An analysis of a ‘community-driven’ reconstruction of the human metabolic network

Following a strategy similar to that used in baker’s yeast (Herrgård et al. Nat Biotechnol 26:1155–1160, 2008). A consensus yeast metabolic network obtained from a community approach to systems biology (Herrgård et al. 2008; Dobson et al. BMC Syst Biol 4:145, 2010). Further developments towards a genome-scale metabolic model of yeast (Dobson et al. 2010; Heavner et al. BMC Syst Biol 6:55, 2012). Yeast 5—an expanded reconstruction of the Saccharomyces cerevisiae metabolic network (Heavner et al. 2012) and in Salmonella typhimurium (Thiele et al. BMC Syst Biol 5:8, 2011). A community effort towards a knowledge-base and mathematical model of the human pathogen Salmonella typhimurium LT2 (Thiele et al. 2011), a recent paper (Thiele et al. Nat Biotechnol 31:419–425, 2013). A community-driven global reconstruction of human metabolism (Thiele et al. 2013) described a much improved ‘community consensus’ reconstruction of the human metabolic network, called Recon 2, and the authors (that include the present ones) have made it freely available via a database at http://humanmetabolism.org/ and in SBML format at Biomodels (http://identifiers.org/biomodels.db/MODEL1109130000). This short analysis summarises the main findings, and suggests some approaches that will be able to exploit the availability of this model to advantage.     

A model of direction selectivity in the starburst amacrine cell network

Displaced starburst amacrine cells (SACs) are retinal interneurons that exhibit GABA _A receptor-mediated and Cl ^? cotransporter-mediated, directionally selective (DS) light responses in the rabbit retina. They depolarize to stimuli that move centrifugally through the receptive field surround and hyperpolarize to stimuli that move centripetally through the surround (Gavrikov et al, PNAS 100(26):16047–16052, 2003, PNAS 103(49):18793–18798, 2006). They also play a key role in the activity of DS ganglion cells (DS GC; Amthor et al, Vis Neurosci 19:495–509 2002; Euler et al, Nature 418:845–852, 2002; Fried et al, Nature 420:411– 414, 2002; Gavrikov et al, PNAS 100(26):16047–16052, 2003, PNAS 103(49):18793–18798, 2006; Lee and Zhou, Neuron 51:787–799 2006; Yoshida et al, Neuron 30:771–780, 2001). In this paper we present a model of strong DS behavior of SACs which relies on the GABA-mediated communication within a tightly interconnected network of these cells and on the glutamate signal that the SACs receive from bipolar cells (a presynaptic cell that receives input from cones). We describe how a moving light stimulus can produce a large, sustained depolarization of the SAC dendritic tips that point in the direction that the stimulus moves (i.e., centrifugal motion), but produce a minimal depolarization of the dendritic tips that point in the opposite direction (i.e., centripetal motion). This DS behavior, which is quantified based on the relative size and duration of the depolarizations evoked by stimulus motion at dendritic tips pointing in opposite directions, is robust to changes of many different parameter values and consistent with experimental data. In addition, the DS behavior is strengthened under the assumptions that the Cl^? cotransporters Na^?+?-K^?+?-Cl^?? and K^?+?-Cl^?? are located in different regions of the SAC dendritic tree (Gavrikov et al, PNAS 103(49):18793–18798, 2006) and that GABA evokes a long-lasting response (Gavrikov et al, PNAS 100(26):16047–16052, 2003, PNAS 103(49):18793–18798, 2006; Lee and Zhou, Neuron 51:787–799, 2006). A possible mechanism is discussed based on the generation of waves of local glutamate and GABA secretion, and their postsynaptic interplay as the waves travel between cell compartments.     

Heckerocrinus, a new substitute generic name for fossil crinoid Bockia Hecker 1940 (Echinodermata: Crinoidea) non Reisinger 1924 (Vermes: Turbellaria)

Heckerocrinus nom. nov., a new generic name of fossil Ordovician crinoid, is proposed for preoccupied fossil generic name Bockia Hecker 1940 non Reisinger 1924 [Vermes: Turbellaria??Typhloplanidae-Protoplanellinae]. Illegitimate family name Bockiidae Ubaghs 1972 is replaced with a new valid family name Heckerocrinidae nom. nov.     

The (Paleo)Geography of Evolution: Making Sense of Changing Biology and Changing Continents

During the voyage of the H.M.S. Beagle, Charles Darwin quickly realized that geographic isolation led to significant changes in the adaptation of local flora and fauna (Darwin 1859). Genetic isolation is one of the well-known mechanisms by which adaptation (allopatric speciation) can occur (Palumbi, Annu Rev Ecol Syst 25:547?C72, 1994; Ricklefs, J Avian Biol 33:207?C11, 2002; Burns et al., Evolution 56:1240?C52, 2002; Hendry et al., Science 290:516?C8, 2009). Evolutionary changes can also occur when landmasses converge or are ??bridged.?? An important and relatively recent (Pliocene Epoch) example known as the ??Great American Biotic Interchange?? allowed for the migration of previously isolated species into new ecological niches between North and South America (Webb 1985, Ann Mo Bot Gard 93:245?C57, 2006; Kirby and MacFadden, Palaeogeogr Palaeoclimatol Palaeoecol 228:193?C202, 2005). Geographic isolation (vicariance) or geographic merging (geodispersal) can occur for a variety of reasons (sea level rise, splitting of continents, mountain building). In addition, the growth of a large supercontinent (or breakup) may change the climatic zonation on the globe and form a different type of barrier for species migration. This short review paper focuses on changing paleogeography throughout the Phanerozoic and the close ties between paleogeography and the evolutionary history of life on Earth.     

Constructions and headedness in derivation and compounding

The ??traditional?? distinction of compounds into endocentric (Eng. doorknob) and exocentric (pickpocket) is based on the presence or absence of a head constituent (Bloomfield, Language, Holt, New York, 1933); since the early eighties, the syntactic notion of ??head?? has been extended also to derivation, claiming that English derivational suffixes, as e.g. -ness, are heads, either in an absolute sense or in a categorial sense (see Williams Linguist Inq 12:245?C274, 1981; Lieber On the organization of the lexicon, Indiana university Linguistics Club, Bloomington, 1981; Lieber, in Yearbook of morphology 1989, Foris, Dordrecht, 1989; among others). In this paper, we shall first review some key issues in the morphological notion of head, illustrating well-known problematic cases, and then we shall discuss the Construction Morphology approach to headedness in derivation and compounding (Booij in The Oxford handbook of compounding, Oxford University Press, Oxford, 2009; Booij, in Cross-disciplinary issues in compounding, John Benjamins, Amsterdam, 2010a, 2010 Booij, Construction morphology, Oxford University Press, Oxford, 2010b). The stipulation of a hierarchical lexicon with subschemas expressing intermediate generalizations is a powerful theoretical device in accounting for a phenomenon as headedness variation, as we shall show with a Vietnamese case study; also, inconsistencies in word-class assignment in derivation will be dealt with in a constructionist perspective. Moreover, we shall discuss the consequences of a constructionist approach to the distinction between compounding and derivation.     

Alien shrimps in evidence: new records of the genus Athanas Leach, 1814 on the coast of S?o Paulo, southern Brazil (Caridea: Alpheidae)

The occurrence of two alien alpheid shrimps of the genus Athanas Leach, 1814 [in Leach 1813–1814], the Indo-West Pacific A. dimorphus Ortmann, 1894 and the Eastern Atlantic A. nitescens (Leach, 1813 [in Leach 1813–1814]), on the coast of the state of S?o Paulo, Brazil, is reported. The presence of A. dimorphus extends the range of this species in the western Atlantic farther to the south in Brazil, whereas A. nitescens is reported for the first time in the western Atlantic, representing the second alien alpheid species on this side of the Atlantic and the twenty-first decapod crustacean introduced in Brazil. We provide morphological accounts of the material examined and illustrate the most important diagnostic characters of both species. An overview of the possible mechanisms of their introduction on the coast of S?o Paulo is also provided.     

Neural Crest and Olfactory System: New Prospective

Sensory neurons in vertebrates are derived from two embryonic transient cell sources: neural crest (NC) and ectodermal placodes. The placodes are thickenings of ectodermal tissue that are responsible for the formation of cranial ganglia as well as complex sensory organs that include the lens, inner ear, and olfactory epithelium. The NC cells have been indicated to arise at the edges of the neural plate/dorsal neural tube, from both the neural plate and the epidermis in response to reciprocal interactions Moury and Jacobson (Dev Biol 141:243?C253, 1990). NC cells migrate throughout the organism and give rise to a multitude of cell types that include melanocytes, cartilage and connective tissue of the head, components of the cranial nerves, the dorsal root ganglia, and Schwann cells. The embryonic definition of these two transient populations and their relative contribution to the formation of sensory organs has been investigated and debated for several decades (Basch and Bronner-Fraser, Adv Exp Med Biol 589:24?C31, 2006; Basch et al., Nature 441:218?C222, 2006) review (Baker and Bronner-Fraser, Dev Biol 232:1?C61, 2001). Historically, all placodes have been described as exclusively derived from non-neural ectodermal progenitors. Recent genetic fate-mapping studies suggested a NC contribution to the olfactory placodes (OP) as well as the otic (auditory) placodes in rodents (Murdoch and Roskams, J Neurosci Off J Soc Neurosci 28:4271?C4282, 2008; Murdoch et al., J Neurosci 30:9523?C9532, 2010; Forni et al., J Neurosci Off J Soc Neurosci 31:6915?C6927, 2011b; Freyer et al., Development 138:5403?C5414, 2011; Katoh et al., Mol Brain 4:34, 2011). This review analyzes and discusses some recent developmental studies on the OP, placodal derivatives, and olfactory system.     

Two ants (Insecta: Hymenoptera: Formicidae: Formicinae) from the Late Pliocene of Willershausen, Germany, with a nomenclatural note on the genus Camponotites

Two species of the genus Camponotites (Formicidae, Formicinae) are described from the Late Pliocene deposits of Willershausen, Lower Saxony, northern Germany: C. silvestris Steinbach, 1967, and C. steinbachi n. sp. The generic name Camponotites has been established for fossil (Tertiary) ants independently by Steinbach (Bericht der Naturhistorischen Gesellschaft zu Hannover 111:95–102, 1967) and by Dlussky (Trudy paleontologi?eskogo instituta, akademiâ nauk SSSR, 1981), each for materials of different stratigraphical and geographical origin. Though poorly described, Camponotites Steinbach, 1967, and the single included (type) species C. silvestris Steinbach, 1967 (a monotypic species from the Late Pliocene of Willershausen), were based upon indication in the sense of the ICZN. Therefore, both the generic and specific names are valid and available. Camponotites Dlussky, 1981 (and its type species C. macropterus Dlussky, 1981) were certainly introduced correctly and are therefore available, too; but due to its homonymy the generic name is not valid. The revision shows that in this rare case both generic names are not only homonyms but also synonyms.     

Integrating participatory approaches into social life cycle assessment: the SLCA participatory approach

Purpose

This article discusses the choice of stakeholder categories and the integration of stakeholders into participatory processes to define impact categories and select indicators.

Methods

We undertook a literature review concerning the roles and the importance of stakeholders in participatory processes, and the use of such processes in environmental and social LCAs (Biswas et al. Int J Life Cycle Assess 3(4):184-190, 1998; Sonnemann et al. Int J Life Cycle Assess 6(6):325-333, 2001; Baldo Int J Life Cycle Assess 7(5):269-275, 2002; James et al. Int J Life Cycle Assess 7(3):151-157, 2002; Bras-Kapwijk Int J Life Cycle Assess 8(5):266-272, 2003; Mettier et al. Int J Life Cycle Assess 11(6):468-476, 2006). As part of the French National Research Agency Piscenlit project, we adapted the Principle, Criteria, Indicator (PCI) method (Rey-Valette et al. 2008), which is an assessment method of sustainable development, as a way to integrate the participatory approach into Social Life Cycle Assessment (SLCA) methodology, mainly at the impact definition stage.

Results and discussion

Different views of participation were found in the literature; there is no consensual normative approach for the implication of stakeholders in LCA development. Some attempts have been made to integrate stakeholders into environmental LCAs but these attempts have not been generalized. However, they strongly emphasize the interrelationship between research on the growing integration of stakeholders and on the choice of stakeholders. We then propose criteria from stakeholder theory (Freeman 1984; Mitchell et al. Acad Manage Rev 22(4):853-886, 1997; Geibler et al. Bus Strat Environ 15:334-346, 2006) in order to identify relevant stakeholders for SLCA participatory approach. The adaptation of the PCI method to Principles, Impacts, and Indicators (PII) enables stakeholders to express themselves and hence leads to definitions of relevant social indicators that they can appropriate. The paper presents results regarding the selection of stakeholders but no specific results regarding the choice of impact categories and indicators.

Conclusions and recommendations

Integrating a participatory approach into SLCAs is of interest at several levels. It enables various factors to be taken into account: plurality of stakeholder interests, local knowledge, and impact categories that make sense for stakeholders in different contexts. It also promotes dialogue and simplifies the search for indicators. However, it requires a multidisciplinary approach and the integration of new knowledge and skills for the SLCA practitioners.     

Thanetian gastropods from the Mesopotamian high folded zone in northern Iraq

An assemblage of gastropods from the Thanetian of the Kolosh Formation from the Zakho region in northern Iraq is documented for the first time. The ten species represent the families Campanilidae Douvillé 1904, Potamididae H. & A. Adams 1854, Batillariidae Thiele 1929, Thiaridae Gill 1871, Pachychilidae Fischer & Crosse 1892, Cerithiidae Fleming 1822 and Pseudolividae de Gregorio 1880, suggesting a littoral to shallow sublittoral depositional environment. Six of the species are new and five are formally described as new species. At least seven species are also known from the Thanetian and/or Early Ypresian of the Ankara region in Turkey. Only a single species occurs also in the Paleocene of the Paris Basin. No relation to Paleocene and Eocene faunas of Pakistan and India is detectable. This points to a considerably bioprovincialism along the northern coast of the Tethys. Consequently we suppose the existence of an Anatolian Province in the Thanetian/Ypresian Mediterranean Region of the Tethys Realm, represented by rather homogeneous mollusc faunas from western Turkey and northern Iraq. Campanile zakhoense nov. sp., Pyrazopsis hexagonpyramidalis nov. sp., Pachymelania islamogluae nov. sp., “Faunus” dominicii nov. sp. and Pseudoaluco mesopotamicus nov. sp. are introduced as new species. Varicipotamides Pacaud & Harzhauser nov. nom. is proposed as the replacement name for Exechestoma Cossmann (1889) non Brandt (1837).     

Taxonomic review of Kyphosus (Pisces: Kyphosidae) in the Atlantic and Eastern Pacific Oceans

The taxonomy of the Atlantic and Eastern Pacific species of Kyphosus is reviewed with K. bosquii (Lacepède 1802), K. incisor (Cuvier 1831), K. analogus (Gill 1862) and K. elegans (Peters 1869) considered valid, and K. atlanticus sp. nov. newly described. Kyphosus bosquii and K. atlanticus are both characterized by 12 dorsal- and 11 anal-fin soft rays, but differ in the number of longitudinal scale rows along the midbody (61–66, mode 63 vs. 50–56, mode 54). Kyphosus incisor and K. analogus, characterized by 14 dorsal- and 13 anal-fin soft rays, similarly differ from each other in midbody longitudinal scale row counts (57–64, mode 60 vs. 68–74, mode 70 or 72). Kyphosus elegans is characterized by 13 dorsal- and 12 anal-fin soft rays, and 51–57 midbody longitudinal scale rows. Kyphosus bosquii, K. atlanticus and K. incisor are distributed in the Atlantic Ocean, K. analogus and K. elegans occurring in the Eastern Pacific. The holotype of Pimelepterus flavolineatus Poey 1866, here regarded as a junior synonym of K. incisor, was located within a collection of Cuban fishes donated to the Smithsonian Institution by Poey in 1873. A neotype is designated here for K. analogus. Pimelepterus gallveii Cunningham 1910, Kyphosus palpebrosus Miranda-Ribeiro 1919 and K. metzelaari Jordan and Evermann 1927 are recognized as junior synonyms of K. bosquii. Pimelepterus sandwicensis Sauvage 1880 is a junior synonym of K. elegans. Perca saltatrix Linnaeus 1758, together with the replacement name Perca sectatrix Linnaeus 1766, is regarded as nomina dubia.     

Neither touch nor vision: sensory substitution as artificial synaesthesia?

Block (Trends Cogn Sci 7:285–286, 2003) and Prinz (PSYCHE 12:1–19, 2006) have defended the idea that SSD perception remains in the substituting modality (auditory or tactile). Hurley and Noë (Biol Philos 18:131–168, 2003) instead argued that after substantial training with the device, the perceptual experience that the SSD user enjoys undergoes a change, switching from tactile/auditory to visual. This debate has unfolded in something like a stalemate where, I will argue, it has become difficult to determine whether the perception acquired through the coupling with an SSD remains in the substituting or the substituted modality. Within this puzzling deadlock two new approaches have been recently suggested. Ward and Meijer (Conscious Cogn 19:492–500, 2010) describe SSD perception as visual-like but characterize it as a kind of artificially induced synaesthesia. Auvray et al. (Perception 36:416–430, 2007) and Auvray and Myin (Cogn Sci 33:1036–1058, 2009) suggest that SSDs let their users experience a new kind of perception. Deroy and Auvray (forthcoming) refine this position, and argue that this new kind of perception depends on pre-existing senses without entirely aligning with any of them. So, they have talked about perceptual experience in SSDs as going "beyond vision". In a similar vein, MacPherson (Oxford University Press, New York, 2011a) claims that “if the subjects (SSD users) have experiences with both vision-like and touch-like representational characteristics then perhaps they have a sense that ordinary humans do not” (MacPherson in Oxford University Press, New York, 2011a, p. 139).     

Stukalinia, a new substitute generic name for fossil crinoid Lobocrinus Stukalina non Wachsmuth and Springer 1897 (Echinodermata: Crinoidea)

A new generic name, Stukalinia nom. nov., is proposed for a fossil Ordoviacian crinoid that currently has the preoccupied fossil generic name Lobocrinus Stukalina 1982 non Wachsmuth and Springer (1897), along with a new family name, Stukaliniidae nom. nov., instead of the illegitimate family name Lobocrinidae Stukalina (1982).     

A radically non-morphemic approach to bidirectional syncretism

This paper addresses the question of how certain kinds of overlapping syncretisms in inflectional paradigms can be accounted for that Baerman et al. (Language 80:807–824, 2005) refer to as convergent/divergent bidirectional syncretisms (based on earlier work by Stump, Inflectional morphology, 2001). Bidirectional syncretism strongly resists accounts in terms of standard rules of exponence (or similar devices) that correlate inflection markers with (often underspecified) morpho-syntactic specifications (such rules are used in many morphological theories; e.g., Anderson, A-morphous morphology, 1992; Halle and Marantz in The view from building, pp. 111–176, 1993; Aronoff, Morphology by itself, 1994; Wunderlich in Yearbook of morphology 1995, pp. 93–114, 1996; and Stump, Inflectional morphology, 2001). The reason is that it is difficult to capture overlapping distributions by natural classes. In view of this, rules of referral have been proposed to derive bidirectional syncretism (Stump, Inflectional morphology, 2001; Baerman et al. (Language 80:807–824, 2005)). In contrast, I would like to pursue the hypothesis that systematic instances of overlapping syncretism ultimately motivate a new approach to inflectional morphology—one that fully dispenses with the assumption that morphological exponents are paired with morpho-syntactic feature specifications (and that therefore qualifies as radically non-morphemic): First, rules of exponence are replaced with feature co-occurrence restrictions (FCRs; Gazdar et al., Generalized Phrase Structure Grammar, 1985). For phonologically determined natural classes of exponents, FCRs state incompatibilites with morpho-syntactic feature specifications. Second, marker competition is resolved by a principle of Phonology-driven Marker Selection (PMS). PMS takes over the role of the Specificity (Blocking, Elsewhere, Panini) Principle of standard analyses. Empirically, the main focus is on Bonan declension; the analysis is subsequently extended to Gujarati conjugation and Latin o-declension, with further remarks on bidirectional syncretism in other inflectional paradigms.     

Leucothoid and Maerid Amphipods (Crustacea) from deep regions of the North Atlantic

From amphipod collections from the deep Norwegian Sea, three species are here redescribed: Maera loveni (Bruzelius 1859) (Maeridae), Leucothoe aff. spinicarpa (Abildgaard, 1789) and L. uschakovi Gurjanova, 1951 (Leucothoidae). A key to all Atlantic and Mediterranean Leucothoe species (males only) is provided.     

Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene

MYH9 has been proposed as a major genetic risk locus for a spectrum of nondiabetic end stage kidney disease (ESKD). We use recently released sequences from the 1000 Genomes Project to identify two western African-specific missense mutations (S342G and I384M) in the neighboring APOL1 gene, and demonstrate that these are more strongly associated with ESKD than previously reported MYH9 variants. The APOL1 gene product, apolipoprotein L-1, has been studied for its roles in trypanosomal lysis, autophagic cell death, lipid metabolism, as well as vascular and other biological activities. We also show that the distribution of these newly identified APOL1 risk variants in African populations is consistent with the pattern of African ancestry ESKD risk previously attributed to MYH9. Mapping by admixture linkage disequilibrium (MALD) localized an interval on chromosome 22, in a region that includes the MYH9 gene, which was shown to contain African ancestry risk variants associated with certain forms of ESKD (Kao et al. 2008; Kopp et al. 2008). MYH9 encodes nonmuscle myosin heavy chain IIa, a major cytoskeletal nanomotor protein expressed in many cell types, including podocyte cells of the renal glomerulus. Moreover, 39 different coding region mutations in MYH9 have been identified in patients with a group of rare syndromes, collectively termed the Giant Platelet Syndromes, with clear autosomal dominant inheritance, and various clinical manifestations, sometimes also including glomerular pathology and chronic kidney disease (Kopp 2010; Sekine et al. 2010). Accordingly, MYH9 was further explored in these studies as the leading candidate gene responsible for the MALD signal. Dense mapping of MYH9 identified individual single nucleotide polymorphisms (SNPs) and sets of such SNPs grouped as haplotypes that were found to be highly associated with a large and important group of ESKD risk phenotypes, which as a consequence were designated as MYH9-associated nephropathies (Bostrom and Freedman 2010). These included HIV-associated nephropathy (HIVAN), primary nonmonogenic forms of focal segmental glomerulosclerosis, and hypertension affiliated chronic kidney disease not attributed to other etiologies (Bostrom and Freedman 2010). The MYH9 SNP and haplotype associations observed with these forms of ESKD yielded the largest odds ratios (OR) reported to date for the association of common variants with common disease risk (Winkler et al. 2010). Two specific MYH9 variants (rs5750250 of S-haplotype and rs11912763 of F-haplotype) were designated as most strongly predictive on the basis of Receiver Operating Characteristic analysis (Nelson et al. 2010). These MYH9 association studies were then also extended to earlier stage and related kidney disease phenotypes and to population groups with varying degrees of recent African ancestry admixture (Behar et al. 2010; Freedman et al. 2009a, b; Nelson et al. 2010), and led to the expectation of finding a functional African ancestry causative variant within MYH9. However, despite intensive efforts including re-sequencing of the MYH9 gene no suggested functional mutation has been identified (Nelson et al. 2010; Winkler et al. 2010). This led us to re-examine the interval surrounding MYH9 and to the detection of novel missense mutations with predicted functional effects in the neighboring APOL1 gene, which are significantly more associated with ESKD than all previously reported SNPs in MYH9.     

Typical Cyclical Behavioural Patterns: The Case of Routines,Rituals and Celebrations

The dynamics inherent to the life activity of all living systems presents itself in the form of regular patterns viewed by the observer as taking place in an extended timeline. Routines, rituals and celebrations, each in their own way, are defined by the typical cyclical behavioural patterns exhibited by individuals embedded in specific semiospheres. The particular nature of these semiospheres will determine the distinct patterns of behaviour to be adopted in different life contexts so that existential functions are fulfilled. The restricted and protected family circle normally provides the initial learning environment where the definition of the individual’s Umwelt (von Uexküll 1909, 1934; Ferreira, Biosemiotics 3(1):107–130, 2010, 2011) his/her meaningful world, starts to take shape. This learning process comprehends the progressive identification of distinct physical entities, the development of basic patterns of physical and social behaviour- the incorporation of basic routines and the assignment of meaning to particular events.     

Mitochondrial complex I inhibitors, acetogenins, induce HepG2 cell death through the induction of the complete apoptotic mitochondrial pathway

The development of new anti-neoplastic drugs is a key issue for cancer chemotherapy due to the reality that, most likely, certain cancer cells are resistant to current chemotherapy. The past two decades have witnessed tremendous advances in our understanding of the pathogenesis of cancer. These advances have allowed identification new targets as oncogenes, tumor supressor genes and the possible implication of the mitochondria (Fulda et al. Nat Rev Drug Discov 9:447–464, 2010). Annonaceous Acetogenins (ACGs) have been described as the most potent inhibitors of the respiratory chain because of their interaction with mitochondrial Complex I (Degli Esposti and Ghelli Biochim Biophys Acta 1187:116–120, 1994; Zafra-Polo et al. Phytochemistry 42:253–271, 1996; Miyoshi et al. Biochim Biophys Acta 1365:443–452, 1998; Tormo et al. Arch Biochem Biophys 369:119–126, 1999; Motoyama et al. Bioorg Med Chem Lett 12:2089–2092, 2002). To explore a possible application of natural products from Annonaceous plants to cancer treatment, we have selected four bis-tetrahydrofuranic ACGs, three from Annona cherimolia (cherimolin-1, motrilin and laherradurin) and one from Rollinia mucosa (rollinianstatin-1) in order to fully describe their mechanisms responsible within the cell (Fig. 1). In this study, using a hepato-carcinoma cell line (HepG2) as a model, we showed that the bis-THF ACGs caused cell death through the induction of the apoptotic mitochondrial pathway. Their potency and behavior were compared with the classical mitochondrial respiratory chain Complex I inhibitor rotenone in every apoptotic pathway step.