bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alternative splicing dysregulation secondary to skeletal muscle regeneration
Authors: Orengo James P. , Ward Amanda J. , Cooper Thomas A. 
Published: October 2010

AbstractObjectiveDysregulation of alternative splicing has become a molecular hallmark of myotonic dystrophy type 1 (DM1), in which neonatal splice variants are expressed in adult skeletal muscle. Splicing dysregulation is induced by RNA containing expanded CUG repeats expressed from the expanded mutant allele by sequestration of muscleblindlike 1 (MBNL1) protein within nuclear RNA foci and increased CUGBP, ELAV‐like family member 1 (CELF1) protein levels. Dysregulated splicing has also been identified in other neuromuscular disorders, suggesting either that diseases with different molecular causes share a common pathogenic mechanism or that dysregulated splicing can also be a common secondary consequence of muscle degeneration and regeneration.MethodsIn this study, we examined regulation of alternative splicing in 4 different mouse models of muscular dystrophy, including DM1, limb‐girdle muscular dystrophy, congenital merosin‐deficient muscular dystrophy, and Duchenne muscular dystrophy, and 2 myotoxin (cardiotoxin and notexin) muscle injury models.ResultsWe show that DM1‐like alternative splicing dysregulation and altered expression of MBNL1 and CELF1 occur in non‐DM1 mouse models of muscular dystrophy and muscle injury, most likely due to recapitulation of neonatal splicing patterns in regenerating fibers. In contrast, CELF1 was elevated in nuclei of mature myofibers of the DM1 model, consistent with a primary effect of pathogenic RNA expression.InterpretationSplicing dysregulation in DM1 is a primary effect of RNA containing expanded CUG repeats. However, we conclude that splicing changes can also be observed secondary to muscle regeneration, and this possibility must be taken into account when evaluating cause‐effect relationships between dysregulated splicing and disease processes. Ann Neurol 2010;
Age‐specific progression of nigrostriatal dysfunction in Parkinson's disease
Authors: de la Fuente‐Fernández Raúl , Schulzer Michael , Kuramoto Lisa , Cragg Jacquelyn , Ramachandiran Nandhagopal , Au Wing L. , Mak Edwin , McKenzie Jess , McCormick Siobhan , Sossi Vesna , Ruth Thomas J. , Lee Chong S. , Calne Donald B. , Stoessl A. Jon 
Published: October 2010

AbstractObjective:To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinson's disease (PD).Methods:PD patients (n = 78) and healthy control subjects (n = 35) underwent longitudinal positron emission tomography assessments using 3 presynaptic dopamine markers: (1) [11C](±)dihydrotetrabenazine (DTBZ), to estimate the density of the vesicular monoamine transporter type 2; (2) [11C]d‐threo‐methylphenidate, to estimate the density of the plasma membrane dopamine transporter; and (3) 6‐[18F]‐fluoro‐L‐dopa, to estimate the activity of the enzyme dopa‐decarboxylase.Results:The study comprised 438 PD scans and 241 control scans (679 scans in total). At symptom onset, the loss of putamen DTBZ binding was substantially greater in younger compared to older PD patients (p = 0.015). Remarkably, however, the rate of progression of DTBZ binding loss was significantly slower in younger patients (p < 0.05). The estimated presymptomatic phase of the disease spanned more than 2 decades in younger patients, compared to 1 decade in older patients.Interpretation:Our results suggest that, compared to older patients, younger PD patients progress more slowly and are able to endure more damage to the dopaminergic system before the first motor symptoms appear. These observations suggest that younger PD patients have more efficient compensatory mechanisms. Ann Neurol 2011;
Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis
Authors: Irani Sarosh R. , Michell Andrew W. , Lang Bethan , Pettingill Philippa , Waters Patrick , Johnson Michael R. , Schott Jonathan M. , Armstrong Richard J. E. , S. Zagami Alessandro , Bleasel Andrew , Somerville Ernest R. , Smith Shelagh M. J. , Vincent Angela 
Published: October 2010

AbstractObjective:To describe a distinctive seizure semiology that closely associates with voltage‐gated potassium channel (VGKC)‐complex/Lgi1 antibodies and commonly precedes the onset of limbic encephalitis (LE).Methods:Twenty‐nine patients were identified by the authors (n = 15) or referring clinicians (n = 14). The temporal progression of clinical features and serum sodium, brain magnetic resonance imaging (MRI), positron emission tomography/single photon emission computed tomography, and VGKC‐complex antibodies was studied.Results:Videos and still images showed a distinctive adult‐onset, frequent, brief dystonic seizure semiology that predominantly affected the arm and ipsilateral face. We have termed these faciobrachial dystonic seizures (FBDS). All patients tested during their illness had antibodies to VGKC complexes; the specific antigenic target was Lgi1 in 89%. Whereas 3 patients never developed LE, 20 of the remaining 26 (77%) experienced FBDS prior to the development of the amnesia and confusion that characterize LE. During the prodrome of FBDS alone, patients had normal sodium and brain MRIs, but electroencephalography demonstrated ictal epileptiform activity in 7 patients (24%). Following development of LE, the patients often developed other seizure semiologies, including typical mesial temporal lobe seizures. At this stage, investigations commonly showed hyponatremia and MRI hippocampal high T2 signal; functional brain imaging showed evidence of basal ganglia involvement in 5/8. Antiepileptic drugs (AEDs) were generally ineffective and in 41% were associated with cutaneous reactions that were often severe. By contrast, immunotherapies produced a clear, and often dramatic, reduction in FBDS frequency.Interpretation:Recognition of FBDS should prompt testing for VGKC‐complex/Lgi1 antibodies. AEDs often produce adverse effects; treatment with immunotherapies may prevent the development of LE with its potential for cerebral atrophy and cognitive impairment. ANN NEUROL 2010;
SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk
Authors: Reitz Christiane , Tokuhiro Shinya , Clark Lorraine N. , Conrad Christopher , Vonsattel Jean‐Paul , Hazrati Lili‐Naz , Palotás András , Lantigua Raphael , Medrano Martin , Z. Jiménez ‐Velázquez Ivonne , Vardarajan Badri , Simkin Irene , Haines Jonathan L. , Pericak ‐Vance Margaret A. , Farrer Lindsay A. , Lee Joseph H. , Rogaeva Ekaterina , George‐ Hyslop Peter St. , Mayeux Richard 
Published: October 2010

AbstractObjective:Sorting mechanisms that cause the amyloid precursor protein (APP) and the β‐secretases and γ‐secretases to colocalize in the same compartment play an important role in the regulation of Aβ production in Alzheimer's disease (AD). We and others have reported that genetic variants in the Sortilin‐related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that underexpression of SORL1 leads to overproduction of Aβ. Here we explored the role of one of its homologs, the sortilin‐related VPS10 domain containing receptor 1 (SORCS1), in AD.Methods:We analyzed the genetic associations between AD and 16 SORCS1–single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real‐time polymerase chain reaction (RT‐PCR) sets, explored the effects of significant SORCS1‐SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aβ generation.Results:Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p
< 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced γ‐secretase activity and Aβ levels, the suppression of SorCS1 increased γ‐secretase processing of APP and the levels of Aβ.Interpretations:These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD. Ann Neurol 2011;69:47–64.
Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression
Authors: Shi Min , Bradner Joshua , Hancock Aneeka M. , Chung Kathryn A. , Quinn Joseph F. , Peskind Elaine R. , Galasko Douglas , Jankovic Joseph , Zabetian Cyrus P. , Kim Hojoong M. , Leverenz James B. , Montine Thomas J. , Ginghina Carmen , Kang Un Jung , Cain Kevin C. , Wang Yu , Aasly Jan , Goldstein David , Zhang Jing 
Published: October 2010

AbstractObjective:There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of Parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ‐1 and/or α‐synuclein in the cerebrospinal fluid (CSF) is a potential index for Parkinson disease diagnosis, but not for PD severity.Methods:Using highly sensitive and quantitative Luminex assays, we measured total tau, phosphorylated tau, amyloid beta peptide 1–42 (Aβ1–42), Flt3 ligand, and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. The utility of these 5 markers was evaluated for disease diagnosis and severity/progression correlation alone, as well as in combination with DJ‐1 and α‐synuclein. The major results were further validated in an independent cohort of cross‐sectional PD patients as well as in PD cases with CSF samples collected longitudinally.Results:The results demonstrated that combinations of these biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease (AD) and multiple system atrophy. Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from multiple system atrophy, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). In addition, we identified CSF fractalkine/Aβ1–42 that positively correlated with PD severity in cross‐sectional samples as well as with PD progression in longitudinal samples.Interpretation:We have demonstrated that this panel of 7 CSF proteins could aid in Parkinson disease diagnosis, differential diagnosis, and correlation with disease severity and progression. ANN NEUROL 2010
Autoantibodies to low‐density lipoprotein receptor–related protein 4 in myasthenia gravis
Authors: Higuchi Osamu , Hamuro Johko , Motomura Masakatsu , Yamanashi Yuji 
Published: October 2010

AbstractMyasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction, where acetylcholine receptor (AChR), muscle‐specific kinase (MuSK), and low‐density lipoprotein (LDL) receptor‐related protein 4 (Lrp4) are essential. About 80% and 0% to 10% of patients with generalized MG have autoantibodies to AChR and MuSK, respectively, but pathogenic factors are elusive in others. Here we show that a proportion of AChR antibody‐negative patients have autoantibodies to Lrp4. These antibodies inhibit binding of Lrp4 to its ligand and predominantly belong to the immunoglobulin G1 (IgG1) subclass, a complement activator. These findings together indicate the involvement of Lrp4 antibodies in the pathogenesis of AChR antibody‐negative MG. Ann Neurol 2011
Increased brain atrophy rates in cognitively normal older adults with low cerebrospinal fluid Aβ1‐42
Authors: Schott Jonathan M. , Bartlett Jonathan W. , Fox Nick C. , Barnes Josephine ,   for the Alzheimer's Disease Neuroimaging Initiative Investigators
Published: October 2010

AbstractObjectiveTo identify cognitively normal individuals at risk of Alzheimer disease (AD) based on cerebrospinal fluid (CSF) Aβ1‐42, and to determine rates of cerebral atrophy.MethodsControl subjects from the Alzheimer's Disease Neuroimaging Initiative with CSF and serial magnetic resonance imaging (MRI) were dichotomized on CSF Aβ1‐42 (normal control [NC]‐high >192pg/ml; NC‐low ≤192pg/ml). Baseline and 1‐year MRIs were registered, and brain, hippocampal, and ventricular volumes and annualized volume changes were calculated. Baseline characteristics, CSF profiles, neuropsychology, brain volumes and atrophy rates, and APOE, PICALM, CLU, and TOMM40 genotypes were compared. Sample sizes to power presymptomatic clinical trials based on rate of atrophy were calculated.ResultsForty of 105 (38%) were classified as NC‐low, and 65 (62%) as NC‐high. There were no differences in age (76.3 ± 5.1 vs 74.9 ± 5.1 years), gender, brain volumes, and all but 1 cognitive score (Trails B; p = 0.015). The NC‐low group had higher tau (p = 0.005) and p‐tau (p < 0.001), and was more likely to be APOE4 positive (48% vs 11%, p < 0.001). The NC‐low group had significantly higher whole brain loss (9.3 vs 4.4ml/yr, p < 0.001), ventricular expansion (2.04 vs 0.95ml/yr, p = 0.002), and hippocampal atrophy rate (0.07 vs 0.03ml/yr, p = 0.029). Baseline Aβ1‐42 level was strongly correlated with rate of brain atrophy only in the NC‐low group (p < 0.001). Using 141 (95% confidence interval, 86–287) patients per arm provides 80% power in a 1‐year treatment trial to show 25% slowing of brain atrophy in the NC‐low group.InterpretationA significant percentage of healthy older adults have CSF profiles consistent with AD and increased rates of brain atrophy, suggesting that they may be in the earliest stages of neurodegeneration. Brain atrophy may be a feasible outcome measure for AD prevention studies. Ann Neurol 2010.
Glut1/SLC2A1 is crucial for the development of the blood‐brain barrier in vivo
Authors: Zheng Ping‐Pin , Romme Edwin , Spek Peter J. van der , Dirven Clemens M.F. , Willemsen Rob , Kros Johan M. 
Published: October 2010

AbstractObjectiveThe overall permeability of the blood‐brain barrier (BBB) is regulated by specialized cerebral endothelial cells and their junctional complexes, consisting of adherens junctions (AJs) and tight junctions (TJs). Among the members of the glucose transporters (Glut), Glut1 is a unique molecule expressed in the cerebral endothelial cells. Glut1 and the junctional proteins are concomitantly downregulated in situations in which breakdown of the BBB has taken place. We hypothesized that the expression of Glut1 may play a significant role in the development of the cerebral microvasculature with BBB properties. To date, there is no information on the role of Glut1 during the development of BBB. In the present study, the in vivo effects of Glut1 knockdown on the cerebral vascular development were investigated.MethodsZebrafish was used as a model organism. We confirmed that the structure of the zebrafish homologue of Glut1 is highly similar to the human Glut1 and that the function of the Glut1‐mediated cerebral uptake of glucose is evolutionally conserved.ResultsIn the Glut1 knockdown model, we observed loss of the cerebral endothelial cells, with concomitant downregulation of the junctional proteins important for intactness of the AJs/TJs and impaired cerebral circulation. The resulting leaky BBB caused vasogenic brain edema.InterpretationThe data suggest a crucial role of Glut1 in the development of the cerebral endothelial cells with BBB properties in vivo. The findings suggest that modulation of Glut1 expression and function may open new directions of research for therapeutic strategies to prevent vasogenic brain edema. Ann Neurol 2010;
Independent and joint effects of the MAPT and SNCA genes in Parkinson disease
Authors: Elbaz Alexis , Ross Owen A. , Ioannidis John P. A. , Soto‐Ortolaza Alexandra I. , Moisan Frédéric , Aasly Jan , Annesi Grazia , Bozi Maria , Brighina Laura , Chartier‐Harlin Marie‐Christine , Destée Alain , Ferrarese Carlo , Ferraris Alessandro , Gibson J. Mark , Gispert Suzana , Hadjigeorgiou Georgios M. , Jasinska‐Myga Barbara , Klein Christine , Krüger Rejko , Lambert Jean‐Charles , Lohmann Katja , van de Loo Simone , Loriot Marie‐Anne , Lynch Timothy , Mellick George D. , Mutez Eugénie , Nilsson Christer , Opala Grzegorz , Puschmann Andreas , Quattrone Aldo , Sharma Manu , Silburn Peter A. , Stefanis Leonidas , Uitti Ryan J. , Valente Enza Maria , Vilariño‐Güell Carles , Wirdefeldt Karin , Wszolek Zbigniew K. , Xiromerisiou Georgia , Maraganore Demetrius M. , Farrer Matthew J. ,   on behalf of the Genetic Epidemiology of Parkinson's Disease (GEO‐PD) consortium
Published: October 2010

AbstractObjective:We studied the independent and joint effects of the genes encoding alpha‐synuclein (SNCA) and microtubule‐associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta‐analysis of individual data from case–control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO‐PD) consortium.Methods:Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed‐ and random‐effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case–control and case‐only approach.Results:Fifteen GEO‐PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1‐haplotype–defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3′ end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale.Interpretation:This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects. ANN NEUROL 2011
Oxetanes as Versatile Elements in Drug Discovery and Synthesis
Authors: Burkhard Johannes A. , Wuitschik Georg , Rogers‐Evans Mark , Müller Klaus , Carreira Erick M. 
Published: October 2010

AbstractSizable resources, both financial and human, are invested each year in the development of new pharmaceutical agents. However, despite improved techniques, the new compounds often encounter difficulties in satisfying and overcoming the numerous physicochemical and many pharmacological constraints and hurdles. Oxetanes have been shown to improve key properties when grafted onto molecular scaffolds. Of particular interest are oxetanes that are substituted only in the 3‐position, since such units remain achiral and their introduction into a molecular scaffold does not create a new stereocenter. This Minireview gives an overview of the recent advances made in the preparation and use of 3‐substituted oxetanes. It also includes a discussion of the site‐dependent modifications of various physicochemical and biochemical properties that result from the incorporation of the oxetane unit in molecular architectures.
A Bond by Any Other Name
Authors: Desiraju Gautam R. 
Published: October 2010

AbstractA hydrogen bond is an interaction wherein a hydrogen atom is attracted to two atoms, rather than just one, and acts like a bridge between them. The strength of this attraction increases with the increasing electronegativity of either of the atoms, and in the classical view, all hydrogen bonds are highly electrostatic and sometimes even partly covalent. Gradually, the concept of a hydrogen bond has become more relaxed to include weaker and more dispersive interactions, provided some electrostatic character remains. A great variety of very strong, strong, moderately strong, weak, and very weak hydrogen bonds are observed in practice. Weak hydrogen bonds are now invoked in several matters in structural chemistry and biology. While strong hydrogen bonds are easily covered by all existing definitions of the phenomenon, the weaker ones may pose a challenge with regard to nomenclature and definitions. Recently, a recommendation has been made to the International Union of Pure and Applied Chemistry (IUPAC) suggesting an updated definition of the term hydrogen bond. This definition will be discussed in greater detail.
A new heterogeneous chiral (salen)manganese(III) system for enantioselective epoxidation of non‐functionalized olefins
Authors: Wei Saili , Tang Yuhai , Xu Xiaoqian , Xu Guojin , Yu Yong , Sun Yang , Zheng Yuansuo 
Published: October 2010

AbstractThis communication describes the design and application of a novel catalytic epoxidation system derived from the initial immobilization of a homogeneous sulfonato (salen)Mn(III) complex on two solid carriers (silica gel and siliceous earth) and subsequent dispersion of the supported manganese complexes into ionic liquid 1‐butyl‐3‐methylimidazolium hexafluorophosphate (BMImPF6) and 1‐butyl‐3‐methylimidazolium tetrafluoroborate (BMImBF4) for recycling. The performance of chiral (salen)Mn(III) system in enantioselective epoxidation of olefins was investigated systematically. Even higher enantioselectivity than that of the homogeneous counterpart was obtained with similar catalytic activity. In particular, the best catalytic result is that the combination of the silica gel‐supported (salen)Mn(III) catalyst and BMImPF6 affords 97–100% ee for epoxidation of α‐methylstyrene, and high ee values were retained even after three cycles. Copyright © 2010 John Wiley & Sons, Ltd.
Ontogenetic Variation in the Bony Labyrinth of Monodelphis domestica (Mammalia: Marsupialia) Following Ossification of the Inner Ear Cavities
Authors: Ekdale Eric G. 
Published: October 2010

AbstractOntogeny, or the development of an individual from conception to death, is a major source of variation in vertebrate morphology. All anatomical systems are affected by ontogeny, and knowledge of the ontogenetic history of these systems is important to understand when formulating biological interpretations of evolutionary history and physiology. The present study is focused on how variation affects the bony labyrinth across a growth series of an extant mammal after ossification of the inner ear chambers. Digital endocasts of the bony labyrinth were constructed using CT data across an ontogenetic sequence of Monodelphis domestica, an important experimental animal. Various aspects of the labyrinth were measured, including angles between the semicircular canals, number of turns of the cochlea, volumes of inner ear constituents, as well as linear dimensions of semicircular canals. There is a strong correlation between skull length and age, but from 27 days after birth onward, there is no correlation with age among most of the inner ear measurements. Exceptions are the height of the arc of the lateral semicircular canal, the angular deviation of the lateral canal from planarity, the length of the slender portion of the posterior semicircular canal, and the length of the canaliculus cochleae. Adult dimensions of several of the inner ear structures, such as the arcs of the semicircular canals, are achieved before the inner ear is functional, and the non‐ontogenetic variation in the bony labyrinth serves as an important source for behavioral, physiological, and possibly phylogenetic information. Anat Rec, 2010. © 2010 Wiley‐Liss, Inc.