Effect of Leukemia Inhibitory Factor on Human Cytotrophoblast Differentiation Along the Invasive Pathway

PROBLEM : Leukemia inhibitory factor (LIF) is a pleiotropic secreted cytokine that was shown to be essential for blastocyst implantation in mice. Since it is well documented that LIF is produced by the human endometrium, we wondered if this cytokine was capable of modulating the invasive behaviour of human cytotrophoblastic cells (CTB). METHODS : CTB were isolated and purified from first trimester abortions, separated or not into cells bearing a laminin or a fibronectin receptor (α6β4 or α5β1 respectively) using specific monoclonal antibodies and magnetic particles. RESULTS : We observed that rhLIF inhibited the secretion of gelatinases and of hCG by CTB but remained without effects on the secretion of fetal fibronectin (fFN). These effects were exerted on different CTB subsets: although rhLIF inhibited the secretion of gelatinases by α6 positive cells, it stimulated the fFN secretion by α5 positive cells. The inhibitory effect of rhLIF on the secretion of hCG was mainly due to its effect on the hCG secretion of α5 positive CTB. CONCLUSIONS : Taken together these results suggest that in vitro LIF inhibits the differentiation of CTB towards an invasive phenotype by inhibiting the secretion of metalloproteinases, by increasing the deposition of fFN into the extracellular matrix and by inhibiting the differentiation of CTB into syncytium.     

A Study on Asymmetry of Spatial Visual Field by Analysis of the fMRI BOLD Response

The asymmetry of the left-right and upper-lower visual field is analyzed in this paper by a model approach based on the functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) response. The model consists of the convolution between a Gaussian function and the perfusion function of neural response to stimulus. The model parameters are estimated by a nonlinear optimal algorithm, and te asymmetry of the left-right and upper-lower visual field is investigated by the differences of the model parameters. The results from eight subjects show that reaction time is significant shorter and the response is significant stronger when the lower field is stimulated than that when the upper field is stimulated. For the left and right fields, the response is different. These results provide the fMRI BOLD response evidence of the asymmetry of spatial visual fields.     

脑静息功能连接自发波动的可变性分析

静息脑功能连接的动态性被认为能够反映大尺度功能脑网络的基本性质,近年来受到越来越多的关注。过去很少有研究分析静息脑连接自发波动的空间分布特点。采用远程功能连接度结合滑动窗口方法,分析一组大样本(n=396)年轻成年人脑静息功能连接低频自发波动的可变性。首先采用36 s滑动窗,计算全脑动态连接时间序列;然后在每个窗口内,以半径为14 mm的球形邻域计算每个体素的远程连接度;最后引入低频振荡幅值(ALFF)指标,评估各体素连接度波动的大小。研究结果表明: 默认网络具有最小的波动性(ALFF=402.3±79.9),暗示该网络在稳定脑自发神经活动中起主要作用。与之对比,感觉运动网络相关连接波动呈现出最大的可变性(ALFF=551.2±74.7),可能与被试在无任务状态下不定期感知外界环境有关。首次揭示静息态认知网络与感觉运动网络在静息功能连接波动性方面存在显著差异(双样本t检验: t=-6.38, P<0.000 1),有助于进一步理解无任务状态下脑功能的动态组织方式, 并为研究神经心理疾病提供新的方法。     

手背皮肤血流自然波动的观察与数据处理

研究皮肤血流量的变化规律和数据分析方法,为进一步研究针刺影响奠定方法学基础。使用PeriSean PIM Ⅱ激光多普勒血流成像仪对10例健康入手背部的血流量进行7次共28min的连续扫描测量。将手背分成五个手指、手指以外的无手指手背部分及整个手背7个区域,分区域计算平均血流量。结果表明,其中五个手指的流量平均血流量显著高于无手指手背的血流量。整个手背的血流量存在小幅度的自然波动,五个手指的波动比较明显,而无手指手背部分的波动较小,且中五个手指之间的血流量变化有很强的相关性（r＝0．756±0．284）,显著高于手指与无手指手背之间的相关性（r=0．491±0．453）（P〈0．05）。结果提示,血流的这种自然波动可能是环境和心理因素所致。相对于整个手区域的血流,血流波动在手指区域为6．5％±4．0％,在无手指手背区域为4．1％±2．5％,因此皮肤血流的的相对波动率比绝对波动率显著减弱（P〈0．05）。该数据处理方法为研究针刺外周效应的空间特异性提供了有力的工具。     

Tryptophan Metabolism Along the Kynurenine Pathway Downstream of Toll‐like Receptor Stimulation in Peripheral Monocytes

Tryptophan degradation along the kynurenine pathway is of central importance for the immune function. Toll‐like receptors (TLRs), representing the first line of immune defence against pathogens, are expressed in various cell types. The most abundant expression is found on monocytes, macrophages and dendritic cells. The aim of this study was to investigate whether stimulation with different TLR ligands induces the kynurenine pathway in human peripheral monocytes. Cell supernatants were analysed using a liquid chromatography/mass spectrometry to measure kynurenine, kynurenic acid (KYNA), quinolinic acid (QUIN) and tryptophan. Stimulation of TLR‐2, TLR‐3, TLR‐4, TLR‐7/8 and TLR‐9 was found to induce the production of kynurenine, but only stimulation of TLR‐3 increased levels of further downstream metabolites, such as KYNA and QUIN. Stimulation of TLR‐1, TLR‐5 and TLR‐6 did not induce the kynurenine pathway. Taken together, this study provides novel evidence demonstrating that TLR activation induces a pattern of downstream tryptophan degradation along the kynurenine pathway in monocytes. The results of this study may implicate that TLRs can be used as new drug targets for the regulation of aberrant tryptophan metabolism along this pathway, a potential therapeutic strategy that may be of importance in several disorders.     

Sinusoidal Modeling of Ictal Activity Along a Thalamus-to-Cortex Seizure Pathway I: New Coherence Approaches

Understanding associations in neuronal circuitry is critical for tracing epilepsy pathways. Two new methods of measuring coherence between field potentials and EEG channels are proposed for modeling the level of linear association between channels during epileptic seizures. These methods rely upon modeling the repetitive clonic seizure activity as a sum of sinusoids with varying degrees of phase locking. Estimating the amplitude of sinusoids from correlation and cross-correlation time domain data, we can find the coherences from a ratio of these amplitudes. One method utilizes amplitude finding from the multiple signal classification (MUSIC) technique. The other method uses alterations in amplitude of individual sinusoids and their ratios in a matrix pencil equation formed from cross- and auto-correlation matrices. The corresponding generalized eigenvalues of these equations form the coherence ratios. This utilizes the estimation of signal parameters using rotational invariance techniques (ESPRIT) algorithm to arrive at coherence amplitude ratios. Simulations illustrate that the MUSIC method provides better noise immunity as it out-performs the conventional Fourier transform-based method for coherence estimation. Both coherence estimators reflect presence of sinusoidal components that are propagated or not propagated along a particular transmission pathway. We illustrate the value of both methods by examining the strength of correlation between seizure EEG from specific thalamic nuclei and cortex in a rodent model of generalized epilepsy. The pentylenetetrazol (PTZ) chemoconvulsant model in rats reflects selective activation of the anterior thalamic nucleus. Using both methods, this neuronal element has much larger coherence with cortex than another thalamic region, the posterior thalamus (p < 0.05). These methods isolate the unique contribution of anterior thalamus in the formation of an ictal network and corroborate earlier conventional or periodogram techniques.     

Determining the Number of Independent Sources of the EEG: A Simulation Study on Information Criteria

The separation of signal and noise is an important problem in the analysis of EEG and MEG data. Furthermore, many source localisation strategies need the number of independent signal components as input parameter (e.g., dipole fit, multiple signal classification). Information criteria offer a relatively objective way to separate the space spanned by the principal components of the data covariance matrix into a signal and a noise part. Eighteen such criteria were extensively tested by simulations. They differ with respect to the statistical model of the data, the assumptions on the noise, and the correction term. In the simulations, different dipole sources were used to generate EEG, which was then distorted by Gaussian correlated or uncorrelated noise. The noise level, the accuracy of the noise covariance matrix used by the criteria, the numbers of channels and time samples, and the stochastic or deterministic nature of the source waveforms were varied. The performance of the criteria was very variable. For each criterion, limits for the noise level and the relative inaccuracy of the noise covariance matrix could be established. Taking more channels or time steps did increase the criteria's ability to tolerate noise, but at the same time, made them more vulnerable to inaccuracies in the (estimated) noise covariance matrices. Out of the eighteen criteria investigated, we recommend two criteria that are best suited for the cases of (1) high noise and accurate covariances and (2) low noise and less accurate covariances.     

Inhibitory Humoral Responses to the Plasmodium falciparum Vaccine Candidate EBA-175 Are Independent of the Erythrocyte Invasion Pathway

Plasmodium falciparum utilizes multiple ligand-receptor interactions for invasion. The invasion ligand EBA-175 is being developed as a major blood-stage vaccine candidate. EBA-175 mediates parasite invasion of host erythrocytes in a sialic acid-dependent manner through its binding to the erythrocyte receptor glycophorin A. In this study, we addressed the ability of naturally acquired human antibodies against the EBA-175 RII erythrocyte-binding domain to inhibit parasite invasion of ex vivo isolates, in relationship to the sialic acid dependence of these parasites. We have determined the presence of antibodies to the EBA-175 RII domain by enzyme-linked immunosorbent assay (ELISA) in individuals from areas of Senegal where malaria is endemic with high and low transmission. Using affinity-purified human antibodies to the EBA-175 RII domain from pooled patient plasma, we have measured the invasion pathway as well as the invasion inhibition of clinical isolates from Senegalese patients in ex vivo assays. Our results suggest that naturally acquired anti-EBA-175 RII antibodies significantly inhibit invasion of Senegalese parasites and that these responses can be significantly enhanced through limiting other ligand-receptor interactions. However, the extent of this functional inhibition by EBA-175 antibodies is not associated with the sialic acid dependence of the parasite strain, suggesting that erythrocyte invasion pathway usage by parasite strains is not driven by antibodies targeting the EBA-175/glycophorin A interaction. This work has implications for vaccine design based on the RII domain of EBA-175 in the context of alternative invasion pathways.     

Applying Transcranial Magnetic Stimulation (TMS) Over the Dorsal Visual Pathway Induces Schizophrenia-like Disruption of Perceptual Closure

Perceptual closure ability is postulated to depend upon rapid transmission of magnocellular information to prefrontal cortex via the dorsal stream. In contrast, illusory contour processing requires only local interactions within primary and ventral stream visual regions, such as lateral occipital complex. Schizophrenia is associated with deficits in perceptual closure versus illusory contours processing that is hypothesized to reflect impaired magnocellular/dorsal stream. Perceptual closure and illusory contours performance was evaluated in separate groups of 12 healthy volunteers during no TMS, and during repetitive 10 Hz rTMS stimulation over dorsal stream or vertex (TMS-vertex). Perceptual closure and illusory contours were performed in 11 schizophrenia patients, no TMS was applied in these patients. TMS effects were evaluated with repeated measures ANOVA across treatments. rTMS significantly increased perceptual closure identification thresholds, with significant difference between TMS-dorsal stream and no TMS. TMS-dorsal stream also significantly reduced perceptual closure but not illusory contours accuracy. Schizophrenia patients showed increased perceptual closure identification thresholds relative to controls in the no TMS condition, but similar to controls in the TMS-dorsal stream condition. Conclusions of this study are that magnocellular/dorsal stream input is critical for perceptual closure but not illusory contours performance, supporting both trickledown theories of normal perceptual closure function, and magnocellular/dorsal stream theories of visual dysfunction in schizophrenia.     

基于视通路多感受野朝向性关联的轮廓检测方法

基于视通路中各层次的感受野特性以及层次间感受野的关联特性,提出一种图像轮廓检测新方法。根据神经元的放射状树突接收特性,构建检测空间差异性信息的视网膜神经元网络,对轮廓信息进行前级编码;建立LGN细胞的非经典感受野调节机制,结合感受野的层次变换特性,对前级编码结果进行全局调节;提出简单细胞的多感受野朝向性关联模型,模拟初级视皮层简单细胞的方向选择特性;融合多个方向上的轮廓响应,经过非极大值抑制和阈值处理,得到轮廓检测结果。以RuG图库40幅图片为实验对象,检测结果与基准轮廓图的平均P指标为0.43,结果显示该方法能够有效凸显主体轮廓,强化轮廓与纹理边缘的区分度。利用多感受野的层次关联特性,实现图像轮廓信息的编码与检测应用,为研究高级视皮层的图像理解和视觉认知提供新的思路。     

On the assessment of cerebrovascular reactivity using hypercapnia BOLD MRI

Cerebrovascular reactivity (CVR) reflects the capacity of blood vessels to dilate and is an important marker for brain vascular reserve. It may provide a useful addition to the traditional baseline blood flow measurement when assessing vascular factors in brain disorders. Blood‐oxygenation‐level‐dependent MRI under CO₂ inhalation offers a non‐invasive and quantitative means to estimate CVR in humans. In this study, we investigated several important methodological aspects of this technique with the goal of optimizing the experimental and data processing strategies for clinical use. Comparing 4 min of 5% CO₂ inhalation (less comfortable) to a 1 min inhalation (more comfortable) duration, it was found that the CVR values were 0.31 ± 0.05%/mmHg (N = 11) and 0.31 ± 0.08%/mmHg (N = 9), respectively, showing no significant differences between the two breathing paradigms. Therefore, the 1 min paradigm is recommended for future application studies for patient comfort and tolerability. Furthermore, we have found that end‐tidal CO₂ recording was useful for accurate quantification of CVR because it provided both timing and amplitude information regarding the input function to the brain vascular system, which can be subject‐dependent. Finally, we show that inter‐subject variations in CVR are of physiologic origin and affect the whole brain in a similar fashion. Based on this, it is proposed that relative CVR (normalized against the CVR of the whole brain or a reference tissue) may be a more sensitive biomarker than absolute CVR in clinical applications as it minimizes inter‐subject variations. With these technological optimizations, CVR mapping may become a useful method for studies of neurological and psychiatric diseases. Copyright © 2009 John Wiley & Sons, Ltd.     

Imaging of prolonged BOLD response in the somatosensory cortex of the rat

Blood oxygenation level‐dependent (BOLD) functional MRI is a widely employed methodology in experimental and clinical neuroscience, although its nature is not fully understood. To gain insights into BOLD mechanisms and take advantage of the new functional methods, it is of interest to investigate prolonged paradigms of activation suitable for long experimental protocols and to observe any long‐term modifications induced by these functional challenges. While different types of sustained stimulation paradigm have been explored in human studies, the BOLD response is typically limited to a few minutes in animal models, due to fatigue, anesthesia effects and physiological instability. In the present study, the rat forepaw was electrically stimulated for 2 h, which resulted in a prolonged and localized cortical BOLD response over that period. The stimulation paradigm, including an inter‐stimulus interval (ISI) of 10 s, that is 25% of the total time, was applied at constant or variable frequency over 2 h. The steady‐state level of the BOLD response was reached after 15–20 min of stimulation and was maintained until the end of the stimulation. On average, no substantial loss in activated volume was observed at the end of the stimulation, but less variability in the fraction of remaining activated volume and higher steady‐state BOLD amplitude were observed when stimulation frequency was varied between 2 and 3 Hz every 5 min. We conclude that the combination of ISI and variable stimulus frequency reproducibly results in robust, prolonged and localized BOLD activation. Copyright © 2015 John Wiley & Sons, Ltd.     

基于独立分量分析的大脑视觉诱发电位单次提取

脑电 (Electroencephalography ,EEG)视觉诱发电位 (VisualEvokedPotential,VEP)的单次提取是当前生物医学信号处理领域的一个研究热点。提出一种基于独立分量分析 (IndependentComponentAnalysis,ICA)的多道脑电信号VEP单次提取方法 ,与多次叠加求平均的方法相比较 ,可以得到令人满意的结果。     

Dietary supplementation of creatine monohydrate reduces the human fMRI BOLD signal

Creatine monohydrate is an organic acid that plays a key role in ATP re-synthesis. Creatine levels in the human brain vary considerably and dietary supplementation has been found to enhance cognitive performance in healthy individuals. To explore the possibility that the fMRI Blood Oxygen Level Dependent (BOLD) response is influenced by creatine levels, BOLD responses to visual stimuli were measured in visual cortex before and after a week of creatine administration in healthy human volunteers. The magnitude of the BOLD response decreased by 16% following creatine supplementation of a similar dose to that previously shown to increase cerebral levels of phosphocreatine. We also confirmed that cognitive performance (memory span) is increased. These changes were not found in a placebo group. Possible mechanisms of BOLD change are considered. The results offer potential for insight into the coupling between neural activity and the BOLD response and the more immediate possibility of accounting for an important source of variability during fMRI analysis in clinical studies and other investigations where between-subjects variance is an issue.     

Identification of cerebral networks by classification of the shape of BOLD responses

Changes in regional blood oxygen level dependent (BOLD) signals in response to brief visual stimuli can exhibit a variety of time-courses. To demonstrate the anatomical distribution of BOLD response shapes during a match to sample task, a formal analysis of their time-courses is presented. An event-related design was used to estimate regional BOLD responses evoked by a cue word, which instructed the subject to attend to the motion or color of an upcoming target, and those evoked by a briefly presented moving target consisting of colored dots. Regional BOLD time-courses were adequately represented by the linear combination of three orthogonal waveforms. BOLD response shapes were then classified using a fuzzy clustering scheme. Three classes (sustained, phasic, and negative) best characterized cue responses. Four classes (sustained, sustained-phasic, phasic, and bi-phasic) best characterized target responses. In certain regions, the shape of the BOLD responses was modulated by the instruction to attend to the target's motion or color. A left frontal and a posterior parietal region showed sustained activity when motion was cued and transient activity when color was cued. A right thalamic and a left lateral occipital region showed sustained activity when color was cued and transient activity when motion was cued. Following the target several regions showed more sustained activity during motion than color trials. In summary, the effect of the task variable was focal following the cue and widespread following the target. We conclude that the temporal patterns of neural activity affected the shape of the BOLD signal.     

Origin of the signal undershoot in BOLD studies of the visual cortex.

The nature of the signal undershoot observed in the inter-stimulation intervals in fMRI studies using a block paradigm consisting of alternating periods of visual stimulation and rest was investigated using the following single shot EPI sequences: gradient echo (GRE), spin echo (SE), spin echo with additional flow dephasing gradients and inversion recovery (IR) prepared SE. Both the GRE and SE sequences showed a significant signal undershoot during the inter-stimulation intervals. DeltaR(2)*/DeltaR(2) ratios of 3.7 +/- 0.9 and 3.1 +/- 0.7 were measured in the stimulation and inter-stimulation periods, respectively, with the latter being lower than that which would be consistent with a pure extra-vascular effect arising from an elevated venous blood volume and a normal deoxyhaemoglobin content post-stimulation. The addition of dephasing gradients to the SE sequence in order to attenuate the signal from spins flowing within larger vessels produced a four-fold reduction in the number of activated pixels but had little effect on the time intensity profile. Our interpretation of these results is that both extra- and intra-vascular BOLD effects are present in the inter-stimulation intervals and the lack of any effect of the dephasing gradient on the time-intensity profile indicates that the intra-vascular component probably occurs mainly in smaller vessels, such as venules, which are affected relatively little by the relatively weak dephasing gradient (b = 29 s/mm(2)) used in this study. For the IR-SE sequence the DeltaR(2) measured during the inter-stimulation intervals was similar to that seen with the SE BOLD sequence and thus was consistent with a residual BOLD effect, implying that perfusion changes in the capillary vessels did not contribute significantly to the signal undershoot.