Molecular analysis demonstrates high prevalence of chloroquine resistance but no evidence of artemisinin resistance in Plasmodium falciparum in the Chittagong Hill Tracts of Bangladesh.

PubMed

Alam, Mohammad Shafiul; Ley, Benedikt; Nima, Maisha Khair; Johora, Fatema Tuj; Hossain, Mohammad Enayet; Thriemer, Kamala; Auburn, Sarah; Marfurt, Jutta; Price, Ric N; Khan, Wasif A

2017-08-15

Artemisinin resistance is present in the Greater Mekong region and poses a significant threat for current anti-malarial treatment guidelines in Bangladesh. The aim of this molecular study was to assess the current status of drug resistance in the Chittagong Hill Tracts of Bangladesh near the Myanmar border. Samples were obtained from patients enrolled into a Clinical Trial (NCT02389374) conducted in Alikadam, Bandarban between August 2014 and January 2015. Plasmodium falciparum infections were confirmed by PCR and all P. falciparum positive isolates genotyped for the pfcrt K76T and pfmdr1 N86Y markers. The propeller region of the kelch 13 (k13) gene was sequenced from isolates from patients with delayed parasite clearance. In total, 130 P. falciparum isolates were available for analysis. The pfcrt mutation K76T, associated with chloroquine resistance was found in 81.5% (106/130) of cases and the pfmdr1 mutation N86Y in 13.9% (18/130) cases. No single nucleotide polymorphisms were observed in the k13 propeller region. This study provides molecular evidence for the ongoing presence of chloroquine resistant P. falciparum in Bangladesh, but no evidence of mutations in the k13 propeller domain associated with artemisinin resistance. Monitoring for artemisinin susceptibility in Bangladesh is needed to ensure early detection and containment emerging anti-malarial resistance.

Finding optimal vaccination strategies for pandemic influenza using genetic algorithms.

PubMed

Patel, Rajan; Longini, Ira M; Halloran, M Elizabeth

2005-05-21

In the event of pandemic influenza, only limited supplies of vaccine may be available. We use stochastic epidemic simulations, genetic algorithms (GA), and random mutation hill climbing (RMHC) to find optimal vaccine distributions to minimize the number of illnesses or deaths in the population, given limited quantities of vaccine. Due to the non-linearity, complexity and stochasticity of the epidemic process, it is not possible to solve for optimal vaccine distributions mathematically. However, we use GA and RMHC to find near optimal vaccine distributions. We model an influenza pandemic that has age-specific illness attack rates similar to the Asian pandemic in 1957-1958 caused by influenza A(H2N2), as well as a distribution similar to the Hong Kong pandemic in 1968-1969 caused by influenza A(H3N2). We find the optimal vaccine distributions given that the number of doses is limited over the range of 10-90% of the population. While GA and RMHC work well in finding optimal vaccine distributions, GA is significantly more efficient than RMHC. We show that the optimal vaccine distribution found by GA and RMHC is up to 84% more effective than random mass vaccination in the mid range of vaccine availability. GA is generalizable to the optimization of stochastic model parameters for other infectious diseases and population structures.

A Multisite Cluster Randomized Field Trial of Open Court Reading

ERIC Educational Resources Information Center

Borman, Geoffrey D.; Dowling, N. Maritza; Schneck, Carrie

2008-01-01

In this article, the authors report achievement outcomes of a multisite cluster randomized field trial of Open Court Reading 2005 (OCR), a K-6 literacy curriculum published by SRA/McGraw-Hill. The participants are 49 first-grade through fifth-grade classrooms from predominantly minority and poor contexts across the nation. Blocking by grade level…

One-step random mutagenesis by error-prone rolling circle amplification

PubMed Central

Fujii, Ryota; Kitaoka, Motomitsu; Hayashi, Kiyoshi

2004-01-01

In vitro random mutagenesis is a powerful tool for altering properties of enzymes. We describe here a novel random mutagenesis method using rolling circle amplification, named error-prone RCA. This method consists of only one DNA amplification step followed by transformation of the host strain, without treatment with any restriction enzymes or DNA ligases, and results in a randomly mutated plasmid library with 3–4 mutations per kilobase. Specific primers or special equipment, such as a thermal-cycler, are not required. This method permits rapid preparation of randomly mutated plasmid libraries, enabling random mutagenesis to become a more commonly used technique. PMID:15507684

Improved classification accuracy by feature extraction using genetic algorithms

NASA Astrophysics Data System (ADS)

Patriarche, Julia; Manduca, Armando; Erickson, Bradley J.

2003-05-01

A feature extraction algorithm has been developed for the purposes of improving classification accuracy. The algorithm uses a genetic algorithm / hill-climber hybrid to generate a set of linearly recombined features, which may be of reduced dimensionality compared with the original set. The genetic algorithm performs the global exploration, and a hill climber explores local neighborhoods. Hybridizing the genetic algorithm with a hill climber improves both the rate of convergence, and the final overall cost function value; it also reduces the sensitivity of the genetic algorithm to parameter selection. The genetic algorithm includes the operators: crossover, mutation, and deletion / reactivation - the last of these effects dimensionality reduction. The feature extractor is supervised, and is capable of deriving a separate feature space for each tissue (which are reintegrated during classification). A non-anatomical digital phantom was developed as a gold standard for testing purposes. In tests with the phantom, and with images of multiple sclerosis patients, classification with feature extractor derived features yielded lower error rates than using standard pulse sequences, and with features derived using principal components analysis. Using the multiple sclerosis patient data, the algorithm resulted in a mean 31% reduction in classification error of pure tissues.

Voluntary EMG-to-force estimation with a multi-scale physiological muscle model

PubMed Central

2013-01-01

Background EMG-to-force estimation based on muscle models, for voluntary contraction has many applications in human motion analysis. The so-called Hill model is recognized as a standard model for this practical use. However, it is a phenomenological model whereby muscle activation, force-length and force-velocity properties are considered independently. Perreault reported Hill modeling errors were large for different firing frequencies, level of activation and speed of contraction. It may be due to the lack of coupling between activation and force-velocity properties. In this paper, we discuss EMG-force estimation with a multi-scale physiology based model, which has a link to underlying crossbridge dynamics. Differently from the Hill model, the proposed method provides dual dynamics of recruitment and calcium activation. Methods The ankle torque was measured for the plantar flexion along with EMG measurements of the medial gastrocnemius (GAS) and soleus (SOL). In addition to Hill representation of the passive elements, three models of the contractile parts have been compared. Using common EMG signals during isometric contraction in four able-bodied subjects, torque was estimated by the linear Hill model, the nonlinear Hill model and the multi-scale physiological model that refers to Huxley theory. The comparison was made in normalized scale versus the case in maximum voluntary contraction. Results The estimation results obtained with the multi-scale model showed the best performances both in fast-short and slow-long term contraction in randomized tests for all the four subjects. The RMS errors were improved with the nonlinear Hill model compared to linear Hill, however it showed limitations to account for the different speed of contractions. Average error was 16.9% with the linear Hill model, 9.3% with the modified Hill model. In contrast, the error in the multi-scale model was 6.1% while maintaining a uniform estimation performance in both fast and slow contractions schemes. Conclusions We introduced a novel approach that allows EMG-force estimation based on a multi-scale physiology model integrating Hill approach for the passive elements and microscopic cross-bridge representations for the contractile element. The experimental evaluation highlights estimation improvements especially a larger range of contraction conditions with integration of the neural activation frequency property and force-velocity relationship through cross-bridge dynamics consideration. PMID:24007560

Prevalence of anemia, iron deficiency, thalassemia and glucose-6-phosphate dehydrogenase deficiency among hill-tribe school children in Omkoi District, Chiang Mai Province, Thailand.

PubMed

Yanola, Jintana; Kongpan, Chatpat; Pornprasert, Sakorn

2014-07-01

The prevalaence of anemia, iron deficiency, thalassemia and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency were examined among 265 hill-tribe school children, 8-14 years of age, from Omkoi District, Chiang Mai Province, Thailand. Anemia was observed in 20 school children, of whom 3 had iron deficiency anemia. The prevalence of G-6-PD deficiency and β-thalassemia trait [codon 17 (A>T), IVSI-nt1 (G>T) and codons 71/72 (+A) mutations] was 4% and 8%, respectively. There was one Hb E trait, and no α-thalassemia-1 SEA or Thai type deletion. Furthermore, anemia was found to be associated with β-thalassemia trait in 11 children. These data can be useful for providing appropriate prevention and control of anemia in this region of Thailand.

Atmospheric Propagation Modeling Indicates Homing Pigeons use Loft-Specific Infrasonic 'Map' Cues

NASA Astrophysics Data System (ADS)

Hagstrum, J. T.; Baker, L. M.; Spritzer, J. M.; McKenna, M. H.

2011-12-01

Pigeons (Columba livia) released at distant sites commonly depart in directions significantly off the actual homeward bearing. Such site-dependent deviations, or biases, for birds from a given loft are generally stable over time, but can also change from hour to hour, day to day, and year to year. At some release sites, birds consistently vanish in random directions and have longer flight times and lower return rates. Release sites characterized by frequent disorientation are not uncommon for pigeon lofts in both Europe and the USA. One such site is the Jersey Hill fire tower in upstate New York located ~120 km W of the Cornell loft in Ithaca. Cornell birds released at Jersey Hill between 1968 and 1987 almost always vanished randomly, although birds from other lofts had little difficulty orienting there. The results for one day, however, stand out: on August 13, 1969, Cornell birds released at Jersey Hill vanished consistently to the NE (r = 0.921; n=7) and returned home after normal flight times. Cornell pigeons released the next day again showed 'normal' behavior for the site and departed randomly. If, in fact, the birds are using acoustic cues to navigate, the long-term acoustic 'dead' zone we propose for Jersey Hill, due to prevailing atmospheric conditions, indicates that the cues are coming from a single, relatively restricted area, most likely surrounding the home loft. We have modeled the transmission of infrasonic waves, presumably coupled to the atmosphere from ocean-generated microseisms (0.14 Hz), between the Cornell loft and a number of release sites using HARPA (Hamiltonian Acoustic Ray-tracing Program for the Atmosphere) and rawinsonde data collected near Albany and Buffalo, NY. The HARPA modeling shows that acoustic signals from the Cornell loft reached Jersey Hill only on a few release days with unusual atmospheric conditions, including August 13, and were launched at angles less than ~2° above horizontal, most likely from steep-sided terrain in the loft vicinity. Such low angles would require sound waves to be diffracted around intervening topography, and likely explains why birds released on August 13 vanished from Jersey Hill at a mean direction to the NE (33°) and not closer to the homeward bearing (85°). Cornell birds released at many sites have departure bearings consistent with such topographic effects. At the Dryden III release site just 13 km E of the Cornell loft, pigeons generally departed to the NW (321°, n=630), ~60° off the homeward bearing (258°). Apparently, infrasonic signals from the home loft area were being diffracted around higher terrain between the loft and release site.

Entomofaunal diversity of tree hole mosquitoes in Western and Eastern Ghats hill ranges of Tamilnadu, India.

PubMed

Senthamarai Selvan, P; Jebanesan, A; Reetha, D

2016-07-01

The distribution and abundance of various mosquito vectors is important in the determination of disease prevalence in disease endemic areas. The aim of the present study was to conduct regular entomological surveillance and to determine the relative abundance of tree hole mosquito species in Tamilnadu, India. In addition to this, the impact of weather-conditions on tree hole mosquito population were evaluated between June, 2014 and May, 2015. Six hills ranges viz., Anaimalai hills, Kodaikanal hills, Sitheri hills, Kolli hills, Yercaud hills, and Megamalai were selected, the immatures collected from tree holes by the help of suction tube. Collections were made at dusk and dawn at randomly selected 15 different tree species. The collected samples were stored and morphologically identified to species level in the laboratory. Mosquito diversity was calculated by Simpson's and Shannon-Weiner diversity indicies with spatial and temporal aspects. Over 2642 mosquitoes comprising the primary vectors of dengue, chickungunya, malaria, filariasis were identified. Other species collected from the fifteen sites in each hill during the study included Christophersiomyia annularis, Christophersiomyia thomsoni, Downsiomyia albolateralis, Downsiomyia nivea and Toxorhynchites splendens, etc. Study revealed high species diversity and relative density associated with different study sites. Based on the Shannon diversity index high number of species was recorded with Aedes pseudoalbopicta (0.0829) followed by Ae. aegypti (0.0805) and least species was recorded as Anopheles elegans (0.0059). The distribution of the primary vectors of DF along the high occurrence was evident with most study sites representing proportions of this vector population. This showed the high risk level associated with the livestock movement in amplification and circulation of the virus during the outbreaks. The findings of this study, therefore, demonstrated the potential vulnerability of nomadic communities to infection by arboviral diseases transmitted by mosquito vectors. Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical and UV Mutagenesis.

PubMed

Bose, Jeffrey L

2016-01-01

The ability to create mutations is an important step towards understanding bacterial physiology and virulence. While targeted approaches are invaluable, the ability to produce genome-wide random mutations can lead to crucial discoveries. Transposon mutagenesis is a useful approach, but many interesting mutations can be missed by these insertions that interrupt coding and noncoding sequences due to the integration of an entire transposon. Chemical mutagenesis and UV-based random mutagenesis are alternate approaches to isolate mutations of interest with the potential of only single nucleotide changes. Once a standard method, difficulty in identifying mutation sites had decreased the popularity of this technique. However, thanks to the recent emergence of economical whole-genome sequencing, this approach to making mutations can once again become a viable option. Therefore, this chapter provides an overview protocol for random mutagenesis using UV light or DNA-damaging chemicals.

Variation of mutational burden in healthy human tissues suggests non-random strand segregation and allows measuring somatic mutation rates.

PubMed

Werner, Benjamin; Sottoriva, Andrea

2018-06-01

The immortal strand hypothesis poses that stem cells could produce differentiated progeny while conserving the original template strand, thus avoiding accumulating somatic mutations. However, quantitating the extent of non-random DNA strand segregation in human stem cells remains difficult in vivo. Here we show that the change of the mean and variance of the mutational burden with age in healthy human tissues allows estimating strand segregation probabilities and somatic mutation rates. We analysed deep sequencing data from healthy human colon, small intestine, liver, skin and brain. We found highly effective non-random DNA strand segregation in all adult tissues (mean strand segregation probability: 0.98, standard error bounds (0.97,0.99)). In contrast, non-random strand segregation efficiency is reduced to 0.87 (0.78,0.88) in neural tissue during early development, suggesting stem cell pool expansions due to symmetric self-renewal. Healthy somatic mutation rates differed across tissue types, ranging from 3.5 × 10-9/bp/division in small intestine to 1.6 × 10-7/bp/division in skin.

Genetic Profiles of Korean Patients With Glucose-6-Phosphate Dehydrogenase Deficiency

PubMed Central

Lee, Jaewoong; Choi, Hayoung; Kim, Jiyeon; Kwon, Ahlm; Jang, Woori; Chae, Hyojin; Kim, Myungshin; Kim, Yonggoo; Lee, Jae Wook; Chung, Nack-Gyun

2017-01-01

Background We describe the genetic profiles of Korean patients with glucose-6-phosphate dehydrogenase (G6PD) deficiencies and the effects of G6PD mutations on protein stability and enzyme activity on the basis of in silico analysis. Methods In parallel with a genetic analysis, the pathogenicity of G6PD mutations detected in Korean patients was predicted in silico. The simulated effects of G6PD mutations were compared to the WHO classes based on G6PD enzyme activity. Four previously reported mutations and three newly diagnosed patients with missense mutations were estimated. Results One novel mutation (p.Cys385Gly, labeled G6PD Kangnam) and two known mutations [p.Ile220Met (G6PD São Paulo) and p.Glu416Lys (G6PD Tokyo)] were identified in this study. G6PD mutations identified in Koreans were also found in Brazil (G6PD São Paulo), Poland (G6PD Seoul), United States of America (G6PD Riley), Mexico (G6PD Guadalajara), and Japan (G6PD Tokyo). Several mutations occurred at the same nucleotide, but resulted in different amino acid residue changes in different ethnic populations (p.Ile380 variant, G6PD Calvo Mackenna; p.Cys385 variants, Tomah, Madrid, Lynwood; p.Arg387 variant, Beverly Hills; p.Pro396 variant, Bari; and p.Pro396Ala in India). On the basis of the in silico analysis, Class I or II mutations were predicted to be highly deleterious, and the effects of one Class IV mutation were equivocal. Conclusions The genetic profiles of Korean individuals with G6PD mutations indicated that the same mutations may have arisen by independent mutational events, and were not derived from shared ancestral mutations. The in silico analysis provided insight into the role of G6PD mutations in enzyme function and stability. PMID:28028996

Genetic Profiles of Korean Patients With Glucose-6-Phosphate Dehydrogenase Deficiency.

PubMed

Lee, Jaewoong; Park, Joonhong; Choi, Hayoung; Kim, Jiyeon; Kwon, Ahlm; Jang, Woori; Chae, Hyojin; Kim, Myungshin; Kim, Yonggoo; Lee, Jae Wook; Chung, Nack Gyun; Cho, Bin

2017-03-01

We describe the genetic profiles of Korean patients with glucose-6-phosphate dehydrogenase (G6PD) deficiencies and the effects of G6PD mutations on protein stability and enzyme activity on the basis of in silico analysis. In parallel with a genetic analysis, the pathogenicity of G6PD mutations detected in Korean patients was predicted in silico. The simulated effects of G6PD mutations were compared to the WHO classes based on G6PD enzyme activity. Four previously reported mutations and three newly diagnosed patients with missense mutations were estimated. One novel mutation (p.Cys385Gly, labeled G6PD Kangnam) and two known mutations [p.Ile220Met (G6PD São Paulo) and p.Glu416Lys (G6PD Tokyo)] were identified in this study. G6PD mutations identified in Koreans were also found in Brazil (G6PD São Paulo), Poland (G6PD Seoul), United States of America (G6PD Riley), Mexico (G6PD Guadalajara), and Japan (G6PD Tokyo). Several mutations occurred at the same nucleotide, but resulted in different amino acid residue changes in different ethnic populations (p.Ile380 variant, G6PD Calvo Mackenna; p.Cys385 variants, Tomah, Madrid, Lynwood; p.Arg387 variant, Beverly Hills; p.Pro396 variant, Bari; and p.Pro396Ala in India). On the basis of the in silico analysis, Class I or II mutations were predicted to be highly deleterious, and the effects of one Class IV mutation were equivocal. The genetic profiles of Korean individuals with G6PD mutations indicated that the same mutations may have arisen by independent mutational events, and were not derived from shared ancestral mutations. The in silico analysis provided insight into the role of G6PD mutations in enzyme function and stability.

Genetic diversity study of Chromobacterium violaceum isolated from Kolli Hills by amplified ribosomal DNA restriction analysis (ARDRA) and random amplified polymorphic DNA (RAPD).

PubMed

Ponnusamy, K; Jose, S; Savarimuthu, I; Michael, G P; Redenbach, M

2011-09-01

Chromobacterium are saprophytes that cause highly fatal opportunistic infections. Identification and strain differentiation were performed to identify the strain variability among the environmental samples. We have evaluated the suitability of individual and combined methods to detect the strain variations of the samples collected in different seasons. Amplified ribosomal DNA restriction analysis (ARDRA) and random amplified polymorphic DNA (RAPD) profiles were obtained using four different restriction enzyme digestions (AluI, HaeIII, MspI and RsaI) and five random primers. A matrix of dice similarity coefficients was calculated and used to compare these restriction patterns. ARDRA showed rapid differentiation of strains based on 16S rDNA, but the combined RAPD and ARDRA gave a more reliable differentiation than when either of them was analysed individually. A high level of genetic diversity was observed, which indicates that the Kolli Hills' C. violaceum isolates would fall into at least three new clusters. Results showed a noteworthy bacterial variation and genetic diversity of C. violaceum in the unexplored, virgin forest area. © 2011 The Authors. Letters in Applied Microbiology © 2011 The Society for Applied Microbiology.

Compactness of viral genomes: effect of disperse and localized random mutations

NASA Astrophysics Data System (ADS)

Lošdorfer Božič, Anže; Micheletti, Cristian; Podgornik, Rudolf; Tubiana, Luca

2018-02-01

Genomes of single-stranded RNA viruses have evolved to optimize several concurrent properties. One of them is the architecture of their genomic folds, which must not only feature precise structural elements at specific positions, but also allow for overall spatial compactness. The latter was shown to be disrupted by random synonymous mutations, a disruption which can consequently negatively affect genome encapsidation. In this study, we use three mutation schemes with different degrees of locality to mutate the genomes of phage MS2 and Brome Mosaic virus in order to understand the observed sensitivity of the global compactness of their folds. We find that mutating local stretches of their genomes’ sequence or structure is less disruptive to their compactness compared to inducing randomly-distributed mutations. Our findings are indicative of a mechanism for the conservation of compactness acting on a global scale of the genomes, and have several implications for understanding the interplay between local and global architecture of viral RNA genomes.

Compensatory mutations cause excess of antagonistic epistasis in RNA secondary structure folding.

PubMed

Wilke, Claus O; Lenski, Richard E; Adami, Christoph

2003-02-05

The rate at which fitness declines as an organism's genome accumulates random mutations is an important variable in several evolutionary theories. At an intuitive level, it might seem natural that random mutations should tend to interact synergistically, such that the rate of mean fitness decline accelerates as the number of random mutations is increased. However, in a number of recent studies, a prevalence of antagonistic epistasis (the tendency of multiple mutations to have a mitigating rather than reinforcing effect) has been observed. We studied in silico the net amount and form of epistatic interactions in RNA secondary structure folding by measuring the fraction of neutral mutants as a function of mutational distance d. We found a clear prevalence of antagonistic epistasis in RNA secondary structure folding. By relating the fraction of neutral mutants at distance d to the average neutrality at distance d, we showed that this prevalence derives from the existence of many compensatory mutations at larger mutational distances. Our findings imply that the average direction of epistasis in simple fitness landscapes is directly related to the density with which fitness peaks are distributed in these landscapes.

Compensatory mutations cause excess of antagonistic epistasis in RNA secondary structure folding

PubMed Central

Wilke, Claus O; Lenski, Richard E; Adami, Christoph

2003-01-01

Background The rate at which fitness declines as an organism's genome accumulates random mutations is an important variable in several evolutionary theories. At an intuitive level, it might seem natural that random mutations should tend to interact synergistically, such that the rate of mean fitness decline accelerates as the number of random mutations is increased. However, in a number of recent studies, a prevalence of antagonistic epistasis (the tendency of multiple mutations to have a mitigating rather than reinforcing effect) has been observed. Results We studied in silico the net amount and form of epistatic interactions in RNA secondary structure folding by measuring the fraction of neutral mutants as a function of mutational distance d. We found a clear prevalence of antagonistic epistasis in RNA secondary structure folding. By relating the fraction of neutral mutants at distance d to the average neutrality at distance d, we showed that this prevalence derives from the existence of many compensatory mutations at larger mutational distances. Conclusions Our findings imply that the average direction of epistasis in simple fitness landscapes is directly related to the density with which fitness peaks are distributed in these landscapes. PMID:12590655

A novel mitochondrial genome of Arborophila and new insight into Arborophila evolutionary history.

PubMed

Yan, Chaochao; Mou, Biqin; Meng, Yang; Tu, Feiyun; Fan, Zhenxin; Price, Megan; Yue, Bisong; Zhang, Xiuyue

2017-01-01

The lineage of the Bar-backed Partridge (Arborophila brunneopectus) was investigated to determine the phylogenetic relationships within Arborophila as the species is centrally distributed within an area covered by the distributions of 22 South-east Asian hill partridge species. The complete mitochondrial genome (mitogenome) of A. brunneopectus was determined and compared with four other hill partridge species mitogenomes. NADH subunit genes are radical in hill partridge mitogenomes and contain the most potential positive selective sites around where variable sites are abundant. Together with 44 other mitogenomes of closely related species, we reconstructed highly resolved phylogenetic trees using maximum likelihood (ML) and Bayesian inference (BI) analyses and calculated the divergence and dispersal history of Arborophila using combined datasets composed of their 13-protein coding sequences. Arborophila is reportedly be the oldest group in Phasianidae whose ancestors probably originated in Asia. A. rufipectus shares a closer relationship with A. ardens and A. brunneopectus compared to A. gingica and A. rufogularis, and such relationships were supported and profiled by NADH dehydrogenase subunit 5 (ND5). The intragenus divergence of all five Arborophila species occurred in the Miocene (16.84~5.69 Mya) when there were periods of climate cooling. We propose that these cooling events in the Miocene forced hill partridges from higher to lower altitudes, which led to geographic isolation and speciation. We demonstrated that the apparently deleterious +1 frameshift mutation in NADH dehydrogenase subunit 3 (ND3) found in all Arborophila is an ancient trait that has been eliminated in some younger lineages, such as Passeriformes. It is unclear of the biological advantages of this elimination for the relevant taxa and this requires further investigation.

Origin of Somatic Mutations in β-Catenin versus Adenomatous Polyposis Coli in Colon Cancer: Random Mutagenesis in Animal Models versus Nonrandom Mutagenesis in Humans.

PubMed

Yang, Da; Zhang, Min; Gold, Barry

2017-07-17

Wnt signaling is compromised early in the development of human colorectal cancer (CRC) due to truncating nonsense mutations in adenomatous polyposis coli (APC). CRC induced by chemical carcinogens, such as heterocyclic aromatic amines and azoxymethane, in mice also involves dysregulation of Wnt signaling but via activating missense mutations in the β-catenin oncogene despite the fact that genetically modified mice harboring an inactive APC allele efficiently develop CRC. In contrast, activating mutations in β-catenin are rarely observed in human CRC. Dysregulation of the Wnt signaling pathway by the two distinct mechanisms reveals insights into the etiology of human CRC. On the basis of calculations related to DNA adduct levels produced in mouse CRC models using mutagens, and the number of stem cells in the mouse colon, we show that two nonsense mutations required for biallelic disruption of APC are statistically unlikely to produce CRC in experiments using small numbers of mice. We calculate that an activating mutation in one allele near the critical GSK3β phosphorylation site on β-catenin is >10 5 -times more likely to produce CRC by random mutagenesis due to chemicals than inactivating two alleles in APC, yet it does not occur in humans. Therefore, the mutagenesis mechanism in human CRC cannot be random. We explain that nonsense APC mutations predominate in human CRC because of deamination at 5-methylcytosine at CGA and CAG codons, coupled with the number of human colonic stem cells and lifespan. Our analyses, including a comparison of mutation type and age at CRC diagnosis in U.S. and Chinese patients, also indicate that APC mutations in CRC are not due to environmental mutagens that randomly damage DNA.

How mutation affects evolutionary games on graphs

PubMed Central

Allen, Benjamin; Traulsen, Arne; Tarnita, Corina E.; Nowak, Martin A.

2011-01-01

Evolutionary dynamics are affected by population structure, mutation rates and update rules. Spatial or network structure facilitates the clustering of strategies, which represents a mechanism for the evolution of cooperation. Mutation dilutes this effect. Here we analyze how mutation influences evolutionary clustering on graphs. We introduce new mathematical methods to evolutionary game theory, specifically the analysis of coalescing random walks via generating functions. These techniques allow us to derive exact identity-by-descent (IBD) probabilities, which characterize spatial assortment on lattices and Cayley trees. From these IBD probabilities we obtain exact conditions for the evolution of cooperation and other game strategies, showing the dual effects of graph topology and mutation rate. High mutation rates diminish the clustering of cooperators, hindering their evolutionary success. Our model can represent either genetic evolution with mutation, or social imitation processes with random strategy exploration. PMID:21473871

Wavevector-Frequency Analysis with Applications to Acoustics

DTIC Science & Technology

1994-01-01

Turbulent Boundary Layer Pressure Measured by Microphone Arrays," Journal of the Acoustical Society of America, vol. 49, no. 3, March 1971 , pp. 862-877. 1...ARplications of Green’s FuntionsinScie,.-and Enginlering, Prentice-Hall, Inc., Englewood Hills, NJ, 1971 . 9. 3. Ffowcs-Williams et al., Modern Methods for...variables of a random process are kalled Joint w.merit ,. The m,n-th joint moment of the random variables, v and w, iz flefined by E ,N 1 f (aB) do d- where

Atmospheric propagation modeling indicates homing pigeons use loft-specific infrasonic 'map' cues.

PubMed

Hagstrum, Jonathan T

2013-02-15

Results from an acoustic ray-tracing program using daily meteorological profiles are presented to explain 'release-site biases' for homing pigeons at three experimental sites in upstate New York where W. T. Keeton and his co-workers at Cornell University conducted extensive releases between 1968 and 1987 in their investigations of the avian navigational 'map'. The sites are the Jersey Hill and Castor Hill fire towers, and another near Weedsport, where control pigeons from the Cornell loft vanished in random directions, in directions consistently >50 deg clockwise and in directions ∼15 deg clockwise from the homeward bearing, respectively. Because Cornell pigeons were disoriented at Jersey Hill whereas birds from other lofts were not, it is inferred that Jersey Hill lies within an acoustic 'shadow' zone relative to infrasonic signals originating from the Cornell loft's vicinity. Such signals could arise from ground-to-air coupling of near-continuous microseisms, or from scattering of direct microbaroms off terrain features, both of which are initially generated by wave-wave interactions in the deep ocean. HARPA runs show that little or no infrasound from the loft area arrived at Jersey Hill on days when Cornell pigeons were disoriented there, and that homeward infrasonic signals could have arrived at all three sites from directions consistent with pigeon departure bearings, especially on days when these bearings were unusual. The general stability of release-site biases might be due to influences of terrain on transmission of the homeward signals under prevailing weather patterns, whereas short-term changes in biases might be caused by rapid shifts in atmospheric conditions.

Atmospheric propagation modeling indicates homing pigeons use loft-specific infrasonic ‘map’ cues

USGS Publications Warehouse

Hagstrum, Jonathan T.

2013-01-01

Results from an acoustic ray-tracing program using daily meteorological profiles are presented to explain ‘release-site biases’ for homing pigeons at three experimental sites in upstate New York where W. T. Keeton and his co-workers at Cornell University conducted extensive releases between 1968 and 1987 in their investigations of the avian navigational ‘map’. The sites are the Jersey Hill and Castor Hill fire towers, and another near Weedsport, where control pigeons from the Cornell loft vanished in random directions, in directions consistently >50 deg clockwise and in directions ∼15 deg clockwise from the homeward bearing, respectively. Because Cornell pigeons were disoriented at Jersey Hill whereas birds from other lofts were not, it is inferred that Jersey Hill lies within an acoustic ‘shadow’ zone relative to infrasonic signals originating from the Cornell loft’s vicinity. Such signals could arise from ground-to-air coupling of near-continuous microseisms, or from scattering of direct microbaroms off terrain features, both of which are initially generated by wave–wave interactions in the deep ocean. HARPA runs show that little or no infrasound from the loft area arrived at Jersey Hill on days when Cornell pigeons were disoriented there, and that homeward infrasonic signals could have arrived at all three sites from directions consistent with pigeon departure bearings, especially on days when these bearings were unusual. The general stability of release-site biases might be due to influences of terrain on transmission of the homeward signals under prevailing weather patterns, whereas short-term changes in biases might be caused by rapid shifts in atmospheric conditions.

A method for multi-codon scanning mutagenesis of proteins based on asymmetric transposons.

PubMed

Liu, Jia; Cropp, T Ashton

2012-02-01

Random mutagenesis followed by selection or screening is a commonly used strategy to improve protein function. Despite many available methods for random mutagenesis, nearly all generate mutations at the nucleotide level. An ideal mutagenesis method would allow for the generation of 'codon mutations' to change protein sequence with defined or mixed amino acids of choice. Herein we report a method that allows for mutations of one, two or three consecutive codons. Key to this method is the development of a Mu transposon variant with asymmetric terminal sequences. As a demonstration of the method, we performed multi-codon scanning on the gene encoding superfolder GFP (sfGFP). Characterization of 50 randomly chosen clones from each library showed that more than 40% of the mutants in these three libraries contained seamless, in-frame mutations with low site preference. By screening only 500 colonies from each library, we successfully identified several spectra-shift mutations, including a S205D variant that was found to bear a single excitation peak in the UV region.

Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism

PubMed Central

Yang, Song-Yu; He, Xue-Ying; Olpin, Simon E.; Sutton, Vernon R.; McMenamin, Joe; Philipp, Manfred; Denman, Robert B.; Malik, Mazhar

2009-01-01

Mutations in the HSD17B10 gene were identified in two previously described mentally retarded males. A point mutation c.776G>C was found from a survivor (SV), whereas a potent mutation, c.419C>T, was identified in another deceased case (SF) with undetectable hydroxysteroid (17β) dehydrogenase 10 (HSD10) activity. Protein levels of mutant HSD10(R130C) in patient SF and HSD10(E249Q) in patient SV were about half that of HSD10 in normal controls. The E249Q mutation appears to affect HSD10 subunit interactions, resulting in an allosteric regulatory enzyme. For catalyzing the oxidation of allopregnanolone by NAD+ the Hill coefficient of the mutant enzyme is ≈1.3. HSD10(E249Q) was unable to catalyze the dehydrogenation of 2-methyl-3-hydroxybutyryl-CoA and the oxidation of allopregnanolone, a positive modulator of the γ-aminobutyric acid type A receptor, at low substrate concentrations. Neurosteroid homeostasis is critical for normal cognitive development, and there is increasing evidence that a blockade of isoleucine catabolism alone does not commonly cause developmental disabilities. The results support the theory that an imbalance in neurosteroid metabolism could be a major cause of the neurological handicap associated with hydroxysteroid (17β) dehydrogenase 10 deficiency. PMID:19706438

Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria?

PubMed

Mohr, Sharif B; Gorham, Edward D; Alcaraz, John E; Kane, Christopher I; Macera, Caroline A; Parsons, J Kellogg; Wingard, Deborah L; Garland, Cedric F

2012-04-01

A wide range of epidemiologic and laboratory studies combined provide compelling evidence of a protective role of vitamin D on risk of breast cancer. This review evaluates the scientific evidence for such a role in the context of the A.B. Hill criteria for causality, in order to assess the presence of a causal, inverse relationship, between vitamin D status and breast cancer risk. After evaluation of this evidence in the context of Hill's criteria, it was found that the criteria for a causal relationship were largely satisfied. Studies in human populations and the laboratory have consistently demonstrated that vitamin D plays an important role in the prevention of breast cancer. Vitamin D supplementation is an urgently needed, low cost, effective, and safe intervention strategy for breast cancer prevention that should be implemented without delay. In the meantime, randomized controlled trials of high doses of vitamin D(3) for prevention of breast cancer should be undertaken to provide the necessary evidence to guide national health policy.

Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS).

PubMed

Fukuoka, Masahiro; Wu, Yi-Long; Thongprasert, Sumitra; Sunpaweravong, Patrapim; Leong, Swan-Swan; Sriuranpong, Virote; Chao, Tsu-Yi; Nakagawa, Kazuhiko; Chu, Da-Tong; Saijo, Nagahiro; Duffield, Emma L; Rukazenkov, Yuri; Speake, Georgina; Jiang, Haiyi; Armour, Alison A; To, Ka-Fai; Yang, James Chih-Hsin; Mok, Tony S K

2011-07-20

The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation-positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation-negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation-positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

On the conservative nature of intragenic recombination

PubMed Central

Drummond, D. Allan; Silberg, Jonathan J.; Meyer, Michelle M.; Wilke, Claus O.; Arnold, Frances H.

2005-01-01

Intragenic recombination rapidly creates protein sequence diversity compared with random mutation, but little is known about the relative effects of recombination and mutation on protein function. Here, we compare recombination of the distantly related β-lactamases PSE-4 and TEM-1 to mutation of PSE-4. We show that, among β-lactamase variants containing the same number of amino acid substitutions, variants created by recombination retain function with a significantly higher probability than those generated by random mutagenesis. We present a simple model that accurately captures the differing effects of mutation and recombination in real and simulated proteins with only four parameters: (i) the amino acid sequence distance between parents, (ii) the number of substitutions, (iii) the average probability that random substitutions will preserve function, and (iv) the average probability that substitutions generated by recombination will preserve function. Our results expose a fundamental functional enrichment in regions of protein sequence space accessible by recombination and provide a framework for evaluating whether the relative rates of mutation and recombination observed in nature reflect the underlying imbalance in their effects on protein function. PMID:15809422

On the conservative nature of intragenic recombination.

PubMed

Drummond, D Allan; Silberg, Jonathan J; Meyer, Michelle M; Wilke, Claus O; Arnold, Frances H

2005-04-12

Intragenic recombination rapidly creates protein sequence diversity compared with random mutation, but little is known about the relative effects of recombination and mutation on protein function. Here, we compare recombination of the distantly related beta-lactamases PSE-4 and TEM-1 to mutation of PSE-4. We show that, among beta-lactamase variants containing the same number of amino acid substitutions, variants created by recombination retain function with a significantly higher probability than those generated by random mutagenesis. We present a simple model that accurately captures the differing effects of mutation and recombination in real and simulated proteins with only four parameters: (i) the amino acid sequence distance between parents, (ii) the number of substitutions, (iii) the average probability that random substitutions will preserve function, and (iv) the average probability that substitutions generated by recombination will preserve function. Our results expose a fundamental functional enrichment in regions of protein sequence space accessible by recombination and provide a framework for evaluating whether the relative rates of mutation and recombination observed in nature reflect the underlying imbalance in their effects on protein function.

Molecular heterogeneity of glucose-6-phosphate dehydrogenase deficiency in Gaza Strip Palestinians.

PubMed

Sirdah, Mahmoud; Reading, N Scott; Vankayalapati, Hariprasad; Perkins, Sherrie L; Shubair, Mohammad E; Aboud, Lina; Roper, David; Prchal, Josef T

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, affecting more than 500 million people worldwide, is one of the most common of inherited disorders. There are 186 G6PD mutations published, with mutational clustering within defined ethnic/racial groups. However comprehensive molecular characterization of ethnically associated G6PD mutants and their clinical implications are lacking. Eighty unrelated Palestinian children hospitalized for hemolysis were studied. G6PD activity was determined by quantitative spectrophotometry and G6PD mutations were analyzed by sequencing of gDNA. 65 of 80 children (81%) had G6PD deficiency, accounting for most of the hemolytic disease in this age group. G6PD Mediterranean(c.563T), African G6PD A-(c.202A/c.376G), and G6PD Cairo(c.404C) were common with relative allele frequencies of 0.33 [1], 0.26, and 0.18 respectively. Two other variants were discovered, G6PD Beverly Hills(c.1160A) mutation, and a novel G6PD missense mutation c.536G>A (Ser179Asn), designated G6PD "Gaza". Three samples exhibited enzyme deficiency without detectable exonic or exon/intron boundary mutations. G6PD deficiency accounts for the majority of diagnoses for hemolysis in Palestinian children (81%), providing support for newborn G6PD deficiency screening programs. We report unanticipated molecular heterogeneity of G6PD variants among Gaza Strip Palestinians greater than reported in neighboring Arab populations. We report a high proportion of affected children with G6PD Cairo, which was observed previously in only a single Egyptian, and a novel mutation G6PD "Gaza". Copyright © 2012 Elsevier Inc. All rights reserved.

Somatic mutations in cancer: Stochastic versus predictable.

PubMed

Gold, Barry

2017-02-01

The origins of human cancers remain unclear except for a limited number of potent environmental mutagens, such as tobacco and UV light, and in rare cases, familial germ line mutations that affect tumor suppressor genes or oncogenes. A significant component of cancer etiology has been deemed stochastic and correlated with the number of stem cells in a tissue, the number of times the stem cells divide and a low incidence of random DNA polymerase errors that occur during each cell division. While somatic mutations occur during each round of DNA replication, mutations in cancer driver genes are not stochastic. Out of a total of 2843 codons, 1031 can be changed to stop codons by a single base substitution in the tumor suppressor APC gene, which is mutated in 76% of colorectal cancers (CRC). However, the nonsense mutations, which comprise 65% of all the APC driver mutations in CRC, are not random: 43% occur at Arg CGA codons, although they represent <3% of the codons. In TP53, CGA codons comprise <3% of the total 393 codons but they account for 72% and 39% of the mutations in CRC and ovarian cancer OVC, respectively. This mutation pattern is consistent with the kinetically slow, but not stochastic, hydrolytic deamination of 5-methylcytosine residues at specific methylated CpG sites to afford T·G mismatches that lead to C→T transitions and stop codons at CGA. Analysis of nonsense mutations in CRC, OVC and a number of other cancers indicates the need to expand the predictable risk factors for cancer to include, in addition to random polymerase errors, the methylation status of gene body CGA codons in tumor suppressor genes. Copyright © 2017. Published by Elsevier B.V.

Foundational errors in the Neutral and Nearly-Neutral theories of evolution in relation to the Synthetic Theory: is a new evolutionary paradigm necessary?

PubMed

Valenzuela, Carlos Y

2013-01-01

The Neutral Theory of Evolution (NTE) proposes mutation and random genetic drift as the most important evolutionary factors. The most conspicuous feature of evolution is the genomic stability during paleontological eras and lack of variation among taxa; 98% or more of nucleotide sites are monomorphic within a species. NTE explains this homology by random fixation of neutral bases and negative selection (purifying selection) that does not contribute either to evolution or polymorphisms. Purifying selection is insufficient to account for this evolutionary feature and the Nearly-Neutral Theory of Evolution (N-NTE) included negative selection with coefficients as low as mutation rate. These NTE and N-NTE propositions are thermodynamically (tendency to random distributions, second law), biotically (recurrent mutation), logically and mathematically (resilient equilibria instead of fixation by drift) untenable. Recurrent forward and backward mutation and random fluctuations of base frequencies alone in a site make life organization and fixations impossible. Drift is not a directional evolutionary factor, but a directional tendency of matter-energy processes (second law) which threatens the biotic organization. Drift cannot drive evolution. In a site, the mutation rates among bases and selection coefficients determine the resilient equilibrium frequency of bases that genetic drift cannot change. The expected neutral random interaction among nucleotides is zero; however, huge interactions and periodicities were found between bases of dinucleotides separated by 1, 2... and more than 1,000 sites. Every base is co-adapted with the whole genome. Neutralists found that neutral evolution is independent of population size (N); thus neutral evolution should be independent of drift, because drift effect is dependent upon N. Also, chromosome size and shape as well as protein size are far from random.

Genetic Correlations Greatly Increase Mutational Robustness and Can Both Reduce and Enhance Evolvability

PubMed Central

Greenbury, Sam F.; Schaper, Steffen; Ahnert, Sebastian E.; Louis, Ard A.

2016-01-01

Mutational neighbourhoods in genotype-phenotype (GP) maps are widely believed to be more likely to share characteristics than expected from random chance. Such genetic correlations should strongly influence evolutionary dynamics. We explore and quantify these intuitions by comparing three GP maps—a model for RNA secondary structure, the HP model for protein tertiary structure, and the Polyomino model for protein quaternary structure—to a simple random null model that maintains the number of genotypes mapping to each phenotype, but assigns genotypes randomly. The mutational neighbourhood of a genotype in these GP maps is much more likely to contain genotypes mapping to the same phenotype than in the random null model. Such neutral correlations can be quantified by the robustness to mutations, which can be many orders of magnitude larger than that of the null model, and crucially, above the critical threshold for the formation of large neutral networks of mutationally connected genotypes which enhance the capacity for the exploration of phenotypic novelty. Thus neutral correlations increase evolvability. We also study non-neutral correlations: Compared to the null model, i) If a particular (non-neutral) phenotype is found once in the 1-mutation neighbourhood of a genotype, then the chance of finding that phenotype multiple times in this neighbourhood is larger than expected; ii) If two genotypes are connected by a single neutral mutation, then their respective non-neutral 1-mutation neighbourhoods are more likely to be similar; iii) If a genotype maps to a folding or self-assembling phenotype, then its non-neutral neighbours are less likely to be a potentially deleterious non-folding or non-assembling phenotype. Non-neutral correlations of type i) and ii) reduce the rate at which new phenotypes can be found by neutral exploration, and so may diminish evolvability, while non-neutral correlations of type iii) may instead facilitate evolutionary exploration and so increase evolvability. PMID:26937652

Channel Diversity in Random Wireless Networks

DTIC Science & Technology

2009-01-01

α, α)πR2 , (33) where K , LbwL 2π B (αL + 1/2, αL+ 1/2). (34) The maximum contention density is therefore proportional to ǫ1/L, as ǫ → 0. This...Digital Communications, 5th ed. Mc Graw Hill, 2008. [10] M. W. Subbarao and B . L. Hughes, “Optimal transmission ranges and code rates for frequency...

In Darwinian evolution, feedback from natural selection leads to biased mutations.

PubMed

Caporale, Lynn Helena; Doyle, John

2013-12-01

Natural selection provides feedback through which information about the environment and its recurring challenges is captured, inherited, and accumulated within genomes in the form of variations that contribute to survival. The variation upon which natural selection acts is generally described as "random." Yet evidence has been mounting for decades, from such phenomena as mutation hotspots, horizontal gene transfer, and highly mutable repetitive sequences, that variation is far from the simplifying idealization of random processes as white (uniform in space and time and independent of the environment or context).  This paper focuses on what is known about the generation and control of mutational variation, emphasizing that it is not uniform across the genome or in time, not unstructured with respect to survival, and is neither memoryless nor independent of the (also far from white) environment. We suggest that, as opposed to frequentist methods, Bayesian analysis could capture the evolution of nonuniform probabilities of distinct classes of mutation, and argue not only that the locations, styles, and timing of real mutations are not correctly modeled as generated by a white noise random process, but that such a process would be inconsistent with evolutionary theory. © 2013 New York Academy of Sciences.

Can Random Mutation Mimic Design?: A Guided Inquiry Laboratory for Undergraduate Students

PubMed Central

Kalinowski, Steven T.; Taper, Mark L.; Metz, Anneke M.

2006-01-01

Complex biological structures, such as the human eye, have been interpreted as evidence for a creator for over three centuries. This raises the question of whether random mutation can create such adaptations. In this article, we present an inquiry-based laboratory experiment that explores this question using paper airplanes as a model organism. The main task for students in this investigation is to figure out how to simulate paper airplane evolution (including reproduction, inheritance, mutation, and selection). In addition, the lab requires students to practice analytic thinking and to carefully delineate the implications of their results. PMID:16951065

Amino acid substitutions in random mutagenesis libraries: lessons from analyzing 3000 mutations.

PubMed

Zhao, Jing; Frauenkron-Machedjou, Victorine Josiane; Kardashliev, Tsvetan; Ruff, Anna Joëlle; Zhu, Leilei; Bocola, Marco; Schwaneberg, Ulrich

2017-04-01

The quality of amino acid substitution patterns in random mutagenesis libraries is decisive for the success in directed evolution campaigns. In this manuscript, we provide a detailed analysis of the amino acid substitutions by analyzing 3000 mutations of three random mutagenesis libraries (1000 mutations each; epPCR with a low-mutation and a high-mutation frequency and SeSaM-Tv P/P) employing lipase A from Bacillus subtilis (bsla). A comparison of the obtained numbers of beneficial variants in the mentioned three random mutagenesis libraries with a site saturation mutagenesis (SSM) (covering the natural diversity at each amino acid position of BSLA) concludes the diversity analysis. Seventy-six percent of the SeSaM-Tv P/P-generated substitutions yield chemically different amino acid substitutions compared to 64% (epPCR-low) and 69% (epPCR-high). Unique substitutions from one amino acid to others are termed distinct amino acid substitutions. In the SeSaM-Tv P/P library, 35% of all theoretical distinct amino acid substitutions were found in the 1000 mutation library compared to 25% (epPCR-low) and 26% (epPCR-high). Thirty-six percent of distinct amino acid substitutions found in SeSaM-Tv P/P were unobtainable by epPCR-low. Comparison with the SSM library showed that epPCR-low covers 15%, epPCR-high 18%, and SeSaM-Tv P/P 21% of obtainable beneficial amino acid positions. In essence, this study provides first insights on the quality of epPCR and SeSaM-Tv P/P libraries in terms of amino acid substitutions, their chemical differences, and the number of obtainable beneficial amino acid positions.

Closing the Gap: Early Childhood Education. The Achievement Gap: Early Childhood Education. Info Brief. Number 45

ERIC Educational Resources Information Center

Nelson, Anne

2006-01-01

In popular culture, the age of 40 is sometimes considered "over the hill." This is decidedly not the case for the Perry Preschoolers--a cohort of low-income, predominantly African American children who 37 years ago were randomly assigned to attend a high-quality preschool program. The latest findings from the well-known longitudinal study of this…

Cluster analysis on a sphere: Application to magnetizations from metasediments of the Jack Hills, Western Australia

NASA Astrophysics Data System (ADS)

Bono, Richard K.; Tarduno, John A.; Dare, Matthew S.; Mitra, Gautam; Cottrell, Rory D.

2018-02-01

Metasediments of the Jack Hills contain the oldest known terrestrial minerals in the form of zircons nearly 4.4 billion years old. Paleointensity data from these zircons provide evidence for a Hadean geodynamo as old as 4.2 billion years old. Given the importance of these zircons for constraining the earliest history of the core, it is vital to understand the fidelity of the zircon record. A fundamental aspect providing context for the preservation of primary magnetic signals is the nature of overprints predicted to have been imparted on rocks of the Jack Hills due to Archean to Proterozoic metamorphic events. To be viable magnetic records of a Hadean geodynamo, zircon magnetization directions should differ from these secondary magnetizations. To evaluate these secondary magnetizations, we report paleomagnetic analyses of a comprehensive sampling of 68 quartzite cobble-sized clasts from the Jack Hills metasediments ∼0.5 to 1.0 km from the Discovery Site (which has yielded the oldest zircons and paleofield estimates). While application of standard paleomagnetic tests suggests that the ensemble of cobble directions cannot be distinguished from those drawn from a random distribution, a new cluster analysis of directions on a sphere and non-parametric resampling approaches reveal significant directions amongst subsets of the data. One, isolated at the lowest temperature analyzed [200 to 300 °C, Declination (Dec.) = 316.8°, Inclination (Inc.) = - 51.1 °] appears to be dominated by the present day field. Another, isolated at higher (but still relatively low unblocking temperatures that we call "intermediate", of ∼350-500 °C, Dec. = 243.8°, Inc. = 9.5°) agrees with a magnetic overprint isolated from the secondary Cr-Fe mica fuchsite isolated from the Jack Hills Discovery site, passing a field test at the 80% confidence level. No evidence is found in our data, or in the data of others collected on similar Jack Hills lithologies, for a widespread 1 Ga remagnetization event. Instead, we interpret the most prevalent secondary magnetization of the quartzite (i.e., intermediate unblocking) and the fuchsite characteristic remanent magnetization to be ∼2.65 Ga in age, coincident with peak metamorphism (as high as ca. 475 °C) of the Jack Hills. The presence of this distinct secondary magnetization, its difference from that recorded by Jack Hills zircons at high unblocking temperatures, and the lack of a dominant remagnetization direction at high unblocking temperatures in the cobble data (the expected result for a primary magnetization), lends further support to the fidelity of the Hadean geomagnetic record. The presence of the secondary magnetization also lends support to the conclusion that most of the Jack Hills metasediments were deposited in the Archean, with only minor reworking and potential tectonic interleaving of Proterozoic components. Overall, the application of the new directional cluster analysis presented here has the potential to reveal magnetic directions in highly scattered data sets, typical of weakly magnetized coarse-grained sedimentary rocks

Current prevalence of intestinal parasitic infections and their impact on hematological and nutritional status among Karen hill tribe children in Omkoi District, Chiang Mai Province, Thailand.

PubMed

Yanola, Jintana; Nachaiwieng, Woottichai; Duangmano, Suwit; Prasannarong, Mujalin; Somboon, Pradya; Pornprasert, Sakorn

2018-04-01

Intestinal parasitic infection represents a substantial problem for children living in rural or limited resources areas and significantly relates to anemia and nutritional status. This study aimed to determine the current prevalence of intestinal parasitic infections among school-age children of Karen hill tribe population in Omkoi District, Chiang Mai Province, Thailand and assess the impact of intestinal parasitic infection on hematological and nutritional status in those children. A total of 375 Karen hill tribe children, 6-14 years of age, in Omkoi District were randomly selected to participate in this study. Stool samples were collected and examined for intestinal parasitic infection through formalin-ether concentration method. Blood samples were collected for hematological and iron analysis. The overall prevalence of intestinal parasitic infection was 47.7% (179/375), with single infections (29.3%) and polyparatism (18.4%). The most common pathogenic parasite was Trichuris trichiura (16.0%), followed by Ascaris lumbricoides (13%) and Giardia lamblia (3.5%). In addition, non-pathogenic amoeba, Entamoeba coli was observed with a high prevalence rate (31.2%). Anemia and eosinophilia prevalence were 6.40% (24/375) and 74.7% (280/375), respectively. Eosinophilia was significantly more prevalent in children with intestinal parasitic infection compared to uninfected children. Among 249 children, 13.7% were iron deficiency, 9.6% were thalassemia and hemoglobinophathy and 8% were G-6-PD deficiency. A high prevalence infection rate was significantly associated with eosinophilia, but independently related to anemia and iron deficiency. Intestinal parasitic infections are endemic in school-age children of Karen hill tribe population in Omkoi District. These data highlight the need for an integrated approach to control transmission of intestinal parasites and improve the health and sanitation status of Karen hill tribe children in Thailand. Copyright © 2018 Elsevier B.V. All rights reserved.

Randomness and diversity matter in the maintenance of the public resources

NASA Astrophysics Data System (ADS)

Liu, Aizhi; Zhang, Yanling; Chen, Xiaojie; Sun, Changyin

2017-03-01

Most previous models about the public goods game usually assume two possible strategies, i.e., investing all or nothing. The real-life situation is rarely all or nothing. In this paper, we consider that multiple strategies are adopted in a well-mixed population, and each strategy represents an investment to produce the public goods. Past efforts have found that randomness matters in the evolution of fairness in the ultimatum game. In the framework involving no other mechanisms, we study how diversity and randomness influence the average investment of the population defined by the mean value of all individuals' strategies. The level of diversity is increased by increasing the strategy number, and the level of randomness is increased by increasing the mutation probability, or decreasing the population size or the selection intensity. We find that a higher level of diversity and a higher level of randomness lead to larger average investment and favor more the evolution of cooperation. Under weak selection, the average investment changes very little with the strategy number, the population size, and the mutation probability. Under strong selection, the average investment changes very little with the strategy number and the population size, but changes a lot with the mutation probability. Under intermediate selection, the average investment increases significantly with the strategy number and the mutation probability, and decreases significantly with the population size. These findings are meaningful to study how to maintain the public resource.

A scaling law for accretion zone sizes

NASA Technical Reports Server (NTRS)

Greenzweig, Yuval; Lissauer, Jack J.

1987-01-01

Current theories of runaway planetary accretion require small random velocities of the accreted particles. Two body gravitational accretion cross sections which ignore tidal perturbations of the Sun are not valid for the slow encounters which occur at low relative velocities. Wetherill and Cox have studied accretion cross sections for rocky protoplanets orbiting at 1 AU. Using analytic methods based on Hill's lunar theory, one can scale these results for protoplanets that occupy the same fraction of their Hill sphere as does a rocky body at 1 AU. Generalization to bodies of different sizes is achieved here by numerical integrations of the three-body problem. Starting at initial positions far from the accreting body, test particles are allowed to encounter the body once, and the cross section is computed. A power law is found relating the cross section to the radius of the accreting body (of fixed mass).

Wall-layer model for LES with massive separation

NASA Astrophysics Data System (ADS)

Fakhari, Ahmad; Armenio, Vincenzo; Roman, Federico

2016-11-01

Currently, Wall Functions (WF) work well under specific conditions, mostly exhibit drawbacks specially in flows with separation beyond curvatures. In this work, we propose a more general WF which works well in attached and detached flows, in presence and absence of Immersed Boundaries (IB). First we modified an equilibrium stress WF for boundary-fitted geometry making dynamic the computation of the k (von Karman constant) of the log-law; the model was first applied to a periodic open channel flow, and then to the flow over a 2D single hill using uniform coarse grids; the model captured separation with reasonable accuracy. Thereafter IB Method by Roman et al. was improved to avoid momentum loss at the interface between the fluid-solid regions. This required calibration of interfacial eddy viscosity; also a random stochastic forcing was used in wall-normal direction to increase Reynolds stresses and improve mean velocity profile. Finally, to reproduce flow separation, a simplified boundary layer equation was applied to construct velocity at near wall computational nodes. The new scheme was tested on the 2D single hill and periodic hills applying Cartesian and curvilinear grids; good agreement with references was obtained with reduction in cost and complexity. Financial support from project COSMO "CFD open source per opera morta" PAR FSC 2007-2013, Friuli Venezia Giulia.

Officer Career Development: Analytic Strategy Recommendations

DTIC Science & Technology

1989-07-01

model is perhaps better suited to experimental designs where investigators determine discrete values for each Xi and then randomly sample subjects into... experimental designs . New York: McGraw-Hill. ,Terlove, 4. (1971). Further evidence on the estimation of dynamic economic relations from a time series of...Cunningham. W. R., & Birren, 1. E. (1980). Age chsane in the factor Newseroade. I R., & Labouvie. E V. 1985) Experimental design in structure of

Total Quality Management Guide. Volume 2. A Guide to Implementation

DTIC Science & Technology

1990-02-15

Kaoru . Guide to Quality Control. Asian Productivity Organization. 1984. Ishikawa , Kaoru . What is Total Quality Control? The Japanese Way. Englewood...of the new Systems Age. The theories of Deming, Juran, Ishikawa , and other management methods that still predominate are pioneers of Systems Age...Feigenbaum, Armand V. Total Quality Control. New York: McGraw-Hill Book Company. 1983. bnai, Masaaki. Kaizen. New York: Random House. 1986. Ishikawa

The Effects of Cardio-Syntactic Analysis Instruction on Writing Scores in a 11th Grade High School Classroom

ERIC Educational Resources Information Center

Kariuki, Patrick N.; Blair, Paul W.

2015-01-01

The purpose of this research was to determine the effects of Cardio-Syntactic Analysis instruction on writing scores in an 11th grade English class. The sample consisted of 35 students enrolled in an Honor's English 11 class at Volunteer high School, in Church Hill, TN. The class was randomly assigned into an experimental group of 17 students and…

Prevalence and factors associated with type 2 diabetes mellitus and hypertension among the hill tribe elderly populations in northern Thailand.

PubMed

Apidechkul, Tawatchai

2018-06-05

Type 2 diabetes mellitus (T2DM) and hypertension (HT) are major noncommunicable health problems in both developing and developed countries, including Thailand. Each year, a large amount of money is budgeted for treatment and care. Hill tribe people are a marginalized population in Thailand, and members of its elderly population are vulnerable to health problems due to language barriers, lifestyles, and daily dietary intake. An analytic cross-sectional study was conducted to estimate the prevalence of T2DM and HT and to assess the factors associated with T2DM and HT. The study populations were hill tribe elderly adults aged ≥  60 years living in Chiang Rai Province, Thailand. A simple random method was used to select the targeted hill tribe villages and participants into the study. A validated questionnaire, physical examination form, and 5-mL blood specimen were used as research instruments. Fasting plasma glucose and blood pressure were examined and used as outcome measurements. Chi-square tests and logistic regression were used for detecting the associations between variables at the significance level alpha=0.05. In total, 793 participants participated in the study; 49.6% were male, and 51.7% were aged 60-69 years. A total of 71.5% were Buddhist, 93.8% were uneducated, 62.9% were unemployed, and 89 % earned an income of < 5,000 baht/month. The overall prevalence of T2DM and HT was 16.8% and 45.5%, respectively. Approximately 9.0% individuals had comorbidity of T2DM and HT. Members of the Lahu, Yao, Karen, and Lisu tribes had a greater odds of developing T2DM than did those of the Akha tribe. Being overweight, having a parental history of T2DM, and having high cholesterol were associated with T2DM development. In contrast, those who engaged in highly physical activities and exercise had lower odds of developing T2DM than did those who did not. Regarding HT, being female, having a high dietary salt intake, being overweight, and having a parental history of HT were associated with HT development among the hill tribe elderly populations. The prevalence of T2DH and HT among the hill tribe elderly populations is higher than that among the general Thai population. Public health interventions should focus on encouraging physical activity and reducing personal weight, dietary salt intake, and greasy food consumption among the hill tribe elderly.

The directed mutation controversy and neo-Darwinism.

PubMed

Lenski, R E; Mittler, J E

1993-01-08

According to neo-Darwinian theory, random mutation produces genetic differences among organisms whereas natural selection tends to increase the frequency of advantageous alleles. However, several recent papers claim that certain mutations in bacteria and yeast occur at much higher rates specifically when the mutant phenotypes are advantageous. Various molecular models have been proposed that might explain these directed mutations, but the models have not been confirmed. Critics contend that studies purporting to demonstrate directed mutation lack certain controls and fail to account adequately for population dynamics. Further experiments that address these criticisms do not support the existence of directed mutations.

Effect of decision aid for breast cancer prevention on decisional conflict in women with a BRCA1 or BRCA2 mutation: a multisite, randomized, controlled trial.

PubMed

Metcalfe, Kelly A; Dennis, Cindy-Lee; Poll, Aletta; Armel, Susan; Demsky, Rochelle; Carlsson, Lindsay; Nanda, Sonia; Kiss, Alexander; Narod, Steven A

2017-03-01

Women with a BRCA1 or BRCA2 mutation are at high risk for breast cancer and must make important decisions about breast cancer prevention and screening. In the current study, we report a multisite, randomized, controlled trial evaluating the effectiveness of a decision aid for breast cancer prevention in women with a BRCA mutation with no previous diagnosis of cancer. Within 1 month of receiving a positive BRCA result, women were randomized to receive either usual care (control group) or decision aid (intervention group). Participants were followed at 3, 6, and 12 months; were asked about preventive measures; and completed standardized questionnaires assessing decision making and psychosocial functioning. One hundred fifty women were randomized. Mean cancer-related distress scores were significantly lower in the intervention group compared with the control group at 6 months (P = 0.01) and at 12 months postrandomization (P = 0.05). Decisional conflict scores declined over time for both groups and at no time were there statistical differences between the two groups. The decision aid for breast cancer prevention in women with a BRCA1 or BRCA2 mutation is effective in significantly decreasing cancer-related distress within the year following receipt of positive genetic test results.Genet Med 19 3, 330-336.

Random oligonucleotide mutagenesis: application to a large protein coding sequence of a major histocompatibility complex class I gene, H-2DP.

PubMed Central

Murray, R; Pederson, K; Prosser, H; Muller, D; Hutchison, C A; Frelinger, J A

1988-01-01

We have used random oligonucleotide mutagenesis (or saturation mutagenesis) to create a library of point mutations in the alpha 1 protein domain of a Major Histocompatibility Complex (MHC) molecule. This protein domain is critical for T cell and B cell recognition. We altered the MHC class I H-2DP gene sequence such that synthetic mutant alpha 1 exons (270 bp of coding sequence), which contain mutations identified by sequence analysis, can replace the wild type alpha 1 exon. The synthetic exons were constructed from twelve overlapping oligonucleotides which contained an average of 1.3 random point mutations per intact exon. DNA sequence analysis of mutant alpha 1 exons has shown a point mutant distribution that fits a Poisson distribution, and thus emphasizes the utility of this mutagenesis technique to "scan" a large protein sequence for important mutations. We report our use of saturation mutagenesis to scan an entire exon of the H-2DP gene, a cassette strategy to replace the wild type alpha 1 exon with individual mutant alpha 1 exons, and analysis of mutant molecules expressed on the surface of transfected mouse L cells. Images PMID:2903482

Smoking and multiple sclerosis: A systematic review and meta-analysis using the Bradford Hill criteria for causation.

PubMed

Degelman, Michelle L; Herman, Katya M

2017-10-01

Despite being one of the most common neurological disorders globally, the cause(s) of multiple sclerosis (MS) remain unknown. Cigarette smoking has been studied with regards to both the development and progression of MS. The Bradford Hill criteria for causation can contribute to a more comprehensive evaluation of a potentially causal risk factor-disease outcome relationship. The objective of this systematic review and meta-analysis was to assess the relationship between smoking and both MS risk and MS progression, subsequently applying Hill's criteria to further evaluate the likelihood of causal associations. The Medline, EMBASE, CINAHL, PsycInfo, and Cochrane Library databases were searched for relevant studies up until July 28, 2015. A random-effects meta-analysis was conducted for three outcomes: MS risk, conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS), and progression from relapsing-remitting multiple sclerosis (RRMS) to secondary-progressive multiple sclerosis (SPMS). Dose-response relationships and risk factor interactions, and discussions of mechanisms and analogous associations were noted. Hill's criteria were applied to assess causality of the relationships between smoking and each outcome. The effect of second-hand smoke exposure was also briefly reviewed. Smoking had a statistically significant association with both MS risk (conservative: OR/RR 1.54, 95% CI [1.46-1.63]) and SPMS risk (HR 1.80, 95% CI [1.04-3.10]), but the association with progression from CIS to CDMS was non-significant (HR 1.13, 95% CI [0.73-1.76]). Using Hill's criteria, there was strong evidence of a causal role of smoking in MS risk, but only moderate evidence of a causal association between smoking and MS progression. Heterogeneity in study designs and target populations, inconsistent results, and an overall scarcity of studies point to the need for more research on second-hand smoke exposure in relation to MS prior to conducting a detailed meta-analysis. This first review to supplement systematic review and meta-analytic methods with Hill's criteria to analyze the smoking-MS association provides evidence supporting the causal involvement of smoking in the development and progression of MS. Smoking prevention and cessation programs and policies should consider MS as an additional health risk when aiming to reduce smoking prevalence in the population. Copyright © 2017 Elsevier B.V. All rights reserved.

Ultrasensitivity and sharp threshold theorems for multisite systems

NASA Astrophysics Data System (ADS)

Dougoud, M.; Mazza, C.; Vinckenbosch, L.

2017-02-01

This work studies the ultrasensitivity of multisite binding processes where ligand molecules can bind to several binding sites. It considers more particularly recent models involving complex chemical reactions in allosteric phosphorylation processes and for transcription factors and nucleosomes competing for binding on DNA. New statistics-based formulas for the Hill coefficient and the effective Hill coefficient are provided and necessary conditions for a system to be ultrasensitive are exhibited. It is first shown that the ultrasensitivity of binding processes can be approached using sharp-threshold theorems which have been developed in applied probability theory and statistical mechanics for studying sharp threshold phenomena in reliability theory, random graph theory and percolation theory. Special classes of binding process are then introduced and are described as density dependent birth and death process. New precise large deviation results for the steady state distribution of the process are obtained, which permits to show that switch-like ultrasensitive responses are strongly related to the multi-modality of the steady state distribution. Ultrasensitivity occurs if and only if the entropy of the dynamical system has more than one global minimum for some critical ligand concentration. In this case, the Hill coefficient is proportional to the number of binding sites, and the system is highly ultrasensitive. The classical effective Hill coefficient I is extended to a new cooperativity index I q , for which we recommend the computation of a broad range of values of q instead of just the standard one I  =  I 0.9 corresponding to the 10%-90% variation in the dose-response. It is shown that this single choice can sometimes mislead the conclusion by not detecting ultrasensitivity. This new approach allows a better understanding of multisite ultrasensitive systems and provides new tools for the design of such systems.

Principal component analysis of biometric traits to reveal body confirmation in local hill cattle of Himalayan state of Himachal Pradesh, India.

PubMed

Verma, Deepak; Sankhyan, Varun; Katoch, Sanjeet; Thakur, Yash Pal

2015-12-01

In the present study, biometric traits (body length [BL], heart girth [HG], paunch girth (PG), forelimb length (FLL), hind limb length (HLL), face length, forehead width, forehead length, height at hump, hump length (HL), hook to hook distance, pin to pin distance, tail length (TL), TL up to switch, horn length, horn circumference, and ear length were studied in 218 adult hill cattle of Himachal Pradesh for phenotypic characterization. Morphological and biometrical observations were recorded on 218 hill cattle randomly selected from different districts within the breeding tract. Multivariate statistics and principal component analysis are used to account for the maximum portion of variation present in the original set of variables with a minimum number of composite variables through Statistical software, SAS 9.2. Five components were extracted which accounted for 65.9% of variance. The first component explained general body confirmation and explained 34.7% variation. It was represented by significant loading for BL, HG, PG, FLL, and HLL. Communality estimate ranged from 0.41 (HL) to 0.88 (TL). Second, third, fourth, and fifth component had a high loading for tail characteristics, horn characteristics, facial biometrics, and rear body, respectively. The result of component analysis of biometric traits suggested that indigenous hill cattle of Himachal Pradesh are small and compact size cattle with a medium hump, horizontally placed short ears, and a long tail. The study also revealed that factors extracted from the present investigation could be used in breeding programs with sufficient reduction in the number of biometric traits to be recorded to explain the body confirmation.

Optimum Array Processing for Detecting Binary Signals Corrupted by Directional Interference.

DTIC Science & Technology

1972-12-01

specific cases. Two different series representations of a vector random process are discussed in Van Trees [3]. These two methods both require the... spaci ~ng d, etc.) its detection error represents a lower bound for the performance that might be obtained with other types of array processing (such...Middleton, Introduction to Statistical Communication Theory, New York: McGraw-Hill, 1960. 3. H.L. Van Trees , Detection, Estimation, and Modulation Theory

The influence from combinations of prescribed fire, herbicide injection, and partial overstory removal on restoration of natural oak stands in the Arkansas Ozarks

Treesearch

K. Kyle Cunningham; Michael S. McGowan; H. Christoph Stuhlinger

2016-01-01

Two studies were conducted in the Springfield Plateau province of the Arkansas Ozarks from 2009 to 2014 incorporating the applied silvicultural methods proven beneficial to promote oak natural reproduction. The first study, River Hills, was a completely randomized design with treatments including: partial overstory removal to basal area 50 (BA50), partial overstory...

The conformational requirements for the mechanical precipitation of hemoglobin S and other mutants.

PubMed

Roth, E F; Elbaum, D; Bookchin, R M; Nagel, R L

1976-08-01

The mechanical stability of human hemoglobin mutants was studied for the specific effects of single and double amino acid substitutions, the ligand state of each chain, and the effect of hybrids between oxy and cyanmet partners on precipitability. It was found that the beta6Glu leads to Val and the beta73 Asp leads to Asn mutations increased the degree of mechanical precipitation in the liganded but not in the deoxy form. When these mutations occurred on the same chain, the effects were approximately additive. Heat labile mutants such as Hb Gun Hill and Hb Leiden exhibited mechanical instability, but probably through a different mechanism, as very little dependence on ligand state was apparent. Studies with valency hybrids of HbS(alpha2 betas2-and-alpha2 betas2 where = cyanmet) revealed that instability was primarily determined by the state of the betas chain, which must be liganded to confer instability on the tetramer. A good agreement between surface activity and mechanical precipitability of these mutants has been found.

From Snow to Hill to ALS: An epidemiological odyssey in search of ALS causation.

PubMed

Armon, Carmel

2018-05-21

Establishing mechanisms of disease causation in neurodegenerative diseases has long seemed to be beyond the pale of traditional epidemiological tools. Establishing a plausible mechanism for initiation of amyotrophic lateral sclerosis (ALS) has appeared a particularly elusive goal. This review shows that a likely mechanism for ALS initiation may be inferred by applying classical methods of epidemiological inference. Advances in characterizing the biology of ALS suggest that most cases of ALS are cortically-generated, part of the ALS-FTD spectrum, with focal onset and spread by contiguity within the motor super-network. Evidence-based methods identified the most credible exogenous risk factor - smoking. AB Hill's nine viewpoints to inferring causation from association were invoked. The most likely mechanism consistent with smoking being a risk factor for ALS was inferred: cumulative DNA damage, akin to cumulative somatic mutations in carcinogenesis. Focal onset supports the concept that these changes, occurring in a single cell, may trigger the cascade leading to clinical ALS. The plausibility of this mechanism was affirmed by its coherence/consistency with other observations in sporadic, familial and western Pacific ALS. Application of traditional epidemiological reasoning suggests that cumulative DNA damage may contribute to disease onset in ALS. Copyright © 2018 Elsevier B.V. All rights reserved.

The effects of sex-biased gene expression and X-linkage on rates of sequence evolution in Drosophila.

PubMed

Campos, José Luis; Johnston, Keira; Charlesworth, Brian

2017-12-08

A faster rate of adaptive evolution of X-linked genes compared with autosomal genes (the faster-X effect) can be caused by the fixation of recessive or partially recessive advantageous mutations. This effect should be largest for advantageous mutations that affect only male fitness, and least for mutations that affect only female fitness. We tested these predictions in Drosophila melanogaster by using coding and functionally significant non-coding sequences of genes with different levels of sex-biased expression. Consistent with theory, nonsynonymous substitutions in most male-biased and unbiased genes show faster adaptive evolution on the X. However, genes with very low recombination rates do not show such an effect, possibly as a consequence of Hill-Robertson interference. Contrary to expectation, there was a substantial faster-X effect for female-biased genes. After correcting for recombination rate differences, however, female-biased genes did not show a faster X-effect. Similar analyses of non-coding UTRs and long introns showed a faster-X effect for all groups of genes, other than introns of female-biased genes. Given the strong evidence that deleterious mutations are mostly recessive or partially recessive, we would expect a slower rate of evolution of X-linked genes for slightly deleterious mutations that become fixed by genetic drift. Surprisingly, we found little evidence for this after correcting for recombination rate, implying that weakly deleterious mutations are mostly close to being semidominant. This is consistent with evidence from polymorphism data, which we use to test how models of selection that assume semidominance with no sex-specific fitness effects may bias estimates of purifying selection. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

NPS Solar Cell Array Tester Cubesat Flight Testing and Integration

DTIC Science & Technology

2014-09-01

with current (I). P V I      (2.1) This is significant because the battery discharge test will not lineup perfectly with Figure 12...accordance with the charging procedures [13]. 3. NPS-SCAT Power Budget A power budget analysis was performed to determine if the NPS-SCAT is self...using procedures developed by Marissa Brummitt, and with the assistance of Adam Hill, NPS-SCAT Program Manager. 1. ELaNa IV Random Vibration Levels

Fisher's geometric model predicts the effects of random mutations when tested in the wild.

PubMed

Stearns, Frank W; Fenster, Charles B

2016-02-01

Fisher's geometric model of adaptation (FGM) has been the conceptual foundation for studies investigating the genetic basis of adaptation since the onset of the neo Darwinian synthesis. FGM describes adaptation as the movement of a genotype toward a fitness optimum due to beneficial mutations. To date, one prediction of FGM, the probability of improvement is related to the distance from the optimum, has only been tested in microorganisms under laboratory conditions. There is reason to believe that results might differ under natural conditions where more mutations likely affect fitness, and where environmental variance may obscure the expected pattern. We chemically induced mutations into a set of 19 Arabidopsis thaliana accessions from across the native range of A. thaliana and planted them alongside the premutated founder lines in two habitats in the mid-Atlantic region of the United States under field conditions. We show that FGM is able to predict the outcome of a set of random induced mutations on fitness in a set of A. thaliana accessions grown in the wild: mutations are more likely to be beneficial in relatively less fit genotypes. This finding suggests that FGM is an accurate approximation of the process of adaptation under more realistic ecological conditions. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

Diversity and biogeography of land snails (Mollusca, Gastropoda) in the limestone hills of Perak, Peninsular Malaysia

PubMed Central

Foon, Junn Kitt; Clements, Gopalasamy Reuben; Liew, Thor-Seng

2017-01-01

Abstract Limestone hills are now gaining global conservation attention as hotspots for short-range endemic species. Levels of land snail endemism can be high at limestone hills, especially at hill clusters that are geographically isolated. In the State of Perak, Peninsular Malaysia, limestone hills have been opportunistically surveyed for land snails in the past, but the majority have yet to be surveyed. To address this knowledge gap, we systematically surveyed the terrestrial malacofauna of 12 limestone hills that, based on our opinion, are a representation of the limestone land snail assemblages within the State. Our inventory yielded high sampling completeness (>85%). We found 122 species of land snails, of which 34 species were unique to one of the surveyed hills. We identified 30 species that are potentially new to science. The number of land snail species recorded at each hill ranged between 39 and 63 species. Four of the sampled limestone hills namely, Prk 01 G. Tempurung, Prk 55 G. Pondok, Prk 47 Kanthan, and Prk 64 Bt Kepala Gajah, have high levels of species richness and unique species, representing 91% of the total species recorded in this study. We identified two clusters of limestone hills in central Perak with distinct differences in land snail species composition – a northern hill cluster on elevated granite bedrock and southern hill cluster in a low-lying valley surrounded by alluvial soils. As limestone hills continue to be quarried to meet the cement demand, the four identified limestone hills, along with other hills from the two clusters, warrant urgent conservation attention in order to maintain high species diversity within Perak’s terrestrial malacofauna. PMID:28769723

c-Kit Mutation and Localization Status as Response Predictors in Mast Cell Tumors in Dogs Treated with Prednisone and Toceranib or Vinblastine.

PubMed

Weishaar, K M; Ehrhart, E J; Avery, A C; Charles, J B; Elmslie, R E; Vail, D M; London, C A; Clifford, C A; Eickhoff, J C; Thamm, D H

2018-01-01

KIT inhibitors, such as toceranib (TOC), and vinblastine (VBL) have not been prospectively compared in the treatment of macroscopic mast cell tumors (MCTs). Also, it is unknown whether VBL or TOC is superior for treating MCT without c-kit mutations. To determine the value of KIT genotyping and localization in treatment decisions for dogs with macroscopic MCT. We hypothesized that c-kit mutated MCT would have a better response to TOC than VBL. Eighty-eight client-owned dogs with macroscopic MCT. Prospective, randomized trial. Dogs were randomized to TOC (2.75 mg/kg EOD) or VBL (2.5 mg/m 2 weekly × 4 then EOW) by KIT localization and c-kit mutation status using an adaptive randomization scheme. Sixty dogs were allocated to TOC and 28 to VBL. Of the dogs receiving TOC, 20% had c-kit mutations, compared to 30% receiving VBL (P = 0.74). Overall response rates were 46% (TOC) and 30% (VBL) (odds ratio = 1.56 [0.62-3.92]; P = 0.28). Median progression-free survival (PFS) for dogs receiving VBL was 78 days (7-1,521) and for TOC 95.5 (14-990); hazard ratio (HR) = 1.34 [0.72-2.50]; P = 0.36. Median overall survival (OS) was 241.5 days (10-1,521) for the VBL group and 159 (20-990) for the TOC group; HR = 0.80 ([0.45-1.41]; P = 0.44). Neither PFS nor OS was significantly different between treatment groups. As the proportion of dogs with c-kit mutations was not different between treatment groups in this population of dogs, c-kit mutation status did not predict treatment response. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Efficacy according to blind independent central review: Post-hoc analyses from the phase III, randomized, multicenter, IPASS study of first-line gefitinib versus carboplatin/paclitaxel in Asian patients with EGFR mutation-positive advanced NSCLC.

PubMed

Wu, Yi-Long; Saijo, Nagahiro; Thongprasert, Sumitra; Yang, J C-H; Han, Baohui; Margono, Benjamin; Chewaskulyong, Busayamas; Sunpaweravong, Patrapim; Ohe, Yuichiro; Ichinose, Yukito; Yang, Jin-Ji; Mok, Tony S K; Young, Helen; Haddad, Vincent; Rukazenkov, Yuri; Fukuoka, Masahiro

2017-02-01

The Phase III, randomized, open-label IPASS study (NCT00322452) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) gefitinib versus carboplatin/paclitaxel for Asian patients with advanced non-small-cell lung cancer (NSCLC) showed that investigator-assessed progression-free survival (PFS) and objective response rate (ORR) were significantly prolonged in patients with EGFR mutation-positive NSCLC who received gefitinib versus patients with EGFR mutation-negative NSCLC. We report post-hoc analyses of IPASS data by blind independent central review (BICR), performed at the request of the US FDA, in a subset of patients with EGFR mutation-positive NSCLC. Eligible patients (aged ≥18 years; histologically/cytologically confirmed Stage IIB/IV adenocarcinoma NSCLC; non- or former light-smokers; treatment-naïve) were randomly assigned 1:1 to gefitinib (250mg/day) or carboplatin (dose calculated to produce an area under the curve of 5 or 6 mg/mL/minute)/paclitaxel (200mg/m 2 ). Primary endpoint: PFS. BICR analyses included PFS, ORR, and duration of response (DoR). Scans from 186 IPASS patients (gefitinib n=88, carboplatin/paclitaxel n=98) with EGFR mutation-positive NSCLC were available for BICR. Consistent with investigator-assessed results, in patients with EGFR mutation-positive NSCLC: PFS (hazard ratio 0.54; 95% confidence interval [CI] 0.38, 0.79; p=0.0012) and ORR (odds ratio 3.00; 95% CI 1.63, 5.54; p=0.0004) were significantly longer with gefitinib versus carboplatin/paclitaxel. The median DoR by BICR was 9.6 months with gefitinib and 5.5 months with carboplatin/paclitaxel. BICR analysis of IPASS data support the original, investigator-assessed results. EGFR mutation-positive status remains a significant predictor of response to first-line TKI therapy. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Evolutionary constraints and the neutral theory. [mutation-caused nucleotide substitutions in DNA

NASA Technical Reports Server (NTRS)

Jukes, T. H.; Kimura, M.

1984-01-01

The neutral theory of molecular evolution postulates that nucleotide substitutions inherently take place in DNA as a result of point mutations followed by random genetic drift. In the absence of selective constraints, the substitution rate reaches the maximum value set by the mutation rate. The rate in globin pseudogenes is about 5 x 10 to the -9th substitutions per site per year in mammals. Rates slower than this indicate the presence of constraints imposed by negative (natural) selection, which rejects and discards deleterious mutations.

Do mobile family planning clinics facilitate vasectomy use in Nepal?

PubMed

Padmadas, Sabu S; Amoako Johnson, Fiifi; Leone, Tiziana; Dahal, Govinda P

2014-06-01

Nepal has a distinct topography that makes reproductive health and family planning services difficult to access, particularly in remote mountain and hill regions where over a quarter of modern contraceptive users rely exclusively on vasectomy. A three-level random intercept logistic regression analysis was applied on data from the 2011 Nepal Demographic and Health Survey to investigate the extent of influence of mobile family planning clinics on the odds of a male or a female sterilization, adjusting for relevant characteristics including ecological differences and random effects. The analyses included a sample of 2014 sterilization users, considering responses from currently married women of reproductive ages. The odds of a male sterilization were significantly higher in a mobile clinic than those in a government hospital (odds ratio, 1.65; 95% confidence interval, 1.21-2.25). The effects remained unaltered and statistically significant after adjusting for sociodemographic and clustering effects. Random effects were highly significant, which suggest the extent of heterogeneity in vasectomy use at the community and district levels. The odds of vasectomy use in mobile clinics were significantly higher among couples residing in hill and mountain regions and among those with three or more sons or those with only daughters. Mobile clinics significantly increase the uptake of vasectomy in hard-to-reach areas of Nepal. Reproductive health interventions should consider mobile clinics as an effective strategy to improve access to male-based modern methods and enhance gender equity in family planning. Family planning interventions in hard-to-reach communities could consider mobile clinic as an effective strategy to promote male-based modern methods. Improving access to vasectomy could substantially reduce unmet need for family planning in countries experiencing rapid fertility transition. Copyright © 2014 Elsevier Inc. All rights reserved.

Habitat selection of a declining white-tailed deer herd in the central Black Hills, South Dakota and Wyoming

NASA Astrophysics Data System (ADS)

Deperno, Christopher Shannon

Habitat selection, survival rates, the Black Hills National Forest Habitat Capability Model (HABCAP), and the USDA Forest Service Geographic Information System (GIS) data base were evaluated for a declining white-tailed deer (Odocoileus virginianus dacotensis) herd in the central Black Hills of South Dakota and Wyoming. From July 1993 through July 1996, 73 adult and yearling female and 12 adult and yearling male white-tailed deer were radiocollared and visually monitored. Habitat information was collected at 4,662 white-tailed deer locations and 1,087 random locations. Natural mortality (71%) was the primary cause of female mortality, followed by harvest (22.5%) and accidental causes (6.5%). More females died in spring (53.2%) than in fall (22.6%), winter (14.5%), or summer (9.7%). Male mortality resulted from hunting in fall (66.7%) and natural causes in spring (33.3%). Survival rates for all deer by year were 62.1% in 1993, 51.1% in 1994, 56.4% in 1995, and 53.9% in 1996 and were similar (P = 0.691) across years. During winter, white-tailed deer selected ponderosa pine- (Pinus ponderosa ) deciduous and burned pine cover types. Overstory-understory habitats selected included pine/grass-forb, pine/bearberry (Arctostaphylos uva-ursi), pine/snowberry (Symphoricarpos albus), burned pine/grass-forb, and pine/shrub habitats. Structural stages selected included sapling-pole pine stands with >70% canopy cover, burned pine sapling-pole and saw-timber stands with <40% canopy cover. Bedding locations were represented by saw-timber pine structural stages with >40% canopy cover and all sapling-pole pine structural stages; sapling-pole stands with >70% canopy cover received the greatest use. White-tailed deer primarily fed in pine saw-timber structural stage with less than 40% canopy cover. Overall, selected habitats contained lower amounts of grass/forb, shrubs, and litter than random locations. Male and female deer generally bedded in areas that were characterized by greater horizontal cover than feeding and random sites. When feeding and bedding sites were combined males selected areas that were characterized by greater levels of horizontal cover than females. During summer, white-tailed deer selected pine-deciduous, aspen (Populus tremuloides), aspen-coniferous, spruce (Picea glauca), and spruce-deciduous cover types. Overstory-understory habitats selected included pine/juniper (Juniperus communis), aspen/shrubs, spruce/juniper, and spruce/shrub habitats. Structural stages selected included pine, aspen, and spruce sapling pole stands with all levels (0--40%, 41--70%, 71--100%) of canopy cover. All habitat types (i.e., pine, aspen, and spruce) were used as bedding locations with pine sapling-pole structural stages with >70% canopy cover used most, whereas pine saw-timber structural stage with less than 40% canopy cover was primarily used for feeding. Females bedded in areas that were characterized by greater horizontal cover than feeding and random sites, whereas male feeding sites had greater horizontal cover characteristics than bedding or random locations.

Triggered surface slips in the Salton Trough associated with the 1999 Hector Mine, California, earthquake

USGS Publications Warehouse

Rymer, M.J.; Boatwright, J.; Seekins, L.C.; Yule, J.D.; Liu, J.

2002-01-01

Surface fracturing occurred along the southern San Andreas, Superstition Hills, and Imperial faults in association with the 16 October 1999 (Mw 7.1) Hector Mine earthquake, making this at least the eighth time in the past 31 years that a regional earthquake has triggered slip along faults in the Salton Trough. Fractures associated with the event formed discontinuous breaks over a 39-km-long stretch of the San Andreas fault, from the Mecca Hills southeastward to Salt Creek and Durmid Hill, a distance from the epicenter of 107 to 139 km. Sense of slip was right lateral; only locally was there a minor (~1 mm) vertical component of slip. Dextral slip ranged from 1 to 13 mm. Maximum slip values in 1999 and earlier triggered slips are most common in the central Mecca Hills. Field evidence indicates a transient opening as the Hector Mine seismic waves passed the southern San Andreas fault. Comparison of nearby strong-motion records indicates several periods of relative opening with passage of the Hector Mine seismic wave-a similar process may have contributed to the field evidence of a transient opening. Slip on the Superstition Hills fault extended at least 9 km, at a distance from the Hector Mine epicenter of about 188 to 196 km. This length of slip is a minimum value, because we saw fresh surface breakage extending farther northwest than our measurement sites. Sense of slip was right lateral; locally there was a minor (~1 mm) vertical component of slip. Dextral slip ranged from 1 to 18 mm, with the largest amounts found distributed (or skewed) away from the Hector Mine earthquake source. Slip triggered on the Superstition Hills fault commonly is skewed away from the earthquake source, most notably in 1968, 1979, and 1999. Surface slip on the Imperial fault and within the Imperial Valley extended about 22 km, representing a distance from the Hector Mine epicenter of about 204 to 226 km. Sense of slip dominantly was right lateral; the right-lateral component of slip ranged from 1 to 19 mm. Locally there was a minor (~1-2 mm) vertical component of slip; larger proportions of vertical slip (up to 10 mm) occurred in Mesquite basin, where scarps indicate long-term oblique-slip motion for this part of the Imperial fault. Slip triggered on the Imperial fault appears randomly distributed relative to location along the fault and source direction. Multiple surface slips, both primary and triggered slip, indicate that slip repeatedly is small at locations of structural complexity.

Mutation Frequency of the Major Frontotemporal Dementia Genes, MAPT, GRN and C9ORF72 in a Turkish Cohort of Dementia Patients.

PubMed

Guven, Gamze; Lohmann, Ebba; Bras, Jose; Gibbs, J Raphael; Gurvit, Hakan; Bilgic, Basar; Hanagasi, Hasmet; Rizzu, Patrizia; Heutink, Peter; Emre, Murat; Erginel-Unaltuna, Nihan; Just, Walter; Hardy, John; Singleton, Andrew; Guerreiro, Rita

2016-01-01

'Microtubule-associated protein tau' (MAPT), 'granulin' (GRN) and 'chromosome 9 open reading frame72' (C9ORF72) gene mutations are the major known genetic causes of frontotemporal dementia (FTD). Recent studies suggest that mutations in these genes may also be associated with other forms of dementia. Therefore we investigated whether MAPT, GRN and C9ORF72 gene mutations are major contributors to dementia in a random, unselected Turkish cohort of dementia patients. A combination of whole-exome sequencing, Sanger sequencing and fragment analysis/Southern blot was performed in order to identify pathogenic mutations and novel variants in these genes as well as other FTD-related genes such as the 'charged multivesicular body protein 2B' (CHMP2B), the 'FUS RNA binding protein' (FUS), the 'TAR DNA binding protein' (TARDBP), the 'sequestosome1' (SQSTM1), and the 'valosin containing protein' (VCP). We determined one pathogenic MAPT mutation (c.1906C>T, p.P636L) and one novel missense variant (c.38A>G, p.D13G). In GRN we identified a probably pathogenic TGAG deletion in the splice donor site of exon 6. Three patients were found to carry the GGGGCC expansions in the non-coding region of the C9ORF72 gene. In summary, a complete screening for mutations in MAPT, GRN and C9ORF72 genes revealed a frequency of 5.4% of pathogenic mutations in a random cohort of 93 Turkish index patients with dementia.

Non-Linear Metamodeling Extensions to the Robust Parameter Design of Computer Simulations

DTIC Science & Technology

2016-09-15

design By principal component analysis," Total Quality Management, vol. 8, no. 6, pp. 409-416, 1997. [25] A. Salmasnia, R. B . Kazemzadeh and S. T . A...and D. T . Sturrock, Simulation with Arena (3rd ed.), New York, NY: McGraw-Hill, 2004. [85] A. M. Mathai and S. B . Provost, Quadratic Forms in Random...PhD Member ADEDEJI B . BADIRU, PhD Dean, Graduate School of Engineering and Management iv AFIT-ENS-DS-16-S-026 Abstract Robust

Iterative repair for scheduling and rescheduling

NASA Technical Reports Server (NTRS)

Zweben, Monte; Davis, Eugene; Deale, Michael

1991-01-01

An iterative repair search method is described called constraint based simulated annealing. Simulated annealing is a hill climbing search technique capable of escaping local minima. The utility of the constraint based framework is shown by comparing search performance with and without the constraint framework on a suite of randomly generated problems. Results are also shown of applying the technique to the NASA Space Shuttle ground processing problem. These experiments show that the search methods scales to complex, real world problems and reflects interesting anytime behavior.

Clarification of the Hashin-Shtrikman bounds on the effective elastic moduli of polycrystals with hexagonal, trigonal, and tetragonal symmetries

USGS Publications Warehouse

Watt, J.P.; Peselnick, L.

1980-01-01

Bounds on the effective elastic moduli of randomly oriented aggregates of hexagonal, trigonal, and tetragonal crystals are derived using the variational principles of Hashin and Shtrikman. The bounds are considerably narrower than the widely used Voigt and Reuss bounds. The Voigt-Reuss-Hill average lies within the Hashin-Shtrikman bounds in nearly all cases. Previous bounds of Peselnick and Meister are shown to be special cases of the present results.

Germ-line mutations in the neurofibromatosis 2 gene: Correlations with disease severity and retinal abnormalities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parry, D.M.; Kaiser-Kupfer, M.; Eldridge, R.

Neurofibromatosis 2 (NF2) features bilateral vestibular schwannomas, other benign neural tumors, and cataracts. Patients in some families develop many tumors at an early age and have rapid clinical progression, whereas in other families, patients may not have symptoms until much later and vestibular schwannomas may be the only tumors. The NF2 gene has been cloned from chromosome 22q; most identified germ-line mutations result in a truncated protein and severe NF2. To look for additional mutations and clinical correlations, we used SSCP analysis to screen DNA from 32 unrelated patients. We identified 20 different mutations in 21 patients (66%): 10 nonsensemore » mutations, 2 frameshifts, 7 splice-site mutations, and 1 large in-frame deletion. Clinical information on 47 patients from the 21 families included ages at onset and at diagnosis, numbers of meningiomas, spinal and skin tumors, and presence of cataracts and retinal abnormalities. We compared clinical findings in patients with nonsense or frameshift mutations to those with splice-site mutations. When each patient was considered as an independent random event, the two groups differed (P {le} .05) for nearly every variable. Patients with nonsense or frameshift mutations were younger at onset and at diagnosis and had a higher frequency and mean number of tumors, supporting the correlation between nonsense and frameshift mutations and severe NF2. When each family was considered as an independent random event, statistically significant differences between the two groups were observed only for mean ages at onset and at diagnosis. A larger data set is needed to resolve these discrepancies. We observed retinal hamartomas and/or epiretinal membranes in nine patients from five families with four different nonsense mutations. This finding, which may represent a new genotype-phenotype correlation, merits further study. 58 refs., 2 tabs.« less

Random codon re-encoding induces stable reduction of replicative fitness of Chikungunya virus in primate and mosquito cells.

PubMed

Nougairede, Antoine; De Fabritus, Lauriane; Aubry, Fabien; Gould, Ernest A; Holmes, Edward C; de Lamballerie, Xavier

2013-02-01

Large-scale codon re-encoding represents a powerful method of attenuating viruses to generate safe and cost-effective vaccines. In contrast to specific approaches of codon re-encoding which modify genome-scale properties, we evaluated the effects of random codon re-encoding on the re-emerging human pathogen Chikungunya virus (CHIKV), and assessed the stability of the resultant viruses during serial in cellulo passage. Using different combinations of three 1.4 kb randomly re-encoded regions located throughout the CHIKV genome six codon re-encoded viruses were obtained. Introducing a large number of slightly deleterious synonymous mutations reduced the replicative fitness of CHIKV in both primate and arthropod cells, demonstrating the impact of synonymous mutations on fitness. Decrease of replicative fitness correlated with the extent of re-encoding, an observation that may assist in the modulation of viral attenuation. The wild-type and two re-encoded viruses were passaged 50 times either in primate or insect cells, or in each cell line alternately. These viruses were analyzed using detailed fitness assays, complete genome sequences and the analysis of intra-population genetic diversity. The response to codon re-encoding and adaptation to culture conditions occurred simultaneously, resulting in significant replicative fitness increases for both re-encoded and wild type viruses. Importantly, however, the most re-encoded virus failed to recover its replicative fitness. Evolution of these viruses in response to codon re-encoding was largely characterized by the emergence of both synonymous and non-synonymous mutations, sometimes located in genomic regions other than those involving re-encoding, and multiple convergent and compensatory mutations. However, there was a striking absence of codon reversion (<0.4%). Finally, multiple mutations were rapidly fixed in primate cells, whereas mosquito cells acted as a brake on evolution. In conclusion, random codon re-encoding provides important information on the evolution and genetic stability of CHIKV viruses and could be exploited to develop a safe, live attenuated CHIKV vaccine.

Efficient fractal-based mutation in evolutionary algorithms from iterated function systems

NASA Astrophysics Data System (ADS)

Salcedo-Sanz, S.; Aybar-Ruíz, A.; Camacho-Gómez, C.; Pereira, E.

2018-03-01

In this paper we present a new mutation procedure for Evolutionary Programming (EP) approaches, based on Iterated Function Systems (IFSs). The new mutation procedure proposed consists of considering a set of IFS which are able to generate fractal structures in a two-dimensional phase space, and use them to modify a current individual of the EP algorithm, instead of using random numbers from different probability density functions. We test this new proposal in a set of benchmark functions for continuous optimization problems. In this case, we compare the proposed mutation against classical Evolutionary Programming approaches, with mutations based on Gaussian, Cauchy and chaotic maps. We also include a discussion on the IFS-based mutation in a real application of Tuned Mass Dumper (TMD) location and optimization for vibration cancellation in buildings. In both practical cases, the proposed EP with the IFS-based mutation obtained extremely competitive results compared to alternative classical mutation operators.

On the origin of Hill's causal criteria.

PubMed

Morabia, A

1991-09-01

The rules to assess causation formulated by the eighteenth century Scottish philosopher David Hume are compared to Sir Austin Bradford Hill's causal criteria. The strength of the analogy between Hume's rules and Hill's causal criteria suggests that, irrespective of whether Hume's work was known to Hill or Hill's predecessors, Hume's thinking expresses a point of view still widely shared by contemporary epidemiologists. The lack of systematic experimental proof to causal inferences in epidemiology may explain the analogy of Hume's and Hill's, as opposed to Popper's, logic.

Hypersomnia

MedlinePlus

... 5885 Cumming Highway Suite 108-255 Sugar Hill GA Sugar Hill, GA 30518 http://www.hypersomniafoundation.org Tel: 844-342- ... 5885 Cumming Highway Suite 108-255 Sugar Hill GA Sugar Hill, GA 30518 http://www.hypersomniafoundation.org ...

77 FR 50095 - Combined Notice of Filings #2

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-20

... Combine Hills I LLC, Avenal Park LLC, Sand Drag LLC, Sun City Project LLC, Eurus Combine Hills II LLC... Power Partners, LLC, Crescent Ridge LLC, Eurus Combine Hills I LLC, Avenal Park LLC, Sand Drag LLC, Sun..., Eurus Combine Hills I LLC, Avenal Park LLC, Sand Drag LLC, Sun City Project LLC, Eurus Combine Hills II...

Hume, Mill, Hill, and the Sui Generis Epidemiologic Approach to Causal Inference

PubMed Central

Morabia, Alfredo

2013-01-01

The epidemiologic approach to causal inference (i.e., Hill's viewpoints) consists of evaluating potential causes from the following 2, noncumulative angles: 1) established results from comparative, observational, or experimental epidemiologic studies; and 2) reviews of nonepidemiologic evidence. It does not involve statements of statistical significance. The philosophical roots of Hill's viewpoints are unknown. Superficially, they seem to descend from the ideas of Hume and Mill. Hill's viewpoints, however, use a different kind of evidence and have different purposes than do Hume's rules or Mill's system of logic. In a nutshell, Hume ignores comparative evidence central to Hill's viewpoints. Mill's logic disqualifies as invalid nonexperimental evidence, which forms the bulk of epidemiologic findings reviewed from Hill's viewpoints. The approaches by Hume and Mill cannot corroborate successful implementations of Hill's viewpoints. Besides Hume and Mill, the epidemiologic literature is clueless about a plausible, pre-1965 philosophical origin of Hill's viewpoints. Thus, Hill's viewpoints may be philosophically novel, sui generis, still waiting to be validated and justified. PMID:24071010

Hume, Mill, Hill, and the sui generis epidemiologic approach to causal inference.

PubMed

Morabia, Alfredo

2013-11-15

The epidemiologic approach to causal inference (i.e., Hill's viewpoints) consists of evaluating potential causes from the following 2, noncumulative angles: 1) established results from comparative, observational, or experimental epidemiologic studies; and 2) reviews of nonepidemiologic evidence. It does not involve statements of statistical significance. The philosophical roots of Hill's viewpoints are unknown. Superficially, they seem to descend from the ideas of Hume and Mill. Hill's viewpoints, however, use a different kind of evidence and have different purposes than do Hume's rules or Mill's system of logic. In a nutshell, Hume ignores comparative evidence central to Hill's viewpoints. Mill's logic disqualifies as invalid nonexperimental evidence, which forms the bulk of epidemiologic findings reviewed from Hill's viewpoints. The approaches by Hume and Mill cannot corroborate successful implementations of Hill's viewpoints. Besides Hume and Mill, the epidemiologic literature is clueless about a plausible, pre-1965 philosophical origin of Hill's viewpoints. Thus, Hill's viewpoints may be philosophically novel, sui generis, still waiting to be validated and justified.

The basic science and mathematics of random mutation and natural selection.

PubMed

Kleinman, Alan

2014-12-20

The mutation and natural selection phenomenon can and often does cause the failure of antimicrobial, herbicidal, pesticide and cancer treatments selection pressures. This phenomenon operates in a mathematically predictable behavior, which when understood leads to approaches to reduce and prevent the failure of the use of these selection pressures. The mathematical behavior of mutation and selection is derived using the principles given by probability theory. The derivation of the equations describing the mutation and selection phenomenon is carried out in the context of an empirical example. Copyright © 2014 John Wiley & Sons, Ltd.

A De Novo Germline APC Mutation (3927del5) in a Patient with Familial Adenomatous Polyposis: Case Report and Literature Review

PubMed Central

Zeichner, Simon B.; Raj, Naveen; Cusnir, Mike; Francavilla, Michael; Hirzel, Alicia

2012-01-01

Introduction Characterized by the development of hundreds to thousands of colonic adenomas, classic familial adenomatous polyposis (FAP) is one of the most common hereditary syndromes associated with an increased risk of colorectal cancer. Several studies have attempted to correlate specific APC mutations with clinical phenotype.6 However, there is considerable variability in the expression of specific phenotypes within families and among individuals with identical mutations.7 Case presentation A 30 year-old Hispanic female presented to the emergency department with a 2-week history of persistent, worsening, left lower quadrant abdominal pain. She had no family history of malignancy. Sigmoidoscopy revealed innumerable polyps in the rectum and sigmoid colon and a large mass in the sigmoid colon. Biopsy of the mass revealed a moderately differentiated adenocarcinoma invading the subserosa. Endoscopy revealed innumerable polyps. Genetic testing of the patient via southern blot revealed a germline APC mutation 3927del5, resulting in a premature truncation of the APC protein at amino acid position 1312. Conclusion Genetic information has only recently started being incorporated into clinical care. More research and randomized clinical trials need to be conducted to definitively characterize random mutations. Once these mutations are further understood, FAP patients may be able to be risk stratified and this may ultimately improve the screening, diagnosis, and treatment of this rare condition. PMID:23115482

Mutation as a Stress Response and the Regulation of Evolvability

PubMed Central

Galhardo, Rodrigo S.; Hastings, P. J.; Rosenberg, Susan M.

2010-01-01

Our concept of a stable genome is evolving to one in which genomes are plastic and responsive to environmental changes. Growing evidence shows that a variety of environmental stresses induce genomic instability in bacteria, yeast, and human cancer cells, generating occasional fitter mutants and potentially accelerating adaptive evolution. The emerging molecular mechanisms of stress-induced mutagenesis vary but share telling common components that underscore two common themes. The first is the regulation of mutagenesis in time by cellular stress responses, which promote random mutations specifically when cells are poorly adapted to their environments, i.e., when they are stressed. A second theme is the possible restriction of random mutagenesis in genomic space, achieved via coupling of mutation-generating machinery to local events such as DNA-break repair or transcription. Such localization may minimize accumulation of deleterious mutations in the genomes of rare fitter mutants, and promote local concerted evolution. Although mutagenesis induced by stresses other than direct damage to DNA was previously controversial, evidence for the existence of various stress-induced mutagenesis programs is now overwhelming and widespread. Such mechanisms probably fuel evolution of microbial pathogenesis and antibiotic-resistance, and tumor progression and chemotherapy resistance, all of which occur under stress, driven by mutations. The emerging commonalities in stress-induced-mutation mechanisms provide hope for new therapeutic interventions for all of these processes. PMID:17917874

Impact of nutrition education on knowledge and haemoglobin status of hill women in Uttarakhand State of India.

PubMed

Upadhyay, S; Kumar, A R; Raghuvanshi, R S; Singh, B B

2011-12-01

This study aimed to examine the impact of the use of single vs. combination of media on nutritional knowledge and haemoglobin status of women in a rural hill area in Uttarakhand State, India. Women from three villages were selected randomly and divided into three groups namely, print media group (n = 59), multimedia group (n = 53) and control group (n = 111). The print media group was exposed to nutrition education through the use of calendars on anaemia for 60 days; the multimedia group was given nutrition education through a combination of media including calendars, video films, and group discussions for 60 days. At pre-exposure stage, 62.7% of the women in the print media group, 67.9% of the multimedia group, and 66.7% of the control group had a low nutrition knowledge level. After exposure, the print media group and the multimedia group showed a significant rise in nutrition knowledge, with the multimedia group scoring significantly higher than the print media group. Overall, 69.1% of the women were anaemic with mean haemoglobin concentration of 10.74 +/- 0.86 g/dl. A non-significant rise in mean haemoglobin concentrations in the experimental groups was found at post-exposure stage. Calendars and video films are effective in increasing nutrition knowledge of illiterate hill women. Use of mass media programmes of longer duration should be encouraged to combat the nutritional problems of rural communities.

EFFECTS OF THE GENIUM MICROPROCESSOR KNEE SYSTEM ON KNEE MOMENT SYMMETRY DURING HILL WALKING.

PubMed

Highsmith, M Jason; Klenow, Tyler D; Kahle, Jason T; Wernke, Matthew M; Carey, Stephanie L; Miro, Rebecca M; Lura, Derek J

2016-09-01

Use of the Genium microprocessor knee (MPK) system reportedly improves knee kinematics during walking and other functional tasks compared to other MPK systems. This improved kinematic pattern was observed when walking on different hill conditions and at different speeds. Given the improved kinematics associated with hill walking while using the Genium, a similar improvement in the symmetry of knee kinetics is also feasible. The purpose of this study was to determine if Genium MPK use would reduce the degree of asymmetry (DoA) of peak stance knee flexion moment compared to the C-Leg MPK in transfemoral amputation (TFA) patients. This study used a randomized experimental crossover of TFA patients using Genium and C-Leg MPKs ( n = 20). Biomechanical gait analysis by 3D motion tracking with floor mounted force plates of TFA patients ambulating at different speeds on 5° ramps was completed. Knee moment DoA was significantly different between MPK conditions in the slow and fast uphill as well as the slow and self-selected downhill conditions. In a sample of high-functioning TFA patients, Genium knee system accommodation and use improved knee moment symmetry in slow speed walking up and down a five degree ramp compared with C-Leg. Additionally, the Genium improved knee moment symmetry when walking downhill at comfortable speed. These results likely have application in other patients who could benefit from more consistent knee function, such as older patients and others who have slower walking speeds.

Extensively Parameterized Mutation-Selection Models Reliably Capture Site-Specific Selective Constraint.

PubMed

Spielman, Stephanie J; Wilke, Claus O

2016-11-01

The mutation-selection model of coding sequence evolution has received renewed attention for its use in estimating site-specific amino acid propensities and selection coefficient distributions. Two computationally tractable mutation-selection inference frameworks have been introduced: One framework employs a fixed-effects, highly parameterized maximum likelihood approach, whereas the other employs a random-effects Bayesian Dirichlet Process approach. While both implementations follow the same model, they appear to make distinct predictions about the distribution of selection coefficients. The fixed-effects framework estimates a large proportion of highly deleterious substitutions, whereas the random-effects framework estimates that all substitutions are either nearly neutral or weakly deleterious. It remains unknown, however, how accurately each method infers evolutionary constraints at individual sites. Indeed, selection coefficient distributions pool all site-specific inferences, thereby obscuring a precise assessment of site-specific estimates. Therefore, in this study, we use a simulation-based strategy to determine how accurately each approach recapitulates the selective constraint at individual sites. We find that the fixed-effects approach, despite its extensive parameterization, consistently and accurately estimates site-specific evolutionary constraint. By contrast, the random-effects Bayesian approach systematically underestimates the strength of natural selection, particularly for slowly evolving sites. We also find that, despite the strong differences between their inferred selection coefficient distributions, the fixed- and random-effects approaches yield surprisingly similar inferences of site-specific selective constraint. We conclude that the fixed-effects mutation-selection framework provides the more reliable software platform for model application and future development. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Previous Estimates of Mitochondrial DNA Mutation Level Variance Did Not Account for Sampling Error: Comparing the mtDNA Genetic Bottleneck in Mice and Humans

PubMed Central

Wonnapinij, Passorn; Chinnery, Patrick F.; Samuels, David C.

2010-01-01

In cases of inherited pathogenic mitochondrial DNA (mtDNA) mutations, a mother and her offspring generally have large and seemingly random differences in the amount of mutated mtDNA that they carry. Comparisons of measured mtDNA mutation level variance values have become an important issue in determining the mechanisms that cause these large random shifts in mutation level. These variance measurements have been made with samples of quite modest size, which should be a source of concern because higher-order statistics, such as variance, are poorly estimated from small sample sizes. We have developed an analysis of the standard error of variance from a sample of size n, and we have defined error bars for variance measurements based on this standard error. We calculate variance error bars for several published sets of measurements of mtDNA mutation level variance and show how the addition of the error bars alters the interpretation of these experimental results. We compare variance measurements from human clinical data and from mouse models and show that the mutation level variance is clearly higher in the human data than it is in the mouse models at both the primary oocyte and offspring stages of inheritance. We discuss how the standard error of variance can be used in the design of experiments measuring mtDNA mutation level variance. Our results show that variance measurements based on fewer than 20 measurements are generally unreliable and ideally more than 50 measurements are required to reliably compare variances with less than a 2-fold difference. PMID:20362273

Tumor infiltrating BRAFV600E-specific CD4 T cells correlated with complete clinical response in melanoma. | Office of Cancer Genomics

Cancer.gov

T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune checkpoint inhibitor therapy or adoptive cell transfer. Unfortunately, most neoantigens result from random mutations and are patient specific, and some cancers contain few mutations to serve as potential antigens. We describe a patient with stage IV acral melanoma who obtained a complete response following adoptive transfer of tumor infiltrating lymphocytes (TIL).

Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis clinical strains isolated in the Philippines.

PubMed

Herrera, Laura; Valverde, Azucena; Saiz, Pilar; Sáez-Nieto, Juan A; Portero, José L; Jiménez, M Soledad

2004-06-01

The prevalence of mutations in the katG, inhA and oxyR-ahpC genes of isoniazid (INH)-resistant Mycobacterium tuberculosis isolates in the Philippines were determined. Of 306 M. tuberculosis isolates studied, 81 (26.5%) exhibited INH-resistance. Forty-four strains (54.3%) had mutations in the katG gene, eighteen strains (22.2%) had mutations in the putative inhA locus region, seven had mutations in both regions and five strains had mutations in the oxyR-ahpC operon. Only seven strains had no mutations. A total of 71 of the 81 (87.6%) resistant strains and 65 of the 72 (90.3%) INH sensitive randomly selected strains showed amino acid substitution in codon 463 (Arg to Leu) (88.9%). This fact supports the hypothesis that mutations at codon 463 are independent of INH-resistance and are linked to the geographical origins of the strains. Copyright 2004 Elsevier B.V.

Random Evolutionary Dynamics Driven by Fitness and House-of-Cards Mutations: Sampling Formulae

NASA Astrophysics Data System (ADS)

Huillet, Thierry E.

2017-07-01

We first revisit the multi-allelic mutation-fitness balance problem, especially when mutations obey a house of cards condition, where the discrete-time deterministic evolutionary dynamics of the allelic frequencies derives from a Shahshahani potential. We then consider multi-allelic Wright-Fisher stochastic models whose deviation to neutrality is from the Shahshahani mutation/selection potential. We next focus on the weak selection, weak mutation cases and, making use of a Gamma calculus, we compute the normalizing partition functions of the invariant probability densities appearing in their Wright-Fisher diffusive approximations. Using these results, generalized Ewens sampling formulae (ESF) from the equilibrium distributions are derived. We start treating the ESF in the mixed mutation/selection potential case and then we restrict ourselves to the ESF in the simpler house-of-cards mutations only situation. We also address some issues concerning sampling problems from infinitely-many alleles weak limits.

Audio-magnetotelluric (AMT) study to investigate the genesis of Mujil hill

NASA Astrophysics Data System (ADS)

Rahmania, Suryanto, Wiwit

2017-07-01

Gunung Mujil is an isolated hill located near Pondoworejo village, Kalibawang sub-district, Kulon Progo district, and Special Province of Yogyakarta. The hill is part of the eastern Kulon Progo mountain range extended relatively in the North-South direction. The lithology of the hill consists of andesite breccia and it's similar with the Old Andesite Formation that built the Kulon Progo Mountains. There are at least two hypothesis about the genesis and the formation mechanism of this hill, (1) it was formed by debris mass from Kulon Progo Mountains, and (2) ) it was formed by an intrusion. Our study intended to determine the subsurface resistivity below the hill and to relating those results to with the scenario of the genesis of the Mujil hill. We conducted Audio-magnetotellurics (AMT) measurements along two lines survey crossing the Mujil hill consisting of 20 measurements. Since the measurements are located near the villages, most of the data has a fair to bad quality and only one station yielded an excellent data. A 1D Forward modeling was then applied to find best-fit model of the AMT data. The results shows that the Mujil hill was built by debris mass of the Old Andesite Formation from Kulon Progo mountain which is represented by a lower resistivity value under the Mujil hill.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tumuluru, Jaya Shankar; McCulloch, Richard Chet James

In this work a new hybrid genetic algorithm was developed which combines a rudimentary adaptive steepest ascent hill climbing algorithm with a sophisticated evolutionary algorithm in order to optimize complex multivariate design problems. By combining a highly stochastic algorithm (evolutionary) with a simple deterministic optimization algorithm (adaptive steepest ascent) computational resources are conserved and the solution converges rapidly when compared to either algorithm alone. In genetic algorithms natural selection is mimicked by random events such as breeding and mutation. In the adaptive steepest ascent algorithm each variable is perturbed by a small amount and the variable that caused the mostmore » improvement is incremented by a small step. If the direction of most benefit is exactly opposite of the previous direction with the most benefit then the step size is reduced by a factor of 2, thus the step size adapts to the terrain. A graphical user interface was created in MATLAB to provide an interface between the hybrid genetic algorithm and the user. Additional features such as bounding the solution space and weighting the objective functions individually are also built into the interface. The algorithm developed was tested to optimize the functions developed for a wood pelleting process. Using process variables (such as feedstock moisture content, die speed, and preheating temperature) pellet properties were appropriately optimized. Specifically, variables were found which maximized unit density, bulk density, tapped density, and durability while minimizing pellet moisture content and specific energy consumption. The time and computational resources required for the optimization were dramatically decreased using the hybrid genetic algorithm when compared to MATLAB's native evolutionary optimization tool.« less

Atmospheric Rawinsonde and Pigeon Release Data Implicate Infrasound as the Long- Range Map Cue in Avian Navigation

NASA Astrophysics Data System (ADS)

Hagstrum, J. T.

2007-12-01

Pigeons ( Columba livia) and other birds released from distant familiar and unfamiliar sites generally head in the homeward (loft) direction, but often vanish from view or radio contact consistently off the exact homeward bearing. At some sites the deviation can be a significant and stable amount, while at other sites birds can appear to become completely lost and depart in random directions. These deviations or biases can change from hour to hour, day to day, and year to year, but have not, over the last ~50 years of intensive research, been related to any atmospheric factor. They are, however, still considered to reflect significant irregularities in the pigeons' "map" function. Celestial and geomagnetic "compasses" have been shown to orient avian flight, but how pigeons determine their location in order to select the correct homeward bearing remains controversial. At present the debate is primarily between workers advocating an olfactory "map" and those advocating variations in the direction and intensity of the geomagnetic field as map functions. Alternatively, infrasonic cues can travel 1000s of km in the atmosphere with little attenuation, and can be detected in the laboratory by pigeons at frequencies down to 0.05 Hz. Although infrasound has been considered as a navigational tool for homing and migratory birds, little supporting evidence of its use has been found. Infrasonic ray paths in the atmosphere are controlled primarily by temperature and secondarily by wind. Assuming birds use infrasonic cues, atmospheric conditions could cause the perplexing changes (both geographic and temporal) observed in the mean vanishing bearings (MVBs) of pigeons released from experimental sites. To test for correlations between MVBs and tropospheric conditions, release data collected by the late W.T. Keeton between 1968 and 1980 from around the Cornell University lofts in upstate NY are compared to rawinsonde data from stations near Buffalo and Albany. For example, birds released at the Jersey Hill fire tower 132 km W of Ithaca most often departed at random. A singular exception was August 13, 1969; the Cornell birds released at Jersey Hill that day vanished in a tight cluster to the NE and arrived home the same day. Birds released the next day vanished randomly, and no evidence of what changed at Jersey Hill on August 13 has previously been presented. What did change, compared to the other release dates, were the speed and direction of the upper tropospheric winds over western NY. The jet stream winds are commonly from the SW and oppose infrasonic signals coming from the E, presumably near Ithaca, potentially creating an infrasonic "dead zone" at Jersey Hill. On August 13, 1969, the jet stream winds extraordinarily dropped sharply in speed and reversed direction to come from the NE. By the next day the upper tropospheric winds had returned to their normal westerly pattern explaining the Cornell birds' disorientation just one day later. This and several other examples will be presented indicating that infrasonic cues are a likely candidate for the long-range map cue in avian navigation.

Comparison of Speed-Up Over Hills Derived from Wind-Tunnel Experiments, Wind-Loading Standards, and Numerical Modelling

NASA Astrophysics Data System (ADS)

Safaei Pirooz, Amir A.; Flay, Richard G. J.

2018-03-01

We evaluate the accuracy of the speed-up provided in several wind-loading standards by comparison with wind-tunnel measurements and numerical predictions, which are carried out at a nominal scale of 1:500 and full-scale, respectively. Airflow over two- and three-dimensional bell-shaped hills is numerically modelled using the Reynolds-averaged Navier-Stokes method with a pressure-driven atmospheric boundary layer and three different turbulence models. Investigated in detail are the effects of grid size on the speed-up and flow separation, as well as the resulting uncertainties in the numerical simulations. Good agreement is obtained between the numerical prediction of speed-up, as well as the wake region size and location, with that according to large-eddy simulations and the wind-tunnel results. The numerical results demonstrate the ability to predict the airflow over a hill with good accuracy with considerably less computational time than for large-eddy simulation. Numerical simulations for a three-dimensional hill show that the speed-up and the wake region decrease significantly when compared with the flow over two-dimensional hills due to the secondary flow around three-dimensional hills. Different hill slopes and shapes are simulated numerically to investigate the effect of hill profile on the speed-up. In comparison with more peaked hill crests, flat-topped hills have a lower speed-up at the crest up to heights of about half the hill height, for which none of the standards gives entirely satisfactory values of speed-up. Overall, the latest versions of the National Building Code of Canada and the Australian and New Zealand Standard give the best predictions of wind speed over isolated hills.

Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant

PubMed Central

Spoerke, Jill M.; Gendreau, Steven; Walter, Kimberly; Qiu, Jiaheng; Wilson, Timothy R.; Savage, Heidi; Aimi, Junko; Derynck, Mika K.; Chen, Meng; Chan, Iris T.; Amler, Lukas C.; Hampton, Garret M.; Johnston, Stephen; Krop, Ian; Schmid, Peter; Lackner, Mark R.

2016-01-01

Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy in patients with ER+ metastatic breast cancer. Little is known of the impact of these mutations in patients receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot mutations in ESR1 and PIK3CA from ctDNA were assayed in clinical trial samples from ER+ metastatic breast cancer patients randomized either to the SERD fulvestrant or fulvestrant plus a pan-PI3K inhibitor. ESR1 mutations are present in 37% of baseline samples and are enriched in patients with luminal A and PIK3CA-mutated tumours. ESR1 mutations are often polyclonal and longitudinal analysis shows distinct clones exhibiting divergent behaviour over time. ESR1 mutation allele frequency does not show a consistent pattern of increases during fulvestrant treatment, and progression-free survival is not different in patients with ESR1 mutations compared with wild-type patients. ESR1 mutations are not associated with clinical resistance to fulvestrant in this study. PMID:27174596

Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant.

PubMed

Spoerke, Jill M; Gendreau, Steven; Walter, Kimberly; Qiu, Jiaheng; Wilson, Timothy R; Savage, Heidi; Aimi, Junko; Derynck, Mika K; Chen, Meng; Chan, Iris T; Amler, Lukas C; Hampton, Garret M; Johnston, Stephen; Krop, Ian; Schmid, Peter; Lackner, Mark R

2016-05-13

Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy in patients with ER+ metastatic breast cancer. Little is known of the impact of these mutations in patients receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot mutations in ESR1 and PIK3CA from ctDNA were assayed in clinical trial samples from ER+ metastatic breast cancer patients randomized either to the SERD fulvestrant or fulvestrant plus a pan-PI3K inhibitor. ESR1 mutations are present in 37% of baseline samples and are enriched in patients with luminal A and PIK3CA-mutated tumours. ESR1 mutations are often polyclonal and longitudinal analysis shows distinct clones exhibiting divergent behaviour over time. ESR1 mutation allele frequency does not show a consistent pattern of increases during fulvestrant treatment, and progression-free survival is not different in patients with ESR1 mutations compared with wild-type patients. ESR1 mutations are not associated with clinical resistance to fulvestrant in this study.

Uniform and Multi-Grid Modeling of Acoustic Wave Propagation With Cellular Automaton Techniques

DTIC Science & Technology

2013-03-01

39 Figure 26. CurrvedHillIndices fuction used to created a curved hill in the bottom...to safe passage of a submarine. Driving factors influencing SONAR improvements have alluded to the fact that primary naval missions have shifted from...CurvedHillIndices function after reaching line 12 42 Figure 26. CurrvedHillIndices fuction used to created a curved hill in the bottom of any 2D or

Climate change and apple farming in Indian Himalayas: a study of local perceptions and responses.

PubMed

Basannagari, Basavaraj; Kala, Chandra Prakash

2013-01-01

Apple farming is an important activity and profession of farmer communities in the Himalayan states of India. At present, the traditional apple farming is under stress due to changes in climate. The present study was undertaken in an Indian Himalayan state, Himachal Pradesh, with the major aim of studying perceptions of farmers on the effects of climate change on apple farming along the altitudinal gradient. Through questionnaire survey, the perceptions of farmers were recorded at low hills (<2500 m), mid-hills (2500-3000 m), and upper hills (>3000 m). At all elevation range the majority of farmers reported that there was increase in atmospheric temperature, and hence at low hills 72% farmers believed that this increase in temperature was responsible for decline in fruit size and so that the quality. Thirty five percent farmers at high hills and 30% at mid hills perceived frost as a major cause for damaging apple farming whereas at low hills 24% farmers perceived hailstorm as the major deterrent for apple farming. The majority of farmers, along the altitude (92% at high hills, 79% at mid hills and 83% at low hills), reported decrease in snowfall. The majority of farmers at low altitude and mid altitude reported decline in apple farming whereas 71% farmers at high hill areas refused decline in apple farming. About 73-83% farmers admitted delay in apple's harvesting period. At mid hills apple scab and at low hills pest attack on apple crops are considered as the indicators of climate change. The change in land use practices was attributed to climate change and in many areas the land under apple farming was replaced for production of coarse grains, seasonal vegetables and other horticulture species. Scientific investigation claiming changes in Indian Himalayan climate corroborates perceptions of farmers, as examined during the present study.

77 FR 75120 - Black Hills National Forest Advisory Board

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-19

... DEPARTMENT OF AGRICULTURE Forest Service Black Hills National Forest Advisory Board AGENCY: Forest Service, USDA. ACTION: Notice of meeting. SUMMARY: The Black Hills National Forest Advisory Board will... copying. The public may inspect comments received at the Supervisor's Office, Black Hills National Forest...

78 FR 65962 - Black Hills National Forest Advisory Board

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-04

... DEPARTMENT OF AGRICULTURE Forest Service Black Hills National Forest Advisory Board AGENCY: Forest Service, USDA. ACTION: Notice of cancellation of meeting of the Black Hills National Forest Advisory Board. SUMMARY: The U. S. Department of Agriculture, Forest Service, Black Hills National Forest cancelled the...

Seismic evidence of Quaternary faulting in the Benton Hills area, southeast Missouri

USGS Publications Warehouse

Palmer, J.R.; Shoemaker, M.; Hoffman, D.; Anderson, N.L.; Vaughn, J.D.; Harrison, R.W.

1997-01-01

Two reflection seismic profiles at English Hill, across the southern edge of the Benton Hills escarpment, southeast Missouri, establish that geologic structures at English Hill are of tectonic origin. The lowland area to the south of the escarpment is relatively undisturbed. The geology at English Hill is structurally complex, and reflection seismic and geologic data indicate extensive and episodic faulting of Paleozoic, Cretaceous, Tertiary, and Quaternary strata. The individual faults have near-vertical fault surfaces with maximum vertical separations on the order of 15 m. They appear to be clustered in north-northeast trending zones that essentially parallel one of the dominant Benton Hills structural trends. These observations suggest that previously mapped Quaternary faults at English Hill are deep-seated and tectonic in origin. This paper documents recent faulting at English Hill and is the first time late Quaternary, surface-rupture faulting has been recognized in the middle Mississippi River Valley region outside of the New Madrid seismic zone. This has important implications for earthquake assessment in the midcontinent.

A Constant Rate of Spontaneous Mutation in DNA-Based Microbes

NASA Astrophysics Data System (ADS)

Drake, John W.

1991-08-01

In terms of evolution and fitness, the most significant spontaneous mutation rate is likely to be that for the entire genome (or its nonfrivolous fraction). Information is now available to calculate this rate for several DNA-based haploid microbes, including bacteriophages with single- or double-stranded DNA, a bacterium, a yeast, and a filamentous fungus. Their genome sizes vary by ≈6500-fold. Their average mutation rates per base pair vary by ≈16,000-fold, whereas their mutation rates per genome vary by only ≈2.5-fold, apparently randomly, around a mean value of 0.0033 per DNA replication. The average mutation rate per base pair is inversely proportional to genome size. Therefore, a nearly invariant microbial mutation rate appears to have evolved. Because this rate is uniform in such diverse organisms, it is likely to be determined by deep general forces, perhaps by a balance between the usually deleterious effects of mutation and the physiological costs of further reducing mutation rates.

78 FR 73187 - Black Hills National Forest Advisory Board

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-05

... DEPARTMENT OF AGRICULTURE Forest Service Black Hills National Forest Advisory Board AGENCY: Forest Service, USDA. ACTION: Notice of meeting. SUMMARY: The Black Hills National Forest Advisory Board (Board... the Black Hills National Forest in South Dakota; and (4) update and report on Mountain Pine Beetle...

77 FR 8214 - Black Hills National Forest Advisory Board

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-14

... DEPARTMENT OF AGRICULTURE Forest Service Black Hills National Forest Advisory Board AGENCY: USDA Forest Service. ACTION: Notice of intent to re-establish the Black Hills National Forest Advisory Board...-establish the Black Hills National Forest Advisory Board (Board). The purpose is to obtain advice and...

75 FR 65315 - Combined Notice of Filings #2

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-22

.... Applicants: Black Hills Power, Inc., Black Hills/Colorado Electric Utility Co, Black Hills Wyoming, LLC, Cheyenne Light, Fuel and Power Company. Description: Updated Market Power Analysis of the Black Hills... LLC submits tariff filing per 35.17(b): Amendment to Market-Based Rate Application Reflecting Change...

Genetic diversity and structure in hill rice (Oryza sativa L.) landraces from the North-Eastern Himalayas of India.

PubMed

Roy, Somnath; Marndi, B C; Mawkhlieng, B; Banerjee, A; Yadav, R M; Misra, A K; Bansal, K C

2016-07-13

Hill rices (Oryza sativa L.) are direct seeded rices grown on hill slopes of different gradients. These landraces have evolved under rainfed and harsh environmental conditions and may possess genes governing adaptation traits such as tolerance to cold and moisture stress. In this study, 64 hill rice landraces were collected from the state of Arunachal Pradesh of North-Eastern region of India, and assessed by agro-morphological variability and microsatellite markers polymorphism. Our aim was to use phenotypic and genetic diversity data to understand the basis of farmers' classification of hill rice landraces into two groups: umte and tening. Another goal was to understand the genetic differentiation of hill rices into Indica or japonica subspecies. According to farmers' classification, hill rices were categorized into two groups: umte (large-grained, late maturing) and tening (small-grained, early maturing). We did not find significant difference in days to 50 % flowering between the groups. Principal component analysis revealed that two groups can be distinguished on the basis of kernel length-to-width ration (KLW), kernel length (KL), grain length (GrL), grain length-to-width ration (GrLW) and plant height (Ht). Stepwise canonical discriminant analysis identified KL and Ht as the main discriminatory characters between the cultivar groups. Genetic diversity analysis with 35 SSR markers revealed considerable genetic diversity in the hill rice germplasm (gene diversity: 0.66; polymorphism information content: 0.62). Pair-wise allelic difference between umte and tening groups was not statistically significant. The model-based population structure analysis showed that the hill rices were clustered into two broad groups corresponding to Indica and Japonica. The geographic distribution and cultivars grouping of hill rices were not congruent in genetic clusters. Both distance- and model-based approaches indicated that the hill rices were predominantly japonica or admixture among the groups within the subspecies. These findings were further supported by combined analysis hill rices with 150 reference rice accessions representing major genetic groups of rice. This study collected a valuable set of hill rice germplasm for rice breeding and for evolutionary studies. It also generated a new set of information on genetic and phenotypic diversity of hill rice landraces in North-Eastern region of India. The collected hill rices were mostly japonica or admixture among the subpopulations of Indica or Japonica. The findings are useful for utilization and conservation of hill rice germplasm.

Long-term changes in explosive and effusive behaviour at andesitic arc volcanoes: Chronostratigraphy of the Centre Hills Volcano, Montserrat

NASA Astrophysics Data System (ADS)

Coussens, Maya; Cassidy, Michael; Watt, Sebastian F. L.; Jutzeler, Martin; Talling, Peter J.; Barfod, Dan; Gernon, Thomas M.; Taylor, Rex; Hatter, Stuart J.; Palmer, Martin R.; Montserrat Volcano Observatory

2017-03-01

Volcanism on Montserrat (Lesser Antilles arc) has migrated southwards since the formation of the Silver Hills 2.5 Ma, and has formed three successively active volcanic centres. The Centre Hills volcano was the focus of volcanism from 1-0.4 Ma, before activity commenced at the currently active Soufrière Hills volcano. The history of activity at these two volcanoes provides an opportunity to investigate the pattern of volcano behaviour on an andesitic arc island over the lifetime of individual volcanoes. Here, we describe the pyroclastic stratigraphy of subaerial exposures around central Montserrat; identifying 11 thick (> 1 m) pumiceous units derived from sustained explosive eruptions of Centre Hills from 0.8-0.4 Ma. Over 10 other, less well- exposed pumiceous units have also been identified. The pumice-rich units are interbedded with andesite lava breccias derived from effusive, dome-forming eruptions of Centre Hills. The stratigraphy indicates that large (up to magnitude 5) explosive eruptions occurred throughout the history of Centre Hills, alongside effusive activity. This behaviour at Centre Hills contrasts with Soufrière Hills, where deposits from sustained explosive eruptions are much less common and restricted to early stages of activity at the volcano, from 175-130 ka. Subsequent eruptions at Soufriere Hills have been dominated by andesitic effusive eruptions. The bulk composition, petrography and mineral chemistry of volcanic rocks from Centre Hills and Soufrière Hills are similar throughout the history of both volcanoes, except for occasional, transient departures to different magma compositions, which mark shifts in vent location or dominant eruption style. For example, the final recorded eruption of Centre Hills, before the initiation of activity at Soufrière Hills, was more silicic than any other identified eruption on Montserrat; and the basaltic South Soufrière Hills episode marked the transition to the current stage of predominantly effusive Soufrière Hills activity. The compositional stability observed throughout the history of Centre Hills and Soufrière Hills suggests that a predominance towards effusive or explosive eruption styles is not driven by major compositional shifts of magma, but may reflect local changes in long-term magma storage conditions that characterise individual episodes (on 105 year timescales) of volcanism on Montserrat. Supplementary Table 2: Complete XRF analyses for all analysed samples Supplementary Table 3: Complete ICP-MS analyses for all analysed samples. Supplementary Table 4: Plagioclase composition and precision data from SEM analysis Supplementary Table 5: Clinopyroxene composition and precision data from SEM analysis Supplementary Table 6: Orthopyroxene composition and precision data from SEM analysis Supplementary Table 7: Amphibole composition and precision data from SEM analysis Supplementary Table 8: Glass compositions from EMP analysis Supplementary Table 9: Standard Deviation of glass compositions from EMP analysis. Supplementary Table 10: Isotopic composition of argon from plagioclase crystals from select units. Data obtained using an ARGUS V multi-collector mass spectrometer.

78 FR 48466 - Comcast Cable, West Division Customer Care, Morgan Hill, California; Notice of Negative...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-08

... Division Customer Care, Morgan Hill, California; Notice of Negative Determination on Reconsideration On... Reconsideration for the workers and former workers of Comcast Cable, West Division Customer Care, Morgan Hill... the petition for group eligibility of Comcast Cable, West Division Customer Care, Morgan Hill...

75 FR 28302 - American Food and Vending Spring Hill, TN; Notice of Negative Determination Regarding Application...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-20

... Spring Hill, TN; Notice of Negative Determination Regarding Application for Reconsideration By... negative determination applicable to workers and former workers at American Food and Vending, Spring Hill... eligible for TAA because they are service workers who provided services to General Motors, Spring Hill...

The Shock and Vibration Bulletin. Part 3. Dynamic Analysis, Design Techniques

DTIC Science & Technology

1980-09-01

response at certain discrete frequen- nique for dynamic analysis was pioneered by cies, not over a random-frequence spectrum. Myklestad[l]. Later Pestel and...34Fundamentals of Vibra- v’ angle of rotation due to tion Analysis ," McGraw-Hill, New York, 1956. bending 2. E.C. Pestel and F.A. Leckie, "Matrix o’ angle of...Bulletin 50IC FILE COPY (Part 03ofP,) to THE SHOCK AND VIBRATION BULLETIN Part 3 Dynamic Analysis , Design Techniques IELECTE SEPTEMBER 1980 S NOV 1

Variational method of determining effective moduli of polycrystals with tetragonal symmetry

USGS Publications Warehouse

Meister, R.; Peselnick, L.

1966-01-01

Variational principles have been applied to aggregates of randomly oriented pure-phase polycrystals having tetragonal symmetry. The bounds of the effective elastic moduli obtained in this way show a substantial improvement over the bounds obtained by means of the Voigt and Reuss assumptions. The Hill average is found to be a good approximation in most cases when compared to the bounds found from the variational method. The new bounds reduce in their limits to the Voigt and Reuss values. ?? 1966 The American Institute of Physics.

Neutral evolution of proteins: The superfunnel in sequence space and its relation to mutational robustness

NASA Astrophysics Data System (ADS)

Noirel, Josselin; Simonson, Thomas

2008-11-01

Following Kimura's neutral theory of molecular evolution [M. Kimura, The Neutral Theory of Molecular Evolution (Cambridge University Press, Cambridge, 1983) (reprinted in 1986)], it has become common to assume that the vast majority of viable mutations of a gene confer little or no functional advantage. Yet, in silico models of protein evolution have shown that mutational robustness of sequences could be selected for, even in the context of neutral evolution. The evolution of a biological population can be seen as a diffusion on the network of viable sequences. This network is called a "neutral network." Depending on the mutation rate μ and the population size N, the biological population can evolve purely randomly (μN ≪1) or it can evolve in such a way as to select for sequences of higher mutational robustness (μN ≫1). The stringency of the selection depends not only on the product μN but also on the exact topology of the neutral network, the special arrangement of which was named "superfunnel." Even though the relation between mutation rate, population size, and selection was thoroughly investigated, a study of the salient topological features of the superfunnel that could affect the strength of the selection was wanting. This question is addressed in this study. We use two different models of proteins: on lattice and off lattice. We compare neutral networks computed using these models to random networks. From this, we identify two important factors of the topology that determine the stringency of the selection for mutationally robust sequences. First, the presence of highly connected nodes ("hubs") in the network increases the selection for mutationally robust sequences. Second, the stringency of the selection increases when the correlation between a sequence's mutational robustness and its neighbors' increases. The latter finding relates a global characteristic of the neutral network to a local one, which is attainable through experiments or molecular modeling.

Neutral evolution of proteins: The superfunnel in sequence space and its relation to mutational robustness.

PubMed

Noirel, Josselin; Simonson, Thomas

2008-11-14

Following Kimura's neutral theory of molecular evolution [M. Kimura, The Neutral Theory of Molecular Evolution (Cambridge University Press, Cambridge, 1983) (reprinted in 1986)], it has become common to assume that the vast majority of viable mutations of a gene confer little or no functional advantage. Yet, in silico models of protein evolution have shown that mutational robustness of sequences could be selected for, even in the context of neutral evolution. The evolution of a biological population can be seen as a diffusion on the network of viable sequences. This network is called a "neutral network." Depending on the mutation rate mu and the population size N, the biological population can evolve purely randomly (muN<1) or it can evolve in such a way as to select for sequences of higher mutational robustness (muN>1). The stringency of the selection depends not only on the product muN but also on the exact topology of the neutral network, the special arrangement of which was named "superfunnel." Even though the relation between mutation rate, population size, and selection was thoroughly investigated, a study of the salient topological features of the superfunnel that could affect the strength of the selection was wanting. This question is addressed in this study. We use two different models of proteins: on lattice and off lattice. We compare neutral networks computed using these models to random networks. From this, we identify two important factors of the topology that determine the stringency of the selection for mutationally robust sequences. First, the presence of highly connected nodes ("hubs") in the network increases the selection for mutationally robust sequences. Second, the stringency of the selection increases when the correlation between a sequence's mutational robustness and its neighbors' increases. The latter finding relates a global characteristic of the neutral network to a local one, which is attainable through experiments or molecular modeling.

Experimental design to evaluate directed adaptive mutation in Mammalian cells.

PubMed

Bordonaro, Michael; Chiaro, Christopher R; May, Tobias

2014-12-09

We describe the experimental design for a methodological approach to determine whether directed adaptive mutation occurs in mammalian cells. Identification of directed adaptive mutation would have profound practical significance for a wide variety of biomedical problems, including disease development and resistance to treatment. In adaptive mutation, the genetic or epigenetic change is not random; instead, the presence and type of selection influences the frequency and character of the mutation event. Adaptive mutation can contribute to the evolution of microbial pathogenesis, cancer, and drug resistance, and may become a focus of novel therapeutic interventions. Our experimental approach was designed to distinguish between 3 types of mutation: (1) random mutations that are independent of selective pressure, (2) undirected adaptive mutations that arise when selective pressure induces a general increase in the mutation rate, and (3) directed adaptive mutations that arise when selective pressure induces targeted mutations that specifically influence the adaptive response. The purpose of this report is to introduce an experimental design and describe limited pilot experiment data (not to describe a complete set of experiments); hence, it is an early report. An experimental design based on immortalization of mouse embryonic fibroblast cells is presented that links clonal cell growth to reversal of an inactivating polyadenylation site mutation. Thus, cells exhibit growth only in the presence of both the countermutation and an inducing agent (doxycycline). The type and frequency of mutation in the presence or absence of doxycycline will be evaluated. Additional experimental approaches would determine whether the cells exhibit a generalized increase in mutation rate and/or whether the cells show altered expression of error-prone DNA polymerases or of mismatch repair proteins. We performed the initial stages of characterizing our system and have limited preliminary data from several pilot experiments. Cell growth and DNA sequence data indicate that we have identified a cell clone that exhibits several suitable characteristics, although further study is required to identify a more optimal cell clone. The experimental approach is based on a quantum biological model of basis-dependent selection describing a novel mechanism of adaptive mutation. This project is currently inactive due to lack of funding. However, consistent with the objective of early reports, we describe a proposed study that has not produced publishable results, but is worthy of report because of the hypothesis, experimental design, and protocols. We outline the project's rationale and experimental design, with its strengths and weaknesses, to stimulate discussion and analysis, and lay the foundation for future studies in this field.

Rate of de novo mutations and the importance of father's age to disease risk.

PubMed

Kong, Augustine; Frigge, Michael L; Masson, Gisli; Besenbacher, Soren; Sulem, Patrick; Magnusson, Gisli; Gudjonsson, Sigurjon A; Sigurdsson, Asgeir; Jonasdottir, Aslaug; Jonasdottir, Adalbjorg; Wong, Wendy S W; Sigurdsson, Gunnar; Walters, G Bragi; Steinberg, Stacy; Helgason, Hannes; Thorleifsson, Gudmar; Gudbjartsson, Daniel F; Helgason, Agnar; Magnusson, Olafur Th; Thorsteinsdottir, Unnur; Stefansson, Kari

2012-08-23

Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 × 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.

Stress-induced mutation via DNA breaks in Escherichia coli: A molecular mechanism with implications for evolution and medicine

PubMed Central

Rosenberg, Susan M; Shee, Chandan; Frisch, Ryan L; Hastings, P J

2012-01-01

Abstract Evolutionary theory assumed that mutations occur constantly, gradually, and randomly over time. This formulation from the “modern synthesis” of the 1930s was embraced decades before molecular understanding of genes or mutations. Since then, our labs and others have elucidated mutation mechanisms activated by stress responses. Stress-induced mutation mechanisms produce mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress-induced mutation that are being revealed experimentally in laboratory settings provide compelling models for mutagenesis that propels pathogen–host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double-strand-break-dependent stress-induced mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti-evolvability therapeutics for infectious disease and cancer. PMID:22911060

Stress-induced mutation via DNA breaks in Escherichia coli: a molecular mechanism with implications for evolution and medicine.

PubMed

Rosenberg, Susan M; Shee, Chandan; Frisch, Ryan L; Hastings, P J

2012-10-01

Evolutionary theory assumed that mutations occur constantly, gradually, and randomly over time. This formulation from the "modern synthesis" of the 1930s was embraced decades before molecular understanding of genes or mutations. Since then, our labs and others have elucidated mutation mechanisms activated by stress responses. Stress-induced mutation mechanisms produce mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress-induced mutation that are being revealed experimentally in laboratory settings provide compelling models for mutagenesis that propels pathogen-host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double-strand-break-dependent stress-induced mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti-evolvability therapeutics for infectious disease and cancer. Copyright © 2012 WILEY Periodicals, Inc.

Hill functions for stochastic gene regulatory networks from master equations with split nodes and time-scale separation

NASA Astrophysics Data System (ADS)

Lipan, Ovidiu; Ferwerda, Cameron

2018-02-01

The deterministic Hill function depends only on the average values of molecule numbers. To account for the fluctuations in the molecule numbers, the argument of the Hill function needs to contain the means, the standard deviations, and the correlations. Here we present a method that allows for stochastic Hill functions to be constructed from the dynamical evolution of stochastic biocircuits with specific topologies. These stochastic Hill functions are presented in a closed analytical form so that they can be easily incorporated in models for large genetic regulatory networks. Using a repressive biocircuit as an example, we show by Monte Carlo simulations that the traditional deterministic Hill function inaccurately predicts time of repression by an order of two magnitudes. However, the stochastic Hill function was able to capture the fluctuations and thus accurately predicted the time of repression.

Arcadia Planitia Hills

NASA Image and Video Library

2018-04-25

The rounded hills in this VIS image are located in Arcadia Planitia. Broad linear ridges and groups of hills in this region are part of Phlegra Dorsa (ridges) and Phlegra Montes (hills). Orbit Number: 71248 Latitude: 30.6712 Longitude: 171.018 Instrument: VIS Captured: 2018-01-05 17:05 https://photojournal.jpl.nasa.gov/catalog/PIA22377

75 FR 63465 - Hill-Lake Gas Storage, LLC; Notice of Filing

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-15

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. PR10-137-000] Hill-Lake Gas Storage, LLC; Notice of Filing October 7, 2010. Take notice that on September 30, 2010, Hill-Lake Gas Storage, LLC (Hill-Lake) filed a revised Statement of Operating Conditions (SOC) for its Storage Services...

75. Southeast elevation of Forest Hills station looking Northwest ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

75. Southeast elevation of Forest Hills station - looking Northwest from junction of Washington and Walk Hill Streets. At left is the beginning of Section F-7 the exposed steel portion of elevated structure leading to the Forest Hills storage yard (demolished in 1985). - Boston Elevated Railway, Elevated Mainline, Washington Street, Boston, Suffolk County, MA

Simultaneous Identification of Multiple Driver Pathways in Cancer

PubMed Central

Leiserson, Mark D. M.; Blokh, Dima

2013-01-01

Distinguishing the somatic mutations responsible for cancer (driver mutations) from random, passenger mutations is a key challenge in cancer genomics. Driver mutations generally target cellular signaling and regulatory pathways consisting of multiple genes. This heterogeneity complicates the identification of driver mutations by their recurrence across samples, as different combinations of mutations in driver pathways are observed in different samples. We introduce the Multi-Dendrix algorithm for the simultaneous identification of multiple driver pathways de novo in somatic mutation data from a cohort of cancer samples. The algorithm relies on two combinatorial properties of mutations in a driver pathway: high coverage and mutual exclusivity. We derive an integer linear program that finds set of mutations exhibiting these properties. We apply Multi-Dendrix to somatic mutations from glioblastoma, breast cancer, and lung cancer samples. Multi-Dendrix identifies sets of mutations in genes that overlap with known pathways – including Rb, p53, PI(3)K, and cell cycle pathways – and also novel sets of mutually exclusive mutations, including mutations in several transcription factors or other genes involved in transcriptional regulation. These sets are discovered directly from mutation data with no prior knowledge of pathways or gene interactions. We show that Multi-Dendrix outperforms other algorithms for identifying combinations of mutations and is also orders of magnitude faster on genome-scale data. Software available at: http://compbio.cs.brown.edu/software. PMID:23717195

Competence in Streptococcus pneumoniae Is a Response to an Increasing Mutational Burden

PubMed Central

Gagne, Alyssa L.; Stevens, Kathleen E.; Cassone, Marco; Pujari, Amit; Abiola, Olufunke E.; Chang, Diana J.; Sebert, Michael E.

2013-01-01

Competence for genetic transformation in Streptococcus pneumoniae has previously been described as a quorum-sensing trait regulated by a secreted peptide pheromone. Recently we demonstrated that competence is also activated by reduction in the accuracy of protein biosynthesis. We have now investigated whether errors upstream of translation in the form of random genomic mutations can provide a similar stimulus. Here we show that generation of a mutator phenotype in S. pneumoniae through deletions of mutX, hexA or hexB enhanced the expression of competence. Similarly, chemical mutagenesis with the nucleotide analog dPTP promoted development of competence. To investigate the relationship between mutational load and the activation of competence, replicate lineages of the mutX strain were serially passaged under conditions of relaxed selection allowing random accumulation of secondary mutations. Competence increased with propagation in these lineages but not in control lineages having wild-type mutX. Resequencing of these derived strains revealed between 1 and 9 single nucleotide polymorphisms (SNPs) per lineage, which were broadly distributed across the genome and did not involve known regulators of competence. Notably, the frequency of competence development among the sequenced strains correlated significantly with the number of nonsynonymous mutations that had been acquired. Together, these observations provide support for the hypothesis that competence in S. pneumoniae is regulated in response to the accumulated burden of coding mutations in the bacterial genome. In contrast to previously described DNA damage response systems that are activated by physical lesions in the chromosome, this pneumococcal pathway may represent a unique stress response system that monitors the coding integrity of the genome. PMID:23967325

Directional Site Amplification Effect on Tarzana Hill, California

NASA Astrophysics Data System (ADS)

Graizer, V.; Shakal, A.

2003-12-01

Significantly amplified ground accelerations at the Tarzana Hill station were recorded during the 1987 Mw 5.9 Whittier Narrows and the 1994 Mw 6.7 Northridge earthquakes. Peak horizontal ground acceleration at the Tarzana station during the 1999 Mw 7.1 Hector Mine earthquake was almost twice as large as the accelerations recorded at nearby stations. The Tarzana site was drilled to a depth of 100 m. A low shear-wave velocity near the surface of 100 m/sec increasing to near 750 m/sec at 100 m depth was measured. The 20 m high hill was found to be well drained with a water table near 17 m. Modelo formation (extremely weathered at the surface to fresh at depth) underlies the hill. The subsurface geology and velocities obtained allow classification of this location as a soft-rock site. After the Northridge earthquake the California Strong Motion Instrumentation Program significantly increased instrumentation at Tarzana to study the unusual site amplification effect. Current instrumentation at Tarzana consists of an accelerograph at the top of Tarzana hill (Tarzana - Cedar Hill B), a downhole instrument at 60 m depth, and an accelerograph at the foot of the hill (Tarzana - Clubhouse), 180 m from the Cedar Hill B station. The original station, Tarzana - Cedar Hill Nursery A, was lost in 1999 due to construction. More than twenty events, including the Hector Mine earthquake, were recorded by all these instruments at Tarzana. Comparison of recordings and response spectra demonstrates strong directional resonance on the top of the hill in a direction perpendicular to the strike of the hill in the period range from 0.04 to 0.8 sec (1.2 to 25 Hz). There is practically no amplification from the bottom to the top of the hill for the component parallel to the strike of the hill. In contrast to accelerations recorded during the Hector Mine earthquake (high frequency part of seismic signal), displacements (relatively low frequency part of seismic signal) demonstrate almost no site amplification from the bottom of the hole to the surface at periods greater than 1.5 sec, in either direction. The directional effect at Tarzana hill seems to be azimuth dependent. Relatively higher amplification at the perpendicular component is produced for the earthquake sources located north of the station. We were not able to see any differences in hill response before and after development (a relatively small part of the hill was developed). The source of the site amplification that produces large motions at Tarzana is still under investigation with "the usual suspects" like topography and shear wave velocity profile not providing the explanation. New data recorded at Tarzana in recent years clearly show that the Tarzana effect is a very localized high-frequency effect observed only at the top of the hill. Drilling at Tarzana was co-funded by CSMIP and by the National Science Foundation through the Resolution of Site Response Issues from the Northridge Earthquake Project (ROSRINE).

Are Hill's criteria for causality satisfied for vitamin D and periodontal disease?

PubMed

Grant, William B; Boucher, Barbara J

2010-01-01

There is mounting evidence that periodontal disease (PD) is linked to low serum 25-hydroxyvitamin D [25(OH)D] concentrations in addition to recognized risk factors like diet and smoking. This paper reviews this evidence using Hill's criteria for causality in a biological system. Evidence for strength of association, consistency, cohesion and 'dose-effects' [biological 'gradients'] include strong inverse correlations between serum 25(OH) and PD cross-sectionally and that PD is consistently more prevalent in darker vs. lighter skinned people and increases at higher latitudes with analogy for gingivitis and for disorders associated with PD whose risks also increase with hypovitaminosis D. Evidence for plausibility includes that vitamin D increases calcium absorption and protects bone strength; induces formation of cathelicidin and other defensins that combat bacterial infection; reduces tissue production of destructive matrix metalloproteinases actively associated with PD and that prevalence of PD varies with common vitamin D receptor polymorphisms. Experimental evidence from limited supplementation studies [using calcium and vitamin D] shows that supplementation reduces tooth loss. Thus, existing evidence for hypovitaminosis D as a risk factor for PD to date meets Hill's criteria for causality in a biological system. Further experimental evidence for effectiveness and temporality, preferably from randomized controlled trials of vitamin D supplementation [adjusting for other PD risk factors including diet and smoking to reduce confounding] are necessary to confirm causality. If confirmed, dentists and periodontists could perform a valuable service to their patients by discussing the importance of adequate vitamin D status and how to avoid deficiency.

Are Hill's criteria for causality satisfied for vitamin D and periodontal disease?

PubMed Central

Boucher, Barbara J

2010-01-01

There is mounting evidence that periodontal disease (PD) is linked to low serum 25-hydroxyvitamin D [25(OH)D] concentrations in addition to recognized risk factors like diet and smoking. This paper reviews this evidence using Hill's criteria for causality in a biological system. Evidence for strength of association, consistency, cohesion and ‘dose-effects’ [biological ‘gradients’] include strong inverse correlations between serum 25(OH) and PD cross-sectionally and that PD is consistently more prevalent in darker vs. lighter skinned people and increases at higher latitudes with analogy for gingivitis and for disorders associated with PD whose risks also increase with hypovitaminosis D. Evidence for plausibility includes that vitamin D increases calcium absorption and protects bone strength; induces formation of cathelicidin and other defensins that combat bacterial infection; reduces tissue production of destructive matrix metalloproteinases actively associated with PD and that prevalence of PD varies with common vitamin D receptor polymorphisms. Experimental evidence from limited supplementation studies [using calcium and vitamin D] shows that supplementation reduces tooth loss. Thus, existing evidence for hypovitaminosis D as a risk factor for PD to date meets Hill's criteria for causality in a biological system. Further experimental evidence for effectiveness and temporality, preferably from randomized controlled trials of vitamin D supplementation [adjusting for other PD risk factors including diet and smoking to reduce confounding] are necessary to confirm causality. If confirmed, dentists and periodontists could perform a valuable service to their patients by discussing the importance of adequate vitamin D status and how to avoid deficiency. PMID:21547146

Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial.

PubMed

Chandarlapaty, Sarat; Chen, David; He, Wei; Sung, Patricia; Samoila, Aliaksandra; You, Daoqi; Bhatt, Trusha; Patel, Parul; Voi, Maurizio; Gnant, Michael; Hortobagyi, Gabriel; Baselga, José; Moynahan, Mary Ellen

2016-10-01

Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent receptor activation and resistance to estrogen-deprivation therapy in laboratory models. The prevalence of these mutations and their potential impact on clinical outcomes has not been established. To determine the prevalence of ESR1 mutations (Y537S and D538G) in estrogen receptor (ER)-positive MBC and determine whether mutation is associated with inferior outcomes. From December 16, 2014, to August 26, 2015, we analyzed cell-free DNA (cfDNA) from baseline plasma samples from participants in the BOLERO-2 double-blind phase 3 study that randomized patients from 189 centers in 24 countries with MBC to exemestane plus placebo or exemestane plus everolimus. The study enrolled postmenopausal women with a diagnosis of MBC and prior exposure to an aromatase inhibitor. Baseline plasma samples were available from 541 of 724 patients (74.7%). We assessed the effect of mutation on overall survival of the population and the effect of mutation on progression-free survival (PFS) by treatment arm. Patients were randomized to treatment with exemestane (25 mg oral daily) together with everolimus (10 mg oral daily) or with placebo. The 2 most frequent mutations in ESR1 (Y537S and D538G) were analyzed from cfDNA using droplet digital polymerase chain reaction and samples scored as wild-type, D538G, Y537S, or double mutant. Cox-proportional hazards model was used to assess PFS in patient subgroups defined by mutations, and the effect of each mutation on overall survival. Of 541 evaluable patients, 156 (28.8%) had ESR1 mutation D538G (21.1%) and/or Y537S (13.3%), and 30 had both. These mutations were associated with shorter overall survival (wild-type, 32.1 months [95% CI, 28.09-36.40 months]; D538G, 25.99 months [95% CI, 19.19-32.36 months]; Y537S, 19.98 months [13.01-29.31 months]; both mutations, 15.15 months [95% CI, 10.87-27.43 months]). The D538G group (hazard ratio, 0.34 [95% CI, 0.02-0.57]) derived a similar PFS benefit as wild type from addition of everolimus to exemestane. ESR1 mutations are prevalent in ER-positive aromatase inhibitor-treated MBC. Both Y537S and D538G mutations are associated with more aggressive disease biology. clinicaltrials.gov Identifier: NCT00863655.

Stabilization of luciferase from Renilla reniformis using random mutations.

PubMed

Shigehisa, Megumi; Amaba, Norie; Arai, Shigeki; Higashi, Chisato; Kawanabe, Ryo; Matsunaga, Ayano; Laksmi, Fina Amreta; Tokunaga, Masao; Ishibashi, Matsujiro

2017-01-01

We expressed luciferase (RLuc) from Renilla reniformis in Escherichia coli RLuc was purified using a Ni-NTA column and subsequently characterized. It was unstable in acidic solutions and at 30°C. To increase the stability of RLuc, the Rluc gene was randomly mutated using error-prone polymerase chain reaction. E. coli harboring the mutated gene was screened by detecting luminescence on a plate containing the substrate coelenterazine at 34°C. Three mutants, i.e. N264SS287P, N178D and F116LI137V, were obtained. The solubilities and specific activities of these mutants were higher than those of the wild type. Furthermore, the N264SS287P mutant maintained stability at a temperature approximately 5°C higher than that of the wild type, while denaturation of the F116LI137V mutant started at a temperature that was 5°C lower than the wild type, and ended at a temperature that was 7°C higher. We examined the obtained mutations using thermal shift assays and a computer program Coot in this study. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

APOC3, Coronary Disease, and Complexities of Mendelian Randomization

PubMed Central

Cohen, Jonathan C.; Stender, Stefan; Hobbs, Helen H.

2014-01-01

Two new studies report that triglyceride (TG)-lowering mutations in APOC3 reduce coronary heart disease (CHD) (Crosby et al., 2014; Jørgensen et al., 2014). Here, we explore limitations of using Mendelian randomization to evaluate CHD risk, including potential confounding by the widespread use of statin therapy. PMID:25185943

27 CFR 9.190 - Red Hill Douglas County, Oregon.

Code of Federal Regulations, 2014 CFR

2014-04-01

..., Oregon. 9.190 Section 9.190 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... Areas § 9.190 Red Hill Douglas County, Oregon. (a) Name. The name of the viticultural area described in this section is “Red Hill Douglas County, Oregon”. For purposes of part 4 of this chapter, “Red Hill...

27 CFR 9.190 - Red Hill Douglas County, Oregon.

Code of Federal Regulations, 2012 CFR

2012-04-01

..., Oregon. 9.190 Section 9.190 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... Areas § 9.190 Red Hill Douglas County, Oregon. (a) Name. The name of the viticultural area described in this section is “Red Hill Douglas County, Oregon”. For purposes of part 4 of this chapter, “Red Hill...

27 CFR 9.190 - Red Hill Douglas County, Oregon.

Code of Federal Regulations, 2013 CFR

2013-04-01

..., Oregon. 9.190 Section 9.190 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... Areas § 9.190 Red Hill Douglas County, Oregon. (a) Name. The name of the viticultural area described in this section is “Red Hill Douglas County, Oregon”. For purposes of part 4 of this chapter, “Red Hill...

40 CFR 81.214 - Black Hills-Rapid City Intrastate Air Quality Control Region.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 17 2010-07-01 2010-07-01 false Black Hills-Rapid City Intrastate Air... Air Quality Control Regions § 81.214 Black Hills-Rapid City Intrastate Air Quality Control Region. The Rapid City Intrastate Air Quality Control Region (South Dakota) has been renamed the Black Hills-Rapid...

40 CFR 81.214 - Black Hills-Rapid City Intrastate Air Quality Control Region.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 17 2011-07-01 2011-07-01 false Black Hills-Rapid City Intrastate Air... Air Quality Control Regions § 81.214 Black Hills-Rapid City Intrastate Air Quality Control Region. The Rapid City Intrastate Air Quality Control Region (South Dakota) has been renamed the Black Hills-Rapid...

The timber resources of the Ohio Hill Country

Treesearch

Paul S. DeBald; Roger E. McCay

1969-01-01

This report presents 1967 forest resource statistics for the Hill Country-Ohio's portion of Appalachia. The Hill Country comprises 28 counties, which were divided into three geographic sampling units for this survey. The Hill Country of the 1952 Ohio forest survey contained 26 of these counties. The additional Appalachia counties are Brown and Clermont in the...

The Coalescent Process in Models with Selection

PubMed Central

Kaplan, N. L.; Darden, T.; Hudson, R. R.

1988-01-01

Statistical properties of the process describing the genealogical history of a random sample of genes are obtained for a class of population genetics models with selection. For models with selection, in contrast to models without selection, the distribution of this process, the coalescent process, depends on the distribution of the frequencies of alleles in the ancestral generations. If the ancestral frequency process can be approximated by a diffusion, then the mean and the variance of the number of segregating sites due to selectively neutral mutations in random samples can be numerically calculated. The calculations are greatly simplified if the frequencies of the alleles are tightly regulated. If the mutation rates between alleles maintained by balancing selection are low, then the number of selectively neutral segregating sites in a random sample of genes is expected to substantially exceed the number predicted under a neutral model. PMID:3066685

Understanding and Improving the Activity of Flavin Dependent Halogenases via Random and Targeted Mutagenesis

PubMed Central

Andorfer, Mary C.

2018-01-01

Flavin dependent halogenases (FDHs) catalyze the halogenation of organic substrates by coordinating reactions of reduced flavin, molecular oxygen, and chloride. Targeted and random mutagenesis of these enzymes has been used to both understand and alter their reactivity. These studies have led to insights into residues essential for catalysis and FDH variants with improved stability, expanded substrate scope, and altered site selectivity. Mutations throughout FDH structures have contributed to all of these advances. More recent studies have sought to rationalize the impact of these mutations on FDH function and to identify new FDHs to deepen our understanding of this enzyme class and to expand their utility for biocatalytic applications. PMID:29589959

How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer?: An examination using Hill's criteria for causality.

PubMed

Grant, William B

2009-01-01

The ultraviolet-B (UVB)-vitamin D-cancer hypothesis was proposed in 1980. Since then, several ecological and observational studies have examined the hypothesis, in addition to one good randomized, controlled trial. Also, the mechanisms whereby vitamin D reduces the risk of cancer have been elucidated. This report aims to examine the evidence to date with respect to the criteria for causality in a biological system first proposed by Robert Koch and later systematized by A. Bradford Hill. The criteria of most relevance are strength of association, consistency, biological gradient, plausibility/mechanisms and experimental verification. Results for several cancers generally satisfy these criteria. Results for breast and colorectal cancer satisfy the criteria best, but there is also good evidence that other cancers do as well, including bladder, esophageal, gallbladder, gastric, ovarian, rectal, renal and uterine corpus cancer, as well as Hodgkin's and non-Hodgkin's lymphoma. Several cancers have mixed findings with respect to UVB and/or vitamin D, including pancreatic and prostate cancer and melanoma. Even for these, the benefit of vitamin D seems reasonably strong. Although ecological and observational studies are not generally regarded as able to provide convincing evidence of causality, the fact that humanity has always existed with vitamin D from solar UVB irradiance means that there is a wealth of evidence to be harvested using the ecological and observational approaches. Nonetheless, additional randomized, controlled trials are warranted to further examine the link between vitamin D and cancer incidence, survival and mortality.

76 FR 35101 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-16

... Mobridge, SD, Mobridge Muni, Takeoff Minimums and Obstacle DP, Amdt 1 Spearfish, SD, Black Hills-Clyde Ice Field, GPS RWY 12, Orig-D, CANCELLED Spearfish, SD, Black Hills-Clyde Ice Field, NDB-A, Amdt 1 Spearfish, SD, Black Hills-Clyde Ice Field, RNAV (GPS) RWY 13, Orig Spearfish, SD, Black Hills-Clyde Ice Field...

Structure, stratigraphy, and origin of Husband Hill, Columbia Hills, Gusev Crater, Mars

USGS Publications Warehouse

McCoy, T.J.; Sims, M.; Schmidt, M.E.; Edwards, L.; Tornabene, L.L.; Crumpler, L.S.; Cohen, B. A.; Soderblom, L.A.; Blaney, D.L.; Squyres, S. W.; Arvidson, R. E.; Rica, J.W.; Treguier, E.; d'Uston, C.; Grant, J. A.; McSween, H.Y.; Golombek, M.P.; Haldemann, A.F.C.; de Souza, P.A.

2008-01-01

The strike and dip of lithologic units imaged in stereo by the Spirit rover in the Columbia Hills using three-dimensional imaging software shows that measured dips (15-32??) for bedding on the main edifice of the Columbia Hill are steeper than local topography (???8-10??). Outcrops measured on West Spur are conformable in strike with shallower dips (7-15??) than observed on Husband Hill. Dips are consistent with observed strata draping the Columbia Hills. Initial uplift was likely related either to the formation of the Gusev Crater central peak or ring or through mutual interference of overlapping crater rims. Uplift was followed by subsequent draping by a series of impact and volcaniclastic materials that experienced temporally and spatially variable aqueous infiltration, cementation, and alteration episodically during or after deposition. West Spur likely represents a spatially isolated depositional event. Erosion by a variety of processes, including mass wasting, removed tens of meters of materials and formed the Tennessee Valley primarily after deposition. This was followed by eruption of the Adirondack-class plains basalt lava flows which embayed the Columbia Hills. Minor erosion, impact, and aeolian processes have subsequently modified the Columbia Hills. Copyright 2008 by the American Geophysical Union.

The origin of Mauna Loa's Nīnole Hills: Evidence of rift zone reorganization

USGS Publications Warehouse

Zurek, Jeffrey; Williams-Jones, Glyn; Trusdell, Frank A.; Martin, Simon

2015-01-01

In order to identify the origin of Mauna Loa volcano's Nīnole Hills, Bouguer gravity was used to delineate density contrasts within the edifice. Our survey identified two residual anomalies beneath the Southwest Rift Zone (SWRZ) and the Nīnole Hills. The Nīnole Hills anomaly is elongated, striking northeast, and in inversions both anomalies merge at approximately −7 km above sea level. The positive anomaly, modeled as a rock volume of ~1200 km3 beneath the Nīnole Hills, is associated with old eruptive vents. Based on the geologic and geophysical data, we propose that the gravity anomaly under the Nīnole Hills records an early SWRZ orientation, now abandoned due to geologically rapid rift-zone reorganization. Catastrophic submarine landslides from Mauna Loa's western flank are the most likely cause for the concurrent abandonment of the Nīnole Hills section of the SWRZ. Rift zone reorganization induced by mass wasting is likely more common than currently recognized.

Ascending Aortic Aneurysm Is an Inherited Disease: A Contemporary Literature Review Based on Hill's Criteria of Specificity, Strength of Association, and Biological Coherence.

PubMed

Ahmad, Mirza Mujadil; Kiani, Immad Arif; Ammar, Khawaja Afzal; Ahmad, Mirza Nubair; Khandheria, Bijoy K; Paterick, Timothy E; Jain, Renuka; Tajik, A Jamil

There is growing evidence of a differential etiological basis for thoracic aortic aneurysms (TAA), with ascending (As) TAAs being genetically mediated and descending (Des) TAAs more strongly related to acquired pathologies. A comprehensive literature review of this hypothesis has not been carried out. We carried out a systematic literature review based on the latest guidelines on TAA endorsed by the American Heart Association. The etiologies were classified as genetic and inherited, the studies were tabulated accordingly, and Hill's epidemiological criteria of causality were applied. We found 38 studies addressing the etiology of TAAs. Out of these, 17 were about genetic causes, 9 about acquired causes, and 4 had information regarding both etiologies. Multiple genetic studies showed a strong association of As TAA with different genetic mutations. Contrary to commonly held beliefs, acquired causes, that is, dyslipidemia, diabetes, and atherosclerosis, were negatively associated with As TAA and positively associated with Des TAA. Hypertension was only associated with Des TAA and dissections (TAAD), not with As TAA. Multiple studies fulfilled the criteria of strength of association (n = 4), consistency (n = 9), specificity (n = 5), temporality (24), biological gradient (n = 3), plausibility (n = 38), biological coherence (n = 25), experiment (n = 4), and analogy (n = 6). Our literature review supports the hypothesis that As TAA is genetically mediated and Des TAA is predominantly an acquired pathology, and supports the argument for genetic testing in all cases of As TAA.

Seeing mountains in mole hills: geographical-slant perception

NASA Technical Reports Server (NTRS)

Proffitt, D. R.; Creem, S. H.; Zosh, W. D.; Kaiser, M. K. (Principal Investigator)

2001-01-01

When observers face directly toward the incline of a hill, their awareness of the slant of the hill is greatly overestimated, but motoric estimates are much more accurate. The present study examined whether similar results would be found when observers were allowed to view the side of a hill. Observers viewed the cross-sections of hills in real (Experiment 1) and virtual (Experiment 2) environments and estimated the inclines with verbal estimates, by adjusting the cross-section of a disk, and by adjusting a board with their unseen hand to match the inclines. We found that the results for cross-section viewing replicated those found when observers directly face the incline. Even though the angles of hills are directly evident when viewed from the side, slant perceptions are still grossly overestimated.

Risk of Drug Resistance Among Persons Acquiring HIV Within a Randomized Clinical Trial of Single- or Dual-Agent Preexposure Prophylaxis

PubMed Central

Lehman, Dara A.; Baeten, Jared M.; McCoy, Connor O.; Weis, Julie F.; Peterson, Dylan; Mbara, Gerald; Donnell, Deborah; Thomas, Katherine K.; Hendrix, Craig W.; Marzinke, Mark A.; Frenkel, Lisa; Ndase, Patrick; Mugo, Nelly R.; Celum, Connie; Overbaugh, Julie; Matsen, Frederick A.; Celum, Connie; Baeten, Jared M.; Donnell, Deborah; Coombs, Robert W.; Frenkel, Lisa; Hendrix, Craig W.; Marzinke, Mark A.; Lingappa, Jairam; McElrath, M. Juliana; Fife, Kenneth; Were, Edwin; Tumwesigye, Elioda; Ndase, Patrick; Katabira, Elly; Katabira, Elly; Ronald, Allan; Bukusi, Elizabeth; Cohen, Craig; Wangisi, Jonathan; Campbell, James; Tappero, Jordan; Kiarie, James; Farquhar, Carey; John-Stewart, Grace; Mugo, Nelly Rwamba; Campbell, James; Tappero, Jordan; Wangisi, Jonathan

2015-01-01

Background. Preexposure prophylaxis (PrEP) with emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone reduces the risk of human immunodeficiency virus (HIV) acquisition. Understanding the risk of antiretroviral resistance selected by PrEP during breakthrough infections is important because of the risk of treatment failure during subsequent antiretroviral use. Methods. Within the largest randomized trial of FTC/TDF versus TDF as PrEP, plasma samples were tested for HIV with resistance mutations associated with FTC (K65R and M184IV) and TDF (K65R and K70E), using 454 sequencing. Results. Of 121 HIV seroconverters, 25 received FTC/TDF, 38 received TDF, and 58 received placebo. Plasma drug levels in 26 individuals indicated PrEP use during or after HIV acquisition, of which 5 had virus with resistance mutations associated with their PrEP regimen. Among those with PrEP drug detected during infection, resistance was more frequent in the FTC/TDF arm (4 of 7 [57%]), compared with the TDF arm (1 of 19 [5.3%]; P = .01), owing to the FTC-associated mutation M184IV. Of these cases, 3 had unrecognized acute infection at PrEP randomization, and 2 were HIV negative at enrollment. Conclusions. These results suggest that resistance selected by PrEP is rare but can occur both with PrEP initiation during acute seronegative HIV infection and in PrEP breakthrough infections and that FTC is associated with a greater frequency of resistance mutations than TDF. PMID:25587020

Recessive HYDIN Mutations Cause Primary Ciliary Dyskinesia without Randomization of Left-Right Body Asymmetry

PubMed Central

Olbrich, Heike; Schmidts, Miriam; Werner, Claudius; Onoufriadis, Alexandros; Loges, Niki T.; Raidt, Johanna; Banki, Nora Fanni; Shoemark, Amelia; Burgoyne, Tom; Al Turki, Saeed; Hurles, Matthew E.; Köhler, Gabriele; Schroeder, Josef; Nürnberg, Gudrun; Nürnberg, Peter; Chung, Eddie M.K.; Reinhardt, Richard; Marthin, June K.; Nielsen, Kim G.; Mitchison, Hannah M.; Omran, Heymut

2012-01-01

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder characterized by defective cilia and flagella motility. Chronic destructive-airway disease is caused by abnormal respiratory-tract mucociliary clearance. Abnormal propulsion of sperm flagella contributes to male infertility. Genetic defects in most individuals affected by PCD cause randomization of left-right body asymmetry; approximately half show situs inversus or situs ambiguous. Almost 70 years after the hy3 mouse possessing Hydin mutations was described as a recessive hydrocephalus model, we report HYDIN mutations in PCD-affected persons without hydrocephalus. By homozygosity mapping, we identified a PCD-associated locus, chromosomal region 16q21-q23, which contains HYDIN. However, a nearly identical 360 kb paralogous segment (HYDIN2) in chromosomal region 1q21.1 complicated mutational analysis. In three affected German siblings linked to HYDIN, we identified homozygous c.3985G>T mutations that affect an evolutionary conserved splice acceptor site and that subsequently cause aberrantly spliced transcripts predicting premature protein termination in respiratory cells. Parallel whole-exome sequencing identified a homozygous nonsense HYDIN mutation, c.922A>T (p.Lys307∗), in six individuals from three Faroe Island PCD-affected families that all carried an 8.8 Mb shared haplotype across HYDIN, indicating an ancestral founder mutation in this isolated population. We demonstrate by electron microscopy tomography that, consistent with the effects of loss-of-function mutations, HYDIN mutant respiratory cilia lack the C2b projection of the central pair (CP) apparatus; similar findings were reported in Hydin-deficient Chlamydomonas and mice. High-speed videomicroscopy demonstrated markedly reduced beating amplitudes of respiratory cilia and stiff sperm flagella. Like the hy3 mouse model, all nine PCD-affected persons had normal body composition because nodal cilia function is apparently not dependent on the function of the CP apparatus. PMID:23022101

A molecular and clinical study of Larsen syndrome caused by mutations in FLNB.

PubMed

Bicknell, Louise S; Farrington-Rock, Claire; Shafeghati, Yousef; Rump, Patrick; Alanay, Yasemin; Alembik, Yves; Al-Madani, Navid; Firth, Helen; Karimi-Nejad, Mohammad Hassan; Kim, Chong Ae; Leask, Kathryn; Maisenbacher, Melissa; Moran, Ellen; Pappas, John G; Prontera, Paolo; de Ravel, Thomy; Fryns, Jean-Pierre; Sweeney, Elizabeth; Fryer, Alan; Unger, Sheila; Wilson, L C; Lachman, Ralph S; Rimoin, David L; Cohn, Daniel H; Krakow, Deborah; Robertson, Stephen P

2007-02-01

Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied. Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated. The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G-->A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.

Inference of directional selection and mutation parameters assuming equilibrium.

PubMed

Vogl, Claus; Bergman, Juraj

2015-12-01

In a classical study, Wright (1931) proposed a model for the evolution of a biallelic locus under the influence of mutation, directional selection and drift. He derived the equilibrium distribution of the allelic proportion conditional on the scaled mutation rate, the mutation bias and the scaled strength of directional selection. The equilibrium distribution can be used for inference of these parameters with genome-wide datasets of "site frequency spectra" (SFS). Assuming that the scaled mutation rate is low, Wright's model can be approximated by a boundary-mutation model, where mutations are introduced into the population exclusively from sites fixed for the preferred or unpreferred allelic states. With the boundary-mutation model, inference can be partitioned: (i) the shape of the SFS distribution within the polymorphic region is determined by random drift and directional selection, but not by the mutation parameters, such that inference of the selection parameter relies exclusively on the polymorphic sites in the SFS; (ii) the mutation parameters can be inferred from the amount of polymorphic and monomorphic preferred and unpreferred alleles, conditional on the selection parameter. Herein, we derive maximum likelihood estimators for the mutation and selection parameters in equilibrium and apply the method to simulated SFS data as well as empirical data from a Madagascar population of Drosophila simulans. Copyright © 2015 Elsevier Inc. All rights reserved.

Common and Rare EGFR and KRAS Mutations in a Dutch Non-Small-Cell Lung Cancer Population and Their Clinical Outcome

PubMed Central

Kerner, Gerald S. M. A.; Schuuring, Ed; Sietsma, Johanna; Hiltermann, Thijo J. N.; Pieterman, Remge M.; de Leede, Gerard P. J.; van Putten, John W. G.; Liesker, Jeroen; Renkema, Tineke E. J.; van Hengel, Peter; Platteel, Inge; Timens, Wim; Groen, Harry J. M.

2013-01-01

Introduction In randomly assigned studies with EGFR TKI only a minor proportion of patients with NSCLC have genetically profiled biopsies. Guidelines provide evidence to perform EGFR and KRAS mutation analysis in non-squamous NSCLC. We explored tumor biopsy quality offered for mutation testing, different mutations distribution, and outcome with EGFR TKI. Patient and Methods Clinical data from 8 regional hospitals were studied for patient and tumor characteristics, treatment and overall survival. Biopsies sent to the central laboratory were evaluated for DNA quality and subsequently analyzed for mutations in exons 18–21 of EGFR and exon 2 of KRAS by bidirectional sequence analysis. Results Tumors from 442 subsequent patients were analyzed. For 74 patients (17%) tumors were unsuitable for mutation analysis. Thirty-eight patients (10.9%) had EGFR mutations with 79% known activating mutations. One hundred eight patients (30%) had functional KRAS mutations. The mutation spectrum was comparable to the Cosmic database. Following treatment in the first or second line with EGFR TKI median overall survival for patients with EGFR (n = 14), KRAS (n = 14) mutations and wild type EGFR/KRAS (n = 31) was not reached, 20 and 9 months, respectively. Conclusion One out of every 6 tumor samples was inadequate for mutation analysis. Patients with EGFR activating mutations treated with EGFR-TKI have the longest survival. PMID:23922984

Workshop on Self-Determination in Developing and Evolving Systems

DTIC Science & Technology

1994-02-18

processes of duplication (e.g. gene duplication, cell duplication, structural enlargement), responses to selfish DNA (e.g. suppression of outlaw...direct their development, then the genes would need some form of environmental feedback. Are there any plausible mechanisms for such feedback? 3. What is...evolutionary innovation, what is the contribution of random mutations, directed mutation, gene conversion, symbiogenesis, fusion, jumping genes or other

40 CFR 81.327 - Montana.

Code of Federal Regulations, 2010 CFR

2010-07-01

... County Unclassifiable/Attainment Granite County Unclassifiable/Attainment Hill County (part) excluding... Golden Valley County Unclassifiable/Attainment Granite County Unclassifiable/Attainment Hill County (part... Unclassifiable/Attainment Granite County. Unclassifiable/Attainment Hill County Unclassifiable/Attainment...

40 CFR 81.327 - Montana.

Code of Federal Regulations, 2011 CFR

2011-07-01

... County Unclassifiable/Attainment Granite County Unclassifiable/Attainment Hill County (part) excluding... Golden Valley County Unclassifiable/Attainment Granite County Unclassifiable/Attainment Hill County (part... Unclassifiable/Attainment Granite County. Unclassifiable/Attainment Hill County Unclassifiable/Attainment...

Multi-scale habitat use of male ruffed grouse in the Black Hills National Forest

Treesearch

Cassandra L. Mehls; Kent C. Jensen; Mark A. Rumble; Michael C. Wimberly

2014-01-01

Ruffed grouse (Bonasa umbellus) are native upland game birds and a management indicator species (MIS) for aspen (Populus tremuloides) in the Black Hills National Forest (Black Hills). Our objective was to assess resource selection of male ruffed grouse to identify the most appropriate scale to manage for aspen and ruffed grouse in the Black Hills. During spring 2007...

Low-velocity zone and topography as a source of site amplification effect on Tarzana hill, California

USGS Publications Warehouse

Graizer, V.

2009-01-01

Tarzana station is located in the foothills of the Santa Monica Mountains in California near the crest of a low (<20 m) natural hill with gentle slopes. The hill is about 500 m in length by 130 m in width and is formed of extremely weathered shale at the surface to fresh at depth. Average S-wave is about 250 m/s in the top 17-18 m, and S- and P-wave velocities significantly increase below this depth. According to the NEHRP classification based on VS30???300 m/s it is a site class D. Strong-motion instrumentation at Tarzana consisted of an accelerograph at the top of the hill, a downhole instrument at 60 m depth, and an accelerograph at the base of the hill. More than 20 earthquakes were recorded by at least three instruments at Tarzana from 1998 till 2003. Comparisons of recordings and Fourier spectra indicate strong directional resonance in a direction perpendicular to the strike of the hill. The dominant peaks in ground motion amplification on the top of the hill relative to the base are at frequencies ???3.6 and 8-9 Hz for the horizontal components. Our hypothesis is that the hill acts like a wave trap. This results in an amplification at predominant frequencies f=V/4 h (h is layer's thickness) at f???3.6 Hz for S-waves (using average VS17=246 m/s and h=17 m) and f???7.9 Hz for P-waves (using average VP17=535 m/s and h=17 m). As was shown by Bouchon and Barker [Seismic response of a hill: the example of Tarzana, California. Bull Seism Soc Am 1996;86(1A):66-72], topography of this hill amplifies and polarizes ground motion in the frequency range of 3-5 Hz. Hill acts as a magnifying polarizing glass: It polarizes ground motion in the direction perpendicular to the strike of the hill and also amplifies ground motions that had been also amplified by a low-velocity layer.

Population Heterogeneity in Mutation Rate Increases the Frequency of Higher-Order Mutants and Reduces Long-Term Mutational Load

PubMed Central

Alexander, Helen K.; Mayer, Stephanie I.; Bonhoeffer, Sebastian

2017-01-01

Abstract Mutation rate is a crucial evolutionary parameter that has typically been treated as a constant in population genetic analyses. However, the propensity to mutate is likely to vary among co-existing individuals within a population, due to genetic polymorphisms, heterogeneous environmental influences, and random physiological fluctuations. We review the evidence for mutation rate heterogeneity and explore its consequences by extending classic population genetic models to allow an arbitrary distribution of mutation rate among individuals, either with or without inheritance. With this general new framework, we rigorously establish the effects of heterogeneity at various evolutionary timescales. In a single generation, variation of mutation rate about the mean increases the probability of producing zero or many simultaneous mutations on a genome. Over multiple generations of mutation and selection, heterogeneity accelerates the appearance of both deleterious and beneficial multi-point mutants. At mutation-selection balance, higher-order mutant frequencies are likewise boosted, while lower-order mutants exhibit subtler effects; nonetheless, population mean fitness is always enhanced. We quantify the dependencies on moments of the mutation rate distribution and selection coefficients, and clarify the role of mutation rate inheritance. While typical methods of estimating mutation rate will recover only the population mean, analyses assuming mutation rate is fixed to this mean could underestimate the potential for multi-locus adaptation, including medically relevant evolution in pathogenic and cancerous populations. We discuss the potential to empirically parameterize mutation rate distributions, which have to date hardly been quantified. PMID:27836985

Contributions of Torpedo nicotinic acetylcholine receptor gamma Trp-55 and delta Trp-57 to agonist and competitive antagonist function.

PubMed

Xie, Y; Cohen, J B

2001-01-26

Results of affinity-labeling studies and mutational analyses provide evidence that the agonist binding sites of the nicotinic acetylcholine receptor (nAChR) are located at the alpha-gamma and alpha-delta subunit interfaces. For Torpedo nAChR, photoaffinity-labeling studies with the competitive antagonist d-[(3)H]tubocurarine (dTC) identified two tryptophans, gammaTrp-55 and deltaTrp-57, as the primary sites of photolabeling in the non-alpha subunits. To characterize the importance of gammaTrp-55 and deltaTrp-57 to the interactions of agonists and antagonists, Torpedo nAChRs were expressed in Xenopus oocytes, and equilibrium binding assays and electrophysiological recordings were used to examine the functional consequences when either or both tryptophans were mutated to leucine. Neither substitution altered the equilibrium binding of dTC. However, the deltaW57L and gammaW55L mutations decreased acetylcholine (ACh) binding affinity by 20- and 7,000-fold respectively. For the wild-type, gammaW55L, and deltaW57L nAChRs, the concentration dependence of channel activation was characterized by Hill coefficients of 1.8, 1.1, and 1.7. For the gammaW55L mutant, dTC binding at the alpha-gamma site acts not as a competitive antagonist but as a coactivator or partial agonist. These results establish that interactions with gamma Trp-55 of the Torpedo nAChR play a crucial role in agonist binding and in the agonist-induced conformational changes that lead to channel opening.

Effects of topology on network evolution

NASA Astrophysics Data System (ADS)

Oikonomou, Panos; Cluzel, Philippe

2006-08-01

The ubiquity of scale-free topology in nature raises the question of whether this particular network design confers an evolutionary advantage. A series of studies has identified key principles controlling the growth and the dynamics of scale-free networks. Here, we use neuron-based networks of boolean components as a framework for modelling a large class of dynamical behaviours in both natural and artificial systems. Applying a training algorithm, we characterize how networks with distinct topologies evolve towards a pre-established target function through a process of random mutations and selection. We find that homogeneous random networks and scale-free networks exhibit drastically different evolutionary paths. Whereas homogeneous random networks accumulate neutral mutations and evolve by sparse punctuated steps, scale-free networks evolve rapidly and continuously. Remarkably, this latter property is robust to variations of the degree exponent. In contrast, homogeneous random networks require a specific tuning of their connectivity to optimize their ability to evolve. These results highlight an organizing principle that governs the evolution of complex networks and that can improve the design of engineered systems.

40 CFR 81.327 - Montana.

Code of Federal Regulations, 2013 CFR

2013-07-01

... County Unclassifiable/Attainment Granite County Unclassifiable/Attainment Hill County (part) excluding... Golden Valley County Unclassifiable/Attainment Granite County Unclassifiable/Attainment Hill County (part.... Golden Valley County Unclassifiable/Attainment. Granite County Unclassifiable/Attainment. Hill County...

40 CFR 81.327 - Montana.

Code of Federal Regulations, 2012 CFR

2012-07-01

... County Unclassifiable/Attainment Granite County Unclassifiable/Attainment Hill County (part) excluding... Golden Valley County Unclassifiable/Attainment Granite County Unclassifiable/Attainment Hill County (part.... Golden Valley County Unclassifiable/Attainment. Granite County Unclassifiable/Attainment. Hill County...

[Genotyping of BRCA1, BRCA2 and CHEK2 germline mutations in Russian breast cancer patients using diagnostic biochips].

PubMed

Nasedkina, T V; Gromyko, O E; Emel'ianova, M A; Ignatova, E O; Kazubskaia, T P; Portnoĭ, S M; Zasedatelev, A S; Liubchenko, L N

2014-01-01

Germline mutations of BRCA1/2 genes cause the predisposition of their carriers to breast or/and ovary cancers (BC or/and OC) during the lifetime. Identification of these mutations is a basis of molecular diagnosis for BC susceptibility. Rapid genotyping technique using microarrays for identification of BRCA1 185delAG, 300T>G, 4153delA, 5382insC mutations and 4158 A>G sequence variant; BRCA2 695insT and 6174delT mutations; 1100delC mutation in CHEK2 gene was applied for 412 randomly collected breast cancer samples from the central region of European area of Russia. In 25 (6.0%) patients (6.0%) BC was associated with other tumours: OC, cervical cancer, colorectal cancer etc. BRCA1/2 and CHEK2 mutations were found in 33 (8.0%) BC patients. The most frequent mutation was BRCA1 5382insC, occurred in 16 (3.9%) BC patients, and CHEK2 1100delC, revealed in 7 (1.7%) BC patients. An application of diagnostic BC-microarray for genetic testing of BRCA1/2 and CHEK2 founder mutations has been discussed.

Hypotheses of Spatial Stock Structure in Orange Roughy Hoplostethus atlanticus Inferred from Diet, Feeding, Condition, and Reproductive Activity

PubMed Central

Dunn, Matthew R.; Forman, Jeffrey S.

2011-01-01

We evaluate hypotheses for meso-scale spatial structure in an orange roughy (Hoplostethus atlanticus) stock using samples collected during research trawl surveys off the east coast of New Zealand. Distance-based linear models and generalised additive models were used to identify the most significant biological, environmental, and temporal predictors of variability in diet, proportion of stomachs containing prey, standardised weight of prey, fish somatic weight, fish total weight, and reproductive activity. The diet was similar to that observed elsewhere, and varied with ontogeny, depth, and surface water temperature. Smaller sized and female orange roughy in warmer bottom water were most likely to contain food. Fish condition and reproductive activity were highest at distances more than 20 km from the summit of the hills. Trawl survey catches indicated greater orange roughy densities in hill strata, suggesting hill habitat was favoured. However, analyses of feeding, condition, and reproductive activity indicated hill fish were not superior, despite fish densities on hills being reduced by fishing which, in principle, should have reduced intra-specific competition for food and other resources. Hypotheses for this result include: (1) fish in relatively poor condition visit hills to feed and regain condition and then leave, or (2) commercial fishing has disturbed feeding aggregations and/or caused habitat damage, making fished hills less productive. Mature orange roughy were observed on both flat and hill habitat during periods outside of spawning, and if this spatial structure was persistent then a proportion of the total spawning stock biomass would remain unavailable to fisheries targeting hills. Orange roughy stock assessments informed only by data from hills may well be misleading. PMID:22069464

Stratigraphy and depositional environments of Fox Hills Formation (Late Cretaceous), Williston basin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Daly, D.J.

The Fox Hills Formation (Late Cretaceous, Maestrichtian) was investigated where it crops out along the southern flank of the Williston basin and in the subsurface over the central portion of the basin, using 300 well logs. The formation is conformable and gradational with the underlying Pierre formation and can be either conformable or unconformable with the overlying Hell Creek Formation. The Fox Hills Formation is younger, thicker, and stratigraphically more complex to the east and is comprised of marginal marine sediments deposited during the final Cretaceous regression. To the west, the Fox Hills Formation is an upward-coarsening unit generally 30more » to 45 m thick and usually contains three members: from the base, Trail City, Timber Lake, and Colgate. The lower Fox Hills (Trail City, Timber Lake) is generally dominated by hummocky bedding and contains a variety of trace fossils, most notably Ophiomorpha. The upper Fox Hills (Colgate), where present, is characterized by cross-bedding. To the east, including the type area, the section is generally 80 to 100 m thick and contains four members: from the base, Trail City, Timber Lake, Iron Lightning (Colgate and Bullhead lithofacies), and Linton. In contrast to the section in the west, this section is as much as three times thicker, contains abundant body fossils, generally lacks hummocky bedding, and contains the Bullhead and Linton strata. In the west, the strata represent lower shoreface deposits, predominantly of storm origin (lower Fox Hills), overlain by upper shoreface and fluvial deposits (upper Fox Hills). In the east, the lower Fox Hills contains deposits of the lower shoreface (Trail City) and a barrier bar complex (Timber Lake), overlain by the deltaic deposits of the upper Fox Hills (Iron Lightning, Linton).« less

Abyssal hills: Influence of topography on benthic foraminiferal assemblages

NASA Astrophysics Data System (ADS)

Stefanoudis, Paris V.; Bett, Brian J.; Gooday, Andrew J.

2016-11-01

Abyssal plains, often thought of as vast flat areas, encompass a variety of terrains including abyssal hills, features that constitute the single largest landscape type on Earth. The potential influence on deep-sea benthic faunas of mesoscale habitat complexity arising from the presence of abyssal hills is still poorly understood. To address this issue we focus on benthic foraminifera (testate protists) in the >150-μm fraction of Megacorer samples (0-1 cm layer) collected at five different sites in the area of the Porcupine Abyssal Plain Sustained Observatory (NE Atlantic, 4850 m water depth). Three sites are located on the tops of small abyssal hills (200-500 m elevation) and two on the adjacent abyssal plain. We examined benthic foraminiferal assemblage characteristics (standing stock, diversity, composition) in relation to seafloor topography (hills vs. plain). Density and rarefied diversity were not significantly different between the hills and the plain. Nevertheless, hills do support a higher species density (i.e. species per unit area), a distinct fauna, and act to increase the regional species pool. Topographically enhanced bottom-water flows that influence food availability and sediment type are suggested as the most likely mechanisms responsible for these differences. Our findings highlight the potential importance of mesoscale heterogeneity introduced by relatively modest topography in regulating abyssal foraminiferal diversity. Given the predominance of abyssal hill terrain in the global ocean, we suggest the need to include faunal data from abyssal hills in assessments of abyssal ecology.

Sidescan Sonar Imagery of the Escanaba Trough, Southern Gorda Ridge, Offshore Northern California

USGS Publications Warehouse

Ross, Stephanie L.; Zierenberg, Robert A.

2009-01-01

This map features sidescan imagery of the northern Escanaba (NESCA) site at the Escanaba Trough, southern Gorda Ridge, offshore northern California. The Escanaba Trough, a largely sediment-covered seafloor spreading center, contains at least six large massive sulfide deposits. It is a slow spreading center (2.5 cm/yr) with axial depths locally exceeding 3,300 m. Discrete igneous centers occur at 5- to 10-km intervals along this slow-spreading ridge. Basaltic magma intrudes the sediment fill of the axial valley, creating uplifted sediment hills, and, in some areas, erupts onto the sea floor. Large massive sulfide deposits occur along the margins of the uplifted sediment hills. The only active hydrothermal system is located on Central Hill where 220 deg C fluids construct anhydrite chimneys on pyrrhotite-rich massive sulfide mounds (Campbell and others, 1994). Central Hill is bounded by both ridge-parallel basement faults and a concentric set of faults that rim the top of the hill and may be associated with sill intrusion. Central Hill was one of the primary drill sites for Ocean Drilling Program (ODP) Leg 169. The sidescan sonar data (mosaics A, B, C, D) were collected aboard the National Oceanic and Atmospheric Administration (NOAA) research vessel Discoverer in the summer of 1996 with a 60-kHz system towed 100 to 200 m above the sea floor. Major faults and contacts are interpreted from the sidescan mosaics and 4.5-kHz seismic profiles collected simultaneously, as well as from previously conducted camera transects and submersible dives. The seismic profiles (lines 9, 11, 13) provide high-resolution subbottom structure and stratigraphy to a depth of about 50 m. In the sidescan images (mosaics A, B, C, D), bright areas denote high-energy returns from hard reflectors such as volcanic flows, sulfide deposits, or seafloor scarps. Dark areas denote low-energy returns and generally signify relatively undisturbed surface sediment. The grid lines mark one-minute intervals of latitude and longitude. The large sidescan sonar image (mosaic A) is centered on the NESCA igneous center. The spreading axis is flanked on either side by uplifted, sediment-covered terraces that show relatively continuous and undisturbed turbiditic sediment. These terraces bound the 4- to 5-km-wide neotectonic zone that is characterized by more closely spaced, small offset (<20 m) faults, volcanic flows (brightest area of backscatter), and areas where the seismic layering of the turbidites has been partially to completely disrupted by the intrusion of basaltic sills. The most prominent bathymetric features are the three uplifted sediment hills: Central Hill, Southwest Hill, and an unnamed uplifted hill to the north. These features are interpreted to be uplifted above large-volume basaltic intrusions emplaced near the basalt/sediment interface. Southwest Hill is adjacent to the zone of most recent faulting. This hill no longer retains the circular shape of the other hills due to slumps (lines 9, 11), which may have failed along faults related to the most recent spreading. Central Hill is interpreted to be the most recently uplifted sediment hill based on the morphology of the hill and the presence of an active hydrothermal system. The generally continuous area of volcanic basalt flow east of Central Hill appears as a distinct, bright sonar reflector stretching for approximately 6 km along axis (red contact on mosaic A). This flow may be related to the intrusion that is presumed to have uplifted Central Hill. Submersible observations indicate that lava flowed around the sediment hills and ponded against the eastern up-faulted turbidite-covered sediment terrace. Previously collected, deep-penetration seismic data indicate that the lavas overlie about 450 m of sediment (Morton and Fox, 1994). Late-stage emplacement of magma in the shallow subsurface beneath the exposed lava flow is interpreted to have domed the lava flow, forming the east-west-

78 FR 21817 - Amendment of Restricted Area R-6601; Fort A.P. Hill, VA

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-12

...; Airspace Docket No. 12-AEA-7] RIN 2120-AA66 Amendment of Restricted Area R-6601; Fort A.P. Hill, VA AGENCY... limits and time of designation of restricted area R-6601, Fort A.P. Hill, VA. The U.S. Army requested... limits and increase the time of designation of restricted area R-6601, Fort A.P. Hill, VA, (77 FR 35308...

Conditioning exercises in ski jumping: biomechanical relationship of squat jumps, imitation jumps, and hill jumps.

PubMed

Lorenzetti, Silvio; Ammann, Fabian; Windmüller, Sabrina; Häberle, Ramona; Müller, Sören; Gross, Micah; Plüss, Michael; Plüss, Stefan; Schödler, Berni; Hübner, Klaus

2017-11-22

As hill jumps are very time-consuming, ski jumping athletes often perform various imitation jumps during training. The performed jumps should be similar to hill jumps, but a direct comparison of the kinetic and kinematic parameters has not been performed yet. Therefore, this study aimed to correlate 11 common parameters during hill jumps (Oberstdorf Germany), squat jumps (wearing indoor shoes), and various imitation jumps (rolling 4°, rolling flat, static; jumping equipment or indoor shoes) on a custom-built instrumented vehicle with a catch by the coach. During the performed jumps, force and video data of the take-off of 10 athletes were measured. The imitation and squat jumps were then ranked. The main difference between the hill jumps and the imitation and squat jumps is the higher maximal force loading rate during the hill jumps. Imitation jumps performed on a rolling platform, on flat ground were the most similar to hill jumps in terms of the force-time, and leg joint kinematic properties. Thus, non-hill jumps with a technical focus should be performed from a rolling platform with a flat inrun with normal indoor shoes or jumping equipment, and high normal force loading rates should be the main focus of imitation training.

Mitochondrial DNA sequence variation in human evolution and disease.

PubMed

Wallace, D C

1994-09-13

Germ-line and somatic mtDNA mutations are hypothesized to act together to shape our history and our health. Germ-line mtDNA mutations, both ancient and recent, have been associated with a variety of degenerative diseases. Mildly to moderately deleterious germ-line mutations, like neutral polymorphisms, have become established in the distant past through genetic drift but now may predispose certain individuals to late-onset degenerative diseases. As an example, a homoplasmic, Caucasian, tRNA(Gln) mutation at nucleotide pair (np) 4336 has been observed in 5% of Alzheimer disease and Parkinson disease patients and may contribute to the multifactorial etiology of these diseases. Moderately to severely deleterious germ-line mutations, on the other hand, appear repeatedly but are eliminated by selection. Hence, all extant mutations of this class are recent and associated with more devastating diseases of young adults and children. Representative of these mutations is a heteroplasmic mutation in MTND6 at np 14459 whose clinical presentations range from adult-onset blindness to pediatric dystonia and basal ganglial degeneration. To the inherited mutations are added somatic mtDNA mutations which accumulate in random arrays within stable tissues. These mutations provide a molecular clock that measures our age and may cause a progressive decline in tissue energy output that could precipitate the onset of degenerative diseases in individuals harboring inherited deleterious mutations.

Tissue-specific mutation accumulation in human adult stem cells during life

NASA Astrophysics Data System (ADS)

Blokzijl, Francis; de Ligt, Joep; Jager, Myrthe; Sasselli, Valentina; Roerink, Sophie; Sasaki, Nobuo; Huch, Meritxell; Boymans, Sander; Kuijk, Ewart; Prins, Pjotr; Nijman, Isaac J.; Martincorena, Inigo; Mokry, Michal; Wiegerinck, Caroline L.; Middendorp, Sabine; Sato, Toshiro; Schwank, Gerald; Nieuwenhuis, Edward E. S.; Verstegen, Monique M. A.; van der Laan, Luc J. W.; de Jonge, Jeroen; Ijzermans, Jan N. M.; Vries, Robert G.; van de Wetering, Marc; Stratton, Michael R.; Clevers, Hans; Cuppen, Edwin; van Boxtel, Ruben

2016-10-01

The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer. Extreme variation in cancer risk across tissues was recently proposed to depend on the lifetime number of ASC divisions, owing to unavoidable random mutations that arise during DNA replication. However, the rates and patterns of mutations in normal ASCs remain unknown. Here we determine genome-wide mutation patterns in ASCs of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by sequencing clonal organoid cultures derived from primary multipotent cells. Our results show that mutations accumulate steadily over time in all of the assessed tissue types, at a rate of approximately 40 novel mutations per year, despite the large variation in cancer incidence among these tissues. Liver ASCs, however, have different mutation spectra compared to those of the colon and small intestine. Mutational signature analysis reveals that this difference can be attributed to spontaneous deamination of methylated cytosine residues in the colon and small intestine, probably reflecting their high ASC division rate. In liver, a signature with an as-yet-unknown underlying mechanism is predominant. Mutation spectra of driver genes in cancer show high similarity to the tissue-specific ASC mutation spectra, suggesting that intrinsic mutational processes in ASCs can initiate tumorigenesis. Notably, the inter-individual variation in mutation rate and spectra are low, suggesting tissue-specific activity of common mutational processes throughout life.

VarWalker: Personalized Mutation Network Analysis of Putative Cancer Genes from Next-Generation Sequencing Data

PubMed Central

Jia, Peilin; Zhao, Zhongming

2014-01-01

A major challenge in interpreting the large volume of mutation data identified by next-generation sequencing (NGS) is to distinguish driver mutations from neutral passenger mutations to facilitate the identification of targetable genes and new drugs. Current approaches are primarily based on mutation frequencies of single-genes, which lack the power to detect infrequently mutated driver genes and ignore functional interconnection and regulation among cancer genes. We propose a novel mutation network method, VarWalker, to prioritize driver genes in large scale cancer mutation data. VarWalker fits generalized additive models for each sample based on sample-specific mutation profiles and builds on the joint frequency of both mutation genes and their close interactors. These interactors are selected and optimized using the Random Walk with Restart algorithm in a protein-protein interaction network. We applied the method in >300 tumor genomes in two large-scale NGS benchmark datasets: 183 lung adenocarcinoma samples and 121 melanoma samples. In each cancer, we derived a consensus mutation subnetwork containing significantly enriched consensus cancer genes and cancer-related functional pathways. These cancer-specific mutation networks were then validated using independent datasets for each cancer. Importantly, VarWalker prioritizes well-known, infrequently mutated genes, which are shown to interact with highly recurrently mutated genes yet have been ignored by conventional single-gene-based approaches. Utilizing VarWalker, we demonstrated that network-assisted approaches can be effectively adapted to facilitate the detection of cancer driver genes in NGS data. PMID:24516372

VarWalker: personalized mutation network analysis of putative cancer genes from next-generation sequencing data.

PubMed

Jia, Peilin; Zhao, Zhongming

2014-02-01

A major challenge in interpreting the large volume of mutation data identified by next-generation sequencing (NGS) is to distinguish driver mutations from neutral passenger mutations to facilitate the identification of targetable genes and new drugs. Current approaches are primarily based on mutation frequencies of single-genes, which lack the power to detect infrequently mutated driver genes and ignore functional interconnection and regulation among cancer genes. We propose a novel mutation network method, VarWalker, to prioritize driver genes in large scale cancer mutation data. VarWalker fits generalized additive models for each sample based on sample-specific mutation profiles and builds on the joint frequency of both mutation genes and their close interactors. These interactors are selected and optimized using the Random Walk with Restart algorithm in a protein-protein interaction network. We applied the method in >300 tumor genomes in two large-scale NGS benchmark datasets: 183 lung adenocarcinoma samples and 121 melanoma samples. In each cancer, we derived a consensus mutation subnetwork containing significantly enriched consensus cancer genes and cancer-related functional pathways. These cancer-specific mutation networks were then validated using independent datasets for each cancer. Importantly, VarWalker prioritizes well-known, infrequently mutated genes, which are shown to interact with highly recurrently mutated genes yet have been ignored by conventional single-gene-based approaches. Utilizing VarWalker, we demonstrated that network-assisted approaches can be effectively adapted to facilitate the detection of cancer driver genes in NGS data.

40 CFR 81.327 - Montana.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Unclassifiable/Attainment Granite County Unclassifiable/Attainment Hill County (part)excluding Rocky Boy Indian.../Attainment Granite County Unclassifiable/Attainment Hill County (part) excluding Rocky Boy Indian Reservation.../Attainment. Granite County Unclassifiable/Attainment. Hill County Unclassifiable/Attainment. Jefferson County...

Variational method of determining effective moduli of polycrystals: (A) hexagonal symmetry, (B) trigonal symmetry

USGS Publications Warehouse

Peselnick, L.; Meister, R.

1965-01-01

Variational principles of anisotropic elasticity have been applied to aggregates of randomly oriented pure-phase polycrystals having hexagonal symmetry and trigonal symmetry. The bounds of the effective elastic moduli obtained in this way show a considerable improvement over the bounds obtained by means of the Voigt and Reuss assumptions. The Hill average is found to be in most cases a good approximation when compared to the bounds found from the variational method. The new bounds reduce in their limits to the Voigt and Reuss values. ?? 1965 The American Institute of Physics.

Skating down a steeper slope: Fear influences the perception of geographical slant

PubMed Central

Stefanucci, Jeanine K.; Proffitt, Dennis R.; Clore, Gerald L.; Parekh, Nazish

2008-01-01

Conscious awareness of hill slant is overestimated, but visually guided actions directed at hills are relatively accurate. Also, steep hills are consciously estimated to be steeper from the top as opposed to the bottom, possibly because they are dangerous to walk down. In the present study, participants stood at the top of a hill on either a skateboard or a wooden box of the same height. They gave three estimates of the slant of the hill: a verbal report, a visually matched estimate, and a visually guided action. Fear of descending the hill was also assessed. Those participants that were scared (by standing on the skateboard) consciously judged the hill to be steeper relative to participants who were unafraid. However, the visually guided action measure was accurate across conditions. These results suggest that our explicit awareness of slant is influenced by the fear associated with a potentially dangerous action. “[The phobic] reported that as he drove towards bridges, they appeared to be sloping at a dangerous angle.” (Rachman and Cuk 1992 p. 583). PMID:18414594

Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that the CCC sequence motif is a mutational hot spot in the homogentisate 1,2 dioxygenase gene (HGO).

PubMed Central

Beltrán-Valero de Bernabé, D; Jimenez, F J; Aquaron, R; Rodríguez de Córdoba, S

1999-01-01

We recently showed that alkaptonuria (AKU) is caused by loss-of-function mutations in the homogentisate 1,2 dioxygenase gene (HGO). Herein we describe haplotype and mutational analyses of HGO in seven new AKU pedigrees. These analyses identified two novel single-nucleotide polymorphisms (INV4+31A-->G and INV11+18A-->G) and six novel AKU mutations (INV1-1G-->A, W60G, Y62C, A122D, P230T, and D291E), which further illustrates the remarkable allelic heterogeneity found in AKU. Reexamination of all 29 mutations and polymorphisms thus far described in HGO shows that these nucleotide changes are not randomly distributed; the CCC sequence motif and its inverted complement, GGG, are preferentially mutated. These analyses also demonstrated that the nucleotide substitutions in HGO do not involve CpG dinucleotides, which illustrates important differences between HGO and other genes for the occurrence of mutation at specific short-sequence motifs. Because the CCC sequence motifs comprise a significant proportion (34.5%) of all mutated bases that have been observed in HGO, we conclude that the CCC triplet is a mutational hot spot in HGO. PMID:10205262

Coevolutionary dynamics in large, but finite populations

NASA Astrophysics Data System (ADS)

Traulsen, Arne; Claussen, Jens Christian; Hauert, Christoph

2006-07-01

Coevolving and competing species or game-theoretic strategies exhibit rich and complex dynamics for which a general theoretical framework based on finite populations is still lacking. Recently, an explicit mean-field description in the form of a Fokker-Planck equation was derived for frequency-dependent selection with two strategies in finite populations based on microscopic processes [A. Traulsen, J. C. Claussen, and C. Hauert, Phys. Rev. Lett. 95, 238701 (2005)]. Here we generalize this approach in a twofold way: First, we extend the framework to an arbitrary number of strategies and second, we allow for mutations in the evolutionary process. The deterministic limit of infinite population size of the frequency-dependent Moran process yields the adjusted replicator-mutator equation, which describes the combined effect of selection and mutation. For finite populations, we provide an extension taking random drift into account. In the limit of neutral selection, i.e., whenever the process is determined by random drift and mutations, the stationary strategy distribution is derived. This distribution forms the background for the coevolutionary process. In particular, a critical mutation rate uc is obtained separating two scenarios: above uc the population predominantly consists of a mixture of strategies whereas below uc the population tends to be in homogeneous states. For one of the fundamental problems in evolutionary biology, the evolution of cooperation under Darwinian selection, we demonstrate that the analytical framework provides excellent approximations to individual based simulations even for rather small population sizes. This approach complements simulation results and provides a deeper, systematic understanding of coevolutionary dynamics.

A Novel Mutation in CLCN1 Associated with Feline Myotonia Congenita

PubMed Central

Gandolfi, Barbara; Daniel, Rob J.; O'Brien, Dennis P.; Guo, Ling T.; Youngs, Melanie D.; Leach, Stacey B.; Jones, Boyd R.; Shelton, G. Diane; Lyons, Leslie A.

2014-01-01

Myotonia congenita (MC) is a skeletal muscle channelopathy characterized by inability of the muscle to relax following voluntary contraction. Worldwide population prevalence in humans is 1∶100,000. Studies in mice, dogs, humans and goats confirmed myotonia associated with functional defects in chloride channels and mutations in a skeletal muscle chloride channel (CLCN1). CLCN1 encodes for the most abundant chloride channel in the skeletal muscle cell membrane. Five random bred cats from Winnipeg, Canada with MC were examined. All cats had a protruding tongue, limited range of jaw motion and drooling with prominent neck and proximal limb musculature. All cats had blepharospasm upon palpebral reflex testing and a short-strided gait. Electromyograms demonstrated myotonic discharges at a mean frequency of 300 Hz resembling the sound of a ‘swarm of bees’. Muscle histopathology showed hypertrophy of all fiber types. Direct sequencing of CLCN1 revealed a mutation disrupting a donor splice site downstream of exon 16 in only the affected cats. In vitro translation of the mutated protein predicted a premature truncation and partial lack of the highly conserved CBS1 (cystathionine β-synthase) domain critical for ion transport activity and one dimerization domain pivotal in channel formation. Genetic screening of the Winnipeg random bred population of the cats' origin identified carriers of the mutation. A genetic test for population screening is now available and carrier cats from the feral population can be identified. PMID:25356766

The Two Moons of Mars As Seen from 'Husband Hill'

NASA Technical Reports Server (NTRS)

2005-01-01

Taking advantage of extra solar energy collected during the day, NASA's Mars Exloration Rover Spirit settled in for an evening of stargazing, photographing the two moons of Mars as they crossed the night sky. Spirit took this succession of images at 150-second intervals from a perch atop 'Husband Hill' in Gusev Crater on martian day, or sol, 594 (Sept. 4, 2005), as the faster-moving martian moon Phobos was passing Deimos in the night sky. Phobos is the brighter object on the left and Deimos is the dimmer object on the right. The bright star Aldebaran and some other stars in the constellation Taurus are visible as star trails. Most of the other streaks in the image are the result of cosmic rays lighting up random groups of pixels in the camera.

Scientists will use images of the two moons to better map their orbital positions, learn more about their composition, and monitor the presence of nighttime clouds or haze. Spirit took the five images that make up this c omposite with its panoramic camera using the camera's broadband filter, which was designed specifically for acquiring images under low-light conditions.

Multivariate analysis of subsurface radiometric data in Rongsohkham area, East Khasi Hills district, Meghalaya (India): implication on uranium exploration.

PubMed

Kukreti, B M; Pandey, Pradeep; Singh, R V

2012-08-01

Non-coring based exploratory drilling was under taken in the sedimentary environment of Rangsohkham block, East Khasi Hills district to examine the eastern extension of existing uranium resources located at Domiasiat and Wakhyn in the Mahadek basin of Meghalaya (India). Although radiometric survey and radiometric analysis of surface grab/channel samples in the block indicate high uranium content but the gamma ray logging results of exploratory boreholes in the block, did not obtain the expected results. To understand this abrupt discontinuity between the two sets of data (surface and subsurface) multivariate statistical analysis of primordial radioactive elements (K(40), U(238) and Th(232)) was performed using the concept of representative subsurface samples, drawn from the randomly selected 11 boreholes of this block. The study was performed to a high confidence level (99%), and results are discussed for assessing the U and Th behavior in the block. Results not only confirm the continuation of three distinct geological formations in the area but also the uranium bearing potential in the Mahadek sandstone of the eastern part of Mahadek Basin. Copyright © 2012 Elsevier Ltd. All rights reserved.

1. HISTORIC PHOTOGRAPH, VIEW OF ROUND HILL ROAD BRIDGE, LOOKING ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. HISTORIC PHOTOGRAPH, VIEW OF ROUND HILL ROAD BRIDGE, LOOKING WEST, CA. 1940. CONNECTICUT DEPARTMENT OF TRANSPORTATION. - Merritt Parkway, Round Hill Road Bridge, Spanning Merritt Parkway at 3.5 mile mark, Greenwich, Fairfield County, CT

Development of a Comprehensive Base-Level Environmental Training Program for Total Environmental Compliance

DTIC Science & Technology

1994-09-01

Business Managers. Ed. Betty Seldner. San Francisco : McGraw Hill, Inc., 1994 11. Gunderson, John. "Federal Facilities Compliance Act," in Environmental...Decision Making for Engineering and Business Managers. Ed. Betty Seldner. San Francisco : McGraw Hill, Inc., 1994 105 12. Heyman, Glenn. "The Role and...San Francisco . McGraw Hill, Inc., 1994 13- Hill, Chuck. Environmental Oversight Branch, Headquarters Air Combat Command. Personal Correspondence

Oligovalent Fab display on M13 phage improved by directed evolution.

PubMed

Huovinen, Tuomas; Sanmark, Hanna; Ylä-Pelto, Jani; Vehniäinen, Markus; Lamminmäki, Urpo

2010-03-01

Efficient display of antibody on filamentous phage M13 coat is crucial for successful biopanning selections. We applied a directed evolution strategy to improve the oligovalent display of a poorly behaving Fab fragment fused to phage gene-3 for minor coat protein (g3p). The Fab displaying clones were enriched from a randomly mutated Fab gene library with polyclonal anti-mouse IgG antibodies. Contribution of each mutation to the improved phenotype of one selected mutant was studied. It was found out that two point mutations had significant contribution to the display efficiency of Fab clones superinfected with hyperphage. The most dramatic effect was connected to a start codon mutation, from AUG to GUG, of the PelB signal sequence preceding the heavy chain. The clone carrying this mutation, FabM(GUG), displayed Fab 19-fold better and yielded twofold higher phage titers than the original Fab.

Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria.

PubMed

McDonald, Rebecca; Strang, John

2016-07-01

Fatal outcome of opioid overdose, once detected, is preventable through timely administration of the antidote naloxone. Take-home naloxone provision directly to opioid users for emergency use has been implemented recently in more than 15 countries worldwide, albeit mainly as pilot schemes and without formal evaluation. This systematic review assesses the effectiveness of take-home naloxone, with two specific aims: (1) to study the impact of take-home naloxone distribution on overdose-related mortality; and (2) to assess the safety of take-home naloxone in terms of adverse events. PubMed, MEDLINE and PsychINFO were searched for English-language peer-reviewed publications (randomized or observational trials) using the Boolean search query: (opioid OR opiate) AND overdose AND prevention. Evidence was evaluated using the nine Bradford Hill criteria for causation, devised to assess a potential causal relationship between public health interventions and clinical outcomes when only observational data are available. A total of 1397 records (1164 after removal of duplicates) were retrieved, with 22 observational studies meeting eligibility criteria. Due to variability in size and quality of the included studies, meta-analysis was dismissed in favour of narrative synthesis. From eligible studies, we found take-home naloxone met all nine Bradford Hill criteria. The additional five World Health Organization criteria were all either met partially (two) or fully (three). Even with take-home naloxone administration, fatal outcome was reported in one in 123 overdose cases (0.8%; 95% confidence interval = 0.4, 1.2). Take-home naloxone programmes are found to reduce overdose mortality among programme participants and in the community and have a low rate of adverse events. © 2016 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

Does sufficient evidence exist to support a causal association between vitamin D status and cardiovascular disease risk? An assessment using Hill's criteria for causality.

PubMed

Weyland, Patricia G; Grant, William B; Howie-Esquivel, Jill

2014-09-02

Serum 25-hydroxyvitamin D (25(OH)D) levels have been found to be inversely associated with both prevalent and incident cardiovascular disease (CVD) risk factors; dyslipidemia, hypertension and diabetes mellitus. This review looks for evidence of a causal association between low 25(OH)D levels and increased CVD risk. We evaluated journal articles in light of Hill's criteria for causality in a biological system. The results of our assessment are as follows. Strength of association: many randomized controlled trials (RCTs), prospective and cross-sectional studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors. Consistency of observed association: most studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors in various populations, locations and circumstances. Temporality of association: many RCTs and prospective studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors. Biological gradient (dose-response curve): most studies assessing 25(OH)D levels and CVD risk found an inverse association exhibiting a linear biological gradient. Plausibility of biology: several plausible cellular-level causative mechanisms and biological pathways may lead from a low 25(OH)D level to increased risk for CVD with mediators, such as dyslipidemia, hypertension and diabetes mellitus. Experimental evidence: some well-designed RCTs found increased CVD risk factors with decreasing 25(OH)D levels. Analogy: the association between serum 25(OH)D levels and CVD risk is analogous to that between 25(OH)D levels and the risk of overall cancer, periodontal disease, multiple sclerosis and breast cancer. all relevant Hill criteria for a causal association in a biological system are satisfied to indicate a low 25(OH)D level as a CVD risk factor.

Informal household water market and determinants of price: Evidence from an Indian hill city

NASA Astrophysics Data System (ADS)

Pal, Manoranjan; De, Utpal Kumar

2015-02-01

Pricing of water in the hill cities in India is different from that of plain lands, because water is a scarce resource in most of the hill cities. The supply of water by the municipalities is inadequate. The private vendors come into picture and they put the prices according to the difficulties faced in supplying to the specific locations. Thus prices become variables and are also based on the economic demand-supply mechanism in which the households try to maximise their satisfaction subject to budget and other constraints, while the vendors try to extract as much benefit as possible from the buyers. This paper tries to examine the pricing of household water use in Shillong urban area, India and the impact of various factors including income, house rent, seasonal scarcity of water, capacity of municipal supply, household size on the price-quantity determination. The analysis is made in terms of a simultaneous equation framework and the model is applied to a data collected by stratified random sampling technique across the municipal wards and non-municipal segments of greater Shillong urban Agglomeration. The result of three stage least squares reveals significant positive impacts of income, scarcity of water on the demand price while significantly negative impacts of quantity purchased, extent of municipal supply, house rent paid on the demand price. But the household size does not have any significant impact on the demand price though large household is expected to require more water. The supply of water on the other hand is not significantly affected by price, extent of municipal supply and deficiency though the coefficients are in the expected line.

Genetic architecture, inter-relationship and selection criteria for yield improvement in rice (Oryza sativa L.).

PubMed

Yadav, S K; Pandey, P; Kumar, B; Suresh, B G

2011-05-01

This study has been conducted to determine the extent of genetic association between yield of Rice (Oryza sativa L.) and its components. The present experiment was carried out with 40 Rice (Oryza sativa L.) genotypes which were evaluated in a randomized block design with 3 replications during wet season of 2007 and 2008. Results showed that sufficient amount of variability was found in the entire gene pool for all traits studied. Higher magnitude of genotypic and phenotypic coefficients of variation was recorded for seed yield, harvest index, biological yield, number of spikelets per panicle, flag leaf length, plant height and number of tillers indicates that these characters are least influence by environment. High heritability coupled with high genetic advance as percent of mean was registered for seed yield, harvest index, number of spikelets per panicle, biological yield and flag leaf length, suggesting preponderance of additive gene action in the expression of these characters. Grain yield was significantly and positively associated with harvest index, number of tillers per hill, number of panicle per plant, panicle length, number of spikelet's per panicle and test weight at both genotypic and phenotypic levels. Path coefficient analysis revealed that harvest index, biological yield, number of tillers per hill, panicle length, number of spikelets per panicle, plant height and test weight had direct positive effect on seed yield, indicating these are the main contributors to yield. From this study it may be concluded that harvest index, number of tillers per hill, panicle length and number of spikelet per panicle and test weight are the most important characters that contributed directly to yield. Thus, these characters may serve selection criteria for improving genetic potential of rice.

The California-Kepler Survey. V. Peas in a Pod: Planets in a Kepler Multi-planet System Are Similar in Size and Regularly Spaced

NASA Astrophysics Data System (ADS)

Weiss, Lauren M.; Marcy, Geoffrey W.; Petigura, Erik A.; Fulton, Benjamin J.; Howard, Andrew W.; Winn, Joshua N.; Isaacson, Howard T.; Morton, Timothy D.; Hirsch, Lea A.; Sinukoff, Evan J.; Cumming, Andrew; Hebb, Leslie; Cargile, Phillip A.

2018-01-01

We have established precise planet radii, semimajor axes, incident stellar fluxes, and stellar masses for 909 planets in 355 multi-planet systems discovered by Kepler. In this sample, we find that planets within a single multi-planet system have correlated sizes: each planet is more likely to be the size of its neighbor than a size drawn at random from the distribution of observed planet sizes. In systems with three or more planets, the planets tend to have a regular spacing: the orbital period ratios of adjacent pairs of planets are correlated. Furthermore, the orbital period ratios are smaller in systems with smaller planets, suggesting that the patterns in planet sizes and spacing are linked through formation and/or subsequent orbital dynamics. Yet, we find that essentially no planets have orbital period ratios smaller than 1.2, regardless of planet size. Using empirical mass–radius relationships, we estimate the mutual Hill separations of planet pairs. We find that 93% of the planet pairs are at least 10 mutual Hill radii apart, and that a spacing of ∼20 mutual Hill radii is most common. We also find that when comparing planet sizes, the outer planet is larger in 65% ± 0.4% of cases, and the typical ratio of the outer to inner planet size is positively correlated with the temperature difference between the planets. This could be the result of photo-evaporation. Based on observations obtained at the W. M. Keck Observatory, which is operated jointly by the University of California and the California Institute of Technology. Keck time has been granted by the University of California, and California Institute of Technology, and the University of Hawaii.

Is ginger effective for the treatment of irritable bowel syndrome? A double blind randomized controlled pilot trial.

PubMed

van Tilburg, Miranda A L; Palsson, Olafur S; Ringel, Yehuda; Whitehead, William E

2014-02-01

Ginger is one of the most commonly used herbal medicines for irritable bowel syndrome (IBS) but no data exists about its effectiveness. Double blind randomized controlled trial. University of North Carolina, Chapel Hill, North Carolina, USA. Forty-five IBS patients were randomly assigned to three groups: placebo, 1g of ginger, and 2g of ginger daily for 28 days. The IBS severity scale (IBS-SS) was administered, as well as adequate relief of symptoms scale. A responder was defined as having at least 25% reduction in IBS-SS post-treatment. There were 57.1% responders to placebo, 46.7% to 1g and 33.3% to 2g of ginger. Adequate relief was reported by 53.3% on placebo and 53.3% in both ginger groups combined. Side effects were mild and reported by 35.7% in the placebo and 16.7% in the ginger groups. This double blind randomized controlled pilot study suggests ginger is well tolerated but did not perform better than placebo. Larger trials are needed before any definitive conclusions can be drawn. Copyright © 2014 Elsevier Ltd. All rights reserved.

Internal tide generation by abyssal hills using analytical theory

NASA Astrophysics Data System (ADS)

Melet, Angélique; Nikurashin, Maxim; Muller, Caroline; Falahat, S.; Nycander, Jonas; Timko, Patrick G.; Arbic, Brian K.; Goff, John A.

2013-11-01

Internal tide driven mixing plays a key role in sustaining the deep ocean stratification and meridional overturning circulation. Internal tides can be generated by topographic horizontal scales ranging from hundreds of meters to tens of kilometers. State of the art topographic products barely resolve scales smaller than ˜10 km in the deep ocean. On these scales abyssal hills dominate ocean floor roughness. The impact of abyssal hill roughness on internal-tide generation is evaluated in this study. The conversion of M2 barotropic to baroclinic tidal energy is calculated based on linear wave theory both in real and spectral space using the Shuttle Radar Topography Mission SRTM30_PLUS bathymetric product at 1/120° resolution with and without the addition of synthetic abyssal hill roughness. Internal tide generation by abyssal hills integrates to 0.1 TW globally or 0.03 TW when the energy flux is empirically corrected for supercritical slope (i.e., ˜10% of the energy flux due to larger topographic scales resolved in standard products in both cases). The abyssal hill driven energy conversion is dominated by mid-ocean ridges, where abyssal hill roughness is large. Focusing on two regions located over the Mid-Atlantic Ridge and the East Pacific Rise, it is shown that regionally linear theory predicts an increase of the energy flux due to abyssal hills of up to 100% or 60% when an empirical correction for supercritical slopes is attempted. Therefore, abyssal hills, unresolved in state of the art topographic products, can have a strong impact on internal tide generation, especially over mid-ocean ridges.

First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study.

PubMed

Shi, Y K; Wang, L; Han, B H; Li, W; Yu, P; Liu, Y P; Ding, C M; Song, X; Ma, Z Y; Ren, X L; Feng, J F; Zhang, H L; Chen, G Y; Han, X H; Wu, N; Yao, C; Song, Y; Zhang, S C; Song, W; Liu, X Q; Zhao, S J; Lin, Y C; Ye, X Q; Li, K; Shu, Y Q; Ding, L M; Tan, F L; Sun, Y

2017-10-01

Icotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. Eligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety. Between January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43-0.87; P = 0.006). No significant difference for OS was observed between treatments in the overall population or in EGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%; P < 0.001) and treatment-related AEs (54.1% versus 90.5%; P < 0.001) were significantly fewer in the icotinib group than in the chemotherapy group. First-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients with EGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

AmeriFlux US-Blk Black Hills

DOE Data Explorer

Meyers, Tilden [NOAA/ARL

2016-01-01

This is the AmeriFlux version of the carbon flux data for the site US-Blk Black Hills. Site Description - The Black Hills tower was established by the Institute for Atmospheric Studies of the South Dakota School of Mines and Technology.

APOC3, coronary disease, and complexities of Mendelian randomization.

PubMed

Cohen, Jonathan C; Stender, Stefan; Hobbs, Helen H

2014-09-02

Two new studies report that triglyceride (TG)-lowering mutations in APOC3 reduce coronary heart disease (CHD) (Crosby et al., 2014; Jørgensen et al., 2014). Here, we explore limitations of using Mendelian randomization to evaluate CHD risk, including potential confounding by the widespread use of statin therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

Molecular selection in a unified evolutionary sequence

NASA Technical Reports Server (NTRS)

Fox, S. W.

1986-01-01

With guidance from experiments and observations that indicate internally limited phenomena, an outline of unified evolutionary sequence is inferred. Such unification is not visible for a context of random matrix and random mutation. The sequence proceeds from Big Bang through prebiotic matter, protocells, through the evolving cell via molecular and natural selection, to mind, behavior, and society.

Directional topographic site response at Tarzana observed in aftershocks of the 1994 Northridge, California, earthquake: Implications for mainshock motions

USGS Publications Warehouse

Spudich, P.; Hellweg, M.; Lee, W.H.K.

1996-01-01

The Northridge earthquake caused 1.78 g acceleration in the east-west direction at a site in Tarzana, California, located about 6 km south of the mainshock epicenter. The accelerograph was located atop a hill about 15-m high, 500-m long, and 130-m wide, striking about N78??E. During the aftershock sequence, a temporary array of 21 three-component geophones was deployed in six radial lines centered on the accelerograph, with an average sensor spacing of 35 m. Station COO was located about 2 m from the accelerograph. We inverted aftershock spectra to obtain average relative site response at each station as a function of direction of ground motion. We identified a 3.2-Hz resonance that is a transverse oscillation of the hill (a directional topographic effect). The top/base amplification ratio at 3.2 Hz is about 4.5 for horizontal ground motions oriented approximately perpendicular to the long axis of the hill and about 2 for motions parallel to the hill. This resonance is seen most strongly within 50 m of COO. Other resonant frequencies were also observed. A strong lateral variation in attenuation, probably associated with a fault, caused substantially lower motion at frequencies above 6 Hz at the east end of the hill. There may be some additional scattered waves associated with the fault zone and seen at both the base and top of the hill, causing particle motions (not spectral ratios) at the top of the hill to be rotated about 20?? away from the direction transverse to the hill. The resonant frequency, but not the amplitude, of our observed topographic resonance agrees well with theory, even for such a low hill. Comparisons of our observations with theoretical results indicate that the 3D shape of the hill and its internal structure are important factors affecting its response. The strong transverse resonance of the hill does not account for the large east-west mainshock motions. Assuming linear soil response, mainshock east-west motions at the Tarzana accelerograph were amplified by a factor of about 2 or less compared with sites at the base of the hill. Probable variations in surficial shear-wave velocity do not account for the observed differences among mainshock acceleration observed at Tarzana and at two different sites within 2 km of Tarzana.

Mass, charge, and energy separation by selective acceleration with a traveling potential hill

NASA Astrophysics Data System (ADS)

Tung, L. Schwager; Barr, W. L.; Lowder, R. S.; Post, R. F.

1996-10-01

A traveling electric potential hill has been used to generate an ion beam with an energy distribution that is mass dependent from a monoenergetic ion beam of mixed masses. This effect can be utilized as a novel method for mass separation applied to identification or enrichment of ions (e.g., of elements, isotopes, or molecules). This theory for mass-selective acceleration is presented here and is shown to be confirmed by experiment and by a time-dependent particle-in-cell computer simulation. Results show that monoenergetic ions with the particular mass of choice are accelerated by controlling the hill potential and the hill velocity. The hill velocity is typically 20%-30% faster than the ions to be accelerated. The ability of the hill to pickup a particular mass uses the fact that small kinetic energy differences in the lab frame appear much larger in the moving hill frame. Ions will gain energy from the approaching hill if their relative energy in the moving hill frame is less than the peak potential of the hill. The final energy of these accelerated ions can be several times the source energy, which facilitates energy filtering for mass purification or identification. If the hill potential is chosen to accelerate multiple masses, the heaviest mass will have the greatest final energy. Hence, choosing the appropriate hill potential and collector retarding voltage will isolate ions with the lightest, heaviest, or intermediate mass. In the experimental device, called a Solitron, purified 20Ne and 22Ne are extracted from a ribbon beam of neon that is originally composed of 20Ne:22Ne in the natural ratio of 91:9. The isotopic content of the processed beam is determined by measuring the energy distribution of the detected current. These results agree with the theory. In addition to mass selectivity, our theory can also be applied to the filtration of an ion beam according to charge state or energy. Because of this variety of properties, the Solitron is envisioned to have broad applications. The primary application is for the enrichment of stable isotopes for medical and industrial tracers. Other applications include mass analysis of unknown gases (atomic and molecular) and metals, extracting single charge states from a multiply charged beam, accelerating the high energy tail in a beam or plasma with a velocity distribution, and beam bunching.

Antigravity hills are visual illusions.

PubMed

Bressan, Paola; Garlaschelli, Luigi; Barracano, Monica

2003-09-01

Antigravity hills, also known as spook hills or magnetic hills, are natural places where cars put into neutral are seen to move uphill on a slightly sloping road, apparently defying the law of gravity. We show that these effects, popularly attributed to gravitational anomalies, are in fact visual illusions. We re-created all the known types of antigravity spots in our laboratory using tabletop models; the number of visible stretches of road, their slant, and the height of the visible horizon were systematically varied in four experiments. We conclude that antigravity-hill effects follow from a misperception of the eye level relative to gravity, caused by the presence of either contextual inclines or a false horizon line.

The mutation-drift balance in spatially structured populations.

PubMed

Schneider, David M; Martins, Ayana B; de Aguiar, Marcus A M

2016-08-07

In finite populations the action of neutral mutations is balanced by genetic drift, leading to a stationary distribution of alleles that displays a transition between two different behaviors. For small mutation rates most individuals will carry the same allele at equilibrium, whereas for high mutation rates of the alleles will be randomly distributed with frequencies close to one half for a biallelic gene. For well-mixed haploid populations the mutation threshold is μc=1/2N, where N is the population size. In this paper we study how spatial structure affects this mutation threshold. Specifically, we study the stationary allele distribution for populations placed on regular networks where connected nodes represent potential mating partners. We show that the mutation threshold is sensitive to spatial structure only if the number of potential mates is very small. In this limit, the mutation threshold decreases substantially, increasing the diversity of the population at considerably low mutation rates. Defining kc as the degree of the network for which the mutation threshold drops to half of its value in well-mixed populations we show that kc grows slowly as a function of the population size, following a power law. Our calculations and simulations are based on the Moran model and on a mapping between the Moran model with mutations and the voter model with opinion makers. Copyright © 2016 Elsevier Ltd. All rights reserved.

Investigation of Hill's optical turbulence model by means of direct numerical simulation.

PubMed

Muschinski, Andreas; de Bruyn Kops, Stephen M

2015-12-01

For almost four decades, Hill's "Model 4" [J. Fluid Mech. 88, 541 (1978) has played a central role in research and technology of optical turbulence. Based on Batchelor's generalized Obukhov-Corrsin theory of scalar turbulence, Hill's model predicts the dimensionless function h(κl(0), Pr) that appears in Tatarskii's well-known equation for the 3D refractive-index spectrum in the case of homogeneous and isotropic turbulence, Φn(κ)=0.033C2(n)κ(-11/3) h(κl(0), Pr). Here we investigate Hill's model by comparing numerical solutions of Hill's differential equation with scalar spectra estimated from direct numerical simulation (DNS) output data. Our DNS solves the Navier-Stokes equation for the 3D velocity field and the transport equation for the scalar field on a numerical grid containing 4096(3) grid points. Two independent DNS runs are analyzed: one with the Prandtl number Pr=0.7 and a second run with Pr=1.0 . We find very good agreement between h(κl(0), Pr) estimated from the DNS output data and h(κl(0), Pr) predicted by the Hill model. We find that the height of the Hill bump is 1.79 Pr(1/3), implying that there is no bump if Pr<0.17 . Both the DNS and the Hill model predict that the viscous-diffusive "tail" of h(κl(0), Pr) is exponential, not Gaussian.

Is Mutation Random or Targeted?: No Evidence for Hypermutability in Snail Toxin Genes.

PubMed

Roy, Scott W

2016-10-01

Ever since Luria and Delbruck, the notion that mutation is random with respect to fitness has been foundational to modern biology. However, various studies have claimed striking exceptions to this rule. One influential case involves toxin-encoding genes in snails of the genus Conus, termed conotoxins, a large gene family that undergoes rapid diversification of their protein-coding sequences by positive selection. Previous reconstructions of the sequence evolution of conotoxin genes claimed striking patterns: (1) elevated synonymous change, interpreted as being due to targeted "hypermutation" in this region; (2) elevated transversion-to-transition ratios, interpreted as reflective of the particular mechanism of hypermutation; and (3) much lower rates of synonymous change in the codons encoding several highly conserved cysteine residues, interpreted as strong position-specific codon bias. This work has spawned a variety of studies on the potential mechanisms of hypermutation and on causes for cysteine codon bias, and has inspired hypermutation hypotheses for various other fast-evolving genes. Here, I show that all three findings are likely to be artifacts of statistical reconstruction. First, by simulating nonsynonymous change I show that high rates of dN can lead to overestimation of dS. Second, I show that there is no evidence for any of these three patterns in comparisons of closely related conotoxin sequences, suggesting that the reported findings are due to breakdown of statistical methods at high levels of sequence divergence. The current findings suggest that mutation and codon bias in conotoxin genes may not be atypical, and that random mutation and selection can explain the evolution of even these exceptional loci. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

OVERVIEW OF GOLD HILL MILL, ROAD, AND WARM SPRINGS CAMP ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

OVERVIEW OF GOLD HILL MILL, ROAD, AND WARM SPRINGS CAMP BUILDINGS, LOOKING SOUTH SOUTHEAST. THE FUNCTION OF THE FLAT AREA AT CENTER RIGHT IS UNKNOWN. - Gold Hill Mill, Warm Spring Canyon Road, Death Valley Junction, Inyo County, CA

GHG PSD Permit: Cheyenne Light, Fuel & Power / Black Hills Power, Inc. – Cheyenne Prairie Generating Station

EPA Pesticide Factsheets

This page contains the final PSD permit for the Cheyenne Light, Fuel & Power / Black Hills Power, Inc. Cheyenne Prairie Generating Station, located in Laramie, Wyoming, and operated by Black Hills Service Company.

Synthesis of hemoglobin Gun Hill: increased synthesis of the heme-free βGH globin chain and subunit exchange with a free α-chain pool

PubMed Central

Rieder, Ronald F.

1971-01-01

Hemoglobin Gun Hill is an unstable mutant hemoglobin associated with mild compensated hemolysis. This abnormal protein has a deletion of five amino acids in the β-chains. The deletion includes the heme-binding proximal histidine at position 92. The β-chains of hemoglobin Gun Hill lack heme groups. Approximately 32% of the circulating hemoglobin in heterozygous subjects consists of the mutant hemoglobin. When reticulocytes were incubated with radioactive amino acid the specific activity of hemoglobin Gun Hill was three to six times that of hemoglobin A. Total incorporation of radioactivity into hemoglobin Gun Hill was two to three times that into hemoglobin A. There were 20-50% more total counts in β-Gun Hill (βGH) than in βA. These results indicate that in reticulocytes there was greater synthesis of the abnormal β-chains than βA-chains. The ratio of the specific activities of the α-chains of hemoglobin Gun Hill to the α-chains of hemoglobin A was 20: 1. There was evidence of a free pool of α-chains in the reticulocytes containing hemoglobin Gun Hill. After 10 min of incubation approximately 40% of the total α-chain radioactivity was in the free pool. When protein synthesis was blocked by incubation of reticulocytes with puromycin, the specific activity of the α-chains of hemoglobin Gun Hill continued to increase due to direct exchange of α-subunits between the free pool and preformed hemoglobin Gun Hill. Studies of the assembly of βA and βGH revealed that the rates of translation of the two polypeptide chains were equal and uniform. No evidence was obtained for the existence of “slow points” in the process of globin chain assembly. The studies also suggest that lack of strong heme-globin binding does not hinder the synthesis of globin chains. PMID:5540175

A coevolutionary arms race causes ecological speciation in crossbills.

PubMed

Smith, Julie W; Benkman, Craig W

2007-04-01

We examined three ecological factors potentially causing premating reproductive isolation to determine whether divergent selection as a result of coevolution between South Hills crossbills (Loxia curvirostra complex) and Rocky Mountain lodgepole pine (Pinus contorta latifolia) promotes ecological speciation. One factor was habitat isolation arising because of enhanced seed defenses of lodgepole pine in the South Hills. This caused the crossbill call types (morphologically and vocally differentiated forms) adapted to alternative resources to be rare. Another occurred when crossbills of other call types moved into the South Hills late in the breeding season and feeding conditions were deteriorating so that relatively few non-South Hills crossbills bred ("immigrant infecundity"). Finally, among those crossbills that bred, pairing was strongly assortative by call type (behavioral isolation). Total reproductive isolation between South Hills crossbills and the two other crossbills most common in the South Hills (call types 2 and 5) summed to .9975 and .9998, respectively, on a scale of 0 (no reproductive isolation) to 1 (complete reproductive isolation). These extremely high levels of reproductive isolation indicate that the divergent selection resulting from the coevolutionary arms race between crossbills and lodgepole pine is causing the South Hills crossbill to speciate.

Experimental investigation of flow over two-dimensional multiple hill models.

PubMed

Li, Qing'an; Maeda, Takao; Kamada, Yasunari; Yamada, Keisuke

2017-12-31

The aim of this study is to investigate the flow field characteristics in ABL (Atmospheric Boundary Layer) flow over multiple hills and valleys in two-dimensional models under neutral conditions. Active turbulence grids and boundary layer generation frame were used to simulate the natural winds in wind tunnel experiments. As a result, the mean wind velocity, the velocity vector diagram and turbulence intensity around the hills were investigated by using a PIV (Particle Image Velocimetry) system. From the measurement results, it was known that the average velocity was increased along the upstream slope of upside hill, and then separated at the top of the hills, the acceleration region of U/U ref >1 was generated at the downstream of the hill. Meanwhile, a large clockwise circulation flow was generated between the two hill models. Moreover, the turbulence intensity showed small value in the circulation flow regions. Compared to 1H model, the turbulence intensity in the mainstream direction showed larger value than that in the vertical direction. This paper provided a better understanding of the wind energy distribution on the terrain for proper selection of suitable sites for installing wind farms in the ABL. Copyright © 2017 Elsevier B.V. All rights reserved.

Feature genes predicting the FLT3/ITD mutation in acute myeloid leukemia

PubMed Central

LI, CHENGLONG; ZHU, BIAO; CHEN, JIAO; HUANG, XIAOBING

2016-01-01

In the present study, gene expression profiles of acute myeloid leukemia (AML) samples were analyzed to identify feature genes with the capacity to predict the mutation status of FLT3/ITD. Two machine learning models, namely the support vector machine (SVM) and random forest (RF) methods, were used for classification. Four datasets were downloaded from the European Bioinformatics Institute, two of which (containing 371 samples, including 281 FLT3/ITD mutation-negative and 90 mutation-positive samples) were randomly defined as the training group, while the other two datasets (containing 488 samples, including 350 FLT3/ITD mutation-negative and 138 mutation-positive samples) were defined as the test group. Differentially expressed genes (DEGs) were identified by significance analysis of the micro-array data by using the training samples. The classification efficiency of the SCM and RF methods was evaluated using the following parameters: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and the area under the receiver operating characteristic curve. Functional enrichment analysis was performed for the feature genes with DAVID. A total of 585 DEGs were identified in the training group, of which 580 were upregulated and five were downregulated. The classification accuracy rates of the two methods for the training group, the test group and the combined group using the 585 feature genes were >90%. For the SVM and RF methods, the rates of correct determination, specificity and PPV were >90%, while the sensitivity and NPV were >80%. The SVM method produced a slightly better classification effect than the RF method. A total of 13 biological pathways were overrepresented by the feature genes, mainly involving energy metabolism, chromatin organization and translation. The feature genes identified in the present study may be used to predict the mutation status of FLT3/ITD in patients with AML. PMID:27177049

A screen to identify Drosophila genes required for integrin-mediated adhesion.

PubMed Central

Walsh, E P; Brown, N H

1998-01-01

Drosophila integrins have essential adhesive roles during development, including adhesion between the two wing surfaces. Most position-specific integrin mutations cause lethality, and clones of homozygous mutant cells in the wing do not adhere to the apposing surface, causing blisters. We have used FLP-FRT induced mitotic recombination to generate clones of randomly induced mutations in the F1 generation and screened for mutations that cause wing blisters. This phenotype is highly selective, since only 14 lethal complementation groups were identified in screens of the five major chromosome arms. Of the loci identified, 3 are PS integrin genes, 2 are blistered and bloated, and the remaining 9 appear to be newly characterized loci. All 11 nonintegrin loci are required on both sides of the wing, in contrast to integrin alpha subunit genes. Mutations in 8 loci only disrupt adhesion in the wing, similar to integrin mutations, while mutations in the 3 other loci cause additional wing defects. Mutations in 4 loci, like the strongest integrin mutations, cause a "tail-up" embryonic lethal phenotype, and mutant alleles of 1 of these loci strongly enhance an integrin mutation. Thus several of these loci are good candidates for genes encoding cytoplasmic proteins required for integrin function. PMID:9755209

VIEW TO SOUTHEAST TOWARD QUARTERMASTER BUILDINGS GROUP AND RESERVOIR HILL, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

VIEW TO SOUTHEAST TOWARD QUARTERMASTER BUILDINGS GROUP AND RESERVOIR HILL, FROM AMMUNITION (IGLOO) HILL. (Part 2 of a 3 view panorama; see also CA-2398-J-1 and CA-2398-16.) - Hamilton Field, East of Nave Drive, Novato, Marin County, CA

Black Hills Region, SD, USA

NASA Image and Video Library

1973-06-22

SL2-81-157 (22 June 1973) --- This view of the Black Hills Region, SD (44.0N, 104.0W) shows the scenic Black Hills where Mt. Rushmore and other monuments are located. Cities and towns in this view include: Rapid City, Deadwood, and Belle Fourche with the nearby Belle Fourche Reservoir. Notable in this scene are the recovering burn scars (seen as irregular shaped light toned patches) from a 1959 forest fire in the Black Hills National Forest near the edge of the photo. Photo credit: NASA

Directional Cluster Analysis on a Sphere: Retrieval of Archean Magnetic Directions from Data with High Dispersion

NASA Astrophysics Data System (ADS)

Bono, R. K.; Dare, M. S.; Tarduno, J. A.; Cottrell, R. D.

2016-12-01

Magnetic directions from coarse clastic rocks are typically highly scattered, to the point that the null hypothesis that they are drawn from a random distribution, using the iconic test of Watson (1956), cannot be rejected at a high confidence level (e.g. 95%). Here, we use an alternative approach of searching for directional clusters on a sphere. When applied to a new data set of directions from quartzites from the Jack Hills of Western Australia, we find evidence for distinct and meaningful magnetic directions at low (200 to 300 degrees C) and intermediate ( 350 to 450 degrees C) unblocking temperatures, whereas the test of Watson (1956) fails to draw a distinction from random distributions for the ensemble of directions at these unblocking temperature ranges. The robustness of the directional groups identified by the cluster analysis is confirmed by non-parametric resampling tests. The lowest unblocking temperature directional mode appears related to the present day field, perhaps contaminated by viscous magnetizations. The intermediate temperature magnetization matches an overprint recorded by the secondary mineral fuchsite (Cottrell et al., 2016) acquired at ca. 2.65 Ga. These data thus indicate that the Jack Hills carry an overprint at intermediate unblocking temperatures of Archean age. We find no evidence for a 1 Ga remagnetization. In general, the application of cluster analysis on a sphere, with directions confirmed by nonparametric tests, represents a new approach that should be applied when evaluating data with high dispersion, such as those that typically come from weak coarse-grained clastic sedimentary rocks, and/or rocks that have seen several tectonic events that could have imparted multiple magnetic overprints.

Recursions for the exchangeable partition function of the seedbank coalescent.

PubMed

Kurt, Noemi; Rafler, Mathias

2017-04-01

For the seedbank coalescent with mutation under the infinite alleles assumption, which describes the gene genealogy of a population with a strong seedbank effect subject to mutations, we study the distribution of the final partition with mutation. This generalizes the coalescent with freeze by Dong et al. (2007) to coalescents where ancestral lineages are blocked from coalescing. We derive an implicit recursion which we show to have a unique solution and give an interpretation in terms of absorption problems of a random walk. Moreover, we derive recursions for the distribution of the number of blocks in the final partition. Copyright © 2017 Elsevier Inc. All rights reserved.

Forward-genetics analysis of sleep in randomly mutagenized mice.

PubMed

Funato, Hiromasa; Miyoshi, Chika; Fujiyama, Tomoyuki; Kanda, Takeshi; Sato, Makito; Wang, Zhiqiang; Ma, Jing; Nakane, Shin; Tomita, Jun; Ikkyu, Aya; Kakizaki, Miyo; Hotta-Hirashima, Noriko; Kanno, Satomi; Komiya, Haruna; Asano, Fuyuki; Honda, Takato; Kim, Staci J; Harano, Kanako; Muramoto, Hiroki; Yonezawa, Toshiya; Mizuno, Seiya; Miyazaki, Shinichi; Connor, Linzi; Kumar, Vivek; Miura, Ikuo; Suzuki, Tomohiro; Watanabe, Atsushi; Abe, Manabu; Sugiyama, Fumihiro; Takahashi, Satoru; Sakimura, Kenji; Hayashi, Yu; Liu, Qinghua; Kume, Kazuhiko; Wakana, Shigeharu; Takahashi, Joseph S; Yanagisawa, Masashi

2016-11-17

Sleep is conserved from invertebrates to vertebrates, and is tightly regulated in a homeostatic manner. The molecular and cellular mechanisms that determine the amount of rapid eye movement sleep (REMS) and non-REMS (NREMS) remain unknown. Here we identify two dominant mutations that affect sleep and wakefulness by using an electroencephalogram/electromyogram-based screen of randomly mutagenized mice. A splicing mutation in the Sik3 protein kinase gene causes a profound decrease in total wake time, owing to an increase in inherent sleep need. Sleep deprivation affects phosphorylation of regulatory sites on the kinase, suggesting a role for SIK3 in the homeostatic regulation of sleep amount. Sik3 orthologues also regulate sleep in fruitflies and roundworms. A missense, gain-of-function mutation in the sodium leak channel NALCN reduces the total amount and episode duration of REMS, apparently by increasing the excitability of REMS-inhibiting neurons. Our results substantiate the use of a forward-genetics approach for studying sleep behaviours in mice, and demonstrate the role of SIK3 and NALCN in regulating the amount of NREMS and REMS, respectively.

A new method for the construction of a mutant library with a predictable occurrence rate using Poisson distribution.

PubMed

Seong, Ki Moon; Park, Hweon; Kim, Seong Jung; Ha, Hyo Nam; Lee, Jae Yung; Kim, Joon

2007-06-01

A yeast transcriptional activator, Gcn4p, induces the expression of genes that are involved in amino acid and purine biosynthetic pathways under amino acid starvation. Gcn4p has an acidic activation domain in the central region and a bZIP domain in the C-terminus that is divided into the DNA-binding motif and dimerization leucine zipper motif. In order to identify amino acids in the DNA-binding motif of Gcn4p which are involved in transcriptional activation, we constructed mutant libraries in the DNA-binding motif through an innovative application of random mutagenesis. Mutant library made by oligonucleotides which were mutated randomly using the Poisson distribution showed that the actual mutation frequency was in good agreement with expected values. This method could save the time and effort to create a mutant library with a predictable mutation frequency. Based on the studies using the mutant libraries constructed by the new method, the specific residues of the DNA-binding domain in Gcn4p appear to be involved in the transcriptional activities on a conserved binding site.

Biogeography of the Shimba Hills ecosystem herpetofauna in Kenya

PubMed Central

Malonza, Patrick K.; Mulwa, David M.; Nyamache, Joash O.; Jones, Georgina

2018-01-01

The Shimba Hills ecosystem along the south coast of Kenya is a key East African biodiversity hotspot. Historically, it is biogeographically assignable to the East African coastal biome. We examined the current Shimba Hills herpetofauna and their zoogeographical affinities to the coastal forests and nearby Eastern Arc Mountains biodiversity hotspots. The key studied sites included the Shimba Hills National Reserve, forest reserves, Kaya forests, and adjacent private land. Data on herpetofaunal richness were obtained from recent field surveys, literature, and specimens held at the National Museums of Kenya, Herpetology Section Collection, Nairobi. The Makadara, Mwele, and Longo-Mwagandi forests within the Shimba Hills National Reserve hosted the highest number of unique and rare species. Generally, the forest reserves and Kaya forests were important refuges for forest-associated species. On private land, Mukurumudzi Dam riparian areas were the best amphibian habitat and were host to three IUCN (Red List) Endangered-EN amphibian species, namely, Boulengerula changamwensis, Hyperolius rubrovermiculatus, and Afrixalus sylvaticus, as well as one snake species Elapsoidea nigra. Using herpetofauna as zoogeographic indicators, the Shimba Hills were determined to be at a crossroads between the coastal forests (13 endemic species) and the Eastern Arc Mountains (seven endemic species). Most of the Eastern Arc Mountains endemic species were from recent records, and thus more are likely to be found in the future. This ‘hybrid’ species richness pattern is attributable to the hilly topography of the Shimba Hills and their proximity to the Indian Ocean. This has contributed to the Shimba Hills being the richest herpetofauna area in Kenya, with a total of 89 and 38 reptile and amphibian species, respectively. Because of its unique zoogeography, the Shimba Hills ecosystem is undoubtedly a key biodiversity area for conservation investment. PMID:29515091

Biogeography of the Shimba Hills ecosystem herpetofauna in Kenya.

PubMed

Malonza, Patrick K; Mulwa, David M; Nyamache, Joash O; Jones, Georgina

2018-03-18

The Shimba Hills ecosystem along the south coast of Kenya is a key East African biodiversity hotspot. Historically, it is biogeographically assignable to the East African coastal biome. We examined the current Shimba Hills herpetofauna and their zoogeographical affinities to the coastal forests and nearby Eastern Arc Mountains biodiversity hotspots. The key studied sites included the Shimba Hills National Reserve, forest reserves, Kaya forests, and adjacent private land. Data on herpetofaunal richness were obtained from recent field surveys, literature, and specimens held at the National Museums of Kenya, Herpetology Section Collection, Nairobi. The Makadara, Mwele, and Longo-Mwagandi forests within the Shimba Hills National Reserve hosted the highest number of unique and rare species. Generally, the forest reserves and Kaya forests were important refuges for forest-associated species. On private land, Mukurumudzi Dam riparian areas were the best amphibian habitat and were host to three IUCN (Red List) Endangered-EN amphibian species, namely, Boulengerula changamwensis, Hyperolius rubrovermiculatus, and Afrixalus sylvaticus, as well as one snake species Elapsoidea nigra. Using herpetofauna as zoogeographic indicators, the Shimba Hills were determined to be at a crossroads between the coastal forests (13 endemic species) and the Eastern Arc Mountains (seven endemic species). Most of the Eastern Arc Mountains endemic species were from recent records, and thus more are likely to be found in the future. This 'hybrid' species richness pattern is attributable to the hilly topography of the Shimba Hills and their proximity to the Indian Ocean. This has contributed to the Shimba Hills being the richest herpetofauna area in Kenya, with a total of 89 and 36 reptile and amphibian species, respectively. Because of its unique zoogeography, the Shimba Hills ecosystem is undoubtedly a key biodiversity area for conservation investment.

Parameters affecting frequency of CRISPR/Cas9 mediated targeted mutagenesis in rice.

PubMed

Mikami, Masafumi; Toki, Seiichi; Endo, Masaki

2015-10-01

Frequency of CRISPR/Cas9-mediated targeted mutagenesis varies depending on Cas9 expression level and culture period of rice callus. Recent reports have demonstrated that the CRISPR/Cas9 system can function as a sequence-specific nuclease in various plant species. Induction of mutation in proliferating tissue during embryogenesis or in germline cells is a practical means of generating heritable mutations. In the case of plant species in which cultured cells are used for transformation, non-chimeric plants can be obtained when regeneration occurs from mutated cells. Since plantlets are regenerated from both mutated and non-mutated cells in a random manner, any increment in the proportion of mutated cells in Cas9- and guide RNA (gRNA)-expressing cells will help increase the number of plants containing heritable mutations. In this study, we examined factors affecting mutation frequency in rice calli. Following sequential transformation of rice calli with Cas9- and gRNA- expression constructs, the mutation frequency in independent Cas9 transgenic lines was analyzed. A positive correlation between Cas9 expression level and mutation frequency was found. This positive relationship was observed regardless of whether the transgene or an endogenous gene was used as the target for CRISPR/Cas9-mediated mutagenesis. Furthermore, we found that extending the culture period increased the proportion of mutated cells as well as the variety of mutations obtained. Because mutated and non-mutated cells might proliferate equally, these results suggest that a prolonged tissue culture period increases the chance of inducing de novo mutations in non-mutated cells. This fundamental knowledge will help improve systems for obtaining non-chimeric regenerated plants in many plant species.

77 FR 67640 - Combined Notice of Filings #1

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-13

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Combined Notice of Filings 1 Take notice.... Applicants: Canadian Hills Wind, LLC, Canadian Hills Holdings Company, LLC. Description: Application for... Expedited Consideration and Confidential Treatment of Canadian Hills Wind, LLC, et al. Filed Date: 11/2/12...

Long-Term Monitoring Network Optimization Evaluation for Operable Unit 2, Bunker Hill Mining and Metallurgical Complex Superfund Site, Idaho

EPA Pesticide Factsheets

This report presents a description and evaluation of the ground water and surface water monitoring program associated with the Bunker Hill Mining and Metallurgical Complex Superfund Site (Bunker Hill) Operable Unit (OU) 2.

Genetic drift at expanding frontiers promotes gene segregation

PubMed Central

Hallatschek, Oskar; Hersen, Pascal; Ramanathan, Sharad; Nelson, David R.

2007-01-01

Competition between random genetic drift and natural selection play a central role in evolution: Whereas nonbeneficial mutations often prevail in small populations by chance, mutations that sweep through large populations typically confer a selective advantage. Here, however, we observe chance effects during range expansions that dramatically alter the gene pool even in large microbial populations. Initially well mixed populations of two fluorescently labeled strains of Escherichia coli develop well defined, sector-like regions with fractal boundaries in expanding colonies. The formation of these regions is driven by random fluctuations that originate in a thin band of pioneers at the expanding frontier. A comparison of bacterial and yeast colonies (Saccharomyces cerevisiae) suggests that this large-scale genetic sectoring is a generic phenomenon that may provide a detectable footprint of past range expansions. PMID:18056799

A novel artificial fish swarm algorithm for solving large-scale reliability-redundancy application problem.

PubMed

He, Qiang; Hu, Xiangtao; Ren, Hong; Zhang, Hongqi

2015-11-01

A novel artificial fish swarm algorithm (NAFSA) is proposed for solving large-scale reliability-redundancy allocation problem (RAP). In NAFSA, the social behaviors of fish swarm are classified in three ways: foraging behavior, reproductive behavior, and random behavior. The foraging behavior designs two position-updating strategies. And, the selection and crossover operators are applied to define the reproductive ability of an artificial fish. For the random behavior, which is essentially a mutation strategy, the basic cloud generator is used as the mutation operator. Finally, numerical results of four benchmark problems and a large-scale RAP are reported and compared. NAFSA shows good performance in terms of computational accuracy and computational efficiency for large scale RAP. Copyright © 2015 ISA. Published by Elsevier Ltd. All rights reserved.

Selection of stable scFv antibodies by phage display.

PubMed

Brockmann, Eeva-Christine

2012-01-01

ScFv fragments are popular recombinant antibody formats but often suffer from limited stability. Phage display is a powerful tool in antibody engineering and applicable also for stability selection. ScFv variants with improved stability can be selected from large randomly mutated phage displayed libraries with a specific antigen after the unstable variants have been inactivated by heat or GdmCl. Irreversible scFv denaturation, which is a prerequisite for efficient selection, is achieved by combining denaturation with reduction of the intradomain disulfide bonds. Repeated selection cycles of increasing stringency result in enrichment of stabilized scFv fragments. Procedures for constructing a randomly mutated scFv library by error-prone PCR and phage display selection for enrichment of stable scFv antibodies from the library are described here.

Surface faulting along the Superstition Hills fault zone and nearby faults associated with the earthquakes of 24 November 1987

USGS Publications Warehouse

Sharp, R.V.

1989-01-01

The M6.2 Elmore Desert Ranch earthquake of 24 November 1987 was associated spatially and probably temporally with left-lateral surface rupture on many northeast-trending faults in and near the Superstition Hills in western Imperial Valley. Three curving discontinuous principal zones of rupture among these breaks extended northeastward from near the Superstition Hills fault zone as far as 9km; the maximum observed surface slip, 12.5cm, was on the northern of the three, the Elmore Ranch fault, at a point near the epicenter. Twelve hours after the Elmore Ranch earthquake, the M6.6 Superstition Hills earthquake occurred near the northwest end of the right-lateral Superstition Hills fault zone. We measured displacements over 339 days at as many as 296 sites along the Superstition Hills fault zone, and repeated measurements at 49 sites provided sufficient data to fit with a simple power law. The overall distributions of right-lateral displacement at 1 day and the estimated final slip are nearly symmetrical about the midpoint of the surface rupture. The average estimated final right-lateral slip for the Superstition Hills fault zone is ~54cm. The average left-lateral slip for the conjugate faults trending northeastward is ~23cm. The southernmost ruptured member of the Superstition Hills fault zone, newly named the Wienert fault, extends the known length of the zone by about 4km. -from Authors

Mutation analysis in a German family identified a new cataract-causing allele in the CRYBB2 gene

PubMed Central

Pauli, Silke; Söker, Torben; Klopp, Norman; Illig, Thomas; Engel, Wolfgang

2007-01-01

Purpose The study demonstrates the functional candidate gene analysis in a cataract family of German descent. Methods We screened a German family, clinically documented to have congenital cataracts, for mutation in the candidate genes CRYG (A to D) and CRYBB2 through polymerase chain reaction analyses and sequencing. Results Congenital cataract was first observed in a daughter of healthy parents. Her two children (a boy and a girl) also suffer from congenital cataracts and have been operated within the first weeks of birth. Morphologically, the cataract is characterized as nuclear with an additional ring-shaped cortical opacity. Molecular analysis revealed no causative mutation in any of the CRYG genes. However, sequencing of the exons of the CRYBB2 gene identified a sequence variation in exon 5 (383 A>T) with a substitution of Asp to Val at position 128. All three affected family members revealed this change but it was not observed in any of the unaffected persons of the family. The putative mutation creates a restriction site for the enzyme TaiI. This mutation was checked for in controls of randomly selected DNA samples from ophthalmologically normal individuals from the population-based KORA S4 study (n=96) and no mutation was observed. Moreover, the Asp at position 128 is within a stretch of 12 amino acids, which are highly conserved throughout the animal kingdom. For the mutant protein, the isoelectric point is raised from pH 6.50 to 6.75. Additionally, the random coil structure of the protein between the amino acids 126-139 is interrupted by a short extended strand structure. In addition, this region becomes hydrophobic (from neutral to +1) and the electrostatic potential in the region surrounding the exchanged amino acid alters from a mainly negative potential to an enlarged positive potential. Conclusions The D128V mutation segregates only in affected family members and is not seen in representative controls. It represents the first mutation outside exon 6 of the human CRYBB2 gene. PMID:17653036

Patty Smith Hill, Gifted Early Childhood Educator of the Progressive Era.

ERIC Educational Resources Information Center

Rudnitski, Rose A.

1995-01-01

This article chronicles the development of Patty Smith Hill, eminent educator of the Progressive Era. Hill was largely responsible for adding kindergarten to the elementary school curriculum, was the author of the "Happy Birthday" song, and a member of the Woman's Suffrage Movement. (DB)

Drawing entitled "Planting Plan Pine Hills, Gd. Sta. U.S. Department ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Drawing entitled "Planting Plan Pine Hills, Gd. Sta. U.S. Department of Agriculture, Forest Service, Region 5. L. Glenn Hall, landscape engineer. 11-5-35. - Pine Hills Station, Barracks, West Side of Boulder Creek Road at Engineers Road, Julian, San Diego County, CA

78 FR 34366 - Combined Notice of Filings #1

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-07

... Solar, LLC. Description: Application and Initial Baseline Tariff Filing to be effective 8/1/2013. Filed... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Combined Notice of Filings 1 Take notice.... Applicants: Beech Ridge Energy LLC, Bishop Hill Energy LLC, Bishop Hill Energy III LLC, Bishop Hill...

77 FR 6553 - Combined Notice of Filings #2

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-08

.... Applicants: American Electric Power Service Corporation, AEP Energy Partners, Inc., CSW Energy Services, Inc., Central and South West Services, Inc. Description: Notice of change in status of American Electric Power.... Applicants: Black Hills/Colorado Electric Utility Co, LP, Black Hills Colorado IPP, LLC, Black Hills Power...

78 FR 65634 - Combined Notice of Filings #1

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-01

... Updated Market Power Analysis of the Black Hills Corporation Public Utilities for the Northwest Region..., LLC submits the Triennial Market Power Update Analysis for Markets in the Northwest Region pursuant to...: Black Hills Power, Inc., Cheyenne Light Fuel & Power Company, Black Hills/Colorado Electric Utility Co...

3. BUNKER HILL LEAD SMELTER. VIEW IS FROM CIA TO ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

3. BUNKER HILL LEAD SMELTER. VIEW IS FROM CIA TO THE SOUTHWEST. BUILDINGS NOTED IN ID-29-2 APPEAR, IN ADDITION TO DRY ORE PLANT AND BONNOT COAL PULVERIZING EQUIPMENT BUILDING ON THE RIGHT. - Bunker Hill Lead Smelter, Bradley Rail Siding, Kellogg, Shoshone County, ID

On the estimation of cooperativity in ion channel kinetics: activation free energy and kinetic mechanism of Shaker K+ channel.

PubMed

Banerjee, Kinshuk; Das, Biswajit; Gangopadhyay, Gautam

2013-04-28

In this paper, we have explored generic criteria of cooperative behavior in ion channel kinetics treating it on the same footing with multistate receptor-ligand binding in a compact theoretical framework. We have shown that the characterization of cooperativity of ion channels in terms of the Hill coefficient violates the standard Hill criteria defined for allosteric cooperativity of ligand binding. To resolve the issue, an alternative measure of cooperativity is proposed here in terms of the cooperativity index that sets a unified criteria for both the systems. More importantly, for ion channel this index can be very useful to describe the cooperative kinetics as it can be readily determined from the experimentally measured ionic current combined with theoretical modelling. We have analyzed the correlation between the voltage value and slope of the voltage-activation curve at the half-activation point and consequently determined the standard free energy of activation of the ion channel using two well-established mechanisms of cooperativity, namely, Koshland-Nemethy-Filmer (KNF) and Monod-Wyman-Changeux (MWC) models. Comparison of the theoretical results for both the models with appropriate experimental data of mutational perturbation of Shaker K(+) channel supports the experimental fact that the KNF model is more suitable to describe the cooperative behavior of this class of ion channels, whereas the performance of the MWC model is unsatisfactory. We have also estimated the mechanistic performance through standard free energy of channel activation for both the models and proposed a possible functional disadvantage in the MWC scheme.

The G matrix under fluctuating correlational mutation and selection.

PubMed

Revell, Liam J

2007-08-01

Theoretical quantitative genetics provides a framework for reconstructing past selection and predicting future patterns of phenotypic differentiation. However, the usefulness of the equations of quantitative genetics for evolutionary inference relies on the evolutionary stability of the additive genetic variance-covariance matrix (G matrix). A fruitful new approach for exploring the evolutionary dynamics of G involves the use of individual-based computer simulations. Previous studies have focused on the evolution of the eigenstructure of G. An alternative approach employed in this paper uses the multivariate response-to-selection equation to evaluate the stability of G. In this approach, I measure similarity by the correlation between response-to-selection vectors due to random selection gradients. I analyze the dynamics of G under several conditions of correlational mutation and selection. As found in a previous study, the eigenstructure of G is stabilized by correlational mutation and selection. However, over broad conditions, instability of G did not result in a decreased consistency of the response to selection. I also analyze the stability of G when the correlation coefficients of correlational mutation and selection and the effective population size change through time. To my knowledge, no prior study has used computer simulations to investigate the stability of G when correlational mutation and selection fluctuate. Under these conditions, the eigenstructure of G is unstable under some simulation conditions. Different results are obtained if G matrix stability is assessed by eigenanalysis or by the response to random selection gradients. In this case, the response to selection is most consistent when certain aspects of the eigenstructure of G are least stable and vice versa.

Clinical roundtable monograph: Paroxysmal nocturnal hemoglobinuria: a case-based discussion.

PubMed

Szer, Jeff; Hill, Anita; Weitz, Ilene Ceil

2012-11-01

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder characterized by chronic intravascular hemolysis as the primary clinical manifestation and morbidities that include anemia, thrombosis, renal impairment, pulmonary hypertension, and bone marrow failure. The prevalence of the PNH clone (from <1-100% PNH granulocytes) is approximately 16 per million, and careful monitoring is required. The average age of onset of the clinical disease is the early 30s, although it can present at all ages. PNH is caused by the acquisition of a somatic mutation of the gene phosphatidylinositol glycan anchor (PIG-A) in a multipotent hematopoietic stem cell (HSC), with clonal expansion of the mutated HSC. The mutation causes a deficiency in the synthesis of glycosylphosphatidylinositol (GPI). In cells derived from normal HSCs, the complement regulatory proteins CD55 and CD59 are anchored to the hematopoietic cell membrane surface via GPI, protecting the cells from complement-mediated lysis. However, in patients with PNH, these 2 proteins, along with numerous other GPI-linked proteins, are absent from the cell surface of red cells, granulocytes, monocytes, and platelets, resulting in complement-mediated intravascular hemolysis and other complications. Lysis of red blood cells is the most obvious manifestation, but as other cell lineages are also affected, this complement-mediated attack contributes to additional complications, such as thrombosis. Eculizumab, a humanized monoclonal antibody against the C5 complement protein, is the only effective drug therapy for PNH patients. The antibody prevents cleavage of the C5 protein by C5 convertase, in turn preventing generation of C5b-9 and release of C5a, thereby protecting from hemolysis of cells lacking the CD59 surface protein and other complications associated with complement activation. Drs. Ilene C. Weitz, Anita Hill, and Jeff Szer discuss 3 recent cases of patients with PNH.

Fire history at the eastern Great Plains margin, Missouri River Loess Hills

Treesearch

Michael C. ​Stambaugh; Richard P. Guyette; Erin R. McMurry; Daniel C. Dey

2006-01-01

The purpose of this paper is to provide quantitative fire history information for a geographically unique region, the Loess Hills of northwest Missouri. We sampled 33 bur oak (Quercus macrocarpa Michx.), chinkapin oak (Q. muehlenbergii Engelm.), and black oak (Q. velutina Lam.) trees from the Brickyard Hill...

78 FR 9418 - National Register of Historic Places; Notification of Pending Nominations and Related Actions

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-08

... County Rock Hill Printing and Finishing Company, 400 W. White St., Rock Hill, 12001264 VIRGINIA Augusta... Ellen Henderson, House, 307 S. Maple Ave., Falls Church (Independent City), 12001267 Franklin..., 1739 Jefferson Davis Hwy., Stafford, 12001272 Virginia Beach Independent City Green Hill, 1721 Lovetts...

83. GENERAL VIEW FROM NORTH END OF GUN HILL PLATFORM ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

83. GENERAL VIEW FROM NORTH END OF GUN HILL PLATFORM OF 3RD AVENUE EL SHOWING THE SOUTHBOUND TRACK APPROACH INTO GUN HILL STATION. 7TH AVENUE EXPRESS EL ABOVE. - Interborough Rapid Transit Company, Third Avenue Elevated Line, Borough of the Bronx, New York County, NY

78 FR 72914 - Changes in Flood Hazard Determinations

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-04

.... Forest Hill, Hill, TX 76119. 3219 California Parkway, Forest Hill, TX 76119. Travis City of Austin (13..., Austin, TX Road, 12th 78767. Floor, Austin, TX 78704. Travis Unincorporated The Honorable Travis County..., 700 Austin, TX 78767. Lavaca Street, 5th Floor, Suite 540, Austin, TX 78701. Williamson City of...

The Camp Hill Project: Objectives and Design

ERIC Educational Resources Information Center

Mattingly, John B.

1976-01-01

Available from: EC 090 474. Outlined are the problems and objectives of Pennsylvania's Camp Hill Project--a program designed to complete psychological needs assessments for juveniles incarcerated at Camp Hill, to develop project policies and guidelines in preparation for meeting with juvenile court judges, and to hire staff. (SBH)

"This Delightfull Garden": "Rabbit Hill" and the Pastoral Tradition.

ERIC Educational Resources Information Center

Jordan, Anne Devereaux

1997-01-01

Contends that Robert Lawson's children's book "Rabbit Hill" (1944) falls within the genre of pastoral literature, in the tradition of Edmund Spenser's "Faerie Queen." Examines the history of the genre and finds reasons for classifying Lawson's book as pastoral. Cites classic elements in "Rabbit Hill." Gives five…

76 FR 62461 - Post Office Closing

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-07

... POSTAL REGULATORY COMMISSION [Docket No. A2011-97; Order No. 890] Post Office Closing AGENCY... the closing of the Oak Hill, Alabama post office has been filed. It identifies preliminary steps and... determination to close the Oak Hill post office in Oak Hill, Alabama. The petition for review was filed by the...

7. Photographic copy of construction drawing 6912132 (from record group ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

7. Photographic copy of construction drawing 6912132 (from record group of Civil Engineering, Hill Air Force Base, Utah). 1940. 8'x10' negative and print. HILL FIELD, UTAH, QM GAS & OIL HOUSE PLAN, ELEVATIONS, DETAIL & STRUCTURAL. - Hill Field, Quatermaster Gas & Oil House, 7326 Wardleigh Road, Layton, Davis County, UT

Evidence for Acid-Sulfate Alteration in the Pahrump Hills Region, Gale Crater, Mars

NASA Technical Reports Server (NTRS)

Rampe, E. B.; Ming, D. W.; Blake, D. F.; Morris, R. V.; Bish, D. L.; Bristow, T. F.; Crisp, J. A.; Morookian, J. M.; Vaniman. D. T.; Chipera, S. J.;

Carriers of filaggrin gene (FLG) mutations avoid professional exposure to irritants in adulthood.

PubMed

Bandier, Josefine; Ross-Hansen, Katrine; Carlsen, Berit C; Menné, Torkil; Linneberg, Allan; Stender, Steen; Szecsi, Pal B; Meldgaard, Michael; Thyssen, Jacob P; Johansen, Jeanne D

2013-12-01

Loss-of-function mutations in the filaggrin gene (FLG) are associated with xerosis, atopic dermatitis, and early onset of hand eczema. Irritant exposure is a risk factor for occupational hand eczema, and FLG mutations increase the risk of occupational irritant contact dermatitis on the hands in hospital cohorts. It is unknown whether FLG mutations affect the level of irritant exposure. To evaluate whether exposure to occupational irritants was dependent on FLG mutations, atopic dermatitis, and age at hand eczema onset. Randomly chosen Danish adults completed a questionnaire on general health and occupational exposures. Genotyping for FLG mutations (R501X, 2282del4, and R2447X) and patch testing were performed. Overall, 38.7% of subjects reported present or previous occupational exposure to irritants. Among individuals who reported hand eczema onset before entering their work life, 50.6% (45/89) of FLG non-mutation carriers became exposed to irritants, as compared with 28.6% (4/14) of heterozygous and 0% (0/6) of homozygous mutation carriers (p = 0.006). Avoidance was conspicuous among mutation carriers reporting childhood hand eczema and atopic dermatitis (odds ratio 0.08, 95% confidence interval 0.01-0.65). Carriers of FLG mutations who have had hand eczema onset in childhood avoid occupational exposure to irritants; the association is most marked with homozygous mutation status combined with atopic dermatitis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Incorporating Erlotinib or Irinotecan Plus Cisplatin into Chemoradiotherapy for Stage III Non-small Cell Lung Cancer According to EGFR Mutation Status.

PubMed

Lee, Youngjoo; Han, Ji-Youn; Moon, Sung Ho; Nam, Byung-Ho; Lim, Kun Young; Lee, Geon Kook; Kim, Heung Tae; Yun, Tak; An, Hye Jin; Lee, Jin Soo

2017-10-01

Concurrent chemoradiotherapy (CCRT) is the standard care for stage III non-small cell lung cancer (NSCLC) patients; however, a more effective regimen is needed to improve the outcome by better controlling occult metastases. We conducted two parallel randomized phase II studies to incorporate erlotinib or irinotecan-cisplatin (IP) into CCRT for stage III NSCLC depending on epidermal growth factor receptor (EGFR) mutation status. Patients with EGFR-mutant tumors were randomized to receive three cycles of erlotinib first and then either CCRT with erlotinib followed by erlotinib (arm A) or CCRT with IP only (arm B). Patients with EGFR unknown or wild-type tumors were randomized to receive either three cycles of IP before (arm C) or after CCRT with IP (arm D). Seventy-three patients were screened and the study was closed early because of slow accrual after 59 patients were randomized. Overall, there were seven patients in arm A, five in arm B, 22 in arm C, and 25 in arm D. The response rate was 71.4% and 80.0% for arm A and B, and 70.0% and 73.9% for arm C and D. The median overall survival (OS) was 39.3 months versus 31.2 months for arm A and B (p=0.442), and 16.3 months versus 25.3 months for arm C and D (p=0.050). Patients with sensitive EGFR mutations had significantly longer OS than EGFR-wild patients (74.8 months vs. 25.3 months, p=0.034). There were no unexpected toxicities. Combined-modality treatment by molecular diagnostics is feasible in stage III NSCLC. EGFR-mutant patients appear to be a distinct subset with longer survival.

Directly administered antiretroviral therapy for HIV-infected drug users does not have an impact on antiretroviral resistance: results from a randomized controlled trial.

PubMed

Maru, Duncan Smith-Rohrberg; Kozal, Michael J; Bruce, R Douglas; Springer, Sandra A; Altice, Frederick L

2007-12-15

Directly administered antiretroviral therapy (DAART) is an effective intervention that improves clinical outcomes among HIV-infected drug users. Its effects on antiretroviral drug resistance, however, are unknown. We conducted a community-based, prospective, randomized controlled trial of DAART compared with self-administered therapy (SAT). We performed a modified intention-to-treat analysis among 115 subjects who provided serum samples for HIV genotypic resistance testing at baseline and at follow-up. The main outcomes measures included total genotypic sensitivity score, future drug options, number of new drug resistance mutations (DRMs), and number of new major International AIDS Society (IAS) mutations. The adjusted probability of developing at least 1 new DRM did not differ between the 2 arms (SAT: 0.41 per person-year [PPY], DAART: 0.49 PPY; adjusted relative risk [RR] = 1.04; P = 0.90), nor did the number of new mutations (SAT: 0.76 PPY, DAART: 0.83 PPY; adjusted RR = 0.99; P = 0.99) or the probability of developing new major IAS new drug mutations (SAT: 0.30 PPY, DAART: 0.33 PPY; adjusted RR = 1.12; P = 0.78). On measures of GSS and FDO, the 2 arms also did not differ. In this trial, DAART provided on-treatment virologic benefit for HIV-infected drug users without affecting the rate of development of antiretroviral medication resistance.

Simulation of gene evolution under directional mutational pressure

NASA Astrophysics Data System (ADS)

Dudkiewicz, Małgorzata; Mackiewicz, Paweł; Kowalczuk, Maria; Mackiewicz, Dorota; Nowicka, Aleksandra; Polak, Natalia; Smolarczyk, Kamila; Banaszak, Joanna; R. Dudek, Mirosław; Cebrat, Stanisław

2004-05-01

The two main mechanisms generating the genetic diversity, mutation and recombination, have random character but they are biased which has an effect on the generation of asymmetry in the bacterial chromosome structure and in the protein coding sequences. Thus, like in a case of two chiral molecules-the two possible orientations of a gene in relation to the topology of a chromosome are not equivalent. Assuming that the sequence of a gene may oscillate only between certain limits of its structural composition means that the gene could be forced out of these limits by the directional mutation pressure, in the course of evolution. The probability of the event depends on the time the gene stays under the same mutation pressure. Inversion of the gene changes the directional mutational pressure to the reciprocal one and hence it changes the distance of the gene to its lower and upper bound of the structural tolerance. Using Monte Carlo methods we were able to simulate the evolution of genes under experimentally found mutational pressure, assuming simple mechanisms of selection. We found that the mutation and recombination should work in accordance to lower their negative effects on the function of the products of coding sequences.

Appearance of drug resistance-associated mutations in human immunodeficiency virus type 1 protease and reverse transcriptase derived from drug-treated Indonesian patients.

PubMed

Khairunisa, Siti Qamariyah; Kotaki, Tomohiro; Witaningrum, Adiana Mutamsari; Yunifiar M, Muhammad Qushai; Sukartiningrum, Septhia Dwi; Nasronudin; Kameoka, Masanori

2015-02-01

Although HIV-1 drug resistance is a major obstacle in Indonesia, information on drug resistance is limited. In this study, the viral subtype and appearance of drug resistance mutations in the HIV-1 protease (PR) and reverse transcriptase (RT) genes were determined among drug-treated, HIV-1-infected patients in Surabaya. HIV-1 patients who received antiretroviral therapy (ART) more than 2 years were randomly recruited regardless of the viral load or ART failure. Fifty-eight HIV-1 PR genes and 53 RT genes were sequenced. CRF01_AE viruses were identified as the predominant strain. Major drug resistance mutations were not detected in the PR genes. In contrast, 37.7% (20/53) of the participants had one or more major drug resistance mutations in the RT genes, predominantly M184V (28.3%), K103N (11.3%), and thymidine analogue mutations (TAMs) (20.8%). The high prevalence of drug resistance mutations in RT genes indicated the necessity of monitoring the effectiveness of ART in Indonesia.

The dynamics of genetic draft in rapidly adapting populations.

PubMed

Kosheleva, Katya; Desai, Michael M

2013-11-01

The accumulation of beneficial mutations on competing genetic backgrounds in rapidly adapting populations has a striking impact on evolutionary dynamics. This effect, known as clonal interference, causes erratic fluctuations in the frequencies of observed mutations, randomizes the fixation times of successful mutations, and leaves distinct signatures on patterns of genetic variation. Here, we show how this form of "genetic draft" affects the forward-time dynamics of site frequencies in rapidly adapting asexual populations. We calculate the probability that mutations at individual sites shift in frequency over a characteristic timescale, extending Gillespie's original model of draft to the case where many strongly selected beneficial mutations segregate simultaneously. We then derive the sojourn time of mutant alleles, the expected fixation time of successful mutants, and the site frequency spectrum of beneficial and neutral mutations. Finally, we show how this form of draft affects inferences in the McDonald-Kreitman test and how it relates to recent observations that some aspects of genetic diversity are described by the Bolthausen-Sznitman coalescent in the limit of very rapid adaptation.

Correlation Dimension Estimates of Global and Local Temperature Data.

NASA Astrophysics Data System (ADS)

Wang, Qiang

1995-11-01

The author has attempted to detect the presence of low-dimensional deterministic chaos in temperature data by estimating the correlation dimension with the Hill estimate that has been recently developed by Mikosch and Wang. There is no convincing evidence of low dimensionality with either global dataset (Southern Hemisphere monthly average temperatures from 1858 to 1984) or local temperature dataset (daily minimums at Auckland, New Zealand). Any apparent reduction in the dimension estimates appears to be due large1y, if not entirely, to effects of statistical bias, but neither is it a purely random stochastic process. The dimension of the climatic attractor may be significantly larger than 10.

Primary Ciliary Dyskinesia Caused by Homozygous Mutation in DNAL1, Encoding Dynein Light Chain 1

PubMed Central

Mazor, Masha; Alkrinawi, Soliman; Chalifa-Caspi, Vered; Manor, Esther; Sheffield, Val C.; Aviram, Micha; Parvari, Ruti

2011-01-01

In primary ciliary dyskinesia (PCD), genetic defects affecting motility of cilia and flagella cause chronic destructive airway disease, randomization of left-right body asymmetry, and, frequently, male infertility. The most frequent defects involve outer and inner dynein arms (ODAs and IDAs) that are large multiprotein complexes responsible for cilia-beat generation and regulation, respectively. Although it has long been suspected that mutations in DNAL1 encoding the ODA light chain1 might cause PCD such mutations were not found. We demonstrate here that a homozygous point mutation in this gene is associated with PCD with absent or markedly shortened ODA. The mutation (NM_031427.3: c.449A>G; p.Asn150Ser) changes the Asn at position150, which is critical for the proper tight turn between the β strand and the α helix of the leucine-rich repeat in the hydrophobic face that connects to the dynein heavy chain. The mutation reduces the stability of the axonemal dynein light chain 1 and damages its interactions with dynein heavy chain and with tubulin. This study adds another important component to understanding the types of mutations that cause PCD and provides clinical information regarding a specific mutation in a gene not yet known to be associated with PCD. PMID:21496787

Computational tools for fitting the Hill equation to dose-response curves.

PubMed

Gadagkar, Sudhindra R; Call, Gerald B

2015-01-01

Many biological response curves commonly assume a sigmoidal shape that can be approximated well by means of the 4-parameter nonlinear logistic equation, also called the Hill equation. However, estimation of the Hill equation parameters requires access to commercial software or the ability to write computer code. Here we present two user-friendly and freely available computer programs to fit the Hill equation - a Solver-based Microsoft Excel template and a stand-alone GUI-based "point and click" program, called HEPB. Both computer programs use the iterative method to estimate two of the Hill equation parameters (EC50 and the Hill slope), while constraining the values of the other two parameters (the minimum and maximum asymptotes of the response variable) to fit the Hill equation to the data. In addition, HEPB draws the prediction band at a user-defined confidence level, and determines the EC50 value for each of the limits of this band to give boundary values that help objectively delineate sensitive, normal and resistant responses to the drug being tested. Both programs were tested by analyzing twelve datasets that varied widely in data values, sample size and slope, and were found to yield estimates of the Hill equation parameters that were essentially identical to those provided by commercial software such as GraphPad Prism and nls, the statistical package in the programming language R. The Excel template provides a means to estimate the parameters of the Hill equation and plot the regression line in a familiar Microsoft Office environment. HEPB, in addition to providing the above results, also computes the prediction band for the data at a user-defined level of confidence, and determines objective cut-off values to distinguish among response types (sensitive, normal and resistant). Both programs are found to yield estimated values that are essentially the same as those from standard software such as GraphPad Prism and the R-based nls. Furthermore, HEPB also has the option to simulate 500 response values based on the range of values of the dose variable in the original data and the fit of the Hill equation to that data. Copyright © 2014. Published by Elsevier Inc.

Classification of Broken Hill-Type Pb-Zn-Ag Deposits: A Refinement

NASA Astrophysics Data System (ADS)

Spry, P. G.; Teale, G. S.; Steadman, J. A.

2009-05-01

Broken Hill Hill-type Pb-Zn-Ag (BHT) deposits constitute some of the largest ore deposits in the world. The Broken Hill deposit is the largest accumulation of Pb, Zn, and Ag on Earth and the Cannington deposit is currently the largest silver deposit. Characteristic features of BHT deposits include: 1. high Pb+Zn+Ag values with Pb > Zn; 2. Metamorphism to amphibolite-granulite facies; 3. Paleo-to Mesoprotoerozoic clastic metasedimentary host rocks; 4. Sulfides that are spatially associated with bimodal (felsic and mafic) volcanic rocks, and stratabound gahnite- and garnet-bearing rocks and iron formations, 5. Stacked orebodies with characteristic Pb:Zn:Ag ratios and skarn-like Fe-Mn-Ca-F gangue assemblages, and the presence of Cu, Au, Bi, As, and Sb; and 6. Sulfur-poor assemblages. Broken Hill (Australia) has a prominent footwall feeder zone whereas other BHT deposits have less obvious alteration zones (footwall garnet spotting and stratabound alteration haloes). Deposits previously regarded in the literature as BHT deposits are Broken Hill, Cannington, Oonagalabie, Menninie Dam, and Pegmont (Australia), Broken Hill, Swartberg, Big Syncline, and Gamsberg (South Africa), Zinkgruvan (Sweden), Sullivan, Cottonbelt, and Foster River (Canada), and Boquira (Brazil). Of these deposits, only the Broken Hill (Australia, South Africa), Pinnacles, Cannington, Pegmont, and Swartberg deposits are BHT deposits. Another BHT deposit includes the Green Parrot deposit, Jervois Ranges (Northern Territory). The Foster River, Gamsberg, and Sullivan deposits are considered to be "SEDEX deposits with BHT affinities", and the Oonagalabie, Green Mountain (Colorado), and Zinkgruvan are "VMS deposits with BHT affinities". In the Broken Hill area (Australia), Corruga-type Pb-Zn-Ag deposits occur in calc-silicate rocks and possess some BHT characteristics; the Big Syncline, Cottonbelt, Menninie Dam, and Saxberget deposits are Corruga-type deposits. SEDEX deposits with BHT affinities, VMS deposits with BHT affinities, and Corruga-type deposits represent transitional deposits between BHT and SEDEX, VMS, and metamorphosed base metal calc-silicate deposits, respectively. Although the non-sulfide zinc deposits at Franklin Furnace and Sterling Hill, NJ, do not contain Pb, they resemble sulfur-poor BHT deposits.

A weighted exact test for mutually exclusive mutations in cancer

PubMed Central

Leiserson, Mark D.M.; Reyna, Matthew A.; Raphael, Benjamin J.

2016-01-01

Motivation: The somatic mutations in the pathways that drive cancer development tend to be mutually exclusive across tumors, providing a signal for distinguishing driver mutations from a larger number of random passenger mutations. This mutual exclusivity signal can be confounded by high and highly variable mutation rates across a cohort of samples. Current statistical tests for exclusivity that incorporate both per-gene and per-sample mutational frequencies are computationally expensive and have limited precision. Results: We formulate a weighted exact test for assessing the significance of mutual exclusivity in an arbitrary number of mutational events. Our test conditions on the number of samples with a mutation as well as per-event, per-sample mutation probabilities. We provide a recursive formula to compute P-values for the weighted test exactly as well as a highly accurate and efficient saddlepoint approximation of the test. We use our test to approximate a commonly used permutation test for exclusivity that conditions on per-event, per-sample mutation frequencies. However, our test is more efficient and it recovers more significant results than the permutation test. We use our Weighted Exclusivity Test (WExT) software to analyze hundreds of colorectal and endometrial samples from The Cancer Genome Atlas, which are two cancer types that often have extremely high mutation rates. On both cancer types, the weighted test identifies sets of mutually exclusive mutations in cancer genes with fewer false positives than earlier approaches. Availability and Implementation: See http://compbio.cs.brown.edu/projects/wext for software. Contact: braphael@cs.brown.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27587696

Experimental Determination and Prediction of the Fitness Effects of Random Point Mutations in the Biosynthetic Enzyme HisA

PubMed Central

Lundin, Erik; Tang, Po-Cheng; Guy, Lionel; Näsvall, Joakim; Andersson, Dan I

2018-01-01

Abstract The distribution of fitness effects of mutations is a factor of fundamental importance in evolutionary biology. We determined the distribution of fitness effects of 510 mutants that each carried between 1 and 10 mutations (synonymous and nonsynonymous) in the hisA gene, encoding an essential enzyme in the l-histidine biosynthesis pathway of Salmonella enterica. For the full set of mutants, the distribution was bimodal with many apparently neutral mutations and many lethal mutations. For a subset of 81 single, nonsynonymous mutants most mutations appeared neutral at high expression levels, whereas at low expression levels only a few mutations were neutral. Furthermore, we examined how the magnitude of the observed fitness effects was correlated to several measures of biophysical properties and phylogenetic conservation.We conclude that for HisA: (i) The effect of mutations can be masked by high expression levels, such that mutations that are deleterious to the function of the protein can still be neutral with regard to organism fitness if the protein is expressed at a sufficiently high level; (ii) the shape of the fitness distribution is dependent on the extent to which the protein is rate-limiting for growth; (iii) negative epistatic interactions, on an average, amplified the combined effect of nonsynonymous mutations; and (iv) no single sequence-based predictor could confidently predict the fitness effects of mutations in HisA, but a combination of multiple predictors could predict the effect with a SD of 0.04 resulting in 80% of the mutations predicted within 12% of their observed selection coefficients. PMID:29294020

mtDNA mutation C1494T, haplogroup A, and hearing loss in Chinese

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang Chengye; Laboratory for Conservation and Utilization of Bio-resource, Yunnan University, Kunming 650091; Graduate University of the Chinese Academy of Sciences, Beijing 100039

2006-09-22

Mutation C1494T in mitochondrial 12S rRNA gene was recently reported in two large Chinese families with aminoglycoside-induced and nonsyndromic hearing loss (AINHL) and was claimed to be pathogenic. This mutation, however, was first reported in a sample from central China in our previous study that was aimed to reconstruct East Asian mtDNA phylogeny. All these three mtDNAs formed a subclade defined by mutation C1494T in mtDNA haplogroup A. It thus seems that mutation C1494T is a haplogroup A-associated mutation and this matrilineal background may contribute a high risk for the penetrance of mutation C1494T in Chinese with AINHL. To testmore » this hypothesis, we first genotyped mutation C1494T in 553 unrelated individuals from three regional Chinese populations and performed an extensive search for published complete or near-complete mtDNA data sets (>3000 mtDNAs), we then screened the C1494T mutation in 111 mtDNAs with haplogroup A status that were identified from 1823 subjects across China. The search for published mtDNA data sets revealed no other mtDNA besides the above-mentioned three carrying mutation C1494T. None of the 553 randomly selected individuals and the 111 haplogroup A mtDNAs was found to bear this mutation. Therefore, our results suggest that C1494T is a very rare event. The mtDNA haplogroup A background in general is unlikely to play an active role in the penetrance of mutation C1494T in AINHL.« less

A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML.

PubMed

Knapper, Steven; Russell, Nigel; Gilkes, Amanda; Hills, Robert K; Gale, Rosemary E; Cavenagh, James D; Jones, Gail; Kjeldsen, Lars; Grunwald, Michael R; Thomas, Ian; Konig, Heiko; Levis, Mark J; Burnett, Alan K

2017-03-02

The clinical benefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and AML17 trials, patients with previously untreated AML and confirmed FLT3-activating mutations, mostly younger than 60 years, were randomly assigned either to receive oral lestaurtinib (CEP701) or not after each of 4 cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days. The trials ran consecutively. Primary endpoints were overall survival in AML15 and relapse-free survival in AML17; outcome data were meta-analyzed. Five hundred patients were randomly assigned between lestaurtinib and control: 74% had FLT3 -internal tandem duplication mutations, 23% FLT3 -tyrosine kinase domain point mutations, and 2% both types. No significant differences were seen in either 5-year overall survival (lestaurtinib 46% vs control 45%; hazard ratio, 0.90; 95% CI 0.70-1.15; P = .3) or 5-year relapse-free survival (40% vs 36%; hazard ratio, 0.88; 95% CI 0.69-1.12; P = .3). Exploratory subgroup analysis suggested survival benefit with lestaurtinib in patients receiving concomitant azole antifungal prophylaxis and gemtuzumab ozogamicin with the first course of chemotherapy. Correlative studies included analysis of in vivo FLT3 inhibition by plasma inhibitory activity assay and indicated improved overall survival and significantly reduced rates of relapse in lestaurtinib-treated patients who achieved sustained greater than 85% FLT3 inhibition. In conclusion, combining lestaurtinib with intensive chemotherapy proved feasible in younger patients with newly diagnosed FLT3 -mutated AML, but yielded no overall clinical benefit. The improved clinical outcomes seen in patients achieving sustained FLT3 inhibition encourage continued evaluation of FLT3-directed therapy alongside front-line AML treatment. The UK AML15 and AML17 trials are registered at www.isrctn.com/ISRCTN17161961 and www.isrctn.com/ISRCTN55675535 respectively. © 2017 by The American Society of Hematology.

Ecology, silviculture, and management of Black Hills ponderosa pine

Treesearch

Wayne D. Shepperd; Michael A. Battaglia

2002-01-01

This paper presents a broad-based synthesis of the general ecology of the ponderosa pine ecosystem in the Black Hills. This synthesis contains information and results of research on ponderosa pine from numerous sources within the Black Hills ecosystem. We discuss the silvical characteristics of ponderosa pine, natural disturbances that govern ecosystem processes,...

76 FR 58257 - Combined Notice of Filings #2

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-20

... Hills Wind Farm, LLC. Description: Smoky Hills Wind Farm, LLC submits tariff filing per 35.1: Smoky Hills Wind Farm, LLC MBR Tariff to be effective 10/31/2007. Filed Date: 09/12/2011. Accession Number... Associates, L.P., Golden Spread Panhandle Wind Ranch, LLC. Description: Notice of Change in Status of Golden...

76 FR 76393 - Combined Notice of Filings #1

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-07

...; ER11-4499-002; ER11-4500-002; ER11- 4507-002; ER11-4501-002. Applicants: Smoky Hills Wind Farm, LLC, Smoky Hills Wind Project II, LLC, Enel Stillwater, LLC, Caney River Wind Project, LLC, Canastota Windpower, LLC. Description: Notice of Non-Material Change in Status re Smoky Hills Wind Farm, LLC, et al...

24 CFR 100.303 - 62 or over housing.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Mary, it might qualify for the “55 or over” exemption in § 100.304. Example (2): The Blueberry Hill... persons who were all 62 years of age or older. Blueberry Hill can qualify for the “62 or over” exemption... leave for Blueberry Hill to qualify for the “62 or over” exemption. ...

24 CFR 100.303 - 62 or over housing.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Mary, it might qualify for the “55 or over” exemption in § 100.304. Example (2): The Blueberry Hill... persons who were all 62 years of age or older. Blueberry Hill can qualify for the “62 or over” exemption... leave for Blueberry Hill to qualify for the “62 or over” exemption. ...

24 CFR 100.303 - 62 or over housing.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Mary, it might qualify for the “55 or over” exemption in § 100.304. Example (2): The Blueberry Hill... persons who were all 62 years of age or older. Blueberry Hill can qualify for the “62 or over” exemption... leave for Blueberry Hill to qualify for the “62 or over” exemption. ...

24 CFR 100.303 - 62 or over housing.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Mary, it might qualify for the “55 or over” exemption in § 100.304. Example (2): The Blueberry Hill... persons who were all 62 years of age or older. Blueberry Hill can qualify for the “62 or over” exemption... leave for Blueberry Hill to qualify for the “62 or over” exemption. ...

24 CFR 100.303 - 62 or over housing.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Mary, it might qualify for the “55 or over” exemption in § 100.304. Example (2): The Blueberry Hill... persons who were all 62 years of age or older. Blueberry Hill can qualify for the “62 or over” exemption... leave for Blueberry Hill to qualify for the “62 or over” exemption. ...

33 CFR 80.145 - Race Point, MA, to Watch Hill, RI.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Race Point, MA, to Watch Hill, RI. 80.145 Section 80.145 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY INTERNATIONAL NAVIGATION RULES COLREGS DEMARCATION LINES Atlantic Coast § 80.145 Race Point, MA, to Watch Hill...

33 CFR 80.145 - Race Point, MA, to Watch Hill, RI.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Race Point, MA, to Watch Hill, RI. 80.145 Section 80.145 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY INTERNATIONAL NAVIGATION RULES COLREGS DEMARCATION LINES Atlantic Coast § 80.145 Race Point, MA, to Watch Hill...

33 CFR 80.145 - Race Point, MA, to Watch Hill, RI.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Race Point, MA, to Watch Hill, RI. 80.145 Section 80.145 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY INTERNATIONAL NAVIGATION RULES COLREGS DEMARCATION LINES Atlantic Coast § 80.145 Race Point, MA, to Watch Hill...

33 CFR 80.145 - Race Point, MA, to Watch Hill, RI.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 false Race Point, MA, to Watch Hill, RI. 80.145 Section 80.145 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY INTERNATIONAL NAVIGATION RULES COLREGS DEMARCATION LINES Atlantic Coast § 80.145 Race Point, MA, to Watch Hill...

33 CFR 80.145 - Race Point, MA, to Watch Hill, RI.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Race Point, MA, to Watch Hill, RI. 80.145 Section 80.145 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY INTERNATIONAL NAVIGATION RULES COLREGS DEMARCATION LINES Atlantic Coast § 80.145 Race Point, MA, to Watch Hill...

77 FR 47625 - Laurel Hill Wind Energy, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-09

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. ER12-2313-000] Laurel Hill Wind Energy, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request For... Laurel Hill Wind Energy, LLC's application for market-based rate authority, with an accompanying rate...

Hospital/Health Facilities and the Hill-Burton Obligations: A Secret from the Black Community.

ERIC Educational Resources Information Center

Rice, Mitchell F.

1986-01-01

Uncompensated/free care and community service obligations under the Hill-Burton Act can assist substantially in providing needed health care services to the Black community. Blacks, however, must become knowledgeable about these obligations, develop monitoring projects, and be prepared to take legal steps to bring Hill-Burton facilities into…

78 FR 13870 - Roberto Sella; Notice of Declaration of Intention and Soliciting Comments, Protests, and/or...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-01

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. DI13-3-000] Roberto Sella... 7, 2012. d. Applicant: Roberto Sella. e. Name of Project: Hydro-electric and Geothermal Alternative Energy System at Paper Hill Farm (Paper Hill Farm). f. Location: The proposed Paper Hill Farm project...

76 FR 35396 - Black Hills National Forest, Mystic Ranger District, South Dakota, Section 30 Limestone Mining...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-17

... DEPARTMENT OF AGRICULTURE Forest Service Black Hills National Forest, Mystic Ranger District... INFORMATION CONTACT: Dave Slepnikoff, Project Coordinator, Black Hills National Forest, Mystic Ranger District... regulations at 36 CFR 228 Subpart A. The Project is located between Rapid City and Black Hawk, South Dakota...

76 FR 5580 - Black Hills Colorado IPP, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-01

... proceeding Black Hills Colorado IPP, LLC's application for market-based rate authority, with an accompanying... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. ER11-2724-000] Black Hills Colorado IPP, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request for Blanket...

Case Study on Education Opportunities for Hill Tribes in Northern Thailand: Implications for Sustainable Rural Development.

ERIC Educational Resources Information Center

Fujioka, Rika

This research analyzes the impact of the Thai government's activities to promote educational opportunities for people of the northern hill tribes. In addition to interviews with government and nongovernmental organization staff, field surveys were conducted in hill tribe villages. The introductory chapter provides background information on the…

76 FR 6457 - Hill-Lake Gas Storage, LLC; Notice of Baseline Filings

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-04

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. PR10-134-001] Hill-Lake Gas Storage, LLC; Notice of Baseline Filings January 31, 2011. Take notice that on January 28, 2011, Hill-Lake submitted a revised baseline filing of their Statement of Operating Conditions for services provided under...

76 FR 30338 - Hill-Lake Gas Storage, LLC; Notice of Filing

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-25

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. PR11-110-000] Hill-Lake Gas Storage, LLC; Notice of Filing Take notice that on May 13, 2011, Hill-Lake Gas Storage, LLC filed to update its address and to clarify definitions for Maximum Daily Withdrawal Quantity and Maximum Daily...

76 FR 7186 - Hill-Lake Gas Storage, LLC; Notice of Baseline Filings

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-09

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. PR10-134-002] Hill-Lake Gas Storage, LLC; Notice of Baseline Filings February 2, 2011. Take notice that on February 1, 2011, Hill-Lake submitted a revised baseline filing of their Statement of Operating Conditions for services provided under...

OVERVIEW OF GOLD HILL MILL, ROAD, AND WHITE PINE TALC ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

OVERVIEW OF GOLD HILL MILL, ROAD, AND WHITE PINE TALC MINE LOOKING EAST. THE OPENING TO THE TALC MINE IS IN THE DARK AREA AT CENTER LEFT EDGE. WARM SPRINGS CAMP IS OUT OF FRAME TO THE RIGHT. - Gold Hill Mill, Warm Spring Canyon Road, Death Valley Junction, Inyo County, CA

Report on the Black Hills Alliance.

ERIC Educational Resources Information Center

Ryan, Joe

1979-01-01

A rally to save the Black Hills from coal- and uranium-greedy energy companies was held on July 6 and over 2,000 joined in a 15-mile walk on July 7 in Rapid City, South Dakota. The Black Hills Alliance, an Indian coalition concerned about energy development proposals in the Great Plains, sponsored the gathering. (NQ)

1. BUNKER HILL LEAD SMELTER. VIEW IS FROM CENTRAL IMPOUNDMENT ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. BUNKER HILL LEAD SMELTER. VIEW IS FROM CENTRAL IMPOUNDMENT AREA LOOKING SOUTH. PLANT DRY IS IN CENTER FOREGROUND, SLAG FUMING PLANT IS IN RIGHT FOREGROUND, AND BAG HOUSE IS IN RIGHT BACKGROUND. VARIOUS PLANT STACKS ARE ALSO VISIBLE. - Bunker Hill Lead Smelter, Bradley Rail Siding, Kellogg, Shoshone County, ID

78 FR 18241 - Approval and Promulgation of Air Quality Implementation Plans; Minnesota; Flint Hills Resources...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-26

... ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part 52 [EPA-R05-OAR-2011-0328; FRL-9792-8] Approval and Promulgation of Air Quality Implementation Plans; Minnesota; Flint Hills Resources Pine Bend AGENCY... rule approving a revision to the the Minnesota sulfur dioxide SIP for Flint Hills Resources Pine Bend...

The Bradford Hill criteria and zinc-induced anosmia: a causality analysis.

PubMed

Davidson, Terence M; Smith, Wendy M

2010-07-01

To apply the Bradford Hill criteria, which are widely used to establish causality between an environmental agent and disease, to evaluate the relationship between over-the-counter intranasal zinc gluconate therapy and anosmia. Patient and literature review applying the Bradford Hill criteria on causation. University of California, San Diego, Nasal Dysfunction Clinic. The study included 25 patients who presented to the University of California, San Diego, Nasal Dysfunction Clinic complaining of acute-onset anosmia after intranasal application of homeopathic zinc gluconate gel. Each of the 9 Bradford Hill criteria--strength of association, consistency, specificity, temporality, biological gradient (dose-response), biological plausibility, biological coherence, experimental evidence, and analogy--was applied to intranasal zinc gluconate therapy and olfactory dysfunction using published, peer-reviewed medical literature and reported clinical experiences. Clinical, biological, and experimental data support the Bradford Hill criteria to demonstrate that intranasal zinc gluconate therapy causes hyposmia and anosmia. The Bradford Hill criteria represent an important tool for scientifically determining cause between environmental exposure and disease. Increased Food and Drug Administration oversight of homeopathic medications is needed to monitor the safety of these popular remedies.

Visualizing inequality

NASA Astrophysics Data System (ADS)

Eliazar, Iddo

2016-07-01

The study of socioeconomic inequality is of substantial importance, scientific and general alike. The graphic visualization of inequality is commonly conveyed by Lorenz curves. While Lorenz curves are a highly effective statistical tool for quantifying the distribution of wealth in human societies, they are less effective a tool for the visual depiction of socioeconomic inequality. This paper introduces an alternative to Lorenz curves-the hill curves. On the one hand, the hill curves are a potent scientific tool: they provide detailed scans of the rich-poor gaps in human societies under consideration, and are capable of accommodating infinitely many degrees of freedom. On the other hand, the hill curves are a powerful infographic tool: they visualize inequality in a most vivid and tangible way, with no quantitative skills that are required in order to grasp the visualization. The application of hill curves extends far beyond socioeconomic inequality. Indeed, the hill curves are highly effective 'hyperspectral' measures of statistical variability that are applicable in the context of size distributions at large. This paper establishes the notion of hill curves, analyzes them, and describes their application in the context of general size distributions.

Exact Markov chain and approximate diffusion solution for haploid genetic drift with one-way mutation.

PubMed

Hössjer, Ola; Tyvand, Peder A; Miloh, Touvia

2016-02-01

The classical Kimura solution of the diffusion equation is investigated for a haploid random mating (Wright-Fisher) model, with one-way mutations and initial-value specified by the founder population. The validity of the transient diffusion solution is checked by exact Markov chain computations, using a Jordan decomposition of the transition matrix. The conclusion is that the one-way diffusion model mostly works well, although the rate of convergence depends on the initial allele frequency and the mutation rate. The diffusion approximation is poor for mutation rates so low that the non-fixation boundary is regular. When this happens we perturb the diffusion solution around the non-fixation boundary and obtain a more accurate approximation that takes quasi-fixation of the mutant allele into account. The main application is to quantify how fast a specific genetic variant of the infinite alleles model is lost. We also discuss extensions of the quasi-fixation approach to other models with small mutation rates. Copyright © 2015 Elsevier Inc. All rights reserved.

Holes influence the mutation spectrum of human mitochondrial DNA

NASA Astrophysics Data System (ADS)

Villagran, Martha; Miller, John

Mutations drive evolution and disease, showing highly non-random patterns of variant frequency vs. nucleotide position. We use computational DNA hole spectroscopy [M.Y. Suarez-Villagran & J.H. Miller, Sci. Rep. 5, 13571 (2015)] to reveal sites of enhanced hole probability in selected regions of human mitochondrial DNA. A hole is a mobile site of positive charge created when an electron is removed, for example by radiation or contact with a mutagenic agent. The hole spectra are quantum mechanically computed using a two-stranded tight binding model of DNA. We observe significant correlation between spectra of hole probabilities and of genetic variation frequencies from the MITOMAP database. These results suggest that hole-enhanced mutation mechanisms exert a substantial, perhaps dominant, influence on mutation patterns in DNA. One example is where a trapped hole induces a hydrogen bond shift, known as tautomerization, which then triggers a base-pair mismatch during replication. Our results deepen overall understanding of sequence specific mutation rates, encompassing both hotspots and cold spots, which drive molecular evolution.

Development of potent in vivo mutagenesis plasmids with broad mutational spectra

PubMed Central

Badran, Ahmed H.; Liu, David R.

2015-01-01

Methods to enhance random mutagenesis in cells offer advantages over in vitro mutagenesis, but current in vivo methods suffer from a lack of control, genomic instability, low efficiency and narrow mutational spectra. Using a mechanism-driven approach, we created a potent, inducible, broad-spectrum and vector-based mutagenesis system in E. coli that enhances mutation 322,000-fold over basal levels, surpassing the mutational efficiency and spectra of widely used in vivo and in vitro methods. We demonstrate that this system can be used to evolve antibiotic resistance in wild-type E. coli in <24 h, outperforming chemical mutagens, ultraviolet light and the mutator strain XL1-Red under similar conditions. This system also enables the continuous evolution of T7 RNA polymerase variants capable of initiating transcription using the T3 promoter in <10 h. Our findings enable broad-spectrum mutagenesis of chromosomes, episomes and viruses in vivo, and are applicable to both bacterial and bacteriophage-mediated laboratory evolution platforms. PMID:26443021

Development of potent in vivo mutagenesis plasmids with broad mutational spectra.

PubMed

Badran, Ahmed H; Liu, David R

2015-10-07

Methods to enhance random mutagenesis in cells offer advantages over in vitro mutagenesis, but current in vivo methods suffer from a lack of control, genomic instability, low efficiency and narrow mutational spectra. Using a mechanism-driven approach, we created a potent, inducible, broad-spectrum and vector-based mutagenesis system in E. coli that enhances mutation 322,000-fold over basal levels, surpassing the mutational efficiency and spectra of widely used in vivo and in vitro methods. We demonstrate that this system can be used to evolve antibiotic resistance in wild-type E. coli in <24 h, outperforming chemical mutagens, ultraviolet light and the mutator strain XL1-Red under similar conditions. This system also enables the continuous evolution of T7 RNA polymerase variants capable of initiating transcription using the T3 promoter in <10 h. Our findings enable broad-spectrum mutagenesis of chromosomes, episomes and viruses in vivo, and are applicable to both bacterial and bacteriophage-mediated laboratory evolution platforms.

Association between melanocortin-4 receptor mutations and eating behaviors in obese patients: a case--control study.

PubMed

Valette, M; Poitou, C; Kesse-Guyot, E; Bellisle, F; Carette, C; Le Beyec, J; Hercberg, S; Clément, K; Czernichow, S

2014-06-01

Melanocortin-4 receptor (MC4R) gene mutations are involved in the leptin-melanocortin pathways that control food intake. The effect of these mutations on eating behavior phenotypes is still debated. To determine the association between functional MC4R mutations and eating behaviors, dietary intake and physical activity, we sequenced the MC4R gene in 4653 obese adults. Among them, 19 adults carriers of functional MC4R mutation were matched on age, sex and body mass index with two randomly-paired controls without MC4R mutation (n=57). We found that eating behaviors and physical activity did not differ between groups. In particular, cases were not at increased risk of binge eating disorders. Subjects carriers of MC4R mutation reported a higher proportion of dietary carbohydrates intakes (43.2±7.1 and 39.2±8.1% of total energy intake, respectively, P=0.048) and a lower proportion of dietary lipids (34.3±6.7 and 38.5±6.7% of total energy intake, respectively, P=0.018). In conclusion, mutation carriers differ from controls by a higher consumption of carbohydrates counterbalanced by a lower consumption of lipids expressed as percentage of total energy intake. However, functional MC4R mutations do not have a higher risk of compulsive eating contrary to what was previously suggested.

Contribution of mammography to MRI screening in BRCA mutation carriers by BRCA status and age: individual patient data meta-analysis

PubMed Central

Phi, Xuan-Anh; Saadatmand, Sepideh; De Bock, Geertruida H; Warner, Ellen; Sardanelli, Francesco; Leach, Martin O; Riedl, Christopher C; Trop, Isabelle; Hooning, Maartje J; Mandel, Rodica; Santoro, Filippo; Kwan-Lim, Gek; Helbich, Thomas H; Tilanus-Linthorst, Madeleine MA; van den Heuvel, Edwin R; Houssami, Nehmat

2016-01-01

Background: We investigated the additional contribution of mammography to screening accuracy in BRCA1/2 mutation carriers screened with MRI at different ages using individual patient data from six high-risk screening trials. Methods: Sensitivity and specificity of MRI, mammography and the combination of these tests were compared stratified for BRCA mutation and age using generalised linear mixed models with random effect for studies. Number of screens needed (NSN) for additional mammography-only detected cancer was estimated. Results: In BRCA1/2 mutation carriers of all ages (BRCA1=1219 and BRCA2=732), adding mammography to MRI did not significantly increase screening sensitivity (increased by 3.9% in BRCA1 and 12.6% in BRCA2 mutation carriers, P>0.05). However, in women with BRCA2 mutation younger than 40 years, one-third of breast cancers were detected by mammography only. Number of screens needed for mammography to detect one breast cancer not detected by MRI was much higher for BRCA1 compared with BRCA2 mutation carriers at initial and repeat screening. Conclusions: Additional screening sensitivity from mammography above that from MRI is limited in BRCA1 mutation carriers, whereas mammography contributes to screening sensitivity in BRCA2 mutation carriers, especially those ⩽40 years. The evidence from our work highlights that a differential screening schedule by BRCA status is worth considering. PMID:26908327

Mutations in Mitochondrial DNA From Pancreatic Ductal Adenocarcinomas Associate With Survival Times of Patients and Accumulate as Tumors Progress.

PubMed

Hopkins, Julia F; Denroche, Robert E; Aguiar, Jennifer A; Notta, Faiyaz; Connor, Ashton A; Wilson, Julie M; Stein, Lincoln D; Gallinger, Steven; Boutros, Paul C

2018-05-01

Somatic mutations have been found in the mitochondria in different types of cancer cells, but it is not clear whether these affect tumorigenesis or tumor progression. We analyzed mitochondrial genomes of 268 early-stage, resected pancreatic ductal adenocarcinoma tissues and paired non-tumor tissues. We defined a mitochondrial somatic mutation (mtSNV) as a position where the difference in heteroplasmy fraction between tumor and normal sample was ≥0.2. Our analysis identified 304 mtSNVs, with at least 1 mtSNV in 61% (164 of 268) of tumor samples. The noncoding control region had the greatest proportion of mtSNVs (60 of 304 mutations); this region contains sites that regulate mitochondrial DNA transcription and replication. Frequently mutated genes included ND5, RNR2, and CO1, plus 29 mutations in transfer RNA genes. mtSNVs in 2 separate mitochondrial genes (ND4 and ND6) were associated with shorter overall survival time. This association appeared to depend on the level of mtSNV heteroplasmy. Non-random co-occurrence between mtSNVs and mutations in nuclear genes indicates interactions between nuclear and mitochondrial DNA. In an analysis of primary tumors and metastases from 6 patients, we found tumors to accumulate mitochondrial mutational mutations as they progress. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Contribution of mammography to MRI screening in BRCA mutation carriers by BRCA status and age: individual patient data meta-analysis.

PubMed

Phi, Xuan-Anh; Saadatmand, Sepideh; De Bock, Geertruida H; Warner, Ellen; Sardanelli, Francesco; Leach, Martin O; Riedl, Christopher C; Trop, Isabelle; Hooning, Maartje J; Mandel, Rodica; Santoro, Filippo; Kwan-Lim, Gek; Helbich, Thomas H; Tilanus-Linthorst, Madeleine M A; van den Heuvel, Edwin R; Houssami, Nehmat

2016-03-15

We investigated the additional contribution of mammography to screening accuracy in BRCA1/2 mutation carriers screened with MRI at different ages using individual patient data from six high-risk screening trials. Sensitivity and specificity of MRI, mammography and the combination of these tests were compared stratified for BRCA mutation and age using generalised linear mixed models with random effect for studies. Number of screens needed (NSN) for additional mammography-only detected cancer was estimated. In BRCA1/2 mutation carriers of all ages (BRCA1 = 1,219 and BRCA2 = 732), adding mammography to MRI did not significantly increase screening sensitivity (increased by 3.9% in BRCA1 and 12.6% in BRCA2 mutation carriers, P > 0.05). However, in women with BRCA2 mutation younger than 40 years, one-third of breast cancers were detected by mammography only. Number of screens needed for mammography to detect one breast cancer not detected by MRI was much higher for BRCA1 compared with BRCA2 mutation carriers at initial and repeat screening. Additional screening sensitivity from mammography above that from MRI is limited in BRCA1 mutation carriers, whereas mammography contributes to screening sensitivity in BRCA2 mutation carriers, especially those ⩽ 40 years. The evidence from our work highlights that a differential screening schedule by BRCA status is worth considering.

Geologic and paleoecologic studies of the Nebraska Sand Hills

USGS Publications Warehouse

Ahlbrandt, Thomas S.; Fryberger, S.G.; Hanley, John H.; Bradbury, J. Platt

1980-01-01

PART A: The Nebraska Sand Hills are an inactive, late Quaternary, most probably Holocene, dune field (covering 57,000 km 2 ) that have been eroded along streams and in blowouts, resulting in excellent lateral and vertical exposures of the stratification of dune and interdune sediments. This paper presents new data on the geometry, primary sedimentary structures, modification of sedimentary structures, direction of sand movement, and petrography of these eolian deposits. Eolian deposits of the Sand Hills occur as relatively thin (9-24 m) 'blanket' sands, composed of a complex of dune and discontinuous, diachronous interdune deposits unconformably overlying fluviolacustrine sediments. The internal stratification of large dunes in the Sand Hills (as high as 100 m), is similar to the internal stratification of smaller dunes of the same type in the Sand Hills, differing only in scale. Studies of laminae orientation in the Sand Hills indicate that transverse, barchan, and blowout dunes can be differentiated in rocks of eolian origin using both the mean dip angle of laminae and the mean angular deviation of dip direction. A variety of secondary structures modify or replace primary eolian stratification in the Sand Hills, the more common of which are dissipation structures and bioturbation. Dissipation structures in the Sand Hills may develop when infiltrating water deposits clay adjacent to less permeable layers in the sand, or along the upper margins of frozen layers that form in the sands during winter. Cross-bed measurements from dunes of the Nebraska Sand Hills necessitate a new interpretation of the past sand transport directions. The data from these measurements indicate a general northwest-to-southeast drift of sand, with a more southerly drift in the southeast part of the Sand Hills. A large area of small dunes < 100 m high) described by Smith (1965) as linear or seif in the central part of the Sand Hills was interpreted by him on the basis of morphology only. We interpret these as transverse-ridge dunes that were generally moving to the south. Further, our measurements indicate that dunes in the western part of the Sand Hills did not develop in response to present-day effective wind regimes. The presence of 'transverse' and en echelon barchan dunes in the Sand Hills corresponds to a developmental sequence of barchan to linear dunes proposed by Tsoar (1978). Dune and interdune deposits of the Sand Hills are subfeldsarenites to feldsarenites. Sand grains are commonly coated with montmorillonitic clay, which may be the local source of the clay concentrated in the dissipation structures. Textures of sand samples taken from adjacent layers within a dune were as dissimilar as textures of samples taken from widely separated dunes. This common occurrence indicates that textural data must be used carefully and in combination with other data to recognize ancient rocks of eolian origin. Organic material derived from a variety of flora and fauna that inhabit the interdunes (chapters B and C) generated both oil and gas upon heating. Thus, interdune sediments may be an indigenous hydrocarbon source if buried in eolianites. The twofold stratigraphy of loess and correlative dune deposits in the Sand Hills proposed by Reed and Dreeszen (1965) could not be confirmed by the present study. Rather, available data indicate that the dunes represent a single formation as suggested by Lugn (1935). PART B: Three assemblages of nonmarine Mollusca from paleointerdune deposits in the Nebraska Sand Hills inhabited shallow, quiet, vegetated, subpermanent or temporary, freshwater interdune ponds and adjacent terrestrial habitats. Analysis of factors affecting the taxonomic composition, diversity, and abundance of species in living assemblages of mollusks support this interpretation. The mollusks have long biostratigraphic ranges and broad biogeographic distributions. They fail to establish precise age relations of the faunas othe

Unlocking hidden genomic sequence

PubMed Central

Keith, Jonathan M.; Cochran, Duncan A. E.; Lala, Gita H.; Adams, Peter; Bryant, Darryn; Mitchelson, Keith R.

2004-01-01

Despite the success of conventional Sanger sequencing, significant regions of many genomes still present major obstacles to sequencing. Here we propose a novel approach with the potential to alleviate a wide range of sequencing difficulties. The technique involves extracting target DNA sequence from variants generated by introduction of random mutations. The introduction of mutations does not destroy original sequence information, but distributes it amongst multiple variants. Some of these variants lack problematic features of the target and are more amenable to conventional sequencing. The technique has been successfully demonstrated with mutation levels up to an average 18% base substitution and has been used to read previously intractable poly(A), AT-rich and GC-rich motifs. PMID:14973330

Causal assessment of dietary acid load and bone disease: a systematic review & meta-analysis applying Hill's epidemiologic criteria for causality

PubMed Central

2011-01-01

Background Modern diets have been suggested to increase systemic acid load and net acid excretion. In response, alkaline diets and products are marketed to avoid or counteract this acid, help the body regulate its pH to prevent and cure disease. The objective of this systematic review was to evaluate causal relationships between dietary acid load and osteoporosis using Hill's criteria. Methods Systematic review and meta-analysis. We systematically searched published literature for randomized intervention trials, prospective cohort studies, and meta-analyses of the acid-ash or acid-base diet hypothesis with bone-related outcomes, in which the diet acid load was altered, or an alkaline diet or alkaline salts were provided, to healthy human adults. Cellular mechanism studies were also systematically examined. Results Fifty-five of 238 studies met the inclusion criteria: 22 randomized interventions, 2 meta-analyses, and 11 prospective observational studies of bone health outcomes including: urine calcium excretion, calcium balance or retention, changes of bone mineral density, or fractures, among healthy adults in which acid and/or alkaline intakes were manipulated or observed through foods or supplements; and 19 in vitro cell studies which examined the hypothesized mechanism. Urine calcium excretion rates were consistent with osteoporosis development; however calcium balance studies did not demonstrate loss of whole body calcium with higher net acid excretion. Several weaknesses regarding the acid-ash hypothesis were uncovered: No intervention studies provided direct evidence of osteoporosis progression (fragility fractures, or bone strength as measured using biopsy). The supporting prospective cohort studies were not controlled regarding important osteoporosis risk factors including: weight loss during follow-up, family history of osteoporosis, baseline bone mineral density, and estrogen status. No study revealed a biologic mechanism functioning at physiological pH. Finally, randomized studies did not provide evidence for an adverse role of phosphate, milk, and grain foods in osteoporosis. Conclusions A causal association between dietary acid load and osteoporotic bone disease is not supported by evidence and there is no evidence that an alkaline diet is protective of bone health. PMID:21529374

Causal assessment of dietary acid load and bone disease: a systematic review & meta-analysis applying Hill's epidemiologic criteria for causality.

PubMed

Fenton, Tanis R; Tough, Suzanne C; Lyon, Andrew W; Eliasziw, Misha; Hanley, David A

2011-04-30

Modern diets have been suggested to increase systemic acid load and net acid excretion. In response, alkaline diets and products are marketed to avoid or counteract this acid, help the body regulate its pH to prevent and cure disease. The objective of this systematic review was to evaluate causal relationships between dietary acid load and osteoporosis using Hill's criteria. Systematic review and meta-analysis. We systematically searched published literature for randomized intervention trials, prospective cohort studies, and meta-analyses of the acid-ash or acid-base diet hypothesis with bone-related outcomes, in which the diet acid load was altered, or an alkaline diet or alkaline salts were provided, to healthy human adults. Cellular mechanism studies were also systematically examined. Fifty-five of 238 studies met the inclusion criteria: 22 randomized interventions, 2 meta-analyses, and 11 prospective observational studies of bone health outcomes including: urine calcium excretion, calcium balance or retention, changes of bone mineral density, or fractures, among healthy adults in which acid and/or alkaline intakes were manipulated or observed through foods or supplements; and 19 in vitro cell studies which examined the hypothesized mechanism. Urine calcium excretion rates were consistent with osteoporosis development; however calcium balance studies did not demonstrate loss of whole body calcium with higher net acid excretion. Several weaknesses regarding the acid-ash hypothesis were uncovered: No intervention studies provided direct evidence of osteoporosis progression (fragility fractures, or bone strength as measured using biopsy). The supporting prospective cohort studies were not controlled regarding important osteoporosis risk factors including: weight loss during follow-up, family history of osteoporosis, baseline bone mineral density, and estrogen status. No study revealed a biologic mechanism functioning at physiological pH. Finally, randomized studies did not provide evidence for an adverse role of phosphate, milk, and grain foods in osteoporosis. A causal association between dietary acid load and osteoporotic bone disease is not supported by evidence and there is no evidence that an alkaline diet is protective of bone health.

Distance-Based Functional Diversity Measures and Their Decomposition: A Framework Based on Hill Numbers

PubMed Central

Chiu, Chun-Huo; Chao, Anne

2014-01-01

Hill numbers (or the “effective number of species”) are increasingly used to characterize species diversity of an assemblage. This work extends Hill numbers to incorporate species pairwise functional distances calculated from species traits. We derive a parametric class of functional Hill numbers, which quantify “the effective number of equally abundant and (functionally) equally distinct species” in an assemblage. We also propose a class of mean functional diversity (per species), which quantifies the effective sum of functional distances between a fixed species to all other species. The product of the functional Hill number and the mean functional diversity thus quantifies the (total) functional diversity, i.e., the effective total distance between species of the assemblage. The three measures (functional Hill numbers, mean functional diversity and total functional diversity) quantify different aspects of species trait space, and all are based on species abundance and species pairwise functional distances. When all species are equally distinct, our functional Hill numbers reduce to ordinary Hill numbers. When species abundances are not considered or species are equally abundant, our total functional diversity reduces to the sum of all pairwise distances between species of an assemblage. The functional Hill numbers and the mean functional diversity both satisfy a replication principle, implying the total functional diversity satisfies a quadratic replication principle. When there are multiple assemblages defined by the investigator, each of the three measures of the pooled assemblage (gamma) can be multiplicatively decomposed into alpha and beta components, and the two components are independent. The resulting beta component measures pure functional differentiation among assemblages and can be further transformed to obtain several classes of normalized functional similarity (or differentiation) measures, including N-assemblage functional generalizations of the classic Jaccard, Sørensen, Horn and Morisita-Horn similarity indices. The proposed measures are applied to artificial and real data for illustration. PMID:25000299

Distance-based functional diversity measures and their decomposition: a framework based on Hill numbers.

PubMed

Chiu, Chun-Huo; Chao, Anne

2014-01-01

Hill numbers (or the "effective number of species") are increasingly used to characterize species diversity of an assemblage. This work extends Hill numbers to incorporate species pairwise functional distances calculated from species traits. We derive a parametric class of functional Hill numbers, which quantify "the effective number of equally abundant and (functionally) equally distinct species" in an assemblage. We also propose a class of mean functional diversity (per species), which quantifies the effective sum of functional distances between a fixed species to all other species. The product of the functional Hill number and the mean functional diversity thus quantifies the (total) functional diversity, i.e., the effective total distance between species of the assemblage. The three measures (functional Hill numbers, mean functional diversity and total functional diversity) quantify different aspects of species trait space, and all are based on species abundance and species pairwise functional distances. When all species are equally distinct, our functional Hill numbers reduce to ordinary Hill numbers. When species abundances are not considered or species are equally abundant, our total functional diversity reduces to the sum of all pairwise distances between species of an assemblage. The functional Hill numbers and the mean functional diversity both satisfy a replication principle, implying the total functional diversity satisfies a quadratic replication principle. When there are multiple assemblages defined by the investigator, each of the three measures of the pooled assemblage (gamma) can be multiplicatively decomposed into alpha and beta components, and the two components are independent. The resulting beta component measures pure functional differentiation among assemblages and can be further transformed to obtain several classes of normalized functional similarity (or differentiation) measures, including N-assemblage functional generalizations of the classic Jaccard, Sørensen, Horn and Morisita-Horn similarity indices. The proposed measures are applied to artificial and real data for illustration.

New Downhole Strong-Motion Data Recorded at Tarzana Array

NASA Astrophysics Data System (ADS)

Graizer, V.; Shakal, A.; Haddadi, H.

2001-12-01

Significantly amplified ground accelerations at the Tarzana station were recorded during many, but not all, earthquakes (e.g., Shakal et al., 1988). Peak horizontal ground acceleration at the Tarzana station during the M7.1 Hector Mine earthquake was almost twice as large as the accelerations recorded at nearby stations. After the Northridge earthquake the California Strong Motion Instrumentation Program (CSMIP) significantly increased instrumentation at Tarzana to study the unusual site amplification effect. Current instrumentation at Tarzana consists of an accelerograph at the top of Tarzana hill (Tarzana - Cedar Hill B), a downhole instrument at 60 m depth, and an accelerograph at the foot of the hill (Tarzana - Clubhouse), 180 m from the Cedar Hill B station. The original station, Tarzana - Cedar Hill Nursery A, was lost in 1999 due to construction. Thirteen events, including the Hector Mine earthquake, were simultaneously recorded by these instruments at Tarzana. The downhole instrument (A) was used as a reference site to compare the amplification effects at the top of Tarzana hill (B) and at the foot of the hill (C). Spectral amplification from the bottom of the hole to the top of the hill (B/A) and to the foot of the hill (C/A) is similar along the component parallel to the strike of Tarzana hill. But B/A is almost double C/A along the component transverse to the strike of the hill in period range from 0.04 to 0.8 sec (1.2 to 25 Hz). Comparison of the response spectra demonstrates clear directional site response resonance (perpendicular to the strike of the hill) at Tarzana. In contrast to accelerations recorded during the Mw 7.1 Hector Mine earthquake (high frequency part of seismic signal), displacements (relatively low frequency part of seismic signal) demonstrate almost no site amplification from the bottom of the hole to the surface (B/A) at periods greater than 1.5 sec, in either direction. Ground displacements at other CSMIP downhole arrays which recorded the Hector Mine earthquake also demonstrate almost no near-surface site amplification at long periods. Comparison of empirical and theoretical site amplification effects at Tarzana was performed using SHAKE91 modeling motion separately in the longitudinal and transverse directions. The source of the site amplification that produces large motions at Tarzana is still under investigation. The topography, shear-wave velocity profile and three-dimensional structure of the site apparently all contribute to the higher amplification of ground motion at the Tarzana site. The studies of Tarzana were co-funded by CSMIP and by the National Science Foundation (NSF) through the Resolution of Site Response Issues from the Northridge Earthquake Project (ROSRINE).

Reconstructed Paleo-topography of the Columbia Hills, Mars

NASA Astrophysics Data System (ADS)

Cole, S. B.; Watters, W. A.; Aron, F.; Squyres, S. W.

2013-12-01

From June 2004 through March 2010, the Mars Exploration Rover Spirit conducted a detailed campaign examining the Columbia Hills of Gusev Crater. In addition to mineralogical and chemical investigations, Spirit's stereo panoramic (Pancam) and navigation (Navcam) cameras obtained over 7,000 images of geologic targets along the West Spur of the Columbia Hills and Husband Hill, the highest peak. We have analyzed the entirety of this dataset, which includes stereo coverage of several outcrop exposures with apparent bedding. We have measured the bedding plane orientations of hundreds of fine-scale (~1-100cm) features on all of the potentially in-place outcrops using Digital Terrain Models (DTMs) derived from the rover's Pancam stereo image data, and mapped these orientations on a regional HiRISE image and DTM. Assuming that the bedding material was deposited conformably on the topography at the time of emplacement, we reconstruct the paleo-topography of the Columbia Hills. Our reconstructed paleo-topography is similar to the modern shape of Husband Hill, but with steeper slopes, consistent with a substantial amount of erosion since deposition. The Columbia Hills are an irregular, nearly-triangular edifice of uncertain origin, situated near the center of the 160km-diameter crater and hypothesized to be either the remnant of a central peak structure, or overlapping crater rims. They span ~6.6 km in the northerly direction by ~3.6 km in the easterly direction, and rise 90m above the basaltic plains that fill the floor of Gusev Crater and embay the Hills. The topography is as irregular as the perimeter, and is cut by numerous valleys of varying lengths, widths, and directional trends. Along the traverse, Spirit examined several rock classes as defined by elemental abundances from the Alpha Particle X-ray Spectrometer (APXS) and identified remotely by the Miniature Thermal Emission Spectrometer (Mini-TES). Unlike the Gusev Plains, the rocks of the Columbia Hills show extensive evidence of aqueous alteration. Many of the outcrops are believed to have formed from volcanic and/or impact-related airfall material, which should drape the topography that existed at the time of emplacement. Outcrop bedding plane orientations are not consistent with the depositional material draping the current Columbia Hills edifice: dip magnitudes are steeper than the modern topographic slopes, and dip directions are not correlated with the modern topographic slope directions. There are, however, regional trends consistent with the outcrops draping an ancient underlying topography. Planes representing compositionally similar outcrops on the modern Husband Hill summit and to the northwest converge over the modern Tennessee Valley. If the paleo-structure culminated in the peak suggested by the bedding plane orientations, up to 100m of material may have been removed from the Columbia Hills.

Presence of a consensus DNA motif at nearby DNA sequence of the mutation susceptible CG nucleotides.

PubMed

Chowdhury, Kaushik; Kumar, Suresh; Sharma, Tanu; Sharma, Ankit; Bhagat, Meenakshi; Kamai, Asangla; Ford, Bridget M; Asthana, Shailendra; Mandal, Chandi C

2018-01-10

Complexity in tissues affected by cancer arises from somatic mutations and epigenetic modifications in the genome. The mutation susceptible hotspots present within the genome indicate a non-random nature and/or a position specific selection of mutation. An association exists between the occurrence of mutations and epigenetic DNA methylation. This study is primarily aimed at determining mutation status, and identifying a signature for predicting mutation prone zones of tumor suppressor (TS) genes. Nearby sequences from the top five positions having a higher mutation frequency in each gene of 42 TS genes were selected from a cosmic database and were considered as mutation prone zones. The conserved motifs present in the mutation prone DNA fragments were identified. Molecular docking studies were done to determine putative interactions between the identified conserved motifs and enzyme methyltransferase DNMT1. Collective analysis of 42 TS genes found GC as the most commonly replaced and AT as the most commonly formed residues after mutation. Analysis of the top 5 mutated positions of each gene (210 DNA segments for 42 TS genes) identified that CG nucleotides of the amino acid codons (e.g., Arginine) are most susceptible to mutation, and found a consensus DNA "T/AGC/GAGGA/TG" sequence present in these mutation prone DNA segments. Similar to TS genes, analysis of 54 oncogenes not only found CG nucleotides of the amino acid Arg as the most susceptible to mutation, but also identified the presence of similar consensus DNA motifs in the mutation prone DNA fragments (270 DNA segments for 54 oncogenes) of oncogenes. Docking studies depicted that, upon binding of DNMT1 methylates to this consensus DNA motif (C residues of CpG islands), mutation was likely to occur. Thus, this study proposes that DNMT1 mediated methylation in chromosomal DNA may decrease if a foreign DNA segment containing this consensus sequence along with CG nucleotides is exogenously introduced to dividing cancer cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Retrospective Analysis of Serotype Switching of Vibrio cholerae O1 in a Cholera Endemic Region Shows It Is a Non-random Process.

PubMed

Karlsson, Stefan L; Thomson, Nicholas; Mutreja, Ankur; Connor, Thomas; Sur, Dipika; Ali, Mohammad; Clemens, John; Dougan, Gordon; Holmgren, Jan; Lebens, Michael

2016-10-01

Genomic data generated from clinical Vibrio cholerae O1 isolates collected over a five year period in an area of Kolkata, India with seasonal cholera outbreaks allowed a detailed genetic analysis of serotype switching that occurred from Ogawa to Inaba and back to Ogawa. The change from Ogawa to Inaba resulted from mutational disruption of the methyltransferase encoded by the wbeT gene. Re-emergence of the Ogawa serotype was found to result either from expansion of an already existing Ogawa clade or reversion of the mutation in an Inaba clade. Our data suggests that such transitions are not random events but rather driven by as yet unidentified selection mechanisms based on differences in the structure of the O1 antigen or in the serotype-determining wbeT gene.

Genetic variability and effective population size when local extinction and recolonization of subpopulations are frequent

PubMed Central

Maruyama, Takeo; Kimura, Motoo

1980-01-01

If a population (species) consists of n haploid lines (subpopulations) which reproduce asexually and each of which is subject to random extinction and subsequent replacement, it is shown that, at equilibrium in which mutational production of new alleles and their random extinction balance each other, the genetic diversity (1 minus the sum of squares of allelic frequencies) is given by 2Nev/(1 + 2Nev), where [Formula: see text] in which Ñ is the harmonic mean of the population size per line, n is the number of lines (assumed to be large), λ is the rate of line extinction, and v is the mutation rate (assuming the infinite neutral allele model). In a diploid population (species) consisting of n colonies, if migration takes place between colonies at the rate m (the island model) in addition to extinction and recolonization of colonies, it is shown that effective population size is [Formula: see text] If the rate of colony extinction (λ) is much larger than the migration rate of individuals, the effective population size is greatly reduced compared with the case in which no colony extinctions occur (in which case Ne = nÑ). The stepping-stone type of recolonization scheme is also considered. Bearing of these results on the interpretation of the level of genetic variability at the enzyme level observed in natural populations is discussed from the standpoint of the neutral mutation-random drift hypothesis. PMID:16592920

Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma.

PubMed

Walker, Brian A; Mavrommatis, Konstantinos; Wardell, Christopher P; Ashby, T Cody; Bauer, Michael; Davies, Faith E; Rosenthal, Adam; Wang, Hongwei; Qu, Pingping; Hoering, Antje; Samur, Mehmet; Towfic, Fadi; Ortiz, Maria; Flynt, Erin; Yu, Zhinuan; Yang, Zhihong; Rozelle, Dan; Obenauer, John; Trotter, Matthew; Auclair, Daniel; Keats, Jonathan; Bolli, Niccolo; Fulciniti, Mariateresa; Szalat, Raphael; Moreau, Philippe; Durie, Brian; Stewart, A Keith; Goldschmidt, Hartmut; Raab, Marc S; Einsele, Hermann; Sonneveld, Pieter; San Miguel, Jesus; Lonial, Sagar; Jackson, Graham H; Anderson, Kenneth C; Avet-Loiseau, Herve; Munshi, Nikhil; Thakurta, Anjan; Morgan, Gareth J

2018-06-08

Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1,273 newly diagnosed patients with multiple myeloma we identify 63 driver genes, some of which are novel including IDH1 , IDH2 , HUWE1 , KLHL6 , and PTPN11 Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure. Patients with more mutations in driver genes are associated with a worse outcome, as are those with identified mechanisms of genomic instability. Oncogenic dependencies were identified between mutations in driver genes, common regions of copy number change, and primary translocation and hyperdiploidy events. These dependencies included associations with t(4;14) and mutations in FGFR3 , DIS3 and PRKD2 ; t(11;14) with mutations in CCND1 and IRF4 ; t(14;16) with mutations in MAF , BRAF , DIS3 and ATM ; and hyperdiploidy with gain 11q, mutations in FAM46C and MYC rearrangements. These associations indicate that the genomic landscape of myeloma is pre-determined by the primary events upon which further dependencies are built, giving rise to a non-random accumulation of genetic hits. Understanding these dependencies may elucidate potential evolutionary patterns and lead to better treatment regimens. Copyright © 2018 American Society of Hematology.

Mutation screening of the HGD gene identifies a novel alkaptonuria mutation with significant founder effect and high prevalence.

PubMed

Sakthivel, Srinivasan; Zatkova, Andrea; Nemethova, Martina; Surovy, Milan; Kadasi, Ludevit; Saravanan, Madurai P

2014-05-01

Alkaptonuria (AKU) is an autosomal recessive disorder; caused by the mutations in the homogentisate 1, 2-dioxygenase (HGD) gene located on Chromosome 3q13.33. AKU is a rare disorder with an incidence of 1: 250,000 to 1: 1,000,000, but Slovakia and the Dominican Republic have a relatively higher incidence of 1: 19,000. Our study focused on studying the frequency of AKU and identification of HGD gene mutations in nomads. HGD gene sequencing was used to identify the mutations in alkaptonurics. For the past four years, from subjects suspected to be clinically affected, we found 16 positive cases among a randomly selected cohort of 41 Indian nomads (Narikuravar) settled in the specific area of Tamil Nadu, India. HGD gene mutation analysis showed that 11 of these patients carry the same homozygous splicing mutation c.87 + 1G > A; in five cases, this mutation was found to be heterozygous, while the second AKU-causing mutation was not identified in these patients. This result indicates that the founder effect and high degree of consanguineous marriages have contributed to AKU among nomads. Eleven positive samples were homozygous for a novel mutation c.87 + 1G > A, that abolishes an intron 2 donor splice site and most likely causes skipping of exon 2. The prevalence of AKU observed earlier seems to be highly increased in people of nomadic origin. © 2014 John Wiley & Sons Ltd/University College London.

Spontaneous mutation rate is a plastic trait associated with population density across domains of life.

PubMed

Krašovec, Rok; Richards, Huw; Gifford, Danna R; Hatcher, Charlie; Faulkner, Katy J; Belavkin, Roman V; Channon, Alastair; Aston, Elizabeth; McBain, Andrew J; Knight, Christopher G

2017-08-01

Rates of random, spontaneous mutation can vary plastically, dependent upon the environment. Such plasticity affects evolutionary trajectories and may be adaptive. We recently identified an inverse plastic association between mutation rate and population density at 1 locus in 1 species of bacterium. It is unknown how widespread this association is, whether it varies among organisms, and what molecular mechanisms of mutagenesis or repair are required for this mutation-rate plasticity. Here, we address all 3 questions. We identify a strong negative association between mutation rate and population density across 70 years of published literature, comprising hundreds of mutation rates estimated using phenotypic markers of mutation (fluctuation tests) from all domains of life and viruses. We test this relationship experimentally, determining that there is indeed density-associated mutation-rate plasticity (DAMP) at multiple loci in both eukaryotes and bacteria, with up to 23-fold lower mutation rates at higher population densities. We find that the degree of plasticity varies, even among closely related organisms. Nonetheless, in each domain tested, DAMP requires proteins scavenging the mutagenic oxidised nucleotide 8-oxo-dGTP. This implies that phenotypic markers give a more precise view of mutation rate than previously believed: having accounted for other known factors affecting mutation rate, controlling for population density can reduce variation in mutation-rate estimates by 93%. Widespread DAMP, which we manipulate genetically in disparate organisms, also provides a novel trait to use in the fight against the evolution of antimicrobial resistance. Such a prevalent environmental association and conserved mechanism suggest that mutation has varied plastically with population density since the early origins of life.

Spontaneous mutation rate is a plastic trait associated with population density across domains of life

PubMed Central

Gifford, Danna R.; Hatcher, Charlie; Faulkner, Katy J.; Belavkin, Roman V.; Channon, Alastair; Aston, Elizabeth; McBain, Andrew J.

2017-01-01

Rates of random, spontaneous mutation can vary plastically, dependent upon the environment. Such plasticity affects evolutionary trajectories and may be adaptive. We recently identified an inverse plastic association between mutation rate and population density at 1 locus in 1 species of bacterium. It is unknown how widespread this association is, whether it varies among organisms, and what molecular mechanisms of mutagenesis or repair are required for this mutation-rate plasticity. Here, we address all 3 questions. We identify a strong negative association between mutation rate and population density across 70 years of published literature, comprising hundreds of mutation rates estimated using phenotypic markers of mutation (fluctuation tests) from all domains of life and viruses. We test this relationship experimentally, determining that there is indeed density-associated mutation-rate plasticity (DAMP) at multiple loci in both eukaryotes and bacteria, with up to 23-fold lower mutation rates at higher population densities. We find that the degree of plasticity varies, even among closely related organisms. Nonetheless, in each domain tested, DAMP requires proteins scavenging the mutagenic oxidised nucleotide 8-oxo-dGTP. This implies that phenotypic markers give a more precise view of mutation rate than previously believed: having accounted for other known factors affecting mutation rate, controlling for population density can reduce variation in mutation-rate estimates by 93%. Widespread DAMP, which we manipulate genetically in disparate organisms, also provides a novel trait to use in the fight against the evolution of antimicrobial resistance. Such a prevalent environmental association and conserved mechanism suggest that mutation has varied plastically with population density since the early origins of life. PMID:28837573

Integrating remotely sensed land cover observations and a biogeochemical model for estimating forest ecosystem carbon dynamics

USGS Publications Warehouse

Liu, J.; Liu, S.; Loveland, Thomas R.; Tieszen, L.L.

2008-01-01

Land cover change is one of the key driving forces for ecosystem carbon (C) dynamics. We present an approach for using sequential remotely sensed land cover observations and a biogeochemical model to estimate contemporary and future ecosystem carbon trends. We applied the General Ensemble Biogeochemical Modelling System (GEMS) for the Laurentian Plains and Hills ecoregion in the northeastern United States for the period of 1975-2025. The land cover changes, especially forest stand-replacing events, were detected on 30 randomly located 10-km by 10-km sample blocks, and were assimilated by GEMS for biogeochemical simulations. In GEMS, each unique combination of major controlling variables (including land cover change history) forms a geo-referenced simulation unit. For a forest simulation unit, a Monte Carlo process is used to determine forest type, forest age, forest biomass, and soil C, based on the Forest Inventory and Analysis (FIA) data and the U.S. General Soil Map (STATSGO) data. Ensemble simulations are performed for each simulation unit to incorporate input data uncertainty. Results show that on average forests of the Laurentian Plains and Hills ecoregion have been sequestrating 4.2 Tg C (1 teragram = 1012 gram) per year, including 1.9 Tg C removed from the ecosystem as the consequences of land cover change. ?? 2008 Elsevier B.V.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berryman, J. G.

While the well-known Voigt and Reuss (VR) bounds, and the Voigt-Reuss-Hill (VRH) elastic constant estimators for random polycrystals are all straightforwardly calculated once the elastic constants of anisotropic crystals are known, the Hashin-Shtrikman (HS) bounds and related self-consistent (SC) estimators for the same constants are, by comparison, more difficult to compute. Recent work has shown how to simplify (to some extent) these harder to compute HS bounds and SC estimators. An overview and analysis of a subsampling of these results is presented here with the main point being to show whether or not this extra work (i.e., in calculating bothmore » the HS bounds and the SC estimates) does provide added value since, in particular, the VRH estimators often do not fall within the HS bounds, while the SC estimators (for good reasons) have always been found to do so. The quantitative differences between the SC and the VRH estimators in the eight cases considered are often quite small however, being on the order of ±1%. These quantitative results hold true even though these polycrystal Voigt-Reuss-Hill estimators more typically (but not always) fall outside the Hashin-Shtrikman bounds, while the self-consistent estimators always fall inside (or on the boundaries of) these same bounds.« less

The evolution of recombination rates in finite populations during ecological speciation.

PubMed

Reeve, James; Ortiz-Barrientos, Daniel; Engelstädter, Jan

2016-10-26

Recombination can impede ecological speciation with gene flow by mixing locally adapted genotypes with maladapted migrant genotypes from a divergent population. In such a scenario, suppression of recombination can be selectively favoured. However, in finite populations evolving under the influence of random genetic drift, recombination can also facilitate adaptation by reducing Hill-Robertson interference between loci under selection. In this case, increased recombination rates can be favoured. Although these two major effects on recombination have been studied individually, their joint effect on ecological speciation with gene flow remains unexplored. Using a mathematical model, we investigated the evolution of recombination rates in two finite populations that exchange migrants while adapting to contrasting environments. Our results indicate a two-step dynamic where increased recombination is first favoured (in response to the Hill-Robertson effect), and then disfavoured, as the cost of recombining locally with maladapted migrant genotypes increases over time (the maladaptive gene flow effect). In larger populations, a stronger initial benefit for recombination was observed, whereas high migration rates intensify the long-term cost of recombination. These dynamics may have important implications for our understanding of the conditions that facilitate incipient speciation with gene flow and the evolution of recombination in finite populations. © 2016 The Author(s).

Advancing Our Understanding of the Etiologies and Mutational Landscapes of Basal-Like, Luminal A, and Luminal B Breast Cancers

DTIC Science & Technology

2014-10-01

Under Dr. Li’s supervision, the study coordinator, Ms. Taylor, will oversee the training of the study’s field and random digit dialing (RDD...so that luminal A and luminal B cases can be distinguished from each other. All triple-negative cases will be evaluated for EGFR and cytokeratin 5/6...mutations and small indels will be validated by PCR amplification of the identified exons in tumor and matched normal DNA followed by PCR cleanup using

Advancing Our Understanding of the Etiologies and Mutational Landscapes of Basal-Like, Luminal A, and Luminal B Breast Cancers

DTIC Science & Technology

2013-10-01

will oversee the training of the study’s field and random digit dialing (RDD) interviewers. To support this and on-going training, Ms. Taylor will...luminal A and luminal B cases can be distinguished from each other. All Page 9 triple-negative cases will be evaluated for EGFR and cytokeratin 5/6...point mutations and small indels will be validated by PCR amplification of the identified exons in tumor and matched normal DNA followed by PCR

Multiple Site-Directed and Saturation Mutagenesis by the Patch Cloning Method.

PubMed

Taniguchi, Naohiro; Murakami, Hiroshi

2017-01-01

Constructing protein-coding genes with desired mutations is a basic step for protein engineering. Herein, we describe a multiple site-directed and saturation mutagenesis method, termed MUPAC. This method has been used to introduce multiple site-directed mutations in the green fluorescent protein gene and in the moloney murine leukemia virus reverse transcriptase gene. Moreover, this method was also successfully used to introduce randomized codons at five desired positions in the green fluorescent protein gene, and for simple DNA assembly for cloning.

Rare Plants and Animals of the Texas Hill Country: Educator's Guide.

ERIC Educational Resources Information Center

Texas State Dept. of Parks and Wildlife, Austin.

Texas Hill Country is a land of fresh water springs, stony hills, and steep canyons and home to many rare plants and animals. Six activities for grades 3-5 and six activities for grades 6-12 are contained in this guide. Elementary activity highlights include using "The Lorax" by Dr. Seuss to stimulate critical thinking about…

Indian Hills Community College Vocational Outreach Program: Business/Industry and Indian Hills...Partners in Progress.

ERIC Educational Resources Information Center

Poort, Stephen M.; Williamson, Tom

Structured interviews were conducted by selected vocational education instructors at Indian Hills Community College (IHCC) to determine current and projected employment and training needs of private-sector businesses with 200 employees or less and to assess opinions of IHCC programs. Employers were asked to provide information on the number of…

The "House" in Half Hollow Hills

ERIC Educational Resources Information Center

Karnilow, Sheldon

2006-01-01

In this article, the author relates how he initiated a systemic improvement to Half Hollow Hills school district when he became its superintendent. He relates that although he came to Half Hollow Hills with a deep understanding of the models of systemic change, he did not bring with him a specific prescriptive plan for improvement. His plan for…

Development and Validation of a Tool for Measurement of Patient Satisfaction with Nursing Care at Oak Hill Hospital.

ERIC Educational Resources Information Center

Callow, Elizabeth K.

The Department of Nursing at Oak Hill Hospital, Spring Hill (Florida) did not have a measurement instrument for patient evaluation of hospital nursing services. An instrument to measure patient satisfaction with nursing was developed and validated. Criteria identified through a literature search were reviewed, modified, and validated by a…

27 CFR 9.49 - Central Delaware Valley.

Code of Federal Regulations, 2014 CFR

2014-04-01

... starting point of the following boundary description is the summit of Strawberry Hill, which is located in.... (2) Boundary Description: (i) From the summit of Strawberry Hill (475 feet) in a straight line to the... summit of Strawberry Hill (475 feet). [T.D. ATF-168, 49 FR 10117, Mar. 19, 1984, as amended by T.D. ATF...

27 CFR 9.49 - Central Delaware Valley.

Code of Federal Regulations, 2013 CFR

2013-04-01

... starting point of the following boundary description is the summit of Strawberry Hill, which is located in.... (2) Boundary Description: (i) From the summit of Strawberry Hill (475 feet) in a straight line to the... summit of Strawberry Hill (475 feet). [T.D. ATF-168, 49 FR 10117, Mar. 19, 1984, as amended by T.D. ATF...

27 CFR 9.49 - Central Delaware Valley.

Code of Federal Regulations, 2012 CFR

2012-04-01

... starting point of the following boundary description is the summit of Strawberry Hill, which is located in.... (2) Boundary Description: (i) From the summit of Strawberry Hill (475 feet) in a straight line to the... summit of Strawberry Hill (475 feet). [T.D. ATF-168, 49 FR 10117, Mar. 19, 1984, as amended by T.D. ATF...

27 CFR 9.49 - Central Delaware Valley.

Code of Federal Regulations, 2011 CFR

2011-04-01

... starting point of the following boundary description is the summit of Strawberry Hill, which is located in.... (2) Boundary Description: (i) From the summit of Strawberry Hill (475 feet) in a straight line to the... summit of Strawberry Hill (475 feet). [T.D. ATF-168, 49 FR 10117, Mar. 19, 1984, as amended by T.D. ATF...

Colleges as Shining Cities on a Hill

ERIC Educational Resources Information Center

Townsend, Kathleen Kennedy

2012-01-01

In this article, the author proposes that the notion of America be reintroduced as the "shining city on a hill," that abiding image from American history. The image of the shining city on a hill captures the imagination because it reflects the abiding truth that people become fully human in society, not outside of it. People need one…

AmeriFlux US-SdH Nebraska SandHills Dry Valley

DOE Data Explorer

Arkebauer, Tim J. [University of Nebraska; Billesbach, Dave [University of Nebraska

2016-01-01

This is the AmeriFlux version of the carbon flux data for the site US-SdH Nebraska SandHills Dry Valley. Site Description - The Nebraska SandHills Dry Valley tower is located on public land owned by the University of Nebraska-Lincoln. The site is on a research cattle ranch where grazing primarily takes place.

Species-area relations of song birds in the Black Hills, South Dakota

Treesearch

Mark A. Rumble; Brian L. Dykstra; Lester D. Flake

2000-01-01

We investigated the effects of stand size resulting from current logging practices on occurrence and species richness of song birds in the Black Hills. Richness of forest interior and forest interior/edge songbirds was not related to stand area (P > 0.40) in stands of ponderosa pine (Pinus ponderosa) in the Black Hills. Brown creepers (...

77 FR 36599 - Self-Regulatory Organizations; NYSE Arca, Inc.; Notice of Filing and Immediate Effectiveness of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-19

... Change Relating to the Accuvest Global Long Short ETF (Formerly the Mars Hill Global Relative Value ETF...) applicable to, the Accuvest Global Long Short ETF (``Fund'') (formerly known as the Mars Hill Global Relative... the Exchange of shares (``Shares'') of the Mars Hill Global Relative Value ETF, a series of Advisor...

Conservation assessment for bloodroot in the Black Hills National Forest, South Dakota and Wyoming

Treesearch

J. Hope Hornbeck; Carolyn Hull Sieg; Deanna J. Reyher

2003-01-01

Bloodroot, Sanguinaria canadensis L. (Papaveraceae), is a common spring flowering herb in the deciduous forests of eastern North America. It is disjunctly distributed in the northeastern Black Hills of South Dakota. There are 22 known occurrences of bloodroot on Black Hills National Forest in hardwood forests, shrub thickets, and floodplain habitats of limited...

76 FR 58292 - Announcement of Funding Awards for Fiscal Year 2011; Doctoral Dissertation Research Grant Program

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-20

... Harvard University, Ms. Kathryn Edin, President and Fellows of Harvard University, 1350 Massachusetts...: $25,000 to Tanja Kubas- Meyer. 9. University of North Carolina at Chapel Hill, Mr. William Rohe, University of North Carolina at Chapel Hill, 104 Airport Drive, Ste. 2200 CB 1350, Chapel Hill, NC 27599...

77 FR 9912 - Combined Notice of Filings #1

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-21

....m. ET 3/2/12. Docket Numbers: ER12-743-001. Applicants: Black Hills Power, Inc. Description: GDEMA.... Comments Due: 5 p.m. ET 3/2/12. Docket Numbers: ER12-748-001. Applicants: Black Hills Power, Inc...: 20120210-5178. Comments Due: 5 p.m. ET 3/2/12. Docket Numbers: ER12-750-001. Applicants: Black Hills Power...

Accounting for imperfect detection in Hill numbers for biodiversity studies

USGS Publications Warehouse

Broms, Kristin M.; Hooten, Mevin B.; Fitzpatrick, Ryan M.

2015-01-01

The occupancy-based Hill number estimators are always at their asymptotic values (i.e. as if an infinite number of samples have been taken for the study region), therefore making it easy to compare biodiversity between different assemblages. In addition, the Hill numbers are computed as derived quantities within a Bayesian hierarchical model, allowing for straightforward inference.

Microhabitats of Merriam's turkeys in the Black Hills, South Dakota

Treesearch

Mark A. Rumble; Stanley H. Anderson

1996-01-01

Merriam’s Turkeys (Meleagris gallopavo merriami) are associated with ponderosa pine (Pinus ponderosa) forests in the western United States, but are not native to the ponderosa pine forest of the Black Hills, South Dakota. The Black Hills population was established by transplanting birds from New Mexico and Colorado between 1948 and...

75 FR 20774 - Establishment of Class E Airspace; Fort A.P. Hill, VA

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-21

...-0739; Airspace Docket No. 09-AEA-14] Establishment of Class E Airspace; Fort A.P. Hill, VA AGENCY... December 7, 2009 that establishes Class E airspace at Fort A.P. Hill, VA. DATES: Effective Date: 0901 UTC... Service Center, Federal Aviation Administration, P.O. Box 20636, Atlanta, Georgia 30320; telephone (404...

78 FR 17714 - Notice of Availability of the HiLine District Draft Resource Management Plan and Draft...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-22

... (1988) and Sweet Grass Hills Amendment (1996) and Judith-Valley-Phillips Resource Management Plans (1994..., Kevin Rim, Mountain Plover, Prairie Dog Towns within the 7km Complex, and Sweet Grass Hills; these ACEC... Restrictions: Avoidance area for rights-of-way. Sweet Grass Hills ACEC (7,419 Acres) Relevant and Important...

75 FR 67997 - Notice of Correction to Notice of Intent To Prepare an Environmental Impact Statement for the Gas...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-04

... Hills Uranium Project, Fremont and Natrona Counties, WY AGENCY: Bureau of Land Management, Interior... Notice of Intent to Prepare an Environmental Impact Statement for the Gas Hills Uranium Project, Fremont... land description. The correct legal land description for the Gas Hills Uranium Project location is as...

27 CFR 9.49 - Central Delaware Valley.

Code of Federal Regulations, 2010 CFR

2010-04-01

... starting point of the following boundary description is the summit of Strawberry Hill, which is located in.... (2) Boundary Description: (i) From the summit of Strawberry Hill (475 feet) in a straight line to the... summit of Strawberry Hill (475 feet). [T.D. ATF-168, 49 FR 10117, Mar. 19, 1984, as amended by T.D. ATF...

Management Decisions and the "Dred" Hills

Treesearch

Steven W. Anderson

1992-01-01

An area of public land called the Red Hills was being so abused by the public that it was often called the "Dred" Hills. Some staff work had been accomplished to protect sensitive areas within the 7,200-acre site, but depreciative behavior continued. Primary destructive activities included off-road vehicle use and indiscriminate shooting and dumping. This...

Multiple-scale roost habitat comparisons of female Merriam's wild turkeys in the southern Black Hills, South Dakota

Treesearch

Daniel J. Thompson; Mark A. Rumble; Lester D. Flake; Chad P. Lehman

2009-01-01

Because quantity and quality of roosting habitat can affect Merriam's Wild Turkey (Meleagris gallopavo merriami) distribution, we described habitat characteristics of Merriam's turkey roost sites in the southern Black Hills of South Dakota. Varying proportions of Merriam's turkeys in the southern Black Hills depended on supplemental feed from livestock...

Silviculture of ponderosa pine in the Black Hills: The status of our knowledge

Treesearch

Charles E. Boldt; James L. Van Deusen

1974-01-01

This Paper, intended as a guide for professional foresters, describes major silvicultural conditions likely to be encountered in the Black Hills, reasonable treatment options, and probable results and implications of these treatments. It also describes silvical characteristics and behavior of Black Hills ponderosa pine, and a variety of proven silvicultural tools....

HILL: The High-Intensity Laser Laboratory Core Team's Reply to Questions from the NNSA Experimental Facilities Panel

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albright, B J

2012-08-02

Question 1 - The type of physics regimes that HILL can access for weapons studies is quite interesting. The question that arises for the proposal team is what priority does this type of experimental data have versus data that can be obtained with NIF, and Z. How does HILL rank in priority compared to MARIE 1.0 in terms of the experimental data it will provide? We reiterate that isochoric heating experiments to be conducted with HILL are complementary to the high energy density physics experiments at NIF and Z and uniquely access states of matter that neither other facility canmore » access. It is our belief that HILL will enable several important questions, e.g., as related to mix morphology, radiation transfer from corrugated surfaces, and equations of state, to be run to ground through carefully diagnosed, 'unit-physics' experiments. Such experiments will substantially improve confidence in our computer models and provide a rigorous science basis for certification. Question 2 - A secondary question relates to the interests of LLNL and SNL in the physics that HILL can address. This should be spelled out clearly. I would like to see the other labs be part of the discussion regarding how important this capability would be if built. Both sister Labs have a keen interest in the physics enabled by high-intensity, high-energy lasers, as evinced by the Z Petawatt and NIF ARC upgrades to their signature facilities. LANL scientists have teamed with scientists from both Laboratories in high-intensity laser 'first experiments' envisioned for HILL and we fully intend to continue these profitable discussions going forward. In the preparation of the HILL proposal, feedback was solicited from the broader HEDP and weapons science communities. The consensus view was that HILL filled a critical gap and that there was a need for a facility like HILL to address outstanding questions in weapons science. It was recognized that co-location of HILL with a facility such as MaRIE 1.0, Z, NIF, or Omega may offer additional advantages and we would expect these to be explored and evaluated during the CD process. Question 3 - A laser/optics experts group should review this proposal to ensure the level of R&D is reasonable to provide a sufficient chance of success (>50%). In the preparation of the HILL proposal, we sent our proposal and cost estimates to laser designers/scientists across the complex. Though risks were identified with our design, the prevailing view of those we engaged was that the risks were appropriately represented by the TRL levels assigned and that the enabling R&D planned in our proposal was adequate for risk mitigation. Question 4 - More data and peer review is needed from its sister facilities around the world. It is our specific intent to conduct both scientific and technical workshops with the user community if the High Intensity Science field is further encouraged as part of the NNSA Roadmap. Question 5 - Does HILL have to be co-located with MARIE 1.0? Is that feasible from the point of view of TA-53 real estate? Multiple siting options were considered for HILL, including co-location with MaRIE 1.0 (the most cost-effective and flexible option), as well as in a separate, stand-alone building and in a retro-fitted existing building. The cost estimate included these contingencies and candidate locations for HILL in TA-53 were identified. There is actually significant space at TA-53 on the hill in the northeast end of the mesa. Question 6 - What would be the impact on the weapons program if this facility were NOT built? An inability to elucidate aspects of weapons science in the dense plasma regime and validate computer models for same. This will lead to reduced confidence in the computer tools used for certification. Question 7 - Will HILL allow some of the x-ray vulnerability studies proposed by SPARC? If so what does Sandia's vulnerability group think of this method versus SPARC. It is possible that some of the scope envisioned for SPARC could be achieved on HILL, although likely that the energy produced at HILL not being at all close to requirements. We would welcome these discussions with our SNL colleagues. Question 8 - The committee had the opinion that present laser facilities could better be modified to meet this mission need. HILL satisfies a mission need for rapid isochoric heating of materials into conditions relevant to boost with quantitative control of the variables. This is accomplished through particle generation and acceleration mechanisms that require ultra-short (sub-100 femtosecond, we estimate actually sub-30 femtosecond) laser pulses. To generate such very short pulses, high bandwidth is required in the laser system. However, such bandwidth is not possible with current high-energy glass laser systems, so new lasers must be built to meet this requirement.« less

Gene-targeted Random Mutagenesis to Select Heterochromatin-destabilizing Proteasome Mutants in Fission Yeast.

PubMed

Seo, Hogyu David; Lee, Daeyoup

2018-05-15

Random mutagenesis of a target gene is commonly used to identify mutations that yield the desired phenotype. Of the methods that may be used to achieve random mutagenesis, error-prone PCR is a convenient and efficient strategy for generating a diverse pool of mutants (i.e., a mutant library). Error-prone PCR is the method of choice when a researcher seeks to mutate a pre-defined region, such as the coding region of a gene while leaving other genomic regions unaffected. After the mutant library is amplified by error-prone PCR, it must be cloned into a suitable plasmid. The size of the library generated by error-prone PCR is constrained by the efficiency of the cloning step. However, in the fission yeast, Schizosaccharomyces pombe, the cloning step can be replaced by the use of a highly efficient one-step fusion PCR to generate constructs for transformation. Mutants of desired phenotypes may then be selected using appropriate reporters. Here, we describe this strategy in detail, taking as an example, a reporter inserted at centromeric heterochromatin.

Clustering and Phase Transitions on a Neutral Landscape

NASA Astrophysics Data System (ADS)

Scott, Adam; King, Dawn; Maric, Nevena; Bahar, Sonya

2012-02-01

The problem of speciation and species aggregation on a neutral landscape, subject to random mutational fluctuations rather than selective drive, has been a focus of research since the seminal work of Kimura on genetic drift. These ideas have received increased attention due to the more recent development of a neutral ecological theory by Hubbell. De Aguiar et al. recently demonstrated, in a computational model, that speciation can occur under neutral conditions; this study bears some comparison with more mathematical studies of clustering on neutral landscapes in the context of branching and annihilating random walks. Here, we show that clustering can occur on a neutral landscape where the dimensions specify the simulated organisms' phenotypes. Unlike the De Aguiar et al. model, we simulate sympatric speciation: the organisms cluster phenotypically, but are not spatially separated. Moreover, we find that clustering occurs not only in the case of assortative mating, but also in the case of asexual fission. Clustering is not observed in a control case where organisms can mate randomly. We find that the population size and the number of clusters undergo phase-transition-like behavior as the maximum mutation size is varied.

Random domain name and address mutation (RDAM) for thwarting reconnaissance attacks

PubMed Central

Chen, Xi; Zhu, Yuefei

2017-01-01

Network address shuffling is a novel moving target defense (MTD) that invalidates the address information collected by the attacker by dynamically changing or remapping the host’s network addresses. However, most network address shuffling methods are limited by the limited address space and rely on the host’s static domain name to map to its dynamic address; therefore these methods cannot effectively defend against random scanning attacks, and cannot defend against an attacker who knows the target’s domain name. In this paper, we propose a network defense method based on random domain name and address mutation (RDAM), which increases the scanning space of the attacker through a dynamic domain name method and reduces the probability that a host will be hit by an attacker scanning IP addresses using the domain name system (DNS) query list and the time window methods. Theoretical analysis and experimental results show that RDAM can defend against scanning attacks and worm propagation more effectively than general network address shuffling methods, while introducing an acceptable operational overhead. PMID:28489910

George William Hill, the Great but Unknown 19th Century Celestial Mechanician

NASA Astrophysics Data System (ADS)

Corbin, Brenda G.

2012-01-01

George William Hill (1838-1914) has long been considered one of the most famous and talented celestial mechanicians of the past century and a half. However, many people have never heard of him and his work. Simon Newcomb said he "will easily rank as the greatest master of mathematical astronomy during the last quarter of the nineteenth century.” After receiving a B.A. at Rutgers in 1859, Hill began work in 1861 at the office of the American Ephemeris and Nautical Almanac in Cambridge, MA. He moved to Washington with the group in 1882 which then became part of the U. S. Naval Observatory. Newcomb, beginning his work on planetary motion, assigned the theory of Jupiter and Saturn to him, calling it about the most difficult topic. Hill's work was published by the USNO in 1890 as A New Theory of Jupiter and Saturn. From 1898 to 1901, Hill lectured on the subject of celestial mechanics at Columbia University in a position created just for him. After 1892 and until his death, he lived at the family homestead in West Nyack, NY. He never married, was something of a recluse, and spent most of his time with his books and research. Hill was an amateur botanist and enjoyed exploring on long walks in the countryside. Many honors and awards came to him during his lifetime, both from the U.S. and abroad, including serving as president of the American Mathematical Society. All of Hill's mathematical and astronomical research was incorporated in The Collected Mathematical Works of George William Hill. This work, containing a preface in French by Poincare, was published in 4 large volumes by the Carnegie Institution of Washington in 1905.

Episodic Holocene eruption of the Salton Buttes rhyolites, California, from paleomagnetic, U-Th, and Ar/Ar dating

USGS Publications Warehouse

Wright, Heather M.; Vazquez, Jorge A.; Champion, Duane E.; Calvert, Andrew T.; Mangan, Margaret T.; Stelten, Mark E.; Cooper, Kari M.; Herzig, Charles; Schriener Jr., Alexander

2015-01-01

In the Salton Trough, CA, five rhyolite domes form the Salton Buttes: Mullet Island, Obsidian Butte, Rock Hill, North and South Red Hill, from oldest to youngest. Results presented here include 40Ar/39Ar anorthoclase ages, 238U-230Th zircon crystallization ages, and comparison of remanent paleomagnetic directions with the secular variation curve, which indicate that all domes are Holocene. 238U-230Th zircon crystallization ages are more precise than but within uncertainty of 40Ar/39Ar anorthoclase ages, suggesting that zircon crystallization proceeded until shortly before eruption in all cases except one. Remanent paleomagnetic directions require three eruption periods: (1) Mullet Island, (2) Obsidian Butte, and (3) Rock Hill, North Red Hill, and South Red Hill. Borehole cuttings logs document up to two shallow tephra layers. North and South Red Hills likely erupted within 100 years of each other, with a combined 238U-230Th zircon isochron age of: 2.83 ± 0.60 ka (2 sigma); paleomagnetic evidence suggests this age predates eruption by hundreds of years (1800 cal BP). Rock Hill erupted closely in time to these eruptions. The Obsidian Butte 238U-230Th isochron age (2.86 ± 0.96 ka) is nearly identical to the combined Red Hill age, but its Virtual Geomagnetic Pole position suggests a slightly older age. The age of aphyric Mullet Island dome is the least well constrained: zircon crystals are resorbed and the paleomagnetic direction is most distinct; possible Mullet Island ages include ca. 2300, 5900, 6900, and 7700 cal BP. Our results constrain the duration of Salton Buttes volcanism to between ca. 5900 and 500 years.

Neogene Fault and Feeder Dike Patterns in the Western Ross Sea

NASA Astrophysics Data System (ADS)

Magee, W. R.; Wilson, T. J.

2010-12-01

In Antarctica, where much of the continent is covered by water and ice, geophysical data from the Antarctic submarine continental shelf is a fundamental part of reconstructing geological history. Multibeam sonar from the western Ross Sea has revealed elongate volcanic edifices and fields of elongate submarine hills on the seafloor. Origin of the submarine hills as carbonate mounds and drumlins have been proposed. The hills are up to ~8000m long and ~3500m wide, and rise 50-100m above the seafloor. Morphometric analysis of the hills shows they are elongate, with axial ratios ranging from 1.2:1 to 2:1, and some hills are linked to form elongate ridges. Seismic profiles show significant pull-ups directly below the hills, consistent with narrow, higher-density magmatic bodies; thus we favor an origin as volcanic seamounts above subsurface feeder dikes. If this volcanic hypothesis is correct, feeder dikes below the hills and elongate volcanic ridges may document magmatically-forced extension within the Terror Rift. The seamount field forms part of a regional en echelon array of volcanic ridges extending NNW from Beaufort Island toward Drygalski Ice Tongue. The ridges and elongate seamount cluster trend NNE, subparallel to mapped fault trends in this sector of the Terror Rift. This geometry is compatible with right-lateral transtension along this zone, as previously proposed for the Terror Rift as a whole. Volcanic islands and dredged volcanic ridges within the en echelon array are dated at ~7-4 Ma, implying Neogene deformation. We are completing a detailed analysis of orientation patterns and cross-cutting relations between faults and volcanic hills and their feeder systems to test this model for Neogene rift kinematics.

Spirit's Course

NASA Technical Reports Server (NTRS)

2004-01-01

[figure removed for brevity, see original site] [figure removed for brevity, see original site] Figure 1Figure 2

This digital elevation map shows the topography of the 'Columbia Hills,' just in front of the Mars Exploration Rover Spirit's current position. Rover planners have plotted the safest route for Spirit to climb to the front hill, called 'West Spur.' The black line in the middle of the image represents the rover's traverse path, which starts at 'Hank's Hollow' and ends at the top of 'West Spur.' Scientists are sending Spirit up the hill to investigate the interesting rock outcrops visible in images taken by the rover. Data from the Mars Orbital Camera on the orbiting Mars Global Surveyor were used to create this 3-D map.

In figure 1, the digital map shows the slopes of the 'Columbia Hills,' just in front of the Mars Exploration Rover Spirit's current position. Colors indicate the slopes of the hills, with red areas being the gentlest and blue the steepest. Rover planners have plotted the safest route for Spirit to climb the front hill, called 'West Spur.' The path is indicated here with a curved black line. Stereo images from the Mars Orbital Camera on the orbiting Mars Global Surveyor were used to create this 3-D map.

In figure 2, the map shows the north-facing slopes of the 'Columbia Hills,' just in front of the Mars Exploration Rover Spirit's current position. Bright areas indicate surfaces sloping more toward the north than dark areas. To reach the rock outcrop at the top of the hill, engineers will aim to drive the rover around the dark areas, which would yield less solar power. The curved black line in the middle represents the rover's planned traverse path.

Step-by-Step Technique for Segmental Reconstruction of Reverse Hill-Sachs Lesions Using Homologous Osteochondral Allograft.

PubMed

Alkaduhimi, Hassanin; van den Bekerom, Michel P J; van Deurzen, Derek F P

2017-06-01

Posterior shoulder dislocations are accompanied by high forces and can result in an anteromedial humeral head impression fracture called a reverse Hill-Sachs lesion. This reverse Hill-Sachs lesion can result in serious complications including posttraumatic osteoarthritis, posterior dislocations, osteonecrosis, persistent joint stiffness, and loss of shoulder function. Treatment is challenging and depends on the amount of bone loss. Several techniques have been reported to describe the surgical treatment of lesions larger than 20%. However, there is still limited evidence with regard to the optimal procedure. Favorable results have been reported by performing segmental reconstruction of the reverse Hill-Sachs lesion with bone allograft. Although the procedure of segmental reconstruction has been used in several studies, its technique has not yet been well described in detail. In this report we propose a step-by-step description of the technique how to perform a segmental reconstruction of a reverse Hill-Sachs defect.

Confidence Hills Mineralogy and Chemin Results from Base of Mt. Sharp, Pahrump Hills, Gale Crater, Mars

NASA Technical Reports Server (NTRS)

Cavanagh, P. D.; Bish, D. L.; Blake, D. F.; Vaniman, D. T.; Morris, R. V.; Ming, D. W.; Rampe, E. B.; Achilles, C. N.; Chipera, S. J.; Treiman, A. H.;

Functional Versatility of AGY Serine Codons in Immunoglobulin Variable Region Genes

PubMed Central

Detanico, Thiago; Phillips, Matthew; Wysocki, Lawrence J.

2016-01-01

In systemic autoimmunity, autoantibodies directed against nuclear antigens (Ags) often arise by somatic hypermutation (SHM) that converts AGT and AGC (AGY) Ser codons into Arg codons. This can occur by three different single-base changes. Curiously, AGY Ser codons are far more abundant in complementarity-determining regions (CDRs) of IgV-region genes than expected for random codon use or from species-specific codon frequency data. CDR AGY codons are also more abundant than TCN Ser codons. We show that these trends hold even in cartilaginous fishes. Because AGC is a preferred target for SHM by activation-induced cytidine deaminase, we asked whether the AGY abundance was solely due to a selection pressure to conserve high mutability in CDRs regardless of codon context but found that this was not the case. Instead, AGY triplets were selectively enriched in the Ser codon reading frame. Motivated by reports implicating a functional role for poly/autoreactive specificities in antiviral antibodies, we also analyzed mutations at AGY in antibodies directed against a number of different viruses and found that mutations producing Arg codons in antiviral antibodies were indeed frequent. Unexpectedly, however, we also found that AGY codons mutated often to encode nearly all of the amino acids that are reported to provide the most frequent contacts with Ag. In many cases, mutations producing codons for these alternative amino acids in antiviral antibodies were more frequent than those producing Arg codons. Mutations producing each of these key amino acids required only single-base changes in AGY. AGY is the only codon group in which two-thirds of random mutations generate codons for these key residues. Finally, by directly analyzing X-ray structures of immune complexes from the RCSB protein database, we found that Ag-contact residues generated via SHM occurred more often at AGY than at any other codon group. Thus, preservation of AGY codons in antibody genes appears to have been driven by their exceptional functional versatility, despite potential autoreactive consequences. PMID:27920779

Feature genes predicting the FLT3/ITD mutation in acute myeloid leukemia.

PubMed

Li, Chenglong; Zhu, Biao; Chen, Jiao; Huang, Xiaobing

2016-07-01

In the present study, gene expression profiles of acute myeloid leukemia (AML) samples were analyzed to identify feature genes with the capacity to predict the mutation status of FLT3/ITD. Two machine learning models, namely the support vector machine (SVM) and random forest (RF) methods, were used for classification. Four datasets were downloaded from the European Bioinformatics Institute, two of which (containing 371 samples, including 281 FLT3/ITD mutation-negative and 90 mutation‑positive samples) were randomly defined as the training group, while the other two datasets (containing 488 samples, including 350 FLT3/ITD mutation-negative and 138 mutation-positive samples) were defined as the test group. Differentially expressed genes (DEGs) were identified by significance analysis of the microarray data by using the training samples. The classification efficiency of the SCM and RF methods was evaluated using the following parameters: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and the area under the receiver operating characteristic curve. Functional enrichment analysis was performed for the feature genes with DAVID. A total of 585 DEGs were identified in the training group, of which 580 were upregulated and five were downregulated. The classification accuracy rates of the two methods for the training group, the test group and the combined group using the 585 feature genes were >90%. For the SVM and RF methods, the rates of correct determination, specificity and PPV were >90%, while the sensitivity and NPV were >80%. The SVM method produced a slightly better classification effect than the RF method. A total of 13 biological pathways were overrepresented by the feature genes, mainly involving energy metabolism, chromatin organization and translation. The feature genes identified in the present study may be used to predict the mutation status of FLT3/ITD in patients with AML.

Engineering dihydropteroate synthase (DHPS) for efficient expression on M13 phage.

PubMed

Brockmann, Eeva-Christine; Lamminmäki, Urpo; Saviranta, Petri

2005-06-20

Phage display is a commonly used selection technique in protein engineering, but not all proteins can be expressed on phage. Here, we describe the expression of a cytoplasmic homodimeric enzyme dihydropteroate synthetase (DHPS) on M13 phage, established by protein engineering of DHPS. The strategy included replacement of cysteine residues and screening for periplasmic expression followed by random mutagenesis and phage display selection with a conformation-specific anti-DHPS antibody. Cysteine replacement alone resulted in a 12-fold improvement in phage display of DHPS, but after random mutagenesis and three rounds of phage display selection, phage display efficiency of the library had improved 280-fold. Most of the selected clones had a common Asp96Asn mutation that was largely responsible for the efficient phage display of DHPS. Asp96Asn affected synergistically with the cysteine replacing mutations that were needed to remove the denaturing effect of potential wrong disulfide bridging in phage display. Asp96Asn alone resulted in a 1.8-fold improvement in phage display efficiency, but in combination with the cysteine replacing mutations, a total of 130-fold improvement in phage display efficiency of DHPS was achieved.

A case study of evolutionary computation of biochemical adaptation

NASA Astrophysics Data System (ADS)

François, Paul; Siggia, Eric D.

2008-06-01

Simulations of evolution have a long history, but their relation to biology is questioned because of the perceived contingency of evolution. Here we provide an example of a biological process, adaptation, where simulations are argued to approach closer to biology. Adaptation is a common feature of sensory systems, and a plausible component of other biochemical networks because it rescales upstream signals to facilitate downstream processing. We create random gene networks numerically, by linking genes with interactions that model transcription, phosphorylation and protein-protein association. We define a fitness function for adaptation in terms of two functional metrics, and show that any reasonable combination of them will yield the same adaptive networks after repeated rounds of mutation and selection. Convergence to these networks is driven by positive selection and thus fast. There is always a path in parameter space of continuously improving fitness that leads to perfect adaptation, implying that the actual mutation rates we use in the simulation do not bias the results. Our results imply a kinetic view of evolution, i.e., it favors gene networks that can be learned quickly from the random examples supplied by mutation. This formulation allows for deductive predictions of the networks realized in nature.

Enzymatic and antisense effects of a specific anti-Ki-ras ribozyme in vitro and in cell culture.

PubMed Central

Giannini, C D; Roth, W K; Piiper, A; Zeuzem, S

1999-01-01

Due to their mode of action, ribozymes show antisense effects in addition to their specific cleavage activity. In the present study we investigated whether a hammerhead ribozyme is capable of cleaving mutated Ki-ras mRNA in a pancreatic carcinoma cell line and whether antisense effects contribute to the activity of the ribozyme. A 2[prime]-O-allyl modified hammerhead ribozyme was designed to cleave specifically the mutated form of the Ki- ras mRNA (GUU motif in codon 12). The activity was monitored by RT-PCR on Ki- ras RNA expression by determination of the relative amount of wild type to mutant Ki-ras mRNA, by 5-bromo-2[prime]-deoxy-uridine incorporation on cell proliferation and by colony formation in soft agar on malignancy in the human pancreatic adenocarcinoma cell line CFPAC-1, which is heterozygous for the Ki-ras mutation. A catalytically inactive ribozyme was used as control to differentiate between antisense and cleavage activity and a ribozyme with random guide sequences as negative control. The catalytically active anti-Ki-ras ribozyme was at least 2-fold more potent in decreasing cellular Ki-ras mRNA levels, inhibiting cell proliferation and colony formation in soft agar than the catalytically inactive ribozyme. The catalytically active anti-Ki-ras ribozyme, but not the catalytically inactive or random ribozyme, increased the ratio of wild type to mutated Ki-ras mRNA in CFPAC-1 cells. In conclusion, both cleavage activity and antisense effects contribute to the activity of the catalytically active anti-Ki-ras hammerhead ribozyme. Specific ribozymes might be useful in the treatment of pancreatic carcinomas containing an oncogenic GTT mutation in codon 12 of the Ki-ras gene. PMID:10373591

Diltiazem Treatment for Preclinical Hypertrophic Cardiomyopathy Mutation Carriers: A Pilot Randomized Trial to Modify Disease Expression

PubMed Central

Ho, Carolyn Y.; Lakdawala, Neal K.; Cirino, Allison L.; Lipshultz, Steven E.; Sparks, Elizabeth; Abbasi, Siddique A.; Kwong, Raymond Y.; Antman, Elliott M.; Semsarian, Christopher; González, Arantxa; López, Begoña; Diez, Javier; Orav, E. John; Colan, Steven D.; Seidman, Christine E.

2014-01-01

Background Hypertrophic cardiomyopathy (HCM) is caused by sarcomere mutations and characterized by left ventricular hypertrophy (LVH) with increased risk of heart failure and sudden death. HCM typically cannot be diagnosed early in life, although subtle phenotypes are present. Animal studies indicate alterations in intracellular calcium handling before LVH develops. Furthermore, early treatment with diltiazem appeared to attenuate disease emergence. Objectives To assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy for at-risk HCM mutation carriers. Methods In a pilot, double-blind trial, we randomly assigned 38 sarcomere mutation carriers without LVH (mean age 15.8 years) to therapy with diltiazem 360 mg/day (or 5 mg/kg/day) or placebo. Treatment duration ranged from 12 to 42 months (median 25 months). Study procedures included electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serum biomarker measurement. Results Diltiazem was not associated with serious adverse events. Heart rate and blood pressure did not differ significantly between groups. However, mean left ventricular end diastolic diameter improved towards normal in the diltiazem group but decreased further in controls (change in z-scores, +0.6 vs. −0.5; P<0.001). Mean LV thickness-to-dimension ratio was stable in the diltiazem group, but increased in controls (−0.02 vs. +0.15; P=0.04). Among MYBPC3 mutation carriers, LV wall thickness and mass, diastolic filling, and cardiac troponin I levels improved in those taking diltiazem compared with controls. Four participants developed overt HCM, two in each treatment group. Conclusions Preclinical administration of diltiazem is safe and may improve early LV remodeling in HCM. This novel strategy merits further exploration. PMID:25543971

The Causality of Evolution on Different Fitness Landscapes

NASA Astrophysics Data System (ADS)

Vyawahare, Saurabh; Austin, Robert; Zhang, Qiucen; Kim, Hyunsung; Bestoso, John

2013-03-01

Evolution of antibiotic resistance is a growing problem. One major reason why most antibiotics fail is because of mutations on drug targets (e.g. essential enzymes). Sequencing of clinically resistant isolates have shown that multiple mutational-hotspots exist in coding regions, which could potentially prohibit the binding of drugs. However, it is not clear whether the appearance of each mutation is random or influenced by other factors. In this paper, we compare evolution of resistance to ciprofloxacin from two distinct but well characterized genetic backgrounds. By combining our recently developed evolution reactor and deep whole-genome sequencing, we show different alleles of σs factor lead to fixation of different mutations in gyrA gene that confer ciprofloxacin resistance to bacteria Escherichia coli. Such causality of evolution in different genes provides an opportunity to control the evolution of antibiotic resistance. Sponsored by the NCI/NIH Physical Sciences Oncology Centers

Generation of gene-corrected iPSC line from Parkinson's disease patient iPSC line with alpha-SNCA A53T mutation.

PubMed

Lee, Seo-Young; Jeong, SangKyun; Kim, Janghwan; Chung, Sun-Ku

2018-06-09

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder. PD can result from a mutation of alpha-synuclein (α-SNCA), such as α-SNCA A53T. Using episomal vectors, induced pluripotent stem cells (iPSCs) were generated from skin fibroblasts with the α-SNCA A53T mutation. A huge bacterial artificial chromosome (BAC) harboring the normal α-SNCA gene successfully corrected the α-SNCA A53T-mutant iPSCs. Melting curve analysis for allelic composition indicated that the BAC DNA was precisely targeted to the α-SNCA A53T mutation allele, without random integration. The corrected PD-iPSCs displayed the normal karyotype and pluripotency, with the capability to differentiate to any cell type. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

An Ethyl-Nitrosourea-Induced Point Mutation in Phex Causes Exon Skipping, X-Linked Hypophosphatemia, and Rickets

PubMed Central

Carpinelli, Marina R.; Wicks, Ian P.; Sims, Natalie A.; O’Donnell, Kristy; Hanzinikolas, Katherine; Burt, Rachel; Foote, Simon J.; Bahlo, Melanie; Alexander, Warren S.; Hilton, Douglas J.

2002-01-01

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G1) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease. PMID:12414538

An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets.

PubMed

Carpinelli, Marina R; Wicks, Ian P; Sims, Natalie A; O'Donnell, Kristy; Hanzinikolas, Katherine; Burt, Rachel; Foote, Simon J; Bahlo, Melanie; Alexander, Warren S; Hilton, Douglas J

2002-11-01

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G(1)) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease.

A novel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family.

PubMed

Anderson, S L; Chung, W K; Frezzo, J; Papp, J C; Ekstein, J; DiMauro, S; Rubin, B Y

2008-12-01

Leigh syndrome is a neurodegenerative disorder of infancy or childhood generally due to mutations in nuclear or mitochondrial genes involved in mitochondrial energy metabolism. We performed linkage analysis in an Ashkenazi Jewish (AJ) family without consanguinity with three affected children. Linkage to microsatellite markers D5S1969 and D5S407 led to evaluation of the complex I gene NDUFS4, in which we identified a novel homozygous c.462delA mutation that disrupts the reading frame. The resulting protein lacks a cAMP-dependent protein kinase phosphorylation site required for activation of mitochondrial respiratory chain complex I. In a random sample of 5000 healthy AJ individuals, the carrier frequency of the NDUFS4 mutation c.462delA was 1 in 1000, suggesting that it should be considered in all AJ patients with Leigh syndrome.

Occurrence of etravirine/rilpivirine-specific resistance mutations selected by efavirenz and nevirapine in Kenyan patients with non-B HIV-1 subtypes failing antiretroviral therapy.

PubMed

Crawford, Keith W; Njeru, Dorothy; Maswai, Jonah; Omondi, Milton; Apollo, Duncan; Kimetto, Jane; Gitonga, Lawrence; Munyao, James; Langat, Raphael; Aoko, Appolonia; Tarus, Jemutai; Khamadi, Samoel; Hamm, Tiffany E

2014-01-28

Resistance to efavirenz and nevirapine has not been associated with mutations at position 138 of reverse transcriptase. In an evaluation of virologic suppression rates in PEPFAR (President's Emergency Plan For AIDS Relief) clinics in Kenya among patients on first-line therapy (RV288), 63% (617/975) of randomly selected patients on antiretroviral therapy were suppressed (HIV RNA<400 copies/ml). Among those with non-nucleoside reverse transcriptase inhibitor resistance (n = 101), 14 (13.8%) had substitutions at 138 (A, G, K or Q), mutations selected only by etravirine and rilpivirine in subtype B viruses. All 14 patients received efavirenz or nevirapine, not etravirine or rilpivirine, and were predominantly subtype A1. This may be the first report of efavirenz and nevirapine selecting these mutations in these subtypes.

An Examination of Adaptive Reversion in Saccharomyces Cerevisiae

PubMed Central

Steele, D. F.; Jinks-Robertson, S.

1992-01-01

Reversion to Lys(+) prototrophy in a haploid yeast strain containing a defined lys2 frameshift mutation has been examined. When cells were plated on synthetic complete medium lacking only lysine, the numbers of Lys(+) revertant colonies accumulated in a time-dependent manner in the absence of any detectable increase in cell number. An examination of the distribution of the numbers of early appearing Lys(+) colonies from independent cultures suggests that the mutations to prototrophy occurred randomly during nonselective growth. In contrast, an examination of the distribution of late appearing Lys(+) colonies indicates that the underlying reversion events occurred after selective plating. No accumulation of Lys(+) revertants occurred when cells were starved for tryptophan, leucine or both lysine and tryptophan prior to plating selectively for Lys(+) revertants. These results indicate that mutations accumulate more frequently when they confer a selective advantage, and are thus consistent with the occurrence of adaptive mutations in yeast. PMID:1398066

Enzymatic synthesis of random sequences of RNA and RNA analogues by DNA polymerase theta mutants for the generation of aptamer libraries.

PubMed

Randrianjatovo-Gbalou, Irina; Rosario, Sandrine; Sismeiro, Odile; Varet, Hugo; Legendre, Rachel; Coppée, Jean-Yves; Huteau, Valérie; Pochet, Sylvie; Delarue, Marc

2018-05-21

Nucleic acid aptamers, especially RNA, exhibit valuable advantages compared to protein therapeutics in terms of size, affinity and specificity. However, the synthesis of libraries of large random RNAs is still difficult and expensive. The engineering of polymerases able to directly generate these libraries has the potential to replace the chemical synthesis approach. Here, we start with a DNA polymerase that already displays a significant template-free nucleotidyltransferase activity, human DNA polymerase theta, and we mutate it based on the knowledge of its three-dimensional structure as well as previous mutational studies on members of the same polA family. One mutant exhibited a high tolerance towards ribonucleotides (NTPs) and displayed an efficient ribonucleotidyltransferase activity that resulted in the assembly of long RNA polymers. HPLC analysis and RNA sequencing of the products were used to quantify the incorporation of the four NTPs as a function of initial NTP concentrations and established the randomness of each generated nucleic acid sequence. The same mutant revealed a propensity to accept other modified nucleotides and to extend them in long fragments. Hence, this mutant can deliver random natural and modified RNA polymers libraries ready to use for SELEX, with custom lengths and balanced or unbalanced ratios.

Needs Analysis for the West Hills College at Lemoore, West Hills Community College District. Commission Report.

ERIC Educational Resources Information Center

California State Postsecondary Education Commission, Sacramento.

This report reviews the proposal by the West Hills Community College District (WHCCD) (California) to transition its off-campus center to full college status. The proposal's objectives include: (1) establishing a new comprehensive college that will serve approximately 1,700 full-time-equivalent students by 2015; and (2) providing greater access to…

Sharing the Gift of Jazz: An Interview with Willie L. Hill Jr.

ERIC Educational Resources Information Center

Howe, Brad

2011-01-01

This article presents an interview with Willie L. Hill Jr., founder and director of the Society for Jazz Education. Currently a professor of music education at the University of Massachusetts-Amherst and the director of the UMass Fine Arts Center, Hill has served as director of education for the Thelonious Monk Institute of Jazz. He is a past…

Characteristics of successful puma kill sites of elk in the Black Hills, South Dakota

Treesearch

Chadwick P. Lehman; Christopher T. Rota; Mark A. Rumble; Joshua J. Millspaugh

2017-01-01

Elk Cervus canadensis nelsoni in the Black Hills, South Dakota, have been declining since 2006 and there is concern by resource managers and hunters that puma Puma concolor predation may be contributing to declining herds. We evaluated characteristics at sites where puma successfully killed elk in the Black Hills of South Dakota. We evaluated characteristics at coarse...

Voices across the Hills: Thailand's Hill Areas Education Project. Education for All: Making It Work. Innovation Series.

ERIC Educational Resources Information Center

Guttman, Cynthia

Developed in the early 1980s, the Hill Areas Education project provides basic education to children and adults of Thailand's six ethnic minority groups, who live in the remote mountainous region of northern Thailand. The project delivers a locally relevant curriculum, equivalent to the six compulsory grades of the formal education system; promotes…

Identifying changes in tree form for harvested ponderosa pine in the Black Hills

Treesearch

Michael S. Williams; Raymond L. Czaplewski; Don L. Martinez

1996-01-01

Recent underestimates of total volume for timber sales in the Black Hills National Forest prompted analysis of two felled ponderosa pine (Pinus ponderosa Laws.) data sets that were collected approximately 10 years apart. Though neither data set collected was a representative sample of the Black Hills, both were similar in terms of diameter at breast height and total...

Race, Ruralism, and Reformation: William J. Edwards and Snow Hill Institute, 1894-1915.

ERIC Educational Resources Information Center

Cooper, Arnold

This article examines the Snow Hill Institute, one of several 19th-century industrial schools founded for rural Southern black students, following the model of Booker T. Washington's Tuskegee Institute. This case study provides a sketch of William J. Edwards, an early Tuskegee alumnus and founder of the Snow Hill Institute in Wilcox County,…

2. BUNKER HILL LEAD SMELTER. VIEW IS FROM CIA TO ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

2. BUNKER HILL LEAD SMELTER. VIEW IS FROM CIA TO THE SOUTH. IN FOREGROUND, PLANT DRY, SLAG FUMING PLANT, BLAST FURNACE, SMELTER OFFICE, LEAD AND SILVER REFINERIES ARE VISIBLE, L. TO R. HIGH VELOCITY FLUE LEADS FROM LOWER PLANT TO BAG HOUSE AND STACKS AT TOP OF SMELTING FACILITY. - Bunker Hill Lead Smelter, Bradley Rail Siding, Kellogg, Shoshone County, ID

Autonomous Legged Hill and Stairwell Ascent

DTIC Science & Technology

2011-11-01

environments with little burden to a human operator. Keywords: autonomous robot , hill climbing , stair climbing , sequential composition, hexapod, self...X-RHex robot on a set of stairs with laser scanner, IMU, wireless repeater, and handle payloads. making them useful for both climbing hills and...reconciliation into that more powerful (but restrictive) framework. 1) The Stair Climbing Behavior: RHex robots have been climbing single-flight stairs

Formation Flight of Earth Satellites on KAM Tori

DTIC Science & Technology

2007-09-01

satellite formations, involves using the Hill- Clohessy - Wiltshire (HCW) equations, created originally for the Gemini Program [2]. These equations are given...the Perturbed J2-Modified Hill- Clohessy - Wiltshire Equations. MS thesis, The University of Texas at Arlington, 2006. 7. Kaasalainen, M. and J. Binney...107 xvii List of Abbreviations Abbreviation Page KAM Kolmogorov, Arnold and Moser . . . . . . . . . . . . . . . . . 2 HCW Hill- Clohessy

The Effect of the Cherry Hill Study Skills Program on Eighth Grade Students' Reading Comprehension and Study Skills.

ERIC Educational Resources Information Center

La Marca, Marilyn Tierney

A study was conducted to determine the effects of the "Cherry Hill Study Skills Program" on eighth grade students' reading comprehension and study skills. The "Cherry Hill Study Skills Program" is a process oriented course dealing with the sequential development of nine specific skills deemed essential to the retrieval and retention of information…

Physical modelling of tsunamis generated by three-dimensional deformable granular landslides on planar and conical island slopes

PubMed Central

2016-01-01

Tsunamis generated by landslides and volcanic island collapses account for some of the most catastrophic events recorded, yet critically important field data related to the landslide motion and tsunami evolution remain lacking. Landslide-generated tsunami source and propagation scenarios are physically modelled in a three-dimensional tsunami wave basin. A unique pneumatic landslide tsunami generator was deployed to simulate landslides with varying geometry and kinematics. The landslides were generated on a planar hill slope and divergent convex conical hill slope to study lateral hill slope effects on the wave characteristics. The leading wave crest amplitude generated on a planar hill slope is larger on average than the leading wave crest generated on a convex conical hill slope, whereas the leading wave trough and second wave crest amplitudes are smaller. Between 1% and 24% of the landslide kinetic energy is transferred into the wave train. Cobble landslides transfer on average 43% more kinetic energy into the wave train than corresponding gravel landslides. Predictive equations for the offshore propagating wave amplitudes, periods, celerities and lengths generated by landslides on planar and divergent convex conical hill slopes are derived, which allow an initial rapid tsunami hazard assessment. PMID:27274697

Physical modelling of tsunamis generated by three-dimensional deformable granular landslides on planar and conical island slopes.

PubMed

McFall, Brian C; Fritz, Hermann M

2016-04-01

Tsunamis generated by landslides and volcanic island collapses account for some of the most catastrophic events recorded, yet critically important field data related to the landslide motion and tsunami evolution remain lacking. Landslide-generated tsunami source and propagation scenarios are physically modelled in a three-dimensional tsunami wave basin. A unique pneumatic landslide tsunami generator was deployed to simulate landslides with varying geometry and kinematics. The landslides were generated on a planar hill slope and divergent convex conical hill slope to study lateral hill slope effects on the wave characteristics. The leading wave crest amplitude generated on a planar hill slope is larger on average than the leading wave crest generated on a convex conical hill slope, whereas the leading wave trough and second wave crest amplitudes are smaller. Between 1% and 24% of the landslide kinetic energy is transferred into the wave train. Cobble landslides transfer on average 43% more kinetic energy into the wave train than corresponding gravel landslides. Predictive equations for the offshore propagating wave amplitudes, periods, celerities and lengths generated by landslides on planar and divergent convex conical hill slopes are derived, which allow an initial rapid tsunami hazard assessment.

Two memories for geographical slant: separation and interdependence of action and awareness

NASA Technical Reports Server (NTRS)

Creem, S. H.; Proffitt, D. R.; Kaiser, M. K. (Principal Investigator)

1998-01-01

The present study extended previous findings of geographical slant perception, in which verbal judgments of the incline of hills were greatly overestimated but motoric (haptic) adjustments were much more accurate. In judging slant from memory following a brief or extended time delay, subjects' verbal judgments were greater than those given when viewing hills. Motoric estimates differed depending on the length of the delay and place of response. With a short delay, motoric adjustments made in the proximity of the hill did not differ from those evoked during perception. When given a longer delay or when taken away from the hill, subjects' motoric responses increased along with the increase in verbal reports. These results suggest two different memorial influences on action. With a short delay at the hill, memory for visual guidance is separate from the explicit memory informing the conscious response. With short or long delays away from the hill, short-term visual guidance memory no longer persists, and both motor and verbal responses are driven by an explicit representation. These results support recent research involving visual guidance from memory, where actions become influenced by conscious awareness, and provide evidence for communication between the "what" and "how" visual processing systems.

A Stream Multimetric Macroinvertebrate Index (MMI) for the Sand Hills Ecoregion of the Southeastern Plains, USA

NASA Astrophysics Data System (ADS)

Kosnicki, Ely; Sefick, Stephen A.; Paller, Michael H.; Jerrell, Miller S.; Prusha, Blair A.; Sterrett, Sean C.; Tuberville, Tracey D.; Feminella, Jack W.

2016-10-01

A macroinvertebrate multimetric index is an effective tool for assessing the biological integrity of streams. However, data collected under a single protocol may not be available for an entire region. We sampled macroinvertebrates from the full extent of the Sand Hills ecoregion Level IV of the Southeastern Plains with a standard protocol during the summers of 2010-2012. We evaluated the performance of 94 metrics through a series of screening criteria and built 48 macroinvertebrate multimetric indexs with combinations of the best performing metrics, representing richness, habit, functional feeding guild, sensitivity, and community composition. A series of narrative-response tests for each macroinvertebrate multimetric index was used to find the best performing macroinvertebrate multimetric index which we called the Sand Hills macroinvertebrate multimetric index. The Sand Hills macroinvertebrate multimetric index consisted of the measures Biotic Index, % Shredder taxa, Clinger taxa2/total taxa, Plecoptera and Trichoptera richness, and Tanytarsini taxa2/Chironomidae taxa. Comparison of the Sand Hills macroinvertebrate multimetric index with existing assessment tools calculated with our data indicated that the Sand Hills macroinvertebrate multimetric index performs at a high level with regard to identifying degraded sites and in its response to stress gradients.

Large-scale deforestation for plantation agriculture in the hill country of Sri Lanka and its impacts

NASA Astrophysics Data System (ADS)

Wickramagamage, P.

1998-10-01

The forest cover in the hill country river catchment areas of Sri Lanka has been reduced to isolated patches on hilltops and a handful of reserves above the 1524 m (5000 ft) contour. Most of the land that was under forest cover at the turn of the nineteenth century is now covered with plantation crops. The districts of Kandy, Matale, Nuwara Eliya, Badulla, Ratnapura and Kegalle are the main hill country plantation areas. Within a period of less than half a century most of the forests in the hill country were cleared for plantation crops. Shifting cultivation was responsible for deforestation in the drier parts of the hill country. At the time of the British conquest of the hill country, the population of the whole island was not more than 3/4 to 1 million and they had settled in isolated villages at elevations below 1066 m. Subsistence agriculture was the main occupation of this predominantly rural population.During the first phase (1830-1880) of the plantation industry, large tracts of mostly forest land were cleared for coffee cultivation. By 1878, the extent of the coffee plantations reached its maximum of 111 336 ha most of which was situated in the wet zone hill country. The second phase of plantation agriculture began as the coffee industry was completely wiped out by a leaf disease. Most of the abandoned coffee plantations and the remaining forests were converted to tea, rubber and cinchona estates. The first two crops managed to survive price fluctuations in the world market, while the latter collapsed because of over production.During the period of large-scale deforestation in the hill country, the climate also underwent changes as exemplified by rainfall and temperature trends. However, these trends are not uniform everywhere in the plantation areas of the hill country. The temperature has risen a few degrees over a period of about a century and quarter in the hill country stations, while rainfall has declined significantly at some stations. These changes seem to be a result of the interaction of both global and local factors. Although some of these changes would have been a result of global warming, land use change would also have contributed to regional disparities.

Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.

PubMed

Pack, S D; Zbar, B; Pak, E; Ault, D O; Humphrey, J S; Pham, T; Hurley, K; Weil, R J; Park, W S; Kuzmin, I; Stolle, C; Glenn, G; Liotta, L A; Lerman, M I; Klausner, R D; Linehan, W M; Zhuang, Z

1999-11-01

von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited cancer syndrome predisposing to a variety of tumor types that include retinal hemangioblastomas, hemangioblastomas of the central nervous system, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, endolymphatic sac tumors, and epididymal cystadenomas [W. M. Linehan et al., J. Am. Med. Assoc., 273: 564-570, 1995; E. A. Maher and W. G. Kaelin, Jr., Medicine (Baltimore), 76: 381-391, 1997; W. M. Linehan and R. D. Klausner, In: B. Vogelstein and K. Kinzler (eds.), The Genetic Basis of Human Cancer, pp. 455-473, McGraw-Hill, 1998]. The VHL gene was localized to chromosome 3p25-26 and cloned [F. Latif et al., Science (Washington DC), 260: 1317-1320, 1993]. Germline mutations in the VHL gene have been detected in the majority of VHL kindreds. The reported frequency of detection of VHL germline mutations has varied from 39 to 80% (J. M. Whaley et al., Am. J. Hum. Genet., 55: 1092-1102, 1994; Clinical Research Group for Japan, Hum. Mol. Genet., 4: 2233-2237, 1995; F. Chen et al., Hum. Mutat., 5: 66-75, 1995; E. R. Maher et al., J. Med. Genet., 33: 328-332, 1996; B. Zbar, Cancer Surv., 25: 219-232, 1995). Recently a quantitative Southern blotting procedure was found to improve this frequency (C. Stolle et al., Hum. Mutat., 12: 417-423, 1998). In the present study, we report the use of fluorescence in situ hybridization (FISH) as a method to detect and characterize VHL germline deletions. We reexamined a group of VHL patients shown previously by single-strand conformation and sequencing analysis not to harbor point mutations in the VHL locus. We found constitutional deletions in 29 of 30 VHL patients in this group using cosmid and P1 probes that cover the VHL locus. We then tested six phenotypically normal offspring from four of these VHL families: two were found to carry the deletion and the other four were deletion-free. In addition, germline mosaicism of the VHL gene was identified in one family. In sum, FISH was found to be a simple and reliable method to detect VHL germline deletions and practically useful in cases where other methods of screening have failed to detect a VHL gene abnormality.

Identification of Lethal Mutations in Yeast Threonyl-tRNA Synthetase Revealing Critical Residues in Its Human Homolog*

PubMed Central

Ruan, Zhi-Rong; Fang, Zhi-Peng; Ye, Qing; Lei, Hui-Yan; Eriani, Gilbert; Zhou, Xiao-Long; Wang, En-Duo

2015-01-01

Aminoacyl-tRNA synthetases (aaRSs) are a group of ancient enzymes catalyzing aminoacylation and editing reactions for protein biosynthesis. Increasing evidence suggests that these critical enzymes are often associated with mammalian disorders. Therefore, complete determination of the enzymes functions is essential for informed diagnosis and treatment. Here, we show that a yeast knock-out strain for the threonyl-tRNA synthetase (ThrRS) gene is an excellent platform for such an investigation. Saccharomyces cerevisiae ThrRS has a unique modular structure containing four structural domains and a eukaryote-specific N-terminal extension. Using randomly mutated libraries of the ThrRS gene (thrS) and a genetic screen, a set of loss-of-function mutants were identified. The mutations affected the synthetic and editing activities and influenced the dimer interface. The results also highlighted the role of the N-terminal extension for enzymatic activity and protein stability. To gain insights into the pathological mechanisms induced by mutated aaRSs, we systematically introduced the loss-of-function mutations into the human cytoplasmic ThrRS gene. All mutations induced similar detrimental effects, showing that the yeast model could be used to study pathology-associated point mutations in mammalian aaRSs. PMID:25416776

Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1.

PubMed

Mazor, Masha; Alkrinawi, Soliman; Chalifa-Caspi, Vered; Manor, Esther; Sheffield, Val C; Aviram, Micha; Parvari, Ruti

2011-05-13

In primary ciliary dyskinesia (PCD), genetic defects affecting motility of cilia and flagella cause chronic destructive airway disease, randomization of left-right body asymmetry, and, frequently, male infertility. The most frequent defects involve outer and inner dynein arms (ODAs and IDAs) that are large multiprotein complexes responsible for cilia-beat generation and regulation, respectively. Although it has long been suspected that mutations in DNAL1 encoding the ODA light chain1 might cause PCD such mutations were not found. We demonstrate here that a homozygous point mutation in this gene is associated with PCD with absent or markedly shortened ODA. The mutation (NM_031427.3: c.449A>G; p.Asn150Ser) changes the Asn at position150, which is critical for the proper tight turn between the β strand and the α helix of the leucine-rich repeat in the hydrophobic face that connects to the dynein heavy chain. The mutation reduces the stability of the axonemal dynein light chain 1 and damages its interactions with dynein heavy chain and with tubulin. This study adds another important component to understanding the types of mutations that cause PCD and provides clinical information regarding a specific mutation in a gene not yet known to be associated with PCD. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Tissue or blood: which is more suitable for detection of EGFR mutations in non-small cell lung cancer?

PubMed

Biaoxue, Rong; Shuanying, Yang

2018-01-01

Many studies have evaluated the accuracy of EGFR mutation status in blood against that in tumor tissues as the reference. We conducted this systematic review and meta-analysis to assess whether blood can be used as a substitute for tumor tissue in detecting EGFR mutations. Investigations that provided data on EGFR mutation status in blood were searched in the databases of Medline, Embase, Ovid Technologies and Web of Science. The detect efficiency of EGFR mutations in paired blood and tissues was compared using a random-effects model of meta-analysis. Pooled sensitivity and specificity and diagnostic accuracy were calculated by receiver operating characteristic curve. A total of 19 studies with 2,922 individuals were involved in this meta-analysis. The pooled results showed the positive detection rate of EGFR mutations in lung cancer tissues was remarkably higher than that of paired blood samples (odds ratio [OR] = 1.47, p<0.001). The pooled sensitivity and specificity of blood were 0.65 and 0.91, respectively, and the area under the receiver operating characteristic curve was 0.89. Although blood had a better specificity for detecting EGFR mutations, the absence of blood positivity should not necessarily be construed as confirmed negativity. Patients with negative results for blood should decidedly undergo further biopsies to ascertain EGFR mutations.

Depositional analysis of Hill sand of Rodessa Formation (lower Cretaceous) in north Shongaloo-Red Rock field, Webster Parish, Louisiana

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adamick, J.A.; Sartin, A.A.

1988-09-01

Hill sand is an informal subdivision of the Lower Cretaceous Rodessa Formation and is a common hydrocarbon reservoir in northeastern Texas, northern Louisiana, and southern Arkansas. The Hill sand is lithologically variable within the study area and consists of conglomerate, fine-grained sandstone, siltstone, mottled red-green claystone, black shale, and limestone. Five depositional environments were interpreted for lithofacies present in Hill sand cores from the North Shongaloo-Red Rock field. These include facies A, fluvial point bar; facies B, crevasse system; facies C, interdistributary bay; facies D, swamp; and facies E, carbonate interdistributary bay. Fluvial point bar and crevasse deposits commonly formmore » hydrocarbon reservoirs in the field. On a regional scale, depositional environments observed in the Hill sand include several fluvial deposystems trending northeast-southwest through Webster Parish. These deposystems terminate into deltaic distributary mouth bars along a northwest-southeast-trending coastline. Areas west of the coastline were occupied by shallow marine environments. Interchannel areas east of the coastline were occupied by interdistributary bay, lake, and crevasse environments in lower deltaic areas, and by lake, swamp, and crevasse environments in upper deltaic areas. Lowermost deposits of the Hill sand throughout the region are interpreted to consist of shallow marine environments. These marine deposits were overlain by thick, predominantly nonmarine sediments. Near the end of Hill sand deposition, the entire region was covered by very shallow marine environments, prior to deposition of the overlying First Lower Anhydrite Stringer.« less

Landslide Monitoring and Cultural Heritage At Risk: The Case Study of San Miniato Hill In Florence

NASA Astrophysics Data System (ADS)

Agostini, G.; Casagli, N.; Delmonaco, G.; Fanti, R.; Focardi, P.; Margottini, C.

San Miniato (known also as Monte alle Croci or Mons Florentinus) is the most fa- mous hill bordering the southern side of the historic center of Florence. Included in the SColli FiorentiniT (Florentine hills) overlooking the monuments and artworks of Flo- & cedil;rence, San Miniato provides a wonderful view of the city. The hillside has always been affected by slope instability phenomena, with periodical reactivations documented in several historic records. Most of the monuments and artworks located on the hill are cracked and fissured and have required restoration works in various circumstances in the centuries after their construction. The first documented studies on the stability of the hill were carried out by Leonardo da Vinci in the XV century and subsequently by various commissions appointed for the restoration works. During the XX century the hill was many times monitored with geotechnical instrumentation and some investiga- tions are still in progress today. This work concerns a review of these historical studies on slope instability and the interpretation of past and present monitoring results. An analytical review of the existing data is a necessary condition for the proposal of a reliable hypothesis concerning the slope instability characterization. This is made dif- ficult by the pluri-centenary urbanization of the entire hill which has led to the almost complete obliteration of the evidence of past movements and by the relevant presence of an invaluable artistic and cultural heritage.

Environmental Requirements Management

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cusack, Laura J.; Bramson, Jeffrey E.; Archuleta, Jose A.

2015-01-08

CH2M HILL Plateau Remediation Company (CH2M HILL) is the U.S. Department of Energy (DOE) prime contractor responsible for the environmental cleanup of the Hanford Site Central Plateau. As part of this responsibility, the CH2M HILL is faced with the task of complying with thousands of environmental requirements which originate from over 200 federal, state, and local laws and regulations, DOE Orders, waste management and effluent discharge permits, Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) response and Resource Conservation and Recovery Act (RCRA) corrective action documents, and official regulatory agency correspondence. The challenge is to manage this vast number ofmore » requirements to ensure they are appropriately and effectively integrated into CH2M HILL operations. Ensuring compliance with a large number of environmental requirements relies on an organization’s ability to identify, evaluate, communicate, and verify those requirements. To ensure that compliance is maintained, all changes need to be tracked. The CH2M HILL identified that the existing system used to manage environmental requirements was difficult to maintain and that improvements should be made to increase functionality. CH2M HILL established an environmental requirements management procedure and tools to assure that all environmental requirements are effectively and efficiently managed. Having a complete and accurate set of environmental requirements applicable to CH2M HILL operations will promote a more efficient approach to: • Communicating requirements • Planning work • Maintaining work controls • Maintaining compliance« less

Convection shapes the trade-off between antibiotic efficacy and the selection for resistance in spatial gradients.

PubMed

Gralka, Matti; Fusco, Diana; Martis, Stephen; Hallatschek, Oskar

2017-07-19

Since penicillin was discovered about 90 years ago, we have become used to using drugs to eradicate unwanted pathogenic cells. However, using drugs to kill bacteria, viruses or cancer cells has the serious side effect of selecting for mutant types that survive the drug attack. A crucial question therefore is how one could eradicate as many cells as possible for a given acceptable risk of drug resistance evolution. We address this general question in a model of drug resistance evolution in spatial drug gradients, which recent experiments and theories have suggested as key drivers of drug resistance. Importantly, our model takes into account the influence of convection, resulting for instance from blood flow. Using stochastic simulations, we study the fates of individual resistance mutations and quantify the trade-off between the killing of wild-type cells and the rise of resistance mutations: shallow gradients and convection into the antibiotic region promote wild-type death, at the cost of increasing the establishment probability of resistance mutations. We can explain these observed trends by modeling the adaptation process as a branching random walk. Our analysis reveals that the trade-off between death and adaptation depends on the relative length scales of the spatial drug gradient and random dispersal, and the strength of convection. Our results show that convection can have a momentous effect on the rate of establishment of new mutations, and may heavily impact the efficiency of antibiotic treatment.

Convection shapes the trade-off between antibiotic efficacy and the selection for resistance in spatial gradients

NASA Astrophysics Data System (ADS)

Gralka, Matti; Fusco, Diana; Martis, Stephen; Hallatschek, Oskar

2017-08-01

Since penicillin was discovered about 90 years ago, we have become used to using drugs to eradicate unwanted pathogenic cells. However, using drugs to kill bacteria, viruses or cancer cells has the serious side effect of selecting for mutant types that survive the drug attack. A crucial question therefore is how one could eradicate as many cells as possible for a given acceptable risk of drug resistance evolution. We address this general question in a model of drug resistance evolution in spatial drug gradients, which recent experiments and theories have suggested as key drivers of drug resistance. Importantly, our model takes into account the influence of convection, resulting for instance from blood flow. Using stochastic simulations, we study the fates of individual resistance mutations and quantify the trade-off between the killing of wild-type cells and the rise of resistance mutations: shallow gradients and convection into the antibiotic region promote wild-type death, at the cost of increasing the establishment probability of resistance mutations. We can explain these observed trends by modeling the adaptation process as a branching random walk. Our analysis reveals that the trade-off between death and adaptation depends on the relative length scales of the spatial drug gradient and random dispersal, and the strength of convection. Our results show that convection can have a momentous effect on the rate of establishment of new mutations, and may heavily impact the efficiency of antibiotic treatment.

Distinct signatures for mutator sensitivity of lacZ reversions and for the spectrum of lacI/lacO forward mutations on the chromosome of nondividing Escherichia coli.

PubMed Central

Bharatan, Shanti M; Reddy, Manjula; Gowrishankar, J

2004-01-01

A conditional lethal galE(Ts)-based strategy was employed in Escherichia coli, first to eliminate all growth-associated chromosomal reversions in lacZ or forward mutations in lacI/lacO by incubation at the restrictive temperature and subsequently to recover (as papillae) spontaneous mutations that had arisen in the population of nondividing cells after shift to the permissive temperature. Data from lacZ reversion studies in mutator strains indicated that the products of all genes for mismatch repair (mutHLS, dam, uvrD), of some for oxidative damage repair (mutMT), and of that for polymerase proofreading (dnaQ) are required in dividing cells; some others for oxidative damage repair (mutY, nth nei) are required in both dividing and nondividing cells; and those for alkylation damage repair (ada ogt) are required in nondividing cells. The spectrum of lacI/lacO mutations in nondividing cells was distinguished both by lower frequencies of deletions and IS1 insertions and by the unique occurrence of GC-to-AT transitions at lacO +5. In the second approach to study mutations that had occurred in nondividing cells, lacI/lacO mutants were selected as late-arising papillae from the lawn of a galE+ strain; once again, transitions at lacO +5 were detected among the mutants that had been obtained from populations initially grown on poor carbon sources such as acetate, palmitate, or succinate. Our results indicate that the lacO +5 site is mutable only in nondividing cells, one possible mechanism for which might be that random endogenous alkylation (or oxidative) damage to DNA in these cells is efficiently corrected by the Ada Ogt (or Nth Nei) repair enzymes at most sites but not at lacO +5. Furthermore, the late-arising papillae from the second approach were composed almost exclusively of dominant lacI/lacO mutants. This finding lends support to "instantaneous gratification" models in which a spontaneous lesion, occurring at a random site in DNA of a nondividing cell, is most likely to be fixed as a mutation if it allows the cell to immediately exit the nondividing state. PMID:15020459

Comparison of algorithms for the detection of cancer-drivers at sub-gene resolution

PubMed Central

Porta-Pardo, Eduard; Kamburov, Atanas; Tamborero, David; Pons, Tirso; Grases, Daniela; Valencia, Alfonso; Lopez-Bigas, Nuria; Getz, Gad; Godzik, Adam

2018-01-01

Understanding genetic events that lead to cancer initiation and progression remains one of the biggest challenges in cancer biology. Traditionally most algorithms for cancer driver identification look for genes that have more mutations than expected from the average background mutation rate. However, there is now a wide variety of methods that look for non-random distribution of mutations within proteins as a signal they have a driving role in cancer. Here we classify and review the progress of such sub-gene resolution algorithms, compare their findings on four distinct cancer datasets from The Cancer Genome Atlas and discuss how predictions from these algorithms can be interpreted in the emerging paradigms that challenge the simple dichotomy between driver and passenger genes. PMID:28714987

Mutational optimization of the coelenterazine-dependent luciferase from Renilla.

PubMed

Woo, Jongchan; von Arnim, Albrecht G

2008-09-30

Renilla luciferase (RLUC) is a popular reporter enzyme for gene expression and biosensor applications, but it is an unstable enzyme whose catalytic mechanism remains to be elucidated. We titrated that one RLUC molecule can turn over about one hundred molecules of coelenterazine substrate. Mutagenesis of active site residue Pro220 extended the half-life of photon emission, yielding brighter luminescence in E. coli. Random mutagenesis uncovered two new mutations that stabilized and increased photon emission in vivo and in vitro, while ameliorating substrate inhibition. Further amended with a previously identified mutation, a new triple mutant showed a threefold improved kcat, as well as elevated luminescence in Arabidopsis. This advances the utility of RLUC as a reporter protein, biosensor, or resonance energy donor.

Mutational optimization of the coelenterazine-dependent luciferase from Renilla

PubMed Central

Woo, Jongchan; von Arnim, Albrecht G

2008-01-01

Renilla luciferase (RLUC) is a popular reporter enzyme for gene expression and biosensor applications, but it is an unstable enzyme whose catalytic mechanism remains to be elucidated. We titrated that one RLUC molecule can turn over about one hundred molecules of coelenterazine substrate. Mutagenesis of active site residue Pro220 extended the half-life of photon emission, yielding brighter luminescence in E. coli. Random mutagenesis uncovered two new mutations that stabilized and increased photon emission in vivo and in vitro, while ameliorating substrate inhibition. Further amended with a previously identified mutation, a new triple mutant showed a threefold improved kcat, as well as elevated luminescence in Arabidopsis. This advances the utility of RLUC as a reporter protein, biosensor, or resonance energy donor. PMID:18826616

A novel CDKL5 mutation in a Japanese patient with atypical Rett syndrome.

PubMed

Christianto, Antonius; Katayama, Syouichi; Kameshita, Isamu; Inazu, Tetsuya

2016-08-01

Rett syndrome (RTT) is a severe X-linked dominant inheritance disorder with a wide spectrum of clinical manifestations. Mutations in Methyl CpG binding protein 2 (MECP2), Cyclin dependent kinase-like 5 (CDKL5) and Forkhead box G1 (FOXG1) have been associated with classic and/or variant RTT. This study was conducted to identify the responsible gene(s) in atypical RTT patient, and to examine the effect of the mutation on protein function. DNA sequence analysis showed a novel heterozygous mutation in CDKL5 identified as c.530A>G which resulted in an amino acid substitution at position 177, from tyrosine to cysteine. Genotyping analysis indicated that the mutation was not merely a single nucleotide polymorphism (SNP). We also revealed that patient's blood lymphocytes had random X-chromosome inactivation (XCI) pattern. Further examination by bioinformatics analysis demonstrated the mutation caused damage or deleterious in its protein. In addition, we demonstrated in vitro kinase assay of mutant protein showed impairment of its activity. Taken together, the results suggested the mutant CDKL5 was responsible for the disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Identification of mutated driver pathways in cancer using a multi-objective optimization model.

PubMed

Zheng, Chun-Hou; Yang, Wu; Chong, Yan-Wen; Xia, Jun-Feng

2016-05-01

New-generation high-throughput technologies, including next-generation sequencing technology, have been extensively applied to solve biological problems. As a result, large cancer genomics projects such as the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium are producing large amount of rich and diverse data in multiple cancer types. The identification of mutated driver genes and driver pathways from these data is a significant challenge. Genome aberrations in cancer cells can be divided into two types: random 'passenger mutation' and functional 'driver mutation'. In this paper, we introduced a Multi-objective Optimization model based on a Genetic Algorithm (MOGA) to solve the maximum weight submatrix problem, which can be employed to identify driver genes and driver pathways promoting cancer proliferation. The maximum weight submatrix problem defined to find mutated driver pathways is based on two specific properties, i.e., high coverage and high exclusivity. The multi-objective optimization model can adjust the trade-off between high coverage and high exclusivity. We proposed an integrative model by combining gene expression data and mutation data to improve the performance of the MOGA algorithm in a biological context. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pick Your Poisson: An Educational Primer for Luria and Delbrück's Classic Paper.

PubMed

Meneely, Philip M

2016-02-01

The origin of beneficial mutations is fundamentally important in understanding the processes by which natural selection works. Using phage-resistant mutants in Escherichia coli as their model for identifying the origin of beneficial mutations, Luria and Delbrück distinguished between two different hypotheses. Under the first hypothesis, which they termed "acquired immunity," the phages induced bacteria to mutate to immunity; this predicts that none of the resistant mutants were present before infection by the phages. Under the second hypothesis, termed "mutation to immunity," resistant bacteria arose from random mutations independent of the presence of the phages; this predicts that resistant bacteria were present in the population before infection by the phages. These two hypotheses could be distinguished by calculating the frequencies at which resistant mutants arose in separate cultures infected at the same time and comparing these frequencies to the theoretical results under each model. The data clearly show that mutations arise at a frequency that is independent of the presence of the phages. By inference, natural selection reveals the genetic variation that is present in a population rather than inducing or causing this variation. Copyright © 2016 by the Genetics Society of America.

The timing of UV mutagenesis in yeast: a pedigree analysis of induced recessive mutation.

PubMed

James, A P; Kilbey, B J

1977-10-01

The mechanism of UV-induced mutation in eukaryotes was studied in individual yeast cells by a procedure that combined pedigree analysis and tetrad analysis. The technique involved the induction of recessive lethals and semilethals in G1 diploid cells. Induced frequencies were 25 and 61 percent at survival levels of 90 and 77 percent, respectively. No evidence of gross chromosome aberrations was detected. Recessive mutations that affect only one strand or that affect both strands of the DNA molecule are induced much at random among a population of cells, and both types can occur within the same cell. However, the data confirm that two-strand mutations are in the majority after a low level of irradiation. The simplest explanation involves a mechanism whereby most mutations are fixed in both strands prior to the first round of post-irradiation DNA replication. The recessive mutational consequences of irradiation are exhausted at the conclusion of the first post-irradiation cell division, although dominant-lethal sectoring continues at a high level through the second post-irradiation division. It is concluded that pyrimidine dimers that persist to the second round of DNA replication are rare or ineffective.

Final Environmental Assessment: Proposed Composite Aircraft Inspection Facilities, Hill Air Force Base, Utah

DTIC Science & Technology

2008-10-02

radiography . Two large inspection bays would each accommodate one F-22 aircraft and robotic x-ray inspection equipment. Six smaller bays would accommodate...large aircraft components (two ultrasonic inspection bays, two laser shearography inspection bays, and two digital radiography inspection bays...Hill Air Force Base, Utah Final Environmental Assessment: Proposed Composite Aircraft Inspection Facilities, Hill Air Force Base, Utah

Traps and attractants for wood-boring insects in ponderosa pine stands in the Black Hills, South Dakota

Treesearch

Sheryl L. Costello; Jose F. Negron; William R. Jacobi

2008-01-01

Recent large-scale wildfires have increased populations of wood-boring insects in the Black Hills of South Dakota. Because little is known about possible impacts of wood-boring insects in the Black Hills, land managers are interested in developing monitoring techniques such as flight trapping with semiochemical baits. Two trap designs and four semiochemical attractants...

Home page of Hill Air Force Base

Science.gov Websites

; -- Victor Me... Twitter Logo He may only have one arm, but the youth sports director at #HillAFB doesn't let story on controlled burns at #HillAFB. The next one will be mid-June when firefighters will torch the Motorcycle Rodeo 4th Annual Motorcycle Rodeo It's time to ride 4th Annual Motorcycle Rodeo One arm, no sweat

Conservation assessment for the autumn willow in the Black Hills National Forest, South Dakota and Wyoming

Treesearch

J. Hope Hornbeck; Carolyn Hull Sieg; Deanna J. Reyher

2003-01-01

Autumn willow, Salix serissima (Bailey) Fern., is an obligate wetland shrub that occurs in fens and bogs in the northeastern United States and eastern Canada. Disjunct populations of autumn willow occur in the Black Hills of South Dakota. Only two populations occur on Black Hills National Forest lands: a large population at McIntosh Fen and a small...

Something All His Own: The NBA's Grant Hill Hopes His Collection of African American Art Will Inspire, Excite a Younger Generation

ERIC Educational Resources Information Center

Keels, Crystal L.

2004-01-01

NBA star Grant Hill is known for his skills on the basketball court, his marriage to Grammy award-winning singer, Tamia, and, most recently, for his courageous comeback after several surgeries that jeopardized his professional basketball career. Yet, Hill's off-the-court activities currently are being considered as exemplary as his athletic…

The Changing Colors of Maple Hills: Intersections of Culture, Race, Language, and Exceptionality in a Rural Farming Community

ERIC Educational Resources Information Center

Scanlan, Martin

2016-01-01

This case describes Maple Hills Elementary, a K-8 school in a rural farming community of the Midwest. As a community, Maple Hills has historically experienced a narrow range of diversity across race, ethnicity, language, and religion. Residents have predominantly been White, with German and English heritage, speak English as a mother tongue, and…

Spacecraft Debris Avoidance Using Positively Invariant Constraint Admissible Sets

DTIC Science & Technology

2013-07-11

Search; Bounded Disturbances; Linear Time-Varying (LTV); Clohessy - Wiltshire -Hill (CWH) 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT...spacecraft equilibria in the Clohessy - Wiltshire -Hill (CWH) relative motion frame [2]. The collection of equilibria form a virtual net in the vicinity of...ABBREVIATIONS, AND ACRONYMS CWH Clohessy - Wiltshire -Hill LTV linear time-varying Distribution Statement A: Approved for public release; distribution is unlimited

2. General view of Fort Hill Farm, view looking north ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

2. General view of Fort Hill Farm, view looking north from (F) two-room cabin. From left to right, buildings visible are (I) log tobacco barn; (H and D) shed and center chimney four-room cabin; (E and (A) one-room cabin in front of mansion; (J) hay barn. - Fort Hill Farm, West of Staunton (Roanoke) River between Turkey & Caesar's Runs, Clover, Halifax County, VA

Retrospective Analysis of Serotype Switching of Vibrio cholerae O1 in a Cholera Endemic Region Shows It Is a Non-random Process

PubMed Central

Karlsson, Stefan L.; Thomson, Nicholas; Mutreja, Ankur; Connor, Thomas; Sur, Dipika; Ali, Mohammad; Clemens, John; Dougan, Gordon; Holmgren, Jan; Lebens, Michael

2016-01-01

Genomic data generated from clinical Vibrio cholerae O1 isolates collected over a five year period in an area of Kolkata, India with seasonal cholera outbreaks allowed a detailed genetic analysis of serotype switching that occurred from Ogawa to Inaba and back to Ogawa. The change from Ogawa to Inaba resulted from mutational disruption of the methyltransferase encoded by the wbeT gene. Re-emergence of the Ogawa serotype was found to result either from expansion of an already existing Ogawa clade or reversion of the mutation in an Inaba clade. Our data suggests that such transitions are not random events but rather driven by as yet unidentified selection mechanisms based on differences in the structure of the O1 antigen or in the serotype-determining wbeT gene. PMID:27706170

Multiple Antigenic Sites Are Involved in Blocking the Interaction of GII.4 Norovirus Capsid with ABH Histo-Blood Group Antigens

PubMed Central

Parra, Gabriel I.; Abente, Eugenio J.; Sandoval-Jaime, Carlos; Sosnovtsev, Stanislav V.; Bok, Karin

2012-01-01

Noroviruses are major etiological agents of acute viral gastroenteritis. In 2002, a GII.4 variant (Farmington Hills cluster) spread so rapidly in the human population that it predominated worldwide and displaced previous GII.4 strains. We developed and characterized a panel of six monoclonal antibodies (MAbs) directed against the capsid protein of a Farmington Hills-like GII.4 norovirus strain that was associated with a large hospital outbreak in Maryland in 2004. The six MAbs reacted with high titers against homologous virus-like particles (VLPs) by enzyme-linked immunoassay but did not react with denatured capsid protein in immunoblots. The expression and self-assembly of newly developed genogroup I/II chimeric VLPs showed that five MAbs bound to the GII.4 protruding (P) domain of the capsid protein, while one recognized the GII.4 shell (S) domain. Cross-competition assays and mutational analyses showed evidence for at least three distinct antigenic sites in the P domain and one in the S domain. MAbs that mapped to the P domain but not the S domain were able to block the interaction of VLPs with ABH histo-blood group antigens (HBGA), suggesting that multiple antigenic sites of the P domain are involved in HBGA blocking. Further analysis showed that two MAbs mapped to regions of the capsid that had been associated with the emergence of new GII.4 variants. Taken together, our data map antibody and HBGA carbohydrate binding to proximal regions of the norovirus capsid, showing that evolutionary pressures on the norovirus capsid protein may affect both antigenic and carbohydrate recognition phenotypes. PMID:22532688

A single digital droplet PCR assay to detect multiple KIT exon 11 mutations in tumor and plasma from patients with gastrointestinal stromal tumors.

PubMed

Boonstra, Pieter A; Ter Elst, Arja; Tibbesma, Marco; Bosman, Lisette J; Mathijssen, Ron; Atrafi, Florence; van Coevorden, Frits; Steeghs, Neeltje; Farag, Sheima; Gelderblom, Hans; van der Graaf, Winette T A; Desar, Ingrid M E; Maier, Jacqueline; Overbosch, Jelle; Suurmeijer, Albert J H; Gietema, Jourik; Schuuring, Ed; Reyners, Anna K L

2018-03-02

Gastrointestinal stromal tumors (GISTs) are characterized by oncogenic KIT mutations that cluster in two exon 11 hotspots. The aim of this study was to develop a single, sensitive, quantitative digital droplet PCR (ddPCR) assay for the detection of common exon 11 mutations in both GIST tumor tissue and in circulating tumor DNA (ctDNA) isolated from GIST patients' plasma. A ddPCR assay was designed using two probes that cover both hotspots. Available archival FFPE tumor tissue from 27 consecutive patients with known KIT exon 11 mutations and 9 randomly selected patients without exon 11 mutations were tested. Plasma samples were prospectively collected in a multicenter bio-databank from December 2014. ctDNA was analyzed of 22 patients with an exon 11 mutation and a baseline plasma sample. The ddPCR assay detected the exon 11 mutation in 21 of 22 tumors with exon 11 mutations covered by the assay. Mutations in ctDNA were detected at baseline in 13 of 14 metastasized patients, but in only 1 of 8 patients with localized disease. In serial plasma samples from 11 patients with metastasized GIST, a decrease in mutant droplets was detected during treatment. According to RECIST 1.1, 10 patients had radiological treatment response and one patient stable disease. A single ddPCR assay for the detection of multiple exon 11 mutations in ctDNA is a feasible, promising tool for monitoring treatment response in patients with metastasized GIST and should be further evaluated in a larger cohort.

Brain tumor segmentation in 3D MRIs using an improved Markov random field model

NASA Astrophysics Data System (ADS)

Yousefi, Sahar; Azmi, Reza; Zahedi, Morteza

2011-10-01

Markov Random Field (MRF) models have been recently suggested for MRI brain segmentation by a large number of researchers. By employing Markovianity, which represents the local property, MRF models are able to solve a global optimization problem locally. But they still have a heavy computation burden, especially when they use stochastic relaxation schemes such as Simulated Annealing (SA). In this paper, a new 3D-MRF model is put forward to raise the speed of the convergence. Although, search procedure of SA is fairly localized and prevents from exploring the same diversity of solutions, it suffers from several limitations. In comparison, Genetic Algorithm (GA) has a good capability of global researching but it is weak in hill climbing. Our proposed algorithm combines SA and an improved GA (IGA) to optimize the solution which speeds up the computation time. What is more, this proposed algorithm outperforms the traditional 2D-MRF in quality of the solution.

Field trip report: Observations made at Yucca Mountain, Nye County, Nevada. Special report No. 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hill, C.A.

1993-03-01

A field trip was made to the Yucca Mountain area on December 5-9, 1992 by Jerry Frazier, Don Livingston, Christine Schluter, Russell Harmon, and Carol Hill. Forty-three separate stops were made and 275 lbs. of rocks were collected during the five days of the field trip. Key localities visited were the Bare Mountains, Yucca Mountain, Calico Hills, Busted Butte, Harper Valley, Red Cliff Gulch, Wahmonie Hills, Crater Flat, and Lathrop Wells Cone. This report only describes field observations made by Carol Hill. Drawings are used rather than photographs because cameras were not permitted on the Nevada Test Site during thismore » trip.« less

TP53 mutation and survival in aggressive B cell lymphoma.

PubMed

Zenz, Thorsten; Kreuz, Markus; Fuge, Maxi; Klapper, Wolfram; Horn, Heike; Staiger, Annette M; Winter, Doris; Helfrich, Hanne; Huellein, Jennifer; Hansmann, Martin-Leo; Stein, Harald; Feller, Alfred; Möller, Peter; Schmitz, Norbert; Trümper, Lorenz; Loeffler, Markus; Siebert, Reiner; Rosenwald, Andreas; Ott, German; Pfreundschuh, Michael; Stilgenbauer, Stephan

2017-10-01

TP53 is mutated in 20-25% of aggressive B-cell lymphoma (B-NHL). To date, no studies have addressed the impact of TP53 mutations in prospective clinical trial cohorts. To evaluate the impact of TP53 mutation to current risk models in aggressive B-NHL, we investigated TP53 gene mutations within the RICOVER-60 trial. Of 1,222 elderly patients (aged 61-80 years) enrolled in the study and randomized to six or eight cycles of CHOP-14 with or without Rituximab (NCT00052936), 265 patients were analyzed for TP53 mutations. TP53 mutations were demonstrated in 63 of 265 patients (23.8%). TP53 mutation was associated with higher LDH (65% vs. 37%; p < 0.001), higher international prognostic index-Scores (IPI 4/5 27% vs. 12%; p = 0.025) and B-symptoms (41% vs. 24%; p = 0.011). Patients with TP53 mutation were less likely to obtain a complete remission CR/CRu (CR unconfirmed) 61.9% (mut) vs. 79.7% (wt) (p = 0.007). TP53 mutations were associated with decreased event-free (EFS), progression-free (PFS) and overall survival (OS) (median observation time of 40.2 months): the 3 year EFS, PFS and OS were 42% (vs. 60%; p = 0.012), 42% (vs. 67.5%; p < 0.001) and 50% (vs. 76%; p < 0.001) for the TP53 mutation group. In a Cox proportional hazard analysis adjusting for IPI-factors and treatment arms, TP53 mutation was shown to be an independent predictor of EFS (HR 1.5), PFS (HR 2.0) and OS (HR 2.3; p < 0.001). TP53 mutations are independent predictors of survival in untreated patients with aggressive CD20+ lymphoma. TP53 mutations should be considered for risk models in DLBCL and strategies to improve outcome for patients with mutant TP53 must be developed. © 2017 UICC.

A site specific model and analysis of the neutral somatic mutation rate in whole-genome cancer data.

PubMed

Bertl, Johanna; Guo, Qianyun; Juul, Malene; Besenbacher, Søren; Nielsen, Morten Muhlig; Hornshøj, Henrik; Pedersen, Jakob Skou; Hobolth, Asger

2018-04-19

Detailed modelling of the neutral mutational process in cancer cells is crucial for identifying driver mutations and understanding the mutational mechanisms that act during cancer development. The neutral mutational process is very complex: whole-genome analyses have revealed that the mutation rate differs between cancer types, between patients and along the genome depending on the genetic and epigenetic context. Therefore, methods that predict the number of different types of mutations in regions or specific genomic elements must consider local genomic explanatory variables. A major drawback of most methods is the need to average the explanatory variables across the entire region or genomic element. This procedure is particularly problematic if the explanatory variable varies dramatically in the element under consideration. To take into account the fine scale of the explanatory variables, we model the probabilities of different types of mutations for each position in the genome by multinomial logistic regression. We analyse 505 cancer genomes from 14 different cancer types and compare the performance in predicting mutation rate for both regional based models and site-specific models. We show that for 1000 randomly selected genomic positions, the site-specific model predicts the mutation rate much better than regional based models. We use a forward selection procedure to identify the most important explanatory variables. The procedure identifies site-specific conservation (phyloP), replication timing, and expression level as the best predictors for the mutation rate. Finally, our model confirms and quantifies certain well-known mutational signatures. We find that our site-specific multinomial regression model outperforms the regional based models. The possibility of including genomic variables on different scales and patient specific variables makes it a versatile framework for studying different mutational mechanisms. Our model can serve as the neutral null model for the mutational process; regions that deviate from the null model are candidates for elements that drive cancer development.

Disruption of Transcriptional Coactivator Sub1 Leads to Genome-Wide Re-distribution of Clustered Mutations Induced by APOBEC in Active Yeast Genes

PubMed Central

Dhar, Alok; Polev, Dmitrii E.; Masharsky, Alexey E.; Rogozin, Igor B.; Pavlov, Youri I.

2015-01-01

Mutations in genomes of species are frequently distributed non-randomly, resulting in mutation clusters, including recently discovered kataegis in tumors. DNA editing deaminases play the prominent role in the etiology of these mutations. To gain insight into the enigmatic mechanisms of localized hypermutagenesis that lead to cluster formation, we analyzed the mutational single nucleotide variations (SNV) data obtained by whole-genome sequencing of drug-resistant mutants induced in yeast diploids by AID/APOBEC deaminase and base analog 6-HAP. Deaminase from sea lamprey, PmCDA1, induced robust clusters, while 6-HAP induced a few weak ones. We found that PmCDA1, AID, and APOBEC1 deaminases preferentially mutate the beginning of the actively transcribed genes. Inactivation of transcription initiation factor Sub1 strongly reduced deaminase-induced can1 mutation frequency, but, surprisingly, did not decrease the total SNV load in genomes. However, the SNVs in the genomes of the sub1 clones were re-distributed, and the effect of mutation clustering in the regions of transcription initiation was even more pronounced. At the same time, the mutation density in the protein-coding regions was reduced, resulting in the decrease of phenotypically detected mutants. We propose that the induction of clustered mutations by deaminases involves: a) the exposure of ssDNA strands during transcription and loss of protection of ssDNA due to the depletion of ssDNA-binding proteins, such as Sub1, and b) attainment of conditions favorable for APOBEC action in subpopulation of cells, leading to enzymatic deamination within the currently expressed genes. This model is applicable to both the initial and the later stages of oncogenic transformation and explains variations in the distribution of mutations and kataegis events in different tumor cells. PMID:25941824

Elevated mutation rate during meiosis in Saccharomyces cerevisiae.

PubMed

Rattray, Alison; Santoyo, Gustavo; Shafer, Brenda; Strathern, Jeffrey N

2015-01-01

Mutations accumulate during all stages of growth, but only germ line mutations contribute to evolution. While meiosis contributes to evolution by reassortment of parental alleles, we show here that the process itself is inherently mutagenic. We have previously shown that the DNA synthesis associated with repair of a double-strand break is about 1000-fold less accurate than S-phase synthesis. Since the process of meiosis involves many programmed DSBs, we reasoned that this repair might also be mutagenic. Indeed, in the early 1960's Magni and Von Borstel observed elevated reversion of recessive alleles during meiosis, and found that the revertants were more likely to be associated with a crossover than non-revertants, a process that they called "the meiotic effect." Here we use a forward mutation reporter (CAN1 HIS3) placed at either a meiotic recombination coldspot or hotspot near the MAT locus on Chromosome III. We find that the increased mutation rate at CAN1 (6 to 21 -fold) correlates with the underlying recombination rate at the locus. Importantly, we show that the elevated mutation rate is fully dependent upon Spo11, the protein that introduces the meiosis specific DSBs. To examine associated recombination we selected for random spores with or without a mutation in CAN1. We find that the mutations isolated this way show an increased association with recombination (crossovers, loss of crossover interference and/or increased gene conversion tracts). Polζ appears to contribute about half of the mutations induced during meiosis, but is not the only source of mutations for the meiotic effect. We see no difference in either the spectrum or distribution of mutations between mitosis and meiosis. The correlation of hotspots with elevated mutagenesis provides a mechanism for organisms to control evolution rates in a gene specific manner.

TERT promoter mutation and its interaction with IDH mutations in glioma: Combined TERT promoter and IDH mutations stratifies lower-grade glioma into distinct survival subgroups-A meta-analysis of aggregate data.

PubMed

Vuong, Huy Gia; Altibi, Ahmed M A; Duong, Uyen N P; Ngo, Hanh T T; Pham, Thong Quang; Chan, Aden Ka-Yin; Park, Chul-Kee; Fung, Kar-Ming; Hassell, Lewis

2017-12-01

The clinical significance of telomerase reverse transcriptase (TERT) promoter mutation in glioma remains unclear. The aim of our meta-analysis is to investigate the prognostic impact TERT promoter mutation in glioma patients and its interaction with other molecular markers, particularly Isocitrate Dehydrogenase (IDH) mutation from aggregate level data. Relevant articles were searched in four electronic databases including PubMed, Scopus, Web of Science and Virtual Health Library. Pooled HRs were calculated using random effect model weighted by inverse variance method. From 1010 studies, we finally included 28 studies with 11519 patients for meta-analyses. TERT mutation is significantly associated with compromised overall survival (OS) (HR=1.38; 95% CI=1.15-1.67) and progression-free survival (PFS) (HR=1.31; 95% CI=1.06-1.63) in glioma patients. In studying its reaction with IDH, TERT promoter mutation was associated with reduced OS in both IDH-mutant (IDH-mut) and IDH-wild type (IDH-wt) glioblastomas but shown to have inverse effects on IDH-mut and IDH-wt grade II/III tumors. Our analysis categorized WHO grade II/III glioma patients into four distinct survival subgroups with descending survival as follow: TERT-mut/IDH-mut≫TERT-wt/IDH-mut≫TERT-wt/IDH-wt≫TERT-mut/IDH-wt. Prognostic value of TERT promoter mutations in gliomas is dependent on tumor grade and the IDH mutational status. With the same tumor grade in WHO grade II and III tumors and the same IDH mutation status, TERT-mut is a prognostic factor. Copyright © 2017 Elsevier B.V. All rights reserved.

Incorporating molecular and functional context into the analysis and prioritization of human variants associated with cancer

PubMed Central

Peterson, Thomas A; Nehrt, Nathan L; Park, DoHwan

2012-01-01

Background and objective With recent breakthroughs in high-throughput sequencing, identifying deleterious mutations is one of the key challenges for personalized medicine. At the gene and protein level, it has proven difficult to determine the impact of previously unknown variants. A statistical method has been developed to assess the significance of disease mutation clusters on protein domains by incorporating domain functional annotations to assist in the functional characterization of novel variants. Methods Disease mutations aggregated from multiple databases were mapped to domains, and were classified as either cancer- or non-cancer-related. The statistical method for identifying significantly disease-associated domain positions was applied to both sets of mutations and to randomly generated mutation sets for comparison. To leverage the known function of protein domain regions, the method optionally distributes significant scores to associated functional feature positions. Results Most disease mutations are localized within protein domains and display a tendency to cluster at individual domain positions. The method identified significant disease mutation hotspots in both the cancer and non-cancer datasets. The domain significance scores (DS-scores) for cancer form a bimodal distribution with hotspots in oncogenes forming a second peak at higher DS-scores than non-cancer, and hotspots in tumor suppressors have scores more similar to non-cancers. In addition, on an independent mutation benchmarking set, the DS-score method identified mutations known to alter protein function with very high precision. Conclusion By aggregating mutations with known disease association at the domain level, the method was able to discover domain positions enriched with multiple occurrences of deleterious mutations while incorporating relevant functional annotations. The method can be incorporated into translational bioinformatics tools to characterize rare and novel variants within large-scale sequencing studies. PMID:22319177

Environmental Exposures, Genetic Polymorphisms and p53 Mutational Spectra in a Case-Control Study of Breast Cancer.

DTIC Science & Technology

1998-01-01

Further, preliminary clinical data suggest that serotonin reuptake inhibitors , such as fluoxetinc hydrochloride, may promote smoking cessation (15,16...benefits of serotonin reuptake inhibitors in smoking cessation (16) suggested that this gene may be a plausible candidate for predisposition to... used for random selection of women under age 65; women age 65 and over were randomly selected from the listing of the Health Care Finance

Analysis of the parental origin of de novo MECP2 mutations and X chromosome inactivation in 24 sporadic patients with Rett syndrome in China.

PubMed

Zhu, Xingwang; Li, Meirong; Pan, Hong; Bao, Xinhua; Zhang, Jingjing; Wu, Xiru

2010-07-01

Rett syndrome is an X-linked neurodevelopmental disorder that predominantly affects females. It is caused by mutations in methyl-CpG-binding protein 2 gene. Due to the sex-limited expression, it has been suggested that de novo X-linked mutations may exclusively occur in male germ cells and thus only females are affected. In this study, the authors have analyzed the parental origin of mutations and the X-chromosome inactivation status in 24 sporadic patients with identified methyl-CpG-binding protein 2 gene mutations. The results showed that 22 of 24 patients have a paternal origin. Only 2 patients have a maternal origin. Except for 2 cases which were homozygotic at the androgen receptor gene locus, of the remaining 22 cases, 16 cases have a random X-chromosome inactivation pattern; the other 6 cases have a skewed X-chromosome inactivation and they favor expression of the wild allele. The relationship between X-chromosome inactivation and phenotype may need more cases to explore.

Application of In Vitro Transposon Mutagenesis to Erythromycin Strain Improvement in Saccharopolyspora erythraea.

PubMed

Weber, J Mark; Reeves, Andrew; Cernota, William H; Wesley, Roy K

2017-01-01

Transposon mutagenesis is an invaluable technique in molecular biology for the creation of random mutations that can be easily identified and mapped. However, in the field of microbial strain improvement, transposon mutagenesis has scarcely been used; instead, chemical and physical mutagenic methods have been traditionally favored. Transposons have the advantage of creating single mutations in the genome, making phenotype to genotype assignments less challenging than with traditional mutagens which commonly create multiple mutations in the genome. The site of a transposon mutation can also be readily mapped using DNA sequencing primer sites engineered into the transposon termini. In this chapter an in vitro method for transposon mutagenesis of Saccharopolyspora erythraea is presented. Since in vivo transposon tools are not available for most actinomycetes including S. erythraea, an in vitro method was developed. The in vitro method involves a significant investment in time and effort to create the mutants, but once the mutants are made and screened, a large number of highly relevant mutations of direct interest to erythromycin production can be found.

Gender, professionalization, and the child in the Progressive Era: Patty Smith Hill, 1868-1946.

PubMed

Allen, Ann Taylor

2011-01-01

This article discusses the career of Patty Smith Hill, a major figure in the American kindergarten movement, in the context of the Progressive Era in American history. Hill, an educator and child-welfare activist, became known both as a reformer of early-childhood education and as an advocate of the inclusion of the kindergarten, originally a private institution, in public-school systems. The article acknowledges this as one of the most significant achievements of the woman-led reform movements of the Progressive Era, but at the same time notes that it involved a substantial transfer of power from the women who had originally developed the kindergarten to the male principals and superintendants who now supervised kindergarten teachers, often without much understanding of their distinctive methods and aims. As a professor at Columbia Teachers College, Hill also exercised an international influence. Hill's career exemplifies broader patterns of women's professionalization during the late-nineteenth and early-twentieth centuries.

Educational and Social Development in Doi Ang Khang: A Comparative Study of the Khob Dong and Nor Lae Villages

ERIC Educational Resources Information Center

Frost, Timothy; Gray, Lauren; Lake, John; Roy, Jessica

2007-01-01

Northern Thailand is home to many hill tribes, who have lived for hundreds of years as subsistence farmers or nomadic hunters. In the 1940s, communist insurgencies drove many hill tribes from China, Burma, and other nations south into northern Thailand. Uprooted from their native lands, the hill tribes left behind ties to economic resources and,…

Attacking Urban Poverty: The Role of the SNDT Women's University, Mumbai, India--The "Gilbert Hill Programme". Strategies of Education and Training for Disadvantaged Groups.

ERIC Educational Resources Information Center

Kamath, M.; Udipi, S. A.; Varghese, M. A.

This study examined the role of the SNDT (formerly Shreemati Nathibai Damodar Thackersey) University in reducing poverty in the Gilbert Hill-Gamdevi Dongri area of Mumbai, India. The Gilbert Hill area accommodates around 1 million people, most of whom are migrants form other parts of India. The Department of Post-Graduate Studies and Research in…

4. BUNKER HILL LEAD SMELTER. VIEW IS FROM RIDGE ABOVE ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

4. BUNKER HILL LEAD SMELTER. VIEW IS FROM RIDGE ABOVE GOVERNMENT GULCH LOOKING TO THE EAST. IN THE RIGHT MID GROUND, CARPENTER SHOP BUILDINGS AND FRAMING SHEDS ARE VISIBLE. THE BACKGROUND FACILITIES VISIBLE FROM L. TO R. ARE: SMELTER OFFICE, REFINERIES, SLAG FUMING STACKS, HIGH VELOCITY FLUE, BAG HOUSE, 200-FOOT STACK, AND 715-FOOT STACK. - Bunker Hill Lead Smelter, Bradley Rail Siding, Kellogg, Shoshone County, ID

Environmental Assessment: Proposed Training Facilities, Hill Air Force Base, Utah

DTIC Science & Technology

2013-08-08

FA8201-09-D-0002 Facilities, Hill Air Force Base, Utah 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Klein, Randal 5d...PERFORMING ORGANIZATION REPORT NUMBER Streamline Consulting, LLC 1713 N. Sweetwater Lane Farmington, Utah 84025...proposes to construct new training facilities at Hill Air Force Base, Utah . The findings of this EA indicate that the proposed action would not have

The tectonic fabric of the ocean basins

NASA Astrophysics Data System (ADS)

Matthews, Kara J.; Müller, R. Dietmar; Wessel, Paul; Whittaker, Joanne M.

2011-12-01

We present a global community data set of fracture zones (FZs), discordant zones, propagating ridges, V-shaped structures and extinct ridges, digitized from vertical gravity gradient (VGG) maps. We use a new semi-automatic FZ tracking program to test the precision of our hand-digitized traces and find a Mean Absolute Deviation of less than 3.4 km from the raw VGG minima that most clearly delineate each feature, and less than 5.4 km from the FZ location predicted by fitting model profiles to the VGG data that represent the morphology of the individual FZs. These offsets are small considering gravity data only provide an approximation for the underlying basement morphology. We further investigate the origin of non-FZ seafloor fabric by combining published abyssal hill heights computed from gravity anomalies with global half-spreading rates. A residual abyssal hill height grid, with spreading rate effects removed, combined with our interpreted tectonic fabric reveals several types of seafloor fabric distinct from typical abyssal hills. Where discordant zones do not overprint abyssal hill signals, residual abyssal hill height anomalies correspond to seafloor that accreted near mantle thermal anomalies or zones of melt-depletion. Our analysis reveals several areas where residual abyssal hill height anomalies reflect pseudo-faults and extinct ridges associated with ridge propagation and/or microplate formation in the southern Pacific Ocean.

Lithology and characteristic of landslide in Gombel Hill by 2D geoelectric resistivity method using dipole-dipole configuration

NASA Astrophysics Data System (ADS)

Setyawan, Agus; Satria Fikri, Muhammad; Endro Suseno, Jatmiko; Fuad, Muhamad

2018-05-01

Gombel hill locates at Semarang, Central Java, Indonesia. Base on Semarang’s susceptiblity map zone, Gombel hill is belong to high susceptibility and instability zone. Instability may cause faults to Gombel hill area, unfortunately the geosciences research in Gombel is still lack. The geophysical survey has been conducted using 2D geoelectric resistivity method with dipole – dipole configuration to identify the lithology of landslide at Gombel hill. The data have been collected from three lines. The first and third line have 100 m length, and the second line have 80 m length with 5 m space in each lines. The data were processed and modelled using Res2Dinv software. From the first line, suspected there are two layers which formed the structure of the subsurface. The second line suspected there are three layers which formed the structure of the subsurface. And the last line suspected there are two layers which formed the structure of the subsurface. Overall, the landslide of Gombel hill area can be found with depth 5 m – 6 m and found at contact between clay and clay rock layer. We expect the results can be used for mitigation hazard and planning the developing infrastructure in Gombel area.

Effects of off-road vehicle use on the hydrology and landscape of arid environments in central and southern California

USGS Publications Warehouse

Snyder, Charles T.; Frickel, D.G.; Hadley, R.F.; Miller, R.F.

1976-01-01

Two widely separated sites in California used for motorcycle hill-climbing were studied to evaluate the impact on the landscape and hydrology. At Panoche Hills in central California, an area formerly used by motorcycles together with an adjacent unused area were monitored from 1971 to 1975. Observations in both areas included measurements of precipitation, runoff, soil moisture, soil bulk density, plant cover, and erosion surveys. At Dove Spring Canyon in souther California erosion was measured on a site that is currently being used for motorcycle hill-climbing. At the Panoche Hills site, the area used by motorcycles produced about eight times as nuch runoff as the unused area. Similarly, sediment yield from the used areas was 857 cubic meters/sq km, while the quantity of sediment from the unused area was not measurable by standard methods. At the Dove Spring Canyon site, which is still being used for hill-climbing, erosion surveys show that degradation in trails has been as much as 0.3 m in the period 1973-75. Compaction of soils and reduction of permeability appears to be the most serious hydrologic impact of motorcycle use at Panoche Hills. Increased bulk density of soils reduces depth of moisture penetration which deprives plants of moisture needed for growth. (Woodard-USGS)

Fertility in Hill Korwas -- a primitive tribe of Madhya Pradesh.

PubMed

Pandey, G D; Tiwary, R S

1996-12-01

This study examines fertility behavior among 604 eligible couples in Hill Korwa tribes in Madhya Pradesh state, India. Low fertility patterns are compared to those of neighboring Gonds and nontribals from rural Jabalpur. The Hill Korwa are a subtribe of the Korwa, who remained in the hills and dense forests. Over 60% live in three tehsils of Surguja district, including Ambikapur tehsil where the study was conducted. Data were obtained in March 1991. Eligible couples were those where both partners live together and the noncontracepting wife is under age 50 and nonmenopausal. Only 3% were literate. Female marriage age was about 15 years. The median age was 23.8 years. 92% lived below the poverty line. The average number of children ever born (CEB) per couple was 1.9, compared to 2.5 for the Gond and 2.9 for nontribal couples. The CEB in a reproductive lifetime was 2.9, compared to 5.3 for Gond women and 5.9 for nontribal women. Fecundity among Hill Korwa women was 66% lower at younger ages (16-17 years and 17-18 years), and the differences increased with an increase in age at marriage. Hill Korwas had a low female age at marriage, low literacy, low percentages engaged in agriculture, and higher percentages living above the poverty line.

Quantum theory of rotational isomerism and Hill equation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ugulava, A.; Toklikishvili, Z.; Chkhaidze, S.

2012-06-15

The process of rotational isomerism of linear triatomic molecules is described by the potential with two different-depth minima and one barrier between them. The corresponding quantum-mechanical equation is represented in the form that is a special case of the Hill equation. It is shown that the Hill-Schroedinger equation has a Klein's quadratic group symmetry which, in its turn, contains three invariant subgroups. The presence of these subgroups makes it possible to create a picture of energy spectrum which depends on a parameter and has many merging and branch points. The parameter-dependent energy spectrum of the Hill-Schroedinger equation, like Mathieu-characteristics, containsmore » branch points from the left and from the right of the demarcation line. However, compared to the Mathieu-characteristics, in the Hill-Schroedinger equation spectrum the 'right' points are moved away even further for some distance that is the bigger, the bigger is the less deep well. The asymptotic wave functions of the Hill-Schroedinger equation for the energy values near the potential minimum contain two isolated sharp peaks indicating a possibility of the presence of two stable isomers. At high energy values near the potential maximum, the height of two peaks decreases, and between them there appear chaotic oscillations. This form of the wave functions corresponds to the process of isomerization.« less

The effects of the introduction of the no-smoking policy at HMYOI Warren Hill on bullying behaviour.

PubMed

Lawrence, Sally; Welfare, Heather

2008-01-01

The current research explores the prevalence of bullying behaviour at HMYOI Warren Hill and the Carlford Unit. The introduction of the no-smoking policy at the establishment was also explored in relation to its effect on bullying behaviour given that tobacco has historically been the main item that young people have been bullied for. The Direct and Indirect Prisoner behaviour Checklist--Revised (DIPC-R) and a questionnaire designed to identify the effect of the introduction of the no-smoking policy on bullying behaviour were used within this study to answer the following questions: what is the prevalence of bullying behaviour at Warren Hill and the Carlford Unit, and do young people at Warren Hill and the Carlford Unit think that the rate and nature of bullying has been affected by the introduction of the no-smoking policy? One hundred and fifteen young people took part in the study. At Warren Hill, Bully/Victims were the most prevalent type identified and this was significantly greater than the number of young people identified as Pure Victims or Not Involved. On the Carlford Unit, Not Involved was the most prevalent type identified, and this finding provides limited support for the theories of bullying behaviour identified within the present study. The study found that the rate of bullying decreased following the introduction of the no-smoking policy at Warren Hill. The findings from this study are being used in the development of a new Violence Reduction Policy at HMYOI Warren Hill.

Molecular Characterization of Geographically Different Banana bunchy top virus Isolates in India.

PubMed

Selvarajan, R; Mary Sheeba, M; Balasubramanian, V; Rajmohan, R; Dhevi, N Lakshmi; Sasireka, T

2010-10-01

Banana bunchy top disease (BBTD) caused by Banana bunchy top virus (BBTV) is one of the most devastating diseases of banana and poses a serious threat for cultivars like Hill Banana (Syn: Virupakshi) and Grand Naine in India. In this study, we have cloned and sequenced the complete genome comprised of six DNA components of BBTV infecting Hill Banana grown in lower Pulney hills, Tamil Nadu State, India. The complete genome sequence of this hill banana isolate showed high degree of similarity with the corresponding sequences of BBTV isolates originating from Lucknow, Uttar Pradesh State, India, and from Fiji, Egypt, Pakistan, and Australia. In addition, sixteen coat protein (CP) and thirteen replicase genes (Rep) sequences of BBTV isolates collected from different banana growing states of India were cloned and sequenced. The replicase sequences of 13 isolates showed high degree of similarity with that of South Pacific group of BBTV isolates. However, the CP gene of BBTV isolates from Shervroy and Kodaikanal hills of Tamil Nadu showed higher amino acid sequence variability compared to other isolates. Another hill banana isolate from Meghalaya state had 23 nucleotide substitutions in the CP gene but the amino acid sequence was conserved. This is the first report of the characterization of a complete genome of BBTV occurring in the high altitudes of India. Our study revealed that the Indian BBTV isolates with distinct geographical origins belongs to the South Pacific group, except Shervroy and Kodaikanal hill isolates which neither belong to the South Pacific nor the Asian group.

Optimizing Hill Seeding Density for High-Yielding Hybrid Rice in a Single Rice Cropping System in South China

PubMed Central

Wang, Danying; Chen, Song; Wang, Zaiman; Ji, Chenglin; Xu, Chunmei; Zhang, Xiufu; Chauhan, Bhagirath Singh

2014-01-01

Mechanical hill direct seeding of hybrid rice could be the way to solve the problems of high seeding rates and uneven plant establishment now faced in direct seeded rice; however, it is not clear what the optimum hill seeding density should be for high-yielding hybrid rice in the single-season rice production system. Experiments were conducted in 2010 and 2011 to determine the effects of hill seeding density (25 cm×15 cm, 25 cm×17 cm, 25 cm×19 cm, 25 cm×21 cm, and 25 cm×23 cm; three to five seeds per hill) on plant growth and grain yield of a hybrid variety, Nei2you6, in two fields with different fertility (soil fertility 1 and 2). In addition, in 2012 and 2013, comparisons among mechanical hill seeding, broadcasting, and transplanting were conducted with three hybrid varieties to evaluate the optimum seeding density. With increases in seeding spacing from 25 cm×15 cm to 25 cm×23 cm, productive tillers per hill increased by 34.2% and 50.0% in soil fertility 1 and 2. Panicles per m2 declined with increases in seeding spacing in soil fertility 1. In soil fertility 2, no difference in panicles per m2 was found at spacing ranging from 25 cm×17 cm to 25 cm×23 cm, while decreases in the area of the top three leaves and aboveground dry weight per shoot at flowering were observed. Grain yield was the maximum at 25 cm×17 cm spacing in both soil fertility fields. Our results suggest that a seeding density of 25 cm×17 cm was suitable for high-yielding hybrid rice. These results were verified through on-farm demonstration experiments, in which mechanical hill-seeded rice at this density had equal or higher grain yield than transplanted rice. PMID:25290342

Investigating Mars: Arabia Terra Dunes

NASA Image and Video Library

2018-03-20

The bottom of this image shows the hills and mesas within the crater. The dunes at the top of the image are engulfing and covering the hills. In some locations the hills are still a substantial obstacle to the wind. In these cases the wind is blowing sand up against the windward side, but the hill is causing chaotic wind flow around the hill and rather than depositing sand, the wind is actually removing sand on the leeward side of the hill. With continued winds and sand movement the deposition of material will eventually build up along the leeward side of the hill and then engulf the hill on all sides. Located in eastern Arabia is an unnamed crater, 120 kilometers (75 miles) across. The floor of this crater contains a large exposure of rocky material, a field of dark sand dunes, and numerous patches of what is probably fine-grain sand. The shape of the dunes indicate that prevailing winds have come from different directions over the years. The Odyssey spacecraft has spent over 15 years in orbit around Mars, circling the planet more than 71,000 times. It holds the record for longest working spacecraft at Mars. THEMIS, the IR/VIS camera system, has collected data for the entire mission and provides images covering all seasons and lighting conditions. Over the years many features of interest have received repeated imaging, building up a suite of images covering the entire feature. From the deepest chasma to the tallest volcano, individual dunes inside craters and dune fields that encircle the north pole, channels carved by water and lava, and a variety of other feature, THEMIS has imaged them all. For the next several months the image of the day will focus on the Tharsis volcanoes, the various chasmata of Valles Marineris, and the major dunes fields. We hope you enjoy these images! Orbit Number: 11781 Latitude: 26.3693 Longitude: 62.693 Instrument: VIS Captured: 2004-08-10 10:40 https://photojournal.jpl.nasa.gov/catalog/PIA22299

Altitude of the Top of the Madison Limestone in the Black Hills area, South Dakota, 1999

USGS Publications Warehouse

Carter, Janet M.; Redden, Jack A.

2000-01-01

This map is a product of the Black Hills Hydrology Study, which was initiated in 1990 to assess the quantity, quality, and distribution of surface water and groundwater in the Black Hills area of South Dakota (Driscoll, 1992). This long-term study is a cooperative effort between the U.S. Geological Survey (USGS), the South Dakota Department of Environment and Natural Resources, and the West Dakota Water Development District, which represents various local and county cooperators. This map is part of a series of 1:100,000-scale maps for the study. The maps include a hydrogeologic map, structure-contour maps (altitudes of the tops of formations) for five formations that contain major aquifers in the study area, and potentiometric maps for these five major aquifers (the Inyan Kara, Minnekahta, Minnelusa, Madison, and Deadwood aquifers).The study area consists of the topographically defined Black Hills and adjacent areas located in western South Dakota. The Black Hills area is an elongated, dome-shaped feature, about 125 miles long and 60 miles wide, which was uplifted during the Laramide orogeny (Feldman and Heimlich, 1980). The oldest geologic units in the study arca arc Precambrian metamorphic and igneous rocks, which are exposed in the central core of the Black Hills. Surrounding the Precambrian core is a layered series of sedimentary rocks including limestones, sandstones, and shales that are exposed in roughly concentric rings around the uplifted flanks of the Black Hills. The bedrock sedimentary units typically dip away from the uplifted Black Hills at angles that approach or exceed 10 degrees near the outcrops, and decrease with distance from the uplift. Many of the sedimentary units contain aquifers, both within and beyond the study area. Recharge to these aquifers occurs from infiltration of precipitation upon the outcrops and, in some cases, from infiltration of streamflow (Hortness and Driscoll, 1998). Artesian conditions generally exist within these aquifers where an upper confining layer is present. Flowing wells and artesian springs that originate from confined aquifers are common around the periphery of the Black Hills.The purpose of this map is to show the altitude of the top (structure contours) of the Madison Limestone within the area of the Black Hills Hydrology Study. The depth to the top of the Madison Limestone can be estimated at a specific site by subtracting the altitude of the top of the formation from the topographic elevation. However, caution is urged in determining the depth to the top of the formation in areas on the map where the contours are approximately located.

Altitude of the Top of the Deadwood Formation in the Black Hills area, South Dakota, 1999

USGS Publications Warehouse

Carter, Janet M.; Redden, Jack A.

2000-01-01

This map is a product of the Black Hills Hydrology Study, which was initiated in 1990 to assess the quantity, quality, and distribution of surface water and ground water in the Black Hills area of South Dakota (Driscoll, 1992). This long-term study is a cooperative effort between the U.S. Geological Survey (USGS), the South Dakota Department of Environment and Natural Resources, and the West Dakota Water Development District, which represents various local and county cooperators. This map is part of a series of 1:100,000-scale maps for the study. The maps include a hydrogeologic map, structure-contour maps (altitudes of the tops of formations) for five formations that contain major aquifers in the study area, and potentiometric maps for these five major aquifers (the Inyan Kara, Minnekahta, Minnelusa, Madison, and Deadwood aquifers).The study area consists of the topographically defined Black Hills and adjacent areas located in western South Dakota. The Black Hills area is an elongated, dome-shaped feature, about 125 miles long and 60 miles wide, which was uplifted during the Laramide orogeny (Feldman and Heimlich, 1980). The oldest geologic units in the study area are Precambrian metamorphic and igneous rocks, which are exposed in the central core of the Black Hills. Surrounding the Precambrian core is a layered series of sedimentary rocks including limestones, sandstones, and shales that are exposed in roughly concentric rings around the uplifted flanks of the Black Hills. The bedrock sedimentary units typically dip away from the uplifted Black Hills at angles that approach or exceed 10 degrees near the outcrops, and decrease with distance from the uplift. Many of the sedimentary units contain aquifers, both within and beyond the study area. Recharge to these aquifers occurs from infiltration of precipitation upon the outcrops and, in some cases, from infiltration of streamflow (Hortness and Driscoll, 1998). Artesian conditions generally exist within these aquifers where an upper confining layer is present. Flowing wells and artesian springs that originate from confined aquifers are common around the periphery of the Black Hills.The purpose of this map is to show the altitude of the top (structure contours) of the Deadwood Formation within the area of the Black Hills Hydrology Study. The depth to the top of the Deadwood Formation can be estimated at a specific site by subtracting the altitude of the top of the formation from the topographic elevation, However, caution is urged in determining the depth to the top of the formation in areas on the map where the contours are approximately located.

Altitude of the Top of the Minnelusa Formation in the Black Hills area, South Dakota, 1999

USGS Publications Warehouse

Carter, Janet M.; Redden, Jack A.

2000-01-01

This map is a product of the Black Hills Hydrology Study, which was initiated in 1990 to assess the quantity, quality, and distribution of surface water and ground water in the Black Hills area of South Dakota (Driscoll, 1992). This long-term study is a cooperative effort between the U.S. Geological Survey (USGS), the South Dakota Department of Environment and Natural Resources, and the West Dakota Water Development District, which represents various local and county cooperators. This map is part of a series of 1:100,000-scale maps for the study. The maps include a hydrogeologic map, structure-contour maps (altitudes of the tops of formations) for five formations that contain major aquifers in the study area, and potentiometric maps for these five major aquifers (the Inyan Kara, Minnekahta, Minnelusa, Madison, and Deadwood aquifers).The study area consists of the topographically defined Black Hills and adjacent areas located in western South Dakota. The Black Hills area is an elongated, dome-shaped feature, about 125 miles long and 60 miles wide, which was uplifted during the Laramide orogeny (Feldman and Heimlich, 1980). The oldest geologic units in the study area are Precambrian metamorphic and igneous rocks, which are exposed in the central core of the Black Hills. Surrounding the Precambrian core is a layered series of sedimentary rocks including limestones, sandstones, and shales that are exposed in roughly concentric rings around the uplifted flanks of the Black Hills. The bedrock sedimentary units typically dip away from the uplifted Black Hills at angles that approach or exceed 10 degrees near the outcrops, and decrease with distance from the uplift. Many of the sedimentary units contain aquifers, both within and beyond the study area. Recharge to these aquifers occurs from infiltration of precipitation upon the outcrops and, in some cases, from infiltration of streamflow (Hortness and Driscoll, 1998). Artesian conditions generally exist within these aquifers where an upper confining layer is present. Flowing wells and artesian springs that originate from confined aquifers are common around the periphery of the Black Hills.The purpose of this map is to show the altitude of the top (structure contours) of the Minnelusa Formation within the area of the Black Hills Hydrology Study. The depth to the top of the Minnelusa Formation can be estimated at a specific site by subtracting the altitude of the top of the formation from the topographic elevation. However, caution is urged in determining the depth to the top of the formation in areas on the map where the contours are approximately located.

Altitude of the Top of the Minnekahta Limestone in the Black Hills area, South Dakota, 1999

USGS Publications Warehouse

Carter, Janet M.; Redden, Jack A.

2000-01-01

This map is a product of the Black Hills Hydrology Study, which was initiated in 1990 to assess the quantity, quality, and distribution of surface water and groundwater in the Black Hills area of South Dakota (Driscoli, 1992). This long-term study is a cooperative effort between the U.S. Geological Survey (USGS), the South Dakota Department of environment and Natural Resources, and the West Dakota Water development District, which represents various local and county cooperators. This map is part of a series of 1:100,000-scale maps for the study. The maps include a hydrogeologic map, structure-contour maps (altitudes of the tops of formations) for five formations that contain major aquifers in the study area, and potentiometric maps for these five major aquifers (the Inyan Kara. Minnekahta, Minnelusa, Madison, and Deadwood aquifers).The study area consists of the topographically defined Black Hills and adjacent areas located in western South Dakota. The Black Hills area is an elongated, dome-shaped feature, about 125 miles long and 60 miles wide, which was uplifted during the Laramide orogeny (Feldman and Heimlich, 1980). The oldest geologic units in the study area are Precambrian metamorphic and igneous rocks, which are exposed in the central core of the Black Hills. Surrounding the Precambrian core is a layered series of sedimentary rocks including limestones, sandstones, and shales that are exposed in roughly concentric rings around the uplifted flanks of the Black Hills. The bedrock sedimentary units typically dip away from the uplifted Black Hills at angles that approach or exceed 10 degrees near the outcrops, and decrease with distance from the uplift. Many of the sedimentary units contain aquifers, both within and beyond the study area. Recharge to these aquifers occurs from infiltration of precipitation upon the outcrops and, in some cases, from infiltration of streamflow (Hortness and Driscoll, 1998). Artesian conditions generally exist within these aquifers where an upper confining layer is present. Flowing wells and artesian springs that originate from confined aquifers are common around the periphery of the Black Hills.The purpose of this map is to show the altitude of the top(structure contours) of the Minnekahta limestone within the area of the Black Hills Hydrology Study. The depth to the top of the Minnekahta Limestone can be estimated at a specific site by subtracting the altitude of the top of the formation from the topographic elevation. However, caution is urged in determining the depth to the top of the formation in areas on the map where the contours are approximately located.

The hill forts and castle mounds in Lithuania: interaction between geodiversity and human-shaped landscape

NASA Astrophysics Data System (ADS)

Skridlaite, Grazina; Guobyte, Rimante; Satkunas, Jonas

2015-04-01

Lithuania is famous for its abundant, picturesque hill forts and castle mounds of natural origin. In Lithuania as well as in whole Europe the fortified hills were used as the society dwelling place since the beginning of the Late Bronze Age. Their importance increased when Livonian and Teutonic Orders directed a series of military campaigns against Lithuania with the aim of expansion of Christianity in the region at the end of 1st millennium AD, and they were intensively used till the beginning of the 15th c. when most of them were burned down during fights with the Orders or just abandoned due to the changing political and economical situation. What types of the geodiversity were used for fortified dwellings? The choice in a particular area depended on a variety of geomorphology left behind the retreating ice sheets. High spots dominating their surroundings were of prime interest. In E and SE Lithuania, the Baltic Upland hills marking the eastern margin of the last Weichselian glacier hosted numerous fortified settlements from the end of 2nd millennium BC to the Medieval Ages (Narkunai, Velikuskes etc). In W Lithuania, plateau-like hills of the insular Samogitian Upland had been repeatedly fortified from the beginning of 1st millennium AD to the 14th century (Satrija, Medvegalis etc). Chains of hill forts and castle mounds feature the slopes of glaciofluvial valleys of Nemunas, Neris and other rivers where the slopes were dissected by affluent rivulets and ravines and transformed into isolated, well protected hills (Kernave, Punia, Veliuona etc). Peninsulas and headlands formed by the erosion of fluvial and lacustrine deposits were used in the lowlands, e.g. in central and N Lithuania (Paberze, Mezotne etc). How much the landscape was modified for defense purposes? Long-term erosion and overgrowing vegetation damaged the former fortified sites, however some remains and the archeological excavations allowed their reconstruction. The fortified Bronze Age settlements used naturally-protected sites with only hilltop flattening and small ditches. Wooden fences surrounded the settlements in most cases while stony ditches were used in NW Lithuania (e.g. Ipiltis). From the beginning of 1st millennium AD the fortifications became stronger with multiple rampart-ditch systems and artificial canals. Construction of hill forts with a high-powered fortification system started in 13th c. when wooden castles surrounded by rampart-trench systems appeared. What is a protection status for the hill forts and castle mounds? Near 1000 sites are protected by the Lithuanian State as historical monuments. Many of them are cleaned from vegetation, supplied with an infrastructure and arranged for tourism purposes. Some are parts of the nature or historical reserves or regional and national parks. However, apart from a few cases, geology of the hill forts and other strongholds in Lithuania is yet poorly known. Needless to say, the hill forts and castle mounds are quite a unique and attractive feature of the Lithuanian landscape. For defense purposes, the ancient European countries relied more on stone and brick castles than on steepness of high hill slopes as it was in case of Lithuania.

Mutation analysis of BRCA1/2 mutations with special reference to polymorphic SNPs in Indian breast cancer patients.

PubMed

Shah, Nidhi D; Shah, Parth S; Panchal, Yash Y; Katudia, Kalpesh H; Khatri, Nikunj B; Ray, Hari Shankar P; Bhatiya, Upti R; Shah, Sandip C; Shah, Bhavini S; Rao, Mandava V

2018-01-01

Germline mutations BRCA1 and BRCA2 contribute almost equally in the causation of breast cancer (BC). The type of mutations in the Indian population that cause this condition is largely unknown. In this cohort, 79 randomized BC patients were screened for various types of BRCA1 and BRCA2 mutations including frameshift, nonsense, missense, in-frame and splice site types. The purified extracted DNA of each referral patient was subjected to Sanger gene sequencing using Codon Code Analyzer and Mutation Surveyor and next-generation sequencing (NGS) methods with Ion torrent software, after appropriate care. The data revealed that 35 cases were positive for BRCA1 or BRCA2 (35/79: 44.3%). BRCA2 mutations were higher (52.4%) than BRCA1 mutations (47.6%). Five novel mutations detected in this study were p.pro163 frameshift, p.asn997 frameshift, p.ser148 frameshift and two splice site single-nucleotide polymorphisms (SNPs). Additionally, four nonsense and one in-frame deletion were identified, which all seemed to be pathogenic. Polymorphic SNPs contributed the highest percentage of mutations (72/82: 87.8%) and contributed to pathogenic, likely pathogenic, likely benign, benign and variant of unknown significance (VUS). Young age groups (20-60 years) had a high frequency of germline mutations (62/82;75.6%) in the Indian population. This study suggested that polymorphic SNPs contributed a high percentage of mutations along with five novel types. Younger age groups are prone to having BC with a higher mutational rate. Furthermore, the SNPs detected in exons 10, 11 and 16 of BRCA1 and BRCA2 were higher than those in other exons 2, 3 and 9 polymorphic sites in two germline genes. These may be contributory for BC although missense types are known to be susceptible for cancer depending on the type of amino acid replaced in the protein and associated with pathologic events. Accordingly, appropriate counseling and treatment may be suggested.

Incorporating Temporal Information in Microblog Retrieval

DTIC Science & Technology

2012-11-01

Urbana-Champaign Urbana-Champaign, IL, USA willis8@illinois.edu Richard Medlin School of Information & Library Science University of North Carolina at...Chapel Hill Chapel Hill, NC, USA rich_medlin@med.unc.edu Jaime Arguello † School of Information & Library Science University of North Carolina at...published prior to time tQ. The School of Information and Library Science at the Uni- versity of Carolina at Chapel Hill submitted four runs to the Microblog

Solar heating and hot water system installed at Cherry Hill, New Jersey

NASA Technical Reports Server (NTRS)

1979-01-01

The solar heating and hot water system installed in existing buildings at the Cherry Hill Inn in Cherry Hill, New Jersey is described in detail. The system is expected to furnish 31.5% of the overall heating load and 29.8% of the hot water load. The collectors are liquid evacuated tube type. The storage system is an above ground insulated steel water tank with a capacity of 7,500 gallons.

Abundance of Black-backed woodpeckers and other birds in relation to disturbance and forest structure in the Black Hills and Bear Lodge Mountains of South Dakota and Wyoming

Treesearch

Elizabeth A. Matseur

2017-01-01

Natural disturbances, such as wildfire and mountain pine beetle (Dentroctonus ponderosae, hereafter MPB) infestations, are two sources of large-scale disturbance that can significantly alter forest structure in the Black Hills. The Black Hills has recently experienced one of the largest MPB outbreaks in the last 100 years, along with varying levels of wildfires...

Embracing Role Model Status: Acknowledging That Young People Often Glorify Athletes, Michigan State's Chris Hill Embraces His Responsibility as a Role Model

ERIC Educational Resources Information Center

Keels, Crystal L.

2005-01-01

It was "the unbelievable family atmosphere" that drew Chris Hill to Michigan State University's basketball program. And it has proven to be a good fit for the 6'3" Spartan guard. In his senior season, he has helped his team return to the Sweet Sixteen in the NCAA tournament. In his first year, Hill became the team's second leading…

Effect of Repeated Reading and Self-Directed Behavior on Reading Skills and Generalization of the Reading Skills of Third-Grade Hill Tribe Students.

ERIC Educational Resources Information Center

Compan, Boonlert; Iamsupasit, Sompoch; Samuels, Jay

A study tested a method for developing reading fluency with third-grade Hill Tribe children in a welfare school in Chiang Mai, a city located in northern Thailand. Most of the students were bilingual, speaking their native tongues and Thai, their second language. Only 18.7% of the Hill Tribe population can read Thai, and many students fail to…

PYTi-NiCr Signatures in the Columbia Hills are Present in Certain Martian Meteorites

NASA Technical Reports Server (NTRS)

Clark, B. C.; Gellert, R.; Ming, D. W.; Morris, R. V.; Mittlefehldt, D. W.; Squyres, S. W.

2006-01-01

Uniquely high levels of phosphorus and titanium were observed in several samples [1-3] by the APXS x-ray fluorescence measurements as the MER Spirit rover climbed Husband Hill (Columbia Hills, Gusev crater, Mars). A careful study of many such samples and their geochemical variability has revealed additional elements in this pattern, and that the derived multi-element signature is also unambiguously manifested in several martian meteorites.

Black Hills versus Weinberger: How Useful is It for Other Air Force Bases to Competitively Acquire Electricity.

DTIC Science & Technology

1988-04-01

whether the base must follow state created utility franchise territories. This paper analyzes the court opinion approving the competition, and the...the state franchised electric utility, Black Hills Power & Light Company (Black Hills), Ellswor-th competed for this additional power need. A company...utility franchise laws and regulations when it purchased the additional power. Both the United States District Court for the District of South Dakota

Martha N. Hill: transformational leader.

PubMed

Coombs, V J

1998-01-01

Martha N. Hill, PhD, RN, FAAN, is a world-renowned researcher, educator, and nursing leader. Her election as president of the American Heart Association, effective June 1997, places her in one of the highest regarded positions in the field of cardiology. Despite her success on a national and international level, Dr. Hill has managed to continue to mentor and conduct clinical research with her nursing colleagues and students at The Johns Hopkins University in Baltimore, Maryland.

SOUTH ELEVATION OF GOLD HILL MILL, LOOKING NORTH. THE PRIMARY ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

SOUTH ELEVATION OF GOLD HILL MILL, LOOKING NORTH. THE PRIMARY ORE BIN IS A CENTER, WITH A JAW CRUSHER JUST TO THE RIGHT. A CONVEYOR (MISSING) WAS USED TO CARRY CRUSHED ORE UP AND INTO THE SECONDARY ORE BIN. THE STONE RAMP TO THE LEFT OF THE ORE BIN WAS USED TO DRIVE TRUCKS UP TO DUMPING LEVEL. - Gold Hill Mill, Warm Spring Canyon Road, Death Valley Junction, Inyo County, CA

Publications - PDF 94-40 | Alaska Division of Geological & Geophysical

Science.gov Websites

content DGGS PDF 94-40 Publication Details Title: Geology of the Gagaryah River area, Lime Hills C-5 and C ., Clautice, K.H., and Harris, E.E., 1994, Geology of the Gagaryah River area, Lime Hills C-5 and C-6 Sheet 1 Geologic map of the Gagaryah River Area, Lime Hills C-5 and C-6 quadrangles, Southwestern Alaska

Spacecraft Constrained Maneuver Planning Using Positively Invariant Constraint Admissible Sets (Postprint)

DTIC Science & Technology

2013-08-14

Connectivity Graph; Graph Search; Bounded Disturbances; Linear Time-Varying (LTV); Clohessy - Wiltshire -Hill (CWH) 16. SECURITY CLASSIFICATION OF: 17...the linearization of the relative motion model given by the Hill- Clohessy - Wiltshire (CWH) equations is used [14]. A. Nonlinear equations of motion...equations can be used to describe the motion of the debris. B. Linearized HCW equations in discrete-time For δr << R, the linearized Hill- Clohessy

3. General view of Fort Hill Farm, view looking west ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

3. General view of Fort Hill Farm, view looking west from (B) two-story hall-and-parlor house. Buildings visible, from left to right, are (B) parlor house porch; (E) one-room cabin; (D) center chimney four-room cabin; (J) hay barn; (I) log tobacco barn; (A) mansion, obscured by trees; (M) stable; (K) small barn. - Fort Hill Farm, West of Staunton (Roanoke) River between Turkey & Caesar's Runs, Clover, Halifax County, VA

Saying Goodbye to 'Bonneville' Crater

NASA Technical Reports Server (NTRS)

2004-01-01

[figure removed for brevity, see original site] Annotated Image

NASA's Mars Exploration Rover Spirit took this panoramic camera image on sol 86 (March 31, 2004) before driving 36 meters (118 feet) on sol 87 toward its future destination, the Columbia Hills. This is probably the last panoramic camera image that Spirit will take from the high rim of 'Bonneville' crater, and provides an excellent view of the ejecta-covered path the rover has journeyed thus far. The lander can be seen toward the upper right of the frame and is approximately 321 meters (1060 feet) away from Spirit's current location. The large hill on the horizon is Grissom Hill. The Colombia Hills, located to the left, are not visible in this image.

Possible Ni-Rich Mafic-Ultramafic Magmatic Sequence in the Columbia Hills: Evidence from the Spirit Rover

NASA Technical Reports Server (NTRS)

Mittlefehldt, David W.; Gellert, R.; McCoy, T.; McSween, H. Y., Jr.; Li, R.

2006-01-01

The Spirit rover landed on geologic units of Hesperian age in Gusev Crater. The Columbia Hills rise above the surrounding plains materials, but orbital images show that the Columbia Hills are older [1, 2]. Spirit has recently descended the southeast slope of the Columbia Hills doing detailed measurements of a series of outcrops. The mineralogical and compositional data on these rocks are consistent with an interpretation as a magmatic sequence becoming increasingly olivine-rich down slope. The outcrop sequence is Larry s Bench, Seminole, Algonquin and Comanche. The "teeth" on the Rock Abrasion Tool (RAT) wore away prior to arrival at Larry s Bench; the data discussed are for RAT brushed surfaces.

Random mtDNA mutations modulate proliferation capacity in mouse embryonic fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kukat, Alexandra; Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases; Edgar, Daniel

2011-06-10

Highlights: {yields} Increased mtDNA mutations in MEFs lead to high level of spontaneous immortalization. {yields} This process is independent of endogenous ROS production. {yields} Aerobic glycolysis significantly contributes to spontaneous immortalization of MEFs. -- Abstract: An increase in mtDNA mutation load leads to a loss of critical cells in different tissues thereby contributing to the physiological process of organismal ageing. Additionally, the accumulation of senescent cells that display changes in metabolic function might act in an active way to further disrupt the normal tissue function. We believe that this could be the important link missing in our understanding of themore » molecular mechanisms of premature ageing in the mtDNA mutator mice. We tested proliferation capacity of mtDNA mutator cells in vitro. When cultured in physiological levels of oxygen (3%) their proliferation capacity is somewhat lower than wild-type cells. Surprisingly, in conditions of increased oxidative stress (20% O{sub 2}) mtDNA mutator mouse embryonic fibroblasts exhibit continuous proliferation due to spontaneous immortalization, whereas the same conditions promote senescence in wild-type cells. We believe that an increase in aerobic glycolysis observed in mtDNA mutator mice is a major mechanism behind this process. We propose that glycolysis promotes proliferation and allows a fast turnover of metabolites, but also leads to energy crisis due to lower ATP production rate. This could lead to compromised replication and/or repair and therefore, in rare cases, might lead to mutations in tumor suppressor genes and spontaneous immortalization.« less

The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe.

PubMed

Maugeri, Alessandra; Flothmann, Kris; Hemmrich, Nadine; Ingvast, Sofie; Jorge, Paula; Paloma, Eva; Patel, Reshma; Rozet, Jean-Michel; Tammur, Jaana; Testa, Francesco; Balcells, Susana; Bird, Alan C; Brunner, Han G; Hoyng, Carel B; Metspalu, Andres; Simonelli, Francesca; Allikmets, Rando; Bhattacharya, Shomi S; D'Urso, Michele; Gonzàlez-Duarte, Roser; Kaplan, Josseline; te Meerman, Gerard J; Santos, Rosário; Schwartz, Marianne; Van Camp, Guy; Wadelius, Claes; Weber, Bernhard H F; Cremers, Frans P M

2002-03-01

Inherited retinal dystrophies represent the most important cause of vision impairment in adolescence, affecting approximately 1 out of 3000 individuals. Mutations of the photoreceptor-specific gene ABCA4 (ABCR) are a common cause of retinal dystrophy. A number of mutations have been repeatedly reported for this gene, notably the 2588G>C mutation which is frequent in both patients and controls. Here we ascertained the frequency of the 2588G>C mutation in a total of 2343 unrelated random control individuals from 11 European countries and 241 control individuals from the US, as well as in 614 patients with STGD both from Europe and the US. We found an overall carrier frequency of 1 out of 54 in Europe, compared with 1 out of 121 in the US, confirming that the 2588G>C ABCA4 mutation is one of the most frequent autosomal recessive mutations in the European population. Carrier frequencies show an increasing gradient in Europe from South-West to North-East. The lowest carrier frequency, 0 out of 199 (0%), was found in Portugal; the highest, 11 out of 197 (5.5%), was found in Sweden. Haplotype analysis in 16 families segregating the 2588G>C mutation showed four intragenic polymorphisms invariably present in all 16 disease chromosomes and sharing of the same allele for several markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicate a single origin of the 2588G>C mutation which, to our best estimate, occurred between 2400 and 3000 years ago.

Energy parasites trigger oncogene mutation.

PubMed

Pokorný, Jiří; Pokorný, Jan; Jandová, Anna; Kobilková, Jitka; Vrba, Jan; Vrba, Jan

2016-10-01

Cancer initialization can be explained as a result of parasitic virus energy consumption leading to randomized genome chemical bonding. Analysis of experimental data on cell-mediated immunity (CMI) containing about 12,000 cases of healthy humans, cancer patients and patients with precancerous cervical lesions disclosed that the specific cancer and the non-specific lactate dehydrogenase-elevating (LDH) virus antigen elicit similar responses. The specific antigen is effective only in cancer type of its origin but the non-specific antigen in all examined cancers. CMI results of CIN patients display both healthy and cancer state. The ribonucleic acid (RNA) of the LDH virus parasitizing on energy reduces the ratio of coherent/random oscillations. Decreased effect of coherent cellular electromagnetic field on bonding electrons in biological macromolecules leads to elevating probability of random genome reactions. Overlapping of wave functions in biological macromolecules depends on energy of the cellular electromagnetic field which supplies energy to bonding electrons for selective chemical bonds. CMI responses of cancer and LDH virus antigens in all examined healthy, precancerous and cancer cases point to energy mechanism in cancer initiation. Dependence of the rate of biochemical reactions on biological electromagnetic field explains yet unknown mechanism of genome mutation.

The (not so) immortal strand hypothesis.

PubMed

Tomasetti, Cristian; Bozic, Ivana

2015-03-01

Non-random segregation of DNA strands during stem cell replication has been proposed as a mechanism to minimize accumulated genetic errors in stem cells of rapidly dividing tissues. According to this hypothesis, an "immortal" DNA strand is passed to the stem cell daughter and not the more differentiated cell, keeping the stem cell lineage replication error-free. After it was introduced, experimental evidence both in favor and against the hypothesis has been presented. Using a novel methodology that utilizes cancer sequencing data we are able to estimate the rate of accumulation of mutations in healthy stem cells of the colon, blood and head and neck tissues. We find that in these tissues mutations in stem cells accumulate at rates strikingly similar to those expected without the protection from the immortal strand mechanism. Utilizing an approach that is fundamentally different from previous efforts to confirm or refute the immortal strand hypothesis, we provide evidence against non-random segregation of DNA during stem cell replication. Our results strongly suggest that parental DNA is passed randomly to stem cell daughters and provides new insight into the mechanism of DNA replication in stem cells. Copyright © 2015. Published by Elsevier B.V.

The (not so) Immortal Strand Hypothesis

PubMed Central

Tomasetti, Cristian; Bozic, Ivana

2015-01-01

Background Non-random segregation of DNA strands during stem cell replication has been proposed as a mechanism to minimize accumulated genetic errors in stem cells of rapidly dividing tissues. According to this hypothesis, an “immortal” DNA strand is passed to the stem cell daughter and not the more differentiated cell, keeping the stem cell lineage replication error-free. After it was introduced, experimental evidence both in favor and against the hypothesis has been presented. Principal Findings Using a novel methodology that utilizes cancer sequencing data we are able to estimate the rate of accumulation of mutations in healthy stem cells of the colon, blood and head and neck tissues. We to find that in these tissues mutations in stem cells accumulate at rates strikingly similar to those expected without the protection from the immortal strand mechanism. Significance Utilizing an approach that is fundamentally different from previous efforts to confirm or refute the immortal strand hypothesis, we provide strong evidence against non-random segregation of DNA during stem cell replication. Our results strongly suggest that parental DNA is passed randomly to stem cell daughters and provides new insight into the mechanism of DNA replication in stem cells. PMID:25700960

Identification of the Rdl mutation in laboratory and field strains of the cat flea, Ctenocephalides felis (Siphonaptera: Pulicidae).

PubMed

Bass, Chris; Schroeder, Iris; Turberg, Andreas; Field, Linda M; Williamson, Martin S

2004-12-01

In many insect species, resistance to cyclodiene insecticides is caused by amino acid substitutions at a single residue (A302) within the M2 transmembrane region of the gamma-aminobutyric acid (GABA) receptor sub-unit termed Rdl (resistance to dieldrin). These mutations (A302S and A302G) have also been shown to confer varying levels of cross-resistance to fipronil, a phenylpyrazole insecticide with a similar mode of action to cyclodienes. To investigate the possible occurrence of these mutations in the cat flea, Ctenocephalides felis (Bouché), a 176-bp fragment of the cat flea Rdl gene, encompassing the mutation site, was PCR amplified and sequenced from nine laboratory flea strains. The A302S mutation was found in eight of the nine strains analysed, although the relative frequency of the mutant allele varied between strains. Only one strain (R6) was found to be homozygous for the S302 allele in all the individuals tested, and this correlated with previous reports of low-level fipronil resistance in this strain. A PCR-based diagnostic assay, capable of screening individual fleas for this mutation, was developed and used to survey a range of fleas collected at random from veterinary clinics in the UK and USA. The A302S mutation was present at a high frequency in these domestic pet populations. 2004 Society of Chemical Industry.

Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abeliovich, D.; Lavon, I.P.; Lerer, I.

1992-11-01

To determine the distribution and frequency of cystic fibrosis (CF) mutations in the Israeli population, the authors have screened 96 patients for 11 relatively common mutations. Five mutations - [Delta]F508, G542X, W1282X, N1303K, and 3849 + 10kb C[yields]T-were found to account for 97% of the CF alleles in the Ashkenazi Jews. In contrast, of the 11 mutations tested, only [Delta]F508 was detected in Jewish patients of Sephardic or Oriental origin, accounting for 43% of the CF alleles. Four mutations - [Delta]F508, G542X, W1282X, and N1303K- accounted for 55% of the CF alleles in Arab patients. In a pilot screening study,more » a random sample of 424 Ashkenazi individuals was analyzed for three mutations - [Delta]F508, W128X, and G542X. Thirteen individuals were detected as heterozygotes (six for [Delta]F508 and seven for W1282X), predicting a heterozygote frequency of 1:29. This is similar to the frequency of carriers in the Caucasian population of northern European ancestry. On the basis of these data, the Ashkenazi populations is considered to be a candidate for CF heterozygote screening. 32 refs., 2 tabs.« less

Female mating preferences determine system-level evolution in a gene network model.

PubMed

Fierst, Janna L

2013-06-01

Environmental patterns of directional, stabilizing and fluctuating selection can influence the evolution of system-level properties like evolvability and mutational robustness. Intersexual selection produces strong phenotypic selection and these dynamics may also affect the response to mutation and the potential for future adaptation. In order to to assess the influence of mating preferences on these evolutionary properties, I modeled a male trait and female preference determined by separate gene regulatory networks. I studied three sexual selection scenarios: sexual conflict, a Gaussian model of the Fisher process described in Lande (in Proc Natl Acad Sci 78(6):3721-3725, 1981) and a good genes model in which the male trait signalled his mutational condition. I measured the effects these mating preferences had on the potential for traits and preferences to evolve towards new states, and mutational robustness of both the phenotype and the individual's overall viability. All types of sexual selection increased male phenotypic robustness relative to a randomly mating population. The Fisher model also reduced male evolvability and mutational robustness for viability. Under good genes sexual selection, males evolved an increased mutational robustness for viability. Females choosing their mates is a scenario that is sufficient to create selective forces that impact genetic evolution and shape the evolutionary response to mutation and environmental selection. These dynamics will inevitably develop in any population where sexual selection is operating, and affect the potential for future adaptation.

Comparison of genetic algorithm methods for fuel management optimization

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeChaine, M.D.; Feltus, M.A.

1995-12-31

The CIGARO system was developed for genetic algorithm fuel management optimization. Tests are performed to find the best fuel location swap mutation operator probability and to compare genetic algorithm to a truly random search method. Tests showed the fuel swap probability should be between 0% and 10%, and a 50% definitely hampered the optimization. The genetic algorithm performed significantly better than the random search method, which did not even satisfy the peak normalized power constraint.

A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies

PubMed Central

Nalls, Michael A.; Duran, Raquel; Lopez, Grisel; Kurzawa-Akanbi, Marzena; McKeith, Ian G.; Chinnery, Patrick F.; Morris, Christopher M.; Theuns, Jessie; Crosiers, David; Cras, Patrick; Engelborghs, Sebastiaan; De Deyn, Peter Paul; Van Broeckhoven, Christine; Mann, David M. A.; Snowden, Julie; Pickering-Brown, Stuart; Halliwell, Nicola; Davidson, Yvonne; Gibbons, Linda; Harris, Jenny; Sheerin, Una-Marie; Bras, Jose; Hardy, John; Clark, Lorraine; Marder, Karen; Honig, Lawrence S.; Berg, Daniela; Maetzler, Walter; Brockmann, Kathrin; Gasser, Thomas; Novellino, Fabiana; Quattrone, Aldo; Annesi, Grazia; De Marco, Elvira Valeria; Rogaeva, Ekaterina; Masellis, Mario; Black, Sandra E.; Bilbao, Juan M.; Foroud, Tatiana; Ghetti, Bernardino; Nichols, William C.; Pankratz, Nathan; Halliday, Glenda; Lesage, Suzanne; Klebe, Stephan; Durr, Alexandra; Duyckaerts, Charles; Brice, Alexis; Giasson, Benoit I.; Trojanowski, John Q.; Hurtig, Howard I.; Tayebi, Nahid; Landazabal, Claudia; Knight, Melanie A.; Keller, Margaux; Singleton, Andrew B.; Wolfsberg, Tyra G.; Sidransky, Ellen

2013-01-01

Importance While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders. Objective To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). Design We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity. Setting Eleven centers from sites around the world performing genotyping. Participants Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity. Main Outcome Measures Frequency of GBA1 mutations in cases and controls. Results We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78–14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53–15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P<.001), with higher disease severity scores. Conclusions and Relevance Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease. PMID:23588557

Novel cases of Tunisian patients with mutations in the gene encoding 17β-hydroxysteroid dehydrogenase type 3 and a founder effect.

PubMed

Ben Rhouma, Bochra; Kallabi, Fakhri; Mahfoudh, Nadia; Ben Mahmoud, Afif; Engeli, Roger T; Kamoun, Hassen; Keskes, Leila; Odermatt, Alex; Belguith, Neila

2017-01-01

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed almost exclusively in the testis and converts Δ4-androstene-3,17-dione to testosterone. Mutations in the HSD17B3 gene causing 17β-HSD3 deficiency are responsible for a rare recessive form of 46, XY Disorders of Sex Development (46, XY DSD). We report novel cases of Tunisian patients with 17β-HSD3 deficiency due to previously reported mutations, i.e. p.C206X and p.G133R, as well as a case with the novel compound heterozygous mutations p.C206X and p.Q176P. Moreover, the previously reported polymorphism p.G289S was identified in a heterozygous state in combination with a novel non-coding variant c.54G>T, also in a heterozygous state, in a male patient presenting with micropenis and low testosterone levels. The identification of four different mutations in a cohort of eight patients confirms the generally observed genetic heterogeneity of 17β-HSD3 deficiency. Nevertheless, analysis of DNA from 272 randomly selected healthy controls from the same geographic area (region of Sfax) revealed a high carrier frequency for the p.C206X mutation of approximately 1 in 40. Genotype reconstruction of the affected pedigree members revealed that all p.C206X mutation carriers harbored the same haplotype, indicating inheritance of the mutation from a common ancestor. Thus, the identification of a founder effect and the elevated carrier frequency of the p.C206X mutation emphasize the importance to consider this mutation in the diagnosis and genetic counseling of affected 17β-HSD3 deficiency pedigrees in Tunisia. Copyright © 2016 Elsevier Ltd. All rights reserved.

BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and meta-analysis.

PubMed

Chen, Dong; Huang, Jun-Fu; Liu, Kai; Zhang, Li-Qun; Yang, Zhao; Chuai, Zheng-Ran; Wang, Yun-Xia; Shi, Da-Chuan; Huang, Qing; Fu, Wei-Ling

2014-01-01

Colorectal cancer (CRC) is a heterogeneous disease with multiple underlying causative genetic mutations. The B-type Raf proto-oncogene (BRAF) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade during CRC. The presence of BRAFV600E mutation can determine the response of a tumor to chemotherapy. However, the association between the BRAFV600E mutation and the clinicopathological features of CRC remains controversial. We performed a systematic review and meta-analysis to estimate the effect of BRAFV600E mutation on the clinicopathological characteristics of CRC. We identified studies that examined the effect of BRAFV600E mutation on CRC within the PubMed, ISI Science Citation Index, and Embase databases. The effect of BRAFV600E on outcome parameters was estimated by odds ratios (ORs) with 95% confidence intervals (CIs) for each study using a fixed effects or random effects model. 25 studies with a total of 11,955 CRC patients met inclusion criteria. The rate of BRAFV600 was 10.8% (1288/11955). The BRAFV600E mutation in CRC was associated with advanced TNM stage, poor differentiation, mucinous histology, microsatellite instability (MSI), CpG island methylator phenotype (CIMP). This mutation was also associated with female gender, older age, proximal colon, and mutL homolog 1 (MLH1) methylation. This meta-analysis demonstrated that BRAFV600E mutation was significantly correlated with adverse pathological features of CRC and distinct clinical characteristics. These data suggest that BRAFV600E mutation could be used to supplement standard clinical and pathological staging for the better management of individual CRC patients, and could be considered as a poor prognostic marker for CRC.

A nonadaptive origin of a beneficial trait: in silico selection for free energy of folding leads to the neutral emergence of mutational robustness in single domain proteins.

PubMed

Pagan, Rafael F; Massey, Steven E

2014-02-01

Proteins are regarded as being robust to the deleterious effects of mutations. Here, the neutral emergence of mutational robustness in a population of single domain proteins is explored using computer simulations. A pairwise contact model was used to calculate the ΔG of folding (ΔG folding) using the three dimensional protein structure of leech eglin C. A random amino acid sequence with low mutational robustness, defined as the average ΔΔG resulting from a point mutation (ΔΔG average), was threaded onto the structure. A population of 1,000 threaded sequences was evolved under selection for stability, using an upper and lower energy threshold. Under these conditions, mutational robustness increased over time in the most common sequence in the population. In contrast, when the wild type sequence was used it did not show an increase in robustness. This implies that the emergence of mutational robustness is sequence specific and that wild type sequences may be close to maximal robustness. In addition, an inverse relationship between ∆∆G average and protein stability is shown, resulting partly from a larger average effect of point mutations in more stable proteins. The emergence of mutational robustness was also observed in the Escherichia coli colE1 Rop and human CD59 proteins, implying that the property may be common in single domain proteins under certain simulation conditions. The results indicate that at least a portion of mutational robustness in small globular proteins might have arisen by a process of neutral emergence, and could be an example of a beneficial trait that has not been directly selected for, termed a "pseudaptation."

Determining the origin of enigmatic bedrock structures using apatite (U-Th)/He thermochronology: Alabama and Poverty Hills, Owens Valley, California

NASA Astrophysics Data System (ADS)

Ali, G. A.; Reiners, P. W.; Ducea, M.

2008-12-01

The Alabama and Poverty Hills are enigmatic, topographic highs of crystalline basement surrounded by Neogene sediments in Owens Valley, California. The 150-km long Owens Valley, the westernmost graben of the Basin and Range Province, initiated at about 3 Ma, creating ~2-4 km of vertical relief from the Sierra Nevada and White/Inyos crests to the valley floor. Along the valley, the active right-lateral Owens Valley Fault Zone (OVFZ) accommodates a significant portion of Pacific-North American plate motion, creating an oblique dextral fault zone, with localized transpression along minor left-stepovers. The dominantly granitic Mesozoic rocks of the Alabama Hills are bounded by the OVFZ to the east, and the granitic and metavolcanic Mesozoic rocks of the Poverty Hills are located along an apparent 3-km left stepover of the OVFZ. The tectonic origin and geodynamic significance of both these structures are not known, but previously published hypotheses include: 1) transpressional uplifts as OVFZ-related flower structures; 2) down-dropped normal fault blocks; and 3) giant landslides from adjacent ranges. We measured apatite (U-Th)/He ages on 15 samples from the Alabama and Poverty Hills to understand the history of shallow crustal exhumation of these structures, and to potentially correlate them to rocks from adjacent ranges. Apatite He dating typically yields cooling ages corresponding to closure temperatures of ~55-65 °C, corresponding roughly to depths of ~2-3 km in the crust. The majority of apatite He ages from the Alabama Hills ranged from 58-70 Ma, but the far eastern, and lowest elevation sample showed ages of 51-55 Ma. The Poverty Hills shows younger ages of 40-65 Ma and no recognizable spatial pattern. Although the data do not conclusively rule out a transpressional uplift origin of the Poverty Hills, the rocks within them could not have been exhumed from depths greater than ~2-3 km in Owens Valley. Data from both structures are most consistent with down-dropping from adjacent ranges. Apatite He ages in the Alabama Hills correlate with He ages of rocks about 2.5-3 km higher, near Mt. Whitney in the adjacent Sierra Nevada. This, coupled with the spatial pattern of ages, strongly suggests that the Alabama Hills are a down-dropped normal fault block along the Sierra Nevada frontal fault zone or a related fault. A structural reconstruction using tilt-corrected Sierran apatite He age-elevation correlations requires 2.6 km of vertical, and 1.5 km of eastward motion for the Alabama Hills. The proximity of this extensive down- dropped basement block, directly east of the highest topography in the Sierra Nevada, suggests the possibility of localized isostatic response as a cause for locally high elevation in the Mt. Whitney area.

The role of causal criteria in causal inferences: Bradford Hill's "aspects of association".

PubMed

Ward, Andrew C

2009-06-17

As noted by Wesley Salmon and many others, causal concepts are ubiquitous in every branch of theoretical science, in the practical disciplines and in everyday life. In the theoretical and practical sciences especially, people often base claims about causal relations on applications of statistical methods to data. However, the source and type of data place important constraints on the choice of statistical methods as well as on the warrant attributed to the causal claims based on the use of such methods. For example, much of the data used by people interested in making causal claims come from non-experimental, observational studies in which random allocations to treatment and control groups are not present. Thus, one of the most important problems in the social and health sciences concerns making justified causal inferences using non-experimental, observational data. In this paper, I examine one method of justifying such inferences that is especially widespread in epidemiology and the health sciences generally - the use of causal criteria. I argue that while the use of causal criteria is not appropriate for either deductive or inductive inferences, they do have an important role to play in inferences to the best explanation. As such, causal criteria, exemplified by what Bradford Hill referred to as "aspects of [statistical] associations", have an indispensible part to play in the goal of making justified causal claims.

Waveform classification and statistical analysis of seismic precursors to the July 2008 Vulcanian Eruption of Soufrière Hills Volcano, Montserrat

NASA Astrophysics Data System (ADS)

Rodgers, Mel; Smith, Patrick; Pyle, David; Mather, Tamsin

2016-04-01

Understanding the transition between quiescence and eruption at dome-forming volcanoes, such as Soufrière Hills Volcano (SHV), Montserrat, is important for monitoring volcanic activity during long-lived eruptions. Statistical analysis of seismic events (e.g. spectral analysis and identification of multiplets via cross-correlation) can be useful for characterising seismicity patterns and can be a powerful tool for analysing temporal changes in behaviour. Waveform classification is crucial for volcano monitoring, but consistent classification, both during real-time analysis and for retrospective analysis of previous volcanic activity, remains a challenge. Automated classification allows consistent re-classification of events. We present a machine learning (random forest) approach to rapidly classify waveforms that requires minimal training data. We analyse the seismic precursors to the July 2008 Vulcanian explosion at SHV and show systematic changes in frequency content and multiplet behaviour that had not previously been recognised. These precursory patterns of seismicity may be interpreted as changes in pressure conditions within the conduit during magma ascent and could be linked to magma flow rates. Frequency analysis of the different waveform classes supports the growing consensus that LP and Hybrid events should be considered end members of a continuum of low-frequency source processes. By using both supervised and unsupervised machine-learning methods we investigate the nature of waveform classification and assess current classification schemes.

The role of causal criteria in causal inferences: Bradford Hill's "aspects of association"

PubMed Central

Ward, Andrew C

2009-01-01

As noted by Wesley Salmon and many others, causal concepts are ubiquitous in every branch of theoretical science, in the practical disciplines and in everyday life. In the theoretical and practical sciences especially, people often base claims about causal relations on applications of statistical methods to data. However, the source and type of data place important constraints on the choice of statistical methods as well as on the warrant attributed to the causal claims based on the use of such methods. For example, much of the data used by people interested in making causal claims come from non-experimental, observational studies in which random allocations to treatment and control groups are not present. Thus, one of the most important problems in the social and health sciences concerns making justified causal inferences using non-experimental, observational data. In this paper, I examine one method of justifying such inferences that is especially widespread in epidemiology and the health sciences generally – the use of causal criteria. I argue that while the use of causal criteria is not appropriate for either deductive or inductive inferences, they do have an important role to play in inferences to the best explanation. As such, causal criteria, exemplified by what Bradford Hill referred to as "aspects of [statistical] associations", have an indispensible part to play in the goal of making justified causal claims. PMID:19534788

Hemoglobin E and Glucose-6-Phosphate Dehydrogenase Deficiency and Plasmodium falciparum Malaria in the Chittagong Hill Districts of Bangladesh.

PubMed

Shannon, Kerry L; Ahmed, Sabeena; Rahman, Hafizur; Prue, Chai S; Khyang, Jacob; Ram, Malathi; Haq, M Zahirul; Chowdhury, Ashish; Akter, Jasmin; Glass, Gregory E; Shields, Timothy; Nyunt, Myaing M; Khan, Wasif A; Sack, David A; Sullivan, David J

2015-08-01

Hemoglobin E is largely confined to south and southeast Asia. The association between hemoglobin E (HbE) and malaria is less clear than that of hemoglobin S and C. As part of a malaria study in the Chittagong Hill Districts of Bangladesh, an initial random sample of 202 individuals showed that 39% and 49% of Marma and Khyang ethnic groups, respectively, were positive for either heterozygous or homozygous hemoglobin E. In this group, 6.4% were also found to be severely deficient and 35% mildly deficient for glucose-6-phosphate dehydrogenase (G6PD). In a separate Plasmodium falciparum malaria case-uninfected control study, the odds of having homozygous hemoglobin E (HbEE) compared with normal hemoglobin (HbAA) were higher among malaria cases detected by passive surveillance than age and location matched uninfected controls (odds ratio [OR] = 5.0, 95% confidence interval [CI] = 1.07-46.93). The odds of heterozygous hemoglobin E (HbAE) compared with HbAA were similar between malaria cases and uninfected controls (OR = 0.71, 95% CI = 0.42-1.19). No association by hemoglobin type was found in the initial parasite density or the proportion parasite negative after 2 days of artemether/lumefantrine treatment. HbEE, but not HbAE status was associated with increased passive case detection of malaria. © The American Society of Tropical Medicine and Hygiene.

Potentiometric surface of the Minnekahta Aquifer in the Black Hills area, South Dakota

USGS Publications Warehouse

Strobel, Michael L.; Galloway, Joel M.; Hamade, Ghaith R.; Jarrell, Gregory J.

2000-01-01

This map is a product of the Black Hills Hydrology Study, which was initiated in 1990 to assess the quantity, quality, and distribution of surface water and ground water in the Black Hills area of South Dakota (Driscoll, 1992). This long-term study is a cooperative effort between the U.S. Geological Survey (USGS), the South Dakota Department of Environment and Natural Resources, and the West Dakota Water Development District, which represents various local and county cooperators. This map is part of a series of 1:100,000-scale maps for the study. The maps include a hydrogeologic map, structure-contour maps (altitudes of the tops of formations) for five formations that contain major aquifers in the study area, and potentiometric maps for these five major aquifers (the Inyan Kara, Minnekahta, Minnelusa, Madison, and Deadwood aquifers).The study area consists of the topographically defined Black Hills and adjacent areas located in western South Dakota. The Black Hills area is an elongated, dome-shaped feature, about 125 miles long and 60 miles wide, which was uplifted during the Laramide orogeny (Feldman and Heimlich, 1980). The oldest geologic units in the study area are Precambrian metamorphic and igneous rocks, which are exposed in the central core of the Black Hills. Surrounding the Precambrian core is a layered series of sedimentary rocks including limestones, sandstones, and shales that are exposed in roughly concentric rings around the uplifted flanks of the Black Hills. The bedrock sedimentary units typically dip away from the uplifted Black Hills at angles that approach or exceed 10 degrees near the outcrops, and decrease with distance from the uplift. Many of the sedimentary units contain aquifers, both within and beyond the study area. Recharge to these aquifers occurs from infiltration of precipitation upon the outcrops and, in some cases, from infiltration of streamflow (Hortness and Driscoll, 1998). Artesian conditions generally exist within these aquifers where an upper confining layer is present. Flowing wells and springs that originate from the confined aquifers are common around the periphery of the Black Hills.The purpose of this map is to show the potentiometric surface of the Minnekahta aquifer within the study area. The map provides a tool for evaluating ground-water flow directions and hydraulic gradients in the Minnekahta aquifer.

Potentiometric surface of the Inyan Kara Aquifer in the Black Hills area, South Dakota

USGS Publications Warehouse

Strobel, Michael L.; Galloway, Joel M.; Hamade, Ghaith R.; Jarrell, Gregory J.

2000-01-01

This map is a product of the Black Hills Hydrology Study, which was initiated in 1990 to assess the quantity, quality, and distribution of surface water and ground water in the Black Hills area of South Dakota (Driscoll, 1992). This long-term study is a cooperative effort between the U.S. Geological Survey (USGS), the South Dakota Department of Environment and Natural Resources, and the West Dakota Water Development District, which represents various local and county cooperators. This map is part of a series of 1:100,000-scale maps for the study. The maps include a hydrogeologic map, structure-contour maps (altitudes of the tops of formations) for five formations that contain major aquifers in the study area, and potentiometric maps for these five major aquifers (the Inyan Kara, Minnekahta, Minnelusa, Madison, and Deadwood aquifers).The study area consists of the topographically defined Black Hills and adjacent areas located in western South Dakota. The Black Hills area is an elongated, dome-shaped feature, about 125 miles long and 60 miles wide, which was uplifted during the Laramide orogeny (Feldman and Heimlich, 1980). The oldest geologic units in the study area are Precambrian metamorphic and igneous rocks, which are exposed in the central core of the Black Hills. Surrounding the Precambrian core is a layered series of sedimentary rocks including limestones, sandstones, and shales that are exposed in roughly concentric rings around the uplifted flanks of the Black Hills. The bedrock sedimentary units typically dip away from the uplifted Black Hills at angles that approach or exceed 10 degrees near the outcrops, and decrease with distance from the uplift. Many of the sedimentary units contain aquifers, both within and beyond the study area. Recharge to these aquifers occurs from infiltration of precipitation upon the outcrops and, in some cases, from infiltration of streamflow (Hortness and Driscoll, 1998). Artesian conditions generally exist within these aquifers where an upper confining layer is present. Flowing wells and springs that originate from the confined aquifers are common around the periphery of the Black Hills.The purpose of this map is to show the potentiometric surface of the Inyan Kara aquifer within the study area. The map provides a tool for evaluating ground-water flow directions and hydraulic gradients in the Inyan Kara aquifer.

Potentiometric surface of the Deadwood Aquifer in the Black Hills area, South Dakota

USGS Publications Warehouse

Strobel, Michael L.; Galloway, Joel M.; Hamade, Ghaith R.; Jarrell, Gregory J.

2000-01-01

This map is a product of the Black Hills Hydrology Study, which was initiated in 1990 to assess the quantity, quality, and distribution of surface water and ground water in the Black Hills area of South Dakota (Driscoll, 1992). This long-term study is a cooperative effort between the U.S. Geological Survey (USGS), the South Dakota Department of Environment and Natural Resources, and the West Dakota Water Development District, which represents various local and county cooperators. This map is part of a series of 1:100,000-scale maps for the study. The maps include a hydrogeologic map, structure-contour maps (altitudes of the tops of formations) for five formations that contain major aquifers in the study area, and potentiometric maps for these five major aquifers (the Inyan Kara, Minnekahta, Minnelusa, Madison, and Deadwood aquifers).The study area consists of the topographically defined Black Hills and adjacent areas located in western South Dakota. The Black Hills area is an elongated, dome-shaped feature, about 125 miles long and 60 miles wide, which was uplifted during the Laramide orogeny (Feldman and Heimlich, 1980). The oldest geologic units in the study area are Precambrian metamorphic and igneous rocks, which are exposed in the central core of the Black Hills. Surrounding the Precambrian core is a layered series of sedimentary rocks including limestones, sandstones, and shales that are exposed in roughly concentric rings around the uplifted flanks of the Black Hills. The bedrock sedimentary units typically dip away from the uplifted Black Hills at angles that approach or exceed 10 degrees near the outcrops, and decrease with distance from the uplift. Many of the sedimentary units contain aquifers, both within and beyond the study area. Recharge to these aquifers occurs from infiltration of precipitation upon the outcrops and, in some cases, from infiltration of streamflow (Hortness and Driscoll, 1998). Artesian conditions generally exist within these aquifers where an upper confining layer is present. Flowing wells and springs that originate from the confined aquifers are common around the periphery of the Black Hills.The purpose of this map is to show the potentiometric surface of the Deadwood aquifer within the study area. The map provides a tool for evaluating ground-water flow directions and hydraulic gradients in the Deadwood aquifer.

Potentiometric surface of the Minnelusa Aquifer in the Black Hills area, South Dakota

USGS Publications Warehouse

Strobel, Michael L.; Galloway, Joel M.; Hamade, Ghaith R.; Jarrell, Gregory J.

2000-01-01

This map is a product of the Black Hills Hydrology Study, which was initiated in 1990 to assess the quantity, quality, and distribution of surface water and ground water in the Black Hills area of South Dakota (Driscoll, 1992). This long-term study is a cooperative effort between the U.S. Geological Survey (USGS), the South Dakota Department of Environment and Natural Resources, and the West Dakota Water Development District, which represents various local and county cooperators. This map is part of a series of 1:100,000-scale maps for the study. The maps include a hydrogeologic map, structure-contour maps (altitudes of the tops of formations) for five formations that contain major aquifers in the study area, and potentiometric maps for these five major aquifers (the Inyan Kara, Minnekahta, Minnelusa, Madison, and Deadwood aquifers).The study area consists of the topographically defined Black Hills and adjacent areas located in western South Dakota. The Black Hills area is an elongated, dome-shaped feature, about 125 miles long and 60 miles wide, which was uplifted during the Laramide orogeny (Feldman and Heimlich, 1980). The oldest geologic units in the study area are Precambrian metamorphic and igneous rocks, which are exposed in the central core of the Black Hills. Surrounding the Precambrian core is a layered series of sedimentary rocks including limestones, sandstones, and shales that are exposed in roughly concentric rings around the uplifted flanks of the Black Hills. The bedrock sedimentary units typically dip away from the uplifted Black Hills at angles that approach or exceed 10 degrees near the outcrops, and decrease with distance from the uplift. Many of the sedimentary units contain aquifers, both within and beyond the study area. Recharge to these aquifers occurs from infiltration of precipitation upon the outcrops and, in some cases, from infiltration of streamflow (Hortness and Driscoll, 1998). Artesian conditions generally exist within these aquifers where an upper confining layer is present. Flowing wells and springs that originate from the confined aquifers are common around the periphery of the Black Hills.The purpose of this map is to show the potentiometric surface of the Minnelusa aquifer within the study area. The map provides a tool for evaluating ground-water flow directions and hydraulic gradients in the Minnelusa aquifer.

Potentiometric surface of the Madison Aquifer in the Black Hills area, South Dakota

USGS Publications Warehouse

Strobel, Michael L.; Galloway, Joel M.; Hamade, Ghaith R.; Jarrell, Gregory L.

2000-01-01

This map is a product of the Black Hills Hydrology Study, which was initiated in 1990 to assess the quantity, quality, and distribution of surface water and ground water in the Black Hills area of South Dakota (Driscoll, 1992). This long-term study is a cooperative effort between the U.S. Geological Survey (USGS), the South Dakota Department of Environment and Natural Resources, and the West Dakota Water Development District, which represents various local and county cooperators. This map is part of a series of 1:100,000-scale maps for the study. The maps include a hydrogeologic map, structure-contour maps (altitudes of the tops of formations) for five formations that contain major aquifers in the study area, and potentiometric maps for these five major aquifers (the Inyan Kara, Minnekahta, Minnelusa, Madison, and Deadwood aquifers).The study area consists of the topographically defined Black Hills and adjacent areas located in western South Dakota. The Black Hills area is an elongated, dome-shaped feature, about 125 miles long and 60 miles wide, which was uplifted during the Laramide orogeny (Feldman and Heimlich, 1980). The oldest geologic units in the study area are Precambrian metamorphic and igneous rocks, which are exposed in the central core of the Black Hills. Surrounding the Precambrian core is a layered series of sedimentary rocks including limestones, sandstones, and shales that are exposed in roughly concentric rings around the uplifted flanks of the Black Hills. The bedrock sedimentary units typically dip away from the uplifted Black Hills at angles that approach or exceed 10 degrees near the outcrops, and decrease with distance from the uplift. Many of the sedimentary units contain aquifers, both within and beyond the study area. Recharge to these aquifers occurs from infiltration of precipitation upon the outcrops and, in some cases, from infiltration of streamflow (Hortness and Driscoll, 1998). Artesian conditions generally exist within these aquifers where an upper confining layer is present. Flowing wells and springs that originate from the confined aquifers are common around the periphery of the Black Hills.The purpose of this map is to show the potentiometric surface of the Madison aquifer within the study area. The map provides a tool for evaluating ground-water flow directions and hydraulic gradients in the Madison aquifer.

Tumor progression: chance and necessity in Darwinian and Lamarckian somatic (mutationless) evolution.

PubMed

Huang, Sui

2012-09-01

Current investigation of cancer progression towards increasing malignancy focuses on the molecular pathways that produce the various cancerous traits of cells. Their acquisition is explained by the somatic mutation theory: tumor progression is the result of a neo-Darwinian evolution in the tissue. Herein cells are the units of selection. Random genetic mutations permanently affecting these pathways create malignant cell phenotypes that are selected for in the disturbed tissue. However, could it be that the capacity of the genome and its gene regulatory network to generate the vast diversity of cell types during development, i.e., to produce inheritable phenotypic changes without mutations, is harnessed by tumorigenesis to propel a directional change towards malignancy? Here we take an encompassing perspective, transcending the orthodoxy of molecular carcinogenesis and review mechanisms of somatic evolution beyond the Neo-Darwinian scheme. We discuss the central concept of "cancer attractors" - the hidden stable states of gene regulatory networks normally not occupied by cells. Noise-induced transitions into such attractors provide a source for randomness (chance) and regulatory constraints (necessity) in the acquisition of novel expression profiles that can be inherited across cell divisions, and hence, can be selected for. But attractors can also be reached in response to environmental signals - thus offering the possibility for inheriting acquired traits that can also be selected for. Therefore, we face the possibility of non-genetic (mutation-independent) equivalents to both Darwinian and Lamarckian evolution which may jointly explain the arrow of change pointing toward increasing malignancy. Copyright © 2012 Elsevier Ltd. All rights reserved.

The contribution of mouse models to the understanding of constitutional thrombocytopenia.

PubMed

Léon, Catherine; Dupuis, Arnaud; Gachet, Christian; Lanza, François

2016-08-01

Constitutional thrombocytopenias result from platelet production abnormalities of hereditary origin. Long misdiagnosed and poorly studied, knowledge about these rare diseases has increased considerably over the last twenty years due to improved technology for the identification of mutations, as well as an improvement in obtaining megakaryocyte culture from patient hematopoietic stem cells. Simultaneously, the manipulation of mouse genes (transgenesis, total or conditional inactivation, introduction of point mutations, random chemical mutagenesis) have helped to generate disease models that have contributed greatly to deciphering patient clinical and laboratory features. Most of the thrombocytopenias for which the mutated genes have been identified now have a murine model counterpart. This review focuses on the contribution that these mouse models have brought to the understanding of hereditary thrombocytopenias with respect to what was known in humans. Animal models have either i) provided novel information on the molecular and cellular pathways that were missing from the patient studies; ii) improved our understanding of the mechanisms of thrombocytopoiesis; iii) been instrumental in structure-function studies of the mutated gene products; and iv) been an invaluable tool as preclinical models to test new drugs or develop gene therapies. At present, the genetic determinants of thrombocytopenia remain unknown in almost half of all cases. Currently available high-speed sequencing techniques will identify new candidate genes, which will in turn allow the generation of murine models to confirm and further study the abnormal phenotype. In a complementary manner, programs of random mutagenesis in mice should also identify new candidate genes involved in thrombocytopenia. Copyright© Ferrata Storti Foundation.

Safe uses of Hill's model: an exact comparison with the Adair-Klotz model

PubMed Central

2011-01-01

Background The Hill function and the related Hill model are used frequently to study processes in the living cell. There are very few studies investigating the situations in which the model can be safely used. For example, it has been shown, at the mean field level, that the dose response curve obtained from a Hill model agrees well with the dose response curves obtained from a more complicated Adair-Klotz model, provided that the parameters of the Adair-Klotz model describe strongly cooperative binding. However, it has not been established whether such findings can be extended to other properties and non-mean field (stochastic) versions of the same, or other, models. Results In this work a rather generic quantitative framework for approaching such a problem is suggested. The main idea is to focus on comparing the particle number distribution functions for Hill's and Adair-Klotz's models instead of investigating a particular property (e.g. the dose response curve). The approach is valid for any model that can be mathematically related to the Hill model. The Adair-Klotz model is used to illustrate the technique. One main and two auxiliary similarity measures were introduced to compare the distributions in a quantitative way. Both time dependent and the equilibrium properties of the similarity measures were studied. Conclusions A strongly cooperative Adair-Klotz model can be replaced by a suitable Hill model in such a way that any property computed from the two models, even the one describing stochastic features, is approximately the same. The quantitative analysis showed that boundaries of the regions in the parameter space where the models behave in the same way exhibit a rather rich structure. PMID:21521501

Stratigraphy and depositional environments of Fox Hills Formation in Williston basin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Daly, D.J.

The Fox Hills Formation (Maestrichtian), representing part of a regressive wedge deposited during the withdrawal of the sea from the Western Interior at the close of the Cretaceous, consists of marginal marine strata transitional between the offshore deposits of the underlying Pierre Shale and the terrestrial deltaic and coastal deposits of the overlying Hell Creek Formation. An investigation of outcrops of the Fox Hills Formation along the western and southern flanks of the Williston basin and study of over 300 oil and gas well logs from the central part of the basin indicate that the formation can be divided bothmore » stratigraphically and areally. Stratigraphically, the Fox Hills can be divided into lower and upper sequences; the lower includes the Trail City and Timber Lake Members, and the upper sequence includes the Colgate Member in the west and the Iron Lightning and Linton Members in the east. Areally, the formation can be divided into a northeastern and western part, where the strata are 30-45 m thick and are dominated by the lower sequence, and into a southeastern area where both the lower and upper sequences are well developed in a section 80-130 m thick. Typically, the lower Fox Hills consists of upward-coarsening shoreface or delta-front sequences containing hummocky bedding and a limited suite of trace fossils, most notably Ophiomorpha. In the southeast, however, these strata are dominated by bar complexes, oriented northeast-southwest, composed of cross-bedded medium to very fine-grained sand with abundant trace and body fossils. The upper Fox Hills represents a variety of shoreface, deltaic, and channel environments. The strata of the Fox Hills Formation exhibit facies similar to those reported for Upper Cretaceous gas reservoirs in the northern Great Plains.« less

Mars Exploration Rover APXS Results from Matijevic Hill

NASA Technical Reports Server (NTRS)

Cohen, B. A.; Clark, B. C.; Gellert, R.; Klingelhoefer, G.; Ming, D. W.; Mittlefehldt, D. W.; Morris, R. V.; Schrader, C. M.; Schroeder, C.; Yen, A. S.;

First description of phosphofructokinase deficiency in spain: identification of a novel homozygous missense mutation in the PFKM gene

PubMed Central

Vives-Corrons, Joan-Lluis; Koralkova, Pavla; Grau, Josep M.; Mañú Pereira, Maria del Mar; Van Wijk, Richard

2013-01-01

Phosphofructokinase deficiency is a very rare autosomal recessive disorder, which belongs to group of rare inborn errors of metabolism called glycogen storage disease. Here we report on a new mutation in the phosphofructokinase (PFK) gene PFKM identified in a 65-years-old woman who suffered from lifelong intermittent muscle weakness and painful spasms of random occurrence, episodic dark urines, and slight haemolytic anemia. After ruling out the most common causes of chronic haemolytic anemia, the study of a panel of 24 enzyme activities showed a markedly decreased PFK activity in red blood cells (RBCs) from the patient. DNA sequence analysis of the PFKM gene subsequently revealed a novel homozygous mutation: c.926A>G; p.Asp309Gly. This mutation is predicted to severely affect enzyme catalysis thereby accounting for the observed enzyme deficiency. This case represents a prime example of classical PFK deficiency and is the first reported case of this very rare red blood cell disorder in Spain. PMID:24427140

[High resolution melting analysis for detecting of JAK2V617F mutation in patients with myeloproliferative neoplasms].

PubMed

Chen, Hai-Hua; Yang, Ji-Long; Lu, Hui-Fang; Zhou, Wei-Jun; Yao, Fei; Deng, Lan

2014-02-01

This study was purposed to investigate the feasibility of high resolution melting (HRM) in the detection of JAK2V617F mutation in patients with myeloproliferative neoplasm (MPN). The 29 marrow samples randomly selected from patients with clinically diagnosed MPN from January 2008 to January 2011 were detected by HRM method. The results of HRM analysis were compared with that detected by allele specific polymerase chain reaction (AS-PCR) and DNA direct sequencing. The results showed that the JAK2V617F mutations were detected in 11 (37.9%, 11/29) cases by HRM, and its comparability with the direct sequencing result was 100%. While the consistency of AS-PCR with the direct sequencing was moderate (Kappa = 0.179, P = 0.316). It is concluded that the HRM analysis may be an optimal method for clinical screening of JAK2V617F mutation due to its simplicity and promptness with a high specificity.

Environmental Assessment (EA): Proposed Truck Offload Station, Hill Air Force Base, Utah

DTIC Science & Technology

2012-11-09

AFB storm drainage system . A spill occurred outside the containment area when a fuel trailer struck a concrete wall and the fuel tank ruptured...The trailer was immediately pulled into the containment area, but some fuel had already entered the Hill AFB storm drainage system and flowed to Pond 3...placed in containers for proper disposal. Clean water would then be released to the Hill AFB storm drainage system . The proposed action would

20. Streetscape, South Coronado Boulevard, looking southwest Righttoleft, AZ198(Margaret B. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

20. Streetscape, South Coronado Boulevard, looking southwest Right-to-left, AZ-198(Margaret B. Hill House), AZ-199 (Henry H. Hill House), AZ-200 (Henry H. Hill Rental House), AZ-201 (Otto Rosenthal House), AZ-202 (J. M. Stevens House), AZ-203 (L J. Dunagan House), AZ204 (C. W. Beck House), and AZ-205 (F. D. Connor House) face the street - Clifton Townsite, Confluence of Chase Creek & San Francisco River, Clifton, Greenlee County, AZ

1. General view of Fort Hill Farm, view looking southsoutheast. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. General view of Fort Hill Farm, view looking south-southeast. From left to right, buildings visible are (B) two-story hall-and-parlor house; (k) small barn; (A) mansion' (G( shed; (H) shed; (I) log tobacco barn; (H and D) shed and center chimney four-room cabin; (E and (A) one-room cabin in front of mansion; (J) hay barn. - Fort Hill Farm, West of Staunton (Roanoke) River between Turkey & Caesar's Runs, Clover, Halifax County, VA

Future Drivers for State Alignments

DTIC Science & Technology

2009-02-12

It’s a Flat World, After All,” Global Issues , 07/08 (Dubuque, IA: McGraw Hill, 2008), 7. Thomas Friedman is an op-ed writer for the New York Times... Global Issues , 07/08 (Dubuque, IA: McGraw Hill, 2008), 62. Joseph Stiglitz is a professor of economics at Columbia University, he has been awarded the...Michael Pettis, “Will Globalization Go Bankrupt?” Global Issues , 07/08 (Dubuque, Iowa: McGraw Hill, 2008), 71. Michael Pettis is an investment banker

A comparative study on the forming limit diagram prediction between Marciniak-Kuczynski model and modified maximum force criterion by using the evolving non-associated Hill48 plasticity model

NASA Astrophysics Data System (ADS)

Shen, Fuhui; Lian, Junhe; Münstermann, Sebastian

2018-05-01

Experimental and numerical investigations on the forming limit diagram (FLD) of a ferritic stainless steel were performed in this study. The FLD of this material was obtained by Nakajima tests. Both the Marciniak-Kuczynski (MK) model and the modified maximum force criterion (MMFC) were used for the theoretical prediction of the FLD. From the results of uniaxial tensile tests along different loading directions with respect to the rolling direction, strong anisotropic plastic behaviour was observed in the investigated steel. A recently proposed anisotropic evolving non-associated Hill48 (enHill48) plasticity model, which was developed from the conventional Hill48 model based on the non-associated flow rule with evolving anisotropic parameters, was adopted to describe the anisotropic hardening behaviour of the investigated material. In the previous study, the model was coupled with the MMFC for FLD prediction. In the current study, the enHill48 was further coupled with the MK model. By comparing the predicted forming limit curves with the experimental results, the influences of anisotropy in terms of flow rule and evolving features on the forming limit prediction were revealed and analysed. In addition, the forming limit predictive performances of the MK and the MMFC models in conjunction with the enHill48 plasticity model were compared and evaluated.

Identifying the pollen of an extinct spruce species in the Late Quaternary sediments of the Tunica Hills region, south-eastern United States

USGS Publications Warehouse

Luke Mander,; Jacklyn Rodriguez,; Pietra G. Mueller,; Jackson, Stephen T.; Surangi W. Punyasena,

2014-01-01

Late Quaternary fluvial deposits in the Tunica Hills region of Louisiana and Mississippi are rich in spruce macrofossils of the extinct species Picea critchfieldii, the one recognized plant extinction of the Late Quaternary. However, the morphology of P. critchfieldii pollen is unknown, presenting a barrier to the interpretation of pollen spectra from the last glacial of North America. To address this issue, we undertook a morphometric study of Picea pollen from Tunica Hills. Morphometric data, together with qualitative observations of pollen morphology using Apotome fluorescence microscopy, indicate that Picea pollen from Tunica Hills is morphologically distinct from the pollen of P. glauca, P. mariana and P. rubens. Measurements of grain length, corpus width and corpus height indicate that Picea pollen from Tunica Hills is larger than the pollen of P. mariana and P. rubens, and is slightly larger than P. glauca pollen. We argue that the morphologically distinctive Tunica Hills Picea pollen was probably produced by the extinct spruce species P. critchfieldii. These morphological differences could be used to identify P. critchfieldii in existing and newly collected pollen records, which would refine its paleoecologic and biogeographic history and clarify the nature and timing of its extinction in the Late Quaternary.