A continuous flow process for the synthesis of a metal-organic framework using only water as the reaction medium and requiring only short residence times is described. This affords a new route to ...scale-up of materials incorporating many of the principles of Green Chemistry. The process is demonstrated by the synthesis MIL-53(Al) viacontinuous flow reaction requiring only 5-6 minutes with a space time yield of 1300 kg m super(-3) d super(-1). We have demonstrated the synthesis of 500 g of MIL-53(Al) using this process, which can be scaled-up further by simply feeding further solutions of metal salt and ligand through the reactor. The product has a higher surface area and a better colour than a commercially produced sample of this MOF. In addition, a new and effective method for the extraction of terephthalic acid from within the pores of MIL-53(Al) using supercritical ethanol has been developed, representing a new methodology for activation and removal of substrates from porous hosts.
There is an interesting overlap of function in a wide range of organisms between genes that modulate the stress responses and those that regulate aging phenotypes and, in some cases, lifespan. We ...have therefore screened mutagenized zebrafish embryos for the altered expression of a stress biomarker, senescence-associated beta-galactosidase (SA-beta-gal) in our current study. We validated the use of embryonic SA-beta-gal production as a screening tool by analyzing a collection of retrovirus-insertional mutants. From a pool of 306 such mutants, we identified 11 candidates that showed higher embryonic SA-beta-gal activity, two of which were selected for further study. One of these mutants is null for a homologue of Drosophila spinster, a gene known to regulate lifespan in flies, whereas the other harbors a mutation in a homologue of the human telomeric repeat binding factor 2 (terf2) gene, which plays roles in telomere protection and telomere-length regulation. Although the homozygous spinster and terf2 mutants are embryonic lethal, heterozygous adult fish are viable and show an accelerated appearance of aging symptoms including lipofuscin accumulation, which is another biomarker, and shorter lifespan. We next used the same SA-beta-gal assay to screen chemically mutagenized zebrafish, each of which was heterozygous for lesions in multiple genes, under the sensitizing conditions of oxidative stress. We obtained eight additional mutants from this screen that, when bred to homozygosity, showed enhanced SA-beta-gal activity even in the absence of stress, and further displayed embryonic neural and muscular degenerative phenotypes. Adult fish that are heterozygous for these mutations also showed the premature expression of aging biomarkers and the accelerated onset of aging phenotypes. Our current strategy of mutant screening for a senescence-associated biomarker in zebrafish embryos may thus prove to be a useful new tool for the genetic dissection of vertebrate stress response and senescence mechanisms.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Spinster (Spin) in Drosophila or Spinster homolog 1 (Spns1) in vertebrates is a putative lysosomal H+-carbohydrate transporter, which functions at a late stage of autophagy. The Spin/Spns1 defect ...induces aberrant autolysosome formation that leads to embryonic senescence and accelerated aging symptoms, but little is known about the mechanisms leading to the pathogenesis in vivo. Beclin 1 and p53 are two pivotal tumor suppressors that are critically involved in the autophagic process and its regulation. Using zebrafish as a genetic model, we show that Beclin 1 suppression ameliorates Spns1 loss-mediated senescence as well as autophagic impairment, whereas unexpectedly p53 deficit exacerbates both of these characteristics. We demonstrate that 'basal p53' activity plays a certain protective role(s) against the Spns1 defect-induced senescence via suppressing autophagy, lysosomal biogenesis, and subsequent autolysosomal formation and maturation, and that p53 loss can counteract the effect of Beclin 1 suppression to rescue the Spns1 defect. By contrast, in response to DNA damage, 'activated p53' showed an apparent enhancement of the Spns1-deficient phenotype, by inducing both autophagy and apoptosis. Moreover, we found that a chemical and genetic blockage of lysosomal acidification and biogenesis mediated by the vacuolar-type H+-ATPase, as well as of subsequent autophagosome-lysosome fusion, prevents the appearance of the hallmarks caused by the Spns1 deficiency, irrespective of the basal p53 state. Thus, these results provide evidence that Spns1 operates during autophagy and senescence differentially with Beclin 1 and p53.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The recent discovery of a large number of histone demethylases suggests a central role for these enzymes in regulating histone methylation dynamics. Histone H3K27 trimethylation (H3K27me3) has been ...linked to polycomb-group-protein-mediated suppression of Hox genes and animal body patterning, X-chromosome inactivation and possibly maintenance of embryonic stem cell (ESC) identity. An imbalance of H3K27 methylation owing to overexpression of the methylase EZH2 has been implicated in metastatic prostate and aggressive breast cancers. Here we show that the JmjC-domain-containing related proteins UTX and JMJD3 catalyse demethylation of H3K27me3/2. UTX is enriched around the transcription start sites of many HOX genes in primary human fibroblasts, in which HOX genes are differentially expressed, but is selectively excluded from the HOX loci in ESCs, in which HOX genes are largely silent. Consistently, RNA interference inhibition of UTX led to increased H3K27me3 levels at some HOX gene promoters. Importantly, morpholino oligonucleotide inhibition of a zebrafish UTX homologue resulted in mis-regulation of hox genes and a striking posterior developmental defect, which was partially rescued by wild-type, but not by catalytically inactive, human UTX. Taken together, these findings identify a small family of H3K27 demethylases with important, evolutionarily conserved roles in H3K27 methylation regulation and in animal anterior-posterior development.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Stakeholders increasingly expect ecosystem assessments as part of advice on fisheries management. Quantitative models to support fisheries decision‐making may be either strategic (‘big picture’, ...direction‐setting and contextual) or tactical (focused on management actions on short timescales), with some strategic models informing the development of tactical models. We describe and review ‘Models of Intermediate Complexity for Ecosystem assessments’ (MICE) that have a tactical focus, including use as ecosystem assessment tools. MICE are context‐ and question‐driven and limit complexity by restricting the focus to those components of the ecosystem needed to address the main effects of the management question under consideration. Stakeholder participation and dialogue is an integral part of this process. MICE estimate parameters through fitting to data, use statistical diagnostic tools to evaluate model performance and account for a broad range of uncertainties. These models therefore address many of the impediments to greater use of ecosystem models in strategic and particularly tactical decision‐making for marine resource management and conservation. MICE are capable of producing outputs that could be used for tactical decision‐making, but our summary of existing models suggests this has not occurred in any meaningful way to date. We use a model of the pelagic ecosystem in the Coral Sea and a linked catchment and ocean model of the Gulf of Carpentaria, Australia, to illustrate how MICE can be constructed. We summarize the major advantages of the approach, indicate opportunities for the development of further applications and identify the major challenges to broad adoption of the approach.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Structural characterisation of individual molecules by high‐resolution transmission electron microscopy (HRTEM) is fundamentally limited by the element and electron energy‐specific interactions of ...the material with the high energy electron beam. Here, the key mechanisms controlling the interactions between the e‐beam and C–H bonds, present in all organic molecules, are examined, and the low atomic weight of hydrogen—resulting in its facile atomic displacement by the e‐beam—is identified as the principal cause of the instability of individual organic molecules. It is demonstrated theoretically and proven experimentally that exchanging all hydrogen atoms within molecules with the deuterium isotope, and therefore doubling the atomic weight of the lightest atoms in the structure, leads to a more than two‐fold increase in the stability of organic molecules in the e‐beam. Substitution of H for D significantly reduces the amount of kinetic energy transferred from the e‐beam to the atom (main factor contributing to stability) and also increases the barrier for bond dissociation, primarily due to the changes in the zero‐point energy of the C–D vibration (minor factor). The extended lifetime of coronene‐d12, used as a model molecule, enables more precise analysis of the inter‐molecular spacing and more accurate measurement of the molecular orientations.
Due to the instability of C–H bonds in the electron beam, atomic‐resolution imaging of individual organic molecules in transmission electron microscopy is effectively prohibited. Isotope exchange of protium for deuterium significantly enhances the stability of organic molecules as the higher atomic weight of deuterium simultaneously decreases the amount of energy transferred from the electron beam, and increases the barriers for atom ejection.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Globally, many fish species are overexploited, and many stocks have collapsed. This crisis, along with increasing concerns over flow-on effects on ecosystems, has caused a reevaluation of traditional ...fisheries management practices, and a new ecosystem-based fisheries management (EBFM) paradigm has emerged. As part of this approach, selective fishing is widely encouraged in the belief that nonselective fishing has many adverse impacts. In particular, incidental bycatch is seen as wasteful and a negative feature of fishing, and methods to reduce bycatch are implemented in many fisheries. However, recent advances in fishery science and ecology suggest that a selective approach may also result in undesirable impacts both to fisheries and marine ecosystems. Selective fishing applies one or more of the "6-S" selections: species, stock, size, sex, season, and space. However, selective fishing alters biodiversity, which in turn changes ecosystem functioning and may affect fisheries production, hindering rather than helping achieve the goals of EBFM. We argue here that a "balanced exploitation" approach might alleviate many of the ecological effects of fishing by avoiding intensive removal of particular components of the ecosystem, while still supporting sustainable fisheries. This concept may require reducing exploitation rates on certain target species or groups to protect vulnerable components of the ecosystem. Benefits to society could be maintained or even increased because a greater proportion of the entire suite of harvested species is used.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Biotic communities are shaped by adaptations from generations of exposure to selective pressures by recurrent and often infrequent events. In large rivers, floods can act as significant agents of ...change, causing considerable physical and biotic disturbance while often enhancing productivity and diversity. We show that the relative balance between these seemingly divergent outcomes can be explained by the rhythmicity, or predictability of the timing and magnitude, of flood events. By analyzing biological data for large rivers that span a gradient of rhythmicity in the Neotropics and tropical Australia, we find that systems with rhythmic annual floods have higher fish species richness, more stable avian populations, and elevated rates of riparian forest production compared with those with arrhythmic flood pulses. Intensification of the hydrological cycle driven by climate change, coupled with reductions in runoff due to water extractions for human use and altered discharge from impoundments, is expected to alter the hydrologic rhythmicity of floodplain rivers with significant consequences for both biodiversity and productivity.
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BFBNIB, FZAB, GIS, IJS, INZLJ, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZRSKP
Integrins are transmembrane multi-conformation receptors that mediate interactions with the extracellular matrix. In cancer, integrins influence metastasis, proliferation, and survival. ...Collagen-binding integrin-α11/β1, a marker of aggressive tumors that is involved in stroma-tumor crosstalk, may be an attractive target for anti-cancer therapeutic antibodies. We performed selections with phage-displayed synthetic antibody libraries for binding to either purified integrin-α11/β1 or
on live cells. The
strategy yielded many diverse antibodies, and strikingly, most of these antibodies did not recognize purified integrin-α11/β1. Conversely, none of the antibodies selected for binding to purified integrin-α11/β1 were able to efficiently recognize native cell-surface antigen. Most importantly, only the
selection yielded functional antibodies that were able to compete with collagen-I for binding to cell-surface integrin-α11/β1, and thus inhibited cell adhesion. In-depth characterization of a subset of
-derived clones as full-length immunoglobulins revealed high affinity cellular binding and inhibitory activities in the single-digit nanomolar range. Moreover, the antibodies showed high selectivity for integrin-α11/β1 with minimal cross-reactivity for close homologs. Taken together, our findings highlight the advantages of
selections for generation of anti-integrin antibodies optimized for recognition and inhibition of native cell-surface proteins, and our work establishes general methods that could be extended to many other membrane proteins.
The microporous metal-organic framework {Zn2(L)middle dot(H2O)3}infinity (H4L = 1,2,4,5-tetrakis(4-carboxyphenyl)benzene) has been synthesised using near-critical water (300 degreeC) as a cleaner ...alternative to toxic organic solvents. A single crystal X-ray structure determination confirms that the complex incorporates tetrahedral Zn(ii) centres bridged through the carboxylate anions to form a binuclear building block, which extends into a one dimensional chain along the c axis. Four L4- ligands bind to each Zn(ii) centre and cross-link the one dimensional chains along both a and b axes to afford a three dimensional network structure incorporating pores of ca. 4.3 A in diameter. The complex shows high thermal stability up to 425 degreeC by gravimetric thermal analysis, and on desolvation, displays a high adsorption enthalpy of 11.0 kJ mol-1 for H2 uptake at zero coverage, consistent with the narrow pore diameter for the framework.
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