Topological Analysis of Metabolic Networks Integrating Co-Segregating Transcriptomes and Metabolomes in Type 2 Diabetic Rat Congenic Series

Background: The genetic regulation of metabolic phenotypes (i.e., metabotypes) in type 2 diabetes mellitus is caused by complex organ-specific cellular mechanisms contributing to impaired insulin secretion and insulin resistance. Methods: We used systematic metabotyping by 1H NMR spectroscopy and genome-wide gene expression in white adipose tissue to map molecular phenotypes to genomic blocks associated with obesity and insulin secretion in a series of rat congenic strains derived from spontaneously diabetic Goto-Kakizaki (GK) and normoglycemic Brown-Norway (BN) rats. We implemented a network biology strategy approach to visualise shortest paths between metabolites and genes significantly associated with each genomic block. Results: Despite strong genomic similarities (95-99%) among congenics, each strain exhibited specific patterns of gene expression and metabotypes, reflecting metabolic consequences of series of linked genetic polymorphisms in the congenic intervals. We subsequently used the congenic panel to map quantitative trait loci underlying specific metabotypes (mQTL) and genome-wide expression traits (eQTL). Variation in key metabolites like glucose, succinate, lactate or 3-hydroxybutyrate, and second messenger precursors like inositol was associated with several independent genomic intervals, indicating functional redundancy in these regions. To navigate through the complexity of these association networks we mapped candidate genes and metabolites onto metabolic pathways and implemented a shortest path strategy to highlight potential mechanistic links between metabolites and transcripts at colocalized mQTLs and eQTLs. Minimizing shortest path length drove prioritization of biological validations by gene silencing. Conclusions: These results underline the importance of network-based integration of multilevel systems genetics datasets to improve understanding of the genetic architecture of metabotype and transcriptomic regulations and to characterize novel functional roles for genes determining tissue-specific metabolism

Origins of Chevron Rollovers in Non-Two-State Protein Folding Kinetics

Chevron rollovers of some proteins imply that their logarithmic folding rates are nonlinear in native stability. This is predicted by lattice and continuum G\=o models to arise from diminished accessibilities of the ground state from transiently populated compact conformations under strongly native conditions. Despite these models' native-centric interactions, the slowdown is due partly to kinetic trapping caused by some of the folding intermediates' nonnative topologies. Notably, simple two-state folding kinetics of small single-domain proteins are not reproduced by common G\=o-like schemes.Comment: 10 pages, 4 Postscript figures (will appear on PRL

Estimating logged-over lowland rainforest aboveground biomass in Sabah, Malaysia using airborne LiDAR data

Unprecedented deforestation and forest degradation in recent decades have severely depleted the carbon storage in Borneo. Estimating aboveground biomass (AGB) with high accuracy is crucial to quantifying carbon stocks for Reducing Emissions from Deforestation and Forest Degradation-plus implementation (REDD+). Airborne Light Detection and Ranging (LiDAR) is a promising remote sensing technology that provides fine-scale forest structure variability data. This paper highlights the use of airborne LiDAR data for estimating the AGB of a logged-over tropical forest in Sabah, Malaysia. The LiDAR data was acquired using an Optech Orion C200 sensor onboard a fixed wing aircraft. The canopy height of each LiDAR point was calculated from the height difference between the first returns and the Digital Terrain Model (DTM) constructed from the ground points. Among the obtained LiDAR height metrics, the mean canopy height produced the strongest relationship with the observed AGB. This single-variable model had a root mean squared error (RMSE) of 80.02 t ha-1 or 22.31% of the mean AGB, which performed exceptionally when compared with recent tropical rainforest studies. Overall, airborne LiDAR did provide fine-scale canopy height measurements for accurately and reliably estimating the AGB in a logged-over forest in Sabah, thus supporting the state's effort in realizing the REDD+ mechanism

Energetic Components of Cooperative Protein Folding

A new lattice protein model with a four-helix bundle ground state is analyzed by a parameter-space Monte Carlo histogram technique to evaluate the effects of an extensive variety of model potentials on folding thermodynamics. Cooperative helical formation and contact energies based on a 5-letter alphabet are found to be insufficient to satisfy calorimetric and other experimental criteria for two-state folding. Such proteinlike behaviors are predicted, however, by models with polypeptide-like local conformational restrictions and environment-dependent hydrogen bonding-like interactions.Comment: 11 pages, 4 postscripts figures, Phys. Rev. Lett. (in press

Characterisation of adipocyte-derived extracellular vesicle subtypes identifies distinct protein and lipid signatures for large and small extracellular vesicles

Extracellular vesicles (EVs) are biological vectors that can modulate the metabolism of target cells by conveying signalling proteins and genomic material. The level of EVs in plasma is significantly increased in cardiometabolic diseases associated with obesity, suggesting their possible participation in the development of metabolic dysfunction. With regard to the poor definition of adipocyte-derived EVs, the purpose of this study was to characterise both qualitatively and quantitatively EVs subpopulations secreted by fat cells. Adipocyte-derived EVs were isolated by differential centrifugation of conditioned media collected from 3T3-L1 adipocytes cultured for 24 h in serum-free conditions. Based on morphological and biochemical properties, as well as quantification of secreted EVs, we distinguished two subpopulations of adipocyte-derived EVs, namely small extracellular vesicles (sEVs) and large extracellular vesicles (lEVs). Proteomic analyses revealed that lEVs and sEVs exhibit specific protein signatures, allowing us not only to define novel markers of each population, but also to predict their biological functions. Despite similar phospholipid patterns, the comparative lipidomic analysis performed on these EV subclasses revealed a specific cholesterol enrichment of the sEV population, whereas lEVs were characterised by high amounts of externalised phosphatidylserine. Enhanced secretion of lEVs and sEVs is achievable following exposure to different biological stimuli related to the chronic low-grade inflammation state associated with obesity. Finally, we demonstrate the ability of primary murine adipocytes to secrete sEVs and lEVs, which display physical and biological characteristics similar to those described for 3T3-L1. Our study provides additional information and elements to define EV subtypes based on the characterisation of adipocyte-derived EV populations. It also underscores the need to distinguish EV subpopulations, through a combination of multiple approaches and markers, since their specific composition may cause distinct metabolic responses in recipient cells and tissues

Assessing the Criteria for Definition of Perimembranous Ventricular Septal Defects in Light of the Search for Consensus

Background: Discussions continue as to whether ventricular septal defects are best categorized according to their right ventricular geography or their borders. This is especially true when considering the perimembranous defect. Our aim, therefore, was to establish the phenotypic feature of the perimembranous defect, and to establish the ease of distinguishing its geographical variants. Methods and results: We assessed unrepaired isolated perimembranous ventricular defects from six historic archives, subcategorizing them using the ICD-11 coding system. We identified 365 defects, of which 94 (26%) were deemed to open centrally, 168 (46%) to open to the outlet, and 84 (23%) to the inlet of the right ventricle, with 19 (5%) being confluent. In all hearts, the unifying phenotypic feature was fibrous continuity between the leaflets of the mitral and tricuspid valves. This was often directly between the valves, but in all instances incorporated continuity through the atrioventricular portion of the membranous septum. In contrast, we observed fibrous continuity between the leaflets of the tricuspid and aortic valves in only 298 (82%) of the specimens. When found, discontinuity most commonly was seen in the outlet and central defects. There were no discrepancies between evaluators in distinguishing the borders, but there was occasional disagreement in determining the right ventricular geography of the defect. Conclusions: The unifying feature of perimembranous defects, rather than being aortic-to-tricuspid valvar fibrous continuity, is fibrous continuity between the leaflets of the atrioventricular valves. While right ventricular geography is important in classification, it is the borders which are more objectively defined

Lichenological exploration of Algeria: historical overview and annotated bibliography, 1799-2013

yesDespite more than two centuries of almost uninterrupted surveys and studies of Algerian lichenology, the history and lichen diversity of Algeria are still poorly understood. During the preparation of a forthcoming checklist of Algerian lichens it was considered necessary to provide the present historical overview of lichenological exploration of the country from 1799 to 2013, supported by a reasonably comprehensive annotated bibliography of 171 titles

IL-23 plays a key role in Helicobacter hepaticus–induced T cell–dependent colitis

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that is caused in part by a dysregulated immune response to the intestinal flora. The common interleukin (IL)-12/IL-23p40 subunit is thought to be critical for the pathogenesis of IBD. We have analyzed the role of IL-12 versus IL-23 in two models of Helicobacter hepaticus–triggered T cell–dependent colitis, one involving anti–IL-10R monoclonal antibody treatment of infected T cell–sufficient hosts, and the other involving CD4+ T cell transfer into infected Rag−/− recipients. Our data demonstrate that IL-23 and not IL-12 is essential for the development of maximal intestinal disease. Although IL-23 has been implicated in the differentiation of IL-17–producing CD4+ T cells that alone are sufficient to induce autoimmune tissue reactivity, our results instead support a model in which IL-23 drives both interferon γ and IL-17 responses that together synergize to trigger severe intestinal inflammation