Journal articles on the topic 'Synthetic pioneer factors'

Purpose The quality of construction projects is mainly dependent on the process quality during the construction phase than product quality. The key factors that influence the process quality of building projects in Pakistan during the construction phase of building life cycle are evaluated from literature. This paper aims to discuss these issues. Design/methodology/approach The factors were ranked using the traditional relative importance index (RII) and the second synthetic grey relational analysis method. The findings indicate that during the construction phase the selection of an appropriate contractor is the most important factor. The existence of feedback system and quality of shop drawings received from subcontractors are also very significant factors, according to the grey relational model. Findings Measures for the improvement of process quality in Pakistan are suggested. The results from both methods are not entirely comparable; however, if one considers uncertainty in data, then the second synthetic GRA-based ranking should be preferred over RII in decision making. Originality/value The study is pioneer in the evaluation of key factors influencing process quality during building construction projects in Pakistan using a set of traditional and novel methods. The results of this study are significant in improving the process quality during different phases of construction.

AbstractRegenerative medicine and tissue engineering have been considered pioneer fields in the life sciences, with an ultimate goal of restoring or switching lost or impaired body parts. Graphene oxide (GO) is the product of graphene oxidation and presents a great opportunity to make substantial progress in the field of regenerative medicine; for example, it supports the possibility of creating a cellular niche for stem cells on a nanoparticle surface. GO creates a fascinating structure for regulating stem cell behavior, as it can potentially applied to the noninvasive chase of stem cells in vivo, the liberation of active biological factors from stem cell-containing delivery systems, and the intracellular delivery of factors such as growth factors, DNA, or synthetic proteins in order to modulate stem cell differentiation and proliferation. Due to the interesting physicochemical properties of GO and its possible usage in tissue engineering approaches, the present review aims to elaborate on the ways in which GO can improve current regenerative strategies. In this respect, the applicability of GO to the repair and regeneration of various tissues and organs, including cardiac muscle, skeletal muscle, and nervous, bone, cartilage, adipose, and skin tissues, is discussed.

Androgen receptor (AR) is a ligand-activated transcription factor and a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated gene expression provides new opportunities for therapeutic intervention. Poly(ADP-ribose) Polymerase (PARP) is a family of enzymes, which posttranslationally modify a range of proteins and regulate many different cellular processes. PARP-1 and PARP-2 are two well-characterized PARP members, whose catalytic activity is induced by DNA-strand breaks and responsible for multiple DNA damage repair pathways. PARP inhibitors are promising therapeutic agents that show synthetic lethality against many types of cancer (including PCa) with homologous recombination (HR) DNA-repair deficiency. Here, we show that, beyond DNA damage repair function, PARP-2, but not PARP-1, is a critical component in AR transcriptional machinery through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to genome-wide prostate-specific enhancer regions. Analyses of PARP-2 expression at both mRNA and protein levels show significantly higher expression of PARP-2 in primary PCa tumors than in benign prostate tissues, and even more so in castration-resistant prostate cancer (CRPC) tumors. Selective targeting of PARP-2 by genetic or pharmacological means blocks interaction between PARP-2 and FOXA1, which in turn attenuates AR-mediated gene expression and inhibits AR-positive PCa growth. Next-generation antiandrogens act through inhibiting androgen synthesis (abiraterone) or blocking ligand binding (enzalutamide). Selective targeting of PARP-2, however, may provide an alternative therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA-repair deficiency status.

During development, parasympathetic ciliary ganglion neurons arise from the neural crest and establish synaptic contacts on smooth and striate muscle in the eye. The factors that promote the ciliary ganglion pioneer axons to grow toward their targets have yet to be determined. Here, we show that glial cell line-derived neurotrophic factor (GDNF) and neurturin (NRTN) constitute target-derived factors for developing ciliary ganglion neurons. Both GDNF and NRTN are secreted from eye muscle located in the target and trajectory pathway of ciliary ganglion pioneer axons during the period of target innervation. After this period, however, the synthesis of GDNF declines markedly, while that of NRTN is maintained throughout the cell death period. Furthermore, both in vitro and in vivo function-blocking of GDNF at early embryonic ages almost entirely suppresses ciliary axon outgrowth. These results demonstrate that target-derived GDNF is necessary for ciliary ganglion neurons to innervate ciliary muscle in the eye. Since the down-regulation of GDNF in the eye is accompanied by down-regulation of GFRα1 and Ret, but not of GFRα2, in innervating ciliary ganglion neurons, the results also suggest that target-derived GDNF regulates the expression of its high-affinity coreceptors.

Bernie Mills is remembered globally as an influential pioneer in the evolving field of radio astronomy. His contributions with the ‘Mills Cross' at the CSIRO Division of Radiophysics and later at the University of Sydney's School of Physics and the development of the Molonglo Observatory Synthesis Telescope (MOST) were widely recognized as astronomy evolved in the years 1948–85 and radio astronomy changed the viewpoint of the astronomer as a host of new objects were discovered.

A hallmark of EBV infections is its latent phase, when all viral lytic genes are repressed. Repression results from a high nucleosome occupancy and epigenetic silencing by cellular factors such as the Polycomb repressive complex 2 (PRC2) and DNA methyltransferases that, respectively, introduce repressive histone marks and DNA methylation. The viral transcription factor BZLF1 acts as a molecular switch to induce transition from the latent to the lytic or productive phase of EBV’s life cycle. It is unknown how BZLF1 can bind to the epigenetically silenced viral DNA and whether it directly reactivates the viral genome through chromatin remodeling. We addressed these fundamental questions and found that BZLF1 binds to nucleosomal DNA motifs both in vivo and in vitro. BZLF1 co-precipitates with cellular chromatin remodeler ATPases, and the knock-down of one of them, INO80, impaired lytic reactivation and virus synthesis. In Assay for Transposase-Accessible Chromatin-seq experiments, non-accessible chromatin opens up locally when BZLF1 binds to its cognate sequence motifs in viral DNA. We conclude that BZLF1 reactivates the EBV genome by directly binding to silenced chromatin and recruiting cellular chromatin-remodeling enzymes, which implement a permissive state for lytic viral transcription. BZLF1 shares this mode of action with a limited number of cellular pioneer factors, which are instrumental in transcriptional activation, differentiation, and reprogramming in all eukaryotic cells.

The effects of hydrodynamics on algae growth have received considerable attention, and flow velocity is one of the most frequently discussed factors. For Euglena gracilis, which aggregates resources and is highly resistant to environmental changes, the mechanism underlying the impact of flow velocity on its growth is poorly understood. Experiments were conducted to examine the response of algae growth to different velocities, and several enzymes were tested to determine their physiological mechanisms. Significant differences in the growth of E. gracilis were found at different flow velocities, and this phenomenon is unique compared to the growth of other algal species. With increasing flow velocity and time, the growth of E. gracilis is gradually inhibited. In particular, we found that the pioneer enzyme is peroxidase (POD) and that the main antioxidant enzyme is catalase (CAT) when E. gracilis experiences flow velocity stress. Hysteresis between total phosphorus (TP) consumption and alkaline phosphatase (AKP) synthesis was observed. Under experimental control conditions, the results indicate that flow velocities above 0.1 m/s may inhibit growth and that E. gracilis prefers a relatively slow or even static flow velocity, and this finding could be beneficial for the control of E. gracilis blooms.

AbstractThe concept of Regional Industrialization developed by Rainer Fremdling, Toni Pierenkemper and Richard Tilly is based on a small-scale research approach and composes regions according to criteria of homogeneity. This paper argues that the concept is fruitful in regard to textile regions and their analysis in a long-term perspective from proto-industrialization to the 20th century. It examines relevant factors such as capital, labour, raw materials, transfer of capital, technology and knowledge in order to analyse the specific regional path of growth. Especially the role of migrant pioneer entrepreneurs and the institutional-cultural setting, i.e. the state monopolies of the regional silk and velvet producers are addressed. Mechanisation and the factory system were introduced relatively late in comparison to other regions in the wool and cotton branch of textile industry. But innovations in weaving and energy technology diffused rather rapidly in Krefeld, Mönchengladbach and the rural surroundings. The paper shows how the growing textile industry of the left lower Rhine region diversified during the Great Depression of the 1870s-90s and induced forward and backward linkages to the machinery, tool and chemical industries. In all segments of the textile industry in the region (silk, velvet, cotton, wool, synthetics) path dependencies evolved which still have an effect on research institutions and industrial culture today.

The coloration of grape berries depends on the anthocyanin synthesis during maturation. The quality of berries is often decreased due to the poor color development when berries are grown under unfavorable environments and/or inadequate internal factors are involved. It has been well-known that the level of ABA at ripening is closely associated with anthocyanin synthesis; thus, the external application of ABA results in the increase of anthocyanin content even in berries grown under favorable conditions. However, the agricultural use of natural ABA is not possible because of high prices. This experiment was conducted to study the potential of STC-4771 as a substitute for ABA. The effect of STC-4771 was studied in `Kyoho', `Pione', and `Delaware' grapes. Chemicals were applied when ≈10% of berries in a cluster were colored. In `Kyoho', anthocyanin synthesis was enhanced at a concentration of 100 mg/L and there was a trend in color enhancement in `Pione', regardless of treatment concentration, between 10 to 40 mg/L. However, no clear effect was found in `Delaware' at 50 to 100 mg/L. In an in vitro experiment, anthocyanin was only increased when an adequate amount of sucrose (0.6 m) was added in the incubation medium under light. Natural ABA effectively increased the anthocyanin content of berry segments even under shading condition through four bagging materials, but no effect was confirmed in STC treatment.

Galaxies represent the main form of organization of matter in our universe. Therefore, they are of obvious interest for the new multidisciplinary field of astrobiology. In particular, to study habitability of galaxies represents one of the main emerging challenges of theoretical and numerical astrobiology. Its theoretical underpinnings are, however, often confused and vague. Here we present a systematic attempt to list and categorize major causal factors playing a role in emergent habitability of galaxies. Furthermore, we argue that the methodology of cosmological merger trees is particularly useful in delineating what are systematic and lawful astrobiological properties of galaxies at present epoch vs. those which are product of historical contingency and, in particular, interaction with wider extragalactic environment. Employing merger trees extracted from cosmological N-body simulations as a new and promising research method for astrobiology has been pioneered by Stanway et al. (2018). We analyse the general issue of applicability of merger trees and present preliminary results on a set of trees extracted from the Illustris Project. In a sense, this approach is directly complementary to using large-scale cosmological simulations to study habitable zones of individual galaxies with high mass/spatial resolution; taken together, they usher a new era of synergy and synthesis between cosmology and astrobiology.

Since the late 1980s, satellite-based global positioning systems (GPS) have provided unique and novel data that have been used to track animal movement. Tracking animals with GPS can provide useful information, but the cost of the technology often limits experimental replication. Limitations on the number of devices available to monitor the behaviour of animals, in combination with technical constraints, can weaken the statistical power of experiments and create significant experimental design challenges. The present paper provides a review and synthesis of using GPS for livestock-based studies and suggests some future research directions. Wildlife ecologists working in extensive landscapes have pioneered the use of GPS-based devices for tracking animals. Wildlife researchers have focussed efforts on quantifying and addressing issues associated with technology limitations, including spatial accuracy, rate of data collection, battery life and environmental factors causing loss of data. It is therefore not surprising that there has been a significant number of methodological papers published in the literature that have considered technical developments of GPS-based animal tracking. Livestock scientists have used GPS data to inform them about behavioural differences in free-grazing experiments. With a shift in focus from the environment to the animal comes the challenge of ensuring independence of the experimental unit. Social facilitation challenges independence of the individual in a group. The use of spatial modelling methods to process GPS data provides an opportunity to determine the degree of independence of data collected from an individual animal within behavioural-based studies. By using location and movement information derived from GPS data, researchers have been able to determine the environmental impact of grazing animals as well as assessing animal responses to management activities or environmental perturbations. Combining satellite-derived remote-sensing data with GPS-derived landscape preference indices provides a further opportunity to identify landscape avoidance and selection behaviours. As spatial livestock monitoring tools become more widely used, there will be a greater need to ensure the data and associated processing methods are able to answer a broader range of questions. Experimental design and analytical techniques need to be given more attention if GPS technology is to provide answers to questions associated with free-grazing animals.

This review describes the over half-centennial history of research on insect juvenile hormone (JH) as well as its natural and synthetic bioanalogues (JHA or juvenoids).The leading theories of insect hormone action in growth and metamorphosis were created more than 50 years ago by the pioneers of insect endocrinology, V. B. Wigglesworth, C. M. Williams, V. J. A. Novák, H. Piepho, H. A. Schneiderman and L. I. Gilbert. There are two principal categories of hormones released from the central neuroendocrine system (neurosecretory cells of the brain, corpora cardiaca, corpora allata) that regulate insect growth and metamorphosis. The first is a complex set of neurohormones (neuropeptides) originating in the neurosecretory cells of the insect brain, which are released from the neurohaemal organs, the corpora cardiaca. These neuropeptides are responsible for stimulation of various developmental events, such as the release of the activation hormone, AH. The second category of centrally produced hormones in insects is the morphogenesis inhibiting hormone, or juvenile hormone (JH), produced by the associated endocrine glands, the corpora allata. JH is responsible for induction of the somatic larval growth in young instar larvae and stimulation of reproduction in the feeding adult stages.Wigglesworth (1935) first described JH as an inhibitory hormone; Williams (1957) discovered its active extracts. Sláma (1961) discovered the hormonomimetic or pseudojuvenile effects of various lipid extracts and free fatty acids. In addition to lipid extracts with JH activity, a phenomenon found in various human organs, microorganisms and plants, JH-mimetic materials were found in American paper products in 1964. The source of the so-called “paper factor” was the wood of the Canadian balsam fir. The potential use of these and other analogues of JH as nontoxic, selectively acting “third generation pesticides” stimulated an enormous boom of activity among industrial and academic institutions all over the world, in the pursuit of synthetic JH analogues for replacement of toxic insecticides.For practical reasons, in this review the chemical structures of the synthetic juvenoids have been divided into three categories: a) natural and synthetic, predominantly terpenoid juvenoids known before 1970; b) terpenoid and nonterpenoid juvenoids synthesized and tested before 1980, and; c) predominantly nonterpenoid, polycyclic juvenoids with relatively high JH activity, found and selected for practical use after 1980. Chemical structures of several juvenoids of theoretical or practical importance, together with the essential structure-activity relationships, are outlined in several figures and tables. The total number of all juvenoids reported active in one or more insects species has been estimated to be more than 4000 compounds. A juvenoid molecule has, more or less, a similar molecular size, roughly equivalent to a chain of 15 to 17 carbon atoms, with the presence of some slightly polar functional groups and a more or less lipophilic physico-chemical properties. Beyond these similarities, there are many variations in the structural types of juvenoids, including, derivatives of acyclic terpenoids, arylterpenoids, peptides, heterocyclic and polycyclic juvenoids, phenoxyphenyl juvenoids, juvenoid carbamates, and pyridyl-derivatives.In addition to the generally known and intensively studied effects of juvenoids, such as inhibition of metamorphosis, inhibition of embryogenesis, and stimulation of ovarian growth, there are certain less remarkable and largely unexplored biological effects of juvenoids. Some of those phenomena, which are briefly described in this review, are: a) the effects of juvenoids on embryonic development (ovicidal effects); b) delayed effects of JH on metamorphosis from egg stage; c) sexually transmitted female sterility caused by juvenoid treatments of the males; d) the nonvolatile, biochemically activated juvenogen complexes, generating hormonally active juvenoids by enzymatic hydrolysis of the complex, and; e) antihormones with antijuvenile activity.There are two basic hormonal theories on the regulation of insect metamorphosis by JH that have been proposed during the past 50 years. The first is the theory of Gilbert-Riddiford, which has been widely disseminated at universities worldwide, through textbooks on insect physiology, biochemistry and endocrinology. The second, less renowned, hormonal theory of insect development is that of Novák-Sláma. Briefly, the Gilbert-Riddiford theory is based on several fundamental principles. These are: a) the brain hormone-prothoracic gland (PG) concept created more than 50 years ago and later disproved by Williams; b) the conclusions of Piepho, who suggested that a large concentration of JH would cause a single epidermal cell to develop larval patterns, pupal patterns at medium concentrations, and adult epidermal patterns at zero concentration; c) small amounts of JH are necessary in the last larval instars of endopterygote insects for preventing precocious proliferation of imaginal discs; d) metamorphosis is stimulated by PG through a small endogenous peak of ecdysteroid preceding the large prepupal one; e) ecdysteroids are released from the PG in response to superimposed prothoracicotropic hormone (PTTH) from the brain; f) the true juvenile hormone of the corpora allata is a sesquiterpenoid compound known as epoxy homofarnesoate (JH-I), isolated from the adult male abdomens of the Cecropia silkmoths, and; g) physiological functions of JH and other hormones are regulated at the peripheral level by enzymes (esterase) or genes (methoprene tolerant,Metor a Broad complex gene).The Novák-Sláma theory is based on completely different building blocks. Briefly, these are: a) the PG represent a peripheral organ which is not involved in the regulation of the moulting cycles, instead; b) the PG are a subordinated target of JH (not PTTH), they are inactive during the last larval instar and their removal does not abolish the cycles of moults; c) the PG are used to generate metabolic water during the growth of young larval instars by secreting of an adipokinetic superhormone, which stimulates total combustion of the dietary lipids; d) small, medium, or large concentrations of JH are unimportant, the hormone only needs to be present in the minimum, physiologically effective concentrations; e) an imperative condition for metamorphosis to occur is a virtual absence of JH starting from the second half of the penultimate larval instar; f) JH acts according to an “all-or-none” rule at the single cell level, and the temporal sensitivity to JH is strictly limited to a narrow period at the beginning of the moulting cycle, before the cells begin to divide; g) the corpus allatum never produces JH in a nonfeeding stage, and the sesquiterpenoid juvenoid JH-I cannot be the true JH of insects (it has very low JH activity, 100,000-fold smaller in comparison to human made peptidic juvenoids); h) the developmental cycles are stimulated exclusively by neuropeptides produced by the brain’s neurosecretory cells (AH); i) developmental stimulation by AH has nothing in common with the PTTH or PG; j) when environmental interventions in the hormonal system become obsolete, the regulation of moulting cycles becomes autonomic (hormone independent), supported by the stereotypic instructions coded on the genome; k) during the millions of years of insect evolution, the central neuroendocrine system acquired the superimposed, epigenetic ability to adapt gene functions and synchronize them with essential changes in the environment. A model based on the regulation of insect metamorphosis by simple combination of two hormones (AH, JH) of the central neuroendocrine system is outlined. A possibility that the 4000 known juvenoid molecules act as the feedback or homeostatic factors affecting permeability of the epidermal cell membranes has been suggested. Speculations about possible peptidic or proteinic nature of the corpus allatum hormone have been emphasized.

ABSTRACT An important site for bovine herpesvirus 1 (BoHV-1) latency is sensory neurons within trigeminal ganglia (TG). The synthetic corticosteroid dexamethasone consistently induces BoHV-1 reactivation from latency. Expression of four Krüppel-like transcription factors (KLF), i.e., KLF4, KLF6, PLZF (promyelocytic leukemia zinc finger), and KLF15, are induced in TG neurons early during dexamethasone-induced reactivation. The glucocorticoid receptor (GR) and KLF15 form a feed-forward transcription loop that cooperatively transactivates the BoHV-1 immediate early transcription unit 1 (IEtu1) promoter that drives bovine infected cell protein 0 (bICP0) and bICP4 expression. Since the bICP0 gene also contains a separate early (E) promoter, we tested the hypothesis that GR and KLF family members transactivate the bICP0 E promoter. GR and KLF4, both pioneer transcription factors, cooperated to stimulate bICP0 E promoter activity in a ligand-independent manner in mouse neuroblastoma cells (Neuro-2A). Furthermore, GR and KLF4 stimulated productive infection. Mutating both half GR binding sites did not significantly reduce GR- and KLF4-mediated transactivation of the bICP0 E promoter, suggesting that a novel mechanism exists for transactivation. GR and KLF15 cooperatively stimulated bICP0 activity less efficiently than GR and KL4: however, KLF6, PLZF, and GR had little effect on the bICP0 E promoter. GR, KLF4, and KLF15 occupied bICP0 E promoter sequences in transfected Neuro-2A cells. GR and KLF15, but not KLF4, occupied the bICP0 E promoter at late times during productive infection of bovine cells. Collectively, these studies suggest that cooperative transactivation of the bICP0 E promoter by two pioneer transcription factors (GR and KLF4) correlates with stimulating lytic cycle viral gene expression following stressful stimuli. IMPORTANCE Bovine herpesvirus 1 (BoHV-1), an important bovine pathogen, establishes lifelong latency in sensory neurons. Reactivation from latency is consistently induced by the synthetic corticosteroid dexamethasone. We predict that increased corticosteroid levels activate the glucocorticoid receptor (GR). Consequently, viral gene expression is stimulated by the activated GR. The immediate early transcription unit 1 promoter (IEtu1) drives expression of two viral transcriptional regulatory proteins, bovine infected cell protein 0 (bICP0) and bICP4. Interestingly, a separate early promoter also drives bICP0 expression. Two pioneer transcription factors, GR and Krüppel-like transcription factor 4 (KLF4), cooperatively transactivate the bICP0 early (E) promoter. GR and KLF15 cooperate to stimulate bICP0 E promoter activity but significantly less than GR and KLF4. The bICP0 E promoter contains enhancer-like domains necessary for GR- and KLF4-mediated transactivation that are distinct from those for GR and KLF15. Stress-induced pioneer transcription factors are proposed to activate key viral promoters, including the bICP0 E promoter, during early stages of reactivation from latency.

Streptococcus sanguinis (formerly S. sanguis) is a Gram-positive, facultative anaerobe, nonmotile , normal inhabitant of the human oral cavity, and a member of the viridans group of streptococci. Among the streptococcus, S. sanguinis is a primary colonizer in the human tooth surface or it is recognize as a ‘pioneer’ by forming dental plaque. The aim of this paper is to review the role of Streptococcus sanguinis in the adherence to and invasion of human tissues. S. sanguinis has been reported that it is associated with healthy tooth surfaces but not with caries. S. sanguinis tend to involved in an interspecies interactions with Streptococcus mutans, which is known as competition/coexistence within dental biofilm. In their colonization, this bacteria used enzyme sortase A (SrtA) to cleave LPXTG-containing proteins sequence and anchored the cell wall, while virulence factors in infective endocarditis involved housekeeping functions such as cell wall synthesis, amino acid and nucleic acid synthesis, and the ability to survive under anaerobic conditions.

Enhancer activity drives cell differentiation and cell fate determination, but it remains unclear how enhancers cooperate during these processes. Here we investigate enhancer cooperation during transdifferentiation of human leukemia B-cells to macrophages. Putative enhancers are established by binding of the pioneer factor C/EBPα followed by chromatin opening and enhancer RNA (eRNA) synthesis from H3K4-monomethylated regions. Using eRNA synthesis as a proxy for enhancer activity, we find that most putative enhancers cooperate in an additive way to regulate transcription of assigned target genes. However, transcription from 136 target genes depends exponentially on the summed activity of its putative paired enhancers, indicating that these enhancers cooperate synergistically. The target genes are cell type-specific, suggesting that enhancer synergy can contribute to cell fate determination. Enhancer synergy appears to depend on cell type-specific transcription factors, and such interacting enhancers are not predicted from occupancy or accessibility data that are used to detect superenhancers.

Sensorineural hearing loss is irreversible and is associated with the loss of spiral ganglion neurons (SGNs) and sensory hair cells within the inner ear. Improving spiral ganglion neuron (SGN) survival, neurite outgrowth, and synaptogenesis could lead to significant gains for hearing-impaired patients. There has therefore been intense interest in the use of neurotrophic factors in the inner ear to promote both survival of SGNs and re-wiring of sensory hair cells by surviving SGNs. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) represent the primary neurotrophins in the inner ear during development and throughout adulthood, and have demonstrated potential for SGN survival and neurite outgrowth. We have pioneered a hybrid molecule approach to maximize SGN stimulation in vivo, in which small molecule analogues of neurotrophins are linked to bisphosphonates, which in turn bind to cochlear bone. We have previously shown that a small molecule BDNF analogue coupled to risedronate binds to bone matrix and promotes SGN neurite outgrowth and synaptogenesis in vitro. Because NT-3 has been shown in a variety of contexts to have a greater regenerative capacity in the cochlea than BDNF, we sought to develop a similar approach for NT-3. 1Aa is a small molecule analogue of NT-3 that has been shown to activate cells through TrkC, the NT-3 receptor, although its activity on SGNs has not previously been described. Herein we describe the design and synthesis of 1Aa and a covalent conjugate of 1Aa with risedronate, Ris-1Aa. We demonstrate that both 1Aa and Ris-1Aa stimulate neurite outgrowth in SGN cultures at a significantly higher level compared to controls. Ris-1Aa maintained its neurotrophic activity when bound to hydroxyapatite, the primary mineral component of bone. Both 1Aa and Ris-1Aa promote significant synaptic regeneration in cochlear explant cultures, and both 1Aa and Ris-1Aa appear to act at least partly through TrkC. Our results provide the first evidence that a small molecule analogue of NT-3 can stimulate SGNs and promote regeneration of synapses between SGNs and inner hair cells. Our findings support the promise of hydroxyapatite-targeting bisphosphonate conjugation as a novel strategy to deliver neurotrophic agents to SGNs encased within cochlear bone.

In preparation for a legal implementation of EU-regulation 1829/2003, the Norwegian Scientific Committee for Food Safety (VKM) has been requested by the Norwegian Environment Agency (former Norwegian Directorate for Nature Management) and the Norwegian Food Safety Authority (NFSA) to conduct final food/feed and environmental risk assessments for all genetically modified organisms (GMOs) and products containing or consisting of GMOs that are authorized in the European Union under Directive 2001/18/EC or Regulation 1829/2003/EC. The request covers scope(s) relevant to the Gene Technology Act. The request does not cover GMOs that VKM already has conducted its final risk assessments on. However, the Agency and NFSA requests VKM to consider whether updates or other changes to earlier submitted assessments are necessary. Four notifications/applications for placing on the market of insect resistant genetically modified maize 1507 from Pioneer HiBreed & Dow AgroSciences (Unique Identifier DAS-Ø15Ø7-1) have been taken into account: Application EFSA/GMO/NL/2004/02 for placing on the market of insect-tolerant genetically modified maize 1507 for food use under Regulation (EC) 1829/2003 Food and food ingredients containing, consisting of or produced from maize 1507 approved since 3 March 2006 (Commission Decision 2006/197/EC) Notification C/NL/00/10 for import and processing use under Part C of Diretive 2001/18/EC. Approved for importation, processing and feed use since 3 November 2005 (Commission Decision 2005/772/EC) Application EFSA/GMO/RX/1507 for renewal of authorisation of existing products of maize 1507 under Regulation (EC) no 1829/2003 Renewing of the authorisation of existing feed products from maize 1507 granted since 17 June 2011 (Commission Decision 2011/365/EC). Notification C/ES/01/01 for cultivation, import, processing and use as any other maize (excluding food uses) under Directive 2001/18/EC on the deliberate release of GMOs into the environment. The application is still pending for authorisation. Genetically modified maize 1507 has previously been assessed as food and feed by the VKM GMO Panel commissioned by the Norwegian Food Safety Authority in connection with the EFSA official hearing of the application EFSA/GMO/NL/2004/02 in 2004 (VKM 2004). Maize 1507 has also been evaluated by the VKM GMO Panel as a component of several stacked GM maize events under Regulation (EC) 1829/2003 (VKM 2005b, 2007a,b, 2008a,b, 2009a,b, 2012a,b,c, 2013 a,b,c,d,e). The food/feed and environmental risk assessment of the GM maize 1507 is based on information provided by the applicant in the notifications C/ES/01/01 and C/NL/00/10 and the applications EFSA/GMO/NL/2004/02 and EFSA/GMO/RX/1507, previous risk assessments performed by the VKM GMO Panel and scientific opinions and comments from EFSA and other member states made available on the EFSA website GMO Extranet. The risk assessment is also based on a risk analysis report of 1507 from the Australia New Zealand Food Authority (FSANZ 2002) and a review and assessment of relevant peer-reviewed scientific literature. The VKM GMO Panel has evaluated maize 1507 with reference to its intended uses in the European Economic Area (EEA), and according to the principles described in the Norwegian Food Act, the Norwegian Gene Technology Act and regulations relating to impact assessment pursuant to the Gene Technology Act, Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms, and Regulation (EC) No 1829/2003 on genetically modified food and feed. The Norwegian Scientific Committee for Food Safety has also decided to take account of the appropriate principles described in the EFSA guidelines for the risk assessment of GM plants and derived food and feed (EFSA 2011a), the environmental risk assessment of GM plants (EFSA 2010a), selection of comparators for the risk assessment of GM plants (EFSA 2011b) and for the post-market environmental monitoring of GM plants (EFSA 2011c). The scientific risk assessment of maize 1507 include molecular characterisation of the inserted DNA and expression of novel proteins, comparative assessment of agronomic and phenotypic characteristics, nutritional assessments, toxicology and allergenicity, unintended effects on plant fitness, potential for gene transfer, interactions between the GM plant and target and non-target organisms and effects on biogeochemical processes. It is emphasised that the VKM mandate does not include assessments of contribution to sustainable development, societal utility and ethical considerations, according to the Norwegian Gene Technology Act and Regulations relating to impact assessment pursuant to the Gene Technology Act. These considerations are therefore not part of the risk assessment provided by the VKM Panel on Genetically Modified Organisms. The genetically modified maize 1507 has been developed to provide protection against certain lepidopteran target pests, such as the European corn borer (ECB, Ostrinia nubilalis), and some species belonging to the genus Sesamia. The insect resistence is achieved through expression of a synthetic version of the truncated cry1F gene derived from Bacillus thuringiensis subsp. aizawai, a common soil bacterium. Maize 1507 also expresses the phosphinothricin-N-acetyltransferase (pat) gene, from the soil bacterium Streptomyces viridochromogenes. The encoded PAT protein confers tolerance to the herbicidal active substance glufosinate-ammonium. The PAT protein produced by maize 1507 has been used as a selectable marker to facilitate the selection process of transformed plant cells and is not intended for weed management purposes. Since the scope of the notification C/ES/01/01 does not cover the use of glufosinate-ammonium-containing herbicides on maize 1507, potential effects due to the use of such herbicides on maize 1507 are not considered by VKM. Molecular Characterisation: Appropriate analyses of the transgenic DNA insert, its integration site, number of inserts and flanking sequences in the maize genome, have been performed. The results show that only one copy of the insert is present in maize 1507. Homology searches with databases of known toxins and allergens have not indicated any potential production of harmful proteins or polypeptides caused by the genetic modification in maize 1507. Southern blot analyses and segregation studies show that the introduced genes cry1F and pat are stably inherited and expressed over several generations along with the phenotypic characteristics of maize 1507. The VKM GMO Panel considers the molecular characterisation of maize 1507 satisfactory. Comparative Assessment: Comparative analyses of maize 1507 to its non-GM conventional counterpart have been performed during multiple field trials located at representative sites and environments in Chile (1998/99), USA (1999) and in Europe (1999, 2000 and 2002). With the exception of small intermittent variations, no biologically significant differences were found between maize 1507 and the conventional maize. Based on the assessment of available data, the VKM GMO Panel concludes that maize 1507 is compositionally, agronomically and phenotypically equivalent to its conventional counterpart, except for the introduced characteristics, and that its composition fell within the normal ranges of variation observed among non-GM varieties. Food and Feed Safety Assessment: Whole food feeding studies on rats, broilers, pullets, pigs and cattle have not indicated any adverse health effects of maize 1507. These studies also indicate that maize 1507 is nutritionally equivalent to conventional maize. The PAT and Cry1F proteins do not show sequence resemblance to other known toxins or IgE allergens, nor have they been reported to cause IgE mediated allergic reactions. Some studies have however indicated a potential role of Cry-proteins as adjuvants in allergic reactions. Based on current knowledge, the VKM GMO Panel concludes that maize 1507 is nutritionally equivalent to conventional maize varieties. It is unlikely that the PAT and Cry1F proteins will introduce a toxic or allergenic potential in food or feed based on maize 1507 compared to conventional maize. Environmental Risk: There are no reports of the target lepidopteran species attaining pest status on maize in Norway. Since there are no Bt-based insecticides approved for use in Norway, and lepidopteran pests have not been registered in maize, issues related to resistance evolution in target pests are not relevant at present for Norwegian agriculture. There are only a limited number of published scientific studies on the environmental effects of Cry1F protein. Published scientific studies showed that the likelihood of negative effects of Cry1F protein on non-target arthropods that live on or in the vicinity of maize plants is low. Cultivation of maize 1507 is not considered to represent a threat to the prevalence of red-listed species in Norway. Few studies have been published examining potential effects of Cry1F toxin on ecosystems in soil, mineralization, nutrient turnover and soil communities. Some field studies have indicated that root exudates and decaying plant material containing Cry proteins may affect population size and activity of rhizosphere organisms (soil protozoa and microorganisms). Most studies conclude that effects on soil microorganisms and microbial communities are transient and minor compared to effects caused by agronomic and environmental factors. However, data are only available from short term experiments and predictions of potential long term effects are difficult to deduce. The VKM GMO Panel concludes that, although the data on the fate of the Cry1F protein and its potential interactions in soil are limited, the relevant scientific publications analysing the Cry1F protein, together with the relatively broad knowledge about the environmental fate of other Cry1 proteins, do not indicate significant direct effects on the soil environment. Few studies have assessed the impact of Cry proteins on non-target aquatic arthropods and the fate of these proteins in senescent and decaying maize detritus in aquatic environments, and no specific lower-tier studies, assessing the impact of the Cry1F protein on non-target aquatic arthropods have been reported in the scientific literature so far. However, exposure of non-target organisms to Cry proteins in aquatic ecosystems is likely to be very low, and potential exposure of Bt toxins to nontarget organisms in aquatic ecosystems in Norway is considered to be negligible. Maize is the only representative of the genus Zea in Europe, and there are no cross-compatible wild or weedy relatives outside cultivation with which maize can hybridise and form backcross progeny. Vertical gene transfer in maize therefore depends on cross-pollination with other conventional or organic maize varieties. In addition, unintended admixture of genetically modified material in seeds represents a possible way for gene flow between different crop cultivations. The risk of pollen flow from maize volunteers is negligible under Norwegian growing conditions. Overall Conclusion: Based on current knowledge, the VKM GMO Panel concludes that maize 1507 is nutritionally equivalent to conventional maize varieties. It is unlikely that the Cry1 and PAT proteins will introduce a toxic or allergenic potential in food or feed derived from maize 1507 compared to conventional maize. The VKM GMO Panel likewise concludes that cultivation of maize 1507 is unlikely to have any adverse effect on the environment and agriculture in Norway.