bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene therapy for Fabry disease
Authors: Sitaskas C. , Medin J. A.
Published: December 2002

Fabry disease is an X‐linked metabolic disorder caused by a deficiency ofα‐galactosidase A (α‐Gal A). Lack of this lysosomal hydrolase results in theaccumulation of galactose‐terminal glycosphingolipids in a number of tissues, including vascular endothelial cells. Premature death is predominantly associated withvascular conditions of the heart, kidneys and brain. Historically, treatment has largelybeen palliative. Alternative treatments for many lysosomal storage diseases have beendeveloped, including allogeneic organ and bone marrow transplantation, enzymereplacement therapy, and gene therapy. Significant clinical risks still exist withallogeneic transplantations. α‐Gal A enzyme replacement therapy has beenimplemented in clinical trials. This approach has been effective but may havelimitations for long‐term systemic or cost‐effective correction. As an alternative, genetherapy approaches, involving a variety of gene delivery systems, have been pursuedfor the amelioration of Fabry disease. Fabry disease is a compelling disorder for genetherapy, as target cells are readily accessible and relatively low levels of enzymecorrection may suffice to reduce storage. Importantly, metabolic cooperativity effectsare also manifested in Fabry disease, wherein corrected cells secrete α‐Gal A that cancorrect bystander cells. In addition, a broad therapeutic window probably exists, andmouse models of Fabry disease have been generated to assist studies. As an example, in vitro and in vivo studies using α‐Gal A‐transduced haematopoietic cells from Fabrymice have demonstrated enzymatic correction of recipient cells and dissemination ofα‐Gal A upon transplantation, leading to reduced lipid storage in a number ofclinically relevant organs. This corrective enzymatic effect has recently been shown tobe even further enhanced upon pre‐selection of therapeutically transduced cells priorto transplantation. This review will briefly detail current gene delivery methods andsummarize results to date in the context of gene therapy for Fabry disease.
Effect of ramipril in a patient with glycogen storage disease type I and nephrotic‐range proteinuria
Authors: Pela I. , Donati M. A. , Zammarchi E.
Published: December 2002

We studied the effect of ramipril on urinary protein excretion and arterial pressure in a 27‐year‐old patient with GSD Ia and heavy proteinuria (2–3 g/24 h). Ramipril therapy resulted in an important reduction of proteinuria (0.3–0.5 g/24 h): no changes were observed in arterial pressure and renal function during the 12‐month follow‐up. We conclude that treatment with ramipril can be employed effectively and safely in GSD Ia patients with nephrotic‐range proteinuria.
A fluorimetric enzyme assay for the diagnosis of MPS II (Hunter disease)
Authors: Voznyi Ya. V. , Keulemans J. L. M. , van Diggelen O. P.
Published: December 2002

4‐Methylumbelliferyl‐α‐iduronate 2‐sulphate was synthesized and shown to be a specific substrate for the lysosomal iduronate‐2‐sulphate sulphatase (IDS). Fibroblasts (n = 17), leukocytes (n = 3) and plasmas (n = 9) from different MPS II patients showed <5% of mean normal IDS activity. The enzymatic liberation of the fluorochrome from 4‐methylumbelliferyl‐α‐iduronate 2‐sulphate requires the sequential action of IDS and α‐iduronidase. A normal level of α‐iduronidase activity was insufficient to complete the hydrolysis of the reaction intermediate 4‐methylumbelliferyl‐α‐iduronide formed by IDS. A second incubation step in the presence of excess purified α‐iduronidase is needed to avoid underestimation of the IDS activity.
Self‐rated psychosocial consequences and quality of life in the acute porphyrias
Authors: Millward L. M. , Kelly P. , Deacon A. , Senior V. , Peters T. J.
Published: December 2002

A battery of self‐report psychosocial measures was mailed to 116 patients who had been referred for clinical management (clinic attenders) or laboratory diagnosis (non‐clinic attenders) to the London Supraregional Assay Service Centre for Porphyria over the past decade and who tested positive for porphyria. Usable replies were received from 81 (70%) patients. Our interest focused on the prevalence of psychosocial symptoms in acute porphyrias and the perceived effects of porphyria on quality of life and patient experience. Research questions examined included (i), lifestyle factors; (ii) life events; (iii) mental health; (iv) general health; and (v) perceptions of illness of patients receiving specialist clinical management compared to respondents referred for diagnostic investigations, between patients with latent or manifest symptomology and between patients with different types of porphyria.

Patients with porphyria have an impaired quality of life, particularly manifest cases, compared to controls and to diabetic patients. Depression, and particularly anxiety, is more common than in the general population or general medical outpatient attenders. Quality of life is lower in acute intermittent porphyria (AIP) than in other forms of porphyria and a significant number of patients had major life event consequences, e.g. failure to secure, or loss of, employment, limitation of family size. Patients attending a clinic providing specialist porphyria advice, management and counselling received some perceived lifestyle benefits.
Anderson–Fabry disease: Clinical manifestations of disease in female heterozygotes
Authors: Whybra C. , Kampmann Chr. , Willers I. , Davies J. , Winchester B. , Kriegsmann J. , Brühl K. , Gal A. , Bunge S. , Beck M.
Published: December 2002

Anderson–Fabry disease is a rare, X‐chromosomal lipid storage disorder caused by a deficiency of lysosomal α‐galactosidase A. Clinical manifestations of Anderson–Fabry disease include excruciating pain in the extremities (acroparaesthesia), skin vessel ectasia (angiokeratoma), corneal and lenticular opacity, cardiovascular disease, stroke and renal failure, only renal failure being a frequent cause of death. Heterozygote female carriers have often been reported as being asymptomatic or having an attenuated form of the disease. To evaluate the spectrum of clinical signs in heterozygotes, a comprehensive clinical examination was performed on 20 carriers of Anderson–Fabry disease. This revealed that, in addition to the skin manifestation, various other clinical manifestations of the disease are present, including acroparaesthesia, kidney dysfunction, cerebrovascular disease, and gastrointestinal and heart problems. It therefore appears that Anderson–Fabry disease affects both hemizygotes and heterozyotes and therefore should be considered to be an X‐linked dominant disease.
Recent victimization in women and men with severe mental illness: Prevalence and correlates
Authors: Goodman Lisa A. , Salyers Michelle P. , Mueser Kim T. , Rosenberg Stanley D. , Swartz Marvin , Essock Susan M. , Osher Fred C. , Butterfield Marian I. , Swanson Jeffrey , Lamb‐Pagone Jerilynn , Burns Barbara J. , Meador Keith G. , Swanson Jeffrey W. , Becker Mary E. , Bosworth Hayden B. , Frothingham Richard , Horner Ronnie D. , McIntyre Lauren M. , Spivey Patricia M. , Stechuchak Karen M. , Garber Lisa J. , Gearon Jean S. , Goldberg Richard W. , Herron John D. , Hoffman Raymond S. , Riismandel Corina L. , Auciello Patricia C. , Drake Robert E. , Iber Mark C. , Luckoor Ravindra , Skillman Gemma R. , Wolfe Rosemarie S. , Vidaver Robert M.
Published: December 2002

The problem of violence against individuals with severe mental illness (SMI) has received relatively little notice, despite several studies suggesting an exceptionally high prevalence of victimization in this population. This paper describes the results of an investigation of the prevalence and correlates of past year physical and sexual assault among a large sample of women and men with SMI drawn from inpatient and outpatient settings across 4 states. Results confirmed preliminary findings of a high prevalence of victimization in this population (with sexual abuse more prevalent for women and physical abuse more prevalent for men), and indicated the existence of a range of correlates of recent victimization, including demographic factors and living circumstances, history of childhood abuse, and psychiatric illness severity and substance abuse. The research and clinical implications of these findings are discussed.
Interleukin-6 Enhances Transforming Growth Factor-alpha mRNA Expression in Macrophage-Like Human Monocytoid (U-937-1) Cells
Authors: Hallbeck A. L. , Walz T. M. , Wasteson A.
Published: December 2002

We have previously reported that the human monocytoid cell line U-937-1 constitutively expresses transforming growth factor-alpha (TGF-α) and that the steady-state levels of TGF-α mRNA as well as TGF-α protein release increase when U-937-1 cells are differentiated towards monocytes/macrophages. Interleukin-6 (IL-6), which has been shown to have growth-stimulatory effects on a number of cell types, has recently been shown to enhance TGF-α expression in keratinocytes. In the present study we investigated whether TGF-α expression in macrophage-like cells could be regulated by IL-6 using U-937-1 cells as a model system of monocyte/macrophage differentiation.

U-937-1 cells were differentiated with retinoic acid (RA), vitamin D3 (Vit-D3) or phorbol-12-myristate-13-acetate (PMA) for 4 days and were then treated with human recombinant IL-6 (1000 IU/ml) for up to 24 hr. Northern blot analysis revealed that cells differentiated with PMA, inducing the phenotype of a secretory macrophage, markedly increased their TGF-α mRNA levels (2.7-fold) when treated with IL-6; the response was maximal at 6 hr and remained high at 12 hr. The expression of the TGF-α gene was accompanied by release of TGF-α protein into the cell culture medium, irrespective of differentiating agent, as demonstrated by enzyme-linked immunosorbent assay (ELISA), as well as by surface expression of pro-TGF-α as determined by indirect immunofluorescent cytometry. However, the superinduction of the TGF-α gene by IL-6 in cells differentiated with PMA was not accompanied by any increase in TGF-α protein release or pro-TGF-α surface expression.

We conclude that since IL-6 causes increased steady-state levels of TGF-α mRNA in macrophage-like cells, it may prime these cells for production of this growth factor. Furthermore, we have shown that the IL-6 receptor complex is functional in U-937-1 cells induced to differentiate towards a secretory macrophage by treatment with PMA.
Thermogenesis in Birds
Authors: Bicudo José Eduardo P. W. , Vianna Cláudia R. , Chaui-Berlinck José Guilherme
Published: December 2002

The article discusses the importance of avian skeletal muscle as a source for heat generation by means of both shivering and non-shivering. Non-shivering thermogenesis in birds is still a polemic issue. Recent evidence at the molecular/cellular level indicates, however, that this type of heat generation may also exist among birds. The involvement of the sarcoplasmic reticulum calcium ATPase in non-shivering thermogenesis is discussed in-depth.
Cognitive Measurements of Graph Aesthetics
Authors: Ware Colin , Purchase Helen , Colpoys Linda , McGill Matthew
Published: December 2002

A large class of diagrams can be informally characterized as node–link diagrams. Typically nodes represent entities, and links represent relationships between them. The discipline of graph drawing is concerned with methods for drawing abstract versions of such diagrams. At the foundation of the discipline are a set of graph aesthetics (rules for graph layout) that, it is assumed, will produce graphs that can be clearly understood. Examples of aesthetics include minimizing edge crossings and minimizing the sum of the lengths of the edges. However, with a few notable exceptions, these aesthetics are taken as axiomatic, and have not been empirically tested. We argue that human pattern perception can tell us much that is relevant to the study of graph aesthetics including providing a more detailed understanding of aesthetics and suggesting new ones. In particular, we find the importance of good continuity (ie keeping multi-edge paths as straight as possible) has been neglected. We introduce a methodology for evaluating the cognitive cost of graph aesthetics and we apply it to the task of finding the shortest paths in spring layout graphs. The results suggest that after the length of the path the two most important factors are continuity and edge crossings, and we provide cognitive cost estimates for these parameters. Another important factor is the number of branches emanating from nodes on the path.
Properties of linkage disequilibrium (LD) maps
Authors: Zhang Weilhua , Collins Andrew , Maniatis Nikolas , Tapper William , Morton Newton E.
Published: December 2002

A linkage disequilibrium map is expressed in linkage disequilibrium (LD) units (LDU) discriminating blocks of conserved LD that have additive distances and locations monotonic with physical (kb) and genetic (cM) maps. There is remarkable agreement between LDU steps and sites of meiotic recombination in the one body of data informative for crossing over, and good agreement with another method that defines blocks without assigning an LD location to each marker. The map may be constructed from haplotypes or diplotypes, and efficiency estimated from the empirical variance of LD is substantially greater for the ρ metric based on evolutionary theory than for the absolute correlation
r
, and for the LD map compared with its physical counterpart. The empirical variance is nearly three times as great for the worst alternative (
r
and kb map) as for the most efficient approach (ρ and LD map). According to the empirical variances, blocks are best defined by zero distance between included markers. Because block size is algorithm-dependent and highly variable, the number of markers required for positional cloning is minimized by uniform spacing on the LD map, which is estimated to have ≈1 LDU per locus, but with much variation among regions. No alternative representation of linkage disequilibrium (some of which are loosely called maps) has these properties, suggesting that LD maps are optimal for positional cloning of genes determining disease susceptibility.
Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel β2-subunits
Authors: Chen Chunling , Bharucha Vandana , Chen Yuan , Westenbroek Ruth E. , Brown Angus , Malhotra Jyoti Dhar , Jones Dorothy , Avery Christy , Gillespie Patrick J. , Kazen-Gillespie Kristin A. , Kazarinova-Noyes Katie , Shrager Peter , Saunders Thomas L. , Macdonald Robert L. , Ransom Bruce R. , Scheuer Todd , Catterall William A. , Isom Lori L.
Published: December 2002

Sodium channel β-subunits modulate channel gating, assembly, and cell surface expression in heterologous cell systems. We generated β2
−/−
mice to investigate the role of β2 in control of sodium channel density, localization, and function in neurons
in vivo
. Measurements of [
3
H]saxitoxin (STX) binding showed a significant reduction in the level of plasma membrane sodium channels in β2
−/−
neurons. The loss of β2 resulted in negative shifts in the voltage dependence of inactivation as well as significant decreases in sodium current density in acutely dissociated hippocampal neurons. The integral of the compound action potential in optic nerve was significantly reduced, and the threshold for action potential generation was increased, indicating a reduction in the level of functional plasma membrane sodium channels. In contrast, the conduction velocity, the number and size of axons in the optic nerve, and the specific localization of Na
v
1.6 channels in the nodes of Ranvier were unchanged. β2
−/−
mice displayed increased susceptibility to seizures, as indicated by reduced latency and threshold for pilocarpine-induced seizures, but seemed normal in other neurological tests. Our observations show that β2-subunits play an important role in the regulation of sodium channel density and function in neurons
in vivo
and are required for normal action potential generation and control of excitability.
Genetic variation in the 22q11 locus and susceptibility to schizophrenia
Authors: Liu Hui , Abecasis Gonçalo R. , Heath Simon C. , Knowles Alyson , Demars Sandra , Chen Ying-Jiun , Roos J. Louw , Rapoport Judith L. , Gogos Joseph A. , Karayiorgou Maria
Published: December 2002

An increased prevalence of microdeletions at the 22q11 locus has been reported in samples of patients with schizophrenia. 22q11 microdeletions represent the highest known genetic risk factor for the development of schizophrenia, second only to that of the monozygotic cotwin of an affected individual or the offspring of two schizophrenic parents. It is therefore clear that a schizophrenia susceptibility locus maps to chromosome 22q11. In light of evidence for suggestive linkage for schizophrenia in this region, we hypothesized that, whereas deletions of chromosome 22q11 may account for only a small proportion of schizophrenia cases in the general population (up to ≈2%), nondeletion variants of individual genes within the 22q11 region may make a larger contribution to susceptibility to schizophrenia in the wider population. By studying a dense collection of markers (average one single nucleotide polymorphism/20 kb over 1.5 Mb) in the vicinity of the 22q11 locus, in both family- and population-based samples, we present here results consistent with this assumption. Moreover, our results are consistent with contribution from more than one gene to the strikingly increased disease risk associated with this locus. Finer-scale haplotype mapping has identified two subregions within the 1.5-Mb locus that are likely to harbor candidate schizophrenia susceptibility genes.
The role of feedback in shaping neural representations in cat visual cortex
Authors: Galuske Ralf A. W. , Schmidt Kerstin E. , Goebel Rainer , Lomber Stephen G. , Payne Bertram R.
Published: December 2002

In the primary visual cortex, neurons with similar response preferences are grouped into domains forming continuous maps of stimulus orientation and direction of movement. These properties are widely believed to result from the combination of ascending and lateral interactions in the visual system. We have tested this view by examining the influence of deactivating feedback signals descending from the visuoparietal cortex on the emergence of these response properties and representations in cat area 18. We thermally deactivated the dominant motion-processing region of the visuoparietal cortex and used optical and electrophysiological methods to assay neural activity evoked in area 18 by stimulation with moving gratings and fields of coherently moving randomly distributed dots. Feedback deactivation decreased signal strength in both orientation and direction maps and virtually abolished the global layout of direction maps, whereas the basic structure of the orientation maps was preserved. These findings could be accounted for by a selective silencing of highly direction-selective neurons and by the redirection of preferences of less selective neurons. Our data suggest that signals fed back from the visuoparietal cortex strongly contribute to the emergence of direction selectivity in early visual areas. Thus we propose that higher cortical areas have significant influence over fundamental neuronal properties as they emerge in lower areas.
Genome-wide coexpression dynamics: Theory and application
Authors: Li Ker-Chau
Published: December 2002

High-throughput expression profiling enables the global study of gene activities. Genes with positively correlated expression profiles are likely to encode functionally related proteins. However, all biological processes are interlocked, and each protein may play multiple cellular roles. Thus the coexpression of any two functionally related genes may depend on the constantly varying, yet often-unknown cellular state. To initiate a systematic study on this issue, a theory of coexpression dynamics is presented. This theory is used to rationalize a strategy of conducting a genome-wide search for the most critical cellular players that may affect the coexpression pattern of any two genes. In one example, using a yeast data set, our method reveals how the enzymes associated with the urea cycle are expressed to ensure proper mass flow of the involved metabolites. The correlation between
ARG2
and
CAR2
is found to change from positive to negative as the expression level of
CPA2
increases. This delicate interplay in correlation signifies a remarkable control on the influx and efflux of ornithine and reflects well the intrinsic cellular demand for arginine. In addition to the urea cycle, our examples include
SCH9
and
CYR1
(both implicated in a recent longevity study), cytochrome
c
1 (mitochondrial electron transport), calmodulin (main calcium-binding protein),
PFK1
and
PFK2
(glycolysis), and two genes,
ECM1
and
YNL101W
, the functions of which are newly revealed. The complexity in computation is eased by a new result from mathematical statistics.
Evidence for vestibular regulation of autonomic functions in a mouse genetic model
Authors: Murakami Dean M. , Erkman Linda , Hermanson Ola , Rosenfeld Michael G. , Fuller Charles A.
Published: December 2002

Physiological responses to changes in the gravitational field and body position, as well as symptoms of patients with anxiety-related disorders, have indicated an interrelationship between vestibular function and stress responses. However, the relative significance of cochlear and vestibular information in autonomic regulation remains unresolved because of the difficulties in distinguishing the relative contributions of other proprioceptive and interoceptive inputs, including vagal and somatic information. To investigate the role of cochlear and vestibular function in central and physiological responses, we have examined the effects of increased gravity in wild-type mice and mice lacking the POU homeodomain transcription factor Brn-3.1 (Brn-3b/Pou4f3). The only known phenotype of the Brn-3.1
−/−
mouse is related to hearing and balance functions, owing to the failure of cochlear and vestibular hair cells to differentiate properly. Here, we show that normal physiological responses to increased gravity (2G exposure), such as a dramatic drop in body temperature and concomitant circadian adjustment, were completely absent in Brn-3.1
−/−
mice. In line with the lack of autonomic responses, the massive increase in neuronal activity after 2G exposure normally detected in wild-type mice was virtually abolished in Brn-3.1
−/−
mice. Our results suggest that cochlear and vestibular hair cells are the primary regulators of autonomic responses to altered gravity and provide genetic evidence that these cells are sufficient to alter neural activity in regions involved in autonomic and neuroendocrine control.
Modularity and reshuffling of
Snail
and
Slug
expression during vertebrate evolution
Authors: Locascio Annamaria , Manzanares Miguel , Blanco María J. , Nieto M. Angela
Published: December 2002

Gene duplication has been a major mechanism for increasing genomic complexity and variation during evolution. The evolutionary history of duplicated genes has been poorly studied along the vertebrate lineage. Here, we attempt to study that history by analyzing the expression of two members of the Snail family,
Snail
and
Slug
, in representatives of the major vertebrate groups. We find a surprising degree of variability in a subset of the expression sites for both genes in different species. Although some of the changes can be explained by neofunctionalization or subfunctionalization, others imply reciprocal changes in the expression of the two genes and the reappearance of expression in sites lost earlier in evolution. Because these changes do not fit easily into current models, we need to invoke additional mechanisms acting on enhancer elements to distribute expression domains and functions of duplicated genes unequally during evolution.
Association testing by DNA pooling: An effective initial screen
Authors: Bansal Aruna , van den Boom Dirk , Kammerer Stefan , Honisch Christiane , Adam Gail , Cantor Charles R. , Kleyn Patrick , Braun Andi
Published: December 2002

With an ever-increasing resource of validated single-nucleotide polymorphisms (SNPs), the limiting factors in genome-wide association analysis have become genotyping capacity and the availability of DNA. We provide a proof of concept of the use of pooled DNA as a means of efficiently screening SNPs and prioritizing them for further study. This approach reduces the final number of SNPs that undergo full, sample-by-sample genotyping as well as the quantity of DNA used overall. We have examined 15 SNPs in the cholesteryl ester transfer protein (
CETP
) gene, a gene previously demonstrated to be associated with serum high-density lipoprotein cholesterol levels. The SNPs were amplified in two pools of DNA derived from groups of individuals with extremely high and extremely low serum high-density lipoprotein cholesterol levels, respectively.
P
values <0.05 were obtained for 14 SNPs, supporting the described association. Genotyping of the individual samples showed that the average margin of error in frequency estimate was ≈4% when pools were used. These findings clearly demonstrate the potential of pooling techniques and their associated technologies as an initial screen in the search for genetic associations.
Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT
Authors: Baldanzi Gianluca , Filigheddu Nicoletta , Cutrupi Santina , Catapano Filomena , Bonissoni Sara , Fubini Alberto , Malan Daniela , Baj Germano , Granata Riccarda , Broglio Fabio , Papotti Mauro , Surico Nicola , Bussolino Federico , Isgaard Jorgen , Deghenghi Romano , Sinigaglia Fabiola , Prat Maria , Muccioli Giampiero , Ghigo Ezio , Graziani Andrea
Published: December 2002

Ghrelin is an acyl-peptide gastric hormone acting on the pituitary and hypothalamus to stimulate growth hormone (GH) release, adiposity, and appetite. Ghrelin endocrine activities are entirely dependent on its acylation and are mediated by GH secretagogue (GHS) receptor (GHSR)-1a, a G protein–coupled receptor mostly expressed in the pituitary and hypothalamus, previously identified as the receptor for a group of synthetic molecules featuring GH secretagogue (GHS) activity. Des-acyl ghrelin, which is far more abundant than ghrelin, does not bind GHSR-1a, is devoid of any endocrine activity, and its function is currently unknown. Ghrelin, which is expressed in heart, albeit at a much lower level than in the stomach, also exerts a cardio protective effect through an unknown mechanism, independent of GH release. Here we show that both ghrelin and des-acyl ghrelin inhibit apoptosis of primary adult and H9c2 cardiomyocytes and endothelial cells in vitro through activation of extracellular signal–regulated kinase-1/2 and Akt serine kinases. In addition, ghrelin and des-acyl ghrelin recognize common high affinity binding sites on H9c2 cardiomyocytes, which do not express GHSR-1a. Finally, both MK-0677 and hexarelin, a nonpeptidyl and a peptidyl synthetic GHS, respectively, recognize the common ghrelin and des-acyl ghrelin binding sites, inhibit cell death, and activate MAPK and Akt.

These findings provide the first evidence that, independent of its acylation, ghrelin gene product may act as a survival factor directly on the cardiovascular system through binding to a novel, yet to be identified receptor, which is distinct from GHSR-1a.
InterPreTS: protein

Inter

action

Pre

diction through

T

ertiary

S

tructure
Authors: Aloy Patrick , Russell Robert B.
Published: December 2002

Summary: InterPreTS (Interaction Prediction through Tertiary Structure) is a web-based version of our method for predicting protein–protein interactions (Aloy and Russell, 2002, Proc. Natl Acad. Sci. USA, 99, 5896–5901). Given a pair of query sequences, we first search for homologues in a database of interacting domains (DBID) of known three-dimensional complex structures. Pairs of sequences homologous to a known interacting pair are scored for how well they preserve the atomic contacts at the interaction interface. InterPreTS includes a useful interface for visualising molecular details of any predicted interaction.

Availability: http://www.russell.embl.de/interprets

Contact: aloy@embl.de

* To whom correspondence should be addressed.
Mining gene expression databases for association rules
Authors: Creighton Chad , Hanash Samir
Published: December 2002

Motivation: Global gene expression profiling, both at the transcript level and at the protein level, can be a valuable tool in the understanding of genes, biological networks, and cellular states. As larger and larger gene expression data sets become available, data mining techniques can be applied to identify patterns of interest in the data. Association rules, used widely in the area of market basket analysis, can be applied to the analysis of expression data as well. Association rules can reveal biologically relevant associations between different genes or between environmental effects and gene expression. An association rule has the form LHS ⇒ RHS, where LHS and RHS are disjoint sets of items, the RHS set being likely to occur whenever the LHS set occurs. Items in gene expression data can include genes that are highly expressed or repressed, as well as relevant facts describing the cellular environment of the genes (e.g. the diagnosis of a tumor sample from which a profile was obtained).

Results: We demonstrate an algorithm for efficiently mining association rules from gene expression data, using the data set from Hughes et al. (2000, Cell, 102, 109–126) of 300 expression profiles for yeast. Using the algorithm, we find numerous rules in the data. A cursory analysis of some of these rules reveals numerous associations between certain genes, many of which make sense biologically, others suggesting new hypotheses that may warrant further investigation. In a data set derived from the yeast data set, but with the expression values for each transcript randomly shifted with respect to the experiments, no rules were found, indicating that most all of the rules mined from the actual data set are not likely to have occurred by chance.

Availability: An implementation of the algorithm using Microsoft SQL Server with Access 2000 is available at http://dot.ped.med.umich.edu:2000/pub/assoc_rules/assoc_rules.zip. Our results from mining the yeast data set are available at http://dot.ped.med.umich.edu:2000/pub/assoc_rules/yeast_results.zip.

Contact: ccreight@umich.edu

* To whom correspondence should be addressed.
Eyewitness Testimony
Authors: Wells Gary L. , Olson Elizabeth A.
Published: December 2002

The criminal justice system relies heavily on eyewitness identification for investigating and prosecuting crimes. Psychology has built the only scientific literature on eyewitness identification and has warned the justice system of problems with eyewitness identification evidence. Recent DNA exoneration cases have corroborated the warnings of eyewitness identification researchers by showing that mistaken eyewitness identification was the largest single factor contributing to the conviction of these innocent people. We review major developments in the experimental literature concerning the way that various factors relate to the accuracy of eyewitness identification. These factors include characteristics of the witness, characteristics of the witnessed event, characteristics of testimony, lineup content, lineup instructions, and methods of testing. Problems with the literature are noted with respect to both the relative paucity of theory and the scarcity of base-rate information from actual cases.
Numerical study of the effectivity index for an anisotropic error indicator based on Zienkiewicz–Zhu error estimator
Authors: Picasso M.
Published: December 2002

The framework of Formaggia and Perotto (Numerische Mathematik 2001; 89: 641–667) is considered to derive a new anisotropic error indicator for a Laplace problem in the energy norm. The matrix containing the error gradient is approached using a Zienkiewicz–Zhu error estimator. A numerical study of the effectivity index is proposed for anisotropic unstructured meshes, showing that our indicator is sharp. An anisotropic adaptive algorithm is implemented, aiming at controlling the estimated relative error. Copyright © 2003 John Wiley & Sons, Ltd.
A simple solution for lateral buckling of thin‐walled symmetric members
Authors: Wang Quanfeng
Published: December 2002

The lateral buckling of a simply supported symmetric thin‐walled member is investigated. An energy equation for the lateral buckling of thin‐walled member has been presented in which the effects of torsion and assumed warping are taken into account. Using variation method helps to derive the governing differential equation together with appropriated boundary conditions. The lateral buckling loads are obtained by solving the differential equation numerically using Galerkin's method of weighted residuals. The method presented in this paper yields the formula for computing the lateral buckling load that is very simple and straightforward. By the study, a very complex practical eigenvalue problem can be transformed into a very simple one. The results predicted with the analytical method are in good agreement with the ones obtained by experimental, finite integral, non‐linear finite element methods and optimal analysis. The fast convergence of the method makes it possible to write the resulting formulae in a likely closed form which is very simple and very convenient to use. Copyright © 2003 John Wiley & Sons, Ltd.
Neuropathological evidence for ischemia in the white matter of the dorsolateral prefrontal cortex in late‐life depression
Authors: Thomas Alan J. , Perry Robert , Kalaria Rajesh N. , Oakley Arthur , McMeekin William , O'Brien John T.
Published: December 2002

Background

Signal hyperintensities on magnetic resonance imaging in late‐life depression are associated with treatment resistance and poor outcome. These lesions are probably vascular in origin and proposed sites for vascular damage include the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC).

Methods

We therefore examined white matter in these areas for microvascular disease and evidence of ischemia using intercellular adhesion molecule‐1 (ICAM‐1) and vascular adhesion molecule‐1 (VCAM‐1). We obtained postmortem tissue from elderly depressed (n = 20) and control (n = 20) subjects and blindly rated microvascular disease and ICAM‐1 and VCAM‐1 amount using quantitative image analysis in sections of the DLPFC, ACC and occipital cortex (OC; control area).

Results

We found a significant increase in ICAM‐1 in the deep white matter of the DLPFC in the depressed group (p = 0.01) and a trend towards an increase for VCAM‐1 (p = 0.10). In the gyral white matter there was a trend towards significance for both molecules (p = 0.07 and 0.10). No differences were found in the ACC or OC or for microvascular disease in any area.

Conclusions

These findings are consistent with white matter ischemia in the DLPFC and lend support to the ‘vascular depression’ hypothesis. They implicate the DLPFC as an important site in the pathogenesis of late‐life depression and have major implications for the understanding and management of late‐life depression and raise the possibility of novel treatments being introduced in the future. Copyright © 2002 John Wiley & Sons, Ltd.
On morphometric properties of basins, scale effects and hydrological response
Authors: Moussa Roger
Published: December 2002

One of the important problems in hydrology is the quantitative description of river system structure and the identification of relationships between geomorphological properties and hydrological response. Digital elevation models (DEMs) generally are used to delineate the basin's limits and to extract the channel network considering pixels draining an area greater than a threshold area S. In this paper, new catchment shape descriptors, the geometric characteristics of an equivalent ellipse that has the same centre of gravity, the same principal inertia axes, the same area and the same ratio of minimal inertia moment to maximal inertia moment as the basin, are proposed. They are applied in order to compare and classify the structure of seven basins located in southern France. These descriptors were correlated to hydrological properties of the basins' responses such as the lag time and the maximum amplitude of a geomorphological unit hydrograph calculated at the basin outlet by routing an impulse function through the channel network using the diffusive wave model. Then, we analysed the effects of the threshold area S on the topological structure of the channel network and on the evolution of the source catchment's shape. Simple models based on empirical relationships between the threshold S and the morphometric properties were established and new catchment shape indexes, independent of the observation scale S, were defined. This methodology is useful for geomorphologists dealing with the shape of source basins and for hydrologists dealing with the problem of scale effects on basin topology and on relationships between the basin morphometric properties and the hydrological response. Copyright © 2002 John Wiley & Sons, Ltd.
Effective crystal potential from electronegativity viewpoint
Authors: Koleżyński Andrzej , Ptak Wiesław S. , Tkacz‐Śmiech Katarzyna
Published: December 2002

The model based on the assumption of the existence of an interatomic distance dependent, local, effective crystal field applied to the alkaline metals and diamondlike structure crystals (C, Si, Ge, Sn) is presented. We applied the modified model to the calculation of the binding energy and the bulk modulus for the diamondlike crystals. The results of the calculation of the binding energy and the bulk modulus show that well‐chosen parameters allows reproduction of the proper values of the binding energy at the equilibrium position. The values of the effective charges and, based on them, electronegativity values show very good correlation with electronegativity values due to Görlich, Gordy, and Phillips, giving a method for comparison of the different a priori and a posteriori electronegativity scales. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2003
Density functional theory application to double quantum dots: Influence of mismatch on the addition energy spectra of vertical diatomic artificial molecules
Authors: Austing D. G. , Sasaki S. , Muraki K. , Ono K. , Tarucha S. , Barranco M. , Emperador A. , Pi M. , Garcias F.
Published: December 2002

Local spin density functional theory calculations for double quantum dots are compared with experimental data to explain the evolution of addition energy spectra with the interdot distance. Realistic features such as finite thickness and nonidentical constituent dots are included in the calculation. We can thus evaluate the heteronuclear character of the diatomic artificial quantum molecules due to a small unavoidable mismatch introduced in their fabrication. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2003
Import of proteins into mitochondria: A novel pathomechanism for progressive neurodegeneration
Authors: Bauer M. F. , Neupert W.
Published: December 2002

The vast majority of mitochondrial proteins are encoded as precursors by the nuclear genome. A major aspect of mitochondrial biogenesis is therefore the transfer of nuclear‐encoded, cytosplasmically synthesized precursor proteins across and into the mitochondrial membranes. During the past years the use of simple model organisms such as the yeasts S. cerevisiae and N. crassa has helped considerably to identify and unravel the structure and function of a substantial number of components involved in targeting of nuclear‐encoded preproteins to mitochondria. Several pathways and a number of components were characterized that are involved in guiding mitochondrial preproteins to their specific sites of function. In particular, import of nuclear‐ encoded precursor proteins into and across the mitochondrial inner membrane is mediated by two distinct translocases, the TIM23 complex and the TIM22 complex. Both TIM complexes cooperate with the general preprotein translocase of the outer membrane, TOM complex. The TIM complexes differ in the their substrate specificity. While the TIM23 complex mediates import of preproteins with a positively charged matrix targeting signal, the TIM22 complex facilitates the insertion of a class of hydrophobic proteins with internal targeting signals into the inner membrane. Most recently the rapid progress of research has allowed elucidation of a new mitochondrial disease on the molecular level. This rare X‐linked progressive neurodegenerative disorder, named Mohr–Tranebjaerg (MT syndrome), is caused by mutations in the DDP1 gene and includes sensorineural deafness, blindness, mental retardation and a complex movement disorder. The analysis of the novel pathomechanism is based on the homology of the affected DDP1 protein to a family of conserved yeast components acting along the TIM22 pathway. This contribution briefly summarizes the current knowledge of the pathways of protein import and proposes a mechanism to explain how defective import leads to neurodegeneration.
Enzyme replacement and beyond
Authors: Desnick R. J.
Published: December 2002

During the last decade, enzyme replacement therapy for lysosomal storage diseases became a reality with the demonstration of its safety and effectiveness in type 1 Gaucher disease. Currently, enzyme replacement and several other potential therapeutic strategies are being developed for selected lysosomal storage diseases, including Fabry disease due to the deficient activity of α‐galactosidase A (α‐Gal A). The development and clinical evaluation of these new therapies require a stepwise process, each step being rigorously reviewed and approved by national or international regulatory agencies. For lethal disorders that affect small populations, such as many inherited metabolic diseases, this process can be accelerated by ‘orphan drug’ and ‘fast track’ regulations. As an example of the drug development process, the development of recombinant human α‐Gal A (r‐hαGal A) replacement for Fabry disease is presented, including the preclinical studies in the ‘Fabry mouse’ model, and the clinical phase 1/2, phase 3, and phase 3 extension studies, which demonstrate the safety and efficacy of this new therapy.
Amino acids: Analytical aspects
Authors: Mayne P. D. , Roche G. , Deverell D.
Published: December 2002

This workshop was organized as a direct response to concerns and queries raised by laboratory personnel, both in Europe and in the United States, about the imminent withdrawal of Beckman Coulter from the amino acid analysis market. The topics covered included external quality control schemes, standard operating procedures for amino acid analysis and instrumentation, both from a user's perspective and that of the company representatives. There was a discussion panel of all speakers following the presentations.
Changes in clinical practice with the unravelling of diseases: Connective‐tissue disorders
Authors: Spranger J.
Published: December 2002

Unravelling of diseases is achieved in steps by sequentially describing their phenotype, natural course, aetiology and pathogenesis. Through succinct clinical observation, conglomerates of heterogeneous connective‐tissue disorders, such as various forms of disproportionate dwarfism, have been split into well‐defined entities. They have often been confirmed by biochemical and molecular analysis. On the other hand, seemingly disparate disorders have been shown to be pathogenetically related and to be variable expressions of common defects. Examples are the mucopolysaccharidoses and type II collagenopathies. Disease recognition through splitting and lumping has improved prevention and prognostication. It is the basic requirement for future therapeutic attempts on a pathogenetic or molecular level.
Liver repopulation for the treatment of metabolic diseases
Authors: Grompe M.
Published: December 2002

Orthotopic liver transplantation is the treatment of choice for several inborn errors of metabolism. Unfortunately, the supply of donor organs is limiting and therefore many patients cannot benefit from this therapy. In contrast, hepatocyte transplantation could potentially overcome the shortage in donor livers by use of cells from a single donor for multiple recipients. In classic hepatocyte transplantation, however, only 1% of the liver mass or less can be replaced by donor cells. Recently, though, it has been shown in animal models that >90% of host hepatocytes can be replaced by a small number of transplanted donor cells in a process we term ‘therapeutic liver repopulation’. This phenomenon is analogous to repopulation of the haematopoietic system after bone marrow transplantation. Liver repopulation occurs when transplanted cells have a growth advantage in the setting of damage to recipient liver cells. It has been discovered that transplanted cells from extrahepatic sources such as the adult pancreas or bone marrow can also be used for liver repopulation. Because bone marrow donors are widely available, this finding raises the hope of therapeutic application of these cells in the future. Here, the current knowledge regarding therapeutic liver repopulation and the hopeful implications for treatment of liver diseases will be discussed.
Viral Fusion Peptides: A Tool Set to Disrupt and Connect Biological Membranes
Authors: Tamm Lukas K. , Han Xing
Published: December 2002

The structure and function of viral fusion peptides are reviewed. The fusion peptides of influenza virus hemagglutinin and human immunodeficiency virus are used as paradigms. Fusion peptides associated with lipid bilayers are conformationally polymorphic. Current evidence suggests that the fusion-promoting state is the obliquely inserted α-helix. Fusion peptides also have a tendency to self-associate into γ-sheets at membrane surfaces. Although the conformational conversion between α- and γ-states is reversible under controlled conditions, its physiological relevance is not yet known. The energetics of peptide insertion and self-association could be measured recently using more soluble “second generation” fusion peptides. Fusion peptides have been reported to change membrane curvature and the state of hydration of membrane surfaces. The combined results are built into a model for the mechanism by which fusion peptides are proposed to assist in biological membrane fusion.
Polyunsaturated fatty acid deficiency during dietary treatment of very long‐chain acyl‐CoA dehydrogenase deficiency. Rescue with soybean oil
Authors: Ruiz‐Sanz J. I. , Aldamiz‐Echevarria L. , Arrizabalaga J. , Aquino L. , Jimeno P. , Pérez‐Nanclares G. , Sanjurjo P.
Published: December 2002

Nutritional management of very long‐chain acyl‐CoA dehydro‐genase (VLCAD) deficiency is based on the avoidance of fasting and substitution of medium‐chain triglycerides for long‐ and very long‐chain triglycerides. We report two cases of this disease, which developed ω‐6 essential fatty acid deficiency after three and five months from the beginning of nutritional therapy (SHS product: Monogen). This alteration could be especially dangerous in these patients owing to their possible susceptibility to the development of pigmentary retinopathy. The incorporation of linoleic acid as 3–4% of total caloric intake supported as soybean oil ameliorates this deficiency. We wish to remark on this early complication in the nutritional management of VLCAD deficiency and the possibility of rescue by the incorporation of soybean oil into the diet.