Ligand unbinding pathways from the vitamin D receptor studied by molecular dynamics simulations

Molecular dynamics simulation techniques have been used to study the unbinding pathways of 1α,25-dihydroxyvitamin D₃ from the ligand-binding pocket of the vitamin D receptor (VDR). The pathways observed in a large number of relatively short (<200 ps) random acceleration molecular dynamics (RAMD) trajectories were found to be in fair agreement, both in terms of pathway locations and deduced relative preferences, compared to targeted molecular dynamics (TMD) and streered molecular dynamics simulations (SMD). However, the high-velocity ligand expulsions of RAMD tend to favor straight expulsion trajectories and the observed relative frequencies of different pathways were biased towards the probability of entering a particular exit channel. Simulations indicated that for VDR the unbinding pathway between the H1–H2 loop and the β-sheet between H5 and H6 is more favorable than the pathway located between the H1–H2 loop and H3. The latter pathway has been suggested to be the most likely unbinding path for thyroid hormone receptors (TRs) and a likely path for retinoic acid receptor. Ligand entry/exit through these two pathways would not require displacement of H12 from its agonistic position. Differences in the packing of the H1, H2, H3 and β-sheet region explain the changed relative preference of the two unbinding pathways in VDR and TRs. Based on the crystal structures of the ligand binding domains of class 2 nuclear receptors, whose members are VDR and TRs, this receptor class can be divided in two groups according to the packing of the H1, H2, H3 and β-sheet region. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Evoked Potential Audiograms of the Nurse Shark (Ginglymostoma cirratum) and the Yellow Stingray (Urobatis jamaicensis)

The hearing thresholds of the nurse shark, Ginglymostoma cirratum, and the yellow stingray, Urobatis jamaicensis, were measured using auditory evoked potentials (AEP). Stimuli were calibrated using a pressure-velocity probe so that the acoustic field could be completely characterized. The results show similar hearing thresholds for both species and similar hearing thresholds to previously measured audiograms for the lemon shark, Negaprion brevirostris, and the horn shark, Heterodontis francisi. All of these audiograms suggest poor hearing abilities, raising questions about field studies showing attraction of sharks to acoustic signals. By extrapolating the particle acceleration thresholds into estimates of their equivalent far-field sound pressure levels, it appears that these sharks cannot likely detect most of the sounds that have attracted sharks in the field.     

The contribution of the pleural type 12 interneuron to swim acceleration in Clione limacina

The pteropod mollusc, Clione limacina, swims by alternate dorsal–ventral flapping movements of its wing-like parapodia. The basic swim rhythm is produced by a network of pedal swim interneurons that comprise a swim central pattern generator (CPG). Serotonergic modulation of both intrinsic cellular properties of the swim interneurons and network properties contribute to swim acceleration, the latter including recruitment of type 12 interneurons into the CPG. Here we address the role of the type 12 interneurons in swim acceleration. A single type 12 interneuron is found in each of the pleural ganglia, which contributes to fast swimming by exciting the dorsal swim interneurons while simultaneously inhibiting the ventral swim interneurons. Each type 12 interneuron sends a single process through the pleural–pedal connective that branches in both ipsilateral and contralateral pedal ganglia. This anatomical arrangement allowed us to manipulate the influence of the type 12 interneurons on the swim circuitry by cutting the pleural–pedal connective followed by a “culture” period of 48 h. The mean swim frequency of cut preparations was reduced by 19% when compared to the swim frequency of uncut preparations when stimulated with 10⁻⁶ M serotonin; however, this decrease was not statistically significant. Additional evidence suggests that the type 12 interneurons may produce a short-term, immediate effect on swim acceleration while slower, modulatory inputs are taking shape.     

Moving towards acceleration for estimates of activity-specific metabolic rate in free-living animals: the case of the cormorant

1. Time and energy are key currencies in animal ecology, and judicious management of these is a primary focus for natural selection. At present, however, there are only two main methods for estimation of rate of energy expenditure in the field, heart rate and doubly labelled water, both of which have been used with success; but both also have their limitations. 2. The deployment of data loggers that measure acceleration is emerging as a powerful tool for quantifying the behaviour of free-living animals. Given that animal movement requires the use of energy, the accelerometry technique potentially has application in the quantification of rate of energy expenditure during activity. 3. In the present study, we test the hypothesis that acceleration can serve as a proxy for rate of energy expenditure in free-living animals. We measured rate of energy expenditure as rates of O2 consumption (VO2) and CO2 production (VCO2) in great cormorants (Phalacrocorax carbo) at rest and during pedestrian exercise. VO2 and VCO2 were then related to overall dynamic body acceleration (ODBA) measured with an externally attached three-axis accelerometer. 4. Both VO2 and VCO2 were significantly positively associated with ODBA in great cormorants. This suggests that accelerometric measurements of ODBA can be used to estimate VO2 and VCO2 and, with some additional assumptions regarding metabolic substrate use and the energy equivalence of O2 and CO2, that ODBA can be used to estimate the activity specific rate of energy expenditure of free-living cormorants. 5. To verify that the approach identifies expected trends in from situations with variable power requirements, we measured ODBA in free-living imperial cormorants (Phalacrocorax atriceps) during foraging trips. We compared ODBA during return and outward foraging flights, when birds are expected to be laden and not laden with captured fish, respectively. We also examined changes in ODBA during the descent phase of diving, when power requirements are predicted to decrease with depth due to changes in buoyancy associated with compression of plumage and respiratory air. 6. In free-living imperial cormorants, ODBA, and hence estimated VO2, was higher during the return flight of a foraging bout, and decreased with depth during the descent phase of a dive, supporting the use of accelerometry for the determination of activity-specific rate of energy expenditure.     

Repetitive acceleration swimming performance of brown trout in fresh water and after acute seawater exposure

The effect of acute seawater exposure on repeated swimming performance of brown trout Salmo trutta was investigated by use of a constant acceleration test (CAT). In fresh water, swimming speed was attained regardless of previous exercise, whereas swimming speed in sea water was significantly reduced during consecutive exercise.     

Deceleration of morphological evolution in a cryptic species complex and its link to paleontological stasis

Morphological stasis or the absence of morphological change is a well-known phenomenon in the paleontological record, yet it is poorly integrated with neontological evidence. Recent evidence suggests that cryptic species complexes may remain morphologically identical due to morphological stasis. Here, we describe a case of long-term stasis in the Stygocapitella cryptic species complex (Parergodrilidae, Orbiniida, Annelida). Using phylogenetic methods and morphological data, we find that rates of morphological evolution in Stygocapitella are significantly slower than in closely related taxa (Nerillidae, Orbiniidae). Assessment of quantitative and qualitative morphology revealed the presence of four morphotypes with only subtle differences, whereas molecular data supports 10 reproductively isolated clades. Notably, estimates for the time of Stygocapitella species divergence range from ∼275 million years to ∼18 million years, including one case of two morphologically similar species that have diverged about 140 million years ago. These findings provide evidence for morphological deceleration and long-term morphological stasis in Stygocapitella, and that speciation is not necessarily accompanied by morphological changes. The deceleration of morphological divergence in Stygocapitella can be potentially linked to niche conservatism and tracking, coupled with the fluctuating dynamics of the interstitial environment, or genetic constraints due to progenetic evolution. Finally, we conclude that failing to integrate speciation without morphological evolution in paleontology may bias estimates of rates of speciation and morphological evolution.     

Validation of irtGPUMCD,a GPU-based Monte Carlo internal dosimetry framework for radionuclide therapy

PurposeMonte Carlo (MC) simulations are highly desirable for dose treatment planning and evaluation in radiation oncology. This is true also in emerging nuclear medicine applications such as internal radiotherapy with radionuclides. The purpose of this study is the validation of irtGPUMCD, a GPU-based MC code for dose calculations in internal radiotherapy.MethodsThe female and male phantoms of the International Commission on Radiological Protection (ICRP 110) were used as benchmarking geometries for this study focused on ¹⁷⁷Lu and including ^99mTc and ¹³¹I. Dose calculations were also conducted for a real patient. For phantoms, twelve anatomical structures were considered as target/source organs. The S-values were evaluated with irtGPUMCD simulations (10⁸ photons), with gamma branching ratios of ICRP 107 publication. The ¹⁷⁷Lu electrons S-values were calculated for source organs only, based on local deposition of dose in irtGPUMCD. The S-value relative difference between irtGPUMCD and IDAC-DOSE were evaluated for all targets/sources considered. A DVHs comparison with GATE was conducted. An exponential track length estimator was introduced in irtGPUMCD to increase computational efficiency.ResultsThe relative S-value differences between irtGPUMCD and IDAC-DOSE were <5% while this comparison with GATE was <1%. The DVHs dosimetric indices comparison between GATE and irtGPUMCD for the patient led to an excellent agreement (<2%). The time required for the simulation of 10⁸ photons was 1.5 min for the female phantom, and one minute for the real patient (<1% uncertainty). These results are promising and let envision the use of irtGPUMCD for internal dosimetry in clinical applications.     

基于支持向量机的表面肌电信号和加速度融合跌倒识别方法

目的:针对老人易跌倒和跌倒过后可能产生严重后果这一现实问题,通过将表面肌电信号和加速度融合,进一步优化采用支持向量机分类器下的包含跌倒在内的几种不同动作的分类效果。方法:提出基于表面肌电和加速度信号融合的跌倒识别算法,首先采集股直肌,股内侧肌,胫骨前肌和腓肠肌的表面肌电信号以及位于腰部的三轴加速度信号作为实验数据,然后利用滑动窗口法提取表面肌电和加速度信号的均方根值,最后针对人体日常活动和跌倒的运动特征,构建了支持向量机的分类器。结果:实验数据共计320组数据,包括3种日常活动和向前跌倒,其中160组数据作为训练集,另外160组数据作为测试集。对4种动作进行识别实验,算法的准确度为93.23%、灵敏度为92.4%、特异度为100%,达到了良好的分类效果。结论:基于支持向量机的表面肌电信号和加速度融合的跌倒识别算法分类效果良好,对于老人跌倒防护具有现实意义。     

重复-Gx加速度暴露对家兔心脏结构的影响*

目的: 重复-Gx加速度暴露对新西兰家兔心脏结构的影响。方法: 20只新西兰家兔随机分为2组(n=10):对照组、-Gx加速度暴露组。-3.6 Gx暴露2 s,间隔5 min,每天重复20次,共30 d;对照组不受加速度作用。末次-Gx加速度暴露后,用静脉注射空气法处死动物,迅速取左心室心肌组织,常规取样并采用光学显微镜及透射电镜进行组织学观察。结果: -Gx加速度暴露组家兔心肌切片在光学显微镜下可见心肌细胞的形态及排列等与对照组无显著区别;-Gx加速度暴露组家兔心肌在透射电镜下可见,心肌纤维断裂、排列紊乱、心肌细胞水肿、核膜扩张、血管内皮基膜分离。结论: -Gx加速度暴露可造成家兔心肌细胞超微结构损伤,提示应重视长期重复-Gx加速度暴露对舰载战斗机飞行员心脏功能的影响和防护。     

Pyruvate accumulation may contribute to acceleration-induced impairment of physical and cognitive abilities: an experimental study

Background: Fatigue can be induced after acceleration exposure, however its mechanism is still unclear. The aim of the present study was to examine whether metabolites’ changes can decrease cognitive and physical function after acceleration. Methods: Graybiel scale and Fatigue Self-rating scale were used to assess the seasickness and fatigue degrees of 87 male seafarers respectively after sailing. To test the effect of pyruvate on cognitive and physical functions, five different doses of pyruvate were administrated into rats. Insulin can reduce the accumulation of pyruvate. To observe the insulin effect on pyruvate, cognitive and physical functions after acceleration, insulin administration or treatment of promoting insulin secretion was used. Physical and cognitive functions were assessed using open field test (OFT), morris water maze (MWM) and loaded swimming test (LST) in animals. Results: Physical and cognitive abilities were decreased obviously, and serum pyruvate increased mostly in human and rats after acceleration. Compared with vehicle group, physical and cognitive abilities were significantly decreased after pyruvate administration. Besides, we found a significant decline in adenosine triphosphate (ATP) concentration and pyruvate dehydrogenase (PDH) activity in the hippocampus, prefrontal cortex, liver, and muscle of rats treated with acceleration or pyruvate injection, while insulin administration or treatment of promoting insulin secretion markedly alleviated this decline and the impairment of physical and cognitive abilities, compared with the control group. Conclusion: Our results indicate that pyruvate has a negative effect on physical and cognitive abilities after acceleration. Insulin can inhibit pyruvate accumulation and cognitive and physical function after acceleration exposure.