus 63.7 95% CI, 61.4 to 66.0 yr). Linear regression and renal survival analyses revealed that the location of PKD2 mutations did not influence the age of onset of ESRD. However, patients with splice site mutations appeared to have milder renal disease compared with patients with other mutation types (P < 0.04 by log rank test; adjusted for the gender effect). Considerable renal disease variability was also found among affected individuals with the same PKD2 mutations. This variability can confound the determination of allelic effects and supports the notion that additional genetic and/or environmental factors may modulate the renal disease severity in ADPKD.
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