Method,Measurement, and Management in IPCC Climate Modeling

The IPCC is the world’s leading scientific body addressing climate change, but there is growing dissatisfaction with its heavily economic and econometric approach to analyzing the climate-relevant aspects of human thought and behavior. This article documents and discusses the problem before sketching two examples of how other cultural domains besides the economic—the political and cosmological—might be incorporated into modeling the human dimensions of climate change. In conclusion, the article deploys these examples to explore why the IPCC has been reluctant to model non-economic realms of culture. The results underscore the importance of Victor’s (Nature 520:27–29, 2015) call for a parallel global mechanism to address the IPCC’s evasion of controversial policy-relevant questions.     

Segmental isotopic labeling of HIV-1 capsid protein assemblies for solid state NMR

Recent studies of noncrystalline HIV-1 capsid protein (CA) assemblies by our laboratory and by Polenova and coworkers (Protein Sci 19:716–730, 2010; J Mol Biol 426:1109–1127, 2014; J Biol Chem 291:13098–13112, 2016; J Am Chem Soc 138:8538–8546, 2016; J Am Chem Soc 138:12029–12032, 2016; J Am Chem Soc 134:6455–6466, 2012; J Am Chem Soc 132:1976–1987, 2010; J Am Chem Soc 135:17793–17803, 2013; Proc Natl Acad Sci USA 112:14617–14622, 2015; J Am Chem Soc 138:14066–14075, 2016) have established the capability of solid state nuclear magnetic resonance (NMR) measurements to provide site-specific structural and dynamical information that is not available from other types of measurements. Nonetheless, the relatively high molecular weight of HIV-1 CA leads to congestion of solid state NMR spectra of fully isotopically labeled assemblies that has been an impediment to further progress. Here we describe an efficient protocol for production of segmentally labeled HIV-1 CA samples in which either the N-terminal domain (NTD) or the C-terminal domain (CTD) is uniformly ¹⁵N,¹³C-labeled. Segmental labeling is achieved by trans-splicing, using the DnaE split intein. Comparisons of two-dimensional solid state NMR spectra of fully labeled and segmentally labeled tubular CA assemblies show substantial improvements in spectral resolution. The molecular structure of HIV-1 assemblies is not significantly perturbed by the single Ser-to-Cys substitution that we introduce between NTD and CTD segments, as required for trans-splicing.     

Use of CD40L immunoconjugates to overcome the defective immune response to vaccines for infections and cancer in the aged

Multiple investigators have reported thepresence of defects in the immune response of the elderly [Castle In: Clin Infect Dis 31:578, 2000; Ortqvist et al. In: Eur Respir J 30:414–422, 2007; Saurwein-Teissl et al. In: J Immunol 168:5893, 2002; Haynes et al. In: Proc Natl Acad Sci USA 100:15053–15058, 2003]. These defects reduce the magnitude of the immune response to infection and to vaccination. In individuals greater than 55 years of age, the probability of developing a fully protective neutralizing antibody response to the yearly multivalent particle inactivated influenza vaccine is less than 20% [Jefferson et al. In: Lancet 264:1165–1174, 2005; Goodwin et al. In: Vaccine 24:1159–1169, 2006; Jackson et al. In: Lancet 372:398–405, 2008; Simonsen and Taylor In: Lancet 7:658–666, 2007]. The defects in the aged immune system that are responsible for this limited response to vaccination in the older age groups include functional defects of the antigen presenting cells, functional defects in CD4 helper CD4 T cells and monocytes, and an altered microenvironment [Eaton et al. In: J Exp Med 200:1613–1622, 2004; Dong et al. In: J Gen Virol 84:1623–1628, 2003; Deng et al. In: Immunology 172:3437–3446, 2004; Cella et al. In: J Exp Med 184:747–752, 1996]. Starting at puberty, the involution of the thymus and the consequent reduction of the export of naïve T cells specific to neo-antigens leads to the reduction of the ratio of antigen naïve to memory cells as chronological age advances [Prelog In: AutoimmunRev 5:136–139, 2006; McElhaney et al. In: J Immunology 176:6333–6339, 2006]. Changes in glycosylation of T cells and target antigens acquired during the aging process and the antibodies to these new glycopeptides and glycoproteins may also contribute to a reduction in the functioning of the adaptive immune response [Ishii et al. In: J Clin Neurosci 14:110–115, 2007; Shirai et al. In: Clin Exp Immunol 12:455–464, 1972; Adkins and Riley In: Mech AgeingDev 103:147–164, 1998; Ben-Yehuda and Weksler In: Cancer Investigation 10:525–531, 1992]. One of the more interesting examples of the functional defects in the cells of the adaptive immune response is a reduced level of expression in the surface cytoadhesion and activation receptor molecules on CD4 helper T cells undergoing activation during vaccination. Upon infection or vaccination, CD40L is typically increased on the surface of CD4 helper T cells during activation, and this increased expression is absolutely essential to the CD40L promotion of expansion of antigen-specific B cells and CD 8 effector T cells in response to infection or vaccination [Singh et al. In: Protein Sci 7:1124–1135, 1998; Grewal and Flavell In: Immunol Res 16: 59–70, 1997; Kornbluth In: J Hematother Stem Cell Res 11:787–801, 2002; Garcia de Vinuesa et al. In: Eur J Immunol 29:3216–3224, 1999]. In aged human beings and mice, the reduced levels of expression of CD40 ligand (CD40L) in activated CD4 helper T cells is dramatically reduced [Eaton et al. In: J Exp Med 200:1613–1622, 2004; Dong et al. In: J Gen Virol 84:1623–1628, 2003]. To circumvent the reduction in CD40L expression and the subsequent reduction in immune response in the elderly, we have developed a chimeric vaccine comprised of the CD40L linked to the target antigen, in a replication incompetent adenoviral vector and in booster protein. This review will discuss the implementation the potential use of this approach for the vaccination of the older populations for cancer and infection.     

Multiscale Persistent Functions for Biomolecular Structure Characterization

In this paper, we introduce multiscale persistent functions for biomolecular structure characterization. The essential idea is to combine our multiscale rigidity functions (MRFs) with persistent homology analysis, so as to construct a series of multiscale persistent functions, particularly multiscale persistent entropies, for structure characterization. To clarify the fundamental idea of our method, the multiscale persistent entropy (MPE) model is discussed in great detail. Mathematically, unlike the previous persistent entropy (Chintakunta et al. in Pattern Recognit 48(2):391–401, 2015; Merelli et al. in Entropy 17(10):6872–6892, 2015; Rucco et al. in: Proceedings of ECCS 2014, Springer, pp 117–128, 2016), a special resolution parameter is incorporated into our model. Various scales can be achieved by tuning its value. Physically, our MPE can be used in conformational entropy evaluation. More specifically, it is found that our method incorporates in it a natural classification scheme. This is achieved through a density filtration of an MRF built from angular distributions. To further validate our model, a systematical comparison with the traditional entropy evaluation model is done. It is found that our model is able to preserve the intrinsic topological features of biomolecular data much better than traditional approaches, particularly for resolutions in the intermediate range. Moreover, by comparing with traditional entropies from various grid sizes, bond angle-based methods and a persistent homology-based support vector machine method (Cang et al. in Mol Based Math Biol 3:140–162, 2015), we find that our MPE method gives the best results in terms of average true positive rate in a classic protein structure classification test. More interestingly, all-alpha and all-beta protein classes can be clearly separated from each other with zero error only in our model. Finally, a special protein structure index (PSI) is proposed, for the first time, to describe the “regularity” of protein structures. Basically, a protein structure is deemed as regular if it has a consistent and orderly configuration. Our PSI model is tested on a database of 110 proteins; we find that structures with larger portions of loops and intrinsically disorder regions are always associated with larger PSI, meaning an irregular configuration, while proteins with larger portions of secondary structures, i.e., alpha-helix or beta-sheet, have smaller PSI. Essentially, PSI can be used to describe the “regularity” information in any systems.     

Metabolite targeting: development of a comprehensive targeted metabolomics platform for the assessment of diabetes and its complications

Biomarker studies for metabolic disorders like diabetes mellitus (DM) are an important approach towards a better understanding of the underlying pathophysiological mechanisms of diseases (Roberts and Gerszten in Cell Metab 18:43–50, 2013; Wilson et al. in Proteome Res 4:591–598, 2005). Furthermore, screening of potential metabolic biomarkers opens the opportunity of early diagnosis as well as therapy and drug monitoring of metabolic disorders (Rhee et al. in J Clin Invest 10:1–10, 2011; Wang et al. in Nat Med 17:448–458, 2011; Wenk in Nat Rev Drug Discov 4:594–610, 2005). The aim of the present study was to develop methods for the quantitative determination of 74 potential metabolite biomarkers for DM and diabetic nephropathy (DN) in serum. Several studies have shown that the concentrations of many polar metabolites like amino or organic acids are changed in subjects suffering from diabetes (Wang et al. in Nat Med 17:448–458, 2011; Yuan et al. in J Chromatogr B 813:53–58, 2007). Analyzing polar analytes presents a challenge in liquid chromatography (LC) coupled with ESI–MS/MS (Gika et al. in J Sep Sci 31:1598–1608, 2008; Spagou et al. in J Sep Sci 33:716–727, 2010). Considering those reasons we decided to develop a specific HILIC–ESI–QqQ–MS/MS-method for quantitative determination of these polar metabolites. A subsequent method validation was carried out for both HILIC and RP chromatography with respect to the guidelines of the Food and Drug Administration (FDA in Food and Drug Administration: Guidance for industry, bioanalytical method validation, 2001). The HILIC and RP LC–MS methods were successfully validated. Furthermore, the HILIC method presented here was applied to serum samples of GIPR^dn transgenic mice, a diabetic strain developing DN, and non transgenic littermate controls. Significant, diabetes-associated changes were observed for the concentrations of 21 out of 62 metabolites. The new methods described here accurately quantify 74 metabolites known to be regulated in diabetes, allowing for direct comparison between studies and laboratories. Thus, these methods may be highly adoptable in clinical research, providing a starting point for early diagnosis and metabolic screening.     

What is behind “centromere repositioning”?

An increasing number of observations suggest an evolutionary switch of centromere position on monocentric eukaryotic chromosomes which otherwise display a conserved sequence of genes and markers. Such observations are particularly frequent for primates and equidae (for review see Heredity 108:59–67, 2012) but occur also in marsupials (J Hered 96:217–224, 2005) and in plants (Chromosome Res 25:299–311, 2017 and references therein). The actual mechanism(s) behind remained unclear in many cases (Proc Natl Acad Sci USA 101:6542–6547, 2004; Trends Genet 30:66–74, 2014). The same is true for de novo centromere formation on chromosomes lacking an active centromere. This article focuses on recent reports on centromere repositioning and possible mechanisms behind and addresses open questions.     

Mathematical Model of Bone Remodeling Captures the Antiresorptive and Anabolic Actions of Various Therapies

A better understanding of the molecular pathways regulating the bone remodeling process should help in the development of new antiresorptive regulators and anabolic regulators, that is, regulators of bone resorption and of bone formation. Understanding the mechanisms by which parathyroid hormone (PTH) influences bone formation and how it switches from anabolic to catabolic action is important for treating osteoporosis (Poole and Reeve in Curr Opin Pharmacol 5:612–617, 2005). In this paper we describe a mathematical model of bone remodeling that incorporates, extends, and integrates several models of particular aspects of this biochemical system (Cabal et al. in J Bone Miner Res 28(8):1830–1836, 2013; Lemaire et al. in J Theor Biol 229:293–309, 2004; Peterson and Riggs in Bone 46:49–63, 2010; Raposo et al. in J Clin Endocrinol Metab 87(9):4330–4340, 2002; Ross et al. in J Disc Cont Dyn Sys Series B 17(6):2185–2200, 2012). We plan to use this model as a bone homeostasis platform to develop anabolic and antiresorptive compounds. The model will allow us to test hypotheses about the dynamics of compounds and to test the potential benefits of combination therapies. At the core of the model is the idealized account of osteoclast and osteoblast signaling given by Lemaire et al. (J Theor Biol 229:293–309, 2004). We have relaxed some of their assumptions about the roles of osteoprotegerin, transforming growth factor \(\upbeta \), and receptor activator of nuclear factor \(\upkappa \)B ligand; we have devised more detailed models of the interactions of these species. We have incorporated a model of the effect of calcium sensing receptor antagonists on remodeling (Cabal et al. in J Bone Miner Res 28(8):1830–1836, 2013). We have also incorporated a basic model of the effects of vitamin D on calcium homeostasis. We have included a simple model of the mechanism proposed by Bellido et al. (2003), Ross et al. (J Disc Cont Dyn Sys Series B 17(6):2185–2200, 2012), of the influence of PTH on osteoblast apoptosis, a mechanism that accounts for the anabolic response to pulsatile PTH administration. Finally, we have devised a simple model of the administration and effects of bisphosphonates. The biomarkers in the model are procollagen type 1 amino-terminal propeptide and C-terminal telopeptide. Bone mineral density is the model’s principal endpoint.     

Strong Comma-Free Codes in Genetic Information

Comma-free codes constitute a class of circular codes, which has been widely studied, in particular by Golomb et al. (Biologiske Meddelelser, Kongelige Danske Videnskabernes Selskab 23:1–34, 1958a, Can J Math 10:202–209, 1958b), Michel et al. (Comput Math Appl 55:989–996, 2008a, Theor Comput Sci 401:17–26, 2008b, Inf Comput 212:55–63, 2012), Michel and Pirillo (Int J Comb 2011:659567, 2011), and Fimmel and Strüngmann (J Theor Biol 389:206–213, 2016). Based on a recent approach using graph theory to study circular codes Fimmel et al. (Philos Trans R Soc 374:20150058, 2016), a new class of circular codes, called strong comma-free codes, is identified. These codes detect a frameshift during the translation process immediately after a reading window of at most two nucleotides. We describe several combinatorial properties of strong comma-free codes: enumeration, maximality, self-complementarity and \(CF^3\)-property (comma-free property in all the three possible frames). These combinatorial results also highlight some new properties of the genetic code and its evolution. Each amino acid in the standard genetic code is coded by at least one strong comma-free code of size 1. There are 9 amino acids \(S=\{Asn,Asp,Gln,Gly,Lys,Met,Phe,Pro,Trp\}\) among 20 such that for each amino acid from S, its synonymous trinucleotide set (excluding the necessary periodic trinucleotides \(\{AAA,CCC,GGG,TTT\}\)) is a strong comma-free code. The primeval comma-free RNY code of Eigen and Schuster (Naturwissenschaften 65:341–369, 1978) is a self-complementary \(CF^3\)-code of size 16. Furthermore, it is the union of two strong comma-free codes of size 8 which are complementary to each other.     

First-principle investigation on growth patterns and properties of cobalt-doped lithium nanoclusters

A systematic theoretical investigation on cobalt lithium clusters Li_nCo [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12] was performed with a DFT approach. The location of global minima and structural evolution were carried out using the partical swarm optimization method. Li₆Co is the transition structure in going from low-coordinated structures to three-dimensional torispherical structures with a cobalt atom enclosed by lithium atoms. Maxima of ?₂ E and E _b for Li_nCo were found at n?=?3, 6, 8, 10, indicating that these clusters possess higher relative stability than their neighbors. In comparison with small clusters, n?=?1–6, the greater electron transfer from Li-2s to Co-3d within cage-like clusters Li_nCo (n?=?7–12) strengthens the bonding effect between Li_n and Co, which is reflected in the Wiberg bond index of Co and atomic binding energy analysis. AdNDP analysis verified the presence of both Lewis bonding elements (1c–2e objects) and delocalized bonding elements (6c–2e, 9c–2e and 10c–2e bonds). It is hoped that this theoretical work will provide favorable information to help understand the influence of dopant transition metal atoms on the properties of lithium-based materials.     

Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM)

Objectives

In this review we compare the advantages and disadvantages of different model biological systems for determining the metabolic functions of cells in complex environments, how they may change in different disease states, and respond to therapeutic interventions.

Introduction

All preclinical drug-testing models have advantages and drawbacks. We compare and contrast established cell, organoid and animal models with ex vivo organ or tissue culture and in vivo human experiments in the context of metabolic readout of drug efficacy. As metabolism reports directly on the biochemical state of cells and tissues, it can be very sensitive to drugs and/or other environmental changes. This is especially so when metabolic activities are probed by stable isotope tracing methods, which can also provide detailed mechanistic information on drug action. We have developed and been applying Stable Isotope-Resolved Metabolomics to examine metabolic reprogramming of human lung cancer cells in monoculture, in mouse xenograft/explant models, and in lung cancer patients in situ (Lane et al. in Omics 15:173–182, 2011; Fan et al. in Metabolomics 7(2):257–269, 2011a, in Pharmacol Ther 133:366–391, 2012a, in Metabolomics 8(3):517–527, b; Xie et al. in Cell Metab 19:795–809, 2014; Ren et al. in Sci Rep 4:5414, 2014; Sellers et al. in J Clin Investig 125(2):687–698, 2015). We are able to determine the influence of the tumor microenvironment using these models. We have now extended the range of models to fresh human tissue slices, similar to those originally described by Warburg (Biochem Z 142:317–333, 1923), which retain the native tissue architecture and heterogeneity with a paired benign versus cancer design under defined cell culture conditions. This platform offers an unprecedented human tissue model for preclinical studies on metabolic reprogramming of human cancer cells in their tissue context, and response to drug treatment (Xie et al. 2014). As the microenvironment of the target human tissue is retained and individual patient’s response to drugs is obtained, this platform promises to transcend current limitations of drug selection for clinical trials or treatments

Conclusions

Development of ex vivo human tissue and animal models with humanized organs including bone marrow and liver show considerable promise for analyzing drug responses that are more relevant to humans. Similarly using stable isotope tracer methods with these improved models in advanced stages of the drug development pipeline, in conjunction with tissue biopsy is expected significantly to reduce the high failure rate of experimental drugs in Phase II and III clinical trials.

     

Inheritance by recruitment

Doolittle (Biol Philos 28(2):351–378, 2013) and Ereshefsky and Pedroso (Proc Natl Acad Sci 112:10126–10132, 2013) argue that selection can act at the level of biofilms and other microbial communities. Clarke (Biol Philos 191–212, 2016) is skeptical and argues that selection acts on microbial cells rather than microbial communities. Her main criticism is that biofilms lack one of the ingredients required for selection to operate: heritability. This paper replies to her concern by elaborating how biofilm-level traits can be inheritable     

Life-cycle assessment of the soybean-sunflower production system in the Brazilian Cerrado

Purpose

In the “Cerrado” (Brazilian savanna), sunflower comes mostly from a cropping system where its seeding follows soybean harvest. Soybean has a much higher economic value, but this association with sunflower reduces the environmental impacts from both crops by sharing resources. This study performed a life-cycle assessment (LCA) of the soybean-sunflower cropping system, identified its hotspots, and compared its environmental performance with two hypothetical monocultures, in order to corroborate its benefits.

Methods

Soybean-sunflower cropping system inventory used data from farms of the Parecis region, consolidated by experts. Inventories for soybean and sunflower monocultures were estimated from the cropping system inventory. LUC (land-use changes) were calculated from CONAB (2015), FAOSTAT (2012), and Macedo et al. (P Natl Acad Sci USA 109:1341–1346, 2012). Emissions estimation followed Nemecek and Schnetzer (2011), Milà i Canals (2003), and EC (2010). Land occupation, land-use changes, and liming were allocated by occupation time, but a sensitivity analysis was performed for yield and gross margin as allocation criteria. ReCiPe Midpoint (H) v1.12/World ReCiPe H was the impact assessment method, and some categories were disregarded as not relevant. We used pedigree matrix to estimate uncertainties for inventory and Monte Carlo method for impact uncertainty analysis as in Goedkoop et al. (2008). We used SimaPro 8.0.5.13.

Results and discussion

The soybean-sunflower cropping system generate relevant human toxicity, freshwater toxicity, freshwater eutrophication, climate change, and terrestrial acidification impacts, related to emissions derived from nitrogen and phosphate fertilizers and emissions generated by LUC. Sunflower-soybean cropping system has better environmental performance when compared to the combination of monocultures because of a number of synergies made possible by sharing land use and other resources. Changing the allocation criteria altered the relative performance of some categories, but in all categories the environmental impacts of the cropping system were lower than those of the corresponding monoculture impacts, regardless of the allocation criteria implemented.

Conclusions

We concluded that the environmental performance of the soybean-sunflower cropping system can be improved by optimizing the use of chemical fertilizers. Climate change impacts, which are mostly driven by LUC, could be reduced by production intensification, preventing the clearing of native vegetation for agricultural purposes. This study confirmed the environmental benefits of cropping systems when compared to monocultures and the advantages of association of nitrogen-fixing legumes with other plant species in a production system.

     

Chemical Analysis of a “Miller-Type” Complex Prebiotic Broth

In a famous experiment Stanley Miller showed that a large number of organic substances can emerge from sparking a mixture of methane, ammonia and hydrogen in the presence of water (Miller, Science 117:528–529, 1953). Among these substances Miller identified different amino acids, and he concluded that prebiotic events may well have produced many of Life’s molecular building blocks. There have been many variants of the original experiment since, including different gas mixtures (Miller, J Am Chem Soc 77:2351–2361, 1955; Oró Nature 197:862–867, 1963; Schlesinger and Miller, J Mol Evol 19:376–382, 1983; Miyakawa et al., Proc Natl Acad Sci 99:14,628–14,631, 2002). Recently some of Miller’s remaining original samples were analyzed with modern equipment (Johnson et al. Science 322:404–404, 2008; Parker et al. Proc Natl Acad Sci 108:5526–5531, 2011) and a total of 23 racemic amino acids were identified. To give an overview of the chemical variety of a possible prebiotic broth, here we analyze a “Miller type” experiment using state of the art mass spectrometry and NMR spectroscopy. We identify substances of a wide range of saturation, which can be hydrophilic, hydrophobic or amphiphilic in nature. Often the molecules contain heteroatoms, with amines and amides being prominent classes of molecule. In some samples we detect ethylene glycol based polymers. Their formation in water requires the presence of a catalyst. Contrary to expectations, we cannot identify any preferred reaction product. The capacity to spontaneously produce this extremely high degree of molecular variety in a very simple experiment is a remarkable feature of organic chemistry and possibly prerequisite for Life to emerge. It remains a future task to uncover how dedicated, organized chemical reaction pathways may have arisen from this degree of complexity.     

The phylotypic stage as a boundary of modular memory: non mechanistic perspective

The concept of the phylotypic stage has been strongly integrated into developmental biology, thanks mostly to drawings presented by Haeckel (Anthropogenie oder Entwicklungsgeschichte des Menschen, 1874). They are printed in every textbook as proof of the existence of the phylotypic stage and the fact of its conservation, albeit many times criticized as misleading and simplifying (Richardson in Develop Biol 172:412–421, 1995, Richardson et al. in Anat Embryo 196:91–106, 1997; Bininda-Emons et al. in Proc R Soc Lond 270:341–346, 2003). Although generally accepted by modern biology, doubt still exists concerning the very existence or the usefulness of the concept. What kind of evolutionary and developmental horizons does it open indeed? This article begins with the history of the concept, discusses its validity and draws this into connotation with the idea of a memory activated throughout the development. Barbieri (The organic codes. An introduction to semantic biology, 2003) considers the phylotypic stage to be a crucial boundary when the genetic program ceases to suffice for further development of the embryo, and supracellular memory of the body plan is activated. This moment clearly coincides with the commencing of the modular development of the embryo. In this article the nature of such putative memory will be discussed.     

Analysis of gene copy number changes in tumor phylogenetics

Backgound

Evolution of cancer cells is characterized by large scale and rapid changes in the chromosomal  landscape. The fluorescence in situ hybridization (FISH) technique provides a way to measure the copy numbers of preselected genes in a group of cells and has been found to be a reliable source of data to model the evolution of tumor cells. Chowdhury et al. (Bioinformatics 29(13):189–98, 23; PLoS Comput Biol 10(7):1003740, 24) recently develop a computational model for tumor progression driven by gains and losses in cell count patterns obtained by FISH probes. Their model aims to find the rectilinear Steiner minimum tree (RSMT) (Chowdhury et al. in Bioinformatics 29(13):189–98, 23) and the duplication Steiner minimum tree (DSMT) (Chowdhury et al. in PLoS Comput Biol 10(7):1003740, 24) that describe the progression of FISH cell count patterns over its branches in a parsimonious manner. Both the RSMT and DSMT problems are NP-hard and heuristics are required to solve the problems efficiently.

Methods

In this paper we propose two approaches to solve the RSMT problem, one inspired by iterative methods to address the “small phylogeny” problem (Sankoff et al. in J Mol Evol 7(2):133–49, 27; Blanchette et al. in Genome Inform 8:25–34, 28), and the other based on maximum parsimony phylogeny inference. We further show how to extend these heuristics to obtain solutions to the DSMT problem, that models large scale duplication events.

Results

Experimental results from both simulated and real tumor data show that our methods outperform previous heuristics (Chowdhury et al. in Bioinformatics 29(13):189–98, 23; Chowdhury et al. in PLoS Comput Biol 10(7):1003740, 24) in obtaining solutions to both RSMT and DSMT problems.

Conclusion

The methods introduced here are able to provide more parsimony phylogenies compared to earlier ones which are consider better choices.

     

Lexical splits within periphrasis: mixed perfective auxiliation systems in Italo-Romance

This paper addresses the phenomenon of mixed paradigms, i.e. mixed perfective auxiliation systems, attested in a wide range of Italo-Romance varieties (cf. Loporcaro 2001, 2007a, 2014; Manzini and Savoia 2005, among others). In these varieties, two auxiliary verbs, esse and habere, alternate within one and the same (sub)paradigm, displaying various patterns which can range from morphosyntactically motivated to apparently unmotivated distributions (here termed ‘morphomic’). I propose that, in these varieties, auxiliary selection is no longer a syntactically driven phenomenon, but becomes morphologized. I draw on the notion of ‘lexical split’ (cf. Corbett 2013, 2015, 2016) and describe the attested splits induced by intraparadigmatic auxiliary alternation. Following Bonami (2015), I put forward a typology of such splits. It is shown that, apart from motivated distributions, some morphomic patterns can also be found. The typology becomes more complex insofar as patterns with free variation between both auxiliaries are taken into account, as well as patently morphomic patterns which also seem to display external syntactic relevance (cf. Corbett 2013: 174–176). The phenomena reviewed and discussed in this paper are of major interest because they demonstrate the existence of competing exponence strategies within periphrasis, thus enriching the notion of ‘possible lexeme’ (cf. Corbett 2015: 146).     

Abandonments,Solidarities and Logics of Care: Hospitals as Sites of Sectarian Conflict in Gilgit-Baltistan

Using data collected over nearly three years of ethnographic fieldwork in the Gilgit-Baltistan region of northern Pakistan, my paper explores hospital spaces, clinical services and treatment encounters as conduits for the expression and propagation of conflictive Shia-Sunni sectarianism. Where my prior research has investigated the political etiologies (Hamdy in Am Ethnol 35(4):553–569, 2008) associated with Gilgiti women’s experiences of childbirth during ‘tensions’, as Shia-Sunni hostilities are locally known, this paper focuses on healthcare providers’ professional and personal navigations of an episode of conflict whose epicentre was at the District Headquarter Hospital, Gilgit-Baltistan’s foremost government hospital. Through critical evaluation of the impacts of Shia-Sunni tensions on the social, administrative and clinical practices and consequences of medicine, my paper analyses the complex ways that clinics in crisis serve as zones of contact (Pratt in Profession 91:33–40, 1991) and abandonment (Biehl in Soc Text 68(19):131–149, 2001; Subjectivity: ethnographic investigations, 2007), in which neglect and harm are directed along lines of sectarian affiliation to produce vulnerability, spectacular violence and death for healthcare providers and patients.     

Performance of Biomarker-Based Subgroup Selection Rules in Adaptive Enrichment Designs

In the planning stage of a clinical trial investigating a potentially targeted therapy, there is commonly a high degree of uncertainty whether the treatment is more efficient (or efficient only) in a subgroup compared to the whole population. Recently developed adaptive designs enable to allow for an efficacy assessment both for the whole population and a subgroup and to select the target population mid-course based on interim results (see, e.g., Wang et al., Pharm Stat 6:227–244, 2007, Brannath et al., Stat Med 28:1445–1463, 2009, Wang et al., Biom J 51:358–374, 2009, Jenkins et al., Pharm Stat 10:347–356, 2011, Friede et al., Stat Med 31:4309–4120, 2012). Frequently, predictive biomarkers are used in these trials for identifying patients more likely to benefit from a drug. We consider the situation that the selection of the patient population is based on a biomarker and where the diagnostics that evaluates the biomarker may be perfect, i.e., with 100 % sensitivity and specificity, or not. The performance of the applied subset selection rule is crucial for the overall characteristics of the design. In the setting of an adaptive enrichment design, we evaluate the properties of subgroup selection rules in terms of type I error rate and power by taking into account decision rules with a fixed ad hoc threshold and optimal decision rules developed for the situation of uncertain assumptions. In a simulation study, we demonstrate that designs with optimal decision rules are under certain assumptions more powerful as compared to those with ad hoc decision rules. Throughout the results, a strong impact of sensitivity and specificity of the biomarker on both type I error rate and power is observed.     

Competition between phytoplankton and bacteria: exclusion and coexistence

Resource-based competition between microorganisms species in continuous culture has been studied extensively both experimentally and theoretically, mostly for bacteria through Monod and Contois “constant yield” models, or for phytoplankton through the Droop “variable yield” models. For homogeneous populations of N bacterial species (Monod) or N phytoplanktonic species (Droop), with one limiting substrate and under constant controls, the theoretical studies indicated that competitive exclusion occurs: only one species wins the competition and displaces all the others (Armstrong and McGehee in Am Nat 115:151, 1980; Hsu and Hsu in SIAM J Appl Math 68:1600–1617, 2008). The winning species expected from theory is the one with the lowest “substrate subsistence concentration” \(s^{\star }\), such that its corresponding equilibrium growth rate is equal to the dilution rate \(D\). This theoretical result was validated experimentally with phytoplankton (Tilman and Sterner in Oecologia 61(2):197–200, 1984) and bacteria (Hansen and Hubell in Science 207(4438):1491–1493, 1980), and observed in a lake with microalgae (Tilman in Ecology 58(22):338–348, 1977). On the contrary for aggregating bacterial species described by a Contois model, theory predicts coexistence between several species (Grognard et al. in Discrete Contin Dyn Syst Ser B 8(1):73–93, 2007). In this paper we present a generalization of these results by studying a competition between three different types of microorganisms: planktonic (or free) bacteria (represented by a generalized Monod model), aggregating bacteria (represented by a Contois model) and free phytoplankton (represented by a Droop model). We prove that the outcome of the competition is a coexistence between several aggregating bacterial species with a free species of bacteria or phytoplankton, all the other free species being washed out. This demonstration is based mainly on the study of the substrate concentration’s evolution caused by competition; it converges towards the lowest subsistence concentration \(s^{\star }\), leading to three different types of competition outcomes: (1) the best free bacteria or phytoplankton competitor excludes all other species; (2) only some aggregating bacterial species coexist in the chemostat; (3) A coexistence between the single best free species, with one or several aggregating species.     

Plant individuality: a solution to the demographer’s dilemma

The problem of plant individuality is something which has vexed botanists throughout the ages, with fashion swinging back and forth from treating plants as communities of individuals (Darwin 1800; Braun and Stone 1853; Münch 1938) to treating them as organisms in their own right, and although the latter view has dominated mainstream thought most recently (Harper 1977; Cook 1985; Ariew and Lewontin 2004), a lively debate conducted mostly in Scandinavian journals proves that the issues are far from being resolved (Tuomi and Vuorisalo 1989b; Fagerström 1992; Pan and Price 2001). In this paper I settle the matter once and for all, by showing which elements of each side are correct.