303 research outputs found

    The population genetic structure of the urchin Centrostephanus rodgersii in New Zealand with links to Australia

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    © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021Publishe

    Search algorithms as a framework for the optimization of drug combinations

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    Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms, originally developed for digital communication, modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs with only one third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio

    CUSUM: A tool for early feedback about performance?

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    BACKGROUND: Modern day clinical practice demands evidence justifying our choice of treatment methods. Cumulative sum techniques (cusum) are amongst the simplest statistical methods known. They provide rapid analysis and identification of trends in a series of data. This study highlights use of these techniques as an early performance indicator of a clinical procedure before its implementation. METHODS: Twenty consecutive patients who underwent total hip or knee arthroplasty received a simple dressing – blue gauze and Tegaderm. Cusum charting was used to assess the dressing with regards to skin blistering. At an acceptable level of performance the curve would oscillate about the horizontal axis and the overall trend therefore said to be flat. If performance is unacceptable, the cusum slopes upward. RESULTS: The cusum plot for the twenty patients did not cross the specified control limits. This showed that our simple dressing met specified standards with regards to wound blistering postoperatively. CONCLUSION: We recommend the use of this simple, yet versatile cusum technique in the early evaluation of a clinical procedure before its implementation

    Evidence for multiple alleles effecting muscling and fatness at the Ovine GDF8 locus

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    <p>Abstract</p> <p>Background</p> <p>The current investigation surveyed genetic polymorphism at the ovine <it>GDF8 </it>locus and determined its contribution to variation in muscling and fatness in sheep.</p> <p>Results</p> <p>Re-sequencing 2988 bp from a panel of 15 sires revealed a total of six SNP, none of which were located within exons of the gene. One of the identified SNP, <it>g+6723G>A</it>, is known to increase muscularity within the Belgian Texel. A genetic survey of 326 animals revealed that the mutation is near fixation within Australian Texels and present in additional breeds including White Suffolk, Poll Dorset and Lincoln. Using a resource population comprising 15 sires and 1191 half-sib progeny with genotypic data, the effect of this and other SNP was tested against a set of 50 traits describing growth, muscling, fatness, yield, meat and eating quality. The loss of function allele (<it>g+6723A</it>) showed significant effects on slaughter measurements of muscling and fatness. No effect was detected on objectively assessed meat quality however evidence was found for an association between <it>g+6723G>A</it>, decreased intramuscular fat and reduced eating quality. Haplotype analysis using flanking microsatellites was performed to search for evidence of currently unidentified mutations which might affect production traits. Four haplotypes were identified that do not carry <it>g+6723A </it>but which showed significant associations with muscling and fatness.</p> <p>Conclusion</p> <p>The finding that <it>g+6723G>A </it>is present within Australian sheep facilitated an independent evaluation into its phenotypic consequence. Testing was conducted using a separate genetic background and animals raised in different environments to the Belgian Texel in which it was first identified. The observation that the direction and size of effects for <it>g+6723A </it>is approximately consistent represented a robust validation of the effects of the mutation. Based on observed allele frequencies within breeds, selection for <it>g+6723A </it>will have the largest impact within the White Suffolk. <it>GDF8 </it>may harbour additional mutations which serve to influence economically important traits in sheep.</p

    A study of indoor carbon dioxide levels and sick leave among office workers

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    BACKGROUND: A previous observational study detected a strong positive relationship between sick leave absences and carbon dioxide (CO(2)) concentrations in office buildings in the Boston area. The authors speculated that the observed association was due to a causal effect associated with low dilution ventilation, perhaps increased airborne transmission of respiratory infections. This study was undertaken to explore this association. METHODS: We conducted an intervention study of indoor CO(2) levels and sick leave among hourly office workers employed by a large corporation. Outdoor air supply rates were adjusted periodically to increase the range of CO(2) concentrations. We recorded indoor CO(2) concentrations every 10 minutes and calculated a CO(2) concentration differential as a measure of outdoor air supply per person by subtracting the 1–3 a.m. average CO(2) concentration from the same-day 9 a.m. – 5 a.m. average concentration. The metric of CO(2) differential was used as a surrogate for the concentration of exhaled breath and for potential exposure to human source airborne respiratory pathogens. RESULTS: The weekly mean, workday, CO(2) concentration differential ranged from 37 to 250 ppm with a peak CO(2) concentration above background of 312 ppm as compared with the American Society of Heating, Refrigeration and Air-conditioning Engineers (ASHRAE) recommended maximum differential of 700 ppm. We determined the frequency of sick leave among 294 hourly workers scheduled to work approximately 49,804.2 days in the study areas using company records. We found no association between sick leave and CO(2) differential CONCLUSIONS: The CO(2) differential was in the range of very low values, as compared with the ASHRAE recommended maximum differential of 700 ppm. Although no effect was found, this study was unable to test whether higher CO(2) differentials may be associated with increased sick leave

    DAF-2/Insulin-Like Signaling in C. elegans Modifies Effects of Dietary Restriction and Nutrient Stress on Aging, Stress and Growth

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    Dietary restriction (DR) and reduced insulin/IGF-I-like signaling (IIS) are two regimens that promote longevity in a variety of organisms. Genetic analysis in C. elegans nematodes has shown that DR and IIS couple to distinct cellular signaling pathways. However, it is not known whether these pathways ultimately converge on overlapping or distinct targets to extend lifespan.We investigated this question by examining additional effects of DR in wildtype animals and in daf-2 mutants with either moderate or severe IIS deficits. Surprisingly, DR and IIS had opposing effects on these physiological processes. First, DR induced a stress-related change in intestinal vesicle trafficking, termed the FIRE response, which was suppressed in daf-2 mutants. Second, DR did not strongly affect expression of a daf-2- and stress-responsive transcriptional reporter. Finally, DR-related growth impairment was suppressed in daf-2 mutants.These findings reveal that an important biological function of DAF-2/IIS is to enhance growth and survival under nutrient-limited conditions. However, we also discovered that levels of DAF-2 pathway activity modified the effects of DR on longevity. Thus, while DR and IIS clearly affect lifespan through independent targets, there may also be some prolongevity targets that are convergently regulated by these pathways

    Spontaneous development of Epstein-Barr Virus associated human lymphomas in a prostate cancer xenograft program

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    Prostate cancer research is hampered by the lack of in vivo preclinical models that accurately reflect patient tumour biology and the clinical heterogeneity of human prostate cancer. To overcome these limitations we propagated and characterised a new collection of patient-derived prostate cancer xenografts. Tumour fragments from 147 unsupervised, surgical prostate samples were implanted subcutaneously into immunodeficient Rag2-/-γC-/- mice within 24 hours of surgery. Histologic and molecular characterisation of xenografts was compared with patient characteristics, including androgen-deprivation therapy, and exome sequencing. Xenografts were established from 47 of 147 (32%) implanted primary prostate cancers. Only 14% passaged successfully resulting in 20 stable lines; derived from 20 independent patient samples. Surprisingly, only three of the 20 lines (15%) were confirmed as prostate cancer; one line comprised of mouse stroma, and 16 were verified as human donor-derived lymphoid neoplasms. PCR for Epstein-Barr Virus (EBV) nuclear antigen, together with exome sequencing revealed that the lymphomas were exclusively EBV-associated. Genomic analysis determined that 14 of the 16 EBV+ lines had unique monoclonal or oligoclonal immunoglobulin heavy chain gene rearrangements, confirming their B-cell origin. We conclude that the generation of xenografts from tumour fragments can commonly result in B-cell lymphoma from patients carrying latent EBV. We recommend routine screening, of primary outgrowths, for latent EBV to avoid this phenomenon

    Mantle Pb paradoxes : the sulfide solution

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    Author Posting. © Springer, 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Contributions to Mineralogy and Petrology 152 (2006): 295-308, doi:10.1007/s00410-006-0108-1.There is growing evidence that the budget of Pb in mantle peridotites is largely contained in sulfide, and that Pb partitions strongly into sulfide relative to silicate melt. In addition, there is evidence to suggest that diffusion rates of Pb in sulfide (solid or melt) are very fast. Given the possibility that sulfide melt ‘wets’ sub-solidus mantle silicates, and has very low viscosity, the implications for Pb behavior during mantle melting are profound. There is only sparse experimental data relating to Pb partitioning between sulfide and silicate, and no data on Pb diffusion rates in sulfides. A full understanding of Pb behavior in sulfide may hold the key to several long-standing and important Pb paradoxes and enigmas. The classical Pb isotope paradox arises from the fact that all known mantle reservoirs lie to the right of the Geochron, with no consensus as to the identity of the “balancing” reservoir. We propose that long-term segregation of sulfide (containing Pb) to the core may resolve this paradox. Another Pb paradox arises from the fact that the Ce/Pb ratio of both OIB and MORB is greater than bulk earth, and constant at a value of 25. The constancy of this “canonical ratio” implies similar partition coefficients for Ce and Pb during magmatic processes (Hofmann et al. 1986), whereas most experimental studies show that Pb is more incompatible in silicates than Ce. Retention of Pb in residual mantle sulfide during melting has the potential to bring the bulk partitioning of Ce into equality with Pb if the sulfide melt/silicate melt partition coefficient for Pb has a value of ~ 14. Modeling shows that the Ce/Pb (or Nd/Pb) of such melts will still accurately reflect that of the source, thus enforcing the paradox that OIB and MORB mantles have markedly higher Ce/Pb (and Nd/Pb) than the bulk silicate earth. This implies large deficiencies of Pb in the mantle sources for these basalts. Sulfide may play other important roles during magmagenesis: 1). advective/diffusive sulfide networks may form potent metasomatic agents (in both introducing and obliterating Pb isotopic heterogeneities in the mantle); 2). silicate melt networks may easily exchange Pb with ambient mantle sulfides (by diffusion or assimilation), thus ‘sampling’ Pb in isotopically heterogeneous mantle domains differently from the silicate-controlled isotope tracer systems (Sr, Nd, Hf), with an apparent ‘de-coupling’ of these systems.Our intemperance should not be blamed on the support we gratefully acknowledge from NSF: EAR- 0125917 to SRH and OCE-0118198 to GAG

    Comparative Phylogeography in a Specific and Obligate Pollination Antagonism

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    In specific and obligate interactions the nature and abundance of a given species can have important effects on the survival and population dynamics of associated organisms. In a phylogeographic framework, we therefore expect that the fates of organisms interacting specifically are also tightly interrelated. Here we investigate such a scenario by analyzing the genetic structures of species interacting in an obligate plant-insect pollination lure-and-trap antagonism, involving Arum maculatum (Araceae) and its specific psychodid (Diptera) visitors Psychoda phalaenoides and Psycha grisescens. Because the interaction is asymmetric (i.e., only the plant depends on the insect), we expect the genetic structure of the plant to be related with the historical pollinator availability, yielding incongruent phylogeographic patterns between the interacting organisms

    Inhibition of Fried Meat-Induced Colorectal DNA Damage and Altered Systemic Genotoxicity in Humans by Crucifera, Chlorophyllin, and Yogurt

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    Dietary exposures implicated as reducing or causing risk for colorectal cancer may reduce or cause DNA damage in colon tissue; however, no one has assessed this hypothesis directly in humans. Thus, we enrolled 16 healthy volunteers in a 4-week controlled feeding study where 8 subjects were randomly assigned to dietary regimens containing meat cooked at either low (100°C) or high temperature (250°C), each for 2 weeks in a crossover design. The other 8 subjects were randomly assigned to dietary regimens containing the high-temperature meat diet alone or in combination with 3 putative mutagen inhibitors: cruciferous vegetables, yogurt, and chlorophyllin tablets, also in a crossover design. Subjects were nonsmokers, at least 18 years old, and not currently taking prescription drugs or antibiotics. We used the Salmonella assay to analyze the meat, urine, and feces for mutagenicity, and the comet assay to analyze rectal biopsies and peripheral blood lymphocytes for DNA damage. Low-temperature meat had undetectable levels of heterocyclic amines (HCAs) and was not mutagenic, whereas high-temperature meat had high HCA levels and was highly mutagenic. The high-temperature meat diet increased the mutagenicity of hydrolyzed urine and feces compared to the low-temperature meat diet. The mutagenicity of hydrolyzed urine was increased nearly twofold by the inhibitor diet, indicating that the inhibitors enhanced conjugation. Inhibitors decreased significantly the mutagenicity of un-hydrolyzed and hydrolyzed feces. The diets did not alter the levels of DNA damage in non-target white blood cells, but the inhibitor diet decreased nearly twofold the DNA damage in target colorectal cells. To our knowledge, this is the first demonstration that dietary factors can reduce DNA damage in the target tissue of fried-meat associated carcinogenesis.ClinicalTrials.gov NCT00340743
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