New insights into centromeres from Arabidopsis Col-CEN assembly.

Centromeres have an essential and conserved role in eukaryotes, and represent a paradoxical feature of rapid evolution. A recent study by Naish et al. applied long-read sequencing to survey a genome assembly of all five Arabidopsis (Arabidopsisthaliana) centromeres. Analyses of these centromeres showed characteristic genetic and epigenetic features, providing new insights into centromere evolution.

Unraveling the Electron Transfer Effect of Single-Metal Ce-N4 Sites via Mesopore-Coupling for Boosted Oxygen Reduction Activity.

The development of cerium (Ce) single-atom (SA) electrocatalysts for oxygen reduction reaction (ORR) with high active-site utilization and intrinsic activity has become popular recently but remains challenging. Inspired by an interesting phenomenon that pore-coupling with single-metal cerium sites can accelerate the electron transfer predicted by density functional theory calculations, here, a facile strategy is reported for directional design of a highly active and stable Ce SA catalyst (Ce SA/MC) by the coupling of single-metal Ce-N4 sites and mesopores in nanocarbon via pore-confinement-pyrolysis of Ce/phenanthroline complexes combined with controlling the formation of Ce oxides. This catalyst delivers a comparable ORR catalytic activity with a half-wave potential of 0.845 V versus RHE to the Pt/C catalyst. Also, a Ce SA/MC-based zinc-air battery (ZAB) has exhibited a higher energy density (924 Wh kgZn -1 ) and better long-term cycling durability than a Pt/C-based ZAB. This proposed strategy may open a door for designing efficient rare-earth metal catalysts with single-metal sites coupling with porous structures for next-generation energy devices.

The influence of geographical location on moisture distribution in wood cross sections: a numerical simulation study using Austria as an example.

Wood constantly interacts with the surrounding, locally varying climate, leading to changes in the moisture content. Advanced simulation tools can predict the two-dimensional moisture distributions caused by these changing climate conditions within wood cross sections over time. However, there is a notable absence of systematic simulation results for diverse climatic conditions and various wood cross sections. This study seeks to bridge this gap in research. Here, we present moisture fields in three solid timber and three glued laminated timber cross sections in Austria and show the effect of the location and the altitude on the moisture content distribution. The results reveal decreasing influence of the location on the moisture content development with increasing cross section size, and primarily the altitude affecting the moisture content. In addition, the results are compared with the standard for the design of timber-concrete composite structures (ONR CEN/TS 19103), revealing appropriate values in most of the cases. Only for cross sections with a width of 14 cm and larger, assigned to a specific region, the standard value is assumed underestimated. Furthermore, the distribution of moisture gradients, which are related to the crack depth development, are analyzed for Austria, demonstrating the influence of mountain areas in the moisture gradient development. Supplementary Information: The online version contains supplementary material available at 10.1186/s10086-024-02147-z.

Structure-activity relationship studies of anti-bunyaviral cap-dependent endonuclease inhibitors.

Bunyaviruses, including the Lassa virus (LASV), are known to cause hemorrhagic fever and have a high fatality rate among hospitalized patients, as there are few effective treatments. We focused on the fact that bunyaviruses use cap-dependent endonuclease (CEN) for viral replication, which is similar to influenza viruses. This led us to screen carbamoyl pyridone bicycle (CAB) compounds, which compose a series of baloxavir acid (BXA) derivatives, against lymphocytic choriomeningitis virus (LCMV) and Junin virus (JUNV) among the bunyaviruses. This led to the discovery of 1c, which has potent anti-bunyaviral activities. In SAR studies, we found that a large lipophilic side chain is preferred for the 1-position of the CAB scaffold, similar to the influenza CEN inhibitor, and that a small alkyl group for the 3-position shows high activity. Moreover, the 7­carboxyl group of the scaffold is essential for anti-bunyaviral activities, and the antiviral activity is reduced by conversion to various carboxylic acid bioisosteres. The SAR results are discussed using a binding model of 9d in the active center of the known LCMV CEN crystal structure. These compounds show promise as broad-spectrum anti-bunyavirus therapeutics, given their relatively favorable metabolic stability and PK profiles.

Bioelectrochemical stability improvement by Ce-N modified carbon-based cathode in high-salt stress and mechanism research.

Although microbial fuel cells (MFCs) have potential for high-salt wastewater treatment, their application is limited by poor salt tolerance, deactivation and unstable catalytic performance. This study designed Ce-C, N-C, and Ce-N modified activated carbon (Ce-N-C) based on the catalytic mechanism and salt tolerance performance of Ce and N elements to address these limitations. With activated carbon (AC) as the control, this study analyzed the stability of the four cathodes under different salinity environments using norfloxacin (NOR) as a probe to assess the effect of cathodes and salinity on MFC degradation performance. After three months, comparing with other three cathodes, the Ce-N-C cathode demonstrated superior and stable electrochemical and power generation performance. In particular, the advantages of Ce-N-C in high-salt (600 mM NaCl) environment is more significant than no-salt or low-salt. The potential of Ce-N-C-End at current density of 0 was 14.0% higher than AC-End, and the power density of the MFC with Ce-N-C cathode was 105.7 mW/m2, which was 3.1 times higher than AC. Also, the stability of NOR removal under the function of Ce-N-C improved with the increase of NaCl concentration or operation time. The CeO2(111) crystal form, N-Ce-O bond and pyridine N might be the key factors in improving the catalytic performance and salt tolerance of the Ce-N modified carbon-based cathode using XPS and XRD analysis.

Comparative metabolomic and transcriptomic analysis of Saccharomyces cerevisiae W303a and CEN.PK2-1C.

Saccharomyces cerevisiae is a health microorganism closely related to human life, especially in food and pharmaceutical industries. S. cerevisiae W303a and CEN.PK2-1C are two commonly used strains for synthetic biology-based natural product production. Yet, the metabolomic and transcriptomic differences between these two strains have not been compared. In this study, metabolomics and transcriptomics were applied to analyze the differential metabolites and differential expression genes (DEGs) between W303a and CEN.PK2-1C cultured in YPD and SD media. The growth rate of W303a in YPD medium was the lowest compared with other groups. When cultured in YPD medium, CEN.PK2-1C produced more phenylalanine than W303a; when cultured in SD medium, W303a produced more phospholipids than CEN.PK2-1C. Transcriptomic analysis revealed that 19 out of 22 genes in glycolysis pathway were expressed at higher levels in CEN.PK2-1C than that in W303a no matter which media were used, and three key genes related to phenylalanine biosynthesis including ARO9, ARO7 and PHA2 were up-regulated in CEN.PK2-1C compared with W303a when cultured in YPD medium, whereas seven DEGs associated with phospholipid biosynthesis were up-regulated in W303a compared with CEN.PK2-1C when cultured in SD medium. The high phenylalanine produced by CEN.PK2-1C and high phospholipids produced by W303a indicated that CEN.PK2-1C may be more suitable for synthesis of natural products with phenylalanine as precursor, whereas W303a may be more appropriate for synthesis of phospholipid metabolites. This finding provides primary information for strain selection between W303a and CEN.PK2-1C for synthetic biology-based natural product production.

Identification of bilge oil with lubricant: Recent oil spill case studies.

Oil spills have many adverse effects on the marine environment. Bilge oil spills occur frequently in the sea as a result of maritime accidents or illegal discharge. It is difficult to unambiguously identify the specific sources of such spills because bilge oil contains a mixture of fuel oil and lubricant. In this study, bilge oils with different fuel oil/lubricant ratios were prepared and analyzed using a modified version of the CEN/TR methodology (European Committee for Standardization, 2012). As the lubricant content of bilge oil increased, the intensity of the C20-C24 group, which is the commonly-used normalization compound group for fuel oil in the percentage weathering (PW) plot, also changed. Therefore, the mean area of the C15-C18 group, which was affected by the lubricant content, was used instead. Although heavy fuel oil is usually normalized to a hopane, bilge oil with a high lubricant content cannot be analyzed based on a mass spectrometry (MS)-PW plot; thus, heavy fuel oil-based bilge oil was normalized to a phytane in this study. Although hopanes and styrenes are unsuitable comparison compounds for heavy fuel oil-based bilge oil analysis, for light fuel oil-based bilge oil, hopanes and steranes could be applied as diagnostic ratio comparisons when the lubricant peak was clearly detected in the chromatograms of the spilled and suspected oil samples. By applying the CEN/TR methodology according to this approach, the similarities between spilled and suspected oil samples were more easily revealed. In addition, the field applicability of the proposed method was tested for four actual oil spills.

Regulation of trehalose, a typical stress protectant, on central metabolisms, cell growth and division of Saccharomyces cerevisiae CEN.PK113-7D.

Trehalose could protect the typical food microorganism Saccharomyces cerevisiae cell against environmental stresses; however, the other regulation effects of trehalose on yeast cells during the fermentation are still poorly understood. In this manuscript, different concentrations (i.e., 0, 2 and 5% g/v) of trehalose were respectively added into the medium to evaluate the effect of trehalose on growth, central metabolisms and division of S. cerevisiae CEN.PK113-7D strain that could uptake exogenous trehalose. Results indicated that addition of trehalose could inhibit yeast cell growth in the presence or absence of 8% v/v ethanol stress. Exogenous trehalose inhibited the glucose transporting efficiency and reduced intracellular glucose content. Simultaneously, increased intracellular trehalose content destroyed the steady state of trehalose cycle and caused the imbalance between the upper glycolysis part and the lower part, thereby leading to the dysfunction of glycolysis and further inhibiting the normal yeast cell growth. Moreover, energy metabolisms were impaired and the ATP production was reduced by addition of trehalose. Finally, exogenous trehalose-associated inhibition on yeast cell growth and metabolisms delayed cell cycle. These results also highlighted our knowledge about relationship between trehalose and growth, metabolisms and division of S. cerevisiae cells during fermentation.

Mutagenesis of kiwifruit CENTRORADIALIS-like genes transforms a climbing woody perennial with long juvenility and axillary flowering into a compact plant with rapid terminal flowering.

Annualization of woody perennials has the potential to revolutionize the breeding and production of fruit crops and rapidly improve horticultural species. Kiwifruit (Actinidia chinensis) is a recently domesticated fruit crop with a short history of breeding and tremendous potential for improvement. Previously, multiple kiwifruit CENTRORADIALIS (CEN)-like genes have been identified as potential repressors of flowering. In this study, CRISPR/Cas9- mediated manipulation enabled functional analysis of kiwifruit CEN-like genes AcCEN4 and AcCEN. Mutation of these genes transformed a climbing woody perennial, which develops axillary inflorescences after many years of juvenility, into a compact plant with rapid terminal flower and fruit development. The number of affected genes and alleles and severity of detected mutations correlated with the precocity and change in plant stature, suggesting that a bi-allelic mutation of either AcCEN4 or AcCEN may be sufficient for early flowering, whereas mutations affecting both genes further contributed to precocity and enhanced the compact growth habit. CRISPR/Cas9-mediated mutagenesis of AcCEN4 and AcCEN may be a valuable means to engineer Actinidia amenable for accelerated breeding, indoor farming and cultivation as an annual crop.

Integrating after CEN Excision (ICE) Plasmids: Combining the ease of yeast recombination cloning with the stability of genomic integration.

Yeast recombination cloning is a straightforward and powerful method for recombining a plasmid backbone with a specific DNA fragment. However, the utility of yeast recombination cloning is limited by the requirement for the backbone to contain an CEN/ARS element, which allows for the recombined plasmids to propagate. Although yeast CEN/ARS plasmids are often suitable for further studies, we demonstrate here that they can vary considerably in copy number from cell to cell and from colony to colony. Variation in plasmid copy number can pose an unacceptable and often unacknowledged source of phenotypic variation. If expression levels are critical to experimentation, then constructs generated with yeast recombination cloning must be subcloned into integrating plasmids, a step that often abrogates the utility of recombination cloning. Accordingly, we have designed a vector that can be used for yeast recombination cloning but can be converted into the integrating version of the resulting vector without an additional subcloning. We call these "ICE" vectors, for "Integrating after CEN Excision." The ICE series was created by introducing a "rare-cutter" NotI-flanked CEN/ARS element into the multiple cloning sites of the pRS series yeast integration plasmids. Upon recovery from yeast, the CEN/ARS is excised by NotI digest and subsequently religated without need for purification or transfer to new conditions. Excision by this approach takes ~3 hr, allowing this refinement in the same time frame as standard recombination cloning.

Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors.

Extracellular acidification is an important feature of tumor microenvironments but has yet to be successfully exploited in cancer therapy. The reversal of the pH gradient across the plasma membrane in cells that regulate intracellular pH (pHi) has potential to drive the selective uptake of weak acids at low extracellular pH (pHe). Here, we investigate the dual targeting of low pHe and hypoxia, another key feature of tumor microenvironments. We prepared eight bioreductive prodrugs based on the benzotriazine di-oxide (BTO) nucleus by appending alkanoic or aminoalkanoic acid sidechains. The BTO acids showed modest selectivity for both low pHe (pH 6.5 versus 7.4, ratios 2 to 5-fold) and anoxia (ratios 2 to 8-fold) in SiHa and FaDu cell cultures. Related neutral BTOs were not selective for acidosis, but had greater cytotoxic potency and hypoxic selectivity than the BTO acids. Investigation of the uptake and metabolism of representative BTO acids confirmed enhanced uptake at low pHe, but lower intracellular concentrations than expected for passive diffusion. Further, the modulation of intracellular reductase activity and competition by the cell-excluded electron acceptor WST-1 suggests that the majority of metabolic reductions of BTO acids occur at the cell surface, compromising the engagement of the resulting free radicals with intracellular targets. Thus, the present study provides support for designing bioreductive prodrugs that exploit pH-dependent partitioning, suggesting, however, that that the approach should be applied to prodrugs with obligate intracellular activation.

Natural variation in a CENTRORADIALIS homolog contributed to cluster fruiting and early maturity in cotton.

BACKGROUND: Plant architecture and the vegetative-reproductive transition have major impacts on the agronomic success of crop plants, but genetic mechanisms underlying these traits in cotton (Gossypium spp.) have not been identified. RESULTS: We identify four natural mutations in GoCEN-Dt associated with cluster fruiting (cl) and early maturity. The situ hybridization shows that GhCEN is preferentially expressed in cotton shoot apical meristems (SAM) of the main stem and axillary buds. Constitutive GhCEN-Dt overexpression suppresses the transition of the cotton vegetative apex to a reproductive shoot. Silencing GoCEN leads to early flowering and determinate growth, and in tetraploids causes the main stem to terminate in a floral bud, a novel phenotype that exemplifies co-adaptation of polyploid subgenomes and suggests new research and/or crop improvement approaches. Natural cl variations are enriched in cottons adapted to high latitudes with short frost-free periods, indicating that mutants of GoCEN have been strongly selected for early maturity. CONCLUSION: We show that the cotton gene GoCEN-Dt, a homolog of Antirrhinum CENTRORADIALIS, is responsible for determinate growth habit and cluster fruiting. Insight into the genetic control of branch and flower differentiation offers new approaches to develop early maturing cultivars of cotton and other crops with plant architecture appropriate for mechanical harvesting.

How 'The Urge to Kill' Feels: Articulations of Emic 'Appetitive Aggression' Experiences Among Former Forcefully Recruited Children and Youth in the Acholi Region of Northern Uganda.

Based on 10 months of fieldwork in the Acholi region of northern Uganda among youth and adults who were forcefully recruited into the Lord's Resistance Army (LRA) during the war, this article provides qualitative details to research on 'appetitive aggression.' Through two case-stories the article unfolds first person articulations of how 'appetitive aggression' is experienced as 'the urge to kill' and how it relates to the emic Acholi spiritual concept of 'cen'; a local Luo expression used to describe places and human beings possessed by evil spirits. The analysis illuminates what the individual and social implications of 'the urge to kill' and 'cen' entail for two Acholi men; first in a militia and then in a civil post-war context. The analysis then relates these findings to soldier experiences across cultures and time periods. While our analysis supports the findings in 'appetitive aggression' studies that appetitive aggression serves as a resilient protective factor against developing post-traumatic stress disorder (PTSD), this study documents that once the former forcefully recruited return to civilian life, 'appetitive aggression' and 'the urge to kill' precipitate individual and at times lethal social and moral complications in a fragile post-war community. Thus, the article argues that appetitive aggression and the emic perceptions and experiences of it among the local population are essential to consider in studies, processes and programs targeting demobilization, rehabilitation, reconciliation and re-integration.

Three FT and multiple CEN and BFT genes regulate maturity, flowering, and vegetative phenology in kiwifruit.

Kiwifruit is a woody perennial horticultural crop, characterized by excessive vegetative vigor, prolonged juvenility, and low productivity. To understand the molecular factors controlling flowering and winter dormancy, here we identify and characterize the kiwifruit PEBP (phosphatidylethanolamine-binding protein) gene family. Five CEN-like and three BFT-like genes are differentially expressed and act as functionally conserved floral repressors, while two MFT-like genes have no impact on flowering time. FT-like genes are differentially expressed, with AcFT1 confined to shoot tip and AcFT2 to mature leaves. Both act as potent activators of flowering, but expression of AcFT2 in Arabidopsis resulted in a greater impact on plant morphology than that of AcFT1. Constitutive expression of either construct in kiwifruit promoted in vitro flowering, but AcFT2 displayed a greater flowering activation efficiency than AcFT1, leading to immediate floral transition and restriction of leaf development. Both leaf and flower differentiation were observed in AcFT1 kiwifruit lines. Sequential activation of specific PEBP genes in axillary shoot buds during growth and dormancy cycles indicated specific roles in regulation of kiwifruit vegetative and reproductive phenologies. AcCEN and AcCEN4 marked active growth, AcBFT2 was associated with suppression of latent bud growth during winter, and only AcFT was activated after cold accumulation and dormancy release.

HER2 FISH results in breast cancers with increased CEN17 signals using alternative chromosome 17 probes - reclassifying cases in the equivocal category.

AIMS: HER2 testing of invasive breast cancer by in-situ hybridization guides therapy decisions. Probing HER2 and centromere of chromosome 17 (cen17) simultaneously is supposed to reveal both a potential HER2 gene amplification and polysomy 17. However, a considerable number of breast cancer patients with quasi polysomy 17 are considered 'equivocal', which is diagnostically meaningless. Moreover, patients with equivocal/false polysomic tumours are prevented from a potentially beneficial anti-HER2 treatment. Here we evaluated the RAI1, D17S122 and TP53 hybridization markers to indicate true polysomy reliably and to reclassify equivocal samples accurately as HER2-positive. METHODS AND RESULTS: Samples with (n = 82) and without (n = 52) increased cen17 copy numbers and 78 evidently HER2-amplified specimens were analysed using dual and triple marker hybridization probes. Selected putative polysomic samples were subjected to array-based comparative genomic hybridization (aCGH). We found that 37.8% samples with putative polysomy 17 did not show any gain in RAI1, D17S122 or TP53. Accordingly, aCGH revealed evidence for the presence of HER2/cen17 co-amplification rather than for true polysomy in those cases. Reflex testing using alternate 17p markers reclassified up to 56.3% equivocal cases as HER2-positive and the combined assessment of a 17p and 17q locus allows the differentiation of true versus false polysomy. CONCLUSIONS: An increased cen17 copy number does not necessarily reflect polysomy, and reflex testing facilitates the reclassification of 'equivocals'. Nevertheless, the prognostic and predictive value of a HER2/cen17 co-amplification versus HER2 gene amplification alone must still be evaluated prospectively.

Development of a Candida glabrata dominant nutritional transformation marker utilizing the Aspergillus nidulans acetamidase gene (amdS).

The gene encoding Aspergillus nidulans acetamidase (amdS) was placed under control of Candida albicans ACT1 promoter and terminator sequences and then cloned into a plasmid containing C. glabrata ARS10,CEN8 or ARS10+CEN8 sequences. All plasmids transformed C. glabrata wild-type cells to acetamide+, with the ARS-only containing plasmid transforming cells at the highest frequencies (>1.0 × 10(4) transformants µg(-1)). Plasmids were rapidly lost under non-selective conditions with the frequency dependent on chromosomal element, thus recycling the acetamide- phenotype. The amdS plasmid was used to transform a set of clinical isolates resistant to a variety of antifungal drugs. All strains were successfully transformed to the acetamide+ phenotype at high frequency, confirming that this plasmid construct could be used as a simple dominant marker on virtually any strain. Gap repair experiments demonstrated that just as in Saccharomyces cerevisiae, gap repair functions efficiently inC. glabrata, suggesting that C. glabrata has numerous similarities toS. cerevisiae with regard to ease of molecular manipulation. The amdS system is inexpensive and efficient, and combined with existing C. glabrata plasmid elements, confers a high transformation frequency for C. glabrata with a phenotype that can be easily recycled.

In vitro aerodynamic characterization of the dose emitted during nebulization of tobramycin high strength solution by novel and jet nebulizer delivery systems.

BACKGROUND: Chronic infections with Pseudomonas aeruginosa are a leading cause of morbidity in patients with cystic fibrosis (CF). The aim of tobramycin inhalation therapy in CF patients with chronic pulmonary infection is to deliver high amounts of drug directly to the site of infection. TOBI(®) is a tobramycin nebulizer solution (300 mg/5 ml) approved by FDA for maintenance therapy for patient with CF. The 20% tobramycin sulfate solution was reported as the optimal and maximal concentration. METHODS: Nebulization of high strength tobramycin solution (20% tobramycin sulfate) (HSTS) has been assessed in this study by using different selected high performance nebulizer delivery systems: two different designs of jet nebulizers, and three new nebulizers based on vibrating mesh technology. The aerosol particle size distribution and output characteristics were measured for in vitro performance assessment of the nebulizer systems. The methodology was adapted from the current European standard, EN 13544-1:2001E. RESULTS: The particle size distribution characteristic measurements showed that all tested nebulizers may be suitable for inhalation of HSTS. The mean (SD) of highest percentage of fine particles (<5 µm) was 77.64 (2.3) % for Sidestream(®), at flow rate 16 L/min. The highest respirable inhaled mass was for Pari LC Plus(®) combined with PariBoyN(®) compressor, with mean (SD) 90.85 (8.6) mg. The mean (SD) of highest drug wastage percentage was 63.9 (3.9) % for Sidestream(®) jet nebulizer combined with compressed air cylinder at flow rate 16 L/min, while the lowest was 2.3 (0.26) % for NE-U22 Omron(®) (high frequency). CONCLUSIONS: The HSTS can be nebulized by all tested nebulisers but the high frequency NE-U22 Omron(®) and Aeroneb Go(®) are more efficient. When the HSTS compared to TOBI(®), the respirable inhaled dose was increased to more than 73%.

OntoCR: A CEN/ISO-13606 clinical repository based on ontologies.

OBJECTIVE: To design a new semantically interoperable clinical repository, based on ontologies, conforming to CEN/ISO 13606 standard. MATERIALS AND METHODS: The approach followed is to extend OntoCRF, a framework for the development of clinical repositories based on ontologies. The meta-model of OntoCRF has been extended by incorporating an OWL model integrating CEN/ISO 13606, ISO 21090 and SNOMED CT structure. RESULTS: This approach has demonstrated a complete evaluation cycle involving the creation of the meta-model in OWL format, the creation of a simple test application, and the communication of standardized extracts to another organization. DISCUSSION: Using a CEN/ISO 13606 based system, an indefinite number of archetypes can be merged (and reused) to build new applications. Our approach, based on the use of ontologies, maintains data storage independent of content specification. With this approach, relational technology can be used for storage, maintaining extensibility capabilities. CONCLUSIONS: The present work demonstrates that it is possible to build a native CEN/ISO 13606 repository for the storage of clinical data. We have demonstrated semantic interoperability of clinical information using CEN/ISO 13606 extracts.

A series of conditional shuttle vectors for targeted genomic integration in budding yeast.

The capacity of Saccharomyces cerevisiae to repair exposed DNA ends by homologous recombination has long been used by experimentalists to assemble plasmids from DNA fragments in vivo. While this approach works well for engineering extrachromosomal vectors, it is not well suited to the generation, recovery and reuse of integrative vectors. Here, we describe the creation of a series of conditional centromeric shuttle vectors, termed pXR vectors, that can be used for both plasmid assembly in vivo and targeted genomic integration. The defining feature of pXR vectors is that the DNA segment bearing the centromere and origin of replication, termed CEN/ARS, is flanked by a pair of loxP sites. Passaging the vectors through bacteria that express Cre recombinase reduces the loxP-CEN/ARS-loxP module to a single loxP site, thereby eliminating the ability to replicate autonomously in yeast. Each vector also contains a selectable marker gene, as well as a fragment of the HO locus, which permits targeted integration at a neutral genomic site. The pXR vectors provide a convenient and robust method to assemble DNAs for targeted genomic modifications.

Standardising Responsibility? The Significance of Interstitial Spaces.

Modern society is characterised by rapid technological development that is often socially controversial and plagued by extensive scientific uncertainty concerning its socio-ecological impacts. Within this context, the concept of 'responsible research and innovation' (RRI) is currently rising to prominence in international discourse concerning science and technology governance. As this emerging concept of RRI begins to be enacted through instruments, approaches, and initiatives, it is valuable to explore what it is coming to mean for and in practice. In this paper we draw attention to a realm that is often backgrounded in the current discussions of RRI but which has a highly significant impact on scientific research, innovation and policy-namely, the interstitial space of international standardization. Drawing on the case of nanoscale sciences and technologies to make our argument, we present examples of how international standards are already entangled in the development of RRI and yet, how the process of international standardization itself largely fails to embody the norms proposed as characterizing RRI. We suggest that although current models for RRI provide a promising attempt to make research and innovation more responsive to societal needs, ethical values and environmental challenges, such approaches will need to encompass and address a greater diversity of innovation system agents and spaces if they are to prove successful in their aims.