Can telomere shortening explain sigmoidal growth curves?

A general branching process model is proposed to describe the shortening of telomeres in eukaryotic chromosomes. The model is flexible and incorporates many special cases to be found in the literature. In particular, we show how telomere shortening can give rise to sigmoidal growth curves, an idea first expressed by Portugal et al. [A computational model for telomere-dependent cell-replicative aging, BioSystems 91 (2008), pp. 262-267]. We also demonstrate how other types of growth curves arise if telomere shortening is mitigated by other cellular processes. We compare our results with published data sets from the biological literature.     

Stochastic models of telomere shortening

Shortening of chromosome ends, known as telomeres, is one of the supposed mechanisms of cellular aging and death. We provide a probabilistic analysis of the process of loss of telomere ends. The first work concerned with that issue is the paper by Levy et al. [J. Molec. Biol. 225 (1992) 951-960]. Their deterministic model reproduced the observed frequencies of viable cells in the in vitro experiments. Arino et al. [J. Theor. Biol. 177 (1995) 45-57] reformulated the model of Levy et al. (1992) in the terms of branching processes with denumerable type space. In the present paper, the mathematical results of Arino et al. (1995) are extended to the case in which cell death is present, in cells with telomeres above and below the critical threshold of length, generally with differing probabilities. Both exact and asymptotic results are provided, as well as a discussion of biological relevance of the results.     

Can telomere shortening explain sigmoidal growth curves?

A general branching process model is proposed to describe the shortening of telomeres in eukaryotic chromosomes. The model is flexible and incorporates many special cases to be found in the literature. In particular, we show how telomere shortening can give rise to sigmoidal growth curves, an idea first expressed by Portugal et al. [A computational model for telomere-dependent cell-replicative aging, BioSystems 91 (2008), pp. 262–267]. We also demonstrate how other types of growth curves arise if telomere shortening is mitigated by other cellular processes. We compare our results with published data sets from the biological literature.     

On skin dose estimation software in interventional radiology

In recent years, a growing interest has been shown in the implementation of software dedicated to the skin dose calculation, since the Fluoroscopically Guided Interventions are expanding in various medical areas. In this regard, a review article recently published by Malchair et al. (2020) is of great importance as it provides the reader with useful references to the software currently available to estimate the patient's skin dose. Despite the usefulness of collecting and summarizing in one paper the different software solutions, a few critical issues have emerged related to some parameters and configurations used in the estimation; additional details concerning patient’s size and position can be added to the information cited by the authors, giving greater robustness to the software calculation. Furthermore, software results cited in the benchmarking without reference cause a lack of solid information. Our suggestion is to adopt the given criteria to evaluate every available software solutions thus helping the eventual user to analyse the tool before adopting it.     

Frequency encoding of intracellular Ca2+ signals

In a very recent theoretical study, we showed that simple mitochondrial kinetics, originally proposed by Marhl et al., could be easily used as a plug-in element in other models describing intracellular Ca2+ dynamics. We analysed several previously published models and showed that mitochondria could indeed maintain the constant amplitude of intracellular Ca2+ oscillations very effectively. We also pointed out the importance of amplitude regulation for the frequency encoding of intracellular Ca2+ signals. This paper focuses on giving a more exhaustive demonstration of this phenomenon of frequency encoding for the model of Dupont et al.     

Yes,correct context is indeed the key: An answer to Haave‐Audet et al. 2019

We published a study recently testing the link between brain size and behavioural plasticity using brain size selected guppy (Poecilia reticulata) lines (2019, Journal of Evolutionary Biology, 32, 218‐226). Only large‐brained fish showed habituation to a new, but actually harmless environment perceived as risky, by increasing movement activity over the 20‐day observation period. We concluded that “Our results suggest that brain size likely explains some of the variation in behavioural plasticity found at the intraspecific level”. In a commentary published in the same journal, Haave‐Audet et al. challenged the main message of our study, stating that (a) relative brain size is not a suitable proxy for cognitive ability and (b) habituation measured by us is likely not adaptive and costly. In our response, we first show that a decade's work has proven repeatedly that relative brain size is indeed positively linked to cognitive performance in our model system. Second, we discuss how switching from stressed to unstressed behaviour in stressful situations without real risk is likely adaptive. Finally, we point out that the main cost of behavioural plasticity in our case is the development and maintenance of the neural system needed for information processing, and not the expression of plasticity. We hope that our discussion with Haave‐Audet et al. helps clarifying some central issues in this emerging research field.     

Bacteria from hydrocarbon seep areas growing on short-chain alkanes

Marine hydrocarbon seeps introduce large amounts of organic carbon into the environment. Different microorganisms inhabit these unusual environments using the hydrocarbons as an energy source. A recent paper by Kniemeyer et al. shows, for the first time, that sulfate-reducing bacteria isolated from hydrocarbon seeps can oxidize short-chain hydrocarbons anaerobically. This finding is an important contribution to our understanding of the role of microbes in the recycling of chemically inactive carbon compounds.     

Diphosphoinositol polyphosphates: what are the mechanisms?

In countries where adulthood is considered to be attained at age eighteen, 2011 can be the point at which the diphosphoinositol polyphosphates might formally be described as "coming of age", since these molecules were first fully defined in 1993 (Menniti et al., 1993; Stephens et al., 1993b). But from a biological perspective, these polyphosphates cannot quite be considered to have matured into the status of being independently-acting intracellular signals. This review has discussed several of the published proposals for mechanisms by which the diphosphoinositol polyphosphates might act. We have argued that all of these hypotheses need further development.We also still do not know a single molecular mechanism by which a change in the levels of a particular diphosphoinositol polyphosphate can be controlled. Yet, despite all these gaps in our understanding, there is an enduring anticipation that these molecules have great potential in the signaling field. Reflecting our expectations of all teenagers, it should be our earnest hope that in the near future the diphosphoinositol polyphosphates will finally grow up.     

Distribution of bacterial populations in a stratified fjord (mariager fjord, denmark) quantified by in situ hybridization and related to chemical gradients in the water column

Volume 62, no. 4, p. 1391-1404: after publication of this article, it was brought to the attention of the authors that a more extensive treatment of the hydrodynamics of Mariager Fjord and the vertical distribution of bacteria and protozoa therein was published in a recent article by Fenchel et al. This work contains important information about the studied ecosystem, but unfortunately, the existence of this work was realized only after publication of our article. Thus, the following reference should have been cited in our article: [This corrects the article on p. 1391 in vol. 62.].     

Aripiprazole in the maintenance treatment of bipolar disorder: a critical review of the evidence and its dissemination into the scientific literature

Background

Aripiprazole, a second-generation antipsychotic medication, has been increasingly used in the maintenance treatment of bipolar disorder and received approval from the U.S. Food and Drug Administration for this indication in 2005. Given its widespread use, we sought to critically review the evidence supporting the use of aripiprazole in the maintenance treatment of bipolar disorder and examine how that evidence has been disseminated in the scientific literature.

Methods and Findings

We systematically searched multiple databases to identify double-blind, randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder while excluding other types of studies, such as open-label, acute, and adjunctive studies. We then used a citation search to identify articles that cited these trials and rated the quality of their citations. Our evidence search protocol identified only two publications, both describing the results of a single trial conducted by Keck et al., which met criteria for inclusion in this review. We describe four issues that limit the interpretation of that trial as supporting the use of aripiprazole for bipolar maintenance: (1) insufficient duration to demonstrate maintenance efficacy; (2) limited generalizability due to its enriched sample; (3) possible conflation of iatrogenic adverse effects of abrupt medication discontinuation with beneficial effects of treatment; and (4) a low overall completion rate. Our citation search protocol yielded 80 publications that cited the Keck et al. trial in discussing the use of aripiprazole for bipolar maintenance. Of these, only 24 (30%) mentioned adverse events reported and four (5%) mentioned study limitations.

Conclusions

A single trial by Keck et al. represents the entirety of the literature on the use of aripiprazole for the maintenance treatment of bipolar disorder. Although careful review identifies four critical limitations to the trial''s interpretation and overall utility, the trial has been uncritically cited in the subsequent scientific literature. Please see later in the article for the Editors'' Summary     

Estimation of transformation parameters for microarray data

MOTIVATION AND RESULTS: Durbin et al. (2002), Huber et al. (2002) and Munson (2001) independently introduced a family of transformations (the generalized-log family) which stabilizes the variance of microarray data up to the first order. We introduce a method for estimating the transformation parameter in tandem with a linear model based on the procedure outlined in Box and Cox (1964). We also discuss means of finding transformations within the generalized-log family which are optimal under other criteria, such as minimum residual skewness and minimum mean-variance dependency. AVAILABILITY: R and Matlab code and test data are available from the authors on request.     

Chemical modification studies and the secondary structure of HeLa cell 5.8S rRNA.

Various secondary structure models have been proposed for 5.8 S rRNA. In this paper HeLa cell 5.8 S rRNA is shown to possess several sites that are reactive to carbodiimide at 25 degrees, and other regions that are unreactive. Previous work has established the distribution of reactive and unreactive cytidine residues along the primary structure (11). The secondary structure model of Nazar et al. (7) is fully compatible with the chemical reactivity data whereas other models are partly incompatible. We conclude that the model of Nazar et al. provides the best approximation so far available to the conformation of isolated 5.8 S rRNA. Findings on the effect temperature on the chemical reactivity of different parts of the structure are summarized. The findings described in this paper should provide a basis for examining the specific interaction of 5.8 S rRNA with 28 s rRNA.     

Consistency of Listing’s law and reciprocal innervation with pseudo-inverse control of eye position in 3-D

Pseudo-inverse kinematics, under which small movements are produced by the least possible sum square changes in motor command, has been proposed as a unifying principle for the elimination of redundancy in general biological motor control systems (Pellionisz 1984) and in particular in the oculomotor system (Daunicht 1988, 1991). We have noted elsewhere (Dean et al. 1999) that this principle is incomplete without first specifying a parameterisation of motor command space and we proposed that the relevant motor command parameter is summed motor unit firing rate. Under this assumption we were able to show that pseudo-inverse control of the horizontal extraocular muscles is consistent with available motor pool firing rate data. In this paper we extend this result to three dimensions and all six extraocular muscles, showing that pseudo-inverse control is consistent with published firing rate data for a realistic model of oculomotor kinematics. We suggest that pseudo-inverse control may represent a common currency for modular control of many degree of freedom systems while its implementation may be a consequence of the minimisation of a more ecologically relevant parameter such as post-saccadic retinal slip.     

Testing Genetic Association by Regressing Genotype over Multiple Phenotypes

Complex disorders are typically characterized by multiple phenotypes. Analyzing these phenotypes jointly is expected to be more powerful than dealing with one of them at a time. A recent approach (O''Reilly et al. 2012) is to regress the genotype at a SNP marker on multiple phenotypes and apply the proportional odds model. In the current research, we introduce an explicit expression for the score test statistic and its non-centrality parameter that determines its power. Same simulation studies as those reported in Galesloot et al. (2014) were conducted to assess its performance. We demonstrate by theoretical arguments and simulation studies that, despite its potential usefulness for multiple phenotypes, the proportional odds model method can be less powerful than regular methods for univariate traits. We also introduce an implementation of the proposed score statistic in an R package named iGasso.     

Population dynamics of nitrifying bacteria in an aquatic ecosystem.

In a space environment such as Space Shuttle or Space Station, animal experiments with aquatic species in a closed system pose a crucial problem in maintaining their water quality for a long term. In nature, ammonia as an animal wastes is converted by nitrifying bacteria to nitrite or nitrate compounds, which usually become nitrogen sources for plants. Thus an application of the biological reactor with such bacteria attached on some filters has been suggested and experimentally studied for efficient waste managements of ammonia. Although some successful results were reported (Kozu et al. 1995, Nagaoka et al. 1998, Nakamura et al. 1997, 1998) in the space applications, purely empirical approaches have so far been taken to develop a biological filter having a stable nitrifying activity. In this study, we constructed a mathematical model to deal with the dynamics of the ammonia nitrifying processes in a biological reactor. The model describes population dynamics of the ammonia-oxidizing bacteria and the nitrite-oxidizing bacteria cultivated on the same filter. We estimated parameters involved in the model using the experimental data. The result shows that these estimated parameters could be applied to general cases and that the two bacteria are in a symbiotic relationship; they can better perform when both coexist, as has been empirically recognized. Based on the model analysis, we discuss how to prepare a high performance biological filter.     

Learning rule-based models of biological process from gene expression time profiles using gene ontology

MOTIVATION: Microarray technology enables large-scale inference of the participation of genes in biological process from similar expression profiles. Our aim is to induce classificatory models from expression data and biological knowledge that can automatically associate genes with novel hypotheses of biological process. RESULTS: We report a systematic supervised learning approach to predicting biological process from time series of gene expression data and biological knowledge. Biological knowledge is expressed using gene ontology and this knowledge is associated with discriminatory expression-based features to form minimal decision rules. The resulting rule model is first evaluated on genes coding for proteins with known biological process roles using cross validation. Then it is used to generate hypotheses for genes for which no knowledge of participation in biological process could be found. The theoretical foundation for the methodology based on rough sets is outlined in the paper, and its practical application demonstrated on a data set previously published by Cho et al. (Nat. Genet., 27, 48-54, 2001). AVAILABILITY: The Rosetta system is available at http://www.idi.ntnu.no/~aleks/rosetta. SUPPLEMENTARY INFORMATION: http://www.lcb.uu.se/~hvidsten/bioinf_cho/     

Ionizing radiation-induced mutagenesis: radiation studies in Neurospora predictive for results in mammalian cells.

Ionizing radiation was the first mutagen discovered and was used to develop the first mutagenicity assay. In the ensuing 70+ years, ionizing radiation became a fundamental tool in understanding mutagenesis and is still a subject of intensive research. Frederick de Serres et al. developed and used the Neurospora crassa ad-3 system initially to explore the mutagenic effects of ionizing radiation. Using this system, de Serres et al. demonstrated the dependence of the frequency and spectra of mutations induced by ionizing radiation on the dose, dose rate, radiation quality, repair capabilities of the cells, and the target gene employed. This work in Neurospora predicted the subsequent observations of the mutagenic effects of ionizing radiation in mammalian cells. Modeled originally on the mouse specific-locus system developed by William L. Russell, the N. crassa ad-3 system developed by de Serres has itself served as a model for interpreting the results in subsequent systems in mammalian cells. This review describes the primary findings on the nature of ionizing radiation-induced mutagenesis in the N. crassa ad-3 system and the parallel observations made years later in mammalian cells.     

Scientific data laundering: Chimeric mitogenomes of a sparrowhawk and a nightjar covered-up by forged phylogenies

In 2017, Gang Liu and colleagues published a paper in this journal in which they described the first mitochondrial genome of Japanese Sparrowhawk Accipiter gularis (Aves, Accipitriformes). The paper included two phylogenies (one based on full mitogenomes, the other on mitochondrial 12S/16S rRNA sequences) that placed this species among the goshawks and sparrowhawks (genus Accipiter). These phylogenies also included a previously published mitogenome of Grey Nightjar Caprimulgus indicus. Here, we show that the published mitogenome of A. gularis is a chimera of three species (a sparrowhawk, a buzzard and a dove), and that the published mitogenome of C. indicus is a chimera of two owl species. Phylogenetic re-analysis showed substantial differences from those published by Liu et al. (2017): the A. gularis sequence was placed among Streptopelia doves in the 12S/16S rRNA tree, and the C. indicus sequence was placed among Otus owls in the mitogenomic and mitochondrial 12S/16S rRNA trees. The phylogenies in Liu et al. (2017) showed several other peculiarities: (i) the inclusion of Javan Hawk-eagle Nisaetus bartelsi in the mitogenome tree (whereas no mitogenome is available of this species and no such sequence has been described in the literature), (ii) reciprocal monophyly of the genera Buteo, Leucopternis and Buteogallus (whereas multiple previous studies have shown these to be para- or polyphyletic), and (iii) the placement of Black-chested Buzzard Eagle Geranoaetus melanoleucus and Crane Hawk ‘Geranoaetus’ (=Geranospiza) caerulescens as sister species (whereas all previous studies have shown these to be distantly related). Close examination of the figures in Liu et al. (2017) revealed that both phylogenies have been manually prepared or modified. The evidence indicates that Liu et al. (2017) published phylogenies that were not based on existing data but were fabricated to reflect preconceived ideas about phylogenetic relationships. The phylogenies published by Liu et al. (2017) give the impression that the mitogenomic sequence described in their paper (A. gularis) and another one (C. indicus) described by Zhao et al. (2016) are authentic and correctly identified, whereas in reality these sequences are highly problematic chimeras. The term ‘scientific data laundering’ is proposed for the practice of hiding poor or erroneous research data with fabricated or falsified figures.