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.     

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.     

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.     

Leges sine moribus vanae: does language make moral thinking possible?

Does language make moral cognition possible? Some authors like Andy Clark have argued for a positive answer whereby language and the ways people use it mark a fundamental divide between humans and all other animals with respect to moral thinking (Clark, Mind and morals: essays on cognitive science and ethics. MIT Press, Cambridge, MA, 1996; Moral Epistemol Nat Can J Philos Suppl XXVI, 2000a; Moral Epistemol Nat Can J Philos Suppl XXVI, 2000b; Philosophy of mental representation. Oxford University Press, Oxford, pp 37–43 and discussion, 44–61, 2002). I take issue with Clark’s view and argue that language is probably unnecessary for the emergence of moral cognition. I acknowledge, however, that humans unlike other animals seem to posses what Haugeland in Philosophy of mental representation. Oxford University Press, Oxford (2002) terms ‘norm-hungriness’: an idiosyncratic need or desire to create and abide by a multitude of norms. Our peculiar norm-hungriness, I suggest, depends on what can be called florid control rather than on language.     

Plant biotechnology for food security and bioeconomy

This year is a special year for plant biotechnology. It was 30 years ago, on January 18 1983, one of the most important dates in the history of plant biotechnology, that three independent groups described Agrobacterium tumefaciens—mediated genetic transformation at the Miami Winter Symposium, leading to the production of normal, fertile transgenic plants (Bevan et al. in Nature 304:184–187, 1983; Fraley et al. in Proc Natl Acad Sci USA 80:4803–4807, 1983; Herrera-Estrella et al. in EMBO J 2:987–995, 1983; Vasil in Plant Cell Rep 27:1432–1440, 2008). Since then, plant biotechnology has rapidly advanced into a useful and valuable tool and has made a significant impact on crop production, development of a biotech industry and the bio-based economy worldwide.     

Axillary bud outgrowth in herbaceous shoots: how do strigolactones fit into the picture?

Strigolactones have recently been identified as the long sought-after signal required to inhibit shoot branching (Gomez-Roldan et al. 2008; Umehara et al. 2008; reviewed in Dun et al. 2009). Here we briefly describe the evidence for strigolactone inhibition of shoot branching and, more extensively, the broader context of this action. We address the central question of why strigolactone mutants exhibit a varied branching phenotype across a wide range of experimental conditions. Where knowledge is available, we highlight the role of other hormones in dictating these phenotypes and describe those instances where our knowledge of known plant hormones and their interactions falls considerably short of explaining the phenotypes. This review will focus on bud outgrowth in herbaceous species because knowledge on the role of strigolactones in shoot branching to date barely extends beyond this group of plants.     

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.     

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.     

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.     

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.     

Feature extraction from spike trains with Bayesian binning: ‘Latency is where the signal starts’

The peristimulus time histogram (PSTH) and its more continuous cousin, the spike density function (SDF) are staples in the analytic toolkit of neurophysiologists. The former is usually obtained by binning spike trains, whereas the standard method for the latter is smoothing with a Gaussian kernel. Selection of a bin width or a kernel size is often done in an relatively arbitrary fashion, even though there have been recent attempts to remedy this situation (DiMatteo et al., Biometrika 88(4):1055–1071, 2001; Shimazaki and Shinomoto 2007a, Neural Comput 19(6):1503–1527, 2007b, c; Cunningham et al. 2008). We develop an exact Bayesian, generative model approach to estimating PSTHs. Advantages of our scheme include automatic complexity control and error bars on its predictions. We show how to perform feature extraction on spike trains in a principled way, exemplified through latency and firing rate posterior distribution evaluations on repeated and single trial data. We also demonstrate using both simulated and real neuronal data that our approach provides a more accurate estimates of the PSTH and the latency than current competing methods. We employ the posterior distributions for an information theoretic analysis of the neural code comprised of latency and firing rate of neurons in high-level visual area STSa. A software implementation of our method is available at the machine learning open source software repository (www.mloss.org, project ‘binsdfc’).     

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.

ORIUM: Optimized RDC-based Iterative and Unified Model-free analysis

Residual dipolar couplings (RDCs) are NMR parameters that provide both structural and dynamic information concerning inter-nuclear vectors, such as N–H^N and Cα–Hα bonds within the protein backbone. Two approaches for extracting this information from RDCs are the model free analysis (MFA) (Meiler et al. in J Am Chem Soc 123:6098–6107, 2001; Peti et al. in J Am Chem Soc 124:5822–5833, 2002) and the direct interpretation of dipolar couplings (DIDCs) (Tolman in J Am Chem Soc 124:12020–12030, 2002). Both methods have been incorporated into iterative schemes, namely the self-consistent RDC based MFA (SCRM) (Lakomek et al. in J Biomol NMR 41:139–155, 2008) and iterative DIDC (Yao et al. in J Phys Chem B 112:6045–6056, 2008), with the goal of removing the influence of structural noise in the MFA and DIDC formulations. Here, we report a new iterative procedure entitled Optimized RDC-based Iterative and Unified Model-free analysis (ORIUM). ORIUM unifies theoretical concepts developed in the MFA, SCRM, and DIDC methods to construct a computationally less demanding approach to determine these structural and dynamic parameters. In all schemes, dynamic averaging reduces the actual magnitude of the alignment tensors complicating the determination of the absolute values for the generalized order parameters. To readdress this scaling issue that has been previously investigated (Lakomek et al. in J Biomol NMR 41:139–155, 2008; Salmon et al. in Angew Chem Int Edit 48:4154–4157, 2009), a new method is presented using only RDC data to establish a lower bound on protein motion, bypassing the requirement of Lipari–Szabo order parameters. ORIUM and the new scaling procedure are applied to the proteins ubiquitin and the third immunoglobulin domain of protein G (GB3). Our results indicate good agreement with the SCRM and iterative DIDC approaches and signify the general applicability of ORIUM and the proposed scaling for the extraction of inter-nuclear vector structural and dynamic content.     

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.     

Manufacturing of peptides exhibiting biological activity

Numerous studies have shown that food proteins may be a source of bioactive peptides. Those peptides are encrypted in the protein sequence. They stay inactive within the parental protein until release by proteolytic enzymes (Mine and Kovacs-Nolan in Worlds Poult Sci J 62(1):87–95, 2006; Hartman and Miesel in Curr Opin Biotechnol 18:163–169, 2007). Once released the bioactive peptides exhibit several biofunctionalities and may serve therapeutic roles in body systems. Opioid peptides, peptides lowering high blood pressure, inhibiting platelet aggregation as well as being carriers of metal ions and peptides with immunostimulatory, antimicrobial and antioxidant activities have been described (Hartman and Miesel in Curr Opin Biotechnol 18:163–169, 2007). The biofunctional abilities of the peptides have therefore aroused a lot of scientific, technological and consumer interest with respect to the role of dietary proteins in controlling and influencing health (Möller et al. in Eur J Nutr 47(4):171–182, 2008). Biopeptides may find wide application in food production, the cosmetics industry as well as in the prevention and treatment of various medical conditions. They are manufactured by chemical and biotechnological methods (Marx in Chem Eng News 83(11):17–24. 2005; Hancock and Sahl in Nat Biotechnol 24(12):1551–1557, 2006). Depending on specific needs (food or pharmaceutical industry) different degrees of peptide purifications are required. This paper discusses the practicability of manufacturing bioactive peptides, especially from food proteins.     

Involvement of apoptosis and proliferation of acinar cells in atrophy of rat parotid glands induced by liquid diet

Parotid glands of experimental animals fed a liquid diet are reported to show atrophy (Hall and Schneyer 1964; Wilborn and Schneyer 1970; Hand and Ho 1981; Scott et al. 1990; Scott and Gunn 1991). To clarify whether apoptosis and proliferation of acinar cells participate in atrophy of rat parotid glands induced by liquid diet, rats were fed a liquid diet and compared to pellet-fed controls. Parotid glands were removed at 3, 7, 14 or 21?days, weighed, and examined using transmission electron microscopy (TEM), and studied immunohistochemically for cleaved-caspase-3 (Casp-3), a marker of apoptotic cells, and 5-bromo-2′-deoxyuridine (BrdU), a marker for proliferating cells. Body weights of experimental rats fed liquid diets were not significantly different from controls fed pellet diets; however weights of experimental parotid glands were smaller than those of controls. In the experimental parotid glands, structures like apoptotic bodies were histologically observed in acini at each time point; more Casp-3-positive acinar cells were identified in experimental parotid glands than in the controls on days 3, 7, and 14. Experimental glands showed fewer BrdU-positive acinar cells at each time point. TEM confirmed typical apoptotic acinar cells in the atrophic glands. These findings suggest that increased acinar cell apoptosis and reduced acinar cell proliferation occur in atrophic parotid glands of rats fed a liquid diet.     

A dynamical systems perspective on the relationship between symbolic and non-symbolic computation

It has been claimed that connectionist (artificial neural network) models of language processing, which do not appear to employ “rules”, are doing something different in kind from classical symbol processing models, which treat “rules” as atoms (e.g., McClelland and Patterson in Trends Cogn Sci 6(11):465–472, 2002). This claim is hard to assess in the absence of careful, formal comparisons between the two approaches. This paper formally investigates the symbol-processing properties of simple dynamical systems called affine dynamical automata, which are close relatives of several recurrent connectionist models of language processing (e.g., Elman in Cogn Sci 14:179–211, 1990). In line with related work (Moore in Theor Comput Sci 201:99–136, 1998; Siegelmann in Neural networks and analog computation: beyond the Turing limit. Birkhäuser, Boston, 1999), the analysis shows that affine dynamical automata exhibit a range of symbol processing behaviors, some of which can be mirrored by various Turing machine devices, and others of which cannot be. On the assumption that the Turing machine framework is a good way to formalize the “computation” part of our understanding of classical symbol processing, this finding supports the view that there is a fundamental “incompatibility” between connectionist and classical models (see Fodor and Pylyshyn 1988; Smolensky in Behav Brain Sci 11(1):1–74, 1988; beim Graben in Mind Matter 2(2):29--51,2004b). Given the empirical successes of connectionist models, the more general, super-Turing framework is a preferable vantage point from which to consider cognitive phenomena. This vantage may give us insight into ill-formed as well as well-formed language behavior and shed light on important structural properties of learning processes.     

A New Zamia Species from the Panama Canal Area

There are four terrestrial, above-ground stemmed Zamia taxa in Panama, the species delimitations of which have been a matter of controversy or misplacement at one time or the other (Schutzman et. al., 1998; Stevenson, 1993; Taylor, 1999a, b, 2002). All are allopatrically distributed. Two are in western Panama in Chiriquí province. One of these, Z. pseudomonticola, is found in the northwest of the province at altitudes above 1000 m, while the other, Z. fairchildiana, is found in a relatively small patch of forest in southwestern Chiriquí province. The other two taxa are found around the Canal area or farther east. The species described in this paper is found near the Canal area, and the last of the group, Z. elegantissima, occurs north of the Canal area in the province of Colon and also some distance to the east, including part of the Dule or Kuna aboriginal homeland known as Kuna Yala. After 16 years of research on the new taxon, we have decided to describe it as a new species, pointing out its similarity to Z. elegantissima and its distinctness from Z. pseudomonticola and Z . fairchildiana. The two western species are more alike in structure compared with the eastern species, and the latter are more alike between themselves compared to the western taxa. Even so, there are differences in vegetative and reproductive structures to clearly separate each species. There are even differences in the pollinators, these being, in all cases found, species of the weevil genus Rhopalotria and the snubbed-nosed beetle Pharaxonotha.     

Optimized dendritic cell-based immunotherapy for melanoma: the TriMix-formula

Since decades, the main goal of tumor immunologists has been to increase the capacity of the immune system to mediate tumor regression. In this regard, one of the major focuses of cancer immunotherapy has been the design of vaccines promoting strong tumor-specific cytotoxic T lymphocyte responses in cancer patients. Here, dendritic cells (DCs) play a pivotal role as they are regarded as nature’s adjuvant and as such have become the natural agents for antigen delivery in order to finally elicit strong T cell responses (Villadangos and Schnorrer in Nat Rev Immunol 7:543–555, 2007; Melief in Immunity 29:372–383, 2008; Palucka and Banchereau in Nat Rev Cancer 12:265–277, 2012; Vacchelli et al. in Oncoimmunology 2:e25771, 2013; Galluzzi et al. in Oncoimmunology 1:1111–1134, 2012). Therefore, many investigators are actively pursuing the use of DCs as an efficient way of inducing anticancer immune responses. Nowadays, DCs can be generated at a large scale in closed systems, yielding sufficient numbers of cells for clinical application. In addition, with the identification of tumor-associated antigens, which are either selectively or preferentially expressed by tumors, a whole range of strategies using DCs for immunotherapy have been designed and tested in clinical studies. Despite the evidence that DCs loaded with tumor-associated antigens can elicit immune responses in vivo, clinical responses remained disappointingly low. Therefore, optimization of the cellular product and route of administration was urgently needed. Here, we review the path we have followed in the development of TriMixDC-MEL, a potent DC-based cellular therapy, discussing its development as well as further modifications and applications.