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Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy.
Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation.
Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers.
Conclusions: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.
Pest risk maps are important decision support tools when devising strategies to minimize introductions of invasive organisms and mitigate their impacts. When possible management responses to an invader include costly or socially sensitive activities, decision-makers tend to follow a more certain (i.e., risk-averse) course of action. We presented a new mapping technique that assesses pest invasion risk from the perspective of a risk-averse decision maker. We demonstrated the method by evaluating the likelihood that an invasive forest pest will be transported to one of the U.S. states or Canadian provinces in infested firewood by visitors to U.S. federal campgrounds. We tested the impact of the risk aversion assumption using distributions of plausible pest arrival scenarios generated with a geographically explicit model developed from data documenting camper travel across the study area. Next, we prioritized regions of high and low pest arrival risk via application of two stochastic ordering techniques that employed, respectively, first- and second-degree stochastic dominance rules, the latter of which incorporated the notion of risk aversion. We then identified regions in the study area where the pest risk value changed considerably after incorporating risk aversion. While both methods identified similar areas of highest and lowest risk, they differed in how they demarcated moderate-risk areas. In general, the second-order stochastic dominance method assigned lower risk rankings to moderate-risk areas. Overall, this new method offers a better strategy to deal with the uncertainty typically associated with risk assessments and provides a tractable way to incorporate decisionmaking preferences into final risk estimates, and thus helps to better align these estimates with particular decision-making scenarios about a pest organism of concern. Incorporation of risk aversion also helps prioritize the set of locations to target for inspections and outreach activities, which can be costly. Our results are especially important and useful given the huge number of camping trips that occur each year in the United States and Canada.
Biallelic mutations in TMEM126B cause severe complex i deficiency with a variable clinical phenotype
(2016)
Complex I deficiency is the most common biochemical phenotype observed in individuals with mitochondrial disease. With 44 structural subunits and over 10 assembly factors, it is unsurprising that complex I deficiency is associated with clinical and genetic heterogeneity. Massively parallel sequencing (MPS) technologies including custom, targeted gene panels or unbiased whole-exome sequencing (WES) are hugely powerful in identifying the underlying genetic defect in a clinical diagnostic setting, yet many individuals remain without a genetic diagnosis. These individuals might harbor mutations in poorly understood or uncharacterized genes, and their diagnosis relies upon characterization of these orphan genes. Complexome profiling recently identified TMEM126B as a component of the mitochondrial complex I assembly complex alongside proteins ACAD9, ECSIT, NDUFAF1, and TIMMDC1. Here, we describe the clinical, biochemical, and molecular findings in six cases of mitochondrial disease from four unrelated families affected by biallelic (c.635G>T [p.Gly212Val] and/or c.401delA [p.Asn134Ilefs∗2]) TMEM126B variants. We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy. Functional experimentation including viral rescue and complexome profiling of subject cell lines has confirmed TMEM126B as the tenth complex I assembly factor associated with human disease and validates the importance of both genome-wide sequencing and proteomic approaches in characterizing disease-associated genes whose physiological roles have been previously undetermined.
Representing uncertainty in a spatial invasion model that incorporates human-mediated dispersal
(2013)
Most modes of human-mediated dispersal of invasive species are directional and vector-based. Classical spatial spread models usually depend on probabilistic dispersal kernels that emphasize distance over direction and have limited ability to depict rare but influential long-distance dispersal events. These aspects are problematic if such models are used to estimate invasion risk. Alternatively, a geographic network model may be better at estimating the typically low likelihoods associated with human-mediated dispersal events, but it should also provide a reasonable account of uncertainties that could affect perception of its risk estimates. We developed a network model that assesses the likelihood of dispersal of invasive forest pests in camper-transported firewood in North America. We built the model using data from the U.S. National Recreation Reservation Service, which document visitor travel between populated places and federal campgrounds across the U.S. and Canada. The study area is depicted as a set of coarse-resolution map units. Based on repeated simulations, the model estimates the probability that each unit is a possible origin and destination for firewood-facilitated forest pest invasions. We generated output maps that summarise, for each U.S. state and Canadian province, where (outside the state or province) a camper-transported forest pest likely originated. Treating these output maps as a set of baseline scenarios, we explored the sensitivity of these “origin risk” estimates to additive and multiplicative errors in the probabilities of pest transmission between locations, as well as random changes in the structure of the underlying travel network. We found the patterns of change in the origin risk estimates due to these alterations to be consistent across all states and provinces. This indicates that the network model behaves predictably in the presence of uncertainties, allowing future work to focus on closing knowledge gaps or more sophisticated treatments of the impact of uncertainty on model outputs.
Increasing trends in global trade make it extremely difficult to prevent the entry of all potential invasive species (IS). Establishing early detection strategies thus becomes an important part of the continuum used to reduce the introduction of invasive species. One part necessary to ensure the success of these strategies is the determination of priority survey areas based on invasion pressure. We used a pathway-centred conceptual model of pest invasion to address these questions: what role does global trade play in invasion pressure of plant ecosystems and how could an understanding of this role be used to enhance early detection strategies? We concluded that the relative level of invasion pressure for destination ecosystems can be influenced by the intensity of pathway usage (import volume and frequency), the number and type of pathways with a similar destination, and the number of different ecological regions that serve as the source for imports to the same destination. As these factors increase, pressure typically intensifies because of increasing a) propagule pressure, b) likelihood of transporting pests with higher intrinsic invasion potential, and c) likelihood of transporting pests into ecosystems with higher invasibility. We used maritime containerized imports of live plants into the contiguous U.S. as a case study to illustrate the practical implications of the model to determine hotspot areas of relative invasion pressure for agricultural and forest ecosystems (two ecosystems with high potential invasibility). Our results illustrated the importance of how a pathway-centred model could be used to highlight potential target areas for early detection strategies for IS. Many of the hotspots in agricultural and forest ecosystems were within major U.S. metropolitan areas. Invasion ecologists can utilize pathway-centred conceptual models to a) better understand the role of human-mediated pathways in pest establishment, b) enhance current methodologies for IS risk analysis, and c) develop strategies for IS early detection-rapid response programs.
Bostrichidae (Coleoptera) are a family of beetles with specialized xylophagous feeding habits that allow consumption of dry woody plant tissues. Bostrichids are often polyphagous and therefore pose a significant threat to many agricultural and forestry products, particularly in tropical regions. Bostrichids are commonly detected in solid wood packaging material at in ternational ports of entry. Notably, Sinoxylon anale Lesne has been intercepted in wood crates and pallets worldwide and has now become established in Brazil. This paper reports the first documented establishment of S. anale in Brazil, being found both in domestic wood pallets and within native forest and monoculture. The origin of these populations remains uncertain, but introductions through infested wood packaging at ports of entry is a likely scenario. Similarly, the exact time of establishment is unknown. Given that S. anale adults are attracted to light and ethanol, trapping using light or ethanol could be used in monitoring surveys. This species typically infests dead or decaying woody material, and therefore does not pose a direct threat to healthy, live trees. Although more common in tropical regions, S. anale has exhibited some adaptability to temperate climates, which may allow it to spread across the tropical and subtropical regions of Brazil and potentially to other parts of South America.
ZooBank registration. urn:lsid:zoobank.org:pub:9B47075B-AC63-4AA4-AFB6-E2689346CC11