Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency

An isolated defect of respiratory chain complex I activity is a frequent biochemical abnormality in mitochondrial disorders. Despite intensive investigation in recent years, in most instances, the molecular basis underpinning complex I defects remains unknown. We report whole-exome sequencing of a single individual with severe, isolated complex I deficiency. This analysis, followed by filtering with a prioritization of mitochondrial proteins, led us to identify compound heterozygous mutations in ACAD9, which encodes a poorly understood member of the mitochondrial acyl-CoA dehydrogenase protein family. We demonstrated the pathogenic role of the ACAD9 variants by the correction of the complex I defect on expression of the wildtype ACAD9 protein in fibroblasts derived from affected individuals. ACAD9 screening of 120 additional complex I-defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles.     

Online Automatic Marking of Diagrams

This article describes the way in which the Open University is expanding its online quiz engine to enable students to draw free-form diagrams in response to a quiz question. The new quiz engine automatically marks a student’s diagram and provides feedback either instantaneously when used in formative mode or later when used in summative mode. The new quiz engine is hosted within the Open University’s quiz module, OpenMark, which interfaces to the Moodle VLE which is responsible for rendering both the question and the feedback in the user’s browser. The article outlines the general nature of the diagrams that our system has been designed to deal with. This is followed by an example of the use of the new question type as implemented within our e-assessment system. The article also briefly summarizes the results of experiments carried out on the accuracy of the automatic marker and reports on feedback from students who have used the new diagramming question type.     

Cartilage biology, pathology, and repair

Osteoarthritis is one of the most common forms of musculoskeletal disease and the most prominent type of arthritis encountered in all countries. Although great efforts have been made to investigate cartilage biology and osteoarthritis pathology, the treatment has lagged behind that of other arthritides, as there is a lack of effective disease-modifying therapies. Numerous approaches for dealing with cartilage degradation have been tried, but enjoyed very little success to develop approved OA treatments with not only symptomatic improvement but also structure-modifying effect. In this review we discuss the most recent findings regarding the regulation of cartilage biology and pathology and highlight their potential therapeutic values.     

Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10?1?). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10?3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10?2?, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.     

Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm

The parathyroid hormone (PTH) receptor type 1 (PTHR), a G protein-coupled receptor (GPCR), transmits signals to two hormone systems—PTH, endocrine and homeostatic, and PTH-related peptide (PTHrP), paracrine—to regulate different biological processes. PTHR responds to these hormonal stimuli by activating heterotrimeric G proteins, such as G_S that stimulates cAMP production. It was thought that the PTHR, as for all other GPCRs, is only active and signals through G proteins on the cell membrane, and internalizes into a cell to be desensitized and eventually degraded or recycled. Recent studies with cultured cell and animal models reveal a new pathway that involves sustained cAMP signaling from intracellular domains. Not only do these studies challenge the paradigm that cAMP production triggered by activated GPCRs originates exclusively at the cell membrane but they also advance a comprehensive model to account for the functional differences between PTH and PTHrP acting through the same receptor.     

Common variation at 10p12.31 near MLLT10 influences meningioma risk

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.     

Molecular phylogenetic evidence that the Chinese viviparid genus Margarya (Gastropoda: Viviparidae) is polyphyletic

We investigated the phylogeny of the viviparid genus Margarya,endemic to Yunnan,China,using two mitochondrial gene fragments(COI and 16S rRNA).The molecular phylogeny based on the combined dataset indicates that Margarya is polyphyletic,as two of the three well-supported clades containing species of Margarya also comprise species from other viviparid genera.In one clade,sequences of four species of Margarya even cluster indiscriminately with those of two species of Cipangopaludina,indicating that the current state of Asian viviparid taxonomy needs to be revised.Additionally,these data suggest that shell evolution in viviparids is complex,as even the large and strongly sculptured shells of Margarya,which are outstanding among Asian viviparids,can apparently be easily converted to simple smooth shells.The molecular data also indicate that the species status of the six extant species of Margarya should be re-assessed.     

Distribution records and comments on fleas in southwestern South Dakota

From October 2003 through April 2006, we collected 565 fleas incidental to a distribution survey of mammals in southwestern South Dakota. Sixty-one specimens, representing 18 species of mammals, possessed 20 species of fleas. The geographic distributions of these flea species revealed 8 new records for the Black Hills and its adjacent grasslands. Four species— Megarthroglossus divisus, Stenoponia americana, Odontopsyllus dentatus, and Amaradix euphorbi —constitute new records for South Dakota, thus increasing the state’s known flea fauna to 42 species. Hunters, trappers, and field biologists should be aware that serosurveillance during the 1990s revealed the presence of sylvatic plague and tularemia in the Black Hills area. Desde octubre de 2003 hasta abril de 2006, colectamos 565 pulgas de manera incidental durante un estudio de la distribución de mamíferos en el suroeste del estado de Dakota del Sur. Los 61 especímenes, que representaban 18 especies de mamíferos, albergaban 20 especies de pulgas. Sus distribuciones geográficas revelaron 8 nuevos registros para las Colinas Negras (Black Hills) y las praderas adyacentes. Cuatro de estas especies ( Megarthroglossus divisus, Stenoponia americana, Odontopsyllus dentatus y Amaradix euphorbi ) constituyen nuevos registros para Dakota del Sur. Esto aumenta el número de especies de pulgas conocidas del estado a 42 especies. Los cazadores, tramperos y biólogos de campo deben estar conscientes de que la vigilancia serológica durante la década de los 1990 reveló la presencia de la plaga silvática y la tularemia en el área de las Colinas Negras.     

Grassland bird associations with introduced and native grass Conservation Reserve Program fields in the Southern High Plains

We examined relative abundances of grassland birds among Conservation Reserve Program (CRP) fields seeded with 2 monocultures of introduced grass species and 2 mixes of native grasses in the Southern High Plains of Texas. We assessed bird compositions among these 4 cover types and between the cover types pooled into categories of introduced and native fields. Breeding season bird diversity and total abundance did not differ among cover types or between introduced and native fields. Grasshopper Sparrows ( Ammodramus savannarum ), Cassin’s Sparrows ( Aimophila cassinii ), and Western Meadowlarks ( Sturnella neglecta ) accounted for more than 90% of breeding season detections. Grasshopper Sparrows were the most abundant and found in all cover types. Cassin’s Sparrows were 38% to 170% more abundant among the native seed mix without buffalograss ( Buchloë dactyloides ) compared to 3 other cover types. Although this association was statistically lost when cover types were pooled into introduced or native fields ( U = 93.5, P = 0.91), the species was still 50% more abundant among native CRP than introduced CRP fields. Meadowlarks occurred ubiquitously but at very low numbers during the breeding season. During winter, avian abundance was 44% greater among native CRP than introduced CRP fields. Meadowlarks, Horned Larks ( Eremophila alpestris ), and Savannah Sparrows ( Passerculus sandwichensis ) accounted for 94% of all winter detections. Meadowlarks occurred ubiquitously, but Horned Larks and Savannah Sparrows were 157% and 96% more abundant, respectively, among native CRP than introduced CRP fields. Our data suggest that monocultures of introduced grasses may benefit some bird species but also that native seed mixes may have a more positive influence through increased diversity and abundance of grassland birds. However, pooling cover types into the broader categories of introduced or native grasses may dampen or occlude biologically meaningful results. It may be prudent to avoid broad categorization of CRP fields based solely on native or introduced grass cover when assessing habitat associations of grassland birds.     

Variation in Lewsia kelloggii (Portulacaceae) with description of a new species endemic to Idaho

Lewisia kelloggii has been understood as a rare plant with a disjunct range in California and Idaho. Examination of herbarium specimens and analysis of isozymes in 6 Idaho and 7 California populations revealed consistent differences between plants of the 2 states. Fixed differences in alleles at 2 loci (AAT2 and PGI1) distinguished Idaho from California plants. Genetic identities based on isozymes between Idaho and California populations averaged 0.58, lower than the average for congeneric plant species. Idaho plants were smaller than most California plants, but California plants were variable. The most consistent morphological difference between Idaho and California specimens was the difference in the number of glands on the margins of bracts and sepals. Idaho plants had 0 (-5) pink glands on each margin of these organs, all on teeth near the tips. In California plants these organs had 12-25 glands on each margin, the distal ones elevated on teeth and the proximal ones sessile. We recognize the Idaho plants as a new species, L. sacajaweana , and retain the name L. kelloggii for the California populations.