Trimethyloxonium modification of single batrachotoxin-activated sodium channels in planar bilayers. Changes in unit conductance and in block by saxitoxin and calcium

Single batrachotoxin-activated sodium channels from rat brain were modified by trimethyloxonium (TMO) after incorporation in planar lipid bilayers. TMO modification eliminated saxitoxin (STX) sensitivity, reduced the single channel conductance by 37%, and reduced calcium block of inward sodium currents. These effects always occurred concomitantly, in an all-or-none fashion. Calcium and STX protected sodium channels from TMO modification with potencies similar to their affinities for block. Calcium inhibited STX binding to rat brain membrane vesicles and relieved toxin block of channels in bilayers, apparently by competing with STX for the toxin binding site. These results suggest that toxins, permeant cations, and blocking cations can interact with a common site on the sodium channel near the extracellular surface. It is likely that permeant cations transiently bind to this superficial site, as the first of several steps in passing inward through the channel.     

Value of computed tomography in patients with stroke: Oxfordshire Community Stroke Project.

The usefulness of computed tomography (CT) was assessed in 325 consecutive patients with a "clinically definite first stroke" from a community stroke register. CT detected five "non-stroke" lesions (two cerebral gliomas, one cerebral metastasis, and two subdural haematomas), a frequency of 1.5%. Five patients were identified with cerebellar haemorrhage, but only one survived long enough to have a CT scan. CT was useful in excluding intracranial haemorrhage as the cause of the stroke in four patients receiving anticoagulants and seven receiving antiplatelet treatment; it showed intracranial haemorrhage in one patient taking aspirin. Forty six patients were in atrial fibrillation at the time of their stroke; four had intracranial haemorrhages and three had haemorrhagic cerebral infarcts. Nineteen patients with presumed ischaemic minor stroke were considered suitable for carotid endarterectomy; CT showed small haemorrhages in two. The CT scan provides very useful information in a minority (up to 28%) of patients with first stroke, who can be selected on quite simple criteria: (a) doubt (usually because of an inadequate history) whether the patient has stroke or a treatable intracranial lesion; (b) the possibility of cerebellar haemorrhage or infarction; (c) the exclusion of intracranial haemorrhage in patients who either are already taking or likely to need antihaemostatic drugs or are being considered for carotid endarterectomy; (d) if the patient deteriorates in a fashion atypical of stroke.     

Acceleration Workspace of Cooperating Multi-Finger Robot Systems

We present a mathematical method for acceleration workspace analysis of cooperating multi-finger robot systems using a model of point-contact with friction. A new unified formulation from dynamic equations of cooperating multi-finger robots is derived considering the force and acceleration relationships between the fingers and the object to be handled. From the dynamic equation, maximum translational and rotational acceleration bounds of an object are calculated under given constraints of contact conditions, configurations of fingers, and bounds on the torques of joint actuators for each finger. Here, the rotational acceleration bounds can be applied as an important manipulability index when the multi-finger robot grasps an object. To verify the proposed method, we used a set of case studies with a simple multi-finger mechanism system. The achievable acceleration boundary in task space can be obtained successfully with the proposed method and the acceleration boundary depends on the configurations of fingers.     

Delayed egg‐laying and shortened incubation duration of Arctic‐breeding shorebirds coincide with climate cooling

Biological impacts of climate change are exemplified by shifts in phenology. As the timing of breeding advances, the within‐season relationships between timing of breeding and reproductive traits may change and cause long‐term changes in the population mean value of reproductive traits. We investigated long‐term changes in the timing of breeding and within‐season patterns of clutch size, egg volume, incubation duration, and daily nest survival of three shorebird species between two decades. Based on previously known within‐season patterns and assuming a warming trend, we hypothesized that the timing of clutch initiation would advance between decades and would be coupled with increases in mean clutch size, egg volume, and daily nest survival rate. We monitored 1,378 nests of western sandpipers, semipalmated sandpipers, and red‐necked phalaropes at a subarctic site during 1993–1996 and 2010–2014. Sandpipers have biparental incubation, whereas phalaropes have uniparental incubation. We found an unexpected long‐term cooling trend during the early part of the breeding season. Three species delayed clutch initiation by 5 days in the 2010s relative to the 1990s. Clutch size and daily nest survival showed strong within‐season declines in sandpipers, but not in phalaropes. Egg volume showed strong within‐season declines in one species of sandpiper, but increased in phalaropes. Despite the within‐season patterns in traits and shifts in phenology, clutch size, egg volume, and daily nest survival were similar between decades. In contrast, incubation duration did not show within‐season variation, but decreased by 2 days in sandpipers and increased by 2 days in phalaropes. Shorebirds demonstrated variable breeding phenology and incubation duration in relation to climate cooling, but little change in nonphenological components of traits. Our results indicate that the breeding phenology of shorebirds is closely associated with the temperature conditions on breeding ground, the effects of which can vary among reproductive traits and among sympatric species.     

A Highlights from MBoC Selection: Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson’s disease

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer’s disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 ­hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson’s disease.     

Structural role of Sfi1p-centrin filaments in budding yeast spindle pole body duplication

Centrins are calmodulin-like proteins present in centrosomes and yeast spindle pole bodies (SPBs) and have essential functions in their duplication. The Saccharomyces cerevisiae centrin, Cdc31p, binds Sfi1p on multiple conserved repeats; both proteins localize to the SPB half-bridge, where the new SPB is assembled. The crystal structures of Sfi1p-centrin complexes containing several repeats show Sfi1p as an alpha helix with centrins wrapped around each repeat and similar centrin-centrin contacts between each repeat. Electron microscopy (EM) shadowing of an Sfi1p-centrin complex with 15 Sfi1 repeats and 15 centrins bound showed filaments 60 nm long, compatible with all the Sfi1 repeats as a continuous alpha helix. Immuno-EM localization of the Sfi1p N and C termini showed Sfi1p-centrin filaments spanning the length of the half-bridge with the Sfi1p N terminus at the SPB. This suggests a model for SPB duplication where the half-bridge doubles in length by association of the Sfi1p C termini, thereby providing a new Sfi1p N terminus to initiate SPB assembly.     

Bacteria in cancer therapy: a novel experimental strategy

Resistance to conventional anticancer therapies in patients with advanced solid tumors has prompted the need of alternative cancer therapies. Moreover, the success of novel cancer therapies depends on their selectivity for cancer cells with limited toxicity to normal tissues. Several decades after Coley's work a variety of natural and genetically modified non-pathogenic bacterial species are being explored as potential antitumor agents, either to provide direct tumoricidal effects or to deliver tumoricidal molecules. Live, attenuated or genetically modified non-pathogenic bacterial species are capable of multiplying selectively in tumors and inhibiting their growth. Due to their selectivity for tumor tissues, these bacteria and their spores also serve as ideal vectors for delivering therapeutic proteins to tumors. Bacterial toxins too have emerged as promising cancer treatment strategy. The most potential and promising strategy is bacteria based gene-directed enzyme prodrug therapy. Although it has shown successful results in vivo yet further investigation about the targeting mechanisms of the bacteria are required to make it a complete therapeutic approach in cancer treatment.     

Analysis of factors that influence energy expenditure in honeyeaters (Meliphagidae)

The energy expenditure of the tūī (Prosthemadera novaeseelandiae), a meliphagid endemic to New Zealand, was measured and compared with 20 species of honeyeaters (family Meliphagidae) to determine whether its expenditure is influenced either by life in a moist, temperate climate or an island residence. Body mass in the honeyeaters accounted for 91.5% of the variation in basal rate. The combination of body mass, climate and the maximal limit to an altitudinal distribution explained 98.6% of the variation in basal rate with tropical, low-altitude species having the highest mass-independent rate. The basal rates of meliphagids in tropical highlands are similar to those in temperate lowlands, which may reflect similar food supplies. The tūī mass-independent expenditure appears to reflect an active lifestyle in a temperate climate with no evidence that an island residence influenced its rate, whereas sedentary birds on New Zealand have responded to island life with a depressed basal rate. An effective analysis of the variation in energy expenditure requires the inclusion of the ecological and behavioural characteristics that distinguish species.     

Nonlinear summation of force in cat soleus muscle results primarily from stretch of the common-elastic elements.

The complex connective tissue structure of muscle and tendon suggests that forces from two parts of a muscle may not summate linearly. This study measured the nonlinear summation of force (F(nl)) in whole cat soleus during isometric and ramp movements. In six anesthetized cats, the soleus was attached to a servomechanism to control muscle length and record force. The ventral roots were divided into two bundles, each innervating about half the soleus; thus the two parts could be stimulated alone or together. In all experiments, F(nl) was small (<6% of maximum tetanic tension). Peak F(nl) occurred during changes in muscle force, either as a result of imposed muscle movement or the onset or offset of a stimulus train. The data were fit to a model in which both parts of the muscle were assumed to stretch to a common elasticity. The servomechanism was programmed to compensate for reduced stretch of the common elasticity during partial compared with whole muscle activation. These compensatory movements showed how the model could account for most, but not all, of F(nl).