Frequency responses of cat rapidly adapting mechanoreceptive fibers

The frequency responses of 11 rapidly adapting (RA) fibers in cat were studied by representing the average firing rate as a function of sinusoidal stimulus amplitude and stimulus frequency. Specifically, rate-intensity functions at different stimulation frequencies were fitted by four-parameter (a0, a1, a2, a3), piece-wise linear functions using nonlinear regression (n = 59; R2 > 0.877). Rate-intensity functions at intermediate frequencies were found by linear interpolation. The result of this analysis is rate-amplitude-frequency functions plotted as two-dimensional surfaces. The surfaces consist of five regions separated and sufficiently defined by four space curves. At 14 different frequencies, the statistical distribution of each rate-intensity-function parameter could be approximated by a particular lognormal distribution (n = 56; R2 > 0.796). The Kolmogorov-Smirnov test fails to reject this hypothesis for each combination of frequency and parameter (56 tests; p > 0.39). Therefore, at a given frequency, the variation of the parameters can be represented by lognormal distributions with specific means and standard deviations. Responses of six RA fibers, which are different from the data-set used for modeling, were compared with the stochastic model at different frequencies. The parameters of those fibers were tested against the null hypotheses that they were sampled from the particular parameter distributions dictated by the model. The Kolmogorov-Smirnov test fails to reject all the hypotheses at the alpha = 0.05 level (44 tests). At the alpha = 0.10 level, only a few test parameters were found to be departing from the model (a0 and a1 at 5 Hz; a2 at 20 Hz; a2 and a3 at 50 Hz). The remaining test parameters could be accurately described by the model. Having confirmed the validity of the model, the logarithmic means and the logarithmic standard deviations of the lognormally distributed rate-intensity-function parameters were estimated in the frequency range of 4-200 Hz. The rate-amplitude-frequency surfaces sampled from the established stochastic model completely characterize the rate responses of RA fibers to sinusoidal stimuli and are superior to tuning curves which require selecting criterion responses. The current rate-response model is promising for future computational work, especially on population modeling.     

Modeling population responses of rapidly-adapting mechanoreceptive fibers

The population response of rapidly-adapting (RA) fibers is one component of the physiological substrate of the sense of touch. Herein, we describe a computational scheme based on the population-response model by K.O. Johnson (J. Neurophysiol. 37: 48–72, 1974) which we extended by permitting the capability to include the spatial distributions of receptors in the glabrous skin linked to RA fibers. The hypothetical cases simulated were rectangular, uniformly random and proximo-distally Gaussian distributions. Each spatial organization produced qualitatively distinct population-response profiles that also varied due to stimulus parameters. The effects of stimulus amplitude, average innervation density and contactor-probe location were studied by considering various response measures: number of active fibers, summated firing rate and the average firing rate of a subset of the modeled population. The outcome of the measures were statistically compared among simulated anatomical distributions. The response is the same for rectangular and uniformly random distributions, both of which have a homogeneous innervation density. However, the Gaussian distribution produced statistically different responses when the measure was not averaged over the subset population which represented the receptive field of a higher-order neuron. These results indicate that, as well as stimulus parameters, the anatomical organization is a significant determinant of the population response. Therefore, reconstructing population activity for testing psychophysical hypotheses must presently be done with care until the organization of the receptors within the skin has been clarified.     

Distribution of the intensity-characteristic parameters of cat rapidly adapting mechanoreceptive fibers

Modeling population responses of nerve fibers requires statistical characterization of fiber-response properties. The rate/intensity characteristics of cat rapidly adapting (RA) fibers were fitted by four-parameter, piece-wise linear functions using nonlinear regression (n = 14; R2 > 0.958). The parameters were tested against the null hypothesis that they are log normally distributed. The test fail to reject this hypothesis (Kolmogorov-Smirnov p>0.477). However, a significant statistical difference was found between the specific lognormal distributions obtained from monkey (Johnson, J Neurophysiol 37: 48-72, 1974) and cat for all four parameters (Kolmogorov-Smirnov, p<0.0075, p<0.05, p<0.0001, p<0.00007). Although the stimulus contactor size was not the same in monkey and cat studies, the differences between monkey and cat fibers are attributed to anatomical differences in the glabrous sin of both species. Modeling studies suggest that the absolute firing thresholds of RA fibers have a right-skewed distribution because of the anatomical constraints present in both species' skin. Meissner corpuscles, which are the sensory end-organs of RA fibers, are likely to be found deeper in the skin within dermal papilla, therefore, the thresholds can be elevated. However, the thresholds are bounded at lower end, probably due to the epidermal junction that acts as a superficial mechanical barrier for these corpuscles.     

Asymmetric response properties of rapidly adapting mechanoreceptive fibers in the rat glabrous skin

Previous histological and neurophysiological studies have shown that the innervation density of rapidly adapting (RA) mechanoreceptive fibers increases towards the fingertip. Since the psychophysical detection threshold depends on the contribution of several RA fibers, a high innervation density would imply lower thresholds. However, our previous human study showed that psychophysical detection thresholds for the Non-Pacinian I channel mediated by RA fibers do not improve towards the fingertip. By recording single-unit spike activity from rat RA fibers, here we tested the hypothesis that the responsiveness of RA fibers is asymmetric in the proximo-distal axis which may counterbalance the effects of innervation density. RA fibers (n?=?32) innervating the digital glabrous skin of rat hind paw were stimulated with 40-Hz sinusoidal mechanical bursts at five different stimulus locations relative to the receptive field (RF) center (two distal, one RF center, two proximal). Different contactor sizes (area: 0.39, 1.63, 2.96?mm²) were used. Rate-intensity functions were constructed based on average firing rates, and the absolute spike threshold and the entrainment threshold were obtained for each RA fiber. Thresholds for proximal stimulus locations were found to be significantly higher than those for distal stimulus locations, which suggests that the mechanical stimulus is transmitted better towards the proximal direction. The effect of contactor size was not significant. Mechanical impedance of the rat digital glabrous skin was further measured and a lumped-parameter model was proposed to interpret the relationship between the asymmetric response properties of RA fibers and the mechanical properties of the skin.     

Evidence of fast serotonin transmission in frog slowly adapting type 1 responses

The Merkel cell–neurite (MCN) complex generates slowly adapting type 1 (SA1) response when mechanically stimulated. Both serotonin (5-HT) and glutamate have been implicated in the generation of normal SA1 responses, but previous studies have been inconclusive as to what their roles are or how synaptic transmission occurs. In this study, excised dorsal skin patches from common water frogs (Rana ridibunda) were stimulated by von Frey hairs during perfusion in a tissue bath, and single-unit spike activity was recorded from SA1 fibres. Serotonin had no significant effect on the SA1 response at low (10?µM) concentration, significantly increased activity in a force-independent manner at 100?µM, but decreased activity with reduced responsiveness to force at 1?mM. Glutamate showed no effect on the responsiveness to force at 100?µM. MDL 72222 (100?µM), an ionotropic 5-HT₃ receptor antagonist, completely abolished the responsiveness to force, suggesting that serotonin is released from Merkel cells as a result of mechanical stimulation, and activated 5-HT₃ receptors on the neurite. The metabotropic 5-HT₂ receptor antagonist, ketanserin, greatly reduced the SA1 fibre's responsiveness to force, as did the non-specific glutamate receptor antagonist, kynurenic acid. This supports a role for serotonin and glutamate as neuromodulators in the MCN complex, possibly by activation and/or inhibition of signalling cascades in the Merkel cell associated with vesicle release. Additionally, it was observed that SA1 responses contained a force-independent component, similar to a dynamic response observed during mechanical vibrations.     

Tactile-Evoked Response of Sensory Fibers in Buccal and Submandibular Regions of the Rat

Evoked neural responses to tactile stimulation were recorded electro-physiologically from the mechanoreceptive afferent fibers innervating the buccal and submandibular regions of Wistar rats anesthetized with sodium thiopental. Miniature probes 200 μm in diameter were used, and data analysis was performed on the mechanosensitivity of responses to tactile stimulation in the areas innervated by the mental, mylohyoid, auriculotemporal, and cervical nerves. Mechanosensitivity of each area showed a characteristic distribution of slowly adapting (SA), rapidly adapting (RA), C-fiber (CF), and hair follicle (HF) units in individual receptive fields. The density of the SA units was high in the areas innervated by the mylohyoid and auriculotemporal nerves. The CF units were concentrated in the small dome in the area of the mylohyoid nerve and the auriculotemporal nerve, as shown by a significant response to the dynamic features of stimulation. Estimation of the current needed for tactile acuity suggests an important role of the SA fibers in the areas innervated by the auriculotemporal, mylohyoid, and cervical nerves.     

不同蒿属植物对光强的适应性差异研究

对中国四种蒿属植物(毛莲蒿、蒙古蒿、牡蒿和灰苞蒿)的光合响应曲线进行了研究。结果表明:牡蒿具有高光饱点(411.0μmol·m-2·s-1)和最大光合速率(18.627μmol·m-2·s-1),以及较低的光补偿点(17.867μmol·m-2·s-1),对高光的适应能力最强;灰苞蒿的暗呼吸速率(0.353μmol·m-2·s-1)和表观量子效率(0.038)最低,说明该种对弱光的适应能力较差,且在弱光条件下只能维持较低的生长速率;灰苞蒿水分利用效率随光强的变化趋势与其他三种蒿属植物一致,但总体上维持在一个较高的水平,可能与其对干旱生境的适应有关。光合响应曲线各个拟合指标在种间呈现出了较大的变异,其中光补偿点(L cpμmol·m-2·s-1)和暗呼吸速率(R dayμmol·m-2·s-1)差异达到了显著水平。说明植物功能性状与植物对环境长期适应密切相关,并且这种适应性是稳定可遗传的。     

岩溶植物光合-光响应曲线的两种拟合模型比较

用直角双曲线和非直角双曲线两种模型,对桂林岩溶区石山植物红背山麻杆（Alchornea trewioides）、九龙藤（Bauhinia championii）、青檀（Pteroceltis tatarinowii）和圆叶乌桕（Sapium rotundifolium）光合作用的光响应曲线进行拟合。结果表明,直角双曲线拟合的表观量子效率（α）、最大净光合速率（Pmax）、暗呼吸速率（Rd）、光补偿点（Lcp）和光饱和点（Lφ）数值均高于相应的非直角双曲线拟合结果;直角双曲线模型拟合的参数值大小和曲线变化趋势不符合实际情况;非直角双曲线模型拟合结果更符合生理意义。红背山麻杆和九龙藤具有较高的表观量子效率和较低的光补偿点,对光能的利用效率和耐荫性均强于圆叶乌桕和青檀。     

Linking vertebral number to performance of aquatic escape responses in the axolotl (Ambystoma mexicanum)

Environmental conditions during early development in ectothermic vertebrates can lead to variation in vertebral number among individuals of the same species. It is often seen that individuals of a species raised at cooler temperatures have more vertebrae than individuals raised at warmer temperatures, although the functional consequences of this variation in vertebral number on swimming performance are relatively unclear. To investigate this relationship, we tested how vertebral number in axolotls (Ambystoma mexicanum) affected performance of aquatic escape responses (C-starts). Axolotls were reared at four temperatures (12–24 °C) encompassing their natural thermal range and then transitioned to a mean temperature (18 °C) three months before C-starts were recorded. Our results showed variation in vertebral number, but that variation was not significantly affected by developmental temperature. C-start performance among axolotls was significantly correlated with caudal vertebral number, and individuals with more caudal vertebrae were able to achieve greater curvature more quickly during their responses than individuals with fewer vertebrae. However, our results show that these individuals did not achieve greater displacements or velocities, and that developmental temperature did not have any effect on C-start performance. We highlight that the most important aspects of escape swim performance (i.e., how far individuals get from a threat and how quickly they move the most important parts of the body away from that threat) are consistent across individuals regardless of developmental temperature and morphological variation.     

利用马尾松年轮资料重建江苏暖湿地区气候的初步研究

利用树木年轮气候学方法,根据马尾松生长对气候变量具非线性响应,尝试重建江苏暖湿地区过去１１６年（１８７４～１９９０）的年平均气温和降水量。温度的重建效果优于降水量,实测值与重建值两者的缩减误差（ＲＥ）分别为０．１２和０．１０,两者的平均偏差百分率分别为２．３％和２０％。绝大部分重建结果可从观测记录和历史文献中得到验证,但在温度较高或降水量较多的若干年份,实测值与重建值有较大偏差。     

A Test of Gas Exchange Measurements on Excised Canopy Branches of Ten Tropical Tree Species

We studied gas exchange of leaves on branches that had been cut and then re-cut under water to assess the utility of measuring gas exchange on leaves of excised canopy branches. There was large variation between species in their ability to photosynthesize following excision. Some species maintained up to 86.5% of intact photosynthetic rate 60 min after excision, whereas other species dropped below 40% of intact photosynthetic rates within 3 min. Three species showed significant reductions in maximum rates of gross photosynthetic rate (P _G) on leaves of excised branches relative to intact branches. Excision significantly reduced carboxylation rates (Vc _max) in four species and electron transport (J _max) in two species. There were also significant increases in compensation irradiance and reductions of day rates of respiration relative to intact measurements. While gas exchange on excised branches can provide useful measures for canopy species, responses of individual species to branch excision need to be taken into account. Measurements on pre-screened species allow a greater understanding of canopy photosynthesis of large trees when canopy access is not an option.     

Prediction of methylated CpGs in DNA sequences using a support vector machine

DNA methylation plays a key role in the regulation of gene expression. The most common type of DNA modification consists of the methylation of cytosine in the CpG dinucleotide. At the present time, there is no method available for the prediction of DNA methylation sites. Therefore, in this study we have developed a support vector machine (SVM)-based method for the prediction of cytosine methylation in CpG dinucleotides. Initially a SVM module was developed from human data for the prediction of human-specific methylation sites. This module achieved a MCC and AUC of 0.501 and 0.814, respectively, when evaluated using a 5-fold cross-validation. The performance of this SVM-based module was better than the classifiers built using alternative machine learning and statistical algorithms including artificial neural networks, Bayesian statistics, and decision trees. Additional SVM modules were also developed based on mammalian- and vertebrate-specific methylation patterns. The SVM module based on human methylation patterns was used for genome-wide analysis of methylation sites. This analysis demonstrated that the percentage of methylated CpGs is higher in UTRs as compared to exonic and intronic regions of human genes. This method is available on line for public use under the name of Methylator at http://bio.dfci.harvard.edu/Methylator/.     

Influence of castration-induced testosterone and estradiol deficiency on obesity and glucose metabolism in male Göttingen minipigs

Low testosterone and estradiol concentrations are predictive for the development of the metabolic syndrome in men and women, respectively. The aim of this study was to investigate the influence of sex hormone deficiency on food intake, body weight, body composition and glucose metabolism in male Göttingen minipigs.Five adult male Göttingen minipigs were studied before castration (pre-cast), 10-18 days (post-cast 1) and 10-11 weeks (post-cast 2) after castration. Parameters of interest were food intake, body weight, body fat percentage and sex hormone concentrations. Furthermore glucose tolerance, glucagon suppression, insulin resistance, beta cell function and disposition index were evaluated by oral and intravenous glucose tolerance tests.Castration led to almost complete disappearance of circulating testosterone and estradiol and secondarily to increased food intake, body weight and body fat percentage. Ten-eighteen days sex hormone deficiency (post-cast 1) did not significantly change any of the investigated metabolic parameters compared to pre-cast levels. Ten weeks after castration (post-cast 2) significant insulin resistance, glucose intolerance and hyperglucagonemia was found, and the beta cell function and the disposition index both were decreased.In conclusion, castration-induced sex hormone deficiency in male Göttingen minipigs results in hyperphagia, obesity and disturbed glucose metabolism, which are some of the features typical for the human metabolic syndrome.     

Discovery of two novel branched peptidomimetics containing endomorphin-2 and RF9 pharmacophores: Synthesis and neuropharmacological evaluation

It is well known that opioid analgesics produce side effects including tolerance and constipation. Since neuropeptide FF (NPFF) receptor antagonists reversed opioid-induced hyperalgesia and analgesic tolerance, the present work was performed to synthetize two branched peptidomimetics, EKR and RKE, containing the opioid peptide endomorphin-2 (EM-2) and the NPFF receptor antagonist RF9. Our data obtained from the in vitro cyclic adenosine monophosphate experiment demonstrated that EKR functioned as a mixed mu-, delta-opioid receptors agonist and NPFF₁ receptor antagonist/NPFF₂ receptor partial agonist, whereas RKE acted as a multi-functional peptidomimetic with the mu-opioid agonism and the NPFF₁ antagonism/NPFF₂ partial agonism. Furthermore, EKR and RKE completely blocked the NPFF₂ receptor-mediated neurite outgrowth of Neuro 2A cells. In vivo antinociception studies found that supraspinal administration of EKR and RKE dose-dependently produced potent antinociception via the mu-opioid receptor in the tail-flick test. In carrageenan inflammatory pain model, spinal administration of EKR and RKE induced dose-related analgesia, which was significantly reduced by the opioid antagonist naloxone and the NPFF antagonist RF9. Notably, compared with morphine, intracerebroventricular repeated administration of EKR and RKE maintained prolonged antinociceptive effectiveness. In addition, at the antinociceptive doses, these two branched peptidomimetics did not significantly inhibit gastrointestinal transit. Taken together, the present work suggest that EKR and RKE behave as multi-functional ligands with the opioid agonism and the NPFF₁ antagonism/NPFF₂ partial agonism, and produce prolonged antinociception with limited side effects. Moreover, our results imply that EKR and RKE might be interesting pharmacological tools for further investigating the biological function of the NPFF and opioid systems.     

The impact of confounders on the test performance of natriuretic peptides for cardiac dysfunction in subjects aged 80 and older

The hypothesis that natriuretic peptides could be used to identify ‘pancardiac’ damage has been proposed. However, multiple factors are known to influence circulating levels of natriuretic peptides, especially in the very old. Therefore, the impact of confounders on the association between natriuretic peptide levels and cardiac dysfunction was further explored in subjects aged 80 and older. A diagnostic cross-sectional study embedded within the BELFRAIL study (n = 567) was performed. Baseline BNP and NT-proBNP levels were measured and echocardiograms were performed at the subject's home. Cardiac dysfunction was defined as systolic dysfunction, valvular heart disease or isolated severe diastolic dysfunction. Several functional and structural echocardiographic parameters were independently related to circulating levels of natriuretic peptides. Cystatin C, BMI, β blockers, diabetes, heart frequency, usCRP, age and sex were identified as confounders. The prevalence of cardiac dysfunction was 17.1% in the subjects without and 30.8% in the subjects with chronic atrial fibrillation (CAF) or pacemaker (PM). Only in subjects with CAF or PM the C statistic for cardiac dysfunction improved after correcting for confounders. The post-test probability for a negative test (PTP−) ranged from 3.7% to 12.2% and the PTP+ ranged from 21.9% to 62.2% in different strata of confounders. According to these data adjusting for identified confounders does not improve the diagnostic accuracy of the natriuretic peptides for cardiac dysfunction, except in subjects with CAF or PM. Stratifying for individual confounders showed that different cut-off values could be used to optimize the diagnostic characteristics of natriuretic peptides.     

The MTMR9 rs2293855 polymorphism is associated with glucose tolerance,insulin secretion,insulin sensitivity and increased risk of prediabetes

Background

Polymorphism of rs2293855 in gene MTMR9 has been associated with obesity and metabolic syndrome. We aim to study the association of rs2293855 with type 2 diabetes mellitus (T2DM) intermediate phenotypes in a Han Chinese population.

Methods

The polymorphism was genotyped in 838 Han Chinese individuals using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS); all participants underwent a 75 g oral glucose tolerance test (OGTT); associations between the polymorphism and glucose tolerance, indices of insulin secretion and indices of insulin sensitivity were analyzed.

Results

The frequency of genotypes and alleles differed significantly between normal glucose tolerance and prediabetes (P = 0.043 and P = 0.009, respectively). The GG homozygous presented higher fasting plasma glucose (P = 0.009), higher 2-hour plasma glucose (P = 0.024) and higher glucose area under the curve (AUC, P = 0.01). Moreover, the G allele of rs2293855 was associated with glucose intolerance (fasting glucose, P = 0.012; glucose AUC, P = 0.006; 2-h glucose, P = 0.024); it is also associated with decreased indices of insulin sensitivity (fasting insulin, P = 0.043; insulin sensitivity index composite, P = 0.009; homeostasis model assessment of insulin resistance, HOMA-IR, P = 0.008) and decreased indices of insulin secretion (HOMA of beta cell function, HOMA-B, P = 0.028; insulinogenic index, P = 0.003). In addition, the minor allele G was also associated with increased risk of prediabetes (OR = 1.463, 95%CI: 1.066–2.009, P = 0.018).

Conclusions

Polymorphism of rs2293855 in MTMR9 is associated with measures of glucose tolerance, indices of insulin secretion and indices of insulin sensitivity. We also suggest that allele G is likely to increase the risk of prediabetes by influencing both insulin secretion and insulin sensitivity.