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.     

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.     

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.     

From possessive suffix to affective demonstrative suffix in Hungarian: a grammaticalization analysis

The non-possessive uses of possessive morphology in Uralic languages have been a topic of intense debate (Fraurud 2001; Nikolaeva 2003; Gerland 2014; Janda 2015; É. Kiss and Tánczos to appear). In this paper, I focus on a special use of the poss.3sg suffix in Hungarian constructions such as a hülyéje (the stupid-poss.3sg): lit. ‘its stupid’, meaning ‘that total idiot’. My main claim is that this suffix is an affective demonstrative suffix (Lakoff 1974; Liberman 2008; Potts and Schwarz 2010), and that it has developed as a result of grammaticalization from a full-fledged possessive construction of the form a világ hülyéje (the world stupid-poss.3sg): lit. ‘the world’s stupid’, meaning: ‘the biggest idiot in the world’. I will show that this gradual process can be reconstructed fairly accurately using historical and contemporary corpora. I also claim that this grammaticalization pathway is very natural as it is based on a set-element relationship which is often expressed by possessive constructions cross-linguistically. I also identify two parameters which facilitate this grammaticalization process: the availability of (silent) pro possessors and the lack of gender agreement on the possessive suffix. Since Uralic languages in general have these parameters, I will argue that this grammaticalization pathway should at least be considered as one of the possible sources of the demonstrative (and definiteness marking) uses of poss.3sg suffixes in Uralic languages. Finally, my results are also an important contribution to the debate on whether demonstratives can be derived from other functional elements through grammaticalization (Plank 1979; Traugott 1982; Himmelmann 1997).     

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.     

Plural exponence in the Nez Perce DP: a DM analysis

This paper analyzes two patterns of number marking in the DP in Nez Perce (Sahaptian) within the framework of Distributed Morphology. The first involves under-realization of plural on nouns. Number has classically been understood as a feature inherent to nouns, rather than to adjectives that modify them. In Nez Perce, however, only a small set of nouns show number morphology, whereas number morphology is highly productive on adjectival modifiers. Adjectives in fact may realize the plural more than once per word—an instance of multiple exponence. I show that the puzzle of under-realization for nouns can be solved through conditioned allomorphy, providing new evidence for the presence of gender features on n (Lowenstamm 2007; Kramer 2014). The puzzle of multiple exponence (over-realization) for adjectives can be solved through Local Dislocation (Embick and Noyer 2001) combined with very late insertion of reduplicative content (Haugen 2008, 2011), demonstrating one way the DM architecture may produce multiple exponence without recourse to dedicated mechanisms.     

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.     

Verb-noun compounds in Italian from the 16th century onwards: an increasing exploitation of an available word-formation pattern

Verb-noun compounds are typically considered to be one of the most important innovations in the domain of Romance word-formation (cf. Bauer 2011, among many others). This morphological innovation can also be seen as part of a general tendency in Romance languages to prefer head-initial structures across different levels of the language system (cf., e.g., Ledgeway 2012: 225). However, the question of the productivity of VN compounds arises immediately as there is evidence that the pattern has become extremely productive only recently. This paper investigates the question of the productivity of the VN compounds starting out with a distinction between availability of a word-formation pattern and its profitability (cf., e.g., Bauer 2001). This article shows that the structural presence—availability—of VN compounding seems to be diachronically constant, but that the quantitative exploitation of the pattern—its profitability—turns out to be a recent phenomenon. Following recent research on compounding in Spanish (Moyna 2011) and French (Rosenberg 2007, 2008, 2011), this paper takes one concrete example of the Italian VN compounds and proceeds to show its diachronic evolution from the 16th to the 19th century on the basis of data drawn from diachronic corpora as well as from major historical dictionaries. It demonstrates that the “dramatic increase” alluded to by Bauer (2011: 543) is not to be taken as a sign of a new structural innovation, but rather as a fortuitous exploitation of a well-settled word-formation pattern.     

IFN-γ production in response to <Emphasis Type="Italic">in vitro</Emphasis> stimulation with collagen type II in rheumatoid arthritis is associated with HLA-DRB1<Superscript>*</Superscript>0401 and HLA-DQ8

Introduction

Despite much work over past decades, whether antigen-specific immune reactions occur in rheumatoid arthritis (RA) and to what extent such reactions are directed towards joint-specific autoantigens is still questionable. One strong indicator for antigenic involvement in RA is the fact that certain major histocompatibility complex (MHC) class II genotypes [human leucocyte antigen (HLA)-DR4 and HLA-DR1] predispose for the development of the disease [1]. In the present report, collagen type II (CII) was studied as a putative autoantigen on the basis of both clinical and experimental data that show an increased frequency of antibodies to CII in RA patients [2,3,4] and that show that CII can induce experimental arthritis [5].It is evident from the literature that RA peripheral blood mononuclear cells (PBMCs) respond poorly to antigenic stimulation [6,7,8], and in particular evidence for a partial tolerization to CII has been presented [9]. The strategy of the present work has accordingly been to reinvestigate T-cell reactivity to CII in RA patients, to relate it to the response to commonly used recall antigens and to analyze IFN-γ responses as an alternative to proliferative responses.     

First record of <Emphasis Type="Italic">Pojetaia runnegari</Emphasis> Jell, 1980 and <Emphasis Type="Italic">Fordilla</Emphasis> Barrande, 1881 from the Middle East (Taurus Mountains,Turkey) and critical review of Cambrian bivalves

Cambrian bivalves from the Middle East are reported here for the first time. They come from early “Middle Cambrian” and latest “Early Cambrian” limestones of the lower Çal Tepe Formation at the type locality (near Seydi?ehir, western Taurides). The majority of the new findings consists of Pojetaia runnegari Jell, 1980, but a few specimens of Fordilla sp. represent the first report of this genus from “Middle Cambrian” strata. Based on a compilation of the hitherto reported, but mostly revised Cambrian bivalves, the today widely accepted taxa are discussed. The genera Pojetaia Jell, 1980 and Fordilla Barrande, 1881 are critically evaluated, and three valid species are included in Pojetaia: P. runnegari Jell, 1980, P. sarhroensis Geyer and Streng, 1998, and—with limitations—P. ostseensis Hinz-Schallreuter, 1995. Fordilla also includes three species: F. troyensis Barrande, 1881, F. sibirica Krasilova, 1977, and F. germanica Elicki, 1994. The Cambrian genera Tuarangia MacKinnon, 1982, Camya Hinz-Schallreuter, 1995, and Arhouriella Geyer and Streng, 1998 most probably belong to the class Bivalvia. Palaeoecologically, the Cambrian bivalves of the Western Perigondwanan shelf seem to occur in a relatively small window of low-energy, subtidal, open-marine, warm-water conditions on a muddy carbonate ramp or platform with reduced sedimentation rate. The frequently interpreted infaunal mode of life of Pojetaia and Fordilla is questioned by observations of similarly organized modern bivalves. The palaeogeographical distribution of Pojetaia and Fordilla is discussed with respect to their early ontogeny and to differences in the recent state of knowledge on shelly fossils from Cambrian carbonate successions of Perigondwana.     

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.

     

Production of Estonian case-inflected nouns shows whole-word frequency and paradigmatic effects

Most psycholinguistic models of lexical processing assume that the comprehension and production of inflected forms is mediated by morphemic constituents. Several more recent studies, however, have challenged this assumption by providing empirical evidence that information about individual inflected forms and their paradigmatic relations is available in long-term memory (Baayen et al. 1997; Milin et al. 2009a, 2009b). Here, we investigate how whole-word frequency, inflectional paradigm size and morphological family size affect production latencies and articulation durations when subjects are asked to read aloud isolated Estonian case-inflected nouns. In Experiment 1, we observed that words with a larger morphological family elicited shorter speech onset latencies, and that forms with higher whole-word frequency had shorter acoustic durations. Experiment 2, for which we increased statistical power by using 2,800 words, revealed that higher whole-word frequency, inflectional paradigm size, and morphological family size reduced both speech onset times and acoustic durations. These results extend our knowledge of morphological processing in three ways. First, whole-word frequency effects of inflected forms in morphologically rich languages are not restricted to a small number of very high-frequency forms, contrary to previous claims (Niemi et al. 1994; Hankamer 1989; Yang 2016). Second, we replicated the morphological family size effect in a new domain, the acoustic durations of inflected forms. Third, we showed that a novel paradigmatic measure, inflectional paradigm size, predicts word naming latencies and acoustic durations. These results fit well with Word-and-Paradigm morphology (Blevins 2016) and argue against strictly (de)compositional models of lexical processing.     

Aspect and modality in the interpretation of deverbal -<Emphasis Type="Italic">er</Emphasis> nominals in English

This article presents a corpus study of over 16,000 tokens of -er nominalizations on 62 verbal bases that were extracted from the Corpus of Contemporary American English and the British National Corpus. We show that an individual -er nominal can often be given a range of modal and aspectual readings and that a number of factors influence the availability of different readings for -er nominals, including verb type, syntactic context (verb tenses, adverbs), and encyclopedic information. On the basis of these data, we argue, contra Cohen (2016), that the core meaning of the affix -er (as in writer, printer, etc.) cannot be that of a dynamic modal. We show that neither Cohen’s (2016) analysis nor syntactic analyses such as that of Alexiadou and Schäfer (2010) can account for the range of readings we find. We conclude by sketching one possible analysis in terms of the Lexical Semantic Framework of Lieber (2004, 2016) that postulates underspecified lexical representations of the -er nominals and resolution of underspecification in context.     

Spinicaudata (“Conchostraca,” Crustacea) from the Middle Keuper (Upper Triassic) of the southern Germanic Basin,with a review of Carnian–Norian taxa and suggested biozones

The Coburg Sandstone member of the Hassberge Formation, Middle Keuper, Carnian, Upper Triassic, in the Germanic Basin of Central Europe contains spinicaudatan branchiopods which considerably broaden the known spectrum and provide important data on the phylogenetic history and intercontinental correlation of this systematic group. The spinicaudatan fauna for this lithostratigraphic unit is described in detail and includes Euestheria kozuri sp. nov., E.? sp. nov. A, Gregoriusella striatula sp. nov., Laxitextella freybergi Kelber and Kozur in Kozur and Weems, 2007, L. dorsorecta (Reible, 1962), and Laxitextella? sp. A. Additional discussions deal with Euestheria multicostata (Geyer, 1987), E. winterpockensis (Bock, 1953a), Laxitextella laxitexta (Sandberger in Jones, 1890), Laxitextella multireticulata (Reible, 1962), and “Laxitextella? hausmanni (Schmidt, 1938),” as well as problems with (sub)global zonations that are based on spinicaudatans and suggested to be of Carnian and Norian age.     

New Species and New Records of Eriophyoid Mites (Acari: Eriophyoidea) from West Bengal,India

Two new species viz., Acaricalus indicus n. sp. from Fern (indet) and Neooxycenus dilleniae n. sp. from Dillenia pentagyna Roxb. (Dilleniaceae) are described from West Bengal. Four species viz., Acaphyllisa araucuriae Flechtmann (2000), Aculops pretoriensis Smith Meyer and Ueckermann (1990), Tetra tyrohylae Smith Meyer (1992) and Tetra visci Smith Meyer (1992) are recorded for the first time from India. Besides, 23 other species are reported for the first time from West Bengal. An eriophyoid species is recorded for the first time from a species of Fern in India.     

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.

     

Theoretical study of the interaction between molecular oxygen and tetraaza macrocyclic manganese complexes

Theoretical chemistry calculations using the Density Functional Theory (DFT) were carried out to understand the interaction between oxygen (O₂) and MnN₄ type manganese-based complexes during the formation of MnN₄-O₂ adducts. In order to understand how this interaction is affected by different macrocyclic ligands, O₂ was bonded to manganese-porphyrin (MnP), manganese-octamethylporphyrin (MnOMP), manganese-tetraaza[14]annulene (MnTAA), manganese-dibenzo [b,i] [1, 4, 8, 11]-tetraaza [14] annulene (MnDBTAA), manganese-2,3,9,10-tetramethyl-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene ([(tim)Mn]²⁺), and manganese-2,3,9,10-tetraphenyl-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene ([(ph-tim)Mn]²⁺). The binding and activation of the oxygen molecule was facilitated by an increasing trend in the O-O bond lengths and a decreasing one in the O-O vibrational frequency, with preference for the O₂ side-on interaction among MnN₄ macrocycles. The catalytic activities of the MnN₄ complexes toward the O₂ binding process increased in the following order: [(ph-tim)Mn]²⁺?<?MnP?<?MnOMP?<?MnDBTAA?<?MnTAA?<?[(tim)Mn]²⁺. Therefore, it was concluded that the [(tim)Mn]²⁺complex was the most active for the binding and activation of molecular oxygen.     

Towards a theory without adjacency: hyper-contextual VI-rules

It has been proposed that allomorphy and suppletion is restricted not only by (various conceptions of) cyclic locality, but also by adjacency of elements. Embick (2010) proposes that two elements can only enter into an relationship of allomorphy if they are linearly adjacent to each other, whereas Adger et al. (2003) and Bobaljik (2012) argue that elements must be structurally adjacent.In this paper, we show that there are both empirical and conceptual problems for adjacency based theories and we argue instead in favour of a cyclic locality only view; whereby allomorphic relations are not universally sensitive to adjacency restrictions. Apparent arguments in favour of adjacency are shown to be the result accessibility or of ‘hyper-contextual’ rules of vocabulary insertion, which make reference to multiple nodes, which combine together to serve as the context for suppletion.