Uniqueness of Bipartite Factors in Prime Factorizations Over the Direct Product of Graphs

While it has been known for some time that connected non-bipartite graphs have unique prime factorizations over the direct product, the same cannot be said of bipartite graphs. This is somewhat vexing, as bipartite graphs do have unique prime factorizations over other graph products (the Cartesian product, for example). However, it is fairly easy to show that a connected bipartite graph has only one prime bipartite factor, which begs the question: is such a prime bipartite factor unique? In other words, although a connected bipartite graph may have multiple prime factorizations over the direct product, do such factorizations contain the same prime bipartite factor? It has previously been shown by Hammack that when the prime bipartite factor is K_2, this is in fact true. The goal of this paper is to prove that this is in fact true for any prime bipartite factor, provided the graph being factored is R-thin. The proof of the main result takes the same initial approach as the proof by Hammack, before moving into new territory in order to prove the final result

Office of Research Survey Instrument

Researchers frequently face the daunting task of locating appropriate funding to support their research. A survey by University of Michigan (U-M) Medical School Office of Research (OoR) found that the majority of respondents expressed frustration with the time and effort it takes to search for new funding opportunities. This is the survey instrument that was used.http://deepblue.lib.umich.edu/bitstream/2027.42/115473/1/Office of Research Survey Instrument.pdfDescription of Office of Research Survey Instrument.pdf : U-M Medical School Office of Research Surve

Homozygous Frameshift Mutation in TMCO1 Causes A Syndrome with Craniofacial Dysmorphism, Skeletal Anomalies, and Mental Retardation

We identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. The typical craniofacial dysmorphism included brachycephaly, highly arched bushy eyebrows, synophrys, long eyelashes, low-set ears, microdontism of primary teeth, and generalized gingival hyperplasia, whereas Sprengel deformity of scapula, fusion of spine, rib abnormities, pectus excavatum, and pes planus represented skeletal anomalies. The genome-wide homozygosity mapping using six affected individuals localized the disease gene to a 3.3-Mb region on chromosome 1q23.3-q24.1. Candidate gene sequencing identified a homozygous frameshift mutation, c.139_140delAG, in the transmembrane and coiled-coil domains 1 (TMCO1) gene, as the pathogenic change in all affected members of the extended pedigree. This mutation is predicted to result in a severely truncated protein (p.Ser47Ter) of only one-fourth the original length. The TMCO1 gene product is a member of DUF841 superfamily of several eukaryotic proteins with unknown function. The gene has highly conserved amino acid sequence and is universally expressed in all human tissues examined. The high degree of conservation and the ubiquitous expression pattern in human adult and fetal tissues suggest a critical role for TMCO1. This report shows a TMCO1 sequence variant being associated with a genetic disorder in human. We propose “TMCO1 defect syndrome” as the name of this condition

Homozygous Frameshift Mutation in TMCO1 Causes A Syndrome with Craniofacial Dysmorphism, Skeletal Anomalies, and Mental Retardation

We identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. The typical craniofacial dysmorphism included brachycephaly, highly arched bushy eyebrows, synophrys, long eyelashes, low-set ears, microdontism of primary teeth, and generalized gingival hyperplasia, whereas Sprengel deformity of scapula, fusion of spine, rib abnormities, pectus excavatum, and pes planus represented skeletal anomalies. The genome-wide homozygosity mapping using six affected individuals localized the disease gene to a 3.3-Mb region on chromosome 1q23.3-q24.1. Candidate gene sequencing identified a homozygous frameshift mutation, c.139_140delAG, in the transmembrane and coiled-coil domains 1 (TMCO1) gene, as the pathogenic change in all affected members of the extended pedigree. This mutation is predicted to result in a severely truncated protein (p.Ser47Ter) of only one-fourth the original length. The TMCO1 gene product is a member of DUF841 superfamily of several eukaryotic proteins with unknown function. The gene has highly conserved amino acid sequence and is universally expressed in all human tissues examined. The high degree of conservation and the ubiquitous expression pattern in human adult and fetal tissues suggest a critical role for TMCO1. This report shows a TMCO1 sequence variant being associated with a genetic disorder in human. We propose “TMCO1 defect syndrome” as the name of this condition

The Chemorepellent, Netrin-1, Appears to Signal Through a Tyrosine Kinase in Tetrahymena thermophila

Netrin-1 is a pleiotropic peptide signaling molecule. Its most well-known role in vertebrate development is neuronal guidance. Depending upon the cell type and signal concentration gradient, netrin-1 may serve either as a chemoattractant, causing formation of axonal growth cones, or as a chemorepellent, causing growth cone collapse within the axon. Netrin-1 can bind to at least two types of receptors, and uses a variety of signaling proteins to convey its message. In some vertebrate cell types, the netrin-1 signal is G-protein mediated, while in other cell types, netrin signaling requires a tyrosine kinase or some other combination of kinases in order to signal. Tetrahymena thermophila are free-living, eukaryotic cells that can respond to chemoattractants and chemorepellents by moving toward attractants and away from repellents. By studying the behavior of these organisms, we have found that netrin-1 acts as a chemorepellent in T. thermophila. Response to netrin-1 is concentration dependent, with an EC100 of approximately 1 micromolar, and an EC50 of approximately 10 pM. Netrin-1 avoidance may be effectively eliminated by the addition of the broad-spectrum tyrosine kinase inhibitor, genistein, to the behavioral assay. The IC100 of genistein was approximately 75 micrograms/ml, while the IC50 of this compound was near 50 micrograms/ml. G-protein inhibitors, calcium chelators, and a number of other pharmacological inhibitors had no effect on netrin-1 signaling in this organism. These data show that netrin-1 is a chemorepellent in Tetrahymena thermophila and that netrin signaling appears to implicate a tyrosine kinase in this organism. Further studies will help us to determine whether genistein is specifically acting upon a tyrosine kinase pathway or whether the inhibition is occurring via some other genistein-mediated effect

Abnormal hypermethylation at imprinting control regions in patients with S-adenosylhomocysteine hydrolase (AHCY) deficiency

S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal recessive disorder in methionine metabolism caused by mutations in the AHCY gene. Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, mostly associated with hypermethioninaemia, elevated serum creatine kinase levels and increased genome wide DNA methylation. The prime function of AHCY is to hydrolyse and efficiently remove S-adenosylhomocysteine, the by-product of transmethylation reactions and one of the most potent methyltransferase inhibitors. In this study, we set out to more specifically characterize DNA methylation changes in blood samples from patients with AHCY deficiency. Global DNA methylation was increased in two of three analysed patients. In addition, we analysed the DNA methylation levels at differentially methylated regions (DMRs) of six imprinted genes (MEST, SNRPN, LIT1, H19, GTL2 and PEG3) as well as Alu and LINE1 repetitive elements in seven patients. Three patients showed a hypermethylation in up to five imprinted gene DMRs. Abnormal methylation in Alu and LINE1 repetitive elements was not observed. We conclude that DNA hypermethylation seems to be a frequent but not a constant feature associated with AHCY deficiency that affects different genomic regions to different degrees. Thus AHCY deficiency may represent an ideal model disease for studying the molecular origins and biological consequences of DNA hypermethylation due to impaired cellular methylation status

Identification of disease causing loci using an array-based genotyping approach on pooled DNA

BACKGROUND: Pooling genomic DNA samples within clinical classes of disease followed by genotyping on whole-genome SNP microarrays, allows for rapid and inexpensive genome-wide association studies. Key to the success of these studies is the accuracy of the allelic frequency calculations, the ability to identify false-positives arising from assay variability and the ability to better resolve association signals through analysis of neighbouring SNPs. RESULTS: We report the accuracy of allelic frequency measurements on pooled genomic DNA samples by comparing these measurements to the known allelic frequencies as determined by individual genotyping. We describe modifications to the calculation of k-correction factors from relative allele signal (RAS) values that remove biases and result in more accurate allelic frequency predictions. Our results show that the least accurate SNPs, those most likely to give false-positives in an association study, are identifiable by comparing their frequencies to both those from a known database of individual genotypes and those of the pooled replicates. In a disease with a previously identified genetic mutation, we demonstrate that one can identify the disease locus through the comparison of the predicted allelic frequencies in case and control pools. Furthermore, we demonstrate improved resolution of association signals using the mean of individual test-statistics for consecutive SNPs windowed across the genome. A database of k-correction factors for predicting allelic frequencies for each SNP, derived from several thousand individually genotyped samples, is provided. Lastly, a Perl script for calculating RAS values for the Affymetrix platform is provided. CONCLUSION: Our results illustrate that pooling of DNA samples is an effective initial strategy to identify a genetic locus. However, it is important to eliminate inaccurate SNPs prior to analysis by comparing them to a database of individually genotyped samples as well as by comparing them to replicates of the pool. Lastly, detection of association signals can be improved by incorporating data from neighbouring SNPs

Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup

Mutations of both nuclear and mitochondrial DNA (mtDNA)-encoded mitochondrial proteins can cause cardiomyopathy associated with mitochondrial dysfunction. Hence, the cardiac phenotype of nuclear DNA mitochondrial mutations might be modulated by mtDNA variation. We studied a 13-generation Mennonite pedigree with autosomal recessive myopathy and cardiomyopathy due to an SLC25A4 frameshift null mutation (c.523delC, p.Q175RfsX38), which codes for the heart-muscle isoform of the adenine nucleotide translocator-1. Ten homozygous null (adenine nucleotide translocator-1(-/-)) patients monitored over a median of 6 years had a phenotype of progressive myocardial thickening, hyperalaninemia, lactic acidosis, exercise intolerance, and persistent adrenergic activation. Electrocardiography and echocardiography with velocity vector imaging revealed abnormal contractile mechanics, myocardial repolarization abnormalities, and impaired left ventricular relaxation. End-stage heart disease was characterized by massive, symmetric, concentric cardiac hypertrophy; widespread cardiomyocyte degeneration; overabundant and structurally abnormal mitochondria; extensive subendocardial interstitial fibrosis; and marked hypertrophy of arteriolar smooth muscle. Substantial variability in the progression and severity of heart disease segregated with maternal lineage, and sequencing of mtDNA from five maternal lineages revealed two major European haplogroups, U and H. Patients with the haplogroup U mtDNAs had more rapid and severe cardiomyopathy than those with haplogroup H

Intellectual disability associated with a homozygous missense mutation in THOC6

BACKGROUND: We recently described a novel autosomal recessive neurodevelopmental disorder with intellectual disability in four patients from two related Hutterite families. Identity-by-descent mapping localized the gene to a 5.1 Mb region at chromosome 16p13.3 containing more than 170 known or predicted genes. The objective of this study was to identify the causative gene for this rare disorder. METHODS AND RESULTS: Candidate gene sequencing followed by exome sequencing identified a homozygous missense mutation p.Gly46Arg, in THOC6. No other potentially causative coding variants were present within the critical region on chromosome 16. THOC6 is a member of the THO/TREX complex which is involved in coordinating mRNA processing with mRNA export from the nucleus. In situ hybridization showed that thoc6 is highly expressed in the midbrain and eyes. Cellular localization studies demonstrated that wild-type THOC6 is present within the nucleus as is the case for other THO complex proteins. However, mutant THOC6 was predominantly localized to the cytoplasm, suggesting that the mutant protein is unable to carry out its normal function. siRNA knockdown of THOC6 revealed increased apoptosis in cultured cells. CONCLUSION: Our findings associate a missense mutation in THOC6 with intellectual disability, suggesting the THO/TREX complex plays an important role in neurodevelopment