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Evolution of Benjamin-Ono solitons in the presence of weak Zakharov-Kutznetsov lateral dispersion.

The effect of weak lateral dispersion of Zakharov-Kutznetsov-type on a Benjamin-Ono solitary wave is studied both asymptotically and numerically. The asymptotic solution is based on an approximate variational solution for the solitary wave, which is then modulated in time through the use of conservation equations. The effect of the dispersive radiation shed as the solitary wave evolves is also included in the modulation equations. It is found that the weak lateral dispersion produces a strongly anisotropic, stable solitary wave which decays algebraically in the direction of propagation, as for the Benjamin-Ono solitary wave, and exponentially in the transverse direction. Moreover, it is found that initial conditions with amplitude above a threshold evolve into solitary waves, while those with amplitude below the threshold evolve as lumps for a short time, then merge into radiation. The modulation equations are found to give a quantitatively accurate description of the evolution of an initial condition into an anisotropic solitary wave. The existence of stable solitary waves is in contrast to previous studies of Benjamin-Ono-type equations subject to the stronger Kadomstev-Petviashvili or Benjamin-Ono-type lateral dispersion, for which the solitary waves either decay or collapse. The present study then completes the catalog of possible behaviors under lateral dispersion.

Journal Article↗

A comparison of costs associated with screening for gestational diabetes with two-tiered and one-tiered testing protocols.

OBJECTIVE: The Fourth International Workshop on Gestational Diabetes recently suggested that two techniques, a 2-tiered protocol and a 1-tiered protocol, to screen for gestational diabetes mellitus are acceptable alternatives. This study was undertaken to compare the direct costs and patient time expenditures associated with implementing both techniques. STUDY DESIGN: A MEDLINE search was undertaken to determine the prevalence of positive and negative screening results. Direct costs of testing were estimated by determining the range of supply costs from manufacturers' catalogs and the labor costs by estimating the time required to perform each procedure and multiplying by the appropriate range of wages; these costs were then multiplied by the appropriate range of the number of procedures required to implement both protocols, and the totals were summed. Patient time expended was estimated by assigning test times of 1, 2, and 3 hours for the 50-g screening glucose challenge test, the 75-g oral glucose tolerance test, and the 100-g oral glucose tolerance test, respectively. If additional visits were required, 2 travel-time units were assigned each time a patient underwent a procedure. These units were multiplied by the range of patients undergoing various tests to implement the alternative protocols. RESULTS: We identified low and high direct costs, test times, and travel units per patient screened by the 1- and 2-tiered testing protocols. Low and high direct costs were $3.46 and $7.88, respectively, for the 2-tiered protocol and $5.64 and $10.88, respectively, for the 1-tiered protocol (relative ratios, 1.63 for low direct costs in each protocol and 1.38 for high direct costs in each protocol). Low and high test times were 1.4 and 1.5 hours, respectively, for the 2-tiered protocol and 2.0 and 2.0 hours, respectively, for the 1-tiered protocol (relative ratios, 1.47 for low test times in each protocol and 1.32 for high test times in each protocol). Low and high travel units for the 2-tiered protocol were 0.2 and 0.3, respectively, when the glucose challenge test was given at the prenatal visit, and 2.2 and 2.3, respectively, when the test was not given at that time. Low and high travel units for the 1-tiered protocol were 8.3 and 5.8, respectively, when the glucose challenge test was given at the prenatal visit, and 0.89 and 0.85, respectively, when the test was not given at that time. CONCLUSIONS: The 2-tiered protocol appears to be associated with lower direct implementation costs and less patient time expenditure than the 1-tiered scheme. The 1-tiered protocol is associated with slightly less travel time, but this is unlikely to offset the test time advantage of the 2-tiered protocol. Until further data regarding the relative clinical utility of the 2 protocols become available, these factors may be important for clinicians in deciding which screening format to follow.

Cost-Benefit Analysis↗

Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.

A large number of tiny noncoding RNAs have been cloned and named microRNAs (miRs). Recently, we have reported that miR-15a and miR-16a, located at 13q14, are frequently deleted and/or down-regulated in patients with B cell chronic lymphocytic leukemia, a disorder characterized by increased survival. To further investigate the possible involvement of miRs in human cancers on a genome-wide basis, we have mapped 186 miRs and compared their location to the location of previous reported nonrandom genetic alterations. Here, we show that miR genes are frequently located at fragile sites, as well as in minimal regions of loss of heterozygosity, minimal regions of amplification (minimal amplicons), or common breakpoint regions. Overall, 98 of 186 (52.5%) of miR genes are in cancer-associated genomic regions or in fragile sites. Moreover, by Northern blotting, we have shown that several miRs located in deleted regions have low levels of expression in cancer samples. These data provide a catalog of miR genes that may have roles in cancer and argue that the full complement of miRs in a genome may be extensively involved in cancers.

Chromosome Fragile Sites↗

Quantifying the mechanisms for segmental duplications in mammalian genomes by statistical analysis and modeling.

A large number of the segmental duplications in mammalian genomes have been cataloged by genome-wide sequence analyses. The molecular mechanisms involved in these duplications mostly remain a matter of speculation. To uncover, test, and further quantify the hypotheses on the mechanisms for the recent duplications in the mammalian genomes, we have performed a series of statistical analyses on the sequences flanking the duplicated segments and proposed a dynamic model for the duplication process. The model, when applied to the human duplication data, indicates that approximately 30% of the recent human segmental duplications were caused by a recombination-like mechanism, among which 12% were mediated by the most recently active repeat, Alu. But a significant proportion of the duplications are caused by some mechanism independent of the repeat distribution. A less sure but similar picture is found in the rodent genomes. A further analysis on the physical features of the flanking sequences suggests that one of the uncharacterized duplication mechanisms shared by the mammalian genomes is surprisingly well correlated with the physical instability in the DNA sequences.

Animals↗

The first linkage disequilibrium (LD) maps: delineation of hot and cold blocks by diplotype analysis.

Linkage disequilibrium (LD) provides information about positional cloning, linkage, and evolution that cannot be inferred from other evidence, even when a correct sequence and a linkage map based on more than a handful of families become available. We present theory to construct an LD map for which distances are additive and population-specific maps are expected to be approximately proportional. For this purpose, there is only a modest difference in relative efficiency of haplotypes and diplotypes: resolving the latter into 2-locus haplotypes has significant cost or error and increases information by about 50%. LD maps for a cold spot in 19p13.3 and a more typical region in 3q21 are optimized by interval estimates. For a random sample and trustworthy map the value of LD at large distance can be predicted reliably from information over a small distance and does not depend on the evolutionary variance unless the sample size approaches the population size. Values of the association probability that can be distinguished from the value at large distance are determined not by population size but by time since a critical bottleneck. In these examples, omission of markers with significant Hardy-Weinberg disequilibrium does not improve the map, and widely discrepant draft sequences have similar estimates of the genetic parameters. The LD cold spot in 19p13.3 gives an unusually high estimate of time, supporting an argument that this relationship is general. As predicted for a region with ancient haplotypes or uniformly high recombination, there is no clear evidence of LD clustering. On the contrary, the 3q21 region is resolved into alternating blocks of stable and decreasing LD, as expected from crossover clustering. Construction of a genomewide LD map requires data not yet available, which may be complemented but not replaced by a catalog of haplotypes.

Chromosome Mapping↗

A comprehensive description of the transcriptome of the hypothalamoneurohypophyseal system in euhydrated and dehydrated rats.

The hypothalamoneurohypophyseal system (HNS) consists of the large peptidergic magnocellular neurons of the supraoptic hypo thalamic nucleus (SON) and the paraventricular hypothalamic nucleus (PVN), the axons of which course through the internal zone of the median eminence and terminate at blood capillaries of the posterior lobe of the pituitary gland. The HNS is a specialized brain neurosecretory apparatus responsible for the production of the antidiuretic peptide hormone vasopressin (VP). VP maintains water balance by promoting water conservation at the level of the kidney. Dehydration evokes a massive increase in the regulated release of VP from magnocellular neuron axon terminals in the posterior pituitary, which is accompanied by a plethora of changes in the morphology, electrophysiological properties, and biosynthetic and secretory activity of the HNS. We wish to understand this functional plasticity in terms of the differential expression of genes. We have therefore used microarrays to comprehensively catalog the genes expressed in the PVN, the SON and the neurointermediate lobe of the pituitary gland of control and dehydrated rats. Comparison of these gene lists has enabled us to identify transcripts that are regulated as a consequence of dehydration as well as RNAs that are enriched in the PVN or the SON. We suggest that these differentially expressed genes represent candidate regulators and effectors of HNS activity and remodeling.

Animals↗

Wildfires, complexity, and highly optimized tolerance.

Recent, large fires in the western United States have rekindled debates about fire management and the role of natural fire regimes in the resilience of terrestrial ecosystems. This real-world experience parallels debates involving abstract models of forest fires, a central metaphor in complex systems theory. Both real and modeled fire-prone landscapes exhibit roughly power law statistics in fire size versus frequency. Here, we examine historical fire catalogs and a detailed fire simulation model; both are in agreement with a highly optimized tolerance model. Highly optimized tolerance suggests robustness tradeoffs underlie resilience in different fire-prone ecosystems. Understanding these mechanisms may provide new insights into the structure of ecological systems and be key in evaluating fire management strategies and sensitivities to climate change.

Computer Simulation↗

Discovery of sulfated metabolites in mycobacteria with a genetic and mass spectrometric approach.

The study of the metabolome presents numerous challenges, first among them being the cataloging of its constituents. A step in this direction will be the development of tools to identify metabolites that share common structural features. The importance of sulfated molecules in cell-cell communication motivated us to develop a rapid two-step method for identifying these metabolites in microorganisms, particularly in pathogenic mycobacteria. Sulfurcontaining molecules were initially identified by mass spectral analysis of cell extracts from bacteria labeled metabolically with a stable sulfur isotope (34SO 4 2-). To differentiate sulfated from reduced-sulfur-containing molecules, we employed a mutant lacking the reductive branch of the sulfate assimilation pathway. In these sulfur auxotrophs, heavy sulfate is channeled exclusively into sulfated metabolites. The method was applied to the discovery of several new sulfated molecules in Mycobacterium tuberculosis and Mycobacterium smegmatis. Because a sulfur auxotrophic strain is the only requirement of the approach, many microorganisms can be studied in this manner. Such genetic engineering in combination with stable isotopic labeling can be applied to various metabolic pathways and their products.

Cysteine↗

On the prokaryotic nature of red algal chloroplasts.

The sequences of oligonucleotides released by T1 ribonuclease digestion of 32-P-labeled 16S (chloroplast) and 18S (cytoplasmic) ribosomal RNAs from a marine species of Porphyridium (Rhodophyta) have been determined. The resultant catalogs have been compared to those obtained for three prokaryotes:Escherichia coli, Bacillus subtilis, and Anacystis nidulans (a blud-green alga). There is extensive sequence homology between the Porphyridium chloroplast 16S ribosomal RNA and each of the prokaryotic 16S ribosomal RNAs, but little homology between the Porphyridium cytoplasmic 18S ribosomal RNA and any of the 16S species. These data provide a measure of the evolutionary distance separating existing chloroplasts from contemporary bacteria and blue-green algae, and are discussed in terms of the hypothesis that these organelles evolved from endosymbiotic photosynthetic prokaryotes.

Base Sequence↗

Phylogenetic analysis of the mycoplasmas.

The phylogenetic relationships between the mycoplasmas and bacteria have been established from a comparative analysis of their 16S rRNA oligonucleotide catalogs. The genera Mycoplasma, Spiroplasma, and Acholeplasma arose by degenerative evolution, as a deep branch of the subline of clostridial ancestry that led to Bacillus and Lactobacillus. Thermoplasma has no specific relationship to the other mycoplasmas; it belongs with the archaebacteria.

Acholeplasma↗

Cloning of cDNAs specifying vitamin A-responsive human keratins.

In human cultured epidermal and conjunctival keratinocytes, vitamin A promotes the synthesis of keratins 13 and 19 of the catalog of Moll et al. [Moll, R., Franke, W.W., Schiller, D.L., Geiger, B. & Krepler, R. (1982) Cell 31, 11-24] but does not alter the synthesis of keratins 5 and 6. To study this effect of the vitamin, cDNAs specifying each of these keratins were cloned in pBR322. Characterization of the clones by hybrid selection of mRNA and by hybridization of size-fractionated mRNA indicated that each was specific for a single mRNA. Treatment of epidermal cells with arotinoid Ro 13-6298, a potent synthetic analog of retinoic acid, increased the abundance of mRNA for keratin 13 by 25-fold and for keratin 19 by greater than 40-fold but had no effect on the abundance of mRNA for keratins 5 and 6.

Benzoates↗

Derivation of the cosmological density parameter Omega0 from large-scale flows.

Methods for determining the cosmological density parameter 0 from large-scale flows are reviewed. Very consistent results using infrared astronomical satellite (IRAS) data have been obtained by different groups with completely independent methods. The two main methods involve either using maps of the galaxy distribution to predict the peculiar velocity of the Local Group or directly comparing the density field inferred from the IRAS galaxy distribution with the peculiar velocities inferred from optical distance methods. All methods based on IRAS data are consistent with Omega0 = 0.7 +/- 0.1, or if Omega0 = 1, with a bias parameter b = 1.2 +/- 0.1. Various problems associated with the method are discussed, including the issue of which waveband is optimum for such studies, bias, the universality of the luminosity function, and the convergence of the dipole. The lower values of 0 obtained in optical studies may indicate a higher degree of bias toward regions of high total matter-density for elliptical galaxies. A new study using the whole IRAS point source catalog to 0.6 jansky is described, which gives results consistent with other IRAS studies.

Journal Article↗

Recursive deconvolution of combinatorial chemical libraries.

A recursive strategy that solves for the active members of a chemical library is presented. A pentapeptide library with an alphabet of Gly, Leu, Phe, and Tyr (1024 members) was constructed on a solid support by the method of split synthesis. One member of this library (NH2-Tyr-Gly-Gly-Phe-Leu) is a native binder to a beta-endorphin antibody. A variation of the split synthesis approach is used to build the combinatorial library. In four vials, a member of the library's alphabet is coupled to a solid support. After each coupling, a portion of the resin from each of the four reaction vials was set aside and catalogued. The solid support from each vial is then combined, mixed, and redivided. The steps of (i) coupling, (ii) saving and cataloging, and (iii) randomizing were repeated until a pentapeptide library was obtained. The four pentapeptide libraries where the N-terminal amino acid is defined were screened against the beta-endorphin antibody and quantitated via an ELISA. The amino acid of the four pools that demonstrated the most binding was then coupled to the four tetrapeptide partial libraries that had been set aside and catalogued during the split synthesis. This recursive deconvolution was repeated until the best binders were deduced. Besides the anticipated native binder, two other members of the library displayed significant binding. This recursive method of deconvolution does not use a molecular tag, requires only one split synthesis, and can be applied to the deconvolution of nonlinear small-molecule combinatorial libraries and linear oligomeric combinatorial libraries, since it is based only on the procedure of the synthesis.

Amino Acid Sequence↗

Inactivation of gene expression in plants as a consequence of specific sequence duplication.

Numerous examples now exist in plants where the insertion of multiple copies of a transgene leads to loss of expression of some or all copies of the transgene. Where the transgene contains sequences homologous to an endogenous gene, expression of both transgene and endogenous gene is sometimes found to be impaired. Several examples of these phenomena displaying different features are reviewed. Possible explanations for the observed phenomena are outlined, drawing on known cellular processes in Drosophila, fungi, and mammals as well as plants. It is hypothesized that duplicated sequences can, under certain circumstances, become involved in cycles of hybrid chromatin formation or other processes that generate the potential for modification of inherited chromatin structure and cytosine methylation patterns. These epigenetic changes could lead to altered transcription rates or altered efficiencies of mRNA maturation and export from the nucleus. Where the loss of gene expression is posttranscriptional, antisense RNA could be formed on accumulated, inefficiently processed RNAs by an RNA-dependent RNA polymerase or from a chromosomal promoter and cause the observed loss of homologous mRNAs and possibly the modification of homologous genes. It is suggested that the mechanisms evolved to help silence the many copies of transposable elements in plants. Multicopy genes that are part of the normal gene catalog of a plant species must have evolved to avoid these silencing mechanisms or their consequences.

Biological Evolution↗

Primate photopigments and primate color vision.

The past 15 years have brought much progress in our understanding of several basic features of primate color vision. There has been particular success in cataloging the spectral properties of the cone photopigments found in retinas of a number of primate species and in elucidating the relationship between cone opsin genes and their photopigment products. Direct studies of color vision show that there are several modal patterns of color vision among groupings of primates: (i) Old World monkeys, apes, and humans all enjoy trichromatic color vision, although the former two groups do not seem prone to the polymorphic variations in color vision that are characteristic of people; (ii) most species of New World monkeys are highly polymorphic, with individual animals having any of several types of dichromatic or trichromatic color vision; (iii) less is known about color vision in prosimians, but evidence suggests that at least some diurnal species have dichromatic color vision; and (iv) some nocturnal primates may lack color vision completely. In many cases the photopigments and photopigment gene arrangements underlying these patterns have been revealed and, as a result, hints are emerging about the evolution of color vision among the primates.

Animals↗

Cosmic velocity fields and their interpretation.

We review the current status of our knowledge of cosmic velocity fields, on both small and large scales. A new statistic is described that characterizes the incoherent, thermal component of the velocity field on scales less than 2h-1 Mpc (h is H0/100 km.s-1.Mpc-1, where H0 is the Hubble constant and 1 Mpc = 3.09 x 10(22) m) and smaller. The derived velocity is found to be quite stable across different catalogs and is of remarkably low amplitude, consistent with an effective Omega approximately 0.15 on this scale. We advocate the use of this statistic as a standard diagnostic of the small-scale kinetic energy of the galaxy distribution. The analysis of large-scale flows probes the velocity field on scales of 10-60 h-1 Mpc and should be adequately described by linear perturbation theory. Recent work has focused on the comparison of gravity or density fields derived from whole-sky redshift surveys of galaxies [e.g., the Infrared Astronomical Satellite (IRAS)] with velocity fields derived from a variety of sources. All the algorithms that directly compare the gravity and velocity fields suggest low values of the density parameter, while the POTENT analysis, using the same data but comparing the derived IRAS galaxy density field with the Mark-III derived matter density field, leads to much higher estimates of the inferred density. Since the IRAS and Mark-III fields are not fully consistent with each other, the present discrepancies might result from the very different weighting applied to the data in the competing methods.

Journal Article↗

PRIM: proximity imaging of green fluorescent protein-tagged polypeptides.

We report a serendipitous discovery that extends the impressive catalog of reporter functions performed by green fluorescent protein (GFP) or its derivatives. When two GFP molecules are brought into proximity, changes in the relative intensities of green fluorescence emitted upon excitation at 395 vs. 475 nm result. These spectral changes provide a sensitive ratiometric index of the extent of self-association that can be exploited to quantitatively image homo-oligomerization or clustering processes of GFP-tagged proteins in vivo. The method, which we term proximity imaging (PRIM), complements fluorescence resonance energy transfer between a blue fluorescent protein donor and a GFP acceptor, a powerful method for imaging proximity relationships between different proteins. However, unlike fluorescence resonance energy transfer (which is a spectral interaction), PRIM depends on direct contact between two GFP modules, which can lead to structural perturbations and concomitant spectral changes within a module. Moreover, the precise spatial arrangement of the GFP molecules within a given dimer determines the magnitude and direction of the spectral change. We have used PRIM to detect FK1012-induced dimerization of GFP fused to FK506-binding protein and clustering of glycosylphosphatidylinositol-anchored GFP at cell surfaces.

Amino Acid Sequence↗

Cellular gene expression altered by human cytomegalovirus: global monitoring with oligonucleotide arrays.

Mechanistic insights to viral replication and pathogenesis generally have come from the analysis of viral gene products, either by studying their biochemical activities and interactions individually or by creating mutant viruses and analyzing their phenotype. Now it is possible to identify and catalog the host cell genes whose mRNA levels change in response to a pathogen. We have used DNA array technology to monitor the level of approximately 6,600 human mRNAs in uninfected as compared with human cytomegalovirus-infected cells. The level of 258 mRNAs changed by a factor of 4 or more before the onset of viral DNA replication. Several of these mRNAs encode gene products that might play key roles in virus-induced pathogenesis, identifying them as intriguing targets for further study.

Annexin A1↗