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.     

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.

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.     

QTL mapping of yield-associated traits in Brassica juncea: meta-analysis and epistatic interactions using two different crosses between east European and Indian gene pool lines

Genetic analysis of 12 yield-associated traits was undertaken by dissection of quantitative trait loci (QTL) through meta-analysis and epistatic interaction studies in Brassica juncea. A consensus (integrated) map in B. juncea was constructed using two maps. These were VH map, developed earlier in the laboratory by using a DH population from the cross between Varuna and Heera (Pradhan et al. in Theor Appl Genet 106:607–614, 2003; Ramchiary et al. in Theor Appl Genet. 115:807–817, 2007; Panjabi et al. in BMC Genomics 9:113, 2008), and the TD map, developed in the present study using a DH population of 100 lines from the cross between TM-4 and Donskaja-IV. The TD map was constructed with 911 markers consisting of 585 AFLP, 8 SSR and 318 IP markers covering a total genome length of 1,629.9?cM. The consensus map constructed by using the common markers between the two maps contained a total of 2,662 markers and covered a total genome length of 1,927.1?cM. Firstly, QTL analysis of 12 yield-associated traits was undertaken for the TD population based on three-environment phenotypic data. Secondly, the three-environment phenotypic data for the same 12 quantitative traits generated by Ramchiary et al. (2007) were re-analyzed for the QTL detection in the VH map. Comparative analysis identified both common and population-specific QTL. The study revealed the presence of QTL clusters on LG A7, A8 and A10 in both TD and VH maps. Meta-analyses resolved 187 QTL distributed over nine linkage groups of TD and VH maps into 20 meta-QTL. Maximum resolution was recorded for the LG A10 wherein all the 54 QTL were mapped to a single meta-QTL within a confidence interval of 3.0?cM. Digenic epistatic interactions of QTL in both TD and VH maps revealed substantial additive?×?additive interactions showing a higher frequency of Type 1 and Type 2 interactions than Type 3 interactions. Some of the loci interacted with more than one locus indicating the presence of higher order epistatic interactions. These findings provided some detailed insight into the genetic architecture of the yield-associated traits in B. juncea.     

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.     

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.     

Agrobacterium tumefaciens-mediated transformation of Atropa belladonna

Belladonna or deadly nightshade (Atropa belladonna L.) is an important medicinal plant in the family Solanaceae. It is a model plant for studying plant alkaloid biosynthesis. In this study, a reliable protocol for efficient transformation of A. belladonna using Agrobacterium tumefaciens was developed. Hypocotyl and cotyledon explants were co-cultivated with three opine-type Agrobacterium strains (LBA4404: pBISN1, GV3101: pBISN1, and EHA105: pBISN1). Selection and regeneration of transformed cells were conducted on two regeneration media; RM1 (Murashige and Skoog in Physiol Plant 15:473–497, 1962) medium (MS) salts, Gamborg B5 vitamins (Gamborg et al. in Exp Cell Res 50:151–158, 1968), 4.56 μM zeatin, and 2.9 μM indole-3-acetic acid (IAA)] and RM2 (MS salts, B5 vitamins, 4.65 μM kinetin, and 1.14 μM IAA), each containing 100 mg l^?1 kanamycin and 250 mg l^?1 timentin. Both regeneration media and type of explant had significant effects on frequencies of transformation. Using an optimal regeneration medium and regardless of the strain of Agrobacterium used, over 80 % of hypocotyl explants and 60 % of cotyledons developed at least one transformed shoot after 2–3 months of selection. Most transformants exhibited a normal phenotype while growing in the greenhouse. Southern blot analysis confirmed the stable integration of the nptII transgene in T₁ plants.     

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.     

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.     

Name change for the diplobathrid camerate crinoid Acanthocrinus spinosus Südkamp 2007 from the lower Devonian Hunsrück Slate (Germany)

Südkamp (Paläontologische Zeitschrift 81:181–204, 2007: 198; Figs. 15A, B) described and figured the diplobathrid camerate crinoid Acanthocrinus spinosus n. sp. from the lower Devonian Hunsrück Slate of Karschheck quarry near Oberkirn, Rhineland-Palatinate, Germany. However, this name is preoccupied by Rhodocrinus (=Acanthocrinus Goldring 1926) spinosus Hall 1862 and therefore is invalid. A replacement name is proposed as Acanthocrinus multispina nom. nov.     

Detection of Legionella spp. and Legionella pneumophila in water samples of Spain by specific real-time PCR

Legionella pneumophila is the primary cause of the legionellosis diseases (90 %) (Yu et al. in J Infect Dis 186:127–128, 2002; Doleans et al. in J Clin Microbiol 42:458–460, 2004; Den Boer et al. in Clin Microbiol Infect 14:459–466, 2008). In this study, methodologies based on molecular biology were developed in order to provide a quick diagnosis of the bacterial presence in water samples of Spain. Multiplex real-time polymerase chain reaction assays were realized to target the 16S rRNA and macrophage infectivity potentiator (mip) genes of, respectively, Legionella spp. and L. pneumophila including in the design of an internal control. The results obtained by the culture and the gene amplification methods agreed in 94.44 % for the 16S rRNA gene, and a concordance of 66.67 % of the cases was obtained for the mip gene.     

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.     

EZ-ASSIGN, a program for exhaustive NMR chemical shift assignments of large proteins from complete or incomplete triple-resonance data

For several of the proteins in the BioMagResBank larger than 200 residues, 60 % or fewer of the backbone resonances were assigned. But how reliable are those assignments? In contrast to complete assignments, where it is possible to check whether every triple-resonance Generalized Spin System (GSS) is assigned once and only once, with incomplete data one should compare all possible assignments and pick the best one. But that is not feasible: For example, for 200 residues and an incomplete set of 100 GSS, there are 1.6 × 10²⁶⁰ possible assignments. In “EZ-ASSIGN”, the protein sequence is divided in smaller unique fragments. Combined with intelligent search approaches, an exhaustive comparison of all possible assignments is now feasible using a laptop computer. The program was tested with experimental data of a 388-residue domain of the Hsp70 chaperone protein DnaK and for a 351-residue domain of a type III secretion ATPase. EZ-ASSIGN reproduced the hand assignments. It did slightly better than the computer program PINE (Bahrami et al. in PLoS Comput Biol 5(3):e1000307, 2009) and significantly outperformed SAGA (Crippen et al. in J Biomol NMR 46:281–298, 2010), AUTOASSIGN (Zimmerman et al. in J Mol Biol 269:592–610, 1997), and IBIS (Hyberts and Wagner in J Biomol NMR 26:335–344, 2003). Next, EZ-ASSIGN was used to investigate how well NMR data of decreasing completeness can be assigned. We found that the program could confidently assign fragments in very incomplete data. Here, EZ-ASSIGN dramatically outperformed all the other assignment programs tested.     

Abiotic nitrate incorporation, anaerobic microsites, and the ferrous wheel

Nitrate has long been thought to be chemically unreactive in soil. This view was challenged by the report of an apparently abiotic process whereby nitrate (NO₃ ^?) is incorporated into organic compounds (Dail et al. 2001). In Colman et al. (2007), we examined how common this process might be by testing for it in 45 soils collected from across a range of ecosystem types. We found no evidence of this process occurring in any of the soils, but found evidence of an analytical artifact that creates the appearance of incorporation. We suggested that prior evidence of this process might be due in part or in total to this analytical artifact. Davidson et al. (2008), however, challenged our results and conclusions, suggesting that we failed to observe the abiotic incorporation because we eliminated the anaerobic microsites they argue are necessary for the process. We address the criticisms, and show that they actually raise questions about the robustness of the only study to have reported abiotic NO₃ ^? incorporation in sterile soils. We argue that this area of research needs new artifact-free experiments if the controversy is going to be resolved.     

Range limits in spatially explicit models of quantitative traits

In an influential paper, Kirkpatrick and Barton (Am Nat 150:1–23 1997) presented a system of diffusive partial differential equations modeling the joint evolution of population density and the mean of a quantitative trait when the trait optimum varies over a continuous spatial domain. We present a stability theorem for steady states of a simplified version of the system, originally studied in Kirkpatrick and Barton (Am Nat 150:1–23 1997). We also present a derivation of the system.     

A Mathematical and Numerical Investigation of the Hemodynamical Origins of Oscillations in Microvascular Networks

Evidence is presented to show that self-sustained oscillations of purely hemodynamical origin are possible in some arcade-type microvascular networks supplied with steady boundary conditions, but that in others the oscillations disappear with sufficient reduction of the time step Δt, showing them to be numerical artefacts. In an attempt to elucidate the mechanisms involved in the onset of fluctuations, we proceed to perform a linear stability analysis for the convective model of Kiani et al. (Microvasc. Res. 45:219–232, 1993; Am. J. Physiol. 266(35):H1822–H1828, 1994), and show that this leads via a system of delay differential equations to a nonlinear eigenvalue problem. This result generalises the characteristic equation obtained by Carr et al. (Ann. Biomed. Eng. 33:764–771, 2005) and Geddes et al. (SIAM J. Appl. Dyn. Syst. 6(4):694–727, 2007) who solved a special case in a two node network. An implicit numerical method is proposed for the computation of blood flows in networks using the convective model. In a moderate size subnetwork of one of the networks chosen by Kiani et al. (Am. J. Physiol. 266(35):H1822–H1828, 1994), the topology, vessel lengths, and diameters of which were based on microvascular networks in the rat mesentery, we compare results generated using the original explicit numerical method of Kiani et al. (Am. J. Physiol. 266(35):H1822–H1828, 1994) with those from our implicit scheme. From the linear stability theory, a critical value D _RBC,crit of a red blood cell diameter parameter D _RBC in the plasma skimming model of Fenton et al. (Pflügers Arch. 403:396–401, 1985b) is identified for the onset of oscillations about steady state and both the explicit and implicit methods are used to calculate the inflow hematocrit solutions in all vessels of the subnetwork at the critical parameter value, subject to perturbed initial conditions. The results of the implicit method are demonstrated to be in excellent and superior agreement with the predictions of the linear analysis in this case. For values of D _RBC slightly larger than D _RBC,crit the bifurcating periodic solutions calculated using either the explicit or implicit schemes are characteristic of those of a supercritical Hopf bifurcation and the graphs of D _RBC vs. oscillation amplitude would seem to converge as Δt→0.     

Comparison of cerebral base arteries in antelopes of Tragelaphus,Taurotragus and Boselaphus genera

Studies were conducted on preparations of head arteries, including cerebral base arteries of sitatunga (n = 14), nyala n = 16) and Greater kudu n = 4) of Tragelaphus genus, Common eland n = 7) from the tribe of Tragelaphini and the largest Asiatic Nilgai antelope n = 9) from Boselaphini tribe. Blood vessels of the cerebral arterial circle in studied antelopes were found to arise from terminal division of intracranial segments of internal carotid arteries, which emerge from the pairwise rostral epidural rete mirabile. Due to obliteration of the extracranial segment of internal carotid artery, the cerebral arterial circle of studied antelopes is supplied with blood mainly through maxillary artery, with mediation of blood vessels of rostral epidural rete mirabile. The system of cerebral base arteries in selected representatives of Tragelaphus, Taurotragus and Boselaphus, in contrast to other species of Bovinae subfamily, manifests the absence of caudal epidural rete mirabile. The pattern of cerebral base arteries in studied antelopes is consistent with position of the species in taxonomy worked out by Simpson (Bull Am Mus Nat Hist 85:1–350, 1945) and McKenna and Bell (Classification of mammals above the species level. Columbia University Press, New York, pp I–XII, 1997).     

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’).