Highly stable fullerene-based porous molecular crystals with open metal sites

The synthesis of conventional porous crystals involves building a framework using reversible chemical bond formation, which can result in hydrolytic instability. In contrast, porous molecular crystals assemble using only weak intermolecular interactions, which generally do not provide the same environmental stability. Here, we report that the simple co-crystallization of a phthalocyanine derivative and a fullerene (C60 or C70) forms porous molecular crystals with environmental stability towards high temperature and hot aqueous base or acid. Moreover, by using diamond anvil cells and synchrotron single-crystal measurements, stability towards extreme pressure (>4 GPa) is demonstrated, with the stabilizing fullerene held between two phthalocyanines and the hold tightening at high pressure. Access to open metal centres within the porous molecular co-crystal is demonstrated by in situ crystallographic analysis of the chemisorption of pyridine, oxygen and carbon monoxide. This suggests strategies for the formation of highly stable and potentially functional porous materials using only weak van der Waals intermolecular interactions

Bi-directional gene set enrichment and canonical correlation analysis identify key diet-sensitive pathways and biomarkers of metabolic syndrome

peer-reviewedBackground Currently, a number of bioinformatics methods are available to generate appropriate lists of genes from a microarray experiment. While these lists represent an accurate primary analysis of the data, fewer options exist to contextualise those lists. The development and validation of such methods is crucial to the wider application of microarray technology in the clinical setting. Two key challenges in clinical bioinformatics involve appropriate statistical modelling of dynamic transcriptomic changes, and extraction of clinically relevant meaning from very large datasets. Results Here, we apply an approach to gene set enrichment analysis that allows for detection of bi-directional enrichment within a gene set. Furthermore, we apply canonical correlation analysis and Fisher's exact test, using plasma marker data with known clinical relevance to aid identification of the most important gene and pathway changes in our transcriptomic dataset. After a 28-day dietary intervention with high-CLA beef, a range of plasma markers indicated a marked improvement in the metabolic health of genetically obese mice. Tissue transcriptomic profiles indicated that the effects were most dramatic in liver (1270 genes significantly changed; p < 0.05), followed by muscle (601 genes) and adipose (16 genes). Results from modified GSEA showed that the high-CLA beef diet affected diverse biological processes across the three tissues, and that the majority of pathway changes reached significance only with the bi-directional test. Combining the liver tissue microarray results with plasma marker data revealed 110 CLA-sensitive genes showing strong canonical correlation with one or more plasma markers of metabolic health, and 9 significantly overrepresented pathways among this set; each of these pathways was also significantly changed by the high-CLA diet. Closer inspection of two of these pathways - selenoamino acid metabolism and steroid biosynthesis - illustrated clear diet-sensitive changes in constituent genes, as well as strong correlations between gene expression and plasma markers of metabolic syndrome independent of the dietary effect. Conclusion Bi-directional gene set enrichment analysis more accurately reflects dynamic regulatory behaviour in biochemical pathways, and as such highlighted biologically relevant changes that were not detected using a traditional approach. In such cases where transcriptomic response to treatment is exceptionally large, canonical correlation analysis in conjunction with Fisher's exact test highlights the subset of pathways showing strongest correlation with the clinical markers of interest. In this case, we have identified selenoamino acid metabolism and steroid biosynthesis as key pathways mediating the observed relationship between metabolic health and high-CLA beef. These results indicate that this type of analysis has the potential to generate novel transcriptome-based biomarkers of disease.Department of Agriculture and Food, Ireland - Food Institutional Research Measure (project no. 5254); IRCSET postgraduate scholarship scheme (MJM); Science Foundation Ireland Principal Investigator Programme (HMR) Programme

The electron accelerator for the AWAKE experiment at CERN

The AWAKE collaboration prepares a proton driven plasma wakefield acceleration experiment using the SPS beam at CERN. A long proton bunch extracted from the SPS interacts with a high power laser and a 10 m long rubidium vapour plasma cell to create strong wakefields allowing sustained electron acceleration. The electron bunch to probe these wakefields is supplied by a 20 MeV electron accelerator. The electron accelerator consists of an RF-gun and a short booster structure. This electron source should provide beams with intensities between 0.1 and 1 nC, bunch lengths between 0.3 and 3 ps and an emittance of the order of 2 mm mrad. The wide range of parameters should cope with the uncertainties and future prospects of the planned experiments. The layout of the electron accelerator, its instrumentation and beam dynamics simulations are presented

Beam Dynamics and First Operation of the Sub-Harmonic Bunching System in the CTF3 Injector

The CLIC Test Facility 3 (CTF3), built at CERN by an international collaboration, aims at demonstrating the feasibility of the CLIC scheme by 2010. The CTF3 drive beam generation scheme relies on the use of a fast phase switch of a sub-harmonic bunching system in order to phase-code the bunches. The amount of charge in unwanted satellite bunches is an important quantity, which must be minimized. Beam dynamic simulations have been used to study the problem, showing the limitation of the present CTF3 design and the gain of potential upgrades. In this paper the results are discussed and compared with beam measurements taken during the first operation of the system

Otolith characterization and integrative species identification of adult mesopelagic fishes from the western North Atlantic Ocean

Fish diversity and ecology in the ocean’s mesopelagic zone are understudied compared to other marine regions despite growing interest in harvesting these potential resources. Otoliths can provide a wealth of taxonomic and life history information about fish, which can help fill these knowledge gaps; however, there has been relatively little research to date on the otoliths of mesopelagic species. Here, a species-specific image library was assembled of sagittal otoliths from 70 mesopelagic fishes belonging to 29 families collected in the western North Atlantic Ocean. Images of adult sagittal otoliths from 12 species were documented and photographed for the first time. The fish were identified to species with a combination of morphological characters and DNA barcoding. Regressions between otolith size and fish length are presented for the six species with the largest sample sizes in this study. This otolith image library, coupled with otolith-length and width to fish-length relationships, can be used for prey identification and back-calculation of fish size, making it a valuable tool for studies relating to food webs in the important yet poorly understood mesopelagic zone. In addition, the 44 fish barcodes generated in this study highlight the benefit of using an integrative taxonomic approach to studies of this nature, as well as add to existing public databases that enable cryptic species and metabarcoding analyses of mesopelagic species

Identification of novel subgroup a variants with enhanced receptor binding and replicative capacity in primary isolates of anaemogenic strains of feline leukaemia virus

&lt;b&gt;BACKGROUND:&lt;/b&gt; The development of anaemia in feline leukaemia virus (FeLV)-infected cats is associated with the emergence of a novel viral subgroup, FeLV-C. FeLV-C arises from the subgroup that is transmitted, FeLV-A, through alterations in the amino acid sequence of the receptor binding domain (RBD) of the envelope glycoprotein that result in a shift in the receptor usage and the cell tropism of the virus. The factors that influence the transition from subgroup A to subgroup C remain unclear, one possibility is that a selective pressure in the host drives the acquisition of mutations in the RBD, creating A/C intermediates with enhanced abilities to interact with the FeLV-C receptor, FLVCR. In order to understand further the emergence of FeLV-C in the infected cat, we examined primary isolates of FeLV-C for evidence of FeLV-A variants that bore mutations consistent with a gradual evolution from FeLV-A to FeLV-C.&lt;p&gt;&lt;/p&gt; &lt;b&gt;RESULTS:&lt;/b&gt; Within each isolate of FeLV-C, we identified variants that were ostensibly subgroup A by nucleic acid sequence comparisons, but which bore mutations in the RBD. One such mutation, N91D, was present in multiple isolates and when engineered into a molecular clone of the prototypic FeLV-A (Glasgow-1), enhanced replication was noted in feline cells. Expression of the N91D Env on murine leukaemia virus (MLV) pseudotypes enhanced viral entry mediated by the FeLV-A receptor THTR1 while soluble FeLV-A Env bearing the N91D mutation bound more efficiently to mouse or guinea pig cells bearing the FeLV-A and -C receptors. Long-term in vitro culture of variants bearing the N91D substitution in the presence of anti-FeLV gp70 antibodies did not result in the emergence of FeLV-C variants, suggesting that additional selective pressures in the infected cat may drive the subsequent evolution from subgroup A to subgroup C.&lt;p&gt;&lt;/p&gt; &lt;b&gt;CONCLUSIONS:&lt;/b&gt; Our data support a model in which variants of FeLV-A, bearing subtle differences in the RBD of Env, may be predisposed towards enhanced replication in vivo and subsequent conversion to FeLV-C. The selection pressures in vivo that drive the emergence of FeLV-C in a proportion of infected cats remain to be established

Selective expansion of viral variants following experimental transmission of a reconstituted feline immunodeficiency virus quasispecies

Following long-term infection with virus derived from the pathogenic GL8 molecular clone of feline immunodeficiency virus (FIV), a range of viral variants emerged with distinct modes of interaction with the viral receptors CD134 and CXCR4, and sensitivities to neutralizing antibodies. In order to assess whether this viral diversity would be maintained following subsequent transmission, a synthetic quasispecies was reconstituted comprising molecular clones bearing envs from six viral variants and its replicative capacity compared in vivo with a clonal preparation of the parent virus. Infection with either clonal (Group 1) or diverse (Group 2) challenge viruses, resulted in a reduction in CD4+ lymphocytes and an increase in CD8+ lymphocytes. Proviral loads were similar in both study groups, peaking by 10 weeks post-infection, a higher plateau (set-point) being achieved and maintained in study Group 1. Marked differences in the ability of individual viral variants to replicate were noted in Group 2; those most similar to GL8 achieved higher viral loads while variants such as the chimaeras bearing the B14 and B28 Envs grew less well. The defective replication of these variants was not due to suppression by the humoral immune response as virus neutralising antibodies were not elicited within the study period. Similarly, although potent cellular immune responses were detected against determinants in Env, no qualitative differences were revealed between animals infected with either the clonal or the diverse inocula. However, in vitro studies indicated that the reduced replicative capacity of variants B14 and B28 in vivo was associated with altered interactions between the viruses and the viral receptor and co-receptor. The data suggest that viral variants with GL8-like characteristics have an early, replicative advantage and should provide the focus for future vaccine development