105 research outputs found
Meta-analysis confirms association between TNFA-G238A variant and JIA, and between PTPN22-C1858T variant and oligoarticular, RF-polyarticular and RF-positive polyarticular JIA
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Protecting an ecosystem service: approaches to understanding and mitigating threats to wild insect pollinators
Insect pollination constitutes an ecosystem service of global importance, providing significant economic and aesthetic benefits as well as cultural value to human society, alongside vital ecological processes in terrestrial ecosystems. It is therefore important to understand how insect pollinator populations and communities respond to rapidly changing environments if we are to maintain healthy and effective pollinator services. This paper considers the importance of conserving pollinator diversity to maintain a suite of functional traits to provide a diverse set of pollinator services. We explore how we can better understand and mitigate the factors that threaten insect pollinator richness, placing our discussion within the context of populations in predominantly agricultural landscapes in addition to urban environments. We highlight a selection of important evidence gaps, with a number of complementary research steps that can be taken to better understand: i) the stability of pollinator communities in different landscapes in order to provide diverse pollinator services; ii) how we can study the drivers of population change to mitigate the effects and support stable sources of pollinator services; and, iii) how we can manage habitats in complex landscapes to support insect pollinators and provide sustainable pollinator services for the future. We advocate a collaborative effort to gain higher quality abundance data to understand the stability of pollinator populations and predict future trends. In addition, for effective mitigation strategies to be adopted, researchers need to conduct rigorous field-testing of outcomes under different landscape settings, acknowledge the needs of end-users when developing research proposals and consider effective methods of knowledge transfer to ensure effective uptake of actions
Symptoms of periodontitis and antibody responses to Porphyromonas gingivalis in juvenile idiopathic arthritis
Meta-analysis of four new genome scans for lipid parameters and analysis of positional candidates in positive linkage regions
Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four samples with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the sample-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1cM of major candidate genes, namely APOB (LOD =2.1), LDLR (LOD =1.9) and APOE (LOD =1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate. © 2005 Nature Publishing Group. All rights reserved
Obatoclax is a direct and potent antagonist of membrane-restricted Mcl-1 and is synthetic lethal with treatment that induces Bim
Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations
Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage Ű /CD34 Ű /CD38 Ű /CD90 Ű ) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS i
Efficient Elimination of Cancer Cells by Deoxyglucose-ABT-263/737 Combination Therapy
As single agents, ABT-263 and ABT-737 (ABT), molecular antagonists of the Bcl-2 family, bind tightly to Bcl-2, Bcl-xL and Bcl-w, but not to Mcl-1, and induce apoptosis only in limited cell types. The compound 2-deoxyglucose (2DG), in contrast, partially blocks glycolysis, slowing cell growth but rarely causing cell death. Injected into an animal, 2DG accumulates predominantly in tumors but does not harm other tissues. However, when cells that were highly resistant to ABT were pre-treated with 2DG for 3 hours, ABT became a potent inducer of apoptosis, rapidly releasing cytochrome c from the mitochondria and activating caspases at submicromolar concentrations in a Bak/Bax-dependent manner. Bak is normally sequestered in complexes with Mcl-1 and Bcl-xL. 2DG primes cells by interfering with Bak-Mcl-1 association, making it easier for ABT to dissociate Bak from Bcl-xL, freeing Bak to induce apoptosis. A highly active glucose transporter and Bid, as an agent of the mitochondrial apoptotic signal amplification loop, are necessary for efficient apoptosis induction in this system. This combination treatment of cancer-bearing mice was very effective against tumor xenograft from hormone-independent highly metastasized chemo-resistant human prostate cancer cells, suggesting that the combination treatment may provide a safe and effective alternative to genotoxin-based cancer therapies
Breeding systems in Tolpis (Asteraceae) in the Macaronesian islands: the Azores, Madeira and the Canaries
Plants on oceanic islands often originate from
self-compatible (SC) colonizers capable of seed set by self fertilization. This fact is supported by empirical studies,
and is rooted in the hypothesis that one (or few) individuals
could find a sexual population, whereas two or more would
be required if the colonizers were self-incompatible (SI).
However, a SC colonizer would have lower heterozygosity
than SI colonizers, which could limit radiation and diver sification of lineages following establishment. Limited
evidence suggests that several species-rich island lineages
in the family Asteraceae originated from SI colonizers with
some ââleakinessââ (pseudo-self-compatibility, PSC) such
that some self-seed could be produced. This study of Tolpis
(Asteraceae) in Macaronesia provides first reports of the
breeding system in species from the Azores and Madeira,
and additional insights into variation in Canary Islands.
Tolpis from the Azores and Madeira are predominately SI
but with PSC. This study suggests that the breeding sys tems of the ancestors were either PSC, possibly from a
single colonizer, or from SI colonizers by multiple dis seminules either from a single or multiple dispersals. Long distance colonists capable of PSC combine the advantages
of reproductive assurance (via selfing) in the establishment
of sexual populations from even a single colonizer with the
higher heterozygosity resulting from its origin from an
outcrossed source population. Evolution of Tolpis on the
Canaries and Madeira has generated diversity in breeding
systems, including the origin of SC. Macaronesian Tolpis is
an excellent system for studying breeding system evolution
in a small, diverse lineage.info:eu-repo/semantics/publishedVersio
Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.
Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.JS, DES and ARB thank the Wellcome Trust for funding.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nrd.2016.2
52 Genetic Loci Influencing Myocardial Mass.
BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 à 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets
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