Showing papers by "University of Utah published in 2005"
TL;DR: The development, current features, and some directions for future development of the Amber package of computer programs, which contains a group of programs embodying a number of powerful tools of modern computational chemistry, focused on molecular dynamics and free energy calculations of proteins, nucleic acids, and carbohydrates.
Abstract: We describe the development, current features, and some directions for future development of the Amber package of computer programs. This package evolved from a program that was constructed in the late 1970s to do Assisted Model Building with Energy Refinement, and now contains a group of programs embodying a number of powerful tools of modern computational chemistry, focused on molecular dynamics and free energy calculations of proteins, nucleic acids, and carbohydrates.
7,672 citations
27 Oct 2005
TL;DR: A public database of common variation in the human genome: more than one million single nucleotide polymorphisms for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted.
Abstract: Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.
5,479 citations
31 Jul 2005
3,259 citations
TL;DR: In this article, the trustworthiness or credibility of qualitative research is examined, and a discussion of more transcendent standards for conducting quality research: social validity, subjectivity and reflexivity, adequacy of data, and adequacy for interpretation.
Abstract: This article examines concepts of the trustworthiness, or credibility, of qualitative research. Following a “researcher-as-instrument,” or self-reflective, statement, the paradigmatic underpinnings of various criteria for judging the quality of qualitative research are explored, setting the stage for a discussion of more transcendent standards (those not associated with specific paradigms) for conducting quality research: social validity, subjectivity and reflexivity, adequacy of data, and adequacy of interpretation. Finally, current guidelines for writing and publishing qualitative research are reviewed, and strategies for conducting and writing qualitative research reports are suggested. Qualitative research, ensuing from a variety of disciplines, paradigms, and epistemologies, embraces multiple standards of quality, known variously as validity, credibility, rigor ,o rtrustworthiness. In addition to some standards that may be thought of as somewhat universal across disciplines and paradigms, the “goodness” (Morrow & Smith, 2000) of qualitative inquiry is assessed on the basis of the paradigmatic underpinnings of the research and the standards of the discipline. Thus, a grounded theory study or a consensual qualitative research investigation in counseling psychology that is rooted in a postpositivist or constructivist/interpretivist paradigm will look quite different from a critical ethnography in education; and the standards appropriate for evaluating these studies will vary accordingly. I begin this article by addressing the paradigmatic underpinnings of trustworthiness or rigor in qualitative research. Next, I discuss central topics related to trustworthiness or validity that span paradigms and may be thought of as relevant across most research designs. I then provide an overview of guidelines that have been suggested for evaluating qualitative research, particularly in psychology. Finally, I offer recommendations for enhancing the quality of qualitative research in counseling psychology and suggest strategies for writing and publishing. First, however, in keeping with the standard of reflexivity as a way for researchers to inform their audiences about their perspectives as well as to manage their subjectivities, I describe my own assumptions about qualitative research methodology and quality.
3,100 citations
TL;DR: The physical basis for electrical stimulation of excitable tissue, as used by electrophysiological researchers and clinicians in functional electrical stimulation, is presented with emphasis on the fundamental mechanisms of charge injection at the electrode/tissue interface.
1,875 citations
TL;DR: This review presents the biological components and time course of the acute and chronic tissue reaction in brain tissue, analyses the brain tissue response of current electrode systems, and comments on the various material science and bioactive strategies undertaken by electrode designers to enhance electrode performance.
1,741 citations
TL;DR: It is reported that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury and epithelial cell apoptosis after lung injury.
Abstract: Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.
1,329 citations
TL;DR: It is shown that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding CCL3L1, a potent human immunodeficiency virus–1 (HIV-1)–suppressive chemokine and ligand for the HIV coreceptor CCR5.
Abstract: Segmental duplications in the human genome are selectively enriched for genes involved in immunity, although the phenotypic consequences for host defense are unknown. We show that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding CCL3L1 (MIP-1αP), a potent human immunodeficiency virus–1 (HIV-1)–suppressive chemokine and ligand for the HIV coreceptor CCR5. Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This susceptibility is even greater in individuals who also possess disease-accelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis and indicates that differences in the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases.
1,205 citations
TL;DR: Fast-food consumption has strong positive associations with weight gain and insulin resistance, suggesting that fast food increases the risk of obesity and type 2 diabetes.
1,192 citations
TL;DR: It is concluded that the early, highly significant renoprotection obtained with MSC is of considerable therapeutic promise for the cell-based management of clinical ARF.
Abstract: Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent me...
1,155 citations
TL;DR: It is shown that the intrinsic plasticity of the protein is a key characteristic of catalysis, and the pre-existence of collective dynamics in enzymes before catalysis is a common feature of biocatalysts and that proteins have evolved under synergy pressure between structure and dynamics.
Abstract: A unique feature of chemical catalysis mediated by enzymes is that the catalytically reactive atoms are embedded within a folded protein. Although current understanding of enzyme function has been focused on the chemical reactions and static three-dimensional structures, the dynamic nature of proteins has been proposed to have a function in catalysis. The concept of conformational substates has been described; however, the challenge is to unravel the intimate linkage between protein flexibility and enzymatic function. Here we show that the intrinsic plasticity of the protein is a key characteristic of catalysis. The dynamics of the prolyl cis-trans isomerase cyclophilin A (CypA) in its substrate-free state and during catalysis were characterized with NMR relaxation experiments. The characteristic enzyme motions detected during catalysis are already present in the free enzyme with frequencies corresponding to the catalytic turnover rates. This correlation suggests that the protein motions necessary for catalysis are an intrinsic property of the enzyme and may even limit the overall turnover rate. Motion is localized not only to the active site but also to a wider dynamic network. Whereas coupled networks in proteins have been proposed previously, we experimentally measured the collective nature of motions with the use of mutant forms of CypA. We propose that the pre-existence of collective dynamics in enzymes before catalysis is a common feature of biocatalysts and that proteins have evolved under synergistic pressure between structure and dynamics.
TL;DR: The method is demonstrated by applying it to derive a CG model for the dimyristoylphosphatidylcholine (DMPC) lipid bilayer to accurately reproduce the structural properties of the phospholipid bilayer.
Abstract: A new approach is presented for obtaining coarse-grained (CG) force fields from fully atomistic molecular dynamics (MD) trajectories. The method is demonstrated by applying it to derive a CG model for the dimyristoylphosphatidylcholine (DMPC) lipid bilayer. The coarse-graining of the interparticle force field is accomplished by an application of a force-matching procedure to the force data obtained from an explicit atomistic MD simulation of the biomolecular system of interest. Hence, the method is termed a "multiscale" CG (MS-CG) approach in which explicit atomistic-level forces are propagated upward in scale to the coarse-grained level. The CG sites in the lipid bilayer application were associated with the centers-of-mass of atomic groups because of the simplicity in the evaluation of the forces acting on them from the atomistic data. The resulting CG lipid bilayer model is shown to accurately reproduce the structural properties of the phospholipid bilayer.
TL;DR: It is shown that zebrafish golden mutants share these melanosomal changes and that golden encodes a putative cation exchanger slc24a5 (nckx5) that localizes to an intracellular membrane, likely the melanosome or its precursor.
Abstract: Lighter variations of pigmentation in humans are associated with diminished number, size, and density of melanosomes, the pigmented organelles of melanocytes. Here we show that zebrafish golden mutants share these melanosomal changes and that golden encodes a putative cation exchanger slc24a5 (nckx5) that localizes to an intracellular membrane, likely the melanosome or its precursor. The human ortholog is highly similar in sequence and functional in zebrafish. The evolutionarily conserved ancestral allele of a human coding polymorphism predominates in African and East Asian populations. In contrast, the variant allele is nearly fixed in European populations, is associated with a substantial reduction in regional heterozygosity, and correlates with lighter skin pigmentation in admixed populations, suggesting a key role for the SLC24A5 gene in human pigmentation.
TL;DR: This work has shown how binding specificity is determined, how ubiquitin binding is regulated, and the function of UBDs in the context of full-length proteins is controlled by studying their mechanism of action.
Abstract: Ubiquitin-binding domains (UBDs) are a collection of modular protein domains that non-covalently bind to ubiquitin. These recently discovered motifs interpret and transmit information conferred by protein ubiquitylation to control various cellular events. Detailed molecular structures are known for a number of UBDs, but to understand their mechanism of action, we also need to know how binding specificity is determined, how ubiquitin binding is regulated, and the function of UBDs in the context of full-length proteins. Such knowledge will be key to our understanding of how ubiquitin regulates cellular proteins and processes.
TL;DR: It is demonstrated that PGC-1α is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.
Abstract: The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was targeted in mice. PGC-1α null (PGC-1α−/−) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1α−/− mice. With age, the PGC-1α−/− mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1α−/− mice, leading to reduced muscle performance and exercise capacity. PGC-1α−/− mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1α−/− mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1α−/− mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1α−/− mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1α−/− mice. These results demonstrate that PGC-1α is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.
TL;DR: The precipitation maps show that the greatest potential for applying hydrogen and oxygen isotope forensics exists in mid- to high-latitude continental regions, where strong spatial isotope gradients exist and where strong, mechanistic relationships link precipitation and isotope ratios in biological tissue exist.
Abstract: Stable isotopes are being increasingly used in wildlife forensics as means of determining the origin and movement of animals. The heavy isotope content of precipitated water and snow (dDp, d 18 Op) varies widely and systematically across the globe, providing a label that is incorporated through diet into animal tissue. As a result, these isotopes are potentially ideal tracers of geo- graphic origin. The hydrogen and oxygen isotope tracer method has excellent potential where (1) spatial variation of precipitation isotopes exist, and (2) strong, mechanistic relationships link precipitation and isotope ratios in biological tissue. Here, we present a method for inter- polation of precipitation isotope values and use it to create global basemaps of growing-season (GS) and mean annual (MA) dDp and d 18 Op. The use of these maps for forensic application is demonstrated using previously published isotope data for bird feathers (dDf) in North America and Europe. The precipitation maps show that the greatest potential for applying hydrogen and oxygen isotope forensics exists in mid- to high-latitude conti- nental regions, where strong spatial isotope gradients exist. We demonstrate that dDf/dDp relationships have significant predictive power both in North America and Europe, and show how zones of confidence for the assignment of origin can be described using these predic- tive relationships. Our analysis focuses on wildlife forensics, but the maps and approaches presented here will be equally applicable to criminal forensic studies involving biological materials. These maps are available in GIS format at http://www.waterisotopes.org.
Posted Content•
TL;DR: This article proposed a theoretical model in which the supply of and demand for socially responsible investment opportunities determines whether these activities will improve, reduce, or have no impact on a firm's market value.
Abstract: Debates continue to rage between those that argue that managers should maximize the present value of their firm's cash flows in making strategic choices and those that argue that, sometimes, the wealth maximizing interests of a firm's equity holders should be abandoned for the good of a firm's other stakeholders. This debate is addressed by proposing a theoretical model in which the supply of and demand for socially responsible investment opportunities determines whether these activities will improve, reduce, or have no impact on a firm's market value. The theory shows that managers in publicly traded firms might fund socially responsible activities that do not maximize the present value of its future cash flows yet still maximize the market value of their firm.
TL;DR: A multiscale coarse-graining model for ionic liquids has been extended and it has been found that, with sufficiently long side chains, the tail groups of cations aggregate to form spatially heterogeneous domains, while headgroups of the cations and the anions distribute as uniformly as possible.
Abstract: A multiscale coarse-graining model for ionic liquids has been extended to investigate the unique aggregation of cations in ionic liquids through computer simulation. It has been found that, with sufficiently long side chains, the tail groups of cations aggregate to form spatially heterogeneous domains, while headgroups of the cations and the anions distribute as uniformly as possible. This is understood as the result of competition between the charged electrostatic interactions between headgroups and anions and the collective short-range interactions between the neutral tail groups. This aggregation can help to explain a number of experimentally observed physical phenomena in ionic liquids.
Royal College of Surgeons in Ireland1, Columbia University2, Rotunda Hospital3, Brown University4, University of Utah5, Beaumont Hospital6, Icahn School of Medicine at Mount Sinai7, Yeshiva University8, University of Colorado Denver9, Tufts University10, New York University11, University of North Carolina at Chapel Hill12, Queen Mary University of London13, University College London14
TL;DR: First-trimester combined screening at 11 weeks of gestation is better than secondtrimester quadruple screening but at 13 weeks has results similar to second-tr pregnancy quadruple screened, except for the comparison between serum integrated screening and combined screening.
Abstract: background It is uncertain how best to screen pregnant women for the presence of fetal Down’s syndrome: to perform first-trimester screening, to perform second-trimester screening, or to use strategies incorporating measurements in both trimesters. methods Women with singleton pregnancies underwent first-trimester combined screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free beta subunit of human chorionic gonadotropin at 10 weeks 3 days through 13 weeks 6 days of gestation) and second-trimester quadruple screening (measurement of alpha-fetoprotein, total human chorionic gonadotropin, unconjugated estriol, and inhibin A at 15 through 18 weeks of gestation). We compared the results of stepwise sequential screening (risk results provided after each test), fully integrated screening (single risk result provided), and serum integrated screening (identical to fully integrated screening, but without nuchal translucency). results First-trimester screening was performed in 38,167 patients; 117 had a fetus with Down’s syndrome. At a 5 percent false positive rate, the rates of detection of Down’s syndrome were as follows: with first-trimester combined screening, 87 percent, 85 percent, and 82 percent for measurements performed at 11, 12, and 13 weeks, respectively; with second-trimester quadruple screening, 81 percent; with stepwise sequential screening, 95 percent; with serum integrated screening, 88 percent; and with fully integrated screening with first-trimester measurements performed at 11 weeks, 96 percent. Paired comparisons found significant differences between the tests, except for the comparison between serum integrated screening and combined screening. conclusions First-trimester combined screening at 11 weeks of gestation is better than secondtrimester quadruple screening but at 13 weeks has results similar to second-trimester quadruple screening. Both stepwise sequential screening and fully integrated screening have high rates of detection of Down’s syndrome, with low false positive rates.
TL;DR: The program is rooted in the idea that American Indians can engage in the process of educating themselves, and can do so through both Indigenous wisdom and knowledges often found in dominant society as discussed by the authors.
Abstract: Recently, I attended a celebration for the graduating cohort of the University of Utah’s American Indian Teacher Training Program (AITTP). 1 The AITTP is a program that prepares American Indians to become teachers with the stipulation that they teach in Indian-serving schools upon their graduation. The program is rooted in the idea that American Indians can engage in the process of educating themselves, and can do so through both Indigenous wisdom and knowledges often found in dominant society. The eight graduates had worked for two years in an institution that often devalued their presence. They were joined by 180 family members and supporters for the celebration. During the course of the evening, each graduate had an opportunity to speak to the assembled group. Every graduate thanked the many family members who contributed to their academic successes, and each told a story about why they wanted to be a teacher and what it meant for their communities. One of the graduates said, ‘‘I struggled in school for a long time, not knowing whether or not I was able to do this work. Now I know I am.’’ She continued by stating, ‘‘Now, I
Book•
01 Jan 2005TL;DR: In this paper, the authors discuss the colonial origins of international law and the legacies of the mandate system: toward the present and conclude that the post-colonization and post-colonial state are the peripheries of the universal international law.
Abstract: Acknowledgements Table of cases Table of treaties Introduction 1. Francisco de Vitoria and the colonial origins of international law (i) Introduction (ii) Vitoria and the problem of universal law (iii) War, sovereignty and the transformation of the Indian (iv) Conclusion 2. Finding the peripheries: colonialism in nineteenth-century international law (i) Introduction (ii) Elements of positivist jurisprudence (iii) Defining and excluding the uncivilized (iv) Native personality and managing the colonial encounter (v) Reconceptualizing sovereignty 3. Colonialism and the birth of international institutions: the mandate of the League of Nations (i) Introduction (ii) Creation of the mandate system (iii) The league of nations and the new international law (iv) The mandate system and colonial problems (v) The mandate system and the construction of the non-European state (vi) Government, sovereignty, and economy (vii) The mandate and the discussion of sovereignty (viii) The legacies of the mandate system: toward the present (ix) Conclusion 4. Sovereignty and the post-colonial state (i) Introduction (ii) Decolonization and the universality of international law (iii) Development, nationalism and the post-colonial state (iv) Development and the reform of international law (v) Permanent sovereignty over natural resource and the new international economic order (vi) The 1962 resolution on PSNR (vii) The 1974 charter of rights and duties among states (viii) Colonialism and the emergence of transnational law (ix) Sources of law and international contracts (x) Overview and conclusions 5. Governance and globalization, civilization and commerce (i) Introduction (ii) Good governance and the third world (iii) Governance, human rights and the universal (iv) International financial institutions, human rights and good governance (v) International financial institutions and the mandate system (vi) Conclusions and overview 6. On making war on the terrorists: imperialism as self-defense (i) Introduction (ii) The war against terrorism (WAT) (iii) The United States and imperial democracy (iv) Historical origins: war, conquest and self-defense (v) Terrorism and the United Nations: a Victorian moment (vi) Terrorism, self-defense and third world sovereignty Conclusion.
TL;DR: Total WBC count is confirmed to be an independent predictor of death/MI in patients with or at high risk for CAD, but greater predictive ability is provided by high N (Q4 >6.6 x 10(3)/microl) or low L counts.
TL;DR: Persistent ED1 up-regulation and neuronal loss was not observed in microelectrode stab controls indicating that the phenotype did not result from the initial mechanical trauma of electrode implantation, but was associated with the foreign body response.
TL;DR: In this article, it was shown that the Omo I and Omo II hominid fossils are from similar stratigraphic levels in Member I of the Kibish Formation.
Abstract: In 1967 the Kibish Formation in southern Ethiopia yielded hominid cranial remains identified as early anatomically modern humans, assigned to Homo sapiens. However, the provenance and age of the fossils have been much debated. Here we confirm that the Omo I and Omo II hominid fossils are from similar stratigraphic levels in Member I of the Kibish Formation, despite the view that Omo I is more modern in appearance than Omo II. 40Ar/39Ar ages on feldspar crystals from pumice clasts within a tuff in Member I below the hominid levels place an older limit of 198 +/- 14 kyr (weighted mean age 196 +/- 2 kyr) on the hominids. A younger age limit of 104 +/- 7 kyr is provided by feldspars from pumice clasts in a Member III tuff. Geological evidence indicates rapid deposition of each member of the Kibish Formation. Isotopic ages on the Kibish Formation correspond to ages of Mediterranean sapropels, which reflect increased flow of the Nile River, and necessarily increased flow of the Omo River. Thus the 40Ar/39Ar age measurements, together with the sapropel correlations, indicate that the hominid fossils have an age close to the older limit. Our preferred estimate of the age of the Kibish hominids is 195 +/- 5 kyr, making them the earliest well-dated anatomically modern humans yet described.
TL;DR: Results show that CKIδ is a central component in the mammalian clock, and suggest that mammalian and fly clocks might have different regulatory mechanisms despite the highly conserved nature of their individual components.
Abstract: Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening. It was the first human, mendelian circadian rhythm variant to be well-characterized, and was shown to result from a mutation in a phosphorylation site within the casein kinase I (CKI)-binding domain of the human PER2 gene. To gain a deeper understanding of the mechanisms of circadian rhythm regulation in humans, we set out to identify mutations in human subjects leading to FASPS. We report here the identification of a missense mutation (T44A) in the human CKIdelta gene, which results in FASPS. This mutant kinase has decreased enzymatic activity in vitro. Transgenic Drosophila carrying the human CKIdelta-T44A gene showed a phenotype with lengthened circadian period. In contrast, transgenic mice carrying the same mutation have a shorter circadian period, a phenotype mimicking human FASPS. These results show that CKIdelta is a central component in the mammalian clock, and suggest that mammalian and fly clocks might have different regulatory mechanisms despite the highly conserved nature of their individual components.
TL;DR: It is concluded that the BRAF V600E mutation in microsatellite-stable colon cancer is associated with a significantly poorer survival in stages 2 to 4 colon cancer but has no effect on the excellent prognosis of micros satellite-unstable tumors.
Abstract: The BRAF V600E mutation has been associated with microsatellite instability and the CpG island methylator phenotype (CIMP) in colon cancer. We evaluated a large population-based sample of individuals with colon cancer to determine its relationship to survival and other clinicopathologic variables. The V600E BRAF mutation was seen in 5% (40 of 803) of microsatellite-stable tumors and 51.8% (43 of 83) of microsatellite-unstable tumors. In microsatellite-stable tumors, this mutation was related to poor survival, CIMP high, advanced American Joint Committee on Cancer (AJCC) stage, and family history of colorectal cancer [odds ratio, 4.23; 95% confidence interval (95% CI), 1.65-10.84]. The poor survival was observed in a univariate analysis of 5-year survival (16.7% versus 60.0%; P < 0.01); in an analysis adjusted for age, stage, and tumor site [hazard rate ratio (HRR), 2.97; 95% CI, 2.05-4.32]; in stage-specific, age-adjusted analyses for AJCC stages 2 to 4 (HRR, 4.88, 3.60, and 2.04, respectively); and in Kaplan-Meier survival estimates for AJCC stages 2 to 4 (P < 0.01 for all three stages). Microsatellite-unstable tumors were associated with an excellent 5-year survival whether the V600E mutation was present or absent (76.2% and 75.0%, respectively). We conclude that the BRAF V600E mutation in microsatellite-stable colon cancer is associated with a significantly poorer survival in stages 2 to 4 colon cancer but has no effect on the excellent prognosis of microsatellite-unstable tumors.
TL;DR: Zinc finger nucleases show promise in improving the efficiency of gene targeting by introducing DNA double-strand breaks in target genes, which then stimulate the cell's endogenous homologous recombination machinery.
Abstract: The ability to achieve site-specific manipulation of the mammalian genome has widespread implications for basic and applied research. Gene targeting is a process in which a DNA molecule introduced into a cell replaces the corresponding chromosomal segment by homologous recombination, and thus presents a precise way to manipulate the genome. In the past, the application of gene targeting to mammalian cells has been limited by its low efficiency. Zinc finger nucleases (ZFNs) show promise in improving the efficiency of gene targeting by introducing DNA double-strand breaks in target genes, which then stimulate the cell's endogenous homologous recombination machinery. Recent results have shown that ZFNs can be used to create targeting frequencies of up to 20% in a human disease-causing gene. Future work will be needed to translate these in vitro findings to in vivo applications and to determine whether zinc finger nucleases create undesired genomic instability.
TL;DR: In this paper, the authors evaluate five methods of deducing firm-specific cost of equity capital (r) from the market's future cash flow forecast and current stock price, and conclude that rDIVPREM and rPEGPREM dominate the alternatives.
Abstract: Managers, investors, and researchers have a compelling interest in identifying a reliable empirical proxy for firm‐specific cost of equity capital (r). In theory, deducing r is possible if the market's future cash flow forecast and current stock price are observable. Practically, deducing r is dependent on the ability to estimate the market's forecasted terminal value. We evaluate five methods of deducing firm‐specific r (labeled rDIVPREM, rGLSPREM, rGORPREM, rOJNPREM, and rPEGPREM) that deal with this conundrum differently. The extent to which the estimates are associated with firm risk in a stable and meaningful manner is the basis for our assessment. We find that the rDIVPREM and rPEGPREM estimates are consistently and predictably related to risk, while the alternatives are not. Based on these results, we conclude that rDIVPREM and rPEGPREM dominate the alternatives.
TL;DR: Recent advances in the field of mitochondrial dynamics are reviewed and the importance of these pathways to human health is highlighted.
Abstract: Mitochondria form dynamic tubular networks that continually change their shape and move throughout the cell. In eukaryotes, these organellar gymnastics are controlled by numerous pathways that preserve proper mitochondrial morphology and function. The best understood of these are the fusion and fission pathways, which rely on conserved GTPases and their binding partners to regulate organelle connectivity and copy number in healthy cells and during apoptosis. In budding yeast, mitochondrial shape is also maintained by proteins acting in the tubulation pathway. Novel proteins and pathways that control mitochondrial dynamics continue to be discovered, indicating that the mechanisms governing this organelle's behavior are more sophisticated than previously appreciated. Here we review recent advances in the field of mitochondrial dynamics and highlight the importance of these pathways to human health.
TL;DR: In this paper, a simplified water-balance model is proposed for con- ceptualizing how woody plant encroachment is likely to affect components of the water cycle within these ecosystems.
Abstract: Increases in the abundance or density of woody plants in historically semiarid and arid grassland ecosystems have important ecological, hydrological, and socioeconomic implications. Using a simplified water-balance model, we propose a framework for con- ceptualizing how woody plant encroachment is likely to affect components of the water cycle within these ecosystems. We focus in particular on streamflow and the partitioning of evapotranspiration into evaporation and transpiration. On the basis of this framework, we suggest that streamflow and evaporation processes are affected by woody plant en- croachment in different ways, depending on the degree and seasonality of aridity and the availability of subsurface water. Differences in landscape physiography, climate, and runoff mechanisms mediate the influence of woody plants on hydrological processes. Streamflow is expected to decline as a result of woody plant encroachment in landscapes dominated by subsurface flow regimes. Similarly, encroachment of woody plants can be expected to produce an increase in the fractional contribution of bare soil evaporation to evapotrans- piration in semiarid ecosystems, whereas such shifts may be small or negligible in both subhumid and arid ecosystems. This framework for considering the effects of woody plant encroachment highlights important ecological and hydrological interactions that serve as a basis for predicting other ecological aspects of vegetation change—such as potential changes in carbon cycling within an ecosystem. In locations where woody plant encroach- ment results in increased plant transpiration and concurrently the availability of soil water is reduced, increased accumulation of carbon in soils emerges as one prediction. Thus, explicitly considering the ecohydrological linkages associated with vegetation change pro- vides needed information on the consequences of woody plant encroachment on water yield, carbon cycling, and other processes.