bluuebunny/crossref_metadata_2025 huggingface dataset:
Bempedoic acid: Review of a novel therapy in lipid management
Authors: Delevry Dimittri , Gupta Eric K
Published: January 2021

Purpose

An update on clinical development of a first-in-class oral medication for adjunctive cholesterol lowering in high-risk patients with persistent elevation of low-density lipoprotein cholesterol (LDL-C) despite statin therapy is reviewed.

Despite the proven efficacy of statin therapy, many patients cannot reach LDL-C goals with statins alone, largely due to inadequate response or intolerance. Nonstatin treatment options to reduce LDL-C include ezetimibe, bile acid sequestrants, and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors; however their use has been limited by modest clinical benefit or high treatment costs. Novel nonstatin treatments are in development to further address the needs of this population. Bempedoic acid is a first-in-class oral adenosine triphosphate (ATP) citrate lyase inhibitor being evaluated as an additional treatment option for high-risk patients requiring further reduction in LDL-C. Bempedoic acid has been evaluated in multiple phase 2 and phase 3 trials as monotherapy or for use in combination with ezetimibe and/or statin therapy. Treatment with bempedoic acid has been demonstrated to result in significant reductions in LDL-C and several other cardiovascular risk markers without the myalgia associated with statin therapy.

Conclusion

Bempedoic acid, used alone or with ezetimibe in a fixed-dose combination formulation, may be an effective alternative to current guideline-recommended nonstatin therapies in patients who do not attain adequate LDL-C lowering with maximally tolerated statin therapy and in statin-intolerant patients at risk for atherosclerotic cardiovascular disease.
Jury Selection in Victorian England
Authors: Hanly Conor
Published: January 2021

The process of empanelling a jury in nineteenth-century England was controlled in most of the country by the County Juries Act 1825. At a formal level, the process was orderly and followed three stages: the preparation of a jury panel from the county jurors’ books, the summoning of the men on the jury panel, and the selection of the trial jury from the panel. In practice, the county sheriffs and undersheriffs were able to exert some influence on the process, an influence that at times ran directly contrary to legislative requirements, and sometimes was even corrupt. Contemporaries complained continually about these informal practices, and their impact upon the perceived quality of the trial juries. This article examines each of the three stages in the jury selection process, including both the legislative requirements and the implementation of those requirements, and it charts the complaints made by contemporaries. The article also attempts to assess some of these complaints by reference to archival materials from the counties of Gloucestershire and Wiltshire. Some of these complaints were well-founded, but others – especially the alleged removal from the jurors’ books of men who qualified as special jurors – appear to have been overstated. Nevertheless, the influence of the sheriffs and undersheriffs is clear, and justified or not, the dissatisfaction with the quality of jurors may have contributed to the decline in the use of jury trial over the course of the nineteenth century.
The illegality objection in investor–state arbitration
Authors: Mouawad Caline , Beess und Chrostin Jessica
Published: January 2021

In the past decade, the number of investment tribunals wrestling with allegations of investor illegality and corrupt conduct has soared. Much has been said and written about corruption in investment arbitration, but the treatment and import of objections on the basis of an investor’s illegal conduct other than corruption has not received equal attention. This article seeks to fill that void through a comprehensive, methodical review of investment awards to date that have grappled with the issue.

Allegations of investor misconduct are richly diverse, ranging from the wilful disregard of local foreign investment restrictions to inadvertent administrative omissions a host State knowingly elected not to enforce. Recognizing that the factual matrices giving rise to the illegality objection are highly fact-specific, this article explores the contours of the illegality objection, its typology, the analytical framework tribunals apply, the evolving and competing applicable legal standards, the scenarios when illegality is fatal to jurisdiction or admissibility (or not), and the relevance of the State’s conduct in perhaps overcoming that death knell.
Environmental Variables Influencing FiveSpeyeria(Lepidoptera: Nymphalidae) Species’ Potential Distributions of Suitable Habitat in the Eastern United States
Authors: Geest Emily A , Baum Kristen A
Published: January 2021

Five closely related species of greater fritillaries occur in North America east of the Mississippi River: regal fritillary (Speyeria idalia Drury [Lepidoptera: Nymphalidae]), Diana fritillary (Speyeria diana Cramer [Lepidoptera: Nymphalidae]), great spangled fritillary (Speyeria cybele Fabricius [Lepidoptera: Nymphalidae]), Atlantis fritillary (Speyeria atlantis Edwards [Lepidoptera: Nymphalidae]), and Aphrodite fritillary (Speyeria aphrodite Fabricius [Lepidoptera: Nymphalidae]). The regal fritillary and Diana fritillary are species of concern, whereas the great spangled fritillary, Atlantis fritillary, and Aphrodite fritillary are relatively abundant within their respective ranges. However, the Atlantis fritillary and Aphrodite fritillary have experienced severe population declines within the last few decades. We created ecological niche models for these five species by combining each species’ known occurrences with climate and environmental variables to identify important response variables and determine the potential distribution of suitable habitat for each species. Important climate variables differed among species, although minimum temperature of the coldest month was important for great spangled, Atlantis, and Aphrodite fritillaries. The regal fritillary responded the most to temperature seasonality, whereas the Diana fritillary responded to maximum temperature of warmest month and the great spangled fritillary responded to annual precipitation. Land use was important for all species except the regal fritillary and average annual relative humidity was important for all species except the great spangled fritillary. This study highlights the different climate and habitat needs for greater fritillary species with important implications for how each species is expected to be impacted by climate change. We also demonstrate the value of citizen science and photo sharing websites for providing important data for evaluating species distributions.
Recombinant human lecithin-cholesterol acyltransferase in patients with atherosclerosis: phase 2a primary results and phase 2b design
Authors: Bonaca Marc P , George Richard T , Morrow David A , Bergmark Brian A , Park Jeong-Gun , Abuhatzira Liron , Vavere Andrea L , Karathanasis Sotirios K , Jin ChaoYu , She Dewei , Hirshberg Boaz , Hsia Judy , Sabatine Marc S
Published: January 2021

Aims

Reverse cholesterol transport (RCT) removes cholesterol and stabilizes vulnerable plaques. In addition, high-density lipoprotein (HDL) may be cardioprotective in acute myocardial infarction (MI). Lecithin-cholesterol acyltransferase (LCAT) may enhance RCT. The objective of this study was to investigate the pharmacokinetics, pharmacodynamics, and safety of multiple ascending doses of recombinant human LCAT (MEDI6012) to inform a Phase 2b programme.

Methods and results

This was a randomized, blinded, placebo-controlled, dose-escalation Phase 2a study of MEDI6012. Patients were randomized into one of four cohorts (40, 120, 300 mg IV weekly ×3 doses, or 300 mg IV-push, 150 mg at 48 h and 100 mg at 7 days). All cohorts were planned to randomize 6:2 (MEDI6012 vs. placebo). The primary endpoints were baseline-adjusted area under the curve (AUC) from 0 to 96 h post dose 3 (AUC 0–96 h) for HDL-C, HDL cholesteryl ester (HDL-CE), and total cholesteryl ester (CE). The primary safety endpoints were treatment-emergent adverse events. A total of 32 patients were randomized. MEDI6012 significantly increased AUC 0–96 h for HDL-C, HDL-CE and CE in a graded fashion with increasing doses. Relative to placebo, MEDI6012 increased HDL-C at Day 19 by 66% (95% CI 33–99, P = 0.014) with 120 mg and 144% (95% CI 108–181, P < 0.001) with 300 mg. An IV-push increased HDL-C by 40.8% at 30 min. Overall adverse events were similar between groups with no severe, life-threatening/fatal adverse events, or neutralizing antibodies.

Conclusions

Multiple ascending doses of MEDI6012 were safe and well tolerated and significantly increased HDL-C, HDL-CE and CE in a dose-related manner. These data support the ongoing Phase 2b programme investigating MEDI6012 in ST-elevation MI.
HAPLOID SELECTION FOR LOW TEMPERATURE TOLERANCE OF TOMATO POLLEN
Authors: Zamir Daniel , Tanksley Steven D , Jones Richard A
Published: January 2021

Pollen grains were harvested from an interspecific F1 hybrid between the cultivated tomato, Lycopersicon esculentum Mill., and its wild relative Lycopersicon hirsutum Humb. & Bonpl., a low temperature tolerant accession originating from an altitude of 3200 m in the Peruvian Andes. The two species differ for electrophoretically-detectable loci that mark six (possibly seven) of the 12 tomato chromosomes. Isozyme analysis of the BC1 populations derived from controlled pollinations at normal and low temperatures indicates a significant skewing of allelic frequencies favoring two independent chromosome segments of L. hirsutum at low temperatures. The results demonstrate that gametophytic selection for low temperature tolerance of tomato pollen is determined, at least in part, by genes expressed in the haploid pollen.
MEIOTIC DIPLOID PROGENY AND MEIOTIC NONDISJUNCTION IN SACCHAROMYCES CEREVISIAE
Authors: Sora Silvio , Lucchini Giovanna , Magni Giovanni E
Published: January 2021

Abnormalities in chromosome number that occurred during meiosis were evaluated with a specially-constructed diploid strain of Saccharomyces cerevisiae. The strain is heterozygous for six markers of the right arm of chromosome V and heterozygous for cyh2 (resistance to cycloheximide) on chromosome VII.—Selection of meiotic spores on a medium containing cycloheximide and required nutrilites—except those for the markers of the right arm of chromosome V—allows the growth of aberrant clones belonging only to two classes: a) diploid clones, caused by failure of the second meiotic division, with a frequency of 0.54 × 10-4 per viable spore; and b) diplo V, aneuploids derived from nondisjunctions in meiosis I or meiosis II, with a total spontaneous frequency of 0.95 × 10-4 per viable spore. About two-thirds of the aneuploids originated during meiosis I, the rest during meiosis II. An investigation of these events in control meioses and after treatment with MMS, Benomyl and Amphotericin B suggests that this assay system is suitable for screening environmental mutagens for their effects on meiotic segregation.
GENETIC ANALYSES OF ENDOTHIA PARASITICA: LINKAGE DATA FOR FOUR SINGLE GENES AND THREE VEGETATIVE COMPATIBILITY TYPES
Authors: Anagnostakis Sandra L
Published: January 2021

The loci cre, met and ts segregate independently in Endothia parasitica. The phenotype brown (br) seems to be determined by an allele at or very near the cre locus. The vegetative compatibility types (v-c) 5 and 39 are determined by different alleles at a locus that is not linked to cre, met or ts. Analysis of two crosses of v-c 5 strains by v-c 10 strains provides evidence that these two v-c groups are different at 5 or more v-c loci.
INTERACTIONS OF ZESTE MUTATIONS WITH LOCI EXHIBITING TRANSVECTION EFFECTS IN DROSOPHILA MELANOGASTER
Authors: Gelbart William M , Wu Chao-Ting
Published: January 2021

Zeste (1-1.0; 3A3) mutations have been known to modify the expression of two gene complexes: white (1-1.5; 3C1.5) and bithorax (3-58.8; 89E1-4) in Drosophila melanogaster. Certain mutations of these complexes have been shown to behave in a synapsis-dependent fashion. That is, certain bithorax and white genotypes exhibit one level of expression when the two copies of these loci are able to synapse in somatic tissues and another level when heterozygosity for chromosomal rearrangements interferes with their ability to pair. Such phenomena are termed transvection effects by Lewis (1954). In the case of the white locus, asynapsis leads to a more normal state, whereas at bithorax, asynapsis leads to a more mutant phenotype. Recently, a third case of transvection was described at the decapentaplegic (2-4.0; 22F1-3) gene complex (Gelbart 1982); phenomenologically, it is very similar to transvection at bithorax. In this report, we demonstrate that zeste mutations can also interact with those decapentaplegic mutations that exhibit transvection effects. In addition, we present more information on the zeste interactions with white and bithorax. Interactions with zeste may be diagnostic of loci that can exhibit transvection effects. However, different groups of zeste alleles interact with each complex. z1 interacts with white, za alleles interact with bithorax and all tested zeste mutants interact with decapentaplegic. These differential effects of zeste mutations may be a reflection of the neomorphic nature of the z1 allele.
MUTATIONS IN THE PHO80 GENE CONFER PERMEABILITY TO 5'-MONONUCLEOTIDES IN SACCHAROMYCES CEREVISIAE
Authors: Bisson Linda F , Thorner Jeremy
Published: January 2021

Yeast mutants permeable to dTMP (tup) were selected and two new complementation groups (tup5 and tup7) were identified. Assay of the levels of both acid and alkaline phosphatase in cells grown under either repressing (5 mm PO4  -3) or derepressing (0.03 mm PO4  -3) conditions indicated that, in general, tup mutations cause cells to be defective in their regulation of phosphatase synthesis. In addition, three of the tup mutations (tup1, tup4 and tup7) displayed markedly elevated rates of inorganic phosphate transport. The tup7 locus was found to be tightly centromere-linked on the right arm of chromosome XV, and was shown to be allelic with the pho80 regulatory locus on the basis of both genetic and biochemical criteria. Analysis of other mutations known to affect phosphatase levels (pho) indicated that some also conferred permeability to dTMP. Possible allelic relationships between tup genes and certain of these pho mutations are discussed. Regardless of the culture conditions, wild-type strains were not permeable to dTMP; in contrast, it was found in the course of this work that normal yeast cells were permeable to dUMP and that dUMP permeability was regulated by the concentration of inorganic phosphate present in the medium used to grow the cells. Thus, permeability to 5′-mononucleotides appears to be under coordinate control with phosphatase synthesis.
PROTEIN POLYMORPHISMS, SEGREGATION IN GENETIC CROSSES AND GENETIC DISTANCES AMONG FISHES OF THE GENUS XIPHOPHORUS (POECILIIDAE)
Authors: Morizot Don C , Siciliano Michael J
Published: January 2021

The products of 49 protein-coding loci were examined by starch gel electrophoresis for populational variation in six species of Xiphophorus fishes and/or segregation in intra- and interspecific backcross and intercross hybrids. Electrophoretic variation was observed for 29 of the 35 locus products in a survey of 42 population samples. The highest frequency of polymorphic loci observed in noninbred populations was 0.143. After ten or more generations of inbreeding, all loci studied were monomorphic. Inbred strains generally exhibited the commonest electrophoretic alleles of the population from which they were derived. An assessment of genetic distances among Xiphophorus populations reflected classical systematic relationships and suggested incipient subspeciation between X. maculatus from different drainages as well as several species groups. Thirty-three loci were analyzed with respect to segregation in hybrids. The goodness of fit of segregations to Mendelian expectations at all loci analyzed (except loci in linkage group I) is interpreted as evidence for high genetic compatibility of the genomes of Xiphophorus species. It is anticipated that these data will result in a rapid expansion of the assignment of protein-coding loci to linkage groups in these lower vertebrate species.
ORGANIZATION AND EVOLUTION OF THE MAMMALIAN GENOME: I. POLYMORPHISM OF H-2 LINKED LOCI
Authors: Nadeau Joseph H , Collins Robert L , Klein Jan
Published: January 2021

To test the hypothesis that the H-2 polymorphism is adaptive, the degree of polymorphism of loci linked to the H-2 complex on chromosome 17 of the house mouse was compared to the degree of polymorphism of loci located on other chromosomes. Published theoretical analyses show that polymorphisms subject to natural selection usually reduce the polymorphism of linked neutral loci. The first test of the hypothesis was based on data obtained from a survey of the polymorphism of 12 isozyme-encoding loci in wild house mice from Europe, North Africa and South America. Results of this test showed that, on the average, H-2-linked loci were as polymorphic as loci located on other chromosomes. In fact, the data suggested that H-2 linked loci might be more polymorphic than other loci. To test this hypothesis more rigorously, data for the 12 isozyme-encoding loci were augmented with data from published surveys of the polymorphisms of 59 loci in house mice from Europe and North America. Results of these tests showed that polymorphic loci linked to the H-2 complex tended to be more, rather than less, polymorphic than loci located on other chromosomes. The cluster of highly polymorphic loci seems to be related to linkage of these loci to the highly polymorphic H-2 complex, but the way in which the influence is exerted could not be readily explained.
SEQUENCE OF CENTROMERE SEPARATION: ROLE OF CENTROMERIC HETEROCHROMATIN
Authors: Vig Baldev K
Published: January 2021

The late metaphase-early anaphase cells from various tissues of male Mus musculus, M. poschiavinus, M. spretus, M. castaneus, female and male Bos taurus (cattle) and female Myopus schisticolor (wood lemming) were analyzed for centromeres that showed separation into two daughter centromeres and those that did not show such separation. In all strains and species of mouse the Y chromosome is the first one to separate, as is the X or Y in the cattle. These sex chromosomes are devoid of constitutive heterochromatin, whereas all autosomes in these species carry detectable quantities. In cattle, the late replicating X chromosome appears to separate later than the active X. In the wood lemming the three pairs of autosomes with the least amount of centromeric constitutive heterochromatin separate first. These are followed by the separation of seven pairs of autosomes carrying medium amounts of constitutive heterochromatin. Five pairs of autosomes with the largest amounts of constitutive heterochromatin are the last in the sequence of separation. The sex chromosomes with medium amounts of constitutive heterochromatin around the centromere, and a very large amount of distal heterochromatin, separate among the very late ones but are not the last. These observations assign a specific role to centromeric constitutive heterochromatin and also indicate that nonproximal heterochromatin does not exert control over the sequence in which the centromeres in the genome separate. It appears that qualitative differences among various types of constitutive heterochromatin are as important as quantitative differences in controlling the separation of centromeres.
NEW SUPPRESSORS OF FRAMESHIFT MUTATIONS IN SALMONELLA TYPHIMURIUM
Authors: Kohno Tadahiko , Bossi Lionello , Roth John R
Published: January 2021

Several new types of suppressor mutants have been isolated. These were identified among revertants of mutants originally generated by mutagens other than the acridine-derived ICR191. The new suppressors correct mutations other than those with runs of C or G which are recognized by the previously described suppressors. Several frameshift mutations are corrected by more than one suppressor type. Apparently, the DNA base sequence near these mutant sites includes sites of action for several distinct suppressor types.
MALE PHENOTYPES AND MATING EFFICIENCY IN CAENORHABDITIS ELEGANS
Authors: Hodgkin Jonathan
Published: January 2021

Mating behavior in adult male nematodes can be assayed by mating efficiency, i.e., the number of cross progeny sired by males under standard conditions. Mutant males from 220 strains, representing most of the known complementation groups of C. elegans, have been examined for mating efficiency and for anatomical abnormalities of the specialized male copulatory organs. These data extend the phenotypic description of these mutants and indicate what anatomical and behavioral components are necessary for the ability to mate successfully. Also, mutants with specific defects in the male were sought by establishing superficially wild-type hermaphrodite stocks after mutagenesis and testing the males segregated by these stocks for mating efficiency. Forty-nine of 1119 stocks yielded abnormal males. Seventeen were characterized in detail and found to be abnormal in sensory behavior (carrying mutations in the genes che-2 or che-3) or male genital anatomy (carrying mutations in one of the genes mab-1 to mab-10). Four of the mab (male abnormal) genes affect specific postembryonic cell lineages.
LOCATION OF THE LSP-1 GENES IN DROSOPHILA SPECIES BY IN SITU HYBRIDIZATION
Authors: Brock Hugh W , Roberts David B
Published: January 2021

The locations of the larval serum protein one (LSP-1) α, β and γ genes were determined in Drosophila melanogaster and in 14 other species of Drosophila by in situ hybridization to polytene chromosomes. The LSP-1 α gene mapped to bands 11B on the X chromosome, the LSP-1 β gene mapped to bands 21D-E on chromosome 2L, and the LSP-1 γ gene mapped to band 61A in all the melanogaster subgroup species. In eight other species, both the LSP-1α and β genes mapped to one site on Muller's element E which corresponds to chromosome 3R of D. melanogaster. No hybridization of LSP-1 γ was detected in these eight species. Restriction enzyme digestion and analysis of genomic DNA by filter transfer hybridization confirmed the presence of LSP-1 α-like and β-like genes in seven of these species. These results are discussed with respect to conservation of the chromosomal elements in the genus Drosophila.
A MAJOR ROLE FOR BACTERIOPHAGE T4 DNA POLYMERASE IN FRAMESHIFT MUTAGENESIS
Authors: Ripley Lynn S , Shoemaker Nadja B
Published: January 2021

T4 DNA polymerase strongly influences the frequency and specificity of frameshift mutagenesis. Fifteen of 19 temperature-sensitive alleles of the DNA polymerase gene substantially influenced the reversion frequencies of frameshift mutations measured in the T4 rII genes. Most polymerase mutants increased frameshift frequencies, but a few alleles (previously noted as antimutators for base substitution mutations) decreased the frequencies of certain frameshifts while increasing the frequencies of others. The various patterns of enhanced or decreased frameshift mutation frequencies suggest that T4 DNA polymerase is likely to play a variety of roles in the metabolic events leading to frameshift mutation. A detailed genetic study of the specificity of the mutator properties of three DNA polymerase alleles (tsL56, tsL98 and tsL88) demonstrated that each produces a distinctive frameshift spectrum. Differences in frameshift frequencies at similar DNA sequences within the rII genes, the influence of mutant polymerase alleles on these frequencies, and the presence or absence of the dinucleotide sequence associated with initiation of Okazaki pieces at the frameshift site has led us to suggest that the discontinuities associated with discontinuous DNA replication may contribute to spontaneous frameshift mutation frequencies in T4.
COMPLEMENTATION AND PRELIMINARY LINKAGE ANALYSIS OF ZYGOTE MATURATION MUTANTS OF THE HOMOTHALLIC ALGA, CHLAMYDOMONAS MONOICA
Authors: VanWinkle-Swift Karen P , Burrascano Cynthia G
Published: January 2021

Sexual reproduction in Chlamydomonas monoica is homothallic: pair formation and cell fusion occur in clonal culture and give rise to a heavily walled diploid zygospore. During maturation of the young zygote, a distinctive "primary zygote wall" is released before the development of the highly reticulate zygospore wall. Using ethyl methanesulfonate and ultraviolet irradiation as mutagens, we have isolated 19 maturation-defective (zym) mutant strains which upon self-mating produce inviable zygotes. These zygotes fail to release a primary zygote wall, fail to develop the normal zygospore wall, and eventually undergo spontaneous lysis. In nearly all cases, the mutations appear to be expressed only in the diploid zygote; pleiotropic effects on vegetative cell growth or morphology are not evident.—Complementation testing performed on 17 of these mutants indicates that all are recessive and that they define seven distinct complementation groups. Preliminary tetrad analysis of two-factor and multifactor zym crosses provides no evidence for physical clustering of the maturation genes, and instead suggests that they are widely distributed throughout the nuclear genome.
MODELS OF EVOLUTION OF REPRODUCTIVE ISOLATION
Authors: Nei Masatoshi , Maruyama Takeo , Wu Chung-I
Published: January 2021

Mathematical models are presented for the evolution of postmating and premating reproductive isolation. In the case of postmating isolation it is assumed that hybrid sterility or inviability is caused by incompatibility of alleles at one or two loci, and evolution of reproductive isolation occurs by random fixation of different incompatibility alleles in different populations. Mutations are assumed to occur following either the stepwise mutation model or the infinite-allele model. Computer simulations by using Itô's stochastic differential equations have shown that in the model used the reproductive isolation mechanism evolves faster in small populations than in large populations when the mutation rate remains the same. In populations of a given size it evolves faster when the number of loci involved is large than when this is small. In general, however, evolution of isolation mechanisms is a very slow process, and it would take thousands to millions of generations if the mutation rate is of the order of 10-5 per generation. Since gene substitution occurs as a stochastic process, the time required for the establishment of reproductive isolation has a large variance. Although the average time of evolution of isolation mechanisms is very long, substitution of incompatibility genes in a population occurs rather quickly once it starts. The intrapopulational fertility or viability is always very high. In the model of premating isolation it is assumed that mating preference or compatibility is determined by male- and female-limited characters, each of which is controlled by a single locus with multiple alleles, and mating occurs only when the male and female characters are compatible with each other. Computer simulations have shown that the dynamics of evolution of premating isolation mechanism is very similar to that of postmating isolation mechanism, and the mean and variance of the time required for establishment of premating isolation are very large. Theoretical predictions obtained from the present study about the speed of evolution of reproductive isolation are consistent with empirical data available from vertebrate organisms.
EVOLUTION OF TRANSPOSONS: NATURAL SELECTION FOR Tn5 IN ESCHERICHIA COLI K12
Authors: Biel Susan Wurster , Hartl Daniel L
Published: January 2021

A novel in vivo effect of the transposable element Tn5 has been observed in chemostats when certain isogenic Tn5 and non-Tn5 strains of Escherichia coli compete for a limiting carbon source in the absence of kanamycin. The Tn5-bearing strain has a more rapid growth rate and increases in frequency from 50% to 90% within the first 15 to 20 generations. The effect occurs when Tn5 is inserted at a variety of chromosomal locations or when the element is carried by an episome, but it is strain specific, having been observed in two out of three strains examined. (For reasons unknown, the effect has not been observed with derivatives of strain CSH12.) Although the growth-rate advantage of Tn5 is independent of nutrient concentration and generation time, it can be reduced by prior adaptation of the strains to limiting conditions, and the amount of reduction is proportional to the length of prior adaptation. The growth-rate effect is evidently not caused by beneficial mutations induced by Tn5 transposition, as Tn5-bearing strains selected in chemostats retain their initial Tn5 position and copy number. However, the effect does not occur in Tn5-112, a transpositionless deletion mutation missing the transposase-coding region of the right-hand IS sequence flanking the element. Since Tn5-112 retains a functional kanamycin-phosphotransferase gene, this gene is not responsible for the growth-rate effect. Thus, the effect evidently requires transposase function, but it does not involve actual transposition of the intact element. Altogether, these data provide a mechanism for the maintenance of Tn5 in bacterial populations in the absence of kanamycin, and they suggest a model for the proliferation and the maintenance of IS sequences and transposable elements in the absence of other identifiable selection pressures.
A PRODUCT OF THE TN5 TRANSPOSASE GENE INHIBITS TRANSPOSITION
Authors: Lowe John B , Berg Douglas E
Published: January 2021

The bacterial transposon Tn5 possesses a regulatory mechanism that allows it to move with higher efficiency when it is first introduced into a cell than after it is established. Tn5 is a composite transposable element containing inverted repeats of two nearly identical elements, IS50R, which encodes the transposase protein necessary for Tn5 movement, and IS50L which contains an ochre mutant allele of the transposase gene. Data presented here show that Tn5 transposition is inhibited about 50-fold in cells of Escherichia coli which already carry IS50R in the multicopy plasmid pBR322. If the cells contain a plasmid carrying either IS50L instead of IS50R, or derivatives of IS50R in which the transposase gene has been mutated, little if any inhibition of Tn5 transposition is found. Although inhibition had previously been hypothesized to require interaction between the products of IS50L and IS50R, our results show that IS50R alone is sufficient to mediate inhibition and suggest that the inhibitor is a product of the transposase gene itself.
POPULATION GENETICS OF DROSOPHILA AMYLASE. IV. SELECTION IN LABORATORY POPULATIONS MAINTAINED ON DIFFERENT CARBOHYDRATES
Authors: Powell Jeffrey R , Andjelković Marko
Published: January 2021

Two polymorphic systems impinging on α-amylase in Drosophila pseudoobscura have been studied in laboratory populations maintained on medium in which the only carbohydrate source was starch (the substrate of amylase) and replicas maintained on medium in which the only carbohydrate source was maltose (the product of amylase). The two polymorphic systems were alleles at the structural gene (Amy) coding for the enzyme (allozymes) and variation in the tissue-specific expression along the adult midgut controlled by several genes. In the seven populations on maltose medium little consistent change was noted in either system. In the seven populations on starch medium, both polymorphisms exhibited selective changes. A midgut pattern of very limited expression of amylase rose in frequency in all starch populations, as did the frequency of the "fast" (1.00) Amy allele. The overall specific amylase activity did not differ between starch-adapted and maltose-adapted flies.—The results, along with previous studies, indicate that when a gene-enzyme system is specifically stressed in laboratory populations, allozymes often exhibit selective differences. Such results make the selectionist hypothesis at least tenable. Furthermore, the fact that both types of polymorphisms responded to selection indicates the role of structural gene vs. gene regulation changes in adaptive evolution is not an either/or question but one of relative roles and interactions.
GENE-CENTROMERE MAPPING IN RAINBOW TROUT: HIGH INTERFERENCE OVER LONG MAP DISTANCES
Authors: Thorgaard Gary H , Allendorf Fred W , Knudsen Kathy L
Published: January 2021

Ten enzyme loci were mapped in relation to their centromeres in gynogenetic diploid rainbow trout. Gene-centromere map distances, calculated under the assumption of complete interference, range from 1.1 cM for Ldh4 to 50 cM for Sod1. The Idh2 and Est1 loci are linked on the same chromosome arm.—The observation of close to 100% heterozygous gynogenetic diploids for the Sod1 and Mdh3,4 loci suggests that near-complete interference occurs on the chromosome arms carrying these loci. The high interference observed in this study and in several other species of fish may be related to the small size of fish chromosome arms.—Comparisons of map locations for the Ldh3 and Ldh4 and the Mdh3 and Mdh4 loci, which were duplicated by a tetraploid event in the evolution of salmonid fish, reveal that they are located at similar distances from their centromeres. Comparative mapping of loci duplicated longer ago shows more variation in map location.—The high proportion of heterozygotes for some loci after gynogenesis involving second polar body retention demonstrates that this is not a practical method for producing homozygous inbred lines in rainbow trout; treatments suppressing the first cell division are more promising for this purpose.
ELECTROPHORETIC VARIATION FOR X CHROMOSOME-LINKED HYPOXANTHINE PHOSPHORIBOSYL TRANSFERASE (HPRT) IN WILD-DERIVED MICE
Authors: Chapman Verne M , Kratzer Paul G , Quarantillo Barbara A
Published: January 2021

An electrophoretic variation for hypoxanthine phosphoribosyltransferase, HPRT, has been identified in samples of Mus spretus, a field mouse from southern Europe and in M. m. castaneus, a house mouse from southeast Asia. These mice will interbreed with laboratory mice to produce viable, fertile F1 progeny. The variation for HPRT segregates as an X chromosome gene in F1 and backcross progeny. Linkage analysis involving the markers Pgk-1 and Ags indicated a gene order of centromere—Hprt—Pgk-1—Ags in crosses involving both stocks of wild mice.
STRUCTURE OF GENETIC VARIATION WITHIN AND BETWEEN POPULATIONS OF MYCOPHAGOUS DROSOPHILA
Authors: Lacy Robert C
Published: January 2021

Patterns of genetic variation within and between populations of five species of mycophagous Drosophila were examined by gel electrophoresis of several polymorphic loci. Populations of the five species could not be shown to be subdivided into sympatric host-adapted races. Statistically significant, but small, between-host differences in gene frequencies were observed at three of 15 loci. Mean gene frequencies at all loci were similar in New York and Tennessee, and, with one exception, relatively little genetic differentiation was observed among study sites within those two regions. Gene frequencies generally were stable over several years of collecting as well. The unpredictable nature of the fungal hosts may preclude the site fidelity and continuity of diversifying selection necessary for adaptive divergence of populations.
EXTRACHROMOSOMAL INHERITANCE OF CARBON DIOXIDE SENSITIVITY IN THE MOSQUITO CULEX QUINQUEFASCIATUS
Authors: Shroyer Donald A , Rosen Leon
Published: January 2021

Mosquitoes from a laboratory colony of Culex quinquefasciatus from Matsu Island, China, develop irreversible paralytic symptoms after exposure to carbon dioxide at 1°. This CO2 sensitivity is caused by an inherited infectious agent, probably a virus. Crossing studies between CO2-sensitive and -resistant mosquitoes showed that the sensitivity trait is inherited extrachromosomally in a fashion strictly analogous to the hereditary transmission of sigma virus in Drosophila melanogaster. Sensitivity could be maintained through maternal transmission alone, despite nine generations of backcrossing of "stabilized" CO2-sensitive females to males from a resistant strain. CO2-sensitive males crossed to resistant females transmitted sensitivity to a portion of their F1 progeny, and only the female F1 sensitives were capable of further hereditary transmission.—Matsu, or a very similar hereditary infectious agent, is common in natural populations of Cx. quinquefasciatus on Oahu, Hawaii. Fifty-nine percent of the families reared from field-collected egg rafts contained CO2-sensitive mosquitoes, and some families contained only sensitive mosquitoes.
LENGTH MUTATIONS IN HUMAN MITOCHONDRIAL DNA
Authors: Cann R L , Wilson A C
Published: January 2021

By high-resolution, restriction mapping of mitochondrial DNAs purified from 112 human individuals, we have identified 14 length variants caused by small additions and deletions (from about 6 to 14 base pairs in length). Three of the 14 length differences are due to mutations at two locations within the D loop, whereas the remaining 11 occur at seven sites that are probably within other noncoding sequences and at junctions between coding sequences. In five of the nine regions of length polymorphism, there is a sequence of five cytosines in a row, this sequence being comparatively rare in coding DNA. Phylogenetic analysis indicates that, in most of the polymorphic regions, a given length mutation has arisen several times independently in different human lineages. The average rate at which length mutations have been arising and surviving in the human species is estimated to be many times higher for noncoding mtDNA than for noncoding nuclear DNA. The mystery of why vertebrate mtDNA is more prone than nuclear DNA to evolve by point mutation is now compounded by the discovery of a similar bias toward rapid evolution by length mutation.
GENETIC METHODS FOR ANALYSIS AND MANIPULATION OF INVERSION MUTATIONS IN BACTERIA
Authors: Schmid Molly B , Roth John R
Published: January 2021

A number of genetic methods for the isolation, characterization and manipulation of large chromosomal inversions in Salmonella typhimurium are described. One inversion-carrying mutant is characterized in detail and used to demonstrate a number of unique genetic properties of bacterial inversions.—Contrary to expectation, it was found that large inversion mutations can be repaired by generalized transduction. The repair results from the simultaneous introduction of two wild-type transduced fragments into a single recipient cell. Homologous recombination between the two transduced fragments and the two inversion breakpoints causes the inverted segment to be reinverted. This results in regeneration of the wild-type orientation of this chromosome segment. Similar recombination events allow a large inversion mutation to be introduced into a wild-type strain; two transduced fragments from an inversion strain cause recombination events resulting in inversion of a large chromosome segment.—Genetic methods for mapping the extent of a large inversion mutation by generalized transduction are described and tested. The methods are operationally simple and allow good resolution of the two inversion breakpoints.
ON THE TIME FOR GENE SILENCING AT DUPLICATE LOCI
Authors: Watterson G A
Published: January 2021

A simple approximate formula is found for the mean time for mutant genes to first fix at one or another of two duplicate loci. The fixation is a result of one-way mutation from the wild-type to the mutant alleles, but is retarded by strong selection against the doubly homozygous mutants. The two-dimensional diffusion that models the evolution of the mutant allele frequencies at the two loci is studied by means of a transformation to two univariate diffusions having different time scales. Most of the results, but not all, agree well with the numerical studies by previous authors. Some new simulation results are presented, which agree well with the analytical results and, therefore, cast doubt on some previous simulations.
MALE-SPECIFIC LETHAL MUTATIONS OF DROSOPHILA MELANOGASTER. II. PARAMETERS OF GENE ACTION DURING MALE DEVELOPMENT
Authors: Belote John M
Published: January 2021

The male-specific lethal mutations (msl's) identify loci whose wild-type gene products are essential for male, but not female, viability. Earlier studies in which X-linked gene activities were monitored in msl/msl male larvae demonstrated that these genes are responsible for setting and/or maintaining the level of X chromosome transcription in males (i.e., they are necessary for proper dosage compensation). The present study examines several important questions concerning their mode of action during development—The results of an examination of the effects of an msl-1 deficiency on male-lethal phase and female viability suggest that this mutation is an amorph, or a severe hypomorph. The effects of rendering a fly mutant for more than one male-lethal mutation were also examined. Multiply mutant flies were no more severely affected than singly mutant ones. A gynandromorph analysis revealed that the male-limited lethality associated with msl-2 has no single lethal focus. Somatic clones of homozygous msl-2 cells were initiated at various times during development by X-ray-induced mitotic recombination. An examination of the viability, growth patterns and morphology of marked clones demonstrated that: (1) msl-2  + acts in a cell autonomous manner, (2) msl-2  + function is required not only in larval (polytene) cells as was shown in previous work but is also needed in the diploid cells that give rise to adult structures, (3) the msl-2  + gene is needed fairly late in development and perhaps continuously, (4) the msl-2 mutation does not affect sexual differentiation.
Efficient seismic ray tracing based on the shortest path method
Authors: Sekiguchi Shoji
Published: January 2021

Limiting the number of valid nodes around a reference ray can greatly reduce the calculation time of the shortest-path method (SPM). The calculation is executed by increasing the number of cells and/or nodes in the target area, step by step, until the rays converge. The ray obtained in the previous step is used as a reference ray, and the initial reference rays are given by the ordinary SPM. The Dijkstra algorithm and binary heap sorting method are used, as in the ordinary SPM. As the cell and node numbers increase, the calculation time for the modified SPM (mSPM) is reduced compared to that for the ordinary SPM. In the 3-D (100 × 100 × 100 km3) checkerboard velocity pattern model, the relative calculation time becomes two to four orders of magnitude smaller. The calculation time for the mSPM itself is approximately proportional to E log2(V), where E is the edge (ray path segment) number and V is the vertex (node) number, as seen in the heap sorting algorithm. The mean traveltime and ray path differences between the mSPM and pseudo-bending method (PBM) are small, less than 0.005 s and around 0.6 km, respectively, and slightly larger than those with respect to the ordinary SPM. The total differences from the exact solution are estimated to be less than 0.01 s and 1.0 km, which are sufficiently small for traveltime tomography. The traveltime and ray path can be improved by utilizing iterative calculations, shifting of the starting point and more neighbour nodes. The ray path obtained by the mSPM can be a local minimum, according to velocity models. The relative mean traveltime and ray path differences between adjacent cells and nodes generally show trends similar to those of the traveltime and ray path differences from the PBM. Hence, these relative differences can help reveal the behaviour of the differences from the PBM.
Is the ‘never event’ concept a useful safety management strategy in complex primary healthcare systems?
Authors: Bowie Paul , Baylis Diane , Price Julie , Bradshaw Pallavi , McNab Duncan , Ker Jean , Carson-Stevans Andrew , Ross Alastair
Published: January 2021

Why is the area important?

A sub-group of rare but serious patient safety incidents, known as ‘never events,’ is judged to be ‘avoidable.’ There is growing interest in this concept in international care settings, including UK primary care. However, issues have been raised regarding the well-intentioned coupling of ‘preventable harm’ with zero tolerance ‘never events,’ especially around the lack of evidence for such harm ever being totally preventable.

What is already known and gaps in knowledge?

We consider whether the ideal of reducing preventable harm to ‘never’ is better for patient safety than, for example, the goal of managing risk materializing into harm to ‘as low as reasonably practicable,’ which is well-established in other complex socio-technical systems and is demonstrably achievable.

We reflect on the ‘never event’ concept in the primary care context specifically, although the issues and the polarized opinion highlighted are widely applicable. Recent developments to validate primary care ‘never event’ lists are summarized and alternative safety management strategies considered, e.g. Safety-I and Safety-II.

Future areas for advancing research and practice

Despite their rarity, if there is to be a policy focus on ‘never events,’ then specialist training for key workforce members is necessary to enable examination of the complex system interactions and design issues, which contribute to such events. The ‘never event’ term is well intentioned but largely aspirational—however, it is important to question prevailing assumptions about how patient safety can be understood and improved by offering alternative ways of thinking about related complexities.
Dietary patterns of phyllostomid bats in interior Atlantic Forest of eastern Paraguay
Authors: Stevens Richard D , Amarilla-Stevens Heidi N
Published: January 2021

We examined patterns of dietary overlap of phyllostomid bats in interior Atlantic Forest of Paraguay. In addition, we examined microgeographic, seasonal, and species-specific, differences in dietary patterns. We obtained 4,519 dietary records for bats from two sites in eastern Paraguay representing 26 different kinds of resources. The three most abundant resources made up 85% of all dietary records. No significant difference in diets of phyllostomid bats existed between sites. Overlap was high and significantly greater than random. Overlap at both sites was higher in winter than in summer. Consumption of dietary items was different between seasons and reflected changes in consumption primarily of the three most consumed items. Resource breadth was narrower in winter than summer. Sites, season, and species together accounted for 71% of the variation in dietary items. Unique effects, after controlling for variation shared with other factors, of species and season were significant, whereas that of site was not. While much dietary variation in interior Atlantic Forest falls along phylogenetic lines, such patterns are weak and resource utilization appears to be substantively influenced by generalist ecology of bats and seasonal nature of the environment in this system.
Neuroinvasive West Nile virus in a traveller from the United States to England
Authors: Lewis Robyn , Khan Nuzhath , Lynn William , Sandhu Gurjinder , Papineni Padmasayee
Published: January 2021

Infections with West Nile virus (WNV) are emerging as a significant risk in North America and Europe; however, imported cases to the UK are still rarely seen. We report a case of neuroinvasive WNV in a traveller from the USA to the UK.