Abstract
Plasmids are mobile genetic elements found in many clades of Archaea and Bacteria. They drive horizontal gene transfer, impacting ecological and evolutionary processes within microbial ...communities, and hold substantial importance in human health and biotechnology. To support plasmid research and provide scientists with data of an unprecedented diversity of plasmid sequences, we introduce the IMG/PR database, a new resource encompassing 699 973 plasmid sequences derived from genomes, metagenomes and metatranscriptomes. IMG/PR is the first database to provide data of plasmid that were systematically identified from diverse microbiome samples. IMG/PR plasmids are associated with rich metadata that includes geographical and ecosystem information, host taxonomy, similarity to other plasmids, functional annotation, presence of genes involved in conjugation and antibiotic resistance. The database offers diverse methods for exploring its extensive plasmid collection, enabling users to navigate plasmids through metadata-centric queries, plasmid comparisons and BLAST searches. The web interface for IMG/PR is accessible at https://img.jgi.doe.gov/pr. Plasmid metadata and sequences can be downloaded from https://genome.jgi.doe.gov/portal/IMG_PR.
Graphical Abstract
Graphical Abstract
Osterix (Osx) is essential for osteoblast differentiation and bone formation, because mice lacking Osx die within 1 h of birth with a complete absence of intramembranous and endochondral bone ...formation. Perinatal lethality caused by the disruption of the Osx gene prevents studies of the role of Osx in bones that are growing or already formed. Here, the function of Osx was examined in adult bones using the time‐ and site‐specific Cre/loxP system. Osx was inactivated in all osteoblasts by Col1a1‐Cre with the activity of Cre recombinase under the control of the 2.3‐kb collagen promoter. Even though no bone defects were observed in newborn mice, Osx inactivation with 2.3‐kb Col1a1‐Cre exhibited osteopenia phenotypes in growing mice. BMD and bone‐forming rate were decreased in lumbar vertebra, and the cortical bone of the long bones was thinner and more porous with reduced bone length. The trabecular bones were increased, but they were immature or premature. The expression of early marker genes for osteoblast differentiation such as Runx2, osteopontin, and alkaline phosphatase was markedly increased, but the late marker gene, osteocalcin, was decreased. However, no functional defects were found in osteoclasts. In summary, Osx inactivation in growing bones delayed osteoblast maturation, causing an accumulation of immature osteoblasts and reducing osteoblast function for bone formation, without apparent defects in bone resorption. These findings suggest a significant role of Osx in positively regulating osteoblast differentiation and bone formation in adult bone.
Ligands targeting GPCRs can be categorized according to their intrinsic efficacy to trigger a specific, receptor‐mediated response. A ligand endowed with the same level of efficacy as the endogenous ...agonist can be classified as a full agonist, whereas a compound that displays greater efficacy, that is, higher receptor signalling output than the endogenous agonist, can be called a superagonist. Subsequent to GPCR activation, an intracellular signalling cascade is set in motion, which may generate substantial amplification of the signal. This may obscure superagonism in pharmacological assays and, therefore, the definition of superagonism necessitates a combination of operational approaches, reduction of spare receptors or estimation of receptor activation close to the receptor level to quantify relative agonist efficacies in a particular system.
The first part of this review will compare GPCR superagonism with superagonism in the field of immunology, where this term is well established. In the second part, known GPCR superagonists will be reviewed. Then, the experimental and analytical challenges in the deconvolution of GPCR superagonism will be addressed. Finally, the potential benefit of superagonism is discussed.
The molecular mechanisms behind GPCR superagonism are not completely understood. However, crystallography shows that agonist binding alone is not sufficient for a fully active receptor state and that binding of the G protein is at least equally important. Accordingly, the emerging number of reported superagonists implies that ligand‐induced receptor conformations more active than the ones stabilized by the endogenous agonist are indeed feasible. Superagonists may have therapeutic potential when receptor function is impaired or to induce negative feedback mechanisms.
Linked Articles
This article is part of a themed section on Molecular Pharmacology of G Protein‐Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc
Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the ...genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
Persistence of leukemic stem cells (LSC) after chemotherapy is thought to be responsible for relapse and prevents the curative treatment of acute myeloid leukemia (AML) patients. LSC and normal ...hematopoietic stem cells (HSC) share many characteristics and co-exist in the bone marrow of AML patients. For the development of successful LSC-targeted therapy, enabling eradication of LSC while sparing HSC, the identification of differences between LSC and HSC residing within the AML bone marrow is crucial. For identification of these LSC targets, as well as for AML LSC characterization, discrimination between LSC and HSC within the AML bone marrow is imperative. Here we show that normal CD34+CD38- HSC present in AML bone marrow, identified by their lack of aberrant immunophenotypic and molecular marker expression and low scatter properties, are a distinct sub-population of cells with high ALDH activity (ALDH(bright)). The ALDH(bright) compartment contains, besides normal HSC, more differentiated, normal CD34+CD38+ progenitors. Furthermore, we show that in CD34-negative AML, containing solely normal CD34+ cells, LSC are CD34- and ALDH(low). In CD34-positive AML, LSC are also ALDH(low) but can be either CD34+ or CD34-. In conclusion, although malignant AML blasts have varying ALDH activity, a common feature of all AML cases is that LSC have lower ALDH activity than the CD34+CD38- HSC that co-exist with these LSC in the AML bone marrow. Our findings form the basis for combined functionally and immunophenotypically based identification and purification of LSC and HSC within the AML bone marrow, aiming at development of highly specific anti-LSC therapy.
Olivine, orthopyroxene, clinopyroxene and spinel from 16 different lherzolite mantle xenoliths from Damaping (Hannuoba region, NE-China) have been analyzed by X-ray single crystal diffraction and ...electron microprobe to define their structure, chemistry and cation distribution. LA-ICP-MS analysis has been carried out on clinopyroxenes to determine their LILE (Large-Ion Lithophile Elements), HFSE (High Field Strength Elements) and REE (Rare Earth Elements) contents. These latter define Depleted, Enriched, U-shaped and Transitional CI-normalized patterns suggesting that the xenolith suite here studied experienced at least two metasomatic events related to the porous flow percolation of melts with tholeiitic and alkaline affinity, respectively. The cation distribution of the mineral phases allowed determination of their intra- and inter-crystalline temperatures of equilibration. The closure temperature of intra-crystalline reactions for the constituent phases is in the range 600–800°C, suggesting a relatively slow cooling rate, while the inter-crystalline temperature interval found out is in the range 866–1048°C. The pressure conditions estimated for Hannuoba xenoliths through structural considerations correspond to a depth of about 50–60km, consistent with the Moho depth beneath the Hannuoba area, which is estimated at about 42km. The pressures of equilibration, as estimated from the cell and T site volumes of the clinopyroxenes, have been compared with the trace element and REE signatures; they demonstrate that Enriched, Depleted, U-shaped and Transitional clinopyroxenes formed at different pressures and are not restricted to a specific region of the mantle, testifying that the metasomatism took place at different depths in the mantle.
•Structure and cation distribution of ol, opy, cpx and sp from Damaping mantle xenoliths•Intra- and inter-crystalline temperatures of equilibration•Pressure conditions from structural consideration correspond to a depth of about 50–60km.•Trace and REE contents of cpx define Enriched, Depleted, and U-shaped trends.•Different metasomatism took place at different depths in the mantle.
Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential ...methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.
The Norian magmatic rocks of Jabuka, Brusnik and Vis Islands (Croatia) and their bearing on the evolution of Triassic magmatism in the Northern Mediterranean. The magmatic rocks from Jabuka, Brusnik, ...Vis Islands and the submerged Brusnik plateau have been investigated to define their age and genetic affinity, identifying their role in the geodynamics of the Adria Plate. The plutonic and lava flow samples have been characterized for their petrography, mineral chemistry, whole rock major and trace elements, and Sr and Nd isotopic compositions. The two samples with the freshest plagioclase crystals have been selected for
40
Ar/
39
Ar analysis, which gave ages of 221.5 ± 2.5 Ma (Brusnik) and 227 ± 5 Ma (Jabuka), similar to those of the Triassic magmatism from the northern part of the Adria Plate and neighbouring territories. Geochemical and isotopic data suggest that the magmatism dominantly sourced from spinel peridotites variously metasomatized during pre-Mesozoic subduction events. Furthermore, the investigated rocks evidence interactions of the magmas with Mid-Late Triassic evaporites. The comparison with other coeval magmatic occurrences from the Adria Plate and its edges shows that the subduction signature of the Triassic within-plate magmatism is mainly related to the evolution of the upper mantle of the Adria Plate.
The rocky, seasonally-dry and nutrient-impoverished soils of the Brazilian campos rupestres impose severe growth-limiting conditions on plants. Species of a dominant plant family, Velloziaceae, are ...highly specialized to low-nutrient conditions and seasonal water availability of this environment, where phosphorus (P) is the key limiting nutrient. Despite plant-microbe associations playing critical roles in stressful ecosystems, the contribution of these interactions in the campos rupestres remains poorly studied. Here we present the first microbiome data of Velloziaceae spp. thriving in contrasting substrates of campos rupestres. We assessed the microbiomes of Vellozia epidendroides, which occupies shallow patches of soil, and Barbacenia macrantha, growing on exposed rocks. The prokaryotic and fungal profiles were assessed by rRNA barcode sequencing of epiphytic and endophytic compartments of roots, stems, leaves and surrounding soil/rocks. We also generated root and substrate (rock/soil)-associated metagenomes of each plant species. We foresee that these data will contribute to decipher how the microbiome contributes to plant functioning in the campos rupestres, and to unravel new strategies for improved crop productivity in stressful environments.
The Central Atlantic Magmatic Province (CAMP) is defined by tholeiitic basalts that crop out in once-contiguous parts of North America, Europe, Africa, and South America and is associated with the ...breakup of Pangea. $^{40}$Ar/$^{39}$Ar and paleomagnetic data indicate that CAMP magmatism extended over an area of 2.5 million square kilometers in north and central Brazil, and the total aerial extent of the magmatism exceeded 7 million square kilometers in a few million years, with peak activity at 200 million years ago. The magmatism coincided closely in time with a major mass extinction at the Triassic-Jurassic boundary.
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