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"Howard, Jason"
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Hybrid error correction and de novo assembly of single-molecule sequencing reads
Single-molecule sequencing technologies can produce multikilobase-long reads, which are more useful than short reads for assembling genomes and transcriptomes, but their error rates are too high. Koren
et al
. correct long reads from a PacBio instrument using high-fidelity, short reads from complementary technologies, facilitating assembly of previously intractable sequences.
Single-molecule sequencing instruments can generate multikilobase sequences with the potential to greatly improve genome and transcriptome assembly. However, the error rates of single-molecule reads are high, which has limited their use thus far to resequencing bacteria. To address this limitation, we introduce a correction algorithm and assembly strategy that uses short, high-fidelity sequences to correct the error in single-molecule sequences. We demonstrate the utility of this approach on reads generated by a PacBio RS instrument from phage, prokaryotic and eukaryotic whole genomes, including the previously unsequenced genome of the parrot
Melopsittacus undulatus
, as well as for RNA-Seq reads of the corn (
Zea mays
) transcriptome. Our long-read correction achieves >99.9% base-call accuracy, leading to substantially better assemblies than current sequencing strategies: in the best example, the median contig size was quintupled relative to high-coverage, second-generation assemblies. Greater gains are predicted if read lengths continue to increase, including the prospect of single-contig bacterial chromosome assembly.
Journal Article
Awake
\"Jessica Alba, Hayden Christensen, and Terrence Howard star in first-time director/screenwriter Joby Harold's nerve-jangling psychological thriller about a man who experiences the frighteningly common surgical phenomenon known as \"anesthetic awareness,\" in which those laid out on the operating table remain acutely aware of what is going on around them despite remaining completely paralyzed and unable to cry out for help. When a successful young man (Christensen) goes under the knife and realizes that the anesthesia hasn't quite done its job, the horror quickly sets in as his worried wife (Alba) waits anxiously and a terrifying drama unfolds in the operating room\"--Allmovie.com, viewed November 7, 2017.
DVD
Convergent transcriptional specializations in the brains of humans and song-learning birds
Song-learning birds and humans share independently evolved similarities in brain pathways for vocal learning that are essential for song and speech and are not found in most other species. Comparisons of brain transcriptomes of song-learning birds and humans relative to vocal nonlearners identified convergent gene expression specializations in specific song and speech brain regions of avian vocal learners and humans. The strongest shared profiles relate bird motor and striatal song-learning nuclei, respectively, with human laryngeal motor cortex and parts of the striatum that control speech production and learning. Most of the associated genes function in motor control and brain connectivity. Thus, convergent behavior and neural connectivity for a complex trait are associated with convergent specialized expression of multiple genes.
Journal Article
Core and region-enriched networks of behaviorally regulated genes and the singing genome
Songbirds represent an important model organism for elucidating molecular mechanisms that link genes with complex behaviors, in part because they have discrete vocal learning circuits that have parallels with those that mediate human speech. We found that ~10% of the genes in the avian genome were regulated by singing, and we found a striking regional diversity of both basal and singing-induced programs in the four key song nuclei of the zebra finch, a vocal learning songbird. The region-enriched patterns were a result of distinct combinations of region-enriched transcription factors (TFs), their binding motifs, and presinging acetylation of histone 3 at lysine 27 (H3K27ac) enhancer activity in the regulatory regions of the associated genes. RNA interference manipulations validated the role of the calcium-response transcription factor (CaRF) in regulating genes preferentially expressed in specific song nuclei in response to singing. Thus, differential combinatorial binding of a small group of activity-regulated TFs and predefined epigenetic enhancer activity influences the anatomical diversity of behaviorally regulated gene networks.
Journal Article
Decomposition Rates of Surficial and Buried Organic Matter and the Lability of Soil Carbon Stocks Across a Large Tropical Seagrass Landscape
The paradigm for understanding the accumulation of organic carbon in vegetated coastal “blue carbon” habitats holds that burial of organic carbon (C
org) slows decomposition and leads to stability of carbon stocks. Further, it is generally assumed that the presence of the plant communities contributes to the buried organic matter and the stability of the carbon stocks. In this study, these assumptions were tested and the lability of soil organic carbon was examined as a function of environmental and plant community drivers. Samples of surficial sediment and seagrass community characteristics were collected at 93 locations across the ca. 15,000 km² of seagrass beds in south Florida. Ramped pyrolysis was used to describe the relative lability of soil organic carbon across the landscape. Organic matter (OM) was lost at all temperatures from 180 to 600 °C, suggesting that even the relatively high combustion temperature of 550 °C underestimates OM content by ≈ 10% on average. Additionally, deployments of model substrates (canvas strips) were used to examine decomposition rates of buried and surficial organic material at a subset of these sites. On average, finer, muddier soils contained slightly higher C
org stocks than coarser sediment sites, but the relationships between sediment grain size and seagrass community structure was weak. The lability of soil organic carbon varied with sediment grain size; as much as 80% of the C
org was refractory in coarse-grained soils compared with less than 30% in muddy soils. In muddy soils, burial decreased cellulose decomposition rate by an average of 22–39% compared with surficial breakdown, but in coarse-grained soils, burial enhanced cellulose decomposition rate by at least 55%. Taken as a whole, this study suggests that burial does not enhance C
org storage in all blue carbon environments, and that soil C stores are only weakly correlated with seagrass biomass at the landscape scale.
Journal Article
Maximal active force in skinned muscle fibres from children with cerebral palsy
The aim of this study was to gain insight into the origins of muscle weakness in children with cerebral palsy (CP) by investigating active force in single muscle fibres isolated from the adductor longus (AL) of children with CP. Single skinned muscle fibres (n = 43, from 11 children with CP) were isolated and tested for their maximal active stress, instantaneous stiffness, and the ratio of active stress to stiffness at a sarcomere length (SL) of 2.4 µm, and passive stress at SLs of 2.4, 2.6, 2.8, 3.0, 3.2, and 3.4 µm. The muscle biopsies were tested for their total myofibrillar protein content using a BCA assay, and myosin heavy chain, actin, titin and nebulin content using gel electrophoresis. Muscle biopsies from the vastus lateralis of healthy adults (HA; n = 19 fibres from 4 subjects) were used for comparison. The maximal active stress and the instantaneous stiffness, expressed as active elastic modulus, were lower in the CP fibres compared to the HA fibres (79 ± 4 vs. 170 ± 11 kPa, and 5479 ± 381 vs. 8943 ± 402 kPa, respectively). The maximal active stress to stiffness ratio was not different between CP and HA fibres (0.016 ± 0.001 vs. 0.020 ± 0.002). Actin, titin and nebulin content was reduced in the CP compared to the HA samples. Passive stress was also reduced in the CP fibres at SLs of 2.8, 3.0, 3.2 and 3.6 µm. These results suggest that the contractile ability of muscles from children with CP is compromised at the fibre level and this is likely the result of a decrease in sarcomeric proteins such as actin, titin and nebulin.
Journal Article
The Etiology of Neuromuscular Hip Dysplasia and Implications for Management: A Narrative Review
This study summarizes the current knowledge of the etiology of hip dysplasia in children with neuromuscular disease and the implications for management. This article is based on a review of development of the hip joint from embryology through childhood growth. This knowledge is then applied to selective case reviews to show how the understanding of these developmental principles can be used to plan specific treatments. The development of the hip joint is controlled by genetic shape determination, but the final adult shape is heavily dependent on the mechanical environment experienced by the hip joint during growth and development. Children with neuromuscular conditions show a high incidence of coxa valga, hip dysplasia, and subluxation. The etiology of hip pathology is influenced by factors including functional status, muscular tone, motor control, child’s age, and muscle strength. These factors in combination influence the development of high neck–shaft angle and acetabular dysplasia in many children. The hip joint reaction force (HJRF) direction and magnitude determine the location of the femoral head in the acetabulum, the acetabular development, and the shape of the femoral neck. The full range of motion is required to develop a round femoral head. Persistent abnormal direction and/or magnitude of HJRF related to the muscular tone can lead to a deformed femoral head and a dysplastic acetabulum. Predominating thigh position is the primary cause defining the direction of the HJRF, leading to subluxation in nonambulatory children. The magnitude and direction of the HJRF determine the acetabular shape. The age of the child when these pathomechanics occur acts as a factor increasing the risk of hip subluxation. Understanding the risk factors leading to hip pathology can help to define principles for the management of neurologic hip impairment. The type of neurologic impairment as defined by functional severity assessed by Gross Motor Function Classification System and muscle tone can help to predict the risk of hip joint deformity. A good understanding of the biomechanical mechanisms can be valuable for treatment planning.
Journal Article
Hip Surveillance and Management of Hip Displacement in Children with Cerebral Palsy: Clinical and Ethical Dilemmas
Hip displacement is the second most common musculoskeletal deformity in children with cerebral palsy. Hip surveillance programs have been implemented in many countries to detect hip displacement early when it is usually asymptomatic. The aim of hip surveillance is to monitor hip development to offer management options to slow or reverse hip displacement, and to provide the best opportunity for good hip health at skeletal maturity. The long-term goal is to avoid the sequelae of late hip dislocation which may include pain, fixed deformity, loss of function and impaired quality of life. The focus of this review is on areas of disagreement, areas where evidence is lacking, ethical dilemmas and areas for future research. There is already broad agreement on how to conduct hip surveillance, using a combination of standardised physical examination measures and radiographic examination of the hips. The frequency is dictated by the risk of hip displacement according to the child’s ambulatory status. Management of both early and late hip displacement is more controversial and the evidence base in key areas is relatively weak. In this review, we summarise the recent literature on hip surveillance and highlight the management dilemmas and controversies. Better understanding of the causes of hip displacement may lead to interventions which target the pathophysiology of hip displacement and the pathological anatomy of the hip in children with cerebral palsy. We have identified the need for more effective and integrated management from early childhood to skeletal maturity. Areas for future research are highlighted and a range of ethical and management dilemmas are discussed.
Journal Article
Collagenase treatment does not impair fiber contractile function in muscle biopsies from children with cerebral palsy
Cerebral palsy (CP) often presents with increased passive stiffness of the skeletal muscles, primarily due to increased collagen in the extracellular matrix. Collagenase from Clostridium histolyticum (CCH), an enzyme that degrades collagen, is used clinically to treat fibrotic conditions such as Dupuytren's contracture and Peyronie's disease. Although prior work demonstrated reduced passive stiffness in muscle bundles from children with CP following CCH incubation, its effects on active contractile properties remain unknown. Thus, this study was aimed at investigating the maximal active force, calcium sensitivity, and myofibrillar protein content (myosin and actin) after CCH incubation. Nine muscle biopsies from children with CP were used for skinned fiber mechanical testing at an average sarcomere length of 2.4 μm, and for myosin and actin analysis using 12% SDS‐PAGE. Maximal active stress (control 59.8 ± 24.2 kPa; CCH 63.2 ± 24.5 kPa; p = 0.51) and pCa₅₀ (control 6.04 ± 0.10; CCH 5.99 ± 0.18; p = 0.43) did not significantly differ. Similarly, the normalized myosin (control 1.000 ± 0.167, CCH 1.004 ± 0.178; p = 0.93) and actin (control 1.000 ± 0.336, CCH 1.107 ± 0.330; p = 0.231) content did not differ between conditions. These results suggest that collagenase does not impair the contractile function in muscle fibers from children with CP and thus might be a feasible treatment to reduce stiffness due to muscle fibrosis. Research into whole‐muscle force transmission following collagenase treatment is needed to evaluate its clinical viability.
Journal Article