An investigation of polymorphisms in the 17q11.2-12 CC chemokine gene cluster for association with multiple sclerosis in Australians

BACKGROUND: Multiple sclerosis (MS) is a disorder of the central nervous system (CNS) characterised by inflammation and neuronal degeneration. It is believed to result from the complex interaction of a number of genes, each with modest effect. Chemokines are vital to the migration of cells to sites of inflammation, including the CNS, and many are implicated in MS pathogenesis. Most of the CC chemokine genes are encoded in a cluster on chromosome 17q11.2-12, which has been identified in a number of genome wide screens as being potentially associated with MS. METHODS: We conducted a two-stage analysis to investigate the chemokine gene cluster for association with MS. After sequencing the chemokine genes in several DNA pools to identify common polymorphisms, 12 candidate single-nucleotide polymorphisms (SNPs) were genotyped in a cohort of Australian MS trio families. RESULTS: Marginally significant (uncorrected) transmission distortion was identified for four of the SNPs after stratification for several factors. We also identified marginally significant (uncorrected) transmission distortion for haplotypes encompassing the CCL2 and CCL11 genes, using two independent cohorts, which was consistent with recent reports from another group. CONCLUSION: Our results implicate several chemokines as possibly being associated with MS susceptibility, and given that chemokines and their receptors are suitable targets for therapeutic agents, further investigation is warranted in this region

Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements

Physical interactions between genetic elements located throughout the genome play important roles in gene regulation and can be identified with the Chromosome Conformation Capture (3C) methodology. 3C converts physical chromatin interactions into specific ligation products, which are quantified individually by PCR. Here we present a high-throughput 3C approach, 3C-Carbon Copy (5C), that employs microarrays or quantitative DNA sequencing using 454-technology as detection methods. We applied 5C to analyze a 400-kb region containing the human beta-globin locus and a 100-kb conserved gene desert region. We validated 5C by detection of several previously identified looping interactions in the beta-globin locus. We also identified a new looping interaction in K562 cells between the beta-globin Locus Control Region and the gamma-beta-globin intergenic region. Interestingly, this region has been implicated in the control of developmental globin gene switching. 5C should be widely applicable for large-scale mapping of cis- and trans- interaction networks of genomic elements and for the study of higher-order chromosome structure

Assessing, quantifying and valuing the ecosystem services of coastal lagoons

The natural conservation of coastal lagoons is important not only for their ecological importance, but also because of the valuable ecosystem services they provide for human welfare and wellbeing. Coastal lagoons are shallow semi-enclosed systems that support important habitats such as wetlands, mangroves, salt-marshes and seagrass meadows, as well as a rich biodiversity. Coastal lagoons are also complex social-ecological systems with ecosystem services that provide livelihoods, wellbeing and welfare to humans. This study assessed, quantified and valued the ecosystem services of 32 coastal lagoons. The main findings of the study are: (i) the definitions of ecosystem services are still not generally accepted; (ii) the quantification of ecosystem services is made in many different ways, using different units; (iii) the evaluation in monetary terms of some ecosystem service is problematic, often relying on non-monetary evaluation methods; (iv) when ecosystem services are valued in monetary terms, this may represent very different human benefits; and, (v) different aspects of climate change, including increasing temperature, sea-level rise and changes in rainfall patterns threaten the valuable ecosystem services of coastal lagoons.DEVOTES project, from the European Union's Seventh Framework Programme for research, technological development and demonstration [308392]; networks and communities of Eurolag; Future Earth Coasts; SCOR; Fundacao para a Ciencia e a Tecnologia (FCT) Investigador Programme [IF/00331/2013]; Fundacao para a Ciencia e a Tecnologia [UID/MAR/04292/2013]; CESAM by FCT/MEC national funds (PIDDAC) [UID/AMB/50017/2013 - POCI-01-0145-FEDER-007638]; FEDER; European Commission, under the 7th Framework Programme through the collaborative research project LAGOONS [283157]; FCT [SFRH/BPD/107823/2015, SFRH/BPD/91494/2012

Physical Delithiation of Epitaxial LiCoO2 Battery Cathodes as a Platform for Surface Electronic Structure Investigation

We report a novel delithiation process for epitaxial thin films of LiCoO2(001) cathodes using only physical methods, based on ion sputtering and annealing cycles. Preferential Li sputtering followed by annealing produces a surface layer with a Li molar fraction in the range 0.5 < x < 1, characterized by good crystalline quality. This delithiation procedure allows the unambiguous identification of the effects of Li extraction without chemical byproducts and experimental complications caused by electrolyte interaction with the LiCoO2 surface. An analysis by X-ray photoelectron spectroscopy (XPS) and X-ray absorption spectroscopy (XAS) provides a detailed description of the delithiation process and the role of O and Co atoms in charge compensation. We observe the simultaneous formation of Co4+ ions and of holes localized near O atoms upon Li removal, while the surface shows a (2 × 1) reconstruction. The delithiation method described here can be applied to other crystalline battery elements and provide information on their properties that is otherwise difficult to obtainThis work was supported by the Spanish MICINN (grant nos. PID2021-123295NB-I00 and PID2020-117024GB-C43), MAT2017-83722-R, “María de Maeztu” Programme for Units of Excellence in R&D (CEX2018-000805-M), within the framework of UE M-ERA.NET 2018 program under StressLIC Project (grant no. PCI2019-103594) and by the Comunidad Autónoma de Madrid (contract no. PEJD-2019- PRE/IND-15769 and S2108-NMT4321). The authors acknowledge Elettra Sincrotrone Trieste for providing access to its synchrotron radiation facilities. They thank Ignacio Carabias from the Diffraction Unit CAI UCM for his experimental support and helpful comments. The research leading to this result has been supported by the project CALIPSOplus under Grant Agreement 730872 from the EU Framework Programme for Research and Innovation HORIZON 2020. M.J., P.M., I.P., and F.B. acknowledge funding from EUROFEL (RoadMap Esfri). The work at the University of Maryland was supported by ONR MURI (Award No. N00014-17-1-2661). The work at Sandia National Laboratories was supported by the Laboratory-Directed Research and Development (LDRD) Program and the DOE Basic Energy Sciences Award number DE-SC0021070. Sandia National Laboratories is a multimission laboratory managed and operated by National Technology and Engineering Solutions of Sandia, LLC, a wholly owned subsidiary of Honeywell International, Inc., for the US Department of Energy’s National Nuclear Security Administration under contract DE-NA 000352

Theta-point behavior of diluted polymer solutions: Can one observe the universal logarithmic corrections predicted by field theory?

In recent large scale Monte-Carlo simulations of various models of Theta-point polymers in three dimensions Grassberger and Hegger found logarithmic corrections to mean field theory with amplitudes much larger than the universal amplitudes of the leading logarithmic corrections calculated by Duplantier in the framework of tricritical O(n) field theory. To resolve this issue we calculate the universal subleading correction of field theory, which turns out to be of the same order of magnitude as the leading correction for all chain lengths available in present days simulations. Borel resummation of the renormalization group flow equations also shows the presence of such large corrections. This suggests that the published simulations did not reach the asymptotic regime. To further support this view, we present results of Monte-Carlo simulations on a Domb-Joyce like model of weakly interacting random walks. Again the results cannot be explained by keeping only the leading corrections, but are in fair accord with our full theoretical result. The corrections found for the Domb-Joyce model are much smaller than those for other models, which clearly shows that the effective corrections are not yet in the asymptotic regime. All together our findings show that the existing simulations of Theta-polymers are compatible with tricritical field theory since the crossover to the asymptotic regime is very slow. Similar results were found earlier for self avoiding walks at their upper critical dimension d=4.Comment: 15 pages,6 figure

mQC : a post-mapping data exploration tool for ribosome profiling

Background and objective: Ribosome profiling is a recent next generation sequencing technique enabling the genome-wide study of gene expression in biomedical research at the translation level. Too often, researchers precipitously start trying to test their hypotheses after alignment of their data, without checking the quality and the general features of their mapped data. Despite the fact that these checks are essential to prevent errors and ensure valid conclusions afterwards, easy-to-use tools for visualizing the quality and overall outlook of mapped ribosome profiling data are lacking. Methods: We present mQC, a modular tool implemented as a Bioconda package and also available in the Galaxy tool shed. Herewith both bio-informaticians as well as non-experts can easily perform the indispensable visualization of both the quality and the general features of their mapped P-site corrected ribosome profiling reads. The user manual, the raw code and more information can be found on its GitHub repository (https://github.com/Biobix/mQC). Results: mQC was tested on multiple datasets to assess its general applicability and was compared to other tools that partly perform similar tasks. Conclusions: Our results demonstrate that mQC can accomplish an unfilled but essential position in the ribosome profiling data analysis procedure by performing a thorough RIBO-Seq-specific exploration of aligned and P-site corrected ribosome profiling data

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Multiple Sclerosis Susceptibility-Associated SNPs Do Not Influence Disease Severity Measures in a Cohort of Australian MS Patients

Recent association studies in multiple sclerosis (MS) have identified and replicated several single nucleotide polymorphism (SNP) susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13–14 in addition to the well established allele HLA-DR15. There is potential that these genetic susceptibility factors could also modulate MS disease severity, as demonstrated previously for the MS risk allele HLA-DR15. We investigated this hypothesis in a cohort of 1006 well characterised MS patients from South-Eastern Australia. We tested the MS-associated SNPs for association with five measures of disease severity incorporating disability, age of onset, cognition and brain atrophy. We observed trends towards association between the RPL5 risk SNP and time between first demyelinating event and relapse, and between the CD40 risk SNP and symbol digit test score. No associations were significant after correction for multiple testing. We found no evidence for the hypothesis that these new MS disease risk-associated SNPs influence disease severity

Variants of ST8SIA1 Are Associated with Risk of Developing Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system of unknown etiology with both genetic and environmental factors playing a role in susceptibility. To date, the HLA DR15/DQ6 haplotype within the major histocompatibility complex on chromosome 6p, is the strongest genetic risk factor associated with MS susceptibility. Additional alleles of IL7 and IL2 have been identified as risk factors for MS with small effect. Here we present two independent studies supporting an allelic association of MS with polymorphisms in the ST8SIA1 gene, located on chromosome 12p12 and encoding ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1. The initial association was made in a single three-generation family where a single-nucleotide polymorphism (SNP) rs4762896, was segregating together with HLA DR15/DQ6 in MS patients. A study of 274 family trios ( affected child and both unaffected parents) from Australia validated the association of ST8SIA1 in individuals with MS, showing transmission disequilibrium of the paternal alleles for three additional SNPs, namely rs704219, rs2041906, and rs1558793, with p = 0.001, p = 0.01 and p = 0.01 respectively. These findings implicate ST8SIA1 as a possible novel susceptibility gene for MS

Biological Treatment and the Potential Risk of Adverse Postoperative Outcome in Patients With Inflammatory Bowel Disease: An Open-Source Expert Panel Review of the Current Literature and Future Perspectives

Abstract Background There is widespread concern that treatment with biologic agents may be associated with suboptimal postoperative outcome after surgery for inflammatory bowel diseases (IBD). Aim We aimed to search and analyze the literature regarding the potential association of biologic treatment on adverse postoperative outcome in patients with IBD. We used the subject as a case in point for surgical research. The aim was not to conduct a new systematic review. Method This is an updated narrative review written in a collaborative method by authors invited through Twitter via the following hashtags (#OpenSourceResearch and #SoMe4Surgery). The manuscript was presented as slides on Twitter to allow discussion of each section of the paper sequentially. A Google document was created, which was shared across social media, and comments and edits were verified by the primary author to ensure accuracy and consistency. Results Forty-one collaborators responded to the invitation, and a total of 106 studies were identified that investigated the potential association of preoperative biological treatment on postoperative outcome in patients with IBD. Most of these studies were retrospective observational cohorts: 3 were prospective, 4 experimental, and 3 population-based studies. These studies were previously analyzed in 10 systematic/narrative reviews and 14 meta-analyses. Type of biologic agents, dose, drug concentration, antidrug antibodies, interval between last dose, and types of surgery varied widely among the studies. Adjustment for confounders and bias control ranged from good to very poor. Only 10 studies reported postoperative outcome according to Clavien–Dindo classification. Conclusion Although a large number of studies investigated the potential effect of biological treatment on postoperative outcomes, many reported divergent results. There is a need for randomized controlled trials. Future studies should focus on the avoiding the weakness of prior studies we identified. Seeking collaborators and sharing information via Twitter was integral to widening the contributors/authors and peer review for this article and was an effective method of collaboration