Regulation of AMPA receptor (AMPAR) trafficking is important for neural plasticity. Here we examined the trafficking and synthesis of the GluR1 and GluR2 subunits using ReAsH-EDT(2) and FlAsH-EDT(2) ...staining. Activity blockade of rat cultured neurons increased dendritic GluR1, but not GluR2, levels. Examination of transected dendrites revealed that both AMPAR subunits were synthesized in dendrites and that activity blockade enhanced dendritic synthesis of GluR1 but not GluR2. In contrast, acute pharmacological manipulations increased dendritic synthesis of both subunits. AMPARs synthesized in dendrites were inserted into synaptic plasma membranes and, after activity blockade, the electrophysiological properties of native synaptic AMPARs changed in the manner predicted by the imaging experiments. In addition to providing a novel mechanism for synaptic modifications, these results point out the advantages of using FlAsH-EDT(2) and ReAsH-EDT(2) for studying the trafficking of newly synthesized proteins in local cellular compartments such as dendrites.
Neurotransmitters are released by synaptic vesicle fusion at the active zone. The active zone of a synapse mediates Ca2+-triggered neurotransmitter release, and integrates presynaptic signals in ...regulating this release. Much is known about the structure of active zones and synaptic vesicles, but the functional relation between their components is poorly understood. Here we show that RIM1α, an active zone protein that was identified as a putative effector for the synaptic vesicle protein Rab3A, interacts with several active zone molecules, including Munc13-1 (ref. 6) and α-liprins, to form a protein scaffold in the presynaptic nerve terminal. Abolishing the expression of RIM1α in mice shows that RIM1α is essential for maintaining normal probability of neurotransmitter release, and for regulating release during short-term synaptic plasticity. These data indicate that RIM1α has a central function in integrating active zone proteins and synaptic vesicles into a molecular scaffold that controls neurotransmitter release.
ABSTRACT—Depressed contractility is a central feature of the failing human heart and has been attributed to altered Cai. This study examined the respective roles of the L-type Ca current (ICa), SR Ca ...uptake, storage and release, Ca transport via the Na-Ca exchanger (NCX), and Ca buffering in the altered Ca transients of failing human ventricular myocytes. Electrophysiological techniques were used to measure and control Vm and measure Im, respectively, and Fluo-3 was used to measure Cai in myocytes from nonfailing (NF) and failing (F) human hearts. Ca transients from F myocytes were significantly smaller and decayed more slowly than those from NF hearts. Ca uptake rates by the SR and the amount of Ca stored in the SR were significantly reduced in F myocytes. There were no significant changes in the rate of Ca removal from F myocytes by the NCX, in the density of NCX current as a function of Cai, ICa density, or cellular Ca buffering. However, Ca influx during the late portions of the action potential seems able to elevate Cai in F but not in NF myocytes. A reduction in the rate of net Ca uptake by the SR slows the decay of the Ca transient and reduces SR Ca stores. This leads to reduced SR Ca release, which induces additional Ca influx during the plateau phase of the action potential, further slowing the decay of the Ca transient. These changes can explain the defective Ca transients of the failing human ventricular myocyte.
An analytical model has been developed to describe the compression of a single yeast cell between parallel flat surfaces. Such cells were considered to be thin walled, liquid filled, spheres. Because ...yeast cells can be compressed at high deformation rates, time dependent effects such as water loss during compression and visco-elasticity of the cell wall could be and were neglected in the model. As in previously published work, a linear elastic constitutive equation was assumed for the material of the cell walls. However, yeast compression to failure requires large deformations, with high wall strains and associated rotations. New model equations appropriate to such high strains with rotations were therefore developed, based on work-conjugate Kirchhoff stresses and Hencky strains. This is an improvement on the earlier use of infinitesimal strains, and on the alternative of Green strains and 2nd Piola–Kirchhoff stresses. It is shown that the choice of stress and strain definition has a significant influence on model predictions for given wall material properties, and will affect estimates of the wall elastic modulus or other wall material property parameters obtained by fitting experimental data.
The first African dinosaur to be discovered,
was found in 1845 in the Lower Cretaceous of South Africa. Taxonomically assigned to numerous groups since discovery, in 1981 it was described as a ...stegosaur, a group of armoured ornithischian dinosaurs characterised by bizarre plates and spines extending from the neck to the tail. This assignment has been subsequently accepted. The type material consists of a premaxilla, maxilla, a nasal, and a vertebra, and contains no synapomorphies of Stegosauria. Several features of the maxilla and dentition are reminiscent of Ankylosauria, the sister-taxon to Stegosauria, and the premaxilla appears superficially similar to that of some ornithopods. The vertebral material has never been described, and since the last description of the specimen, there have been numerous discoveries of thyreophoran material potentially pertinent to establishing the taxonomic assignment of the specimen. An investigation of the taxonomic and systematic position of
is therefore warranted. This study provides a detailed re-description, including the first description of the vertebra. Numerous phylogenetic analyses demonstrate that the systematic position of
is highly labile and subject to change depending on which exemplifier for the clade Stegosauria is used. The results indicate that the use of a basal exemplifier may not result in the correct phylogenetic position of a taxon being recovered if the taxon displays character states more derived than those of the basal exemplifier, and we recommend the use, minimally, of one basal and one derived exemplifier per clade.
is most robustly recovered as a stegosaur in our analyses, meaning it is one of the youngest and southernmost stegosaurs.
Calcium alginate microspheres have been studied extensively as carriers in drug delivery systems, for encapsulation of biological materials such as biocatalysts, and as matrices in tissue ...engineering. Understanding the mechanical properties of such microspheres is essential because they may be exposed to mechanical forces during processing and in end applications. In order to characterise their mechanical properties, microspheres may be compressed between two flat surfaces, and a theoretical model applied to the force–displacement and force–time data to extract mechanical property parameters. In previous work, single calcium alginate microspheres were compressed and then held at constant deformation, and the force being imposed on them was measured. It was found that the force increased with deformation, as expected, and that there was significant force relaxation during holding. In this work, force versus displacement/time data corresponding to compression and holding of a single (102
μm) calcium alginate microsphere were modelled by finite element analysis. Since the force relaxation might be due to water loss or microsphere viscoelasticity, a poroelastic material model was first used to assess the potential effect of water loss from the microsphere solid matrix during holding. Using image analysis, the volume loss during compression and relaxation of the microsphere was determined. Assuming all the change in volume was due to water loss, and assuming a literature value of alginate permeability, the poroelastic material model showed that the effect of water loss on the force behaviour was small enough during relaxation that it might be neglected. This allowed a compressible, isotropic and homogeneous linear viscoelastic material model to be evaluated against experimental relaxation data to obtain viscoelastic property parameters of the microsphere. A viscoelastic material model with two relaxation times showed excellent capability in modelling both compression and relaxation. The instantaneous elastic modulus, long-term elastic modulus and the two relaxation times were found to be 490, 68.6
kPa, and 0.013 and 0.085
s, respectively. Deformation parameters of the compressed microsphere such as the contact radius and central lateral extension were also obtained from finite element modelling, and were compared with experimental data, showing good agreement and confirming the validity of the model at least for the microsphere under test.
Abstract Background Liver surgery for perihilar cholangiocarcinoma (PHC) is associated with high rates of morbidity and mortality. Objectives This study investigated the impact of low skeletal muscle ...mass on short- and longterm outcomes following hepatectomy for PHC. Methods Patients included underwent liver surgery for PHC between 1998 and 2013. Total skeletal muscle mass was measured at the level of the third lumbar vertebra using available preoperative computed tomography images. Sex-specific cut-offs for low skeletal muscle mass were determined by optimal stratification. Results In 100 patients, low skeletal muscle mass was present in 42 (42.0%) subjects. The rate of postoperative complications (Clavien–Dindo Grade III and higher) was greater in patients with low skeletal muscle mass (66.7% versus 48.3%; multivariable adjusted P = 0.070). Incidences of sepsis (28.6% versus 5.2%) and liver failure (35.7% versus 15.5%) were increased in patients with low skeletal muscle mass. In addition, 90-day mortality was associated with low skeletal muscle mass in univariate analysis (28.6% versus 8.6%; P = 0.009). Median overall survival was shorter in patients with low muscle mass (22.8 months versus 47.5 months; P = 0.014). On multivariable analysis, low skeletal muscle mass remained a significant prognostic factor (hazard ratio 2.02; P = 0.020). Conclusions Low skeletal muscle mass has a negative impact on postoperative mortality and overall survival following resection of PHC and should therefore be considered in preoperative risk assessment.
The Ramsar Convention (or the Convention on Wetlands), signed in 1971, was one of the first international conservation agreements, promoting global wise use of wetlands. It has three primary ...objectives: national designation and management of wetlands of international importance; general wise use of wetlands; and international cooperation. We examined lessons learnt for improving wetland conservation after Ramsar’s nearly five decades of operation. The number of wetlands in the Ramsar Site Network has grown over time (2,391 Ramsar Sites, 2.5 million km
2
, as at 2020-06-09) but unevenly around the world, with decreasing rate of growth in recent decades. Ramsar Sites are concentrated in countries with a high Gross Domestic Product and human pressure (e.g., western Europe) but, in contrast, Ramsar Sites with the largest wetland extent are in central-west Africa and South America. We identified three key challenges for improving effectiveness of the Ramsar Site Network: increasing number of sites and wetland area, improved representation (functional, geographical and biological); and effective management and reporting. Increasing the number of sites and area in the Ramsar network could benefit from targets, implemented at national scales. Knowledge of representativeness is inadequate, requiring analyses of functional ecotypes, geographical and biological representativeness. Finally, most countries have inadequate management planning and reporting on the ecological character of their Ramsar Sites, requiring more focused attention on a vision and objectives, with regular reporting of key indicators to guide management. There are increasing opportunities to rigorously track ecological character, utilizing new tools and available indicators (e.g., remote sensing). It is critical that the world protect its wetlands, with an effective Ramsar Convention or the Convention on Wetlands at the core.
The armoured dinosaurs, Thyreophora, were a diverse clade of ornithischians known from the Early Jurassic to the end of the Cretaceous. During the Middle and Late Jurassic, the thyreophorans radiated ...to evolve large body size, quadrupedality, and complex chewing mechanisms, and members of the group include some of the most iconic dinosaurs, including the plated
Stegosaurus
and the club-tailed
Ankylosaurus
; however, the early stages of thyreophoran evolution are poorly understood due to a paucity of relatively complete remains from early diverging thyreophoran taxa.
Scutellosaurus lawleri
is generally reconstructed as the earliest-diverging thyreophoran and is known from over 70 specimens from the Lower Jurassic Kayenta Formation of Arizona, USA. Whereas
Scutellosaurus lawleri
is pivotal to our understanding of character-state changes at the base of Thyreophora that can shed light on the early evolution of the armoured dinosaurs, the taxon has received limited study. Herein, we provide a detailed account of the osteology of
Scutellosaurus lawleri
, figuring many elements for the first time.
Scutellosaurus lawleri
was the only definitive bipedal thyreophoran. Histological studies indicate that it grew slowly throughout its life, possessing lamellar-zonal tissue that was a consequence neither of its small size nor phylogenetic position, but may instead be autapomorphic, and supporting other studies that suggest thyreophorans had lower basal metabolic rates than other ornithischian dinosaurs. Faunal diversity of the Kayenta Formation in comparison with other well-known Early Jurassic-aged dinosaur-bearing formations indicates that there was considerable spatial and/or environmental variation in Early Jurassic dinosaur faunas.
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