bluuebunny/crossref_metadata_2025 huggingface dataset:
PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation
Authors: Guiducci Cristiana , Ghirelli Cristina , Marloie-Provost Marie-Annick , Matray Tracy , Coffman Robert L. , Liu Yong-Jun , Barrat Franck J. , Soumelis Vassili
Published: January 2008

Plasmacytoid predendritic cells (pDCs) are the main producers of type I interferon (IFN) in response to Toll-like receptor (TLR) stimulation. Phosphatidylinositol-3 kinase (PI3K) has been shown to be activated by TLR triggering in multiple cell types; however, its role in pDC function is not known. We show that PI3K is activated by TLR stimulation in primary human pDCs and demonstrate, using specific inhibitors, that PI3K is required for type I IFN production by pDCs, both at the transcriptional and protein levels. Importantly, PI3K was not involved in other proinflammatory responses of pDCs, including tumor necrosis factor α and interleukin 6 production and DC differentiation. pDCs preferentially expressed the PI3K δ subunit, which was specifically involved in the control of type I IFN production. Although uptake and endosomal trafficking of TLR ligands were not affected in the presence of PI3K inhibitors, there was a dramatic defect in the nuclear translocation of IFN regulatory factor (IRF) 7, whereas nuclear factor κB activation was preserved. Thus, PI3K selectively controls type I IFN production by regulating IRF-7 nuclear translocation in human pDCs and could serve as a novel target to inhibit pathogenic type I IFN in autoimmune diseases.
A solution to the Baer splitting problem
Authors: Angeleri Hügel Lidia , Bazzoni Silvana , Herbera Dolors
Published: January 2008

Let

R
R

be a commutative domain. We prove that an

R
R

-module

B
B

is projective if and only if

E
x
t

R
1

(
B
,
T
)
=
0

\mathrm {Ext}_R^1(B,T)=0

for any torsion module

T
T

. This answers in the affirmative a question raised by Kaplansky in 1962.
Optimal constants in the exceptional case of Sobolev inequalities on Riemannian manifolds
Authors: Faget Zoé
Published: January 2008

Let

(
M
,
g
)

(M,g)

be a Riemannian compact

n
n

-manifold. We know that for any

ε
>
0

\varepsilon >0

, there exists

C
ε

>
0

C_\varepsilon >0

such that for any

u
∈

H
1
n

(
M
)

u\in H_1^n(M)

,
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="integral Underscript upper M Endscripts e Superscript u Baseline normal d normal v Subscript g Baseline less-than-or-equal-to upper C Subscript epsilon Baseline exp left-bracket left-parenthesis mu Subscript n Baseline plus epsilon right-parenthesis integral Underscript upper M Endscripts StartAbsoluteValue nabla u EndAbsoluteValue Superscript n Baseline normal d normal v Subscript g Baseline plus StartFraction 1 Over normal v normal o normal l left-parenthesis upper M right-parenthesis EndFraction integral Underscript upper M Endscripts u normal d normal v Subscript g Baseline right-bracket">

∫
M

e
u

d
v

g

≤

C
ε

exp
⁡
[
(

μ
n

+
ε
)

∫
M

|

∇
u

|

n

d
v

g

+

1

v
o
l

(
M
)

∫
M

u

d
v

g

]

\int _Me^u\mathrm {dv}_g\le C_\varepsilon \exp [(\mu _n+\varepsilon )\int _M|\nabla u|^n\mathrm {dv}_g+\frac {1}{\mathrm {vol}(M)}\int _Mu\mathrm {dv}_g]

,

μ
n

\mu _n

being the smallest constant possible such that the inequality remains true for any

u
∈

H
1
n

(
M
)

u\in H_1^n(M)

. We call

μ
n

\mu _n

the “first best constant”. We prove in this paper that it is possible to choose

ε
=
0

\varepsilon =0

and keep

C
ε

C_\varepsilon

a finite constant. In other words we prove the existence of a “second best constant” in the exceptional case of Sobolev inequalities on compact Riemannian manifolds.
Symmetries of the hypergeometric function \phantom{}_{𝑚}𝐹_{𝑚-1}
Authors: Gleizer Oleg
Published: January 2008

In this paper, we show that the generalized hypergeometric function

m

F

m
−
1

\phantom {}_mF_{m-1}

has a one parameter group of local symmetries, which is a conjugation of a flow of a rational Calogero-Mozer system. We use the symmetry to construct fermionic fields on a complex torus, which have linear-algebraic properties similar to those of the local solutions of the generalized hypergeometric equation. The fields admit a nontrivial action of the quaternions based on the above symmetry. We use the similarity between the linear-algebraic structures to introduce the quaternionic action on the direct sum of the space of solutions of the generalized hypergeometric equation and its dual. As a side product, we construct a “good” basis for the monodromy operators of the generalized hypergeometric equation inspired by the study of multiple flag varieties with finitely many orbits of the diagonal action of the general linear group by Magyar, Weyman, and Zelevinsky. As an example of computational effectiveness of the basis, we give a proof of the existence of the monodromy invariant hermitian form on the space of solutions of the generalized hypergeometric equation (in the case of real local exponents) different from the proofs of Beukers and Heckman and of Haraoka. As another side product, we prove an elliptic generalization of Cauchy identity.
Fractal Hamilton-Jacobi-KPZ equations
Authors: Karch Grzegorz , Woyczyński Wojbor
Published: January 2008

Nonlinear and nonlocal evolution equations of the form

u
t

=

L

u
±

|

∇
u

|

q

u_t=\mathcal {L} u \pm |\nabla u|^q

, where

L

\mathcal {L}

is a pseudodifferential operator representing the infinitesimal generator of a Lévy stochastic process, have been derived as models for growing interfaces in the case when the continuous Brownian diffusion surface transport is augmented by a random hopping mechanism. The goal of this paper is to study properties of solutions to this equation resulting from the interplay between the strengths of the “diffusive” linear and “hyperbolic” nonlinear terms, posed in the whole space

R

N

\mathbb {R}^N

, and supplemented with nonnegative, bounded, and sufficiently regular initial conditions.
When is the commutant of a Bol loop a subloop?
Authors: Kinyon Michael , Phillips J. , Vojtěchovský Petr
Published: January 2008

A left Bol loop is a loop satisfying

x
(
y
(
x
z
)
)
=
(
x
(
y
x
)
)
z

x(y(xz)) = (x(yx))z

. The commutant of a loop is the set of elements which commute with all elements of the loop. In a finite Bol loop of odd order or of order

2
k

2k

,

k
k

odd, the commutant is a subloop. We investigate conditions under which the commutant of a Bol loop is not a subloop. In a finite Bol loop of order relatively prime to

3
3

, the commutant generates an abelian group of order dividing the order of the loop. This generalizes a well-known result for Moufang loops. After describing all extensions of a loop

K
K

such that

K
K

is in the left and middle nuclei of the resulting loop, we show how to construct classes of Bol loops with a non-subloop commutant. In particular, we obtain all Bol loops of order

16
16

with a non-subloop commutant.
Local and global 𝐶-regularity
Authors: Göğüş Ni̇hat
Published: January 2008

A bounded domainDDis calledcc-regular if the plurisubharmonic envelope of every continuous function onD¯\overline Dextends continuously toD¯\overline D. We show using Gauthier’s Fusion Lemma that a domain is locallycc-regular if and only if it iscc-regular.
Finiteness of cousin cohomologies
Authors: Kawasaki Takesi
Published: January 2008

The notion of the Cousin complex of a module was given by Sharp in 1969. It wasn’t known whether its cohomologies are finitely generated until recently. In 2001, Dibaei and Tousi showed that the Cousin cohomologies of a finitely generated

A
A

-module 

M
M

are finitely generated if the base ring 

A
A

is local, has a dualizing complex,

M
M

satisfies Serre’s

(

S
2

)

(S_2)

-condition and is equidimensional. In the present article, the author improves their result. He shows that the Cousin cohomologies of 

M
M

are finitely generated if

A
A

is universally catenary, all the formal fibers of all the localizations of 

A
A

are Cohen-Macaulay, the Cohen-Macaulay locus of each finitely generated

A
A

-algebra is open and all the localizations of 

M
M

are equidimensional. As a consequence of this, he gives a necessary and sufficient condition for a Noetherian ring to have an arithmetic Macaulayfication.
A model category structure for equivariant algebraic models
Authors: Scull Laura
Published: January 2008

In the equivariant category of spaces with an action of a finite group, algebraic ‘minimal models’ exist which describe the rational homotopy for

G
G

-spaces which are 1-connected and of finite type. These models are diagrams of commutative differential graded algebras. In this paper we prove that a model category structure exists on this diagram category in such a way that the equivariant minimal models are cofibrant objects. We show that with this model structure, there is a Quillen equivalence between the equivariant category of rational

G
G

-spaces satisfying the above conditions and the algebraic category of the models.
Classification of abelian hereditary directed categories satisfying Serre duality
Authors: van Roosmalen Adam-Christiaan
Published: January 2008

In an ongoing project to classify all hereditary abelian categories, we provide a classification of

Ext
\operatorname {Ext}

-finite directed hereditary abelian categories satisfying Serre duality up to derived equivalence. In order to prove the classification, we will study the shapes of Auslander-Reiten components extensively and use appropriate generalizations of tilting objects and coordinates, namely partial tilting sets and probing of objects by quasi-simples.
Higher order PDE’s and iterated processes
Authors: Nane Erkan
Published: January 2008

We introduce a class of stochastic processes based on symmetric

α
\alpha

-stable processes, for

α
∈
(
0
,
2
]

\alpha \in (0,2]

. These are obtained by taking Markov processes and replacing the time parameter with the modulus of a symmetric

α
\alpha

-stable process. We call them

α
\alpha

-time processes. They generalize Brownian time processes studied in Allouba and Zheng (2001), Allouba (2002), (2003), and they introduce new interesting examples. We establish the connection of

α
\alpha

-time processes to some higher order PDE’s for

α
\alpha

rational. We also obtain the PDE connection of subordinate killed Brownian motion in bounded domains of regular boundary.
GenomeVx: simple web-based creation of editable circular chromosome maps
Authors: Conant Gavin C. , Wolfe Kenneth H.
Published: January 2008

We describe GenomeVx, a web-based tool for making editable, publication-quality, maps of mitochondrial and chloroplast genomes and of large plasmids. These maps show the location of genes and chromosomal features as well as a position scale. The program takes as input either raw feature positions or GenBank records. In the latter case, features are automatically extracted and colored, an example of which is given. Output is in the Adobe Portable Document Format (PDF) and can be edited by programs such as Adobe Illustrator.

Availability: GenomeVx is available at http://wolfe.gen.tcd.ie/GenomeVx

Contact:  conantg@tcd.ie
Estimating large-scale signaling networks through nested effect models with intervention effects from microarray data
Authors: Fröhlich Holger , Fellmann Mark , Sültmann Holger , Poustka Annemarie , Beissbarth Tim
Published: January 2008

Motivation: Targeted interventions using RNA interference in combination with the measurement of secondary effects with DNA microarrays can be used to computationally reverse engineer features of upstream non-transcriptional signaling cascades based on the nested structure of effects.

Results: We extend previous work by Markowetz et al., who proposed a statistical framework to score different network hypotheses. Our extensions go in several directions: we show how prior assumptions on the network structure can be incorporated into the scoring scheme by defining appropriate prior distributions on the network structure as well as on hyperparameters. An approach called module networks is introduced to scale up the original approach, which is limited to around 5 genes, to infer large-scale networks of more than 30 genes. Instead of the data discretization step needed in the original framework, we propose the usage of a beta-uniform mixture distribution on the P-value profile, resulting from differential gene expression calculation, to quantify effects. Extensive simulations on artificial data and application of our module network approach to infer the signaling network between 13 genes in the ER-α pathway in human MCF-7 breast cancer cells show that our approach gives sensible results. Using a bootstrapping and a jackknife approach, this reconstruction is found to be statistically stable.

Availability: The proposed method is available within the Bioconductor R-package nem.

Contact:  h.froehlich@dkfz-heidelberg.de
Jane: suggesting journals, finding experts
Authors: Schuemie Martijn J. , Kors Jan A.
Published: January 2008

Summary: With an exponentially growing number of articles being published every year, scientists can use some help in determining which journal is most appropriate for publishing their results, and which other scientists can be called upon to review their work.

Jane (Journal/Author Name Estimator) is a freely available web-based application that, on the basis of a sample text (e.g. the title and abstract of a manuscript), can suggest journals and experts who have published similar articles.

Availability:  http://biosemantics.org/jane

Contact:  m.schuemie@erasmusmc.nl
Compressed indexing and local alignment of DNA
Authors: Lam T. W. , Sung W. K. , Tam S. L. , Wong C. K. , Yiu S. M.
Published: January 2008

Motivation: Recent experimental studies on compressed indexes (BWT, CSA, FM-index) have confirmed their practicality for indexing very long strings such as the human genome in the main memory. For example, a BWT index for the human genome (with about 3 billion characters) occupies just around 1 G bytes. However, these indexes are designed for exact pattern matching, which is too stringent for biological applications. The demand is often on finding local alignments (pairs of similar substrings with gaps allowed). Without indexing, one can use dynamic programming to find all the local alignments between a text T and a pattern P in O(|T||P|) time, but this would be too slow when the text is of genome scale (e.g. aligning a gene with the human genome would take tens to hundreds of hours). In practice, biologists use heuristic-based software such as BLAST, which is very efficient but does not guarantee to find all local alignments.

Results: In this article, we show how to build a software called BWT-SW that exploits a BWT index of a text T to speed up the dynamic programming for finding all local alignments. Experiments reveal that BWT-SW is very efficient (e.g. aligning a pattern of length 3 000 with the human genome takes less than a minute). We have also analyzed BWT-SW mathematically for a simpler similarity model (with gaps disallowed), and we show that the expected running time is O(|T|0.628|P|) for random strings. As far as we know, BWT-SW is the first practical tool that can find all local alignments. Yet BWT-SW is not meant to be a replacement of BLAST, as BLAST is still several times faster than BWT-SW for long patterns and BLAST is indeed accurate enough in most cases (we have used BWT-SW to check against the accuracy of BLAST and found that only rarely BLAST would miss some significant alignments).

Availability:  www.cs.hku.hk/~ckwong3/bwtsw

Contact:  twlam@cs.hku.hk
Antimicrobial, Antioxidant and Cytotoxic Activities and Phytochemical Screening of Some Yemeni Medicinal Plants
Authors: Mothana Ramzi A. A. , Abdo Salah A. A. , Hasson Sidgi , Althawab Faisal M. N. , Alaghbari Sama A. Z. , Lindequist Ulrike
Published: January 2008

The traditional medicine still plays an important role in the primary health care in Yemen. The current study represents the investigation of 16 selected plants, which were collected from different localities of Yemen. The plants were dried and extracted with two different solvents (methanol and hot water) to yield 34 crude extracts. The obtained extracts were tested for their antimicrobial activity against three Gram‐positive bacteria, two Gram‐negative bacteria, one yeast species and three multiresistant Staphylococcus strains using agar diffusion method, for their antioxidant activity using scavenging activity of DPPH radical method and for their cytotoxic activity using the neutral red uptake assay. In addition, a phytochemical screening of the methanolic extracts was done. Antibacterial activity was shown only against Gram‐positive bacteria, among them multiresistant bacteria. The highest antimicrobial activity was exhibited by the methanolic extracts of Acalypha fruticosa, Centaurea pseudosinaica, Dodonaea viscosa, Jatropha variegata, Lippia citriodora, Plectranthus hadiensis, Tragia pungens and Verbascum bottae. Six methanolic extracts especially those of A. fruticosa, Actiniopteris semiflabellata, D. viscosa, P. hadiensis, T. pungens and V. bottae showed high free radical scavenging activity. Moreover, remarkable cytotoxic activity against FL‐cells was found for the methanolic extracts of A. fruticosa, Iris albicans, L. citriodora and T. pungens. The phytochemical screening demonstrated the presence of different types of compounds like flavonoids, terpenoids and others, which could be responsible for the obtained activities.
Cytogenetics and Molecular Genetics of Malignant Gliomas and Medulloblastoma
Authors: Bigner Sandra H. , Vogelstein Bert
Published: January 2008

Malignant gliomas and medulloblastomas which are the most common primary malignant brain tumours of adults and children, respectively, resemble other neurogenic tumours as they frequently contain gene amplification and show non‐random loss of specific chromosomal regions. In gliomas the gene which is most often amplified, is the epidermal growth factor receptor gene. In many cases the gene is rearranged as well, producing abnormally small epidermal growth factor receptor proteins. More than 80% of tumours have lost chromosome 10 and losses of 9p13, 17p and 22 occur in subgroups of cases. 17p loss is associated with point mutations of the p53 gene, but the relevant genes in the other chromosomal regions remain to be identified. For medulloblastoma the most frequent chromosomal abnormality is i (17q). Whether or not p53 gene mutations are the targets of 17p losses in these tumours remains to be determined. Approximately 5% of medulloblastoma biopsies contain gene amplification, although the incidence in medulloblastoma cell lines is more than 80%. c‐myc is the gene which is most frequently amplified in this tumour type. The relationship of these various molecular genetic abnormalities to the biology of the tumours and the course of the patients remains largely unexplored.
Structural and Functional Aspects of the Interaction of Inflammatory Cells with the Blood‐Brain Barrier in Experimental Brain Inflammation
Authors: Wisniewski Henryk M. , Lossinsky Albert S.
Published: January 2008

Interaction between various subclasses of inflammatory cells (ICs) and endothelial cells (ECs) lining selective blood vessels of the mammalian blood‐brain barrier (BBB) is an initial, important event during inflammatory conditions of the central nervous system (CNS). In this review, we will present a brief ultracytochemical and immunocytochemical assessment of our perspective on this intimate cellular interaction which has been described recently in conditions that involve immunological alterations of the BBB. We will discuss some morphological aspects of what is currently known about acute and chronic inflammatory BBB disorders that are involved in inflammatory processes. We will focus, in particular, on experimental allergic encephalomyelitis (EAE), an animal model for human multiple sclerosis (MS). Many of the past and more recent concepts found in the literature concerning IC attachment and diapedesis, as well as our own experimental efforts over more than two decades will be presented.
Immunopathogenesis of HIV Encephalitis
Authors: Achim Cristian L. , Schrier Rachel D. , Wiley Clayton A.
Published: January 2008

HIV infection leads to severe immunosuppression and in a sub‐population of patients, encephalitis. Whether systemic immunosuppression is required for CNS infection is still unclear. However, latent infection of monocytes/macrophages is an important mechanism by which HIV escapes immune surveillance and enters the CNS. Unlike other viral encephalitides, HIV predominantly infects macrophages/microglia and not neurons and glia. These cells produce retroviral proteins and cytokines which may be neurotoxic. Despite significant MHC expression within the CNS, there is a limited infiltration of immune cells, possibly due to a defect in systemic immunity. Anti‐retroviral therapy by decreasing viral replication and reversing immunosuppression, may arrest nervous system damage.
Neurotropism of Human Immunodeficiency Virus
Authors: Chiodi Francesca , Fenyö Eva Maria
Published: January 2008

Three major characteristics of human immunodeficiency virus (HIV) infection define HIV as neurotropic. 1) Clinically, distinct neurological syndromes are associated with HIV infection and 2) presence of the virus as well as 3) pathological changes can be demonstrated in the central nervous system. Spread of HIV to the brain seems to be the general rule. Virus expression appears to be restricted during the asymptomatic period but increases with severity of HIV infection. Whether this reflects the emergence of virus variants with increased replica‐tive capacity in brain cells has yet to be elucidated.
Defects of Mitochondrial DNA
Authors: Zeviani Massimo , Antozzi Carlo
Published: January 2008

In the past few years several syndromes have been associated with lesions of the human mitochondrial DNA. MtDNA is a small, circular extra‐nuclear chromosome encoding essential components of the respiratory chain. MtDNA‐related syndromes can be divided into two groups: mitochondrial encephalomyopathies, characterized by the presence of ragged‐red fibres (RRF) as the morphological hallmark, or “pure” encephalopathies with no gross morphological abnormalities in muscle. The first group includes myoclonic epilepsy with ragged‐red fibres (MERRF), mitochondrial encephalomyopathy with lactic acidosis and stroke‐like episodes (MELAS), Kearns‐Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO) and a new entity, maternally inherited myopathy and cardiomyopathy. The second group includes Leber's Hereditary Optic Neuroretinopathy (LHON) and the newly described ataxia‐retinitis pigmentosa‐dementia complex. Three kinds of molecular lesions have been identified: point mutations of protein encoding mtDNA‐genes (similar to yeast mit‐ mutations); point mutations of mtDNA‐tRNA genes (similar to yeast syn‐ mutations); and large‐scale rearrangements of mtDNA (similar to yeast ρ‐ mutations). In general, “mit‐” mutations are responsible for non‐RRF encephalopathies, while “syn‐” and “ρ‐” mutations are associated with mitochondrial encephalomyopathies with RRF. Furthermore, point mutations [mit‐ and syn‐) are usually maternally‐ inherited, while large‐scale mtDNA rearrangements are either sporadic or inherited as mendelian traits. In most cases, the molecular detection of the known defects of mtDNA can be carried out by non‐invasive techniques, thus making it an easy and relatively inexpensive procedure in the differential diagnosis of the mitochondrial disorders, a rapidly expanding area of clinical neurology.
Dominant and Recessive Molecular Changes in Neuroblastomas
Authors: Aguzzi Adriano , Ellmeier Wilfried , Weith Andreas
Published: January 2008

Of all human tumors, neuroblastomas bear the most prominent genetic changes. Amplifications and deletions of chromosomal DNA can be identified by light microscopy on chromosomal spreads of neuroblastoma cells with remarkable frequency and consistency. Consequently, extensive studies have been undertaken to elucidate the molecular basis of these cytogenetic changes. A rich body of information has accumulated on the role played by dominant oncogenes and recessive tumor suppressor genes in the pathogenesis of this disease. Most notably, it was found that amplification of N‐mvc is responsible for the presence of double minutes and homogeneously staining regions in neuroblastoma chromosomes. It has also been discovered that N‐myc amplification is a prognostic sign of malignancy. More recently, recessive genetic alterations in neuroblastoma, such as deletion of putative tumor‐suppressing genes have received increasing attention, and considerable efforts are being made to identify such genetic elements. Finally, the susceptibility of neuroblastoma cells to differentiating stimuli has made them a popular in vitro system for neurobiological and pharmacological research. The need for suitable in vivo systems has spurred the development of several animal models employing tumor viruses and transgenic technologies.
Pathways of Fluid Drainage from the Brain ‐ Morphological Aspects and Immunological Significance in Rat and Man
Authors: Weller Roy O. , Kida Shinya , Zhang En‐Tan
Published: January 2008

There is firm physiological evidence for the lymphatic drainage of interstitial fluid and cerebrospinal fluid from the brains of rats, rabbits and cats. The object of this review, is to describe firstly the morphological aspects of lymphatic drainage pathways from the rat brain and secondly, to explore through scanning and transmission electron microscope techniques, the possibility of similar lymphatic drainage pathways in man.

Interstitial and oedema fluid spreads diffusely through the white matter in the rat and appears to drain into the ventricular cerebrospinal fluid. In grey matter, however, tracers pass along perivascular spaces to the surface of the brain and into the cerebrospinal fluid. Paravascular compartments in the subarachnoid space follow the course of major arterial branches to the circle of Willis and thence along the ethmoidal arteries to the cribriform plate of the ethmoid bone. Particulate tracers, such as Indian ink, enter channels in the arachnoid beneath the olfactory bulbs and connect directly with nasal lymphatics through channels which pass through holes in the cribriform plate. Proteins and other solutes may also drain along other cranial nerves. Thus, there is a bulk flow pathway for interstitial and cerebrospinal fluid from the rat brain into cervical lymphatics.

In man, it is probable that diffuse interstitial drainage of fluid from the white matter occurs in a similar way to that in the rat. Furthermore, the anatomical pathways exist by which bulk drainage of fluid could occur along perivascular spaces from the grey matter into perivascular spaces of the leptomeningeal arteries and thence into the cerebrospinal fluid (CSF). Compartmentalisation of the subarachnoid space may allow directional flow of CSF to occur. Thus, although the vast bulk of CSF in man drains through arachnoid villi and granulations, anatomical pathways exist by which selective flow for lymphatic drainage of brain interstitial fluid and inflammatory cells could occur. Physiological evidence for traffic along such pathways in man, however, is still sparse. It seems probable that any lymphatic drainage of CSF in man is overshadowed by the high volume passage of CSF through the arachnoid granulations and villi.
The Autosomal Dominant Dystonias
Authors: Gasser Thomas , Fahn Stanley , Breakefield Xandra O.
Published: January 2008

Dystonia is a term used to describe a specific set of abnormal movements that can occur as a symptom of a variety of neurologic disorders, but also as a disease entity in its own right. This review focuses on the primary dystonias and delineates the genetic contribution to these disorders. Included is a description of the well recognized forms of primary dystonias which manifest autosomal dominant inheritance, especially the “classic” type of early onset, generalized torsion dystonia, but also other clinically distinct forms such as myoclonic dystonia, paroxysmal dystonia, and DOPA‐responsive dystonia. Also, a summary of the molecular genetic studies pertinent to these disorders and a discussion of the implications of recent genetic research for delineating the wide spectrum of this pheno‐typically and genetically heterogeneous group of diseases are forthcoming.
Subsets of Glioblastoma Multiforme Defined by Molecular Genetic Analysis
Authors: von Deimling Andreas , von Ammon Klaus , Schoenfeld David , Wiestler Otmar D. , Seizinger Bernd R. , Louis David N.
Published: January 2008

Glioblastoma multiforme is a clinically and histologically heterogeneous lesion; however, to date, it has not been possible to subdivide glioblastomas on a clinical, histopathological or biological basis. Previous studies have demonstrated that loss of portions of chromosomes 10 and 17 and amplification of the epidermal growth factor receptor (EGFR) gene are the most frequent genetic alterations in glioblastoma. We therefore examined 74 glioblastomas from 67 patients for loss of heterozygosity on chromosomes 10 and 17, and for amplification of the epidermal growth factor receptor gene, to determine whether glioblastomas can be subtyped on a genetic basis. Using Southern blot analysis we were able to detect different patterns of genomic alterations. Eighteen of 67 informative patients were characterized by a loss of heterozygosity on the short arm of chromosome 17 in the tumor tissue. Forty‐five of 64 informative patients showed a loss of heterozygosity on chromosome 10. Amplification of the epidermal growth factor receptor gene was noted in 25 of 67 patients and was restricted to those glioblastomas that had lost portions of chromosome 10. Epidermal growth factor receptor gene amplification occurred significantly more often in patients without chromosome 17p loss than in patients with chromosome 17p loss (p = 0.01). In addition, those glioblastomas with a loss of chromosome 17p occurred in patients significantly younger than those with glioblastomas characterized by EGFR gene amplification (p = 0.001). These data emphasize the genetic heterogeneity of glioblastoma and suggest the division of glioblastoma into genetic subsets.
The Regulation of Neurofilament Protein Dynamics by Phosphorylation: Clues to Neurofibrillary Pathobiology
Authors: Nixon Ralph A.
Published: January 2008

Neurofilament proteins are continuously modified during their lifetime by a succession of protein kinases and phosphatases. Site‐specific phosphorylation or dephosphorylation within different polypeptide domains of each neurofilament subunit is now believed to regulate such behaviors of neurofilaments as subunit polymerization and exchange, axonal transport, interactions with other cytoskeletal proteins and degradation. Local regulation of phosphorylation events could account for variations in the size, morphology and dynamics of the neurofilament network in different regions of the neuron. The apparent greater plasticity of the neurofilament network in regions like the perikaryon, initial segment and nodes along the axon may provide some insight into the vulnerability of these regions in neurofibrillary disease.
Ubiquitin in Neurodegenerative Diseases
Authors: Lowe James , Mayer R. John , Landon Michael
Published: January 2008

Immunochemical staining to detect ubiquitin has become an essential technique in evaluating neurodegenerative processes. Age related staining is seen in myelin, in nerve processes in lysosome‐related dense bodies, and in corpora amylacea. There is a constant association between filamentous inclusions and the presence of ubiquitin. Intermediate filaments associated with ubiquitin, α B crystallin and enzymes of the ubiquitin pathway are the basis of Lewy bodies and Rosenthal fibres, as well as related bodies outside the nervous system. Neurofibrillary tangles in diverse diseases are associated with ubiquitin as are several other tau containing inclusions in both neurones and glia. Inclusions in motor neurones and non‐motor cortex characterizing amyotrophic lateral sclerosis (ALS) and certain related forms of frontal lobe dementia can only be readily detected by anti‐ubiquitin. Anti‐ubiquitin also identifies both filamentous and lysosomal structures in neuronal processes as well as in some swollen neurones. Involvement of ubiquitin‐containing elements of the lysosomal system appears important in pathogenesis of prion encephalopathies. Despite great advances in understanding cell biology of the ubiquitin pathway there are as yet few insights into the precise role played by ubiquitin in neuronal disease.
The Ubiquitin‐Mediated Proteolytic Pathway
Authors: Ciechanover Aaron
Published: January 2008

Ubiquitin modification of a variety of protein targets within the cell plays important roles in many cellular processes. Among these are regulation of gene expression, regulation of cell cycle and division, involvement in the cellular stress response, modification of cell surface receptors, DNA repair, and biogenesis of mitochondria and ribosomes. The best studied modification occurs in the ubiquitin‐dependent proteolytic pathway. Degradation of a protein by the ubiquitin system involves two discrete steps. Initially, multiple ubiquitin molecules are covalently linked in an ATP‐dependent mode to the protein substrate. The protein moiety of the conjugate is then degraded by a specific protease into free amino acids with the release of free and reutilizable ubiquitin. This process also requires energy. In addition, stable mono‐ubiquitin adducts are also found intracellularly, for example, those involving nucleosomal histories. Despite the considerable progress that has been made in elucidating the mode of action and roles of the ubiquitin system, many problems remain unsolved. For example, very little is known about the cellular substrates of the system and the signals that target them for conjugation and degradation. The scope of this review is to summarize briefly what is currently known on the role of the ubiquitin system in protein turnover, and to discuss in detail the mechanisms involved in selection of substrates for conjugation and in degradation of ubiquitin‐conjugated proteins.
The Role of Synaptic Proteins in the Pathogenesis of Disorders of the Central Nervous System
Authors: Masliah Eliezer , Terry Robert
Published: January 2008

Complex sets of nervous system functions are dependent on proper working of the synaptic apparatus, and these functions are regulated by diverse synaptic proteins that are distributed in various subcellular compartments of the synapse. The most extensively studied synaptic proteins are synaptophysin, the synapsins, growth associated protein 43 (GAP‐43), SV‐2, and p65. Moreover, synaptic terminals contain a great number of other proteins involved in calcium transport, neurotransmission, signaling, growth and plasticity. Probes against various synaptic proteins have recently been used to study synaptic alterations in human disease, as well as in experimental models of neurological disorders. Such probes are useful markers of synaptic function and synaptic population density in the nervous system. For the present, we will review the role of synaptic proteins in the following conditions: Alzheimer's disease (AD) and other disorders including ischemia, disorders where synapse‐associated proteins are abnormally accumulated in the nerve terminals, synaptic proteins altered after denervation, and synaptic proteins as markers in neoplastic disorders. The study of the molecular alterations of the synapses and of plasticity might yield important clues as to the mechanisms of neurodegeneration in AD, and of the patterns of presynaptic and dendritic damage under diverse pathological conditions.
Immune Protection vs. Immunopathology vs. Autoimmunity: A Question of Balance and of Knowledge
Authors: Zinkernagel Rolf M.
Published: January 2008

Immunological mechanisms have been suspected and have been shown to be involved in many acute or chronic, and also in some neurological diseases. However, in most cases it is unclear whether disease is caused by insufficient immunity, delayed immunity against infectious agents or by autoimmunity (i.e., reactivity to a “normal” self). The present summary is a biased view of immunological pathogenic principles that may explain some of the questions henceforth. Two proposals will be illustrated. Firstly, T cell mediated immune protection is mediated by cell destruction, i.e., pathology, therefore both beneficial and harmful effects of T cell responses against foreign, mostly infectious, antigens will be the result of the balance between kinetics of immune response and infectious agents. Secondly, if one knows the causative agent, the immunologically mediated disease is called “immunopathological” whereas if a new or trivial causative agent is not recognized the disease is called “autoimmune”.
The Pathogenesis of Murine Retroviral Infection of the Central Nervous System
Authors: Wiley Clayton A. , Gardner Murray
Published: January 2008

Several decades have lapsed since the original description of retroviral infection of the central nervous system (CNS) appeared. With the recent arrival of the autoimmune deficiency syndrome (AIDS) epidemic and the associated human retroviral encephalitis (1), interest in murine models has been rekindled. In most of the published studies, susceptible mouse strains are infected as neonates with molecularly cloned type‐C retroviruses. In most models, a spongiform encephalopathy follows an early CNS endothelial cell infection. The subsequent pathogenesis of this encephalopathy is unknown. In some models neuronal and glial infection is seen, while in others only non‐neuroglial elements are infected. This variation can be traced to differences in strains of mice and viruses in addition to differences in assays. The different models offer fertile experimental ground to decipher the role of direct versus indirect neuroglial damage. Reconciliation of these various models where the final neuropathology appears so similar, may be the key to understanding their pathogenesis.
Polyomavirus Models of Brain Infection and the Pathogenesis of Multiple Sclerosis
Authors: Stoner Gerald L.
Published: January 2008

Multiple sclerosis (MS) is generally considered to be an autoimmune disorder with myelin as the target and with several unidentified viruses playing ancillary roles, possibly through molecular mimicry. Although this paradigm has led to important progress on potential mechanisms of myelin loss, neither a target antigen in myelin nor a triggering mechanism has yet been identified, leaving the etiology of MS still unknown. Animal models of viral demyelination and studies showing that JC virus (JCV), the polyomavirus which causes progressive multifocal leukoencephalopathy (PML), may be latent in some normal human brains suggest another possibility. A host immune response targeting proteins expressed at low levels from viral DNA latent in the central nervous system (CNS) might underlie a focal demyelinating disease such as MS. A shift from autoimmunity to a latent‐virus model is not a trivial substitution of target antigens. This shift would expand the search for a definitive laboratory test for MS and could lead to improved therapeutic and preventive approaches.
The New WHO Classification of Brain Tumours
Authors: Kleihues Paul , Burger Peter C. , Scheithauer Bernd W.
Published: January 2008

The new edition of the World Health Organization (WHO) book on ‘Histological Typing of Tumours of the Central Nervous System’ reflects the progress in brain tumour classification which has been achieved since publication of the first edition in 1979. Several new tumour entities have been added, including the pleomorphic xanthoastrocytoma, central neurocytoma, the infantile desmoplastic astrocytoma/ganglioglioma, and the dysembryoplastic neuroepithelial tumour. The list of histological variants has also been expanded. In line with recent morphological and molecular data on glioma progression, the glioblastoma is now grouped together with astrocytic tumours. The classification of childhood tumours has been largely retained, the diagnosis primitive neuroectodermal tumour (PNET) only being recommended as a generic term for cerebellar meduiloblastomas and neoplasms that are histologically indistinguishable from medulloblastoma but located in the CNS at sites other than the cerebellum. The WHO grading scheme was revised and adapted to new entities but its use, as before, remains optional.
Pleomorphic Xanthoastrocytoma: The Birth of a Diagnosis and a Concept
Authors: Kepes John J.
Published: January 2008

This review deals with one of the newly adopted entities in the second edition of the histologic typing of CNS tumours by the World Health Organization: pleomorphic xanthoastrocytoma and reviews the clinical features, gross and microscopic characteristics as well as the common and some of the unusual variants of this tumor. The steps and events leading to the recognition of the basic character of this neoplasm and its designation as an independent entity are recollected and a few characteristic MRI scans and photomicrographs of pleomorphic xanthoastrocytomas are provided.
Desmoplastic Infantile Ganglioglioma and Desmoplastic Cerebral Astrocytoma of Infancy
Authors: VandenBerg Scott R.
Published: January 2008

The desmoplastic infantile ganglioglioma and desmoplastic cerebral astrocytoma of infancy are rare neoplasms arising in the cerebral hemispheres within the first two years of life which are defined by a combination of distinctive clinicopathologic features. The tumours are massive, partially cystic and invariably occur in a supratentorial location. Involvement of multiple lobes is common with a predilection for frontoparietal areas. In one series of 22 desmoplastic infantile gangliogliomas, all patients presented between 2 and 24 months of age (mean = 6 months; median = 4 months) with a male to female ratio of 1.4: 1. In the nine reported cases of the desmoplastic cerebral astrocytoma of infancy, all patients presented between 1.5 and 14 months of age (mean = 6.8 months; median = 6 months) with a male to female ratio 0.8: 1. The hallmark feature of both neoplasms is an abundant and often dense desmoplasia, imparting a characteristic firmness to the neoplasms. In the desmoplastic infantile gangliogliomas, astroglial and neuronal tumour cells in addition to variable numbers of more primitive, mitotic cells comprise the neoplastic neuroepithelial populations. In contrast, the neuroepithelial component of the desmoplastic infantile astrocytomas is restricted to neoplastic astrocytes. Despite the large size, cellular pleomorphism and cellular atypia, prognosis following successful surgical resection in both types of tumours is quite favorable. The longest followup data is available for the desmoplastic infantile gangliogliomas. With the median interval of 8.7 years (range 1 to 14.5 years) following surgery for 14 patients in this series, there were no deaths due to tumour or any evidence of tumour recurrence. Likewise for the astrocytomas, with a median followup of 1.5 years (≥5.5 years), there was no evidence of tumour recurrence.
Central Neurocytoma: A Synopsis of Clinical and Histological Features
Authors: Hassoun Jacques , Söylemezoglu Figen , Gambarelli Danielle , Figarella‐Branger Dominique , von Ammon Klaus , Kleihues Paul
Published: January 2008

The central neurocytoma is a supratentorial, often calcified brain tumour affecting young adults and is typically located in the lateral ventricles in the region of the foramen of Monro. Clinically, the tumour causes signs of increased intracranial pressure, visual and mental disturbances and, occasionally, pyramidal or endocrine symptoms. By light microscopy, the tumour is composed of small round cells in a delicate fibrillary matrix. Tumour cells consistently show features of neuronal differentiation by electron microscopy (synapses, dense‐core vesicles, presynaptic clear vesicles, specialized synaptic junctions) and immunoreactivity for synaptophysin and other neuronal marker proteins. The tumour can be totally removed in nearly half of the cases. After incomplete surgical resection neurocytomas may recur but because of their low proliferation potential, radio‐ or chemotherapy are not generally recommended. Postoperative recurrence‐free survival times of up to 19 years have been reported. Neurocytomas constitute nearly one half of supratentorial intraventricular tumours in adults but amount to less than 1% of all tumours of the central nervous system and its coverings.
Searching for Human Epilepsy Genes: A Progress Report
Authors: Leppert Mark , McMahon William M. , Quattlebaum Thomas G. , Bjerre Ingrid , Zonana Jonathan , Shevell Michael I. , Andermann Eva , Rosales Teodoro O. , Ronen Gabriel M. , Connolly Mary , Anderson V. Elving
Published: January 2008

Application of new genetic techniques has brought remarkable discoveries in the study of genetic diseases. The potential benefits from applying such technology to idiopathic epilepsies include improved understanding of cellular mechanisms and potential new methods of prevention and treatment. The complex problems involved in studying the hereditary epilepsies include: defining of specific phenotypes; detecting genetic and non‐genetic heterogeneity; and specifying the appropriate mode of inheritance and penetrance. The gene loci for three primary epilepsies have been localized to specific chromosomal regions, and serve to demonstrate the process used in generalized linkage studies of hereditary epilepsy syndromes. Benign familial neonatal convulsions (BFNC) and Unverricht‐Lundborg progressive myoclonus epilepsy are rare single‐gene disorders that are sufficiently localized to chromosomal regions that positional cloning studies are likely to succeed. Juvenile myoclonic epilepsy (JME), a common hereditary syndrome with an uncertain mode of inheritance, has been reported to be linked to chromosome 6p. JME presents a challenge for generalized linkage methodology that may be overcome by attending to potential problems reviewed here. The candidategene method, combined with studies using animal models, holds promise for understanding these as well as other hereditary epilepsies.
Consequences of Epileptic Activity in vitro
Authors: Thompson Scott M.
Published: January 2008

Hippocampal sclerosis: a cause or consequence of epileptic activity? This question has concerned neurologists and pathologists for over 150 years. This paper reviews data from an in vitro model system regarding the consequences of epileptic activity of known origin. Exposure of organotypic hippocampal slice cultures to convulsants, such as bicuculline or picrotoxin for three days leads to pronounced neuronal degeneration and a reversible loss of dendritic spines. A similar pathology has been described in hippocampal tissue removed from patients suffering from severe, drug refractory epilepsy. The consequences of such pathological changes are not self‐sustaining epileptic activity, as might be expected if such sclerosis caused epilepsy, but rather a selective decrease in synaptic excitation. Inhibitory synaptic transmission and GABAergic interneurons, in contrast, are preserved. At (east two mechanisms contribute to the depression of synaptic excitation: morphological changes in dendritic spines and a decrease in the expression of genes for some glutamatergic receptors. It is hoped that this model will allow the characterization of the mechanisms underlying the pathological consequences of epileptic activity, and lead to useful therapeutic strategies.