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Abstract
Although evidence indicates that the adult brain retains a considerable capacity for circuit formation, adult wiring has not been broadly considered and remains poorly understood. In this study, we investigate wiring activation in adult neurons. We show that the basic-helix-loop-helix transcription factor Ascl4 can induce wiring in different types of hippocampal neurons of adult mice. The new axons are mainly feedforward and reconfigure synaptic weights in the circuit. Mice with the Ascl4-induced circuits do not display signs of pathology and solve spatial problems equally well as controls. Our results demonstrate reprogrammed connectivity by a single transcriptional factor and provide insights into the regulation of brain wiring in adults.

Watson and Crick's celebrated double helix is a model problem-solution in the study of the conformation of biological macromolecules. It is, in Kuhn's terms, an `exemplar' for that `disciplinary matrix'. In 1976, however, two groups independently suggested essentially the same alternative, non-helical structure for DNA. No disciplinary `crisis' of confidence in the double-helical model preceded this proposal and, although Kuhn allows for such occurrences, he does not explain them. A Kuhnian account of the genesis and reception of the `side-by-side' or `warped zipper' model of DNA is provided. It invokes both explicit methodological norms at variance with the implicit presumptions of the scientific community and the freedom from conceptual constraint of amateurs and scientists outside, or on the fringe of, the disciplinary matrix. On this account the advent of the novel structure is seen as extrinsic to that matrix. But, as Francis Crick acknowledged, the competitive challenge `served a useful purpose'. It demonstrated the need for a `more careful scrutiny' of the empirical evidence for the double helix — with surprising results. This indicates that the effects of an exemplar are not necessarily advantageous.

We demonstrate a novel route for hierarchical self-assembly of sub-micrometer-sized peptide superstructures that respond to subtle changes in Zn2+ concentration. The self-assembly process is triggered by a specific folding-dependent coordination of Zn2+ by a de novo designed nonlinear helix-loop-helix peptide, resulting in a propagating fiber formation and formation of spherical superstructures. The superstructures further form larger assemblies that can be completely disassembled upon removal of Zn2+ or degradation of the nonlinear peptide. This flexible and reversible assembly strategy of the superstructures enables facile encapsulation of nanoparticles and drugs that can be released by means of different stimuli. ; Funding Agencies|Swedish Research Council [621-2011-4319]; Swedish Foundation for Strategic Research [ICA10-0002]; Linkoping University; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoping University [2009 00971]

Triple helix model is a model of a knowledge-based economy, which collaborates with the university, business, and government sectors to help small and medium enterprises (SMEs) boost their business. The issue is the three actors have not yet synergized optimally in the development of SMEs. Hence, this study was to identify the critical success factors of the triple helix model for SMEs. This study employed a meta-ethnography and factor analysis to obtain components and indicators of the success factors. The result showed that 37 items of critical success factors have good content validity and excellent homogeneity reliability. Based on these success factors, a triple helix model consisting of six stages has developed. It indicates that these critical success factors make an essential contribution to the development and success of SMEs to achieve the goal of the program.JEL Classification: L52, L53

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. ; Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)). ; European Union LSHM-CT-2006-037761 PIAP-GA-2008-218251 HEALTH-F2-2009-223423 National Genome Research Network of the German Federal Ministry of Education and Research (BMBF) 01GS08144 01GS08147 National Institute of Mental Health R01 MH078075 N01 MH900001 MH074027 Centre of Excellence for Complex Disease Genetics of the Academy of Finland 213506 129680 Biocentrum Helsinki Foundation Faculty of Medicine, University of Helsinki Stanley Medical Research Institute Danish Council for Strategic Research 2101-07-0059 H. Lundbeck A/S Research Council of Norway 163070/V50 South-East Norway Health Authority 2004-123 Medical Research Council Ministerio de Sanidad y Consumo, Spain PI081522 Xunta de Galicia 08CSA005208PR Swedish Research Council Wellcome Trust 083948/Z/07/Z Max Planck Society Eli Lilly and Company ; info:eu-repo/grantAgreement/EC/FP7/218251

The performance of clusters has been linked in several studies to their historical and geographical contexts as well as to the drivers that shape the competitive strength of nations. Among these drivers, the human factor and universities play a key role in the competitiveness of nations, as well as that of industries, regions, and firms. In the new knowledge economy, the Triple Helix model is a mechanism of coordination that brings together government, industry and universities. The main objective of this paper is to analyze the Triple Helix influence on the competitiveness factors of clusters as proposed by Zaccarelli, Telles, Siqueira, Boaventura, and Donnaire (2008). An analysis has been performed to verify how the Triple Helix axes influence the competitiveness factors of wine clusters by comparing the Chilean Valle del Maule to the Brazilian Serra Gaucha. The theoretical framework is that of the Triple Helix, coupled to Zaccarelli et al.'s (2008) model. The method employed was the multiple case study and data was collected from secondary sources. The main results indicate that only four out of Zaccarelli et al.'s (2008) eleven model factors of competitiveness are influenced by the three axes of the Triple Helix. The main contribution of this paper is to bring together the Triple Helix and competitiveness. There are nevertheless analytical and methodological constraints.

Genome wide association studies (GWAS) for type 2 diabetes (T2D) have identified genetic loci that often localise in non-coding regions of the genome, suggesting gene regulation effects. We combined genetic and transcriptomic analysis from human islets obtained from brain-dead organ donors or surgical patients to detect expression quantitative trait loci (eQTLs) and shed light into the regulatory mechanisms of these genes. Pancreatic islets were isolated either by laser capture microdissection (LCM) from surgical specimens of 103 metabolically phenotyped pancreatectomized patients (PPP) or by collagenase digestion of pancreas from 100 brain-dead organ donors (OD). Genotyping (> 8.7 million single nucleotide polymorphisms) and expression (> 47,000 transcripts and splice variants) analyses were combined to generate cis-eQTLs. After applying genome-wide false discovery rate significance thresholds, we identified 1,173 and 1,021 eQTLs in samples of OD and PPP, respectively. Among the strongest eQTLs shared between OD and PPP were CHURC1 (OD p-value=1.71 × 10 -24 ; PPP p-value = 3.64 × 10 -24 ) and PSPH (OD p-value = 3.92 × 10 -26 ; PPP p-value = 3.64 × 10 -24 ). We identified eQTLs in linkage-disequilibrium with GWAS loci T2D and associated traits, including TTLL6, MLX and KIF9 loci, which do not implicate the nearest gene. We found in the PPP datasets 11 eQTL genes, which were differentially expressed in T2D and two genes (CYP4V2 and TSEN2) associated with HbA1c but none in the OD samples. eQTL analysis of LCM islets from PPP led us to identify novel genes which had not been previously linked to islet biology and T2D. The understanding gained from eQTL approaches, especially using surgical samples of living patients, provides a more accurate 3-dimensional representation than those from genetic studies alone.

The MAX network transcriptional repressor (MNT) is an MXD family transcription factor of the basic helix-loop-helix (bHLH) family. MNT dimerizes with another transcriptional regulator, MYC-associated factor X (MAX), and down-regulates genes by binding to E-boxes. MAX also dimerizes with MYC, an oncogenic bHLH transcription factor. Upon E-box binding, the MYC-MAX dimer activates gene expression. MNT also binds to the MAX dimerization protein MLX (MLX), and MNT-MLX and MNT-MAX dimers co-exist. However, all MNT functions have been attributed to MNT-MAX dimers, and no functions of the MNT-MLX dimer have been described. MNT's biological role has been linked to its function as a MYC oncogene modulator, but little is known about its regulation. We show here that MNT localizes to the nucleus of MAX-expressing cells and that MNT-MAX dimers bind and repress the MNT promoter, an effect that depends on one of the two E-boxes on this promoter. In MAX-deficient cells, MNT was overexpressed and redistributed to the cytoplasm. Interestingly, MNT was required for cell proliferation even in the absence of MAX. We show that in MAX-deficient cells, MNT binds to MLX, but also forms homodimers. RNA-sequencing experiments revealed that MNT regulates the expression of several genes even in the absence of MAX, with many of these genes being involved in cell cycle regulation and DNA repair. Of note, MNT-MNT homodimers regulated the transcription of some genes involved in cell proliferation. The tight regulation of MNT and its functionality even without MAX suggest a major role for MNT in cell proliferation. ; This work was supported by Grant SAF2017-88026-R from Agencia Estatal de Investigación, Spanish Government (to J. L. and M. D. D.), funded in part by FEDER Program from the European Union, National Institutes of Health Grant CA57138/CA from NCI (to R. N. E.), and grants from Shriners Hospitals for Children (to P. J. H.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Creative economy is the area of knowledge that explores the intangible and symbolic aspects and feeds on creative talents, individually and/or collectively organized, in order to produce creative goods and services. This type of economy has its own dynamics, and it disturbs the traditional economic models. This study investigated creative economy comprehensively and aims to analyze the critical factors inherent in the dynamics of creative economy for regional development, considering the helix model of innovation (quintuple helix innovation model), aligned with entrepreneurship and innovation. To this end, the methodology used was systematized exploratory research, treated within three dimensions – the economic-financial, the socio-anthropological, and the techno-innovative. The conclusion of the study was the identification of fifteen critical factors, the direct creative economy relationship with the quintuple helix innovation model in all its helixes, as well as its "Mode 3" of the dynamics of knowledge generation, creation, and dissemination. The study also highlighted the importance of creative economy as one of the "engines" of regional development, in an economic, financial, social, technological, and sustainable way, driven by the government, its networks, and its actors.

While the Triple Helix relationship between university, industry and government, called 'innovation in innovation' by Etzkowitz, has frequently been a key concept guiding national and regional innovation policies around the world, there is an emerging awareness that no one-size-fits-all approach can be used in developing innovation systems. Criticism has been expressed that the conceptualization of the Triple Helix model in the most recent literature pays little attention to contextual effects. The present article seeks to enhance the context sensitivity of the Triple Helix model by integrating it with the insights of institutional logics. More specifically, seven 'ideal' institutional logics aligned with 'ideal' Triple Helix activities in Western society are identified. These have a potential to be used as a conceptual/benchmarking framework for understanding how institutional settings, particularly institutional logics, influence the development of Triple Helix innovation systems in different national contexts. To verify such a proposition, some alternative Triple Helix models as well as associated institutional logics are compared to the ideal-type, demonstrating that different institutional logics may divert the Triple Helix interactions in other directions. Meanwhile, it is claimed that institutional logics do not necessarily lead to a Triple Helix model but serve only as enabling conditions. To what extent the Triple Helix will be developed depends on innovation policies and on the key actors involved in the innovation process. The framework constructed in this study aims to provide a solid basis from which policymakers, especially those from developing and transition countries, may improve the design of these innovation policies by employing appropriate Triple Helix approaches.

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

Numerous efforts are underway to determine gene regulatory networks that describe physical relationships between transcription factors (TFs) and their target DNA sequences. Members of paralogous TF families typically recognize similar DNA sequences. Knowledge of the molecular determinants of protein–DNA recognition by paralogous TFs is of central importance for understanding how small differences in DNA specificities can dictate target gene selection. Previously, we determined the in vitro DNA binding specificities of 19 Caenorhabditis elegans basic helix-loop-helix (bHLH) dimers using protein binding microarrays. These TFs bind E-box (CANNTG) and E-box-like sequences. Here, we combine these data with logics, bHLH–DNA co-crystal structures and computational modeling to infer which bHLH monomer can interact with which CAN E-box half-site and we identify a critical residue in the protein that dictates this specificity. Validation experiments using mutant bHLH proteins provide support for our inferences. Our study provides insights into the mechanisms of DNA recognition by bHLH dimers as well as a blueprint for system-level studies of the DNA binding determinants of other TF families in different model organisms and humans. ; National Institute of General Medical Sciences (U.S.) (DK068429) ; National Institute of General Medical Sciences (U.S.) (HG003985) ; European Union (PROSPECTS HEALTH-F4-2008-201648)

Published ; This is the final version of the article. Available from Wiley via the DOI in this record. ; Pathogens target phytohormone signalling pathways to promote disease. Plants deploy salicylic acid (SA)-mediated defences against biotrophs. Pathogens antagonize SA immunity by activating jasmonate signalling, for example Pseudomonas syringae pv. tomato DC3000 produces coronatine (COR), a jasmonic acid (JA) mimic. This study found unexpected dynamics between SA, JA and COR and co-operation between JAZ jasmonate repressor proteins during DC3000 infection. We used a systems-based approach involving targeted hormone profiling, high-temporal-resolution micro-array analysis, reverse genetics and mRNA-seq. Unexpectedly, foliar JA did not accumulate until late in the infection process and was higher in leaves challenged with COR-deficient P. syringae or in the more resistant JA receptor mutant coi1. JAZ regulation was complex and COR alone was insufficient to sustainably induce JAZs. JAZs contribute to early basal and subsequent secondary plant defence responses. We showed that JAZ5 and JAZ10 specifically co-operate to restrict COR cytotoxicity and pathogen growth through a complex transcriptional reprogramming that does not involve the basic helix-loop-helix transcription factors MYC2 and related MYC3 and MYC4 previously shown to restrict pathogen growth. mRNA-seq predicts compromised SA signalling in a jaz5/10 mutant and rapid suppression of JA-related components on bacterial infection. ; We grat efully acknowledge support from the British Biotechnol-ogy and Science Research Council (Grants BB/C514115/1 andBB/F005903/1) and a Chinese Government Studentship to B.Z.The members of the Plant Responses to Environmenta l STressconsortium are thanked for microarray design, labelling and dataextraction. We thank Selena Gimenez-Ibanez for the HopXderivatives, Paul O'Neil for assistance with clustering and OrkunSoyer for helpful discussions. Pathogen work was carried outunder Plant Health License PHL 204B/6739.