Showing papers by "University of Utah published in 1997"
TL;DR: In this paper, the authors provide a theory that explains under what conditions network governance, rigorously defined, has comparative advantage and is therefore likely to emerge and thrive, and in broad strokes, they claim that the network form of governance is a response to exchange conditions of asset specificity, demand uncertainty, task complexity, and frequency.
Abstract: A phenomenon of the last 20 years has been the rapid rise of the network form of governance. This governance form has received significant scholarly attention, but. to date, no comprehensive theory for it has been advanced, and no sufficiently detailed and theoretically consistent definition has appeared. Our objective in this article is to provide a theory that explains under what conditions network governance, rigorously defined, has comparative advantage and is therefore likely to emerge and thrive. Our theory integrates transaction cost economics and social network theories, and, in broad strokes, asserts that the network form of governance is a response to exchange conditions of asset specificity, demand uncertainty, task complexity, and frequency. These exchange conditions drive firms toward structurally embedding their transactions, which enables firms to use social mechanisms for coordinating and safeguarding exchanges. When all of these conditions are in place, the network governance form has adv...
2,551 citations
TL;DR: The genome of the bacterium Borrelia burgdorferi B31, the aetiologic agent of Lyme disease, contains a linear chromosome of 910,725 base pairs and at least 17 linear and circular plasmids with a combined size of more than 533,000 base pairs, which suggest their limited metabolic capacities reflect convergent evolution by gene loss from more metabolically competent progenitors.
Abstract: The genome of the bacterium Borrelia burgdorferi B31, the aetiologic agent of Lyme disease, contains a linear chromosome of 910,725 base pairs and at least 17 linear and circular plasmids with a combined size of more than 533,000 base pairs. The chromosome contains 853 genes encoding a basic set of proteins for DNA replication, transcription, translation, solute transport and energy metabolism, but, like Mycoplasma genitalium, it contains no genes for cellular biosynthetic reactions. Because B. burgdorferi and M. genitalium are distantly related eubacteria, we suggest that their limited metabolic capacities reflect convergent evolution by gene loss from more metabolically competent progenitors. Of 430 genes on 11 plasmids, most have no known biological function; 39% of plasmid genes are paralogues that form 47 gene families. The biological significance of the multiple plasmid-encoded genes is not clear, although they may be involved in antigenic variation or immune evasion.
2,025 citations
TL;DR: The synthesis of a thermosensitive, biodegradable hydrogel consisting of blocks of poly(ethylene oxide) and poly(L-lactic acid) and aqueous solutions of these copolymers exhibit temperature-dependent reversible gel–sol transitions.
Abstract: Polymers that display a physicochemical response to stimuli are widely explored as potential drug-delivery systems. Stimuli studied to date include chemical substances and changes in temperature, pH and electric field. Homopolymers or copolymers of N-isopropylacrylamide and poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (known as poloxamers) are typical examples of thermosensitive polymers, but their use in drug delivery is problematic because they are toxic and non-biodegradable. Biodegradable polymers used for drug delivery to date have mostly been in the form of injectable microspheres or implant systems, which require complicated fabrication processes using organic solvents. Such systems have the disadvantage that the use of organic solvents can cause denaturation when protein drugs are to be encapsulated. Furthermore, the solid form requires surgical insertion, which often results in tissue irritation and damage. Here we report the synthesis of a thermosensitive, biodegradable hydrogel consisting of blocks of poly(ethylene oxide) and poly(L-lactic acid). Aqueous solutions of these copolymers exhibit temperature-dependent reversible gel-sol transitions. The hydrogel can be loaded with bioactive molecules in an aqueous phase at an elevated temperature (around 45 degrees C), where they form a sol. In this form, the polymer is injectable. On subcutaneous injection and subsequent rapid cooling to body temperature, the loaded copolymer forms a gel that can act as a sustained-release matrix for drugs.
1,930 citations
TL;DR: For example, this paper found that between 8 and 6 million years ago, there was a global increase in the biomass of plants using C4 photosynthesis as indicated by changes in the carbon isotope ratios of fossil tooth enamel in Asia, Africa, North America and South America.
Abstract: Between 8 and 6 million years ago, there was a global increase in the biomass of plants using C4 photosynthesis as indicated by changes in the carbon isotope ratios of fossil tooth enamel in Asia, Africa, North America and South America. This abrupt and widespread increase in C4 biomass may be related to a decrease in atmospheric CO2 concentrations below a threshold that favoured C3-photosynthesizing plants. The change occurred earlier at lower latitudes, as the threshold for C3 photosynthesis is higher at warmer temperatures.
1,886 citations
TL;DR: Analysis of melting curves can extend the dynamic range of initial template quantification when amplification is monitored with double-stranded DNA specific dyes.
1,767 citations
TL;DR: Rapid cycle DNA amplification was continuously monitored by three different fluorescence techniques and the double-strand-specific dye SYBR Green I improved the efficiency of these techniques.
Abstract: Rapid cycle DNA amplification was continuously monitored by three different fluorescence techniques. Fluorescence was monitored by (i) the double-strand-specific dye SYBR Green I, (ii) a decrease in fluorescein quenching by rhodamine after exonuclease cleavage of a dual-labeled hydrolysis probe and (iii) resonance energy transfer of fluorescein to Cy5 by adjacent hybridization probes. Fluorescence data acquired once per cycle provides rapid absolute quantification of initial template copy number. The sensitivity of SYBR Green I detection is limited by nonspecific product formation. Use of a single exonuclease hydrolysis probe or two adjacent hybridization probes offers increasing levels of specificity. In contrast to fluorescence measurement once per cycle, continuous monitoring throughout each cycle monitors the temperature dependence of fluorescence. The cumulative, irreversible signal of hydrolysis probes can be distinguished easily from the temperature-dependent, reversible signal of hybridization probes. By using SYBR Green I, product denaturation, annealing and extension can be followed within each cycle. Substantial product-to-product annealing occurs during later amplification cycles, suggesting that product annealing is a major cause of the plateau effect. Continuous within-cycle monitoring allows rapid optimization of amplification conditions and should be particularly useful in developing new, standardized clinical assays.
1,396 citations
TL;DR: Mutational analysis of ABCR in STGD families revealed a total of 19 different mutations including homozygous mutations in two families with consanguineous parentage, indicating that ABCR is the causal gene of STGD/FFM.
Abstract: Stargardt disease (STGD, also known as fundus flavimaculatus; FFM) is an autosomal recessive retinal disorder characterized by a juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material A gene encoding an ATP-binding cassette (ABC) transporter was mapped to the 2-cM (centiMorgan) interval at 1p13-p21 previously shown by linkage analysis to harbour the STGD gene This gene, ABCR, is expressed exclusively and at high levels in the retina, in rod but not cone photoreceptors, as detected by in situ hybridization Mutational analysis of ABCR in STGD families revealed a total of 19 different mutations including homozygous mutations in two families with consanguineous parentage These data indicate that ABCR is the causal gene of STGD/FFM
1,363 citations
TL;DR: A convergence of repression pathways for bHLH-Zip proteins and nuclear receptors is established and suggests this type of regulation may be more widely conserved than previously suspected.
1,303 citations
1,278 citations
TL;DR: It is suggested that C4 dicots may not have been selected until CO2 concentrations reached their lowest levels during glacial maxima in the Quaternary, and it is proposed that leaf venation patterns play a role in increasing the light-use efficiency of most C4 monocots.
Abstract: The objectives of this synthesis are (1) to review the factors that influence the ecological, geographical, and palaeoecological distributions of plants possessing C4 photosynthesis and (2) to propose a hypothesis/model to explain both the distribution of C4 plants with respect to temperature and CO2 and why C4 photosynthesis is relatively uncommon in dicotyledonous plants (hereafter dicots), especially in comparison with its widespread distribution in monocotyledonous species (hereafter monocots). Our goal is to stimulate discussion of the factors controlling distributions of C4 plants today, historically, and under future elevated CO2 environments. Understanding the distributions of C3/C4 plants impacts not only primary productivity, but also the distribution, evolution, and migration of both invertebrates and vertebrates that graze on these plants. Sixteen separate studies all indicate that the current distributions of C4 monocots are tightly correlated with temperature: elevated temperatures during the growing season favor C4 monocots. In contrast, the seven studies on C4 dicot distributions suggest that a different environmental parameter, such as aridity (combination of temperature and evaporative potential), more closely describes their distributions. Differences in the temperature dependence of the quantum yield for CO2 uptake (light-use efficiency) of C3 and C4 species relate well to observed plant distributions and light-use efficiency is the only mechanism that has been proposed to explain distributional differences in C3/C4 monocots. Modeling of C3 and C4 light-use efficiencies under different combinations of atmospheric CO2 and temperature predicts that C4-dominated ecosystems should not have expanded until atmospheric CO2 concentrations reached the lower levels that are thought to have existed beginning near the end of the Miocene. At that time, palaeocarbonate and fossil data indicate a simultaneous, global expansion of C4-dominated grasslands. The C4 monocots generally have a higher quantum yield than C4 dicots and it is proposed that leaf venation patterns play a role in increasing the light-use efficiency of most C4 monocots. The reduced quantum yield of most C4 dicots is consistent with their rarity, and it is suggested that C4 dicots may not have been selected until CO2 concentrations reached their lowest levels during glacial maxima in the Quaternary. Given the intrinsic light-use efficiency advantage of C4 monocots, C4 dicots may have been limited in their distributions to the warmest ecosystems, saline ecosystems, and/or to highly disturbed ecosystems. All C4 plants have a significant advantage over C3 plants under low atmospheric CO2 conditions and are predicted to have expanded significantly on a global scale during full-glacial periods, especially in tropical regions. Bog and lake sediment cores as well as pedogenic carbonates support the hypothesis that C4 ecosystems were more extensive during the last glacial maximum and then decreased in abundance following deglaciation as atmospheric CO2 levels increased.
1,238 citations
TL;DR: Linkage data provide unique new evidence that the alpha 7-nicotinic receptor gene may be responsible for the inheritance of a pathophysiological aspect of the illness.
Abstract: Inheritance of a defect in a neuronal mechanism that regulates response to auditory stimuli was studied in nine families with multiple cases of schizophrenia. The defect, a decrease in the normal inhibition of the P50 auditory-evoked response to the second of paired stimuli, is associated with attentional disturbances in schizophrenia. Decreased P50 inhibition occurs not only in most schizophrenics, but also in many of their nonschizophrenic relatives, in a distribution consistent with inherited vulnerability for the illness. Neurobiological investigations in both humans and animal models indicated that decreased function of the α7-nicotinic cholinergic receptor could underlie the physiological defect. In the present study, a genome-wide linkage analysis, assuming autosomal dominant transmission, showed that the defect is linked [maximum logarithm of the odds (lod) score = 5.3 with zero recombination] to a dinucleotide polymorphism at chromosome 15q13-14, the site of the α7-nicotinic receptor. Despite many schizophrenics’ extremely heavy nicotine use, nicotinic receptors were not previously thought to be involved in schizophrenia. The linkage data thus provide unique new evidence that the α7-nicotinic receptor gene may be responsible for the inheritance of a pathophysiological aspect of the illness.
TL;DR: In this article, the authors compare and contrast the mode of foreign market entry decision from the transaction cost/internalization and organizational capability perspectives, and demonstrate the implications of a shift in frame from cost to value in the analysis of decisions related to firm boundaries.
Abstract: This paper compares and contrasts the mode of foreign market entry decision from the transaction cost/internalization and organizational capability perspectives. Each of these perspectives operates at a different level of analysis, respectively the transaction and the firm, and consequently differs in the primary arena of attention, namely transaction characteristics and the capabilities of firms. In making the comparison, a key distinction is made between the cost and the value aspects in the management of know-how, based on which issues pertaining to the transfer of knowledge within and across firm boundaries and the exploitation and enhancement of competitive advantage are closely examined. The main purpose of this paper is to demonstrate the implications of a shift in frame from cost to value in the analysis of decisions related to firm boundaries. Entry into foreign markets is used primarily as a vehicle for the accomplishment of this purpose. The paper shows how the value-based framework of the organizational capability perspective radically and fundamentally shifts the approach towards the governance of firm boundaries and argues that, even though TC/internalization theory raises some valid concerns, the organizational capability framework may be more in tune with today’s business context. Some of the assumptions of the TC/internalization perspective, both direct— ‐opportunism, exploitation of existing advantage—and indirect—preservation of the value of know-how across locational contexts, asymmetry between bounded rationality for transaction and production purposes—are critically examined and questioned. Implications of a shift from a cost to a value-based framework are discussed and the need for a shift in research focus is emphasized.
TL;DR: It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.
Abstract: Objective. —To provide recommendations for cancer surveillance and risk reduction for individuals carrying mutations in the BRCA1 or BRCA2 genes. Participants. —A task force with expertise in medical genetics, oncology, primary care, gastroenterology, and epidemiology convened by the Cancer Genetics Studies Consortium (CGSC), organized by National Human Genome Research Institute (previously the National Center for Human Genome Research). Evidence. —Studies evaluating cancer risk, surveillance, and risk reduction in individuals genetically susceptible to breast and ovarian cancer were identified using MEDLINE (National Library of Medicine) and from bibliographies of articles thus identified. Indexing terms used were "genetics" in combination with "breast cancer," "ovarian cancer," and "screening," or "surveillance" in combination with "cancer family" and " BRCA1 " and " BRCA2 ." For studies evaluating specific interventions, quality of evidence was assessed using criteria of the US Preventive Services Task Force. Consensus Process. —The task force developed recommendations through discussions over a 14-month period. Conclusions. —Efficacy of cancer surveillance or other measures to reduce risk in individuals who carry cancer-predisposing mutations is unknown. Based on expert opinion concerning presumptive benefit, early breast cancer and ovarian cancer screening are recommended for individuals with BRCA1 mutations and early breast cancer screening for those with BRCA2 mutations. No recommendation is made for or against prophylactic surgery (eg, mastectomy, oophorectomy); these surgeries are an option for mutation carriers, but evidence of benefit is lacking, and case reports have documented the occurrence of cancer following prophylactic surgery. It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.
TL;DR: Characterizing the mechanism by which YFH1 regulates iron homeostasis in yeast may help to define the pathologic process leading to cell damage in Friedreich's ataxia.
Abstract: The gene responsible for Friedreich's ataxia, a disease characterized by neurodegeneration and cardiomyopathy, has recently been cloned and its product designated frataxin. A gene in Saccharomyces cerevisiae was characterized whose predicted protein product has high sequence similarity to the human frataxin protein. The yeast gene (yeast frataxin homolog, YFH1) encodes a mitochondrial protein involved in iron homeostasis and respiratory function. Human frataxin also was shown to be a mitochondrial protein. Characterizing the mechanism by which YFH1 regulates iron homeostasis in yeast may help to define the pathologic process leading to cell damage in Friedreich's ataxia.
TL;DR: Estimates of amelioration times indicate that the entire Escherichia coli chromosome contains more than 600 kb of horizontally transferred, protein-coding DNA, which predicts that the E. coli and Salmonella enterica lineages have each gained and lost more than 3 megabases of novel DNA since their divergence.
Abstract: Although bacterial species display wide variation in their overall GC contents, the genes within a particular species' genome are relatively similar in base composition. As a result, sequences that are novel to a bacterial genome—i.e., DNA introduced through recent horizontal transfer—often bear unusual sequence characteristics and can be distinguished from ancestral DNA. At the time of introgression, horizontally transferred genes reflect the base composition of the donor genome; but, over time, these sequences will ameliorate to reflect the DNA composition of the new genome because the introgressed genes are subject to the same mutational processes affecting all genes in the recipient genome. This process of amelioration is evident in a large group of genes involved in host-cell invasion by enteric bacteria and can be modeled to predict the amount of time required after transfer for foreign DNA to resemble native DNA. Furthermore, models of amelioration can be used to estimate the time of introgression of foreign genes in a chromosome. Applying this approach to a 1.43-megabase continuous sequence, we have calculated that the entire Escherichia coli chromosome contains more than 600 kb of horizontally transferred, protein-coding DNA. Estimates of amelioration times indicate that this DNA has accumulated at a rate of 31 kb per million years, which is on the order of the amount of variant DNA introduced by point mutations. This rate predicts that the E. coli and Salmonella enterica lineages have each gained and lost more than 3 megabases of novel DNA since their divergence.
TL;DR: A rat homologue of unc-47 is expressed by central GABA neurons and confers vesicular GABA transport in transfected cells with kinetics and substrate specificity similar to those previously reported for synaptic vesicles from the brain, and thus VGAT is the first of a new family of neurotransmitter transporters.
Abstract: Synaptic transmission involves the regulated exocytosis of vesicles filled with neurotransmitter. Classical transmitters are synthesized in the cytoplasm, and so must be transported into synaptic vesicles. Although the vesicular transporters for monoamines and acetylcholine have been identified, the proteins responsible for packaging the primary inhibitory and excitatory transmitters, γ-aminobutyric acid (GABA) and glutamate remain unknown1,2. Studies in the nematode Caenorhabditis elegans have implicated the gene unc-47 in the release of GABA3. Here we show that the sequence of unc-47 predicts a protein with ten transmembrane domains, that the gene is expressed by GABA neurons, and that the protein colocalizes with synaptic vesicles. Further, a rat homologue of unc-47 is expressed by central GABA neurons and confers vesicular GABA transport in transfected cells with kinetics and substrate specificity similar to those previously reported for synaptic vesicles from the brain. Comparison of this vesicular GABA transporter (VGAT) with a vesicular transporter for monoamines shows that there are differences in the bioenergetic dependence of transport, and these presumably account for the differences in structure. Thus VGAT is the first of a new family of neurotransmitter transporters.
TL;DR: This is the first description of KCNE1 as an LQT gene and confirms that hminK is an integral protein of the IKS channel, which reduced IKS by shifting the voltage dependence of activation and accelerating channel deactivation.
Abstract: Ion-channel beta-subunits are ancillary proteins that co-assemble with alpha-subunits to modulate the gating kinetics and enhance stability of multimeric channel complexes. Despite their functional importance, dysfunction of potassium-channel beta-subunits has not been associated with disease. Recent physiological studies suggest that KCNE1 encodes beta-subunits (hminK) that co-assemble with KvLQT1 alpha-subunits to form the slowly activating delayed rectifier K+ (IKs) channel. Because KVLQT1 mutations cause arrhythmia susceptibility in the long QT syndrome (LQT), we hypothesized that mutations in KCNE1 also cause this disorder. Here, we define KCNE1 missense mutations in affected members of two LQT families. Both mutations (S74L, D76N) reduced IKs by shifting the voltage dependence of activation and accelerating channel deactivation. D76N hminK also had a strong dominant-negative effect. The functional consequences of these mutations would be delayed cardiac repolarization and an increased risk of arrhythmia. This is the first description of KCNE1 as an LQT gene and confirms that hminK is an integral protein of the IKs channel.
TL;DR: It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.
Abstract: Objective. —To provide recommendations for cancer surveillance and risk reduction for individuals carrying mutations associated with hereditary nonpolyposis colon cancer (HNPCC). Participants. —A task force with expertise in medical genetics, oncology, primary care, gastroenterology, and epidemiology convened by the Cancer Genetics Studies Consortium (CGSC), organized by the National Human Genome Research Institute (previously the National Center for Human Genome Research). Evidence. —Studies evaluating cancer risk, surveillance, and risk reduction in individuals genetically susceptible to colon cancer were identified using MEDLINE and bibliographies of articles thus identified. Indexing terms used were "genetics" in combination with "colon cancer," and "screening" in combination with "cancer family" and "HNPCC." For studies evaluating specific interventions, quality of evidence was assessed using criteria of the US Preventive Services Task Force. Consensus Process. —The task force developed recommendations through discussions over a 14-month period. Conclusions. —Efficacy of cancer surveillance or other measures to reduce risk in individuals who carry cancer-predisposing mutations is unknown. Based on observational studies, colonoscopy every 1 to 3 years starting at age 25 years is recommended for individuals known to have HNPCC-associated mutations. Endometrial cancer screening is also recommended, based on expert opinion concerning presumptive benefit. No recommendation is made for or against prophylactic surgery (ie, colectomy, hysterectomy); these surgeries are an option for mutation carriers, but evidence of benefit is lacking. It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.
TL;DR: The question arises as to whether aggregation is possible under suitable hypotheses on the transition rules and the production of a control species that modulates the transition rates of the myxobacteria.
Abstract: In many biological systems, movement of an organism occurs in response to a diffusible or otherwise transported signal, and in its simplest form this can be modeled by diffusion equations with advection terms of the form first derived by Patlak [Bull. of Math. Biophys., 15 (1953), pp. 311--338]. However, other systems are more accurately modeled by random walkers that deposit a nondiffusible signal that modifies the local environment for succeeding passages. In these systems, one example of which is the myxobacteria, the question arises as to whether aggregation is possible under suitable hypotheses on the transition rules and the production of a control species that modulates the transition rates. Davis [Probab. Theory Related Fields, 84 (1990), pp. 203--229] has studied this question for a certain class of random walks, and here we extend this analysis to the continuum limit of such walks. We first derive several general classes of partial differential equations that depend on how the movement rules are...
TL;DR: In this paper, the authors proposed a method to take into account the effect of temperature deviations on kinetic evaluations by combining the isoconversional principle of evaluating the activation energy with numerical integration of the equation.
Abstract: The thermal effect of a reaction makes the temperature inside the reaction system deviate from a prescribed heating program. To take into account the effect of such temperature deviations on kinetic evaluations, a computational method applicable to an arbitrary variation in temperature has been developed. The method combines the isoconversional principle of evaluating the activation energy with numerical integration of the equation, dα/dt = k[T(t)]f(α), over the actual variation of the temperature with the time, T(t). Details of the numerical algorithm are reported. A model example has been used to verify the reliability of this method as compared to an analogous method which does not account for the deviations of the temperature from a prescribed program. The method has been tested for tolerance for noise in the temperature. © 1997 by John Wiley & Sons, Inc.
TL;DR: In this article, the authors investigated the permeability structure of a fault zone in granitic rocks by laboratory testing of intact core samples from the unfaulted protolith and the two principal fault zone components; the fault core and damaged zone.
TL;DR: Mutational analysis showed that the enhanced tumorigenicity was dependent on intrinsic tyrosine kinase activity and was mediated through the carboxyl terminus, suggesting that the biological functions of ΔEGFR are due to low constitutive activation with mitogenic effects amplified by failure to attenuate signaling by receptor down-regulation.
TL;DR: Alignment of the CA(146-231) dimer with the crystal structure of the capsid amino-terminal domain provides a model for the intact protein and extends models for assembly of the central conical core of HIV-1.
Abstract: The carboxyl-terminal domain, residues 146 to 231, of the human immunodeficiency virus-1 (HIV-1) capsid protein [CA(146-231)] is required for capsid dimerization and viral assembly. This domain contains a stretch of 20 residues, called the major homology region (MHR), which is conserved across retroviruses and is essential for viral assembly, maturation, and infectivity. The crystal structures of CA(146-231) and CA(151-231) reveal that the globular domain is composed of four helices and an extended amino-terminal strand. CA(146-231) dimerizes through parallel packing of helix 2 across a dyad. The MHR is distinct from the dimer interface and instead forms an intricate hydrogen-bonding network that interconnects strand 1 and helices 1 and 2. Alignment of the CA(146-231) dimer with the crystal structure of the capsid amino-terminal domain provides a model for the intact protein and extends models for assembly of the central conical core of HIV-1.
TL;DR: It is concluded that recordings from small populations of neurons, not single units, provide a reliable source of sufficiently stimulus selective signals which should be suitable for a BCI.
Journal Article•
TL;DR: Data suggest that inactivation of PTCH function is involved in the development of at least a subset of sporadic medulloblastomas, and it is interesting that all three mutations occur in exon 17 of the PTCH gene.
Abstract: Nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin's syndrome, is an autosomal dominant disorder that predisposes to developmental defects and various forms of cancer. PTCH was recently proposed as a candidate gene for NBCCS due to its frequent mutation in basal cell carcinomas, the cancer most often associated with this syndrome. Another NBCCS-associated cancer is medulloblastoma, a common central nervous system tumor in children. Most medulloblastomas, however, occur without indication of an inherited predisposition. We have examined 24 sporadic medulloblastomas for loss of heterozygosity (LOH) at loci flanking as well as within PTCH. In cases with LOH, single-strand conformational polymorphism and sequencing analysis were performed to determine the status of the remaining PTCH allele. Microsatellite analysis indicated LOH of PTCH in 5 of 24 tumors, and in three of these cases a mutation of the remaining allele was identified. Two of the mutations were duplication insertions, and the third consisted of a single base deletion. It is interesting that all three mutations occur in exon 17 of the PTCH gene. These data suggest that inactivation of PTCH function is involved in the development of at least a subset of sporadic medulloblastomas.
TL;DR: In this article, the existence, uniqueness, stability and regularity properties of traveling-wave solutions of a bistable nonlinear integrodifferential equation are established, as well as their global asymptotic stability in the case of zero-velocity continuous waves.
Abstract: The existence, uniqueness, stability and regularity properties of traveling-wave solutions of a bistable nonlinear integrodifferential equation are established, as well as their global asymptotic stability in the case of zero-velocity continuous waves. This equation is a direct analog of the more familiar bistable nonlinear diffusion equation, and shares many of its properties. It governs gradient flows for free-energy functionals with general nonlocal interaction integrals penalizing spatial nonuniformity.
TL;DR: A common variant in the proximal promoter, the presence of an adenine, instead of a guanine, 6 bp upstream from the initiation site of transcription, in significant association with the disorder.
Abstract: In earlier studies, we provided statistical evidence that individual differences in the angiotensinogen gene, the precursor of the vasoactive hormone angiotensin II, constitute inherited predispositions to essential hypertension in humans. We have now identified a common variant in the proximal promoter, the presence of an adenine, instead of a guanine, 6 bp upstream from the initiation site of transcription, in significant association with the disorder. Tests of promoter activity and DNA binding studies with nuclear proteins suggest that this nucleotide substitution affects the basal transcription rate of the gene. These observations provide some biological insight about the possible mechanism of a genetic predisposition to essential hypertension; they may also have important evolutionary implications.
TL;DR: Two algorithms for the rejection of sinusoidal disturbances with unknown frequency are presented and the indirect algorithm is found to have a larger capture region for the parameter estimates, whereas the direct algorithm has superior convergence properties locally about the optimum parameter estimates.
TL;DR: It is demonstrated that mutations in human T8X3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families and suggested that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.
Abstract: Ulnar-mammary syndrome is a rare pleiotropic disorder affecting limb, apocrine gland, tooth and genital development. We demonstrate that mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families. Each mutation (a single nucleotide deletion and a splice-site mutation) is predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Limb abnormalities of ulnar-mammary syndrome involve posterior elements. Mutations in TBX5, a related and linked gene, cause anterior limb abnormalities in Holt-Oram syndrome. We suggest that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.
TL;DR: These animals should provide a useful genetic background on which to express other mutant opsin transgenes, as well as a model to assess the therapeutic potential of re-introducing functional rhodopsin genes into degenerating retinal tissues.
Abstract: Retinitis pigmentosa (RP) represents the most common mendelian degenerative retinopathy of man, involving death of rod photoreceptors, cone cell degeneration, retinal vessel attenuation and pigmentary deposits1,2. The patient experiences night blindness, usually followed by progressive loss of visual field. Genetic linkage between an autosomal dominant RP locus and rhodopsin3, the photoreactive pigment of the rod cells, led to the identification of mutations within the rhodopsin gene in both dominant and recessive forms of RP3–7. To better understand the functional and structural role of rhodopsin in the normal retina and in the pathogenesis of retinal disease, we generated mice carrying a targeted disruption of the rhodopsin gene. Rho−/− mice do not elaborate rod outer segments, losing their photoreceptors over 3 months. There is no rod ERG response in 8-week-old animals. Rho+/− animals retain the majority of their photoreceptors although the inner and outer segments of these cells display some structural disorganization, the outer segments becoming shorter in older mice. These animals should provide a useful genetic background on which to express other mutant opsin transgenes, as well as a model to assess the therapeutic potential of re-introducing functional rhodopsin genes into degenerating retinal tissues.