The type and severity of daytime symptoms reported by insomnia sufferers may vary markedly. Whether distinctive daytime symptom profiles are related to different insomnia diagnoses has not been studied previously. Using profile analysis via multidimensional scaling, we investigated the concurrent validity of ICSD-2 insomnia diagnoses by analysing the relationship of prototypical profiles of daytime symptoms with a subset of ICSD-2 diagnoses, including insomnia associated to a mental disorder, psychophisiological insomnia, paradoxical insomnia, inadequate sleep hygiene, idiopathic insomnia, obstructive sleep apnea and restless legs syndrome. In a sample of 332 individuals meeting research diagnostic criteria for insomnia (221 women, Mage=46 yrs.), the profile analysis identified four prototypical patterns of daytime features. Pearson correlation coefficients indicated that the diagnoses of insomnia associated to a mental disorder and idiopathic insomnia were associated with a daytime profile characterized by mood disturbance and low sleepiness; whereas the diagnoses of psychophysiological insomnia and inadequate sleep hygiene were related to a profile marked by poor sleep hygiene, daytime tension and low fatigue. Furthermore, whereas paradoxical insomnia was consistently associated to lower daytime impairment, insomnia associated to a mental disorder was related to the most severe daytime impairment. This classification of insomnia sufferers along multiple defining dimensions provides initial validation for two basic insomnia subtypes, with a presumably distinct aetiology: insomnia characterized mainly by an “internal” component, and a “learned” insomnia. Research to determine which dimensions are critical for inclusion or differential weighting for defining a general typological system for insomnia sufferers is warranted.
Insomnia; ICSD-2; Daytime symptoms; Concurrent validity
The crystal structure of the already known binary title compound LaZn5 (lanthanum pentazinc) (space group P6/mmm, Pearson symbol hP6, CaCu5 structure type) has been redetermined from single-crystal X-ray diffraction data. In contrast to previous determinations based on X-ray powder data [Nowotny (1942). Z. Metallkd.
34, 247–253; de Negri et al. (2008). Intermetallics, 16, 168–178], where unit-cell parameters and assignment of the structure type were reported, the present study reveals anisotropic displacement parameters for all atoms. The crystal structure consists of three crytallographically distinct atoms. The La atom (Wyckoff site 1a, site symmetry 6/mmm) is surrounded by 18 Zn atoms and two La atoms. The coordination polyhedron around one of the Zn atoms (Wyckoff site 2c, site symmetry -6m2) is an icosahedron made up from three La and nine Zn atoms. The other Zn atom (Wyckoff site 3g, site symmetry mmm) is surrounded by four La and eight Zn atoms. Bonding between atoms is explored by means of the TB–LMTO–ASA (tight-binding linear muffin-tin orbital atomic spheres approximation) program package. The positive charge density is localized around La atoms, and the negative charge density is around Zn atoms, with weak covalent bonding between the latter.
Restless legs syndrome (RLS) is known to be associated with depression. We hypothesized that RLS in depression is linked to the severity, duration, and frequency of depressive episodes.
Materials and Methods:
Subjects fulfilling DSM-IV-TR criteria of depressive disorders were included in this study after seeking informed consent. Using structured interview of MINI-Plus their demographic data and history were recorded. Severity of depression was assessed with the help of HAM-D. Insomnia was diagnosed following ICSD-2 criteria. RLS was diagnosed according to IRLSSG criteria. Descriptive statistics, Chi-square test, independent sample t test and MANOVA were computed with the help of SPSS v 17.0.
RLS was reported by 31.48% of sample. There was no gender difference in prevalence of RLS (X2 =0.46; P=0.33). There was no difference in the age , total duration of depressive illness and number of depressive episodes between RLS and non-RLS groups (F=0.44; P=0.77; Wilk's Lambda=0.96). The HAM-D score was higher in the non-RLS group (P=0.03). Onset of RLS symptoms was not related to onset of depressive symptoms.
RLS is prevalent in depressive disorder. However, onset of RLS is unrelated to age and number or duration of depressive disorders.
Adults; depression; prevalance; restless leg syndrome
Although the epidemiology of insomnia in the general population has received considerable attention in the past 20 years, few studies have investigated the prevalence of insomnia using operational definitions such as those set forth in the ICSD and DSM-IV, specifying what proportion of respondents satisfied the criteria to reach a diagnosis of insomnia disorder.
This is a cross-sectional study involving 25,579 individuals aged 15 years and over representative of the general population of France, the United Kingdom, Germany, Italy, Portugal, Spain and Finland. The participants were interviewed on sleep habits and disorders managed by the Sleep-EVAL expert system using DSM-IV and ICSD classifications.
At the complaint level, too short sleep (15.8%), light sleep (16.6%), and global sleep dissatisfaction (8.5%) were reported by 37% of the subjects. At the symptom level (difficulty initiating or maintaining sleep and non-restorative sleep at least 3 nights per week), 34.5% of the sample reported at least one of them. At the criterion level, (symptoms + daytime consequences), 9.8% of the total sample reported having them. At the diagnostic level, 6.6% satisfied the DSM-IV requirement for positive and differential diagnosis. However, many respondents failed to meet diagnostic criteria for duration, frequency and severity in the two classifications, suggesting that multidimensional measures are needed.
A significant proportion of the population with sleep complaints do not fit into DSM-IV and ICSD classifications. Further efforts are needed to identify diagnostic criteria and dimensional measures that will lead to insomnia diagnoses and thus provide a more reliable, valid and clinically relevant classification.
Insomnia; Epidemiology; classifications; mental disorders
To explore how insomnia symptoms are hierarchically organized in individuals reporting daytime consequences of their sleep disturbances.
This is a cross-sectional study conducted in the general population of the states of California, New York and Texas. The sample included 8,937 individuals aged 18 years or older representative of the general population. Telephone interviews on sleep habits and disorders were managed with the Sleep-EVAL expert system and using DSM-IV and ICSD classifications. Insomnia symptoms and Global Sleep Dissatisfaction (GSD) had to occur at least three times per week for at least three months.
A total of 26.2% of the sample had a GSD. Individuals with GSD reported at least one insomnia symptom in 73.1% of the cases. The presence of GSD in addition to insomnia symptoms considerably increased the proportion of individuals with daytime consequences related to insomnia. In the classification trees performed, GSD arrived as the first predictor for daytime consequences related to insomnia. The second predictor was nonrestorative sleep followed by difficulty resuming sleep and difficulty initiating sleep.
Classification trees are a useful way to hierarchically organize symptoms and to help diagnostic classifications. In this study, GSD was found to be the foremost symptom in identifying individuals with daytime consequences related to insomnia.
At the DNA/RNA level, biological signals are defined by a combination of spatial structures and sequence motifs. Until now, few attempts had been made in writing general purpose search programs that take into account both sequence and structure criteria. Indeed, the most successful structure scanning programs are usually dedicated to particular structures and are written using general purpose programming languages through a complex and time consuming process where the biological problem of defining the structure and the computer engineering problem of looking for it are intimately intertwined. In this paper, we describe a general representation of structures, suitable for database scanning, together with a programming language, Palingol, designed to manipulate it. Palingol has specific data types, corresponding to structural elements-basically helices-that can be arranged in any way to form a complex structure. As a consequence of the declarative approach used in Palingol, the user should only focus on 'what to search for' while the language engine takes care of 'how to look for it'. Therefore, it becomes simpler to write a scanning program and the structural constraints that define the required structure are more clearly identified.
The title compound, Eu11Zn6As12, crystallizes with the Sr11Cd6Sb12 structure type (Pearson’s symbol mC58). The complex monoclinic structure of the first arsenide to form with this type features chains made of corner-sharing ZnAs4 tetrahedra, separated by Eu atoms. There are a total of 15 unique positions in the asymmetric unit. Except for one Eu atom with site symmetry 2/m, all atoms are located on mirror planes. An usual aspect of the structure are some Zn—As distances, which are much longer than the sum of the covalent radii, indicating weaker interactions.
To evaluate the effectiveness of occlusal splints to reduce the signs and symptoms of temporomandibular disorders (TMD), dental wear and anxiety in a group of bruxist children.
All of the subjects were 3 to 6 years old, had complete primary dentition, class I occlusion and were classified as bruxist according to the minimal criteria of the ICSD for bruxism. For each child, anxiety was evaluated with the Conners’ Parent Rating Scales (CPRS). The TMD were evaluated using the RDC/TMD. The dental wear was processed in digital format with Mat Lab® and Lab view® software to determine its size and form. The children were randomized into an experimental (n=19) and a control (n=17) group. The children in the experimental group used rigid bite plates for a two-year period, until mixed dentition. Afterwards, the CPRS and the RDC/TMD were applied again and dental casts were taken. Comparisons of the variables regarding dental wear, signs and symptoms of TMD and anxiety before and after treatment among the groups were analyzed using the t-test, the Wilcoxon rank sum test and the Mann-Whitney test.
The subjects in the experimental group showed no statistically significant difference regarding anxiety levels and dental wear when compared with the control group. The signs and symptoms of TMD were not reduced except for the deviation in mouth opening.
The use of rigid occlusal bite plates was not efficient in reducing the signs of bruxism as a whole but did reduce the deviation in mouth opening.
Bruxism; Rigid occlusal bite plates; TMD; Dental wear; Anxiety
The recent development of large multielectrode recording arrays has made it affordable for an increasing number of laboratories to record from multiple brain regions simultaneously. The development of analytical tools for array data, however, lags behind these technological advances in hardware. In this paper, we present a method based on forward modeling for estimating current source density from electrophysiological signals recorded on a two-dimensional grid using multi-electrode rectangular arrays. This new method, which we call two-dimensional inverse Current Source Density (iCSD 2D), is based upon and extends our previous one- and three-dimensional techniques. We test several variants of our method, both on surrogate data generated from a collection of Gaussian sources, and on model data from a population of layer 5 neocortical pyramidal neurons. We also apply the method to experimental data from the rat subiculum. The main advantages of the proposed method are the explicit specification of its assumptions, the possibility to include system-specific information as it becomes available, the ability to estimate CSD at the grid boundaries, and lower reconstruction errors when compared to the traditional approach. These features make iCSD 2D a substantial improvement over the approaches used so far and a powerful new tool for the analysis of multielectrode array data. We also provide a free GUI-based MATLAB toolbox to analyze and visualize our test data as well as user datasets.
Electronic supplementary material
The online version of this article (doi:10.1007/s12021-011-9111-4) contains supplementary material, which is available to authorized users.
Current source density; Local field potentials; Evoked potentials; Inverse problems; Rat; Hippocampus; Subiculum; Cortical model
Studies have shown that insomnia is a common sleep disorder among patients with end-stage renal disease (ESRD). This study aimed to assess the prevalence of insomnia in Saudi patients with ESRD who are on maintenance dialysis.
This was an observational cross-sectional study carried out over a period of five months in two hemodialysis centers in Saudi Arabia. To assess the prevalence of insomnia, we used the ICSD-2 definition. We also examined the association between insomnia and other sleep disorders, the underlying causes of renal failure, dialysis duration, dialysis shift, and other demographic data.
Out of 227 enrolled patients, insomnia was reported by 60.8%. The mean patient age was 55.7 ± 17.2 years; 53.7% were male and 46.3% were female. Insomnia was significantly associated with female gender, afternoon hemodialysis, Restless Legs Syndrome, high risk for obstructive Sleep Apnea Syndrome and excessive daytime sleepiness (P-values: 0.05, 0.01, < 0.0001, < 0.0001, and < 0.0001, respectively). No significant association was found between insomnia and other variables, including BMI, smoking habits, underlying etiology of renal failure, dialysis duration, association with hemoglobin, ferritin, and phosphorus or dialysis adequacy as measured by the Kt/V index.
Insomnia is common in dialysis patients and was significantly associated with other sleep disorders. Greater attention needs to be given to the care of dialysis patients with regard to the diagnosis and management of insomnia and associated sleep disorders.
Complex sleep behaviors (CSBs) are classified as “parasomnias” in the International Classifcation of Sleep Disorders, Second Edition (ICSD-2). To realize the potential danger after taking two short-acting Z-hypnosedative drugs, we estimated the incidence of CSBs in nonpsychotic patients in Taiwan.
Subjects (N = 1,220) using zolpidem or zopiclone were enrolled from the psychiatric outpatient clinics of a medical center in Taiwan over a 16-month period in 2006–2007. Subjects with zolpidem (N = 1,132) and subjects with zopiclone (N = 88) were analyzed. All subjects completed a questionnaire that included demographic data and complex sleep behaviors after taking hypnotics.
Among zolpidem and zopiclone users, 3.28% of patients reported incidents of somnambulism or amnesic sleep-related behavior problems. The incidence of CSBs with zolpidem and zopiclone were 3.27%, and 3.41%, respectively, which was signifcantly lower than other studies in Taiwan.
These results serve as a reminder for clinicians to make inquiries regarding any unusual performance of parasomnic activities when prescribing zolpidem or zopiclone.
parasomnia; somnambulism; amnesic sleep-related behavior; sleepwalking; zolpidem; zopiclone
A hierarchical in silico screening procedure using the crystal structure of an agonist bound chimeric α7/Ls-AChBP protein was successfully applied to both proprietary and commercial databases containing drug-like molecules. An overall hit rate of 26% (pKi ⩾5.0) was obtained, with an even better hit rate of 35% for the commercial compound collection. Structurally novel and diverse ligands were identified. Binding studies with [3H]epibatidine on chimeric α7/5-HT3 receptors yielded submicromolar inhibition constants for identified hits. Compared to a previous screening procedure that utilized the wild type Ls-AChBP crystal structure, the current study shows that the recently obtained α7/Ls-AChBP chimeric protein crystal structure is a better template for the identification of novel α7 receptor ligands.
α7 Receptor; nAChR; AChBP; Virtual screening; In silico screening; Docking; Cys-loop
An improved algorithm has been written for assigning chemical structures to incoming entries to the Cambridge Structural Database.
An improved algorithm has been developed for assigning chemical structures to incoming entries to the Cambridge Structural Database, using only the information available in the deposited CIF. Steps in the algorithm include detection of bonds, selection of polymer unit, resolution of disorder, and assignment of bond types and formal charges. The chief difficulty is posed by the large number of metallo-organic crystal structures that must be processed, given our aspiration that assigned chemical structures should accurately reflect properties such as the oxidation states of metals and redox-active ligands, metal coordination numbers and hapticities, and the aromaticity or otherwise of metal ligands. Other complications arise from disorder, especially when it is symmetry imposed or modelled with the SQUEEZE algorithm. Each assigned structure is accompanied by an estimate of reliability and, where necessary, diagnostic information indicating probable points of error. Although the algorithm was written to aid building of the Cambridge Structural Database, it has the potential to develop into a general-purpose tool for adding chemical information to newly determined crystal structures.
Cambridge Structural Database; structure assignment; catena structure; disorder resolution; Bayesian statistics
Since its inception in 1994, The RNA Modification Database (RNAMDB, http://rna-mdb.cas.albany.edu/RNAmods/) has served as a focal point for information pertaining to naturally occurring RNA modifications. In its current state, the database employs an easy-to-use, searchable interface for obtaining detailed data on the 109 currently known RNA modifications. Each entry provides the chemical structure, common name and symbol, elemental composition and mass, CA registry numbers and index name, phylogenetic source, type of RNA species in which it is found, and references to the first reported structure determination and synthesis. Though newly transferred in its entirety to The RNA Institute, the RNAMDB continues to grow with two notable additions, agmatidine and 8-methyladenosine, appended in the last year. The RNA Modification Database is staying up-to-date with significant improvements being prepared for inclusion within the next year and the following year. The expanded future role of The RNA Modification Database will be to serve as a primary information portal for researchers across the entire spectrum of RNA-related research.
The Drosophila brain is formed by an invariant set of lineages, each of which is derived from a unique neural stem cell (neuroblast) and forms a genetic and structural unit of the brain. The task of reconstructing brain circuitry at the level of individual neurons can be made significantly easier by assigning neurons to their respective lineages. In this paper we address the automatization of neuron and lineage identification. We focused on the Drosophila brain lineages at the larval stage when they form easily recognizable secondary axon tracts (SATs) that were previously partially characterized. We now generated an annotated digital database containing all lineage tracts reconstructed from five registered wild-type brains, at higher resolution and including some that were previously not characterized. We developed a method for SAT structural comparisons based on a dynamic programming approach akin to nucleotide sequence alignment, and a machine learning classifier trained on the annotated database of reference SATs. We quantified the stereotypy of SATs by measuring the residual variability of aligned wild-type SATs. Next, we employed our method for the identification of SATs within wild-type larval brains, and found it highly accurate (93–99 %). The method proved highly robust for the identification of lineages in mutant brains, and in brains that differed in developmental time or labeling. We describe for the first time an algorithm that quantifies neuronal projection stereotypy in the Drosophila brain, and use the algorithm for automatic neuron and lineage recognition.
The title compound, lead trimanganese tris(orthophosphate), has been synthesized by hydrothermal methods. In this structure, only two O atoms are in general positions and all others atoms are in the special positions of the Imma space group. Indeed, the atoms in the Wyckoff positions are namely: Pb1 and P1 on 4e (mm2); Mn1 on 4b (2/m); Mn2 and P2 on 8g (2); O1 on 8h (m); O2 on 8i (m). The crystal structure can be viewed as a three-dimensional network of corner- and edge-sharing PO4 tetrahedra and MnO6 octahedra, building two types of chains running along the b axis. The first is an infinite linear chain, formed by alternating MnIIIO6 octahedra and PO4 tetrahedra which share one vertex. The second chain is built up from two adjacent edge-sharing octahedra (MnII
2O10 dimers) whose ends are linked to two PO4 tetrahedra by a common edge. These chains are linked together by common vertices of polyhedra in such a way as to form porous layers parallel to (001). These sheets are bonded by the first linear chains, leading to the appearance of two types of tunnels, one propagating along the a axis and the other along b. The PbII ions are located within the intersections of the tunnels with eight neighbouring O atoms in form of a trigonal prism that is capped by two O atoms on one side. The three-dimensional framework of this structure is compared with similar phosphates such as Ag2Co3(HPO4)(PO4)2 and Ag2Ni3(HPO4)(PO4)2.
Single crystals of garnet-type trimanganese(II) dichromium(III) tris[orthogermanate(IV)], MnII
2(GeO4)3, were obtained by utilizing a chemical transport reaction. Corresponding to the mineral garnet with the general formula A
2(SiO4)3, each of the four elements occupies only one crystallographically distinct position. Mn2+ occupies the respective A position (Wyckoff site 24c, site symmetry 2.22), being surrounded by eight O atoms that form a distorted cube [d(Mn—O) = 2.291 (2) and 2.422 (2) Å, 4× each], while Cr3+ on the B position (Wyckoff site 16a, site symmetry .-3.) is situated in a slightly distorted octahedron of six O2− anions [d(Cr—O) = 1.972 (2) Å, 6×]. In addition, the O atoms on general site 96h form isolated [GeO4]4− tetrahedra with Ge4+ on site 24d [site symmetry -4..; d(Ge—O) = 1.744 (2) Å, 4×].
The structure of hexadecapraseodymium henicosamolybdenum hexapentacontaoxide, Pr16Mo21O56, is isotypic with other rare earth representatives of formula type RE
16Mo21O56 (RE = La, Ce, Nd). It is characterized by Mo10O18
a units (where i = inner and a = apical O atoms) containing bioctahedral Mo10 clusters and octahedral MoO6 units that share some of their O atoms to form the Mo–O framework. The two independent Mo10 cluster units are centred at Wyckoff positions 2b and 2c and have point-group symmetry . The Mo atom of the MoO6 unit is likewise situated at an inversion centre (2d). The eight crystallographically different Pr3+ cations occupy irregular voids in the framework with coordination numbers to the O atoms varying between 8 and 11.
Colorimetric sensing, which transduces environmental changes into visible color changes, provides a simple yet powerful detection mechanism that is well-suited to the development of low-cost and low-power sensors. A new approach in colorimetric sensing exploits the structural color of photonic crystals (PCs) to create environmentally-influenced color-changeable materials. PCs are composed of periodic dielectrics or metallo-dielectric nanostructures that affect the propagation of electromagnetic waves (EM) by defining the allowed and forbidden photonic bands. Simultaneously, an amazing variety of naturally occurring biological systems exhibit iridescent color due to the presence of PC structures throughout multi-dimensional space. In particular, some kinds of the structural colors in living organisms can be reversibly changed in reaction to external stimuli. Based on the lessons learned from natural photonic structures, some specific examples of PCs-based colorimetric sensors are presented in detail to demonstrate their unprecedented potential in practical applications, such as the detections of temperature, pH, ionic species, solvents, vapor, humidity, pressure and biomolecules. The combination of the nanofabrication technique, useful design methodologies inspired by biological systems and colorimetric sensing will lead to substantial developments in low-cost, miniaturized and widely deployable optical sensors.
photonic crystals; structure color; colorimetric sensors
The FSSP database presents a continuously updated classification of 3-D protein folds based on an all-against-all comparison of structures currently in the Protein Data Bank (PDB) [Bernstein et al. (1977) J. Mol. Biol., 112, 535- 542]. The database currently contains an extended structural family for each of 600 representative protein chains which have <25% mutual sequence identity. The results of the exhaustive pairwise structure comparisons are reported in the form of a fold tree generated by hierarchical clustering and as a series of structurally representative sets of folds at varying levels of uniqueness. For each query structure from the representative set, there is a database entry containing structure-structure alignments with its structural neighbours in the representative set and its sequence homologs in the PDB. All alignments are based purely on the 3-D co-ordinates of the proteins and are derived by an automatic structure comparison program (Dali). The FSSP database is accessible electronically on the World Wide Web and by anonymous ftp.
The new terbium (lithium zinc) distannide, TbLi1–xZnxSn2 (x = 0.2) crystallizes in the orthorhombic CeNiSi2 structure type with space group Cmcm and Pearson symbol oS16. Of the four independent 4c atom positions (m2m site symmetry), three are fully occupied by individual atoms (two by Sn and one by Tb atoms) and the fourth is occupied by Li and Zn atoms with a statistical distribution. The Tb coordination polyhedron is a 21-vertex pseudo-Frank–Kasper polyhedron. One Sn atom is enclosed in a tricapped trigonal prism, the second Sn atom is in a cuboctahedron and the statistically distributed (Li,Zn) site is in a tetragonal antiprism with one added atom. Electronic structure calculations were used for the elucidation of reasons for and the ability of mutual substitution of lithium and transition metals. Positive charge density was observed around the rare earth atom and the Li and Zn atoms, the negative charge density in the proximity of the Sn atoms.
Gene expression as governed by the interplay of the components of regulatory networks is indeed one of the most complex fundamental processes in biological systems. Although several methods have been published to unravel the hierarchical structure of regulatory networks, weaknesses such as the incorrect or inconsistent assignment of elements to their hierarchical levels, the incapability to cope with cyclic dependencies within the networks or the need for a manual curation to retrieve non-overlapping levels remain unsolved.
We developed HiNO as a significant improvement of the so-called breadth-first-search (BFS) method. While BFS is capable of determining the overall hierarchical structures from gene regulatory networks, it especially has problems solving feed-forward type of loops leading to conflicts within the level assignments. We resolved these problems by adding a recursive correction approach consisting of two steps. First each vertex is placed on the lowest level that this vertex and its regulating vertices are assigned to (downgrade procedure). Second, vertices are assigned to the next higher level (upgrade procedure) if they have successors with the same level assignment and have themselves no regulators. We evaluated HiNO by comparing it with the BFS method by applying them to the regulatory networks from Saccharomyces cerevisiae and Escherichia coli, respectively. The comparison shows clearly how conflicts in level assignment are resolved in HiNO in order to produce correct hierarchical structures even on the local levels in an automated fashion.
We showed that the resolution of conflicting assignments clearly improves the BFS-method. While we restricted our analysis to gene regulatory networks, our approach is suitable to deal with any directed hierarchical networks structure such as the interaction of microRNAs or the action of non-coding RNAs in general. Furthermore we provide a user-friendly web-interface for HiNO that enables the extraction of the hierarchical structure of any directed regulatory network.
HiNO is freely accessible at http://mips.helmholtz-muenchen.de/hino/.
The Systematized Nomenclature of Medicine, Third Edition, SNOMED International, is a comprehensive structured nomenclature of human and veterinary medicine, the terms of which are detailed, fine grained and semantically typed. Terms are assigned to eleven independent modules (fields), each of which is systematized. Terms may be linked to on another to represent complex entities or manifestations or alternately complex terms dissected into their elemental parts. Terms are illustrated utilizing a frame representation. Efforts are in progress to build both a conceptual graph and a frame-based semantic network encompassing each SNOMED term, effectively building a knowledge base. In this way, the knowledge contained in each alphanumeric representation is made explicit. SNOMED is a linked data structure capable of faithfully representing the activities, observations and diagnoses found in the medical record in a computer processable form.
Liquid chromatography (LC) coupled with mass spectrometry (MS) and database assignment methods have been used to conduct a large-scale proteome survey of the R6/2 mouse model of Huntington’s disease (HD). Although the neuropathological mechanisms of HD are not known, the mutant huntingtin gene that causes the disease is thought to alter gene transcription, leading to a cascade of neurotoxic events. In this report, we have focused on characterizing changes in the brain proteome associated with HD pathophysiology. Differences in the relative abundances of proteins (R6/2 compared to wild type) in brain tissue from the striatum and cortex, two primary loci of dysfunction in HD, were assessed by using a label-free approach based on calibrations to internal standards. In total, assignments were made for ~400 proteins. A set of criteria was used to establish 160 high confidence assignments, ~30% of which appear to show differences in expression relative to WT (wild type) animals. Many of the proteins that were differentially expressed are known to be associated with neurotransmission, and likely play key roles in HD etiology. This study is the first to report that the majority of differentially expressed proteins in the striatum are up-regulated, while the majority of the expressed proteins in the cortex are down-regulated. The differentially expressed proteins identified in this proteomic screen may be potential biomarkers and drug targets for HD, and may further our understanding of the disease pathology.
Huntington’s disease; liquid chromatography; mass spectrometry; brain proteome; label-free quantification; striatum; cortex
Longitudinal studies of a variety of transgenic mouse models for lens development can create substantial challenges in database management and analysis. We report a novel, automated, feature-based informatics approach to screening lens phenotypes in a large database of slit lamp images. Digital slit lamp images of normal and abnormal lenses in eyes of wild type (wt), SC1 null and SPARC null transgenic mice were recorded for quantitative evaluation of their structural phenotype. The images were processed to improve the contrast of structural features that corresponded to rings of opacity and fluctuations in scattering intensity in the lenses. Measurable attributes were assigned to the features in the lens images and given as an output vector of 46 dimensions. Characteristic patterns correlated with the structural phenotype of each mutant and wt lens and a statistical fit for each phenotype was defined. The genotype was identified correctly in nearly 85% of the slit lamp images on the basis of an automated computer analysis of the lens structural phenotype. The automated computer algorithm has the potential to evaluate a large database of slit lamp images and distinguish mouse genotypes on the basis of lens phenotypes objectively using a neural network analysis of the structural features observed in the slit lamp images. The neural network approach is a promising technology for objective evaluation of genotype/phenotype relationships based on structural features and light scattering in lenses. Further improvements in the automated method can be expected to simplify and increase the accuracy and efficiency of the feature based analysis of structural phenotypes linked to genetic variation.
informatics; phenotype; genotype; slit lamp; imaging; lens