Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis

BACKGROUND: We sought to investigate the diagnostic yield and mutation spectrum in previously reported genes for early-onset epilepsy and disorders of severe developmental delay. METHODS: In 400 patients with these disorders with no known underlying aetiology and no major structural brain anomaly, we analysed 46 genes using a combination of targeted sequencing on an Illumina MiSeq platform and targeted, exon-level microarray copy number analysis. RESULTS: We identified causative mutations in 71/400 patients (18%). The diagnostic rate was highest among those with seizure onset within the first two months of life (39%), although overall it was similar in those with and without seizures. The most frequently mutated gene was SCN2A (11 patients, 3%). Other recurrently mutated genes included CDKL5, KCNQ2, SCN8A (six patients each), FOXG1, MECP2, SCN1A, STXBP1 (five patients each), KCNT1, PCDH19, TCF4 (three patients each) and ATP1A3, PRRT2 and SLC9A6 (two patients each). Mutations in EHMT1, GABRB3, LGI1, MBD5, PIGA, UBE3A and ZEB2 were each found in single patients. We found mutations in a number of genes in patients where either the electroclinical features or dysmorphic phenotypes were atypical for the identified gene. In only 11 cases (15%) had the clinician sufficient certainty to specify the mutated gene as the likely cause before testing. CONCLUSIONS: Our data demonstrate the considerable utility of a gene panel approach in the diagnosis of patients with early-onset epilepsy and severe developmental delay disorders., They provide further insights into the phenotypic spectrum and genotype-phenotype correlations for a number of the causative genes and emphasise the value of exon-level copy number testing in their analysis

Grouping behavior of Sumatran orangutans (Pongo abelii) and Tapanuli orangutans (Pongo tapanuliensis) living in forest with low fruit abundance

In contrast to the African great apes, orangutans (Pongo spp.) are semisolitary: Individuals are often on their own, but form aggregations more often than expected by chance. These temporary aggregations provide social benefits such as mating opportunities. When fruit availability is high, costs of aggregating should be lower, because competition is less pronounced. Therefore, average party size is expected to be higher when fruit availability is high. This hypothesis would also explain why orangutans in highly fruit‐productive habitats on Sumatra are more gregarious than in the usually less productive habitats of Borneo. Here, we describe the aggregation behavior of orangutans in less productive Sumatran habitats (Sikundur and Batang Toru), and compare results with those of previously surveyed field sites. Orangutans in Sikundur were more likely to form parties when fruit availability was higher, but the size of daily parties was not significantly affected by fruit availability. With regard to between‐site comparisons, average party sizes of females and alone time of parous females in Sikundur and Batang Toru were substantially lower than those for two previously surveyed Sumatran sites, and both fall in the range of values for Bornean sites. Our results indicate that the assessment of orangutans on Sumatra as being more social than those on Borneo needs revision. Instead, between‐site differences in sociality seem to reflect differences in average fruit availability

Effect of Ce and Sb on Primary Graphite Growth in Cast Irons

It is well-known that if certain trace elements are present in cast iron melts the morphology of the graphite precipitates can be altered. In order to understand the effect of doping elements on primary growth of graphite, pure Fe–Sb alloys were prepared by induction melting. They were then placed in graphite crucibles and heated to a temperature above the Fe–C eutectic so that the charge became saturated in carbon and melted. To obtain Fe–Ce alloys, metallic Ce was added at the bottom of a graphite crucible and covered with iron, and then heated as for the Fe–Sb charge. In both cases, the melt was then cooled and held slightly above the eutectic temperature so that primary graphite crystals, which had nucleated on the crucible walls and then detached from it, could grow freely in the melt. The influence of the added elements on graphite growth was revealed by the change in the shape and distribution of the crystals compared to those obtained in similar experiments carried out with pure Fe. The experiments were made in air and vacuum so as to point out possible interactions between the elements present in the melt and oxygen

Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS

Congenital melanocytic nevi (CMN) can be associated with neurological abnormalities and an increased risk of melanoma. Mutations in NRAS, BRAF, and Tp53 have been described in individual CMN samples; however, their role in the pathogenesis of multiple CMN within the same subject and development of associated features has not been clear. We hypothesized that a single postzygotic mutation in NRAS could be responsible for multiple CMN in the same individual, as well as for melanocytic and nonmelanocytic central nervous system (CNS) lesions. From 15 patients, 55 samples with multiple CMN were sequenced after site-directed mutagenesis and enzymatic digestion of the wild-type allele. Oncogenic missense mutations in codon 61 of NRAS were found in affected neurological and cutaneous tissues of 12 out of 15 patients, but were absent from unaffected tissues and blood, consistent with NRAS mutation mosaicism. In 10 patients, the mutation was consistently c.181C>A, p.Q61K, and in 2 patients c.182A>G, p.Q61R. All 11 non-melanocytic and melanocytic CNS samples from 5 patients were mutation positive, despite NRAS rarely being reported as mutated in CNS tumors. Loss of heterozygosity was associated with the onset of melanoma in two cases, implying a multistep progression to malignancy. These results suggest that single postzygotic NRAS mutations are responsible for multiple CMN and associated neurological lesions in the majority of cases

Assessing the impact of forest structure disturbances on the arboreal movement and energetics of orangutans—An agent-based modeling approach

This is the final version. Available from Frontiers Media via the DOI in this record. Data availability statement: The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary material.Agent-based models have been developed and widely employed to assess the impact of disturbances or conservation management on animal habitat use, population development, and viability. However, the direct impacts of canopy disturbance on the arboreal movement of individual primates have been less studied. Such impacts could shed light on the cascading effects of disturbances on animal health and fitness. Orangutans are an arboreal primate that commonly encounters habitat quality deterioration due to land-use changes and related disturbances such as forest fires. Forest disturbance may, therefore, create a complex stress scenario threatening orangutan populations. Due to forest disturbances, orangutans may adapt to employ more terrestrial, as opposed to arboreal, movements potentially prolonging the search for fruiting and nesting trees. In turn, this may lead to changes in daily activity patterns (i.e., time spent traveling, feeding, and resting) and available energy budget, potentially decreasing the orangutan's fitness. We developed the agent-based simulation model BORNEO (arBOReal aNimal movEment mOdel), which explicitly describes both orangutans' arboreal and terrestrial movement in a forest habitat, depending on distances between trees and canopy structures. Orangutans in the model perform activities with a motivation to balance energy intake and expenditure through locomotion. We tested the model using forest inventory data obtained in Sebangau National Park, Central Kalimantan, Indonesia. This allowed us to construct virtual forests with real characteristics including tree connectivity, thus creating the potential to expand the environmental settings for simulation experiments. In order to parameterize the energy related processes of the orangutans described in the model, we applied a computationally intensive evolutionary algorithm and evaluated the simulation results against observed behavioral patterns of orangutans. Both the simulated variability and proportion of activity budgets including feeding, resting, and traveling time for female and male orangutans confirmed the suitability of the model for its purpose. We used the calibrated model to compare the activity patterns and energy budgets of orangutans in both natural and disturbed forests. The results confirm field observations that orangutans in the disturbed forest are more likely to experience deficit energy balance due to traveling to the detriment of feeding time. Such imbalance is more pronounced in males than in females. The finding of a threshold of forest disturbances that affects a significant change in activity and energy budgets suggests potential threats to the orangutan population. Our study introduces the first agent-based model describing the arboreal movement of primates that can serve as a tool to investigate the direct impact of forest changes and disturbances on the behavior of species such as orangutans. Moreover, it demonstrates the suitability of high-performance computing to optimize the calibration of complex agent-based models describing animal behavior at a fine spatio-temporal scale (1-m and 1-s granularity).UKR

Using Simulation Models to Evaluate Ape Nest Survey Techniques

BACKGROUND: Conservationists frequently use nest count surveys to estimate great ape population densities, yet the accuracy and precision of the resulting estimates are difficult to assess. METHODOLOGY/PRINCIPAL FINDINGS: We used mathematical simulations to model nest building behavior in an orangutan population to compare the quality of the population size estimates produced by two of the commonly used nest count methods, the 'marked recount method' and the 'matrix method.' We found that when observers missed even small proportions of nests in the first survey, the marked recount method produced large overestimates of the population size. Regardless of observer reliability, the matrix method produced substantial overestimates of the population size when surveying effort was low. With high observer reliability, both methods required surveying approximately 0.26% of the study area (0.26 km(2) out of 100 km(2) in this simulation) to achieve an accurate estimate of population size; at or above this sampling effort both methods produced estimates within 33% of the true population size 50% of the time. Both methods showed diminishing returns at survey efforts above 0.26% of the study area. The use of published nest decay estimates derived from other sites resulted in widely varying population size estimates that spanned nearly an entire order of magnitude. The marked recount method proved much better at detecting population declines, detecting 5% declines nearly 80% of the time even in the first year of decline. CONCLUSIONS/SIGNIFICANCE: These results highlight the fact that neither nest surveying method produces highly reliable population size estimates with any reasonable surveying effort, though either method could be used to obtain a gross population size estimate in an area. Conservation managers should determine if the quality of these estimates are worth the money and effort required to produce them, and should generally limit surveying effort to 0.26% of the study area, unless specific management goals require more intensive sampling. Using site- and time- specific nest decay rates (or the marked recount method) are essential for accurate population size estimation. Marked recount survey methods with sufficient sampling effort hold promise for detecting population declines