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The tarantula toxin GxTx detains K+ channel gating charges in their resting conformation.
Allosteric ligands modulate protein activity by altering the energy landscape of conformational space in ligand-protein complexes. Here we investigate how ligand binding to a K+ channel's voltage sensor allosterically modulates opening of its K+-conductive pore. The tarantula venom peptide guangxitoxin-1E (GxTx) binds to the voltage sensors of the rat voltage-gated K+ (Kv) channel Kv2.1 and acts as a partial inverse agonist. When bound to GxTx, Kv2.1 activates more slowly, deactivates more rapidly, and requires more positive voltage to reach the same K+-conductance as the unbound channel. Further, activation kinetics are more sigmoidal, indicating that multiple conformational changes coupled to opening are modulated. Single-channel current amplitudes reveal that each channel opens to full conductance when GxTx is bound. Inhibition of Kv2.1 channels by GxTx results from decreased open probability due to increased occurrence of long-lived closed states; the time constant of the final pore opening step itself is not impacted by GxTx. When intracellular potential is less than 0 mV, GxTx traps the gating charges on Kv2.1's voltage sensors in their most intracellular position. Gating charges translocate at positive voltages, however, indicating that GxTx stabilizes the most intracellular conformation of the voltage sensors (their resting conformation). Kinetic modeling suggests a modulatory mechanism: GxTx reduces the probability of voltage sensors activating, giving the pore opening step less frequent opportunities to occur. This mechanism results in K+-conductance activation kinetics that are voltage-dependent, even if pore opening (the rate-limiting step) has no inherent voltage dependence. We conclude that GxTx stabilizes voltage sensors in a resting conformation, and inhibits K+ currents by limiting opportunities for the channel pore to open, but has little, if any, direct effect on the microscopic kinetics of pore opening. The impact of GxTx on channel gating suggests that Kv2.1's pore opening step does not involve movement of its voltage sensors
The influence of hydrogen on plasticity in pure iron-theory and experiment
Tensile stress relaxation is combined with transmission electron microscopy
to reveal dramatic changes in dislocation structure and sub structure in pure
alpha iron as a result of the effects of dissolved hydrogen. We find that
hydrogen charged specimens after plastic deformation display a very
characteristic pattern of trailing dipoles and prismatic loops which are absent
in uncharged pure metal. We explain these observations by use of a new self
consistent kinetic Monte Carlo model, which in fact was initially used to
predict the now observed microstructure. The results of this combined theory
and experimental study is to shed light on the fundamental mechanism of
hydrogen enhanced localised plasticity
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Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines
To test the hypothesis that nitric oxide (NO) limits endothelial activation, we treated cytokine-stimulated human saphenous vein endothelial cells with several NO donors and assessed their effects on the inducible expression of vascular cell adhesion molecule-1 (VCAM-1). In a concentration-dependent manner, NO inhibited interleukin (IL)-1 alpha-stimulated VCAM-1 expression by 35-55% as determined by cell surface enzyme immunoassays and flow cytometry. This inhibition was paralleled by reduced monocyte adhesion to endothelial monolayers in nonstatic assays, was unaffected by cGMP analogues, and was quantitatively similar after stimulation by either IL-1 alpha, IL-1 beta, IL-4, tumor necrosis factor (TNF alpha), or bacterial lipopolysaccharide. NO also decreased the endothelial expression of other leukocyte adhesion molecules (E-selectin and to a lesser extent, intercellular adhesion molecule-1) and secretable cytokines (IL-6 and IL-8). Inhibition of endogenous NO production by L-N-monomethyl-arginine also induced the expression of VCAM-1, but did not augment cytokine-induced VCAM-1 expression. Nuclear run-on assays, transfection studies using various VCAM-1 promoter reporter gene constructs, and electrophoretic mobility shift assays indicated that NO represses VCAM-1 gene transcription, in part, by inhibiting NF-kappa B. We propose that NO's ability to limit endothelial activation and inhibit monocyte adhesion may contribute to some of its antiatherogenic and antiinflammatory properties within the vessel wall
Partitioning the contributions of minerogenic particles and bioseston to particulate phosphorus and turbidity
Protocols to partition the contributions of bioseston and minerogenic particles to turbidity (Tn) and particulate phosphorus (PP), as described by summations of the 2 components, are developed, tested, and applied. The analysis is based on coincident observations of Tn, PP, chlorophyll a (Chl), and the summation of the projected areas of individual minerogenic particles per unit volume (PAVm) for the wide variations encountered in time and between near-shore and pelagic sites over an 8-year study of Cayuga Lake, New York. PAVm was determined from an individual particle analysis technique, scanning electron microscopy interfaced with automated image, and X-ray analyses (SAX). The partitionings are based on a stoichiometric approach that adopts Chl and PAVm as the metrics of bioseston and minerogenic particles, respectively, and estimates developed here for stoichiometric ratios that relate Tn and PP to these 2 components. The systematically higher Tn and PP levels at the near-shore site, particularly following runoff events, are demonstrated to be a result of elevated PAVm associated with allochthonous inputs. A reasonably good match of the partitioned 2-component summations with bulk observations is reported. Application of the 2-component PP model establishes minerogenic particles made, on average, noteworthy (~10%) to substantial (≥20%) contributions to PP. The minerogenic particle component of PP was largely responsible for the greater summer average total phosphorus (TP) concentrations at the near-shore versus the pelagic site, the interannual variations in the differences between these sites, and exceedance of the TP water quality limit at the near-shore site. Minerogenic particles were the dominant component of Tn, a finding that is demonstrated to be consistent with optical theory, based on the much greater efficiency of side-scattering for minerogenic versus organic particles
Phosphoenolpyruvate carboxylase dentified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism
Phospoenolpyruvate carboxylase (PEPC) is absent from humans but encoded in thePlasmodium falciparum genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in P. falciparum, we generated a pepc null mutant (D10Δpepc), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10Δpepc had a severe growth defect in vitro, which was partially reversed by addition of malate or fumarate, suggesting that pepc may be essential in vivo. Targeted metabolomics using 13C-U-D-glucose and 13C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10Δpepc and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of 13C,15N-U-glutamine was similar in both parasite lines, although the flux was lower in D10Δpepc; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery
Which Is the Most Suitable Classification for Colorectal Cancer, Log Odds, the Number or the Ratio of Positive Lymph Nodes?
Objective: The aim of the current study was to investigate which is the most suitable classification for colorectal cancer, log odds of positive lymph nodes (LODDS) classification or the classifications based on the number of positive lymph nodes (pN) and positive lymph node ratio(LNR) in a Chinese single institutional population. Design: Clinicopathologic and prognostic data of 1297 patients with colorectal cancer were retrospectively studied. The log-rank statistics, Cox’s proportional hazards model, the Nagelkerke R 2 index and a Harrell’s C statistic were used. Results: Univariate and three-step multivariate analyses identified that LNR was a significant prognostic factor and LNR classification was superior to both the pN and LODDS classifications. Moreover, the results of the Nagelkerke R 2 index (0.130) and a Harrell’s C statistic (0.707) of LNR showed that LNR and LODDS classifications were similar and LNR was a little better than the other two classifications. Furthermore, for patients in each LNR classification, prognosis was homologous between those in different pN or LODDS classifications. However, for patients in pN1a, pN1b, LODDS2 and LODDS3 classifications, significant differences in survival were observed among patients in different LNR classifications. Conclusions: For patients with colorectal cancer, the LNR classification is more suitable than pN and LODDS classification
Partial rupture of a locked patch of the Sumatra megathrust during the 2007 earthquake sequence
The great Sumatra–Andaman earthquake and tsunami of 2004 was a dramatic reminder of the importance of understanding the seismic and tsunami hazards of subduction zones [1,2,3,4]. In March 2005, the Sunda megathrust ruptured again, producing an event [5] of moment magnitude (Mw) 8.6 south of the 2004 rupture area, which was the site of a similar event in 1861 (ref. 6). Concern was then focused on the Mentawai area, where large earthquakes had occurred in 1797 (Mw = 8.8) and 1833 (Mw = 9.0) [6,7]. Two earthquakes, one of Mw = 8.4 and, twelve hours later, one of Mw = 7.9, indeed occurred there on 12 September 2007. Here we show that these earthquakes ruptured only a fraction of the area ruptured in 1833 and consist of distinct asperities within a patch of the megathrust that had remained locked in the interseismic period. This indicates that the same portion of a megathrust can rupture in different patterns depending on whether asperities break as isolated seismic events or cooperate to produce a larger rupture. This variability probably arises from the influence of non-permanent barriers, zones with locally lower pre-stress due to the past earthquakes. The stress state of the portion of the Sunda megathrust that had ruptured in 1833 and 1797 was probably not adequate for the development of a single large rupture in 2007. The moment released in 2007 amounts to only a fraction both of that released in 1833 and of the deficit of moment that had accumulated as a result of interseismic strain since 1833. The potential for a large megathrust event in the Mentawai area thus remains large
Too Hot to Handle: An Evaluation of the Effect of Thermal Visual Representation on User Grasping Interaction in Virtual Reality
Influence of interaction fidelity and rendering quality on perceived user experience have been largely explored in Virtual Reality (VR). However, differences in interaction choices triggered by these rendering cues have not yet been explored. We present a study analysing the effect of thermal visual cues and contextual information on 50 participants' approach to grasp and move a virtual mug. This study comprises 3 different temperature cues (baseline empty, hot and cold) and 4 contextual representations; all embedded in a VR scenario. We evaluate 2 different hand representations (abstract and human) to assess grasp metrics. Results show temperature cues influenced grasp location, with the mug handle being predominantly grasped with a smaller grasp aperture for the hot condition, while the body and top were preferred for baseline and cold conditions
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