From the endoplasmic reticulum to the plasma membrane: mechanisms of CFTR folding and trafficking

CFTR biogenesis starts with its co-translational insertion into the membrane of endoplasmic reticulum and folding of the cytosolic domains, towards the acquisition of a fully folded compact native structure. Efficiency of this process is assessed by the ER quality control system that allows the exit of folded proteins but targets unfolded/misfolded CFTR to degradation. If allowed to leave the ER, CFTR is modified at the Golgi and reaches the post-Golgi compartments to be delivered to the plasma membrane where it functions as a cAMP- and phosphorylation-regulated chloride/bicarbonate channel. CFTR residence at the membrane is a balance of membrane delivery, endocytosis, and recycling. Several adaptors, motor, and scaffold proteins contribute to the regulation of CFTR stability and are involved in continuously assessing its structure through peripheral quality control systems. Regulation of CFTR biogenesis and traffic (and its dysregulation by mutations, such as the most common F508del) determine its overall activity and thus contribute to the fine modulation of chloride secretion and hydration of epithelial surfaces. This review covers old and recent knowledge on CFTR folding and trafficking from its synthesis to the regulation of its stability at the plasma membrane and highlights how several of these steps can be modulated to promote the rescue of mutant CFTR.     

Horses damp the spring in their step.

The muscular work of galloping in horses is halved by storing and returning elastic strain energy in spring-like muscle-tendon units.These make the legs act like a child's pogo stick that is tuned to stretch and recoil at 2.5 strides per second. This mechanism is optimized by unique musculoskeletal adaptations: the digital flexor muscles have extremely short fibres and significant passive properties, whereas the tendons are very long and span several joints. Length change occurs by a stretching of the spring-like digital flexor tendons rather than through energetically expensive length changes in the muscle. Despite being apparently redundant for such a mechanism, the muscle fibres in the digital flexors are well developed. Here we show that the mechanical arrangement of the elastic leg permits it to vibrate at a higher frequency of 30-40 Hz that could cause fatigue damage to tendon and bone. Furthermore, we show that the digital flexor muscles have minimal ability to contribute to or regulate significantly the 2.5-Hz cycle of movement, but are ideally arranged to damp these high-frequency oscillations in the limb.     

Magma storage beneath Axial volcano on the Juan de Fuca mid-ocean ridge.

Axial volcano, which is located near the intersection of the Juan de Fuca ridge and the Cobb-Eickelberg seamount chain beneath the northeast Pacific Ocean, is a locus of volcanic activity thought to be associated with the Cobb hotspot. The volcano rises 700 metres above the ridge, has substantial rift zones extending about 50 kilometres to the north and south, and has erupted as recently as 1998 (ref. 2). Here we present seismological data that constrain the three-dimensional velocity structure beneath the volcano. We image a large low-velocity zone in the crust, consisting of a shallow magma chamber and a more diffuse reservoir in the lower crust, and estimate the total magma volume in the system to be between 5 and 21 km3. This volume is two orders of magnitude larger than the amount of melt emplaced during the most recent eruption (0.1-0.2 km3). We therefore infer that such volcanic events remove only a small portion of the reservoir that they tap, which must accordingly be long-lived compared to the eruption cycle. On the basis of magma flux estimates, we estimate the crustal residence time of melt in the volcanic system to be a few hundred to a few thousand years.     

Site and stand characteristics related to white pine blister rust in high-elevation forests of southern Idaho and western Wyoming

Successful infection of white pine species by white pine blister rust (WPBR) is contingent upon environmental conditions that are favorable to the spread and development of Cronartium ribicola . Site and stand factors related to this process have been studied elsewhere within the distribution of the disease, but few studies have concentrated on the high-elevation white pine forests of southern Idaho and western Wyoming. We found that mean summer precipitation, average tree diameter, and elevation were the most important variables in 3 logistic regression models of WPBR presence and intensity. The models were tested on a randomly chosen portion of our data set. The model with 9 variables correctly predicted categories of low-, moderate-, and high-disease incidence in 79% of cases. The 2 models with fewer variables had lower predictive efficiencies but were more parsimonious and generally easy to measure. The ability to use easily measured or remotely sensed site and stand characteristics to predict WPBR spread or intensification could be an important asset to land managers who need to decide where to focus disease mitigation efforts and predict disease effects on water quality, wildlife habitat, recreation potential, and other land-management activities.     

Vegetation characteristics of mountainous northeastern Nevada sagebrush community types

Vegetation characteristics of 15 sagebrush community types identified on the Humboldt National Forest, northeastern Nevada, are described. A total of 218 plant species were found over the 372 relatively undisturbed rangeland communities sampled. The dominant plant families encountered were the Asteraceae (45 taxa), Poaceae (32 taxa), Scrophulariaceae (14 taxa), and the Fabaceae (12 taxa). Average annual dry weight production of the community types ranged from about 400 kg/ha/yr on types with Artemisia nova as the dominant sagebrush species to 1,200 kg/ha/yr on some A. tridentata ssp. vaseyana community types. A general increase in species richness and vegetation plus litter ground cover was observed within community types as the dominant sagebrush species changed from A. nova to A. arbuscula to A. longiloba to A. tridentata spp. tridentata to A. tridentata ssp. vaseyana . Major differences in plant species production and constancy exist between the sagebrush community types studied.     

Distribution of the milliped Tylobolus utahensis Chamberlin, with remarks on T. fredericksoni (Causey) (Spirobolida: Spirobolidae)

Tylobolus utahensis Chamberlin, the only representative of the genus occurring in the southwestern deserts, ranges from central Inyo County, California, to the western periphery of Kane County, Utah. This distribution roughly corresponds to the northern limit of the Mojave Desert ecosystem and is also shown by the millipede Piedolus utus Chamberlin. (Spirobolida: Atopetholidae) and the centipede Theatops posticus (Say) (Scolopendromorpha: Cryptopidae). Tylobolus fredericksoni Causey, ostensibly from Douglas County, Kansas, is designated "" nomen dubium "" and disregarded pending collection of fresh material; Narceus gordanus (Chamberlin) is deleted from South Carolina and Tennessee. Tyobolus uncigerus (Wood) occurs north of the Columbia River in Klickitat County, Washington, and Hiltonius thebanus Chamberlin is referable to Onychelus Cook in the family Atopetholidae.     

Quadrat and sample sizes for frequency sampling mountain meadow vegetation

Proper quadrat and sample sizes for sampling species frequency vary among vegetation types. This study found 10 × 10-cm quadrats most appropriate for frequency sampling dry mountain meadows when using a single quadrat size. If large, broad-leaved forbs are of special interest, 25 × 25-cm, 25 × 50-cm, or 50 × 50-cm quadrats may be useful. One hundred 10 × 10-cm quadrats adequately sampled most common species at alpha = 0.20 ± 10% frequency. In contrast, more than five hundred 0.29-m 2 circular plots usually were needed to sample individual species yield at alpha = 0.20 ± 20% of the mean.     

Richard Watson

The development of the circular dividing engine in England is traced from Henry Hindley and Jesse Ramsden through the improvements introduced by Ramsden's successors to the self-acting engine of William Simms. Particular emphasis is given to the invention, evolution and transmission of the methods used to achieve accuracy in: dividing the wheel; ratching the teeth and matching them to the endless screw; and mounting the cutter. The procedures adopted by Ramsden and Troughton for correcting initial dividing marks are also described.