Cerebral growth in Fragile X syndrome: review and comparison with Down syndrome

Neuroimaging studies have shown selective changes in brain size in Fragile X syndrome (FraX), which include reductions in the posterior cerebellar vermis, age-dependent increases in hippocampal volume, and enlarged caudate nucleus and thalamus. Contrasting with these limbic and subcortical anomalies, much less is known about the neocortex in FraX. The present study attempted to examine cerebral and lobar-level volumetric changes in young males with FraX (2-7 years), by comparing groups of subjects with full mutation (FM) and mosaicism (Mos) with both age-matched controls and subjects with developmental language delay (DLD) and Down syndrome (DS). For this purpose, we used high resolution (i.e, SPGR) MRI scans and semi-automated methods for segmenting (tissue class) and parcellating (i.e., Talairach) the brain. In agreement with previous studies, we found no changes in overall brain or cerebrum size in FraX. Nevertheless, boys with FM FraX had relative reductions in temporal lobe volume (primarily gray matter) and relative preservation/enlargement of parietal white matter volume. While temporal lobe reductions were not specific, since they were also observed in DLD and DS subjects, parietal preservation/enlargement was only seen in FraX. The relevance of these preliminary findings was emphasized by comparisons between FraX groups, which revealed more marked changes in FM FraX than in Mos FraX (i.e., gene dosage). While cross-sectional analyses revealed marked age-dependent decreases in DS, a group showing marked global and lobar volumetric reductions, there were no changes over time in FraX. These neuroimaging data are discussed in the context of FraX neurobiology and other developmental disorders.     

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.     

A developmental approach to understanding Fragile X syndrome in females

The psychological phenotype of females with fragile X syndrome (FraX) is discussed, focusing primarily on empirical findings over the past decade and on studies of probands with the full mutation (FM). A developmental approach is used to help characterize specific patterns of cognitive, neuropsychological, social, emotional, and behavioral functioning across the lifespan of females with FraX. Approximately half of females with the syndrome present with cognitive abilities that fall in the borderline to mentally retarded range, and the remaining females with average intellectual functioning may experience relative deficits in math achievement and problems with attention and executive functioning. Reports of socio-emotional functioning are somewhat inconsistent, due in part, perhaps, to methodological differences in study design. To date, much of what we understand about the psychological phenotype of FraX is based on cross-sectional studies of girls and women with the disorder. Symptoms associated with shyness, and social anxiety and avoidance have been reported in some school-age, adolescent, and adult females with FraX. Only recently have efforts begun to identify the developmental trajectory of FraX in infants and toddlers. There is a void of information specific to these developmental periods. Identifying key deficits in cognitive and socio-emotional functioning has important implications for early detection and intervention for girls with FraX. Directions for future research are discussed.     

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.     

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.     

Quantitative feedback synthesis of sampled-data systems with time-delay by approximate Z-transform

In this paper, the equivalent disturbance rejection (EDR) in QFT design methodology is proposed for dealing with sampled-data systems with time-delay. This EDR is mainly to overcome the non-minimum phase zero generated by the first order Pade' approximation of the time-delay factor. Due to plant parameter uncertainty, the analogue controller is to be designed so that the system response lies within permissible bounds. By approximate Z-transform, the analogue controller can be transformed directly into a digital one and then the analogue plant is transformed into the digital plant, with sampling time as a free parameter. By adjusting the sampling time, the uncertain sampled-data system can be stabilized. In comparison with other approaches, our design framework is much more systematic by using only algebraic manipulations and transparent enough to guide the designer to realize the physical controller for the plant with prescribed bounds on its parameters.     

Evaluation of multi-holed orifice flowmeters under developing flow conditions – An experimental study

This study focuses on multi-holed orifice plates, which have superior flow measuring characteristics as compared to their conventional counterparts. However, literature is scant on quantitative parametric investigations. In this experimental study, the performance of a multi-holed orifice plate is evaluated for variable number of holes (n), equivalent diameter ratio (EDR), compactness ratio (C), plate thickness ratio (s/d) and upstream developing length (L/D) in developing flow regimes for the Reynolds number range of 24,500–55,500 by using Central Composite Design. A total number of 324 experiments were performed. It was found that EDR has the most significant effect on pressure loss coefficient, followed by ‘n’ and ‘C’. Moreover, it was found out that single orifice (SO) and multi-holed orifice (MO) have almost the same pressure losses for the same value of EDR/β. However, flow develops quickly for MOs. Higher values of coefficient of discharge were observed in the case of MOs as compared to the SOs with little effect of upstream disturbances. The effect of developing length is significant on the accuracy of orifice meter. However, when the multi-holed orifice plates are installed at 2D upstream length, the effect of upstream disturbances are diminished. This result provides the flexibility of installation, which means that multi-holed orifices can be installed at 2D. The experimental data is in good agreement with literature. Finally, an optimum orifice plate (5,0.4,0.7) was selected for flow developing region with minimum pressure loss coefficient based upon the experimental results.     

End depth computation in inverted semicircular channels using ANNs

The paper presents the application of artificial neural network (ANN) to determine the end-depth-ratio (EDR) for a smooth inverted semicircular channel in all flow regimes (subcritical and supercritical). The experimental data were used to train and validate the network. In subcritical flow, the end depth is related to the critical depth, and the value of EDR is found to be 0.705 for a critical depth–diameter ratio up to 0.40, which agrees closely with the value of 0.695 given by Dey [Flow Meas. Instrum. 12 (4) (2001) 253]. On the other hand, in supercritical flow, the empirical relationships for EDR and non-dimensional discharge with the non-dimensional streamwise slope of the channel are established.     

Free over-fall in exponential channel cross-sections based on free vortex theory in supercritical flow regimes

Free over-fall can be used as a flow metering hydraulic structure by a single measurement of an end depth. Many theoretical and experimental researches carried out on free over-fall with various approaches for different cross-sectional shapes. This paper presents a theoretical method to compute the end depth ratio (EDR) and the end depth discharge (EDD) relationships in steep sloping channel for the exponential cross-section. The exponential cross-section is a general section which can reduce to rectangular, wide rectangular, parabolic, semi-parabolic, triangular, and semi-triangular channels. Applying the momentum equation based on the free vortex theory, a theoretical approach is presented to obtain the EDR for the exponential channel cross-section in supercritical flow regime. Experimental and theoretical studies are then utilized to verify the proposed EDR and EDD relationships. The computed results are in acceptable agreement with the relevant experimental and theoretical studies. Direct solutions of the discharge for the known end depth for each cross-section are provided in tabular forms where two empirical discharge expressions with their relevant range of applications for each channel cross-section are detailed as the main outcome of this study.     

基于UDS协议的汽车事件数据记录系统的数据提取和分析

针对汽车事件数据记录系统(EDR)设计了一种基于统一诊断服务(UDS)协议的数据提取方法,使用UDS中常用的读取数据流服务通过OBD口来读取EDR中的事件数据。分析了数据传送过程,并使用C#语言开发了上位机软件,通过通信接口模块可对EDR存储的事件数据进行提取、存储、显示和自动生成报告。     

Prediction of the key parameters of free over-fall flows within the generalized circular cross-section with varying flat bases

Free over-fall occurring due to the sudden bed drop at the channel end that referred as the brink, facilitates the determination of the flow amount (discharge) by only trailing the value of the water depth at that section. This paper mainly focuses on a new theoretical approach that analysis the free over-fall within a channel of circular cross-section with flat base at different elevation levels by applying the continuity and the energy equations based on one velocity point method. The hydraulic behaviors of the circular cross-section especially having different elevation of the flat base have been investigated in sub-critical flow regime to obtain the end depth ratio (EDR) from which the end depth discharge (EDD) values are computed. The non-horizontal free surface profile at the upstream of the end section due to the accelerated flow velocity is also computed based on the extended energy equation. Subsequently, due to its practical importance direct equations for the free surface profile are provided for each channel cross-section for different values of the non-dimensional critical depth. Furthermore, in order to ease the use of the solution for practitioner in this field, the generalized unique relationships for the EDR, the non-dimensional discharge, and the free surface profile are presented, since there is no direct general equation for all the derivatives of the circular channel as a single solution in the previous studies due to its complexity. Even, relevant experimental and theoretical studies are used to obtain more robust assessment of the applied approach.     

Free overall in circular channels with flat base: a method of open channel flow measurement

A free overfall at the end of an open channel offers a simple means of measuring flow discharge. In this paper, two methods are presented for the computation of end-depth and discharge of a free overfall from smooth circular channels with flat base. Firstly, applying the momentum equation based on the Boussinesq approximation, the flow upstream of a free overfall is theoretically analyzed to calculate the end-depth-ratio (EDR). This approach eliminates the need of an experimentally determined pressure coefficient. In subcritical flows, the EDR is related to the critical-depth that occurs far upstream. In supercritical flows, the Manning equation is used to express the end-depth as a function of streamwise slope of the channel. Methods to estimate discharge from the end-depth in subcritical and supercritical flows are presented. The upstream flow profiles of a free overfall are computed using the streamline curvature at free surface. Secondly, an alternate method for analyzing free overfall from circular channels with flat base is also presented, where a free overfall in a circular channel with flat base is simulated by the flow over a sharp-crested weir to calculate the EDR. The comparisons of the computed results with the experimental data are satisfactory for subcritical flow and acceptable for supercritical flow.     

Predictive carbon nanotube models using the eigenvector dimension reduction (EDR) method

It has been reported that a carbon nanotube (CNT) is one of the strongest materials with its high failure stress and strain. Moreover, the nanotube has many favorable features, such as high toughness, great flexibility, low density, and so on. This discovery has opened new opportunities in various engineering applications, for example, a nanocomposite material design. However, recent studies have found a substantial discrepancy between computational and experimental material property predictions, in part due to defects in the fabricated nanotubes. It is found that the nanotubes are highly defective in many different formations (e.g., vacancy, dislocation, chemical, and topological defects). Recent parametric studies with vacancy defects have found that the vacancy defects substantially affect mechanical properties of the nanotubes. Given random existence of the nanotube defects, the material properties of the nanotubes can be better understood through statistical modeling of the defects. This paper presents predictive CNT models, which enable to estimate mechanical properties of the CNTs and the nanocomposites under various sources of uncertainties. As the first step, the density and location of vacancy defects will be randomly modeled to predict mechanical properties. It has been reported that the eigenvector dimension reduction (EDR) method performs probability analysis efficiently and accurately. In this paper, molecular dynamics (MD) simulation with a modified Morse potential model is integrated with the EDR method to predict the mechanical properties of the CNTs. To demonstrate the feasibility of the predicted model, probabilistic behavior of mechanical properties (e.g., failure stress, failure strain, and toughness) is compared with the precedent experiment results.     

Flow measurement by the end-depth method in inverted semicircular channels

A free overfall at the end of an open channel provides a simple means for measuring flow discharge. The paper presents a simplified approach for the computation of end-depth of a free overfall in horizontal or mildly sloping inverted semicircular channels. Using a known end-depth the discharge can be estimated. The flow over a free overfall in an inverted semicircular channel is simulated by that over a sharp-crested weir to calculate the end-depth-ratio (EDR). The mathematical model is calibrated by the experimental data, making the coefficient of velocity a free parameter. The EDR, related to the critical depth, is around 0.705 for a critical depth–diameter ratio up to 0.42. The computed results agree satisfactorily with the experimental data.     

Free overfalls in flat-based circular and U-shaped channels

This paper presents a theoretical model based on the free vortex theorem that is capable of predicting the pressure head distribution at the brink of free overfalls in open channels. This approach is coupled with the momentum equations to obtain the end-depth-ratio (EDR) from which the discharge can be estimated. In order to illustrate its flexibility, the theory is successfully applied to flat-based circular and U-shaped channels. Using previous experimental data, the proposed method is validated.     

Exocytosis determination of SH-SY5Y single cell stimulated by different stimulants on indium tin oxide (ITO) micro-pore electrode

The human neuroblastoma SH-SY5Y cell line has been used as a model to study mechanisms of neurotransmitter release. In order to study the mechanism of SH-SY5Y single cell exocytosis stimulated by different stimulants, including high K+, 3-(1-nitroso-2-pyrrolidinyl) pyridine and nicotine, a type of indium tin oxide (ITO) micro-pore electrode was used to obtain the corresponding amperometric response time. When the cell is stimulated by 0.1 M K+ , almost immediate exocytosis could be detected, due to the rapid depolarization of cell membrane. However, the stimulations with 1 mM nicotine and 3-(1-nitroso-2-pyrrolidinyl) pyridine result in a short delay between stimulation and exocytosis, which can be correlated with the time needed for binding of the stimulant to the nicotinic acetylcholine (ACh) receptor and the induction of post-binding phenomena. Thus, the response time of SH-SY5Y single cell exocytosis is significantly affected by the exocytosis mechanisms.     

Nuclear AgNOR protein enhancement in nucleoplasms of peripheral blood lymphocytes of babies/children with down syndrome

Down syndrome (DS) is one of the most common chromosomal disorders. The factors contributing to the mental retardation together with other defects in this syndrome have not been fully explained. Individuals with DS have extra rRNA gene family since they carry an extra chromosome 21. The few reports available are on the relationship between the nucleolus organizer regions (NORs) and DS phenotype. The in vivo regulation of NORs expression on the extra chromosome 21 is not completely understood. Previous studies have shown that nucleoli of lymphocytes from infants (mostly neonates) with DS contain more in vivo and in vitro nucleolar AgNOR proteins when compared with healthy infants. The objective of this study is to compare the in vivo nuclear AgNOR protein level in nucleoplasms (also called as karyoplasm) of nonstimulated peripheral blood lymphocytes from babies/children with DS and healthy controls. Peripheral blood samples obtained from 20 babies/children with DS and 20 matched healthy controls were smeared on clean glass slides and then AgNOR staining was performed. The AgNOR protein level in nucleoplasms of lymphocytes from both groups was calculated using a computer program. Nearly 100 interphase nuclei per individual were analysed. Average nuclear AgNOR protein levels in nucleoplasms of lymphocytes from babies/children with DS were found to be significantly higher than those of the controls (P < 0.001). On the basis of our present results, we propose that the increase of nuclear AgNOR protein in in vivo conditions may contribute to the formation of DS phenotypes. Microsc. Res. Tech. 79:133–139, 2016. © 2016 Wiley Periodicals, Inc.     

Composition of nasal airway surface liquid in cystic fibrosis and other airway diseases determined by X-ray microanalysis

The ionic composition of the airway surface liquid (ASL) in healthy individuals and in patients with cystic fibrosis (CF) has been debated. Ion transport properties of the upper airway epithelium are similar to those of the lower airways and it is easier to collect nasal ASL from the nose. ASL was collected with ion exchange beads, and the elemental composition of nasal fluid was determined by X-ray microanalysis in healthy subjects, CF patients, CF heterozygotes, patients with rhinitis, and with primary ciliary dyskinesia (PCD). In healthy subjects, the ionic concentrations were approximately isotonic. In CF patients, CF heterozygotes, rhinitis, and PCD patients, [Na] and [Cl] were significantly higher compared when compared with those in controls. [K] was significantly higher in CF and PCD patients compared with that in controls. Severely affected CF patients had higher ionic concentrations in their nasal ASL than in patients with mild or moderate symptoms. Female CF patients had higher levels of Na, Cl, and K than male patients. As higher salt concentrations in the ASL are also found in other patients with airway diseases involving chronic inflammation, it appears likely that inflammation-induced epithelial damage is important in determining the ionic composition of the ASL.     

Detection of erythrocytes in patients with multiple myeloma using atomic force microscopy

The goal of this study was to examine the pathophysiological changes to erythrocytes in multiple myeloma (MM) patients at a nanometer scale. We hypothesize that studying changes in red blood cells may be important for early diagnosis and effective treatment of MM. Blood samples were taken from ten healthy volunteers and ten MM patients before and after treatment. Changes in the morphological and biomechanical properties of the erythrocytes were studied at a nanometer scale with atomic force microscopy (AFM). There were dramatic deformations in the overall shape and surface membrane of the erythrocytes from pre‐ and post therapeutic MM patients compared with the healthy controls. Healthy and pathological MM erythrocytes could be distinguished by several morphologic parameters, including the width, length, length to width ratio, valley, peak, valley‐to‐peak, standard deviation, and surface fluctuation. The effectiveness of disease treatment could also be evaluated by studying these red blood cell parameters. AFM was able to detect noticeable morphological differences in the red blood cells from MM patients compared with healthy controls. Therefore, erythrocyte morphology is an important parameter for diagnosing MM, as well as evaluating the efficacy of disease treatment. SCANNING 34: 295–301, 2012. © 2012 Wiley Periodicals, Inc.