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Search Results: 1 - 10 of 156034 matches for " Alan H Beggs "
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Genomic organization and single-nucleotide polymorphism map of desmuslin, a novel intermediate filament protein on chromosome 15q26.3
Yuji Mizuno, Annibale A Puca, Kristine F O'Brien, Alan H Beggs, Louis M Kunkel
BMC Genetics , 2001, DOI: 10.1186/1471-2156-2-8
Abstract: The desmuslin gene was localized to chromosome 15q26.3 by electronic screening of the human DNA sequence database. Primer pairs were designed to amplify the 5 exons of the desmuslin gene in 11 overlapping DNA segments. The desmuslin gene was screened for mutations in 71 patients with various forms of myopathy for which there was no known cause. In this analysis, 10 common and 2 rare amino acid altering single-nucleotide polymorphisms were identified, all of which were seen in a control population of individuals thus making these unlikely causes of the phenotype. Interestingly, one of the single-nucleotide polymorphisms found in a patient resulted in a premature stop codon in the first exon. The nonsense mutation was also detected in the patient's unaffected father and one unaffected control; it was detected in 0.44% (2/454) of unrelated chromosomes and is therefore predicted to have a homozygous frequency of 0.002%.No causative mutations were found in the desmuslin gene. However, the single-nucleotide polymorphisms mapped in this study represent a well-mapped group that can be used for disequilibrium studies of this region of chromosome 15q26.3.Dystrophin and its associated proteins are thought to be involved in the anchoring of the muscle cell membrane to the extracellular matrix [1], and the absence of many of these proteins can lead to the phenotype of muscular dystrophy [2]. The dystrophin-associated protein complex (DAPC) consists of several subgroups of protein complexes, each associated either directly or indirectly with dystrophin. The sarcoglycans are four transmembrane proteins [3] that are organized by a fifth protein called sarcospan [4]. This complex is thought to be involved in signalling at the cell membrane [5]. A second subcomplex, known as the dystroglycan complex [6], interacts directly with dystrophin in the cytoplasm and laminin in the extracellular matrix, thus providing a structural link between the inside and the outside of the cell. A third
Reproducibility of gene expression across generations of Affymetrix microarrays
Ashish Nimgaonkar, Despina Sanoudou, Atul J Butte, Judith N Haslett, Louis M Kunkel, Alan H Beggs, Isaac S Kohane
BMC Bioinformatics , 2003, DOI: 10.1186/1471-2105-4-27
Abstract: Correlation coefficients were computed for gene expression values across chip generations based on different measures of similarity. Comparing the absolute calls assigned to the individual probe sets across the generations found them to be largely unchanged.We show that experimental replicates are highly reproducible, but that reproducibility across generations depends on the degree of similarity of the probe sets and the expression level of the corresponding transcript.Expression microarrays provide a vehicle for exploring the gene expression in a manner that is rapid, sensitive, systematic and comprehensive [1-6]. Thousands of genes can now be studied simultaneously without the need of an a priori candidate gene list. In order to keep up with advances in genome sequencing, the number and composition of representative gene sequences are frequently updated and probe sets representing newly discovered expressed sequences are added on commercial microarrays. Furthermore, existing probe sets are revised because probe sequences once thought to be unique for a single gene are occasionally found to be less specific. This leads to the question of whether results from newer microarray generations are comparable to those of previous generations. The cost, time and irreplaceable nature of some of the samples used for microarray analysis require that a method to compare data from different generations be developed.Although Affymetrix Chips can each measure the expression of over 12,000 genes and ESTs, the true transcript level is confounded by a substantial amount of noise and variability induced by both the large number of observations and the wide range of gene expression values [7]. Microarrays are sensitive to noise from many sources including the manufacturing process and the experimental (RNA isolation, labeling, hybridization, staining, washing and scanning) processes. Even within the same generation of chips and for replicates of single tissue samples, there may be sub
Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy
Michael W Lawlor, Coen A Ottenheijm, Vilma-Lotta Lehtokari, Kiyomi Cho, Katarina Pelin, Carina Wallgren-Pettersson, Henk Granzier, Alan H Beggs
Skeletal Muscle , 2011, DOI: 10.1186/2044-5040-1-23
Abstract: We describe two siblings with severe NM, arthrogryposis and neonatal death caused by two novel NEB mutations: a point mutation in intron 13 and a frameshift mutation in exon 81. Levels of detectable nebulin protein were significantly lower than those in normal control muscle biopsies or those from patients with less severe NM due to deletion of NEB exon 55. Mechanical studies of skinned myofibers revealed marked impairment of force development, with an increase in tension cost.Our findings demonstrate that the mechanical phenotype of severe NM is the consequence of mutations that severely reduce nebulin protein levels and suggest that the level of nebulin expression may correlate with the severity of disease.With an estimated incidence of 1 in 50,000 live births, nemaline myopathy (NM) is the most common of the congenital myopathies, accounting for roughly one-half of the cases of these conditions [1]. Clinically, NM is heterogeneous, producing symptoms ranging from profound perinatal weakness and hypotonia to mild, nonprogressive weakness with onset in adolescence or adulthood. A diagnosis of NM requires symptoms of skeletal muscle weakness and the presence of nemaline rods in muscle fibers, in the absence of findings diagnostic of other unrelated conditions [1]. To date, mutations of seven genes have been implicated in NM, including tropomyosin 3 (TPM3) [2], skeletal α-actin (ACTA1) [3], nebulin (NEB) [4], tropomyosin 2 (TPM2) [5], troponin T (TNNT1) [6], cofilin 2 (CFL2) [7] and KBTBD13 [8]. With the exception of KBTBD13, whose function is unknown, these genes share the unifying feature that they all encode proteins of the sarcomeric thin filament, suggesting that weakness and rod formation in NM is related to improper thin-filament structure and function [9].The skeletal muscle-specific NEB gene is large, with a total of 183 exons spanning 249 kb of genomic sequence and a theoretical full-length transcript of 26 kb, and is predicted to encode an approximately 80
A Splice Site Mutation in Laminin-α2 Results in a Severe Muscular Dystrophy and Growth Abnormalities in Zebrafish
Vandana A. Gupta, Genri Kawahara, Jennifer A. Myers, Aye T. Chen, Thomas E. Hall, M. Chiara Manzini, Peter D. Currie, Yi Zhou, Leonard I. Zon, Louis M. Kunkel, Alan H. Beggs
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043794
Abstract: Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. In patients, muscle weakness is usually present at or shortly after birth and is progressive in nature. Merosin deficient congenital muscular dystrophy (MDC1A) is a form of CMD caused by a defect in the laminin-α2 gene (LAMA2). Laminin-α2 is an extracellular matrix protein that interacts with the dystrophin-dystroglycan (DGC) complex in membranes providing stability to muscle fibers. In an N-ethyl-N-nitrosourea mutagenesis screen to develop zebrafish models of neuromuscular diseases, we identified a mutant fish that exhibits severe muscular dystrophy early in development. Genetic mapping identified a splice site mutation in the lama2 gene. This splice site is highly conserved in humans and this mutation results in mis-splicing of RNA and a loss of protein function. Homozygous lama2 mutant zebrafish, designated lama2cl501/cl501, exhibited reduced motor function and progressive degeneration of skeletal muscles and died at 8–15 days post fertilization. The skeletal muscles exhibited damaged myosepta and detachment of myofibers in the affected fish. Laminin-α2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-α2 deficient mutant fish represents a novel disease model to develop therapies for modulating splicing defects in congenital muscular dystrophies and to restore the muscle function in human patients with CMD.
Automated DNA mutation detection using universal conditions direct sequencing: application to ten muscular dystrophy genes
Richard R Bennett, Hal E Schneider, Elicia Estrella, Stephanie Burgess, Andrew S Cheng, Caitlin Barrett, Va Lip, Poh Lai, Yiping Shen, Bai-Lin Wu, Basil T Darras, Alan H Beggs, Louis M Kunkel
BMC Genetics , 2009, DOI: 10.1186/1471-2156-10-66
Abstract: These factors have severely hampered diagnostic testing services, leaving many families without an answer for the exact cause of a familial genetic disease. A search of GeneTests for sequencing analysis of the entire coding sequence for genes that are known to cause muscular dystrophies returns only a small list of laboratories that perform comprehensive gene panels.The hypothesis for the study was that a complete set of universal assays can be designed to amplify and sequence any gene or family of genes using computer aided design tools. If true, this would allow automation and optimization of the mutation detection process resulting in reduced cost and increased throughput.An automated process has been developed for the detection of deletions, duplications/insertions and point mutations in any gene or family of genes and has been applied to ten genes known to bear mutations that cause muscular dystrophy: DMD; CAV3; CAPN3; FKRP; TRIM32; LMNA; SGCA; SGCB; SGCG; SGCD. Using this process, mutations have been found in five DMD patients and four LGMD patients (one in the FKRP gene, one in the CAV3 gene, and two likely causative heterozygous pairs of variations in the CAPN3 gene of two other patients). Methods and assay sequences are reported in this paper.This automated process allows laboratories to discover DNA variations in a short time and at low cost.This study focused on ten muscular dystrophy genes described in Online Mendelian Inheritance in Man [1], (Table 1); however the resulting process can be applied to any gene or family of genes.There are over 40 primary congenital muscle disorders (Additional file 1) determined now more by the defective genes causing the disorders rather than specific clinical descriptions. Many of these diseases are rare. The incidence, defined as the number of new cases per million live births, (or alternatively as the fraction of live births represented by one new case) is not known for many of the more rare diseases; nevertheless, th
Loss of Catalytically Inactive Lipid Phosphatase Myotubularin-related Protein 12 Impairs Myotubularin Stability and Promotes Centronuclear Myopathy in Zebrafish
Vandana A. Gupta,Karim Hnia,Laura L. Smith,Stacey R. Gundry,Jessica E. McIntire,Junko Shimazu,Jessica R. Bass,Ethan A. Talbot,Leonela Amoasii,Nathaniel E. Goldman,Jocelyn Laporte,Alan H. Beggs
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003583
Abstract: X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by mutations of the myotubularin gene, MTM1. Myotubularin belongs to a large family of conserved lipid phosphatases that include both catalytically active and inactive myotubularin-related proteins (i.e., “MTMRs”). Biochemically, catalytically inactive MTMRs have been shown to form heteroligomers with active members within the myotubularin family through protein-protein interactions. However, the pathophysiological significance of catalytically inactive MTMRs remains unknown in muscle. By in vitro as well as in vivo studies, we have identified that catalytically inactive myotubularin-related protein 12 (MTMR12) binds to myotubularin in skeletal muscle. Knockdown of the mtmr12 gene in zebrafish resulted in skeletal muscle defects and impaired motor function. Analysis of mtmr12 morphant fish showed pathological changes with central nucleation, disorganized Triads, myofiber hypotrophy and whorled membrane structures similar to those seen in X-linked myotubular myopathy. Biochemical studies showed that deficiency of MTMR12 results in reduced levels of myotubularin protein in zebrafish and mammalian C2C12 cells. Loss of myotubularin also resulted in reduction of MTMR12 protein in C2C12 cells, mice and humans. Moreover, XLMTM mutations within the myotubularin interaction domain disrupted binding to MTMR12 in cell culture. Analysis of human XLMTM patient myotubes showed that mutations that disrupt the interaction between myotubularin and MTMR12 proteins result in reduction of both myotubularin and MTMR12. These studies strongly support the concept that interactions between myotubularin and MTMR12 are required for the stability of their functional protein complex in normal skeletal muscles. This work highlights an important physiological function of catalytically inactive phosphatases in the pathophysiology of myotubular myopathy and suggests a novel therapeutic approach through identification of drugs that could stabilize the myotubularin-MTMR12 complex and hence ameliorate this disorder.
Teaching global climate change  [PDF]
Alan H. McGowan
Natural Science (NS) , 2013, DOI: 10.4236/ns.2013.51A018

Although there is strong consensus among scientists that global climate change is real and dangerous, and there is increasing belief of this among the general public, there still remains a significant gap between scientific opinion and that of the public. The academic environmental community, therefore, has a clear opportunity and responsibility to teach the facts of global climate change, particularly to non-environmental majors, those people who are the voters of the future. The article presents several ideas along these lines, and calls for a revitalized effort to teach climate change to undergraduate students.

Extending Transfer Entropy Improves Identification of Effective Connectivity in a Spiking Cortical Network Model
Shinya Ito, Michael E. Hansen, Randy Heiland, Andrew Lumsdaine, Alan M. Litke, John M. Beggs
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027431
Abstract: Transfer entropy (TE) is an information-theoretic measure which has received recent attention in neuroscience for its potential to identify effective connectivity between neurons. Calculating TE for large ensembles of spiking neurons is computationally intensive, and has caused most investigators to probe neural interactions at only a single time delay and at a message length of only a single time bin. This is problematic, as synaptic delays between cortical neurons, for example, range from one to tens of milliseconds. In addition, neurons produce bursts of spikes spanning multiple time bins. To address these issues, here we introduce a free software package that allows TE to be measured at multiple delays and message lengths. To assess performance, we applied these extensions of TE to a spiking cortical network model (Izhikevich, 2006) with known connectivity and a range of synaptic delays. For comparison, we also investigated single-delay TE, at a message length of one bin (D1TE), and cross-correlation (CC) methods. We found that D1TE could identify 36% of true connections when evaluated at a false positive rate of 1%. For extended versions of TE, this dramatically improved to 73% of true connections. In addition, the connections correctly identified by extended versions of TE accounted for 85% of the total synaptic weight in the network. Cross correlation methods generally performed more poorly than extended TE, but were useful when data length was short. A computational performance analysis demonstrated that the algorithm for extended TE, when used on currently available desktop computers, could extract effective connectivity from 1 hr recordings containing 200 neurons in ~5 min. We conclude that extending TE to multiple delays and message lengths improves its ability to assess effective connectivity between spiking neurons. These extensions to TE soon could become practical tools for experimentalists who record hundreds of spiking neurons.
Differential and holomorphic differential operators on noncommutative algebras
Edwin Beggs
Mathematics , 2012,
Abstract: This paper deals with sheaves of differential operators on noncommutative algebras. The sheaves are defined by quotienting a the tensor algebra of vector fields (suitably deformed by a covariant derivative) to ensure zero curvature. As an example we can obtain enveloping algebra like relations for Hopf algebras with differential structures which are not bicovariant. Symbols of differential operators are defined, but not studied. These sheaves are shown to be in the center of as category of bimodules with flat bimodule covariant derivatives. Also holomorphic differential operators are considered, though without the quotient to ensure zero curvature.
Maximum Entropy Approaches to Living Neural Networks
Fang-Chin Yeh,Aonan Tang,Jon P. Hobbs,Pawel Hottowy,Wladyslaw Dabrowski,Alexander Sher,Alan Litke,John M. Beggs
Entropy , 2010, DOI: 10.3390/e12010089
Abstract: Understanding how ensembles of neurons collectively interact will be a key step in developing a mechanistic theory of cognitive processes. Recent progress in multineuron recording and analysis techniques has generated tremendous excitement over the physiology of living neural networks. One of the key developments driving this interest is a new class of models based on the principle of maximum entropy. Maximum entropy models have been reported to account for spatial correlation structure in ensembles of neurons recorded from several different types of data. Importantly, these models require only information about the firing rates of individual neurons and their pairwise correlations. If this approach is generally applicable, it would drastically simplify the problem of understanding how neural networks behave. Given the interest in this method, several groups now have worked to extend maximum entropy models to account for temporal correlations. Here, we review how maximum entropy models have been applied to neuronal ensemble data to account for spatial and temporal correlations. We also discuss criticisms of the maximum entropy approach that argue that it is not generally applicable to larger ensembles of neurons. We conclude that future maximum entropy models will need to address three issues: temporal correlations, higher-order correlations, and larger ensemble sizes. Finally, we provide a brief list of topics for future research.
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