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PubMed2025

Investigating the genomic landscape of mouse models of breast cancer metastasis.

Metastasis remains a major cause of cancer mortality. AbstractThis study, expanding upon previous findings in the MMTV-PyMT model, investigated four independent mouse models, representing luminal (MMTV-PyMT, MMTV-Myc), HER2-amplified (MMTV-Her2) and triple negative (C3(1)TAg) breast cancer subtypes. Consistent with previous results, limited evidence for metastasis-associated somatic point mutations was found for all models. We also found that oncogenic drivers significantly influenced the number and size of metastasis-specific copy number variations (MSCNVs), but common driver-independent MSCNVs were rare. Furthermore, analyzing a cohort with varying genetic backgrounds while maintaining a constant oncogenic driver (PyMT) revealed that genetic background profoundly impacts MSCNVs. Transcriptome analysis demonstrated that oncogenic drivers strongly shaped metastasis-specific gene expression (MSGE), with each driver exhibiting distinct expression profiles. In contrast, MSGE in the PyMT-F1 cohort was more variable across strains. Despite the diversity of MSCNV and MSGE, functional analysis revealed that both mechanisms converge on the modulation of key cellular processes, including immune responses, metabolism, and extracellular matrix interactions. These findings emphasize the complex interplay between oncogenic drivers and genetic background in shaping the genomic and transcriptional landscapes of metastatic lesions.

Journal Article↗
PubMed1994

Genotypes of the Common Bean (Phaseolus vulgaris L.) Lacking the Nodule-Enhanced Isoform of Glutamine Synthetase.

Glutamine synthetase (GS) is an octameric enzyme. The nodule cytosol of the common bean (Phaseolus vulgaris L.) has two major types of GS subunit polypeptides ([beta] and [gamma]). As a result, nine different isozymes containing varied proportions of [beta] and [gamma] can be generated. The isozymes are resolvable by native polyacrylamide gel electrophoresis. Staining the gel for GS activity reveals two isoforms, GSn1, which is nodule enhanced and is composed of the eight [gamma] polypeptide-containing isozymes, and GSn2, which is the isozyme [beta]8. We screened 104 cultivars and genotypes of common beans for variations in isozyme formation and found two, PI317350 and PI326054, that had no GSn1. The PI beans appeared to nodulate normally and had cytosolic protein concentrations and total GS activities similar to those of the cultivar UI-111, which has GSn1. They accumulated the [gamma] polypeptide, which had the same molecular weight (46,000) and isoelectric point (6.3) as the [gamma] polypeptide of UI-111. Experiments with extracts prepared by mixing UI-111 and the PI bean nodules suggested that the PI bean nodule extracts did not have an inhibitor or a proteolytic system that specifically inhibited or degraded GSn1. Nodules from UI-111 and the PI beans were dissected into cortex and central infection zone tissue fractions. GSn2 was found in the cortex and the central infection zone tissue of all beans. Our results suggested that the reason we were unable to detect GSn1 from the PI beans was not because their GSn1 and GSn2 had an identical electrophoretic mobility, nor was it due to an inhibited or unstable GSn1. Our results suggested that either their [gamma] gene had mutated in the region that is essential for the [gamma] polypeptide to assemble or the assembly of GS may require a chaperone. In the two PI beans, the chaperone accumulated to a lower level than it did in UI-111. This lower amount limited the assembly of the [gamma] polypeptide into GS.

Journal Article↗
PubMed1998

Optimized homomorphic unsharp masking for MR grayscale inhomogeneity correction.

Grayscale inhomogeneities in magnetic resonance (MR) images confound quantitative analysis of these images. Homomorphic unsharp masking and its variations have been commonly used as a post-processing method to remove inhomogeneities in MR images. However, little data is available in the literature assessing the relative effectiveness of these algorithms to remove inhomogeneities, or describing how these algorithms can affect image data. In this study, we address these questions quantitatively using simulated images with artificially constructed and empirically measured bias fields. Our results show that mean-based filtering is consistently more effective than median-based algorithms for removing inhomogeneities in MR images, and that artifacts are frequently introduced into images at the most commonly used window sizes. Our results demonstrate dramatic improvement in the effectiveness of the algorithms with significantly larger windows than are commonly used.

Algorithms↗
PubMed2003

Analysis and simulation of changes in EMG amplitude during high-level fatiguing contractions.

Changes in surface electromyographic (EMG) amplitude during sustained, fatiguing contractions are commonly attributed to variations in muscle fiber conduction velocity (MFCV), motor unit firing rates, transmembrane action potentials and the synchronization or recruitment of motor units. However, the relative contribution of each factor remains unclear. Analytical relationships relating changes in MFCV and mean motor unit firing rates to the root mean square (RMS) and average rectified (AR) value of the surface EMG signal are derived. The relationships are then confirmed using model simulation. The simulations and analysis illustrate the different behaviors of the surface EMG RMS and AR value with changing MFCV and firing rate, as the level of motor unit superposition varies. Levels of firing rate modulation and short-term synchronization that, combined with variations in MFCV, could cause changes in EMG amplitude similar to those observed during sustained isometric contraction of the brachioradialis at 80% of maximum voluntary contraction were estimated. While it is not possible to draw conclusions about changes in neural control without further information about the underlying motor unit activation patterns, the examples presented illustrate how a combined analytical and simulation approach may provide insight into the manner in which different factors affect EMG amplitude during sustained isometric contractions.

Adult↗
PubMed2003

Solution structure of Vibrio cholerae protein VC0424: a variation of the ferredoxin-like fold.

The structure of Vibrio cholerae protein VC0424 was determined by NMR spectroscopy. VC0424 belongs to a conserved family of bacterial proteins of unknown function (COG 3076). The structure has an alpha-beta sandwich architecture consisting of two layers: a four-stranded antiparallel beta-sheet and three side-by-side alpha-helices. The secondary structure elements have the order alphabetaalphabetabetaalphabeta along the sequence. This fold is the same as the ferredoxin-like fold, except with an additional long N-terminal helix, making it a variation on this common motif. A cluster of conserved surface residues on the beta-sheet side of the protein forms a pocket that may be important for the biological function of this conserved family of proteins.

Amino Acid Sequence↗
PubMed1979

Ultrastructure of the human mucocutaneous end organ.

The ultrastructure of the human mucocutaneous end organ is described. The corpuscle is divided into sublobular units comprising axon terminals surrounded by generally concentric lamellar processes which are derived from laminar cells whose nuclei are situated towards the periphery of the sublobules. Interlamellar substance which contains elastic tissue, collagen and coarse periodicity crossbanded structures intervenes between lamellar processes. Specialized zones of contact resembling desmosomes are found at intervals seemingly connecting adjacent lamellar processes and axons with lamellar processes. The ultrastructural features of this end organ are similar to that of the Meissner corpuscle despite minor differences of the light microscopical appearance, which supports the view that differences in sensory end organs are merely variations on a common organizational basis.

Aged↗
PubMed2004

Superficial palmar arch: an arterial diameter study.

Although anatomical variations in the arterial pattern of the hand have been the subject of many studies, information on the diameter of the superficial palmar arch contributing vessels and its branches are rarely found in the literature. The objective of the current study was to evaluate these arterial variations, with special attention to the diameter of the superficial palmar arch contributing vessels and its major branches. Forty-six hands from male embalmed human cadavers were evaluated, 21 right hands and 25 left hands. Complete arches were present in 43% on the right and in 52% on the left. Arches were completed by the median artery in two cases. Variations were more common at the radial side of the arch and on left hands. Comparison of vessel diameters revealed the radial artery to be significantly larger than the ulnar artery but the ulnar artery to be larger than the superficial branch of the radial artery. The diameters of the common digital arteries were not different with regard to complete or incomplete arches, or with regard to the presence of the median artery.

Arteries↗
PubMed1990

Heterotrophic plate counts and the isolation of bacteria from mineral waters on selective and enrichment media.

The heterotrophic plate counts of 15 brands of bottled non-carbonated mineral waters were examined and found to be generally high and variable. Four selective or enrichment media for the enumeration of coliforms (m-Endo LES and m-lauryl sulphate agar) and Pseudomonas aeruginosa (cetrimide-nalidixic acid agar and malachite green broth) were used to isolate several species of Gram-negative bacteria. Strains identified as CDC gr IVc-2 and Comamonas (Ps.) acidovorans were the two most commonly isolated. Considerable variation in populations was seen between the brands, as well as between two batches of the same mineral water.

Colony Count, Microbial↗
PubMed2004

A single amino acid substitution in the Arabidopsis FIERY1/HOS2 protein confers cold signaling specificity and lithium tolerance.

Low temperature induces the expression of many plant genes through undefined signaling pathways. To gain insight into cold signal transduction mechanisms, we isolated Arabidopsis mutants that exhibited altered regulation of low temperature-induced gene expression. One such mutant, hos2, was shown previously to have an enhanced induction of stress-responsive genes by cold, whereas the expression of these genes under osmotic stress or the phytohormone absciscic acid (ABA) treatments was not affected. Here we further define the targets of HOS2 by examining the regulation of upstream cold-specific CBF transcription factor genes. It was found that the transcript levels of CBF2 and CBF3 were significantly higher in hos2 mutant plants than in the wild type under cold treatments, suggesting that HOS2 may act upstream of CBFs. The HOS2 gene was cloned using a map-based strategy. Surprisingly, HOS2 is identical to the FIERY1 gene that we had described previously. FIERY1 is a general negative regulator that controls cold, osmotic stress, and ABA signal transduction and possesses inositol polyphosphate 1-phosphatase activity. The hos2 mutation rendered the HOS2/FIERY1 recombinant protein completely inactive in the cold but did not substantially affect its activity at warm temperatures. Interestingly, the hos2 mutant protein is extremely tolerant to Li+. This study provides a unique example of a single amino acid substitution in a critical regulator that can lead to conditional changes in protein functions and distinct plant phenotypes. The results reinforce the notion that phosphoinositols are important second messengers in cold signal transduction, and shed light on how the diversity of plant tolerance to cold and other abiotic stresses may evolve due to variations in a common molecular switch.

Amino Acid Sequence↗
PubMed1994

Fast inhibition of inwardly rectifying K+ channels by multiple neurotransmitter receptors in oligodendroglia.

An essential function of myelinating oligodendroglia in the mammalian central nervous system is the regulation of extracellular potassium levels by means of a prominent inwardly rectifying K+ current. Cardiac and neuronal K+ inward rectifiers are either activated by hyperpolarizing voltages or controlled by neurotransmitters through the action of receptor-activated G proteins. Neuromodulation of inward rectifiers has not previously been considered as a way to regulate oligodendrocyte function. Here we report the expression of serotonin, somatostatin and muscarinic acetylcholine G protein-coupled receptors in rat brain oligodendrocytes. Activation of these receptors leads to pertussis toxin-sensitive inhibition of inwardly rectifying K+ channels within < 1 s. By contrast, in the heart and in neurons, similar pathways activate an inwardly rectifying conductance. Thus, transmitter-mediated blockade of inward rectifiers appears to be an oligodendrocyte-specific variation of a common motif for convergent signalling pathways. In vivo, expression of this mechanism, which may be dependent on neuron-glia signalling, may have a regulatory role in K+ homeostasis during neuron activity in the central nervous system.

Animals↗
PubMedDate not supplied

Quality management organizational structures: history and trends.

Quality management (QM), utilization management, and risk management each evolved in response to different external demands. Practices that evolved in response to the real or perceived influences of accreditors, regulators, and payers may be easier to modify if we understand their origins and can identify why those practices are or are not warranted in today's environment. Also, if an individual works exclusively in one of the three traditional areas of quality (QM, utilization management, and risk management), history provides insight into the demands faced by individuals working in the other two areas. Finally, history should be of interest as we prepare for another wave of healthcare reform, which may result in additional changes in our QM organizational structures. This article traces the roots of quality management, utilization management, and risk management for their impact on the organizational structure of hospitals, and summarizes the most common current design variations employed for different situations.

History, 20th Century↗
PubMed2003

The synergy between speech production and perception.

Speech intelligibility is known to be relatively unaffected by certain deformations of the acoustic spectrum. These include translations, stretching or contracting dilations, and shearing of the spectrum (represented along the logarithmic frequency axis). It is argued here that such robustness reflects a synergy between vocal production and auditory perception. Thus, on the one hand, it is shown that these spectral distortions are produced by common and unavoidable variations among different speakers pertaining to the length, cross-sectional profile, and losses of their vocal tracts. On the other hand, it is argued that these spectral changes leave the auditory cortical representation of the spectrum largely unchanged except for translations along one of its representational axes. These assertions are supported by analyses of production and perception models. On the production side, a simplified sinusoidal model of the vocal tract is developed which analytically relates a few "articulatory" parameters, such as the extent and location of the vocal tract constriction, to the spectral peaks of the acoustic spectra synthesized from it. The model is evaluated by comparing the identification of synthesized sustained vowels to labeled natural vowels extracted from the TIMIT corpus. On the perception side a "multiscale" model of sound processing is utilized to elucidate the effects of the deformations on the representation of the acoustic spectrum in the primary auditory cortex. Finally, the implications of these results for the perception of generally identifiable classes of sound sources beyond the specific case of speech and the vocal tract are discussed.

Auditory Cortex↗
PubMed2005

Remote sensing of sediment density and velocity gradients in the transition layer.

The geoacoustic properties of marine sediments, e.g., bulk density and compressional velocity, commonly exhibit large variations in depth near the water-sediment interface. This layer, termed the transition layer, is typically of 0(10(-1)-10(0)) m in thickness. Depth variations within the transition layer may have important implications for understanding and modeling acoustic interaction with the seabed, including propagation and reverberation. In addition, the variations may contain significant clues about the underlying depositional or erosional processes. Characteristics of the transition layer can be measured directly (e.g., coring) or remotely. Remote measurements have the advantage of sampling without disturbing the sediment properties; they also have the potential to be orders of magnitude faster and less expensive than direct methods. It is shown that broadband seabed reflection data can be exploited to remotely obtain the depth dependent density and velocity profiles in the transition layer to high accuracy. A Bayesian inversion approach, which accounts for correlated data errors, provides estimates and uncertainties for the geoacoustic properties. These properties agree with direct (i.e., core) measurements within the uncertainty estimates.

Journal Article↗
PubMed1995

Expressive timing in Schumann's "Träumerei:" an analysis of performances by graduate student pianists.

Statistical analyses were conducted on the expressive timing patterns of performances of Schumann's "Träumerei" by ten graduate student pianists who played from the score on a Yamaha Disclavier after a brief rehearsal. A previous study of acoustic recordings of "Träumerei" by 24 famous pianists [B. H. Repp, J. Acoust. Soc. Am. 92, 2546-2568 (1992)] provided "expert" timing data for comparison. In terms of group average timing pattern, individual shaping of ritardandi, and within-performance consistency, the students turned out to be quite comparable to the experts. This demonstrates that precision in expressive timing does not require extensive study and practice of the music at hand, only general musical and technical competence. Subsequent principal components analyses on the students' timing patterns revealed that they were much more homogeneous than the experts'. Individual differences among student pianists seemed to represent mainly variations around a common performance standard (the first principal component), whereas expert performances exhibited a variety of underlying timing patterns, especially at a detailed level of analysis. Experienced concert artists evidently feel less constrained by a performance norm, which makes their performances more interesting and original, hence less typical. Since the norm may represent the most natural or prototypical timing pattern, relatively spontaneous performances by young professionals may be a better starting point for modeling expressive timing than distinguished artists' performances.

Adult↗
PubMed2006

Inversion polymorphisms and non-contiguous terminal deletions: the cause and the (unpredicted) effect of our genome architecture.

Molecular definition at the BAC level of an 8p dicentric chromosome and an 8p deleted chromosome is reported in a patient with two different cell lines. The dicentric, which differed from that generating the recurrent inv dup del(8p) for the location of its break point, originated during the paternal meiosis on the background of the classical 8p23.1 inversion polymorphism. The breakage of this dicentric gave rise to the 8p deleted chromosome which, as a result of the inversion, had two non-contiguous deletions. These findings confirm previous data on 1p distal deletions, showing that at least some of the deletions stem from the breakage of dicentric chromosomes. They suggest that non-contiguous deletions may be frequent among distal deletions. This type of rearrangement can easily be overlooked when two contiguous clones, one absent and the other present by FISH analysis, are taken as boundaries of the deletion break point; in this case only high resolution array-CGH will reveal their real frequency. The definition of such non-contiguous distal deletions is relevant for phenotype/karyotype correlations. There are historical examples of blunders caused by overlooking a second non-contiguous deletion. This paper shows how small scale structural variations, such as common polymorphic inversions, may cause complex rearrangements such as terminal deletions.

Abnormalities, Multiple↗
PubMed2000

How universal are fold recognition parameters. A comprehensive study of alignment and scoring function parameters influence on recognition of distant folds.

A choice of sequence-structure similarity scoring function parameters can significantly alter results of the performance of the recognition of distantly related folds. It therefore constitutes a critical part of fold recognition process. In order to increase an understanding of the influence of parameter choice, a comprehensive benchmark of very hard (SFOLD) and medium hard (SFAM) fold recognition examples has been derived from the SCOP database of protein structure families. These benchmarks have subsequently been used to optimize, validate and analyze dependence of recognition sensitivity on alignment and fold similarity score parameters for different scoring functions. Significant variation of the common parameters has been observed for different functions, leading to the conclusion that optimal parameter sets are not universal. The scope of solutions common to any pair of scoring function is relatively small, hence, using jury method for fold prediction seems not appropriate. Also, using a redundant version of fold libraries significantly increases odds of identification of distantly related fold.

Algorithms↗
PubMed1998

Clinical subtypes of Alzheimer's disease.

Alzheimer's disease (AD) can present as a variety of clinical profiles. Although the most common presentation is that of a progressive amnestic disorder with subsequent involvement of other cognitive functions and personality alterations, there are numerous other clinical profiles. AD can present as a focal cortical degenerative syndrome with the clinical features dependent on the regions of the brain involved. Some of these syndromes include disturbances of language, visuospatial skills, attentional functions, executive processes and praxis. The neuropathological substrate of these disorders is variable and can include AD. Recently, the Lewy body variant of AD has been described. Finally, other modifying features that affect the progression of AD, such as extrapyramidal symptoms and myoclonus, are also discussed. Although the progressive amnestic form of AD is the most common presentation, other variations on the clinical syndrome can be important to identify because they may have implications for prognosis and treatment.

Aged↗
PubMed2000

Common and rare ABCA1 variants affecting plasma HDL cholesterol.

Mutations in ABCA1, a member of the ATP-binding cassette family, have been shown to underlie Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA), which are genetic disorders that are characterized by depressed concentrations of plasma high density lipoprotein (HDL) cholesterol. An important question is whether common variants within the coding sequence of ABCA1 can affect plasma HDL cholesterol in the general population. To address this issue, we developed a screening strategy to find common ABCA1 variants. This strategy involved long-range amplification of genomic DNA by using coding sequences only, followed by deep sequencing into the introns. This method helped us to characterize a new set of amplification primers, which permitted amplification of virtually all of the coding sequence of ABCA1 and its intron-exon boundaries with a single DNA amplification program. With these new sequencing primers, we found 3 novel ABCA1 mutations: a frameshift mutation (4570insA, A1484S-->X1492), a missense mutation (A986D) in a TD family, and a missense mutation (R170C) in aboriginal subjects with FHA. We also used these sequencing primers to characterize 4 novel common amino acid variants in ABCA1, in addition to 5 novel common silent variants. We tested for association of the ABCA1 I/M823 variant with plasma HDL cholesterol in Canadian Inuit and found that M823/M823 homozygotes had significantly higher plasma HDL cholesterol compared with subjects with the other genotypes. The results provide proof of principle of the effectiveness of this approach to identify both rare and common ABCA1 genomic variants and also suggest that common amino acid variation in ABCA1 is a determinant of plasma HDL cholesterol in the general population.

ATP Binding Cassette Transporter 1↗