Early development in males with Fragile X syndrome: a review of the literature

This article reviews the current bibliographic knowledge on early neurobehavioral development and milestones in Fragile X syndrome (FraX), with emphasis on males affected by the condition. Three broad areas of early development were examined: (1) gross and fine motor, (2) speech and language, and (3) social. The result of the current review indicates very limited information on the developmental milestones in all three areas. The scarce literature on motor development shows that in FraX there is an early developmental delay. Research on speech and language demonstrates pervasive deficits in conversational skills and severe developmental delay, with increasing discrepancy between language level and chronological age in young males with FraX. Finally, deficits in social development in FraX include abnormal gaze, approach and avoidance conflict, and high incidence of autistic spectrum disorders.     

Fragile X syndrome,the Fragile X related proteins,and animal models

The Fragile X syndrome (FraX), which is characterized among other physical and neurologic impairments by mental retardation, is caused by the absence of the product of the FMR1 gene. The Fragile X Mental Retardation Protein (FMRP) is a member of a novel family of RNA-binding proteins. The latter includes two other proteins highly homologous with FMRP: the fragile X related proteins 1 and 2 (FXRP1 and FXRP2). Characterization of FXRPs, including their interaction with FMRP, will provide critical information about the mechanisms of action of FMRP and the role of this group of proteins in FMRP-deficient conditions such as FraX. Genetic manipulations of FMRP and the FXRPs should also provide valuable tools for investigating pathophysiology and gene therapies in FraX. The present review summarizes the strategies used for identifying the FXRPs, their chromosomal localization, molecular structure, and tissue distribution. It also reviews interactions between different members of this family of RNA-binding proteins. Animal models, both knockout and transgenic, of FMRP and the FXRPs are discussed. Phenotypic features of the FMR1 knockout mouse, the FMR1 transgenic rescue mouse, and other novel strategies for manipulating and delivering FMRP and FXRPs to the brain and other tissues are described.     

Molecular phenotype of Fragile X syndrome: FMRP,FXRPs, and protein targets

Fragile X syndrome (FraX) is one of the most prevalent genetic causes of mental retardation. FraX is associated with an unstable expansion of a polymorphism within the 5' untranslated region of the FMR1 gene. The main consequence of this mutation is a reduction in the levels of the gene product (FMRP). FMRP is an RNA-binding protein with multiple spliced variants (isoforms) and high levels of expression in a variety of tissues, including neurons. In the latter cells, it is localized not only to the perikaryon but also to dendrites and dendritic spines. FMRP belongs to a family of proteins that includes the Fragile X Related Proteins or FXRPs. FXRPs share high homology in their functional domains with FMRP, and also associate with mRNA and components of the protein synthesis apparatus. However, FXRPs do not have the same temporo-spatial pattern of distribution (and other properties) of FMRP. Immunochemical assays have confirmed that a functionally uncompensated FMRP deficit is the essence of the FraX molecular phenotype. Here, we report our preliminary study on FXRPs levels in leukocytes from FraX males. By immunoblotting, we found that a marked reduction in FMRP levels is associated with a modest increase in FXR1P and no changes in FXR2P levels. The consequences of this reduced FMRP expression on protein synthesis, in other words, the identification of FMRP targets, can be studied by different molecular approaches including protein interaction and proteomics methods. By two-dimensional gel electrophoresis, we showed that in FraX leukocytes there is a defect in acetylation that involves prominently the regulatory protein annexin-1. Extension of current studies of the molecular phenotype to more brain-relevant tissue samples, a wider range of proteomics-based methods, and correlative analyses of FMRP homologues and FMRP targets with multiple behavioral measures, will greatly expand our understanding of FraX pathogenesis and it will help to develop and monitor new therapeutic strategies.     

Effects of Fragile X syndrome and an FMR1 knockout mouse model on forebrain neuronal cell biology

The neurological deficits exhibited by patients with Fragile X syndrome (FraX) have been attributed to the absence of the Fragile X Mental Retardation Protein (FMRP), the product of the FMR1 gene, which is nonfunctional in these individuals. While a great deal has been learned about FraX using non-invasive techniques and autopsy tissue from humans, the limited availability of subjects and specimens severely restricts the rate at which such data can be collected and the types of experimental questions posed. In view of these limitations, a transgenic mouse model of FraX has been constructed in which the FMR1 gene is selectively knocked out (KO) [Bakker et al. (1994) Cell 78:23-33]. These mice show molecular, morphological, and behavioral alterations consistent with phenotypes observed in FraX patients, making them good models to study the absence of FMRP expression.     

Influence of stimulants on electrodermal studies in Fragile X syndrome

Attention Deficit Hyperactivity Disorder (ADHD) is seen in the majority of children with Fragile X Syndrome (FraX). Previous work has documented an enhanced sweat response to stimuli in children with FraX compared to controls utilizing electrodermal response (EDR) measures. The present study assesses the EDRs both on and off stimulants in 19 children with ADHD and FraX compared to 17 age- and IQ-matched control patients with ADHD and developmental delays. Although the baseline EDRs were comparable between FraX patients and controls, the patients with FraX had a significant decrease in EDR amplitude and number of peaks when treated with stimulants compared to controls. This suggests that patients with FraX are more responsive to the enhancement of inhibitory systems that occur with stimulant use for ADHD. The use of a quantifiable measure, such as EDR, is recommended in future studies of treatment efficacy.     

MasterCAM X7环境下标志图案的自动编程

基于MasterCAM X7软件环境,通过典型实例,介绍了复杂标志图案位图图像的矢量化处理以及自动编程和数控加工的过程,阐述了图案图形数控雕刻加工的实现方法,对表面文字雕刻、曲面雕花等的高效数控加工具有示范作用。     

X80管线钢在水饱和碱性沙土中的腐蚀行为

采用电化学测试、SEM观察及EDS分析等方法,研究了X80管线钢在水饱和碱性沙土中的腐蚀行为。结果表明:随着腐蚀时间的延长,X80钢腐蚀速率的变化趋势为先缓慢增大后快速增大;腐蚀50d后,腐蚀产物中主要为铁的氧化物、铁的硫化物,其中混杂着土壤中盐类;X80钢的耐蚀性及腐蚀形态与其表面生成的腐蚀产物膜的完整性和致密性有关。     

临界区加速冷却对X100管线钢组织性能的影响

采用热模拟技术、显微分析方法和力学性能测试等手段,对X100管线钢在(α+γ)临界区加速冷却工艺下组织性能的变化规律进行研究。结果表明,通过临界区的加速冷却方法,可使X100获得(B+F)双相组织。这种双相组织使得X100管线钢具有连续屈服的能力,表现为高的初始应变硬化倾向和大的均匀变形能力。在初始加速冷却温度为830～850℃时的加速冷却,使得X100具有高的强度、塑性、形变强化指数、韧性和低的屈强比,表现出了优良的强韧水平。此时形成的以细小的贝氏体为主,辅以少量细小、高密度位错的铁素体的组织结构赋予了材料高的强韧特性。研究还表明,随初始加速冷却温度降低,铁素体体积分数增加,引起材料强度的降低和形变强化指数的增加。     

Wrinkling initiation and growth in modified Yoshida buckling test: Finite element analysis and experimental comparison

Wrinkling is one of the major defects in sheet metal products and may also play a significant role in the wear of the tool. The initiation and growth of wrinkles are influenced by many factors such as stress ratios, mechanical properties of the sheet material, geometry of the workpiece, contact condition, etc. It is difficult to analyze the wrinkling initiation and growth considering all the factors because the effects of the factors are very complex and the wrinkling behavior may show a wide scatter of data even for small deviations of factors. In this study, the bifurcation theory is introduced for the finite element analysis of wrinkling initiation and growth. All the above-mentioned factors are conveniently considered by the finite element method. The wrinkling initiation is found by checking the determinant of the stiffness matrix at each iteration and the wrinkling behavior is analyzed by successive iteration with the perturbed guess along the eigenvector. The effect of magnitude of perturbation on the wrinkling behavior can be avoided by the Newton-type iteration method. The finite element formulation is based on the incremental deformation theory and elastic-plastic material modeling. The finite element analysis is carried out using the continuum-based resultant shell elements considering the anisotropy of the sheet metal. For the verification of the analysis, the postbuckling of columns and circular plates are analyzed by finite element analysis using the bifurcation algorithm introduced in the study, and the results are compared with the exact solutions. In order to investigate the effects of geometry and stress ratio on the wrinkling initiation and growth, a modified Yoshida buckling test is proposed as an improved effective buckling test. In the modified Yoshida buckling test, the dimensions of the sheet specimen are varied to change the stress ratio and the degree of constraint. The finite element analysis is carried out for the modified Yoshida buckling test and compared with the experimental results.     

待温厚度与终轧温度对X80管线钢组织中马氏体/奥氏体岛的影响

利用光学显微镜、扫描电镜及透射电镜分析了经不同工艺热轧得到的22 mm厚X80管线钢中马氏体/奥氏体(M/A)岛的形貌及分布.结果表明:M/A岛的形貌及分布与待温厚度和终轧温度密切相关,适当增加待温厚度,降低终轧温度有利于细化M/A岛的组织,减小M/A岛的尺寸,降低M/A岛的体积分数,使X80管线钢的落锤性能得到改善.     

Q235与X70钢在新加坡土壤中的应力腐蚀行为现场试验研究

通过国产Q235钢与X70钢U形试样在新加坡现场埋样试验,应用腐蚀形貌观察、裂纹扩展形貌观察、腐蚀产物的分析以及土壤理化性质分析等手段研究Q235钢和X70钢在新加坡土壤中的应力腐蚀行为特征,初步研究国产钢在国外典型土壤环境中的耐蚀性。结果发现,新加坡土壤中含有较多的硫化菌,硫化菌降低了硫酸盐还原菌的破坏作用;Q235钢与X70钢U形试样在新加坡酸性土壤中埋样1年后均发现了应力腐蚀开裂(Stress corrosion cracking,SCC),表现出明显的SCC敏感性,X70钢应力腐蚀敏感性强于Q235钢,钢的强度对于应力腐蚀敏感性有一定的影响;点蚀的发生和酸性土壤环境促进了应力腐蚀的发生,其应力腐蚀过程主要受阳极溶解(Anodic dissolution,AD)控制,同时可能存在氢致开裂(Hydrogen induced cracking,HIC)的混合控制。     

GND accumulation in bi-crystal deformation: Crystal plasticity analysis and comparison with experiments

A three-dimensional, large deformation crystal plasticity model is presented in which the lengthscale effect is incorporated through the explicit coupling of the density of geometrically necessary dislocations (GNDs) with the crystallographic slip rule.The channel-die bi-crystal compression tests carried out by Sun et al. [1998. Mesoscale investigation of the deformation field of an aluminium bicrystal. Scripta Material 39(4/5), 501-508; Sun, S., Adams, B.L., King, W.E., et al., 2000. Observations of lattice curvature near the interface of a deformed aluminium bicrystal. Philosophical Magazine 80 (1), 9-25] have been assessed and the crystal plasticity model has been employed to predict the distributions of GNDs local to the grain boundary. Quantitative comparisons of the predicted distributions with those determined experimentally show reasonable agreement. The qualitative comparisons of crystal reorientation predicted by the model with those observed by Zaefferer et al. [2003. On the influence of the grain boundary misorientation on the plastic deformation of aluminium bicrystals. Acta Materialia 51, 4719-4735] show good agreement. Further analyses of the bi-crystal have been carried out both with and without the development of GNDs. The results show that the crystal re-orientations local to the grain boundary are different if GND accumulation is included, suggesting that conventional, non-lengthscale crystal plasticity models are unlikely to be capable of capturing correctly the deformations arising at grain boundaries.     

A review and comparison of fault detection and diagnosis methods for squirrel-cage induction motors: State of the art

Preventing induction motors (IMs) from failure and shutdown is important to maintain functionality of many critical loads in industry and commerce. This paper provides a comprehensive review of fault detection and diagnosis (FDD) methods targeting all the four major types of faults in IMs. Popular FDD methods published up to 2010 are briefly introduced, while the focus of the review is laid on the state-of-the-art FDD techniques after 2010, i.e. in 2011–2015 and some in 2016. Different FDD methods are introduced and classified into four categories depending on their application domains, instead of on fault types like in many other reviews, to better reveal hidden connections and similarities of different FDD methods. Detailed comparisons of the reviewed papers after 2010 are given in tables for fast referring. Finally, a dedicated discussion session is provided, which presents recent developments, trends and remaining difficulties regarding to FDD of IMs, to inspire novel research ideas and new research possibilities.     

Applications of gold cluster compounds in immunocytochemistry and correlative microscopy: comparison with colloidal gold

In this review, we discuss the immunocytochemical literature with respect to a comparison between conventional colloidal gold and gold cluster compounds as immunoprobes. The relative advantages and disadvantages of each of these types of particle for immunocytochemical applications are discussed. We present results from our own laboratories and those of others on the comparison of these immunoprobes in selected experimental situations. These results show the use of gold cluster compounds at both light and electron microscope levels. At the ultrastructural level, gold cluster compounds have been used in pre-embedding labelling of cultured cells, and for labelling of ultrathin cryosections and freeze-fracture preparations. Recently, fluorescently tagged gold cluster compounds have become available. Using ultrathin cryosections of human neutrophils as a model system, we demonstrate that a single immunoprobe (i.e. a fluorescently tagged gold cluster compound) is a robust probe for correlative fluorescence and electron microscopy.     

Sequential pulse defibrillation in man: comparison of thresholds in normal subjects and those with cardiac disease

We compared the parameters describing the defibrillation threshold in patients with normal hearts and in patients with ischemic heart disease, using a special electrode system and sequential pulses of current. Twenty-eight patients consented to the study (mean age: 36.6 +/- 10.1 years; mean mass: 80.7 +/- 13.8 kg). Twenty-one patients underwent surgery for Wolff-Parkinson-White syndrome (relatively normal hearts). Six patients had a history of previous myocardial infarction and aneurysm or coronary artery disease; and one patient had been resuscitated from an episode of sudden death, without evidence of consequent myocardial damage. For 26 patients, defibrillation thresholds were determined intraoperatively by passing sequential pulses through a catheter electrode and epicardial mesh electrode. For 2 patients defibrillation thresholds were determined during electrophysiologic study, after ventricular fibrillation was induced by programmed stimulation, by passing sequential pulses through a catheter and skin-patch electrode. Parameters for sequential pulse defibrillation thresholds between the two groups did not differ appreciably. Total energy for patients with normal hearts averaged 9.9 +/- 6.3 J compared to 8.9 +/- 4.6 J for patients with cardiac disease. No patient with cardiac disease had defibrillation parameters that exceeded the range of the normal patients. These results suggest that the presence of cardiac disease may not significantly alter the parameters necessary for successful defibrillation when using sequential pulses for delivery of energy.     

Rotary shadowing with platinum-carbon in biological electron microscopy: A review of methods and applications

Rotary shadowing when combined with such specimen preparation techniques as quick freezing and deep etching, critical point drying, and glycerol spraying is a highly versatile method of visualizing cell and macromolecular ultrastructure. This review outlines the procedures commonly used to prepare specimens for rotary shadowing and evaluates the relative merits of rotary shadowing when compared to unidirectional shadowing and negative staining.     

Nuclear microscopy: a tool for imaging elemental distribution and percutaneous absorption in vivo

Nuclear microscopy is a technique based on a focused beam of accelerated particles that has the ability of imaging the morphology of the tissue in vivo and of producing the correspondent elemental maps, whether in major, minor, or trace concentrations. These characteristics constitute a strong advantage in studying the morphology of human skin, its elemental distributions and the permeation mechanisms of chemical compounds. In this study, nuclear microscopy techniques such as scanning transmission ion microscopy and particle induced X-ray emission were applied simultaneously, to cryopreserved human skin samples with the purpose of obtaining high-resolution images of cells and tissue morphology. In addition, quantitative elemental profiling and mapping of phosphorus, calcium, chlorine, and potassium in skin cross-sections were obtained. This procedure accurately distinguishes the epidermal strata and dermis by overlapping in real time the elemental information with density images obtained from the transmitted beam. A validation procedure for elemental distributions in human skin based on differential density of epidermal strata and dermis was established. As demonstrated, this procedure can be used in future studies as a tool for the in vivo examination of trans-epidermal and -dermal delivery of products.     

Improvement of microanatomical research by combining corrosion casts with MicroCT and 3D reconstruction, exemplified in the circulatory organs of the woodlouse

A SkyScan-1072 high-resolution desktop microtomograph was used to visualize the 3D morphology of the circulatory system of Porcellio scaber (Crustacea, Malacostraca, Isopoda) at the micrometer level. Prior to MicroCT investigation, the circulatory system was injected with a fast-hardening resin, permitting a better contrast of the vascular structures that are normally hollow after fixation. Stacks of tomographic images were used to reconstruct the circulatory system three-dimensionally. The spatial resolution achieved by the microtomograph is about 3.5 microm. The technique provides detailed tomographic images of the inner organs and makes precise 3D reconstructions of the circulatory system in arthropods possible. The results were compared with conventional histological data. MicroCT permits a high number of specimens to be screened in a short time, which is essential for the improvement of modern morphological research in a cladistic framework. Histological techniques, however, are still essential for gathering information at the cellular level.     

Histatin-induced alterations in Candida albicans: a microscopic and submicroscopic comparison

Despite the numerous studies performed in an attempt to clarify the issue, the mechanism of action of salivary histatins remains unclear. The aim of the present study was to correlate histatin-induced morphological changes in Candida albicans by fluorescence microscopy (FM), transmission electron microscopy (TEM), and high resolution scanning electron microscopy (HRSEM). Each of the fluorescent dyes used by FM (i.e., tetramethylrhodamine methyl ester perchlorate for mitochondrial potential, Lysotracker for lysosome acidic compartment, and 4',6-diamino-2-phenylindole dihydrochloride for DNA) exhibited a specific staining in control cells. Following histatin treatment, we observed a recurring staining pattern, corresponding to fluorescence concentration along the cell periphery, suggesting a loss of dye specificity. To assess histatin-induced cytoplasmic modifications, ultrastructural analysis was then carried out. After treatments with histatins, TEM revealed characteristic intracellular modifications including: vacuole overgrowth, nuclear disappearance, loss of organelle identity, as well as the appearance of electron-dense membranes, likely of mitochondrial origin. Additionally, structures resembling autophagosomes were occasionally observed. By HRSEM, mitochondrial swelling was invariably the first sign of a histatin-induced effect. Other modifications included intracellular membrane disarrangement, organelles in disarray, and a large central cavity with deformed bodies displaced to the cell periphery, similar to what was detected by TEM. In summary, our study illustrates the occurrence of ultrastructural modifications following administration of histatins. Observations made with FM, TEM, and HRSEM provided different views of the same signs, demonstrating a definite action of histatins on C. albicans morphology. The possible functional meanings of these morphological results is discussed in light of the most recent biochemical data on histatin fungicidal activity.