A bayesian approach to improved estimation of causal effect predictiveness for a principal surrogate endpoint

Summary The literature on potential outcomes has shown that traditional methods for characterizing surrogate endpoints in clinical trials based only on observed quantities can fail to capture causal relationships between treatments, surrogates, and outcomes. Building on the potential-outcomes formulation of a principal surrogate, we introduce a Bayesian method to estimate the causal effect predictiveness (CEP) surface and quantify a candidate surrogate's utility for reliably predicting clinical outcomes. In considering the full joint distribution of all potentially observable quantities, our Bayesian approach has the following features. First, our approach illuminates implicit assumptions embedded in previously-used estimation strategies that have been shown to result in poor performance. Second, our approach provides tools for making explicit and scientifically-interpretable assumptions regarding associations about which observed data are not informative. Through simulations based on an HIV vaccine trial, we found that the Bayesian approach can produce estimates of the CEP surface with improved performance compared to previous methods. Third, our approach can extend principal-surrogate estimation beyond the previously considered setting of a vaccine trial where the candidate surrogate is constant in one arm of the study. We illustrate this extension through an application to an AIDS therapy trial where the candidate surrogate varies in both treatment arms.     

Indirect Genetic Effects for Survival in Domestic Chickens (Gallus gallus) Are Magnified in Crossbred Genotypes and Show a Parent-of-Origin Effect

Through social interactions, individuals can affect one another’s phenotype. The heritable effect of an individual on the phenotype of a conspecific is known as an indirect genetic effect (IGE). Although IGEs can have a substantial impact on heritable variation and response to selection, little is known about the genetic architecture of traits affected by IGEs. We studied IGEs for survival in domestic chickens (Gallus gallus), using data on two purebred lines and their reciprocal cross. Birds were kept in groups of four. Feather pecking and cannibalism caused mortality, as beaks were kept intact. Survival time was shorter in crossbreds than in purebreds, indicating outbreeding depression and the presence of nonadditive genetic effects. IGEs contributed the majority of heritable variation in crossbreds (87 and 72%) and around half of heritable variation in purebreds (65 and 44%). There was no evidence of dominance variance, neither direct nor indirect. Absence of dominance variance in combination with considerable outbreeding depression suggests that survival is affected by many loci. Direct–indirect genetic correlations were moderately to highly negative in crossbreds (−0.37 ± 0.17 and −0.83 ± 0.10), but low and not significantly different from zero in purebreds (0.20 ± 0.21 and −0.28 ± 0.18). Consequently, unlike purebreds, crossbreds would fail to respond positively to mass selection. The direct genetic correlation between both crosses was high (0.95 ± 0.23), whereas the indirect genetic correlation was moderate (0.41 ± 0.26). Thus, for IGEs, it mattered which parental line provided the sire and which provided the dam. This indirect parent-of-origin effect appeared to be paternally transmitted and is probably Z chromosome linked.     

Cytoplasmic and genomic effects on meiotic pairing in brassica hybrids and allotetraploids from pair crosses of three cultivated diploids

Interspecific hybridization and allopolyploidization contribute to the origin of many important crops. Synthetic Brassica is a widely used model for the study of genetic recombination and "fixed heterosis" in allopolyploids. To investigate the effects of the cytoplasm and genome combinations on meiotic recombination, we produced digenomic diploid and triploid hybrids and trigenomic triploid hybrids from the reciprocal crosses of three Brassica diploids (B. rapa, AA; B. nigra, BB; B. oleracea, CC). The chromosomes in the resultant hybrids were doubled to obtain three allotetraploids (B. juncea, AA.BB; B. napus, AA.CC; B. carinata, BB.CC). Intra- and intergenomic chromosome pairings in these hybrids were quantified using genomic in situ hybridization and BAC-FISH. The level of intra- and intergenomic pairings varied significantly, depending on the genome combinations and the cytoplasmic background and/or their interaction. The extent of intragenomic pairing was less than that of intergenomic pairing within each genome. The extent of pairing variations within the B genome was less than that within the A and C genomes, each of which had a similar extent of pairing. Synthetic allotetraploids exhibited nondiploidized meiotic behavior, and their chromosomal instabilities were correlated with the relationship of the genomes and cytoplasmic background. Our results highlight the specific roles of the cytoplasm and genome to the chromosomal behaviors of hybrids and allopolyploids.     

Dynamics of γH2AX formation and elimination in mammalian cells after X-irradiation

Phosphorylation of the replacement histone H2AX occurs in megabase chromatin domains around DNA double-strand breaks (DSBs), and this modification called γH2AX can be used as an effective marker for DSB repair and DNA damage response. In this study, we examined a bystander effect (BE) in locally irradiated embryonic human fibroblasts. Using fluorescence microscopy, we found that BE could be observed 1 h after X-ray irradiation (IR) and was completely eliminated 24 h after IR. Using immunohistochemistry and immunoblotting, we also studied kinetics of γH2AX formation and elimination in Syrian hamster and mouse tissues after whole body IR of animals. Analysis of hamster tissues at different times after IR at the dose 5 Gy showed that γH2AX-associated fluorescence in heart was decreased slowly with about a half level remaining 24 h after IR; at the same time, in brain, the level of γH2AX was about 3 times increased over the control level, and in liver, γH2AX level decreased to control values. We also report that in mouse heart the level of γH2AX measured by immunoblotting is lower than in brain, kidney and liver at different times after IR at the dose 3 Gy. Our observations indicate that there are significant variations in dynamics of γH2AX formation and elimination between non-proliferating mammalian tissues. These variations in γH2AX dynamics in indicated organs partially correlated with the expression level of the major kinase genes involved in H2AX phosphorylation (ATM and DNA-PK).     

Evaluation of bactericidal effects of low-temperature nitrogen gas plasma towards application to short-time sterilization

To develop a novel low-temperature plasma sterilizer using pure N(2) gas as a plasma source, we evaluated bactericidal ability of a prototype apparatus provided by NGK Insulators. After determination of the sterilizing conditions without the cold spots, the D value of the BI of Geobacillus stearothermophilus endospores on the filter paper was determined as 1.9 min. However, the inactivation efficiency of BI carrying the same endospores on SUS varied to some extent, suggesting that the bactericidal effect might vary by materials of sterilized instruments. Staphylococcus aureus and Escherichia coli were also exposed to the N(2) gas plasma and confirmed to be inactivated within 30 min. Through the evaluation of bactericidal efficiency in a sterilization bag, we concluded that the UV photons in the plasma and the high-voltage pulse to generate the gas plasma were not concerned with the bactericidal effect of the N(2) gas plasma. Bactericidal effect might be exhibited by activated nitrogen atoms or molecular radicals.     

Temperature and solvent dependence of the dynamical landscape of tau protein conformations

We report the variation with temperature of the ensemble distribution of conformations spanned by the tau protein in its dynamical states measured by small-angle X-ray scattering (SAXS) using synchrotron radiation. The SAXS data show a clear temperature variation of the distribution of occupied protein conformations from 293 to 318 K. More conformations with a smaller radius of gyration are occupied at higher temperature. The protein–solvent interactions are shown by computer simulation to be essential for controlling the dynamics of protein conformations, providing evidence for the key role of water solvent in the protein dynamics, as proposed by Giorgio Careri.     

Time‐Varying Latent Effect Model for Longitudinal Data with Informative Observation Times

Summary In analysis of longitudinal data, it is not uncommon that observation times of repeated measurements are subject‐specific and correlated with underlying longitudinal outcomes. Taking account of the dependence between observation times and longitudinal outcomes is critical under these situations to assure the validity of statistical inference. In this article, we propose a flexible joint model for longitudinal data analysis in the presence of informative observation times. In particular, the new procedure considers the shared random‐effect model and assumes a time‐varying coefficient for the latent variable, allowing a flexible way of modeling longitudinal outcomes while adjusting their association with observation times. Estimating equations are developed for parameter estimation. We show that the resulting estimators are consistent and asymptotically normal, with variance–covariance matrix that has a closed form and can be consistently estimated by the usual plug‐in method. One additional advantage of the procedure is that it provides a unified framework to test whether the effect of the latent variable is zero, constant, or time‐varying. Simulation studies show that the proposed approach is appropriate for practical use. An application to a bladder cancer data is also given to illustrate the methodology.     

Fungi are involved in the effects of litter mixtures on consumption by shredders

1. Decomposition of litter mixtures in both terrestrial and aquatic ecosystems often shows non‐additive diversity effects on decomposition rate, generally interpreted in streams as a result of the feeding activity of macroinvertebrates. The extent to which fungal assemblages on mixed litter may influence consumption by macroinvertebrates remains unknown. 2. We assessed the effect of litter mixing on all possible three‐species combinations drawn from four tree species (Alnus glutinosa, Betula pendula, Juglans regia and Quercus robur) on both fungal assemblages and the rate of litter consumption by a common shredder, Gammarus fossarum. After a 9‐week inoculation in a stream, batches of leaf discs were taken from all leaf species within litter mixture combinations. Ergosterol, an indicator of fungal biomass, and the composition of fungal assemblages, assessed from the conidia released, were determined, and incubated litter offered to G. fossarum in a laboratory‐feeding experiment. 3. Mixing leaf litter species enhanced both the Simpson’s index of the fungal assemblage and the consumption of litter by G. fossarum, but had no clear effect on mycelial biomass. Specifically, consumption rates of J. regia were consistently higher for mixed‐species litter packs than for single‐species litter. In contrast, the consumption rates of B. pendula were not affected by litter mixing, because of the occurrence of both positive and negative litter‐mixing effects in different litter species combinations that counteracted each other. 4. In some litter combinations, the greater development of some fungal species (e.g. Clavariopsis aquatica) as shown by higher sporulation rates coincided with increased leaf consumption, which may have resulted from feeding preferences by G. fossarum for these fungi. 5. Where litter mixture effects on decomposition rate are mediated via shredder feeding, this could be due to indirect effects of the fungal assemblage.     

A Report of the James Watson Lecture at Yale University

In March 2012, Nobel Prize winner James Watson gave a seminar at Yale University entitled “Driven by Ideas.” In his lecture, Watson discussed his personal vision for the future of science, specifically addressing how the scientific community should approach developing anticancer agents. He discussed the use of glycolytic inhibitors as anticancer agents due to the Warburg effect, as well as the benefits of metformin and anti-inflammatory drugs to help prevent cancer. He also compared drugs that target cell proliferation instead of targeting cell growth. Additionally, Watson commented on the mechanisms for how research should be conducted in the laboratory.