ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome

Walker-Warburg syndrome (WWS) is clinically defined as congenital muscular dystrophy that is accompanied by a variety of brain and eye malformations. It represents the most severe clinical phenotype in a spectrum of diseases associated with abnormal post-translational processing of a-dystroglycan that share a defect in laminin-binding glycan synthesis1. Although mutations in six genes have been identified as causes of WWS, only half of all individuals with the disease can currently be diagnosed on this basis2. A cell fusion complementation assay in fibroblasts from undiagnosed individuals with WWS was used to identify five new complementation groups. Further evaluation of one group by linkage analysis and targeted sequencing identified recessive mutations in the ISPD gene (encoding isoprenoid synthase domain containing). The pathogenicity of the identified ISPD mutations was shown by complementation of fibroblasts with wild-type ISPD. Finally, we show that recessive mutations in ISPD abolish the initial step in laminin-binding glycan synthesis by disrupting dystroglycan O-mannosylation. This establishes a new mechanism for WWS pathophysiology.     

CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium

Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.     

Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia

The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature. Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1-12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4alpha-phorbol 12,13-didecanoate (4alphaPDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis.     

Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine--choline, trimethylamine N-oxide (TMAO) and betaine--were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.     

An Erigeron from Nevada and a Penstemon from Idaho

Described as new species are Erigeron cavernensis Welsh & Atwood from the Schell Creek Range and Currant Mountain, White Pine County, Nevada, and Penstemon idahoensis Atwood     

Comparative habitat use in a juniper woodland bird community

We compared vegetation structure used by 14 bird species during the 1998 and 1999 breeding seasons to determine what habitat features best accounted for habitat division and community organization in Utah juniper ( Juniperus osteosperma ) woodlands of southwestern Wyoming. Habitat use was quantified by measuring 24 habitat variables in 461 bird-centered quadrats, each 0.04 ha in size. Using discriminant function analysis, we differentiated between habitat used by 14 bird species along 3 habitat dimensions: (1) variation in shrub cover, overstory juniper cover, mature tree density, understory height, and decadent tree density; (2) a gradient composed of elevation and forb cover; and (3) variation in grass cover, tree height, seedling/sapling cover, and bare ground/rock cover. Of 14 species considered, 9 exhibited substantial habitat partitioning: Mourning Dove ( Zenaida macroura ), Bewick's Wren ( Thryomanes bewickii ), Blue-gray Gnatcatcher ( Polioptila caerulea ), Mountain Bluebird ( Sialia currucoides ), Plumbeous Vireo ( Vireo plumbeus ), Green-tailed Towhee ( Pipilo chlorurus ), Brewer's Sparrow ( Spizella breweri ), Dark-eyed Junco ( Junco hyemalis ), and Cassin's Finch ( Carpodacus cassinii ). Our results indicate juniper bird communities of southwestern Wyoming are organized along a 3-dimensional habitat gradient composed of woodland maturity, elevation, and juniper recruitment. Because juniper birds partition habitat along successional and altitudinal gradients, indiscriminate woodland clearing as well as continued fire suppression will alter species composition. Restoration efforts should ensure that all successional stages of juniper woodland are present on the landscape.     

New ideas about atrial fibrillation 50 years on.

Atrial fibrillation is a condition in which control of heart rhythm is taken away from the normal sinus node pacemaker by rapid activity in different areas within the upper chambers (atria) of the heart. This results in rapid and irregular atrial activity and, instead of contracting, the atria only quiver. It is the most common cardiac rhythm disturbance and contributes substantially to cardiac morbidity and mortality. For over 50 years, the prevailing model of atrial fibrillation involved multiple simultaneous re-entrant waves, but in light of new discoveries this hypothesis is now undergoing re-evaluation.     

Food habits and nest characteristics of breeding raptors in southwestern Wyoming

Food habits and nest site features of the Golden Eagle ( Aquila chrysaetos ), Prairie Falcon ( Falco mexicanus ), Red-tailed Hawk ( Buteo jamaicensis ), and Ferruginous Hawk ( B. regalis ) were studied near Medicine Bow, Wyoming, during 1981 and 1982. Foods consisted primarily of leporids and sciurids. The Wyoming ground squirrel ( Spemiophilus richardsonii ) dominated the diet of Prairie Falcons, while Golden Eagles preyed on leporids more than did the other raptors. Diet overlap ranged from 59 to 99% between the species. Mean height of Golden Eagle nests was greater than nest height of other species. Most raptor nests (78%) were not visible from other active nests and were in view of roads. Prairie Falcons were the most specialized and Ferruginous Hawks the most versatile raptor species in terms of food habits and use of nest sites.     

New taxa of thistles ( Cirsium ; Asteraceae) in Utah

  Described are several new taxa of the genus Cirsium that occur in the state of Utah: C. eatonii (Gray) Robins, var. harrisonii Welsh; C. eatonii var. murdockii Welsh; C. ownbeyi Welsh; C. scariosum Nutt. var. thorneae ; and C. virginensis Welsh.     

Forecasting from fallible data: Correcting prediction bias with stein-rule least squares

In the presence of fallible data, standard estimation and forecasting techniques are biased and inconsistent. Surprisingly, the magnitude of this bias tends to increase, and not diminish, in time series applications as more observations become available. A solution to this ever-present problem, Stein-rule least squares (SRLS), is offered. It corrects for the bias and inconsistency of traditional estimators and provides a means for significantly improving the predictive accuracy of regression-based forecasting techniques. A Monte Carlo study of the forecasting accuracy of SRLS, compared to its alternatives reveals its practical significance and small sample behaviour.