Clustering Phase Transitions and Hysteresis: Pitfalls in Constructing Network Ensembles

Ensembles of networks are used as null models in many applications. However, simple null models often show much less clustering than their real-world counterparts. In this paper, we study a model where clustering is enhanced by means of a fugacity term as in the Strauss (or "triangle") model, but where the degree sequence is strictly preserved -- thus maintaining the quenched heterogeneity of nodes found in the original degree sequence. Similar models had been proposed previously in [R. Milo et al., Science 298, 824 (2002)]. We find that our model exhibits phase transitions as the fugacity is changed. For regular graphs (identical degrees for all nodes) with degree k > 2 we find a single first order transition. For all non-regular networks that we studied (including Erdos - Renyi and scale-free networks) we find multiple jumps resembling first order transitions, together with strong hysteresis. The latter transitions are driven by the sudden emergence of "cluster cores": groups of highly interconnected nodes with higher than average degrees. To study these cluster cores visually, we introduce q-clique adjacency plots. We find that these cluster cores constitute distinct communities which emerge spontaneously from the triangle generating process. Finally, we point out that cluster cores produce pitfalls when using the present (and similar) models as null models for strongly clustered networks, due to the very strong hysteresis which effectively leads to broken ergodicity on realistic time scales.Comment: 13 pages, 11 figure

Collagen 24 α1 Is Increased in Insulin-Resistant Skeletal Muscle and Adipose Tissue

Aberrant extracellular matrix (ECM) remodelling in muscle, liver and adipose tissue is a key characteristic of obesity and insulin resistance. Despite its emerging importance, the effective ECM targets remain largely undefined due to limitations of current approaches. Here, we developed a novel ECM-specific mass spectrometry-based proteomics technique to characterise the global view of the ECM changes in the skeletal muscle and liver of mice after high fat (HF) diet feeding. We identified distinct signatures of HF-induced protein changes between skeletal muscle and liver where the ECM remodelling was more prominent in the muscle than liver. In particular, most muscle collagen isoforms were increased by HF diet feeding whereas the liver collagens were differentially but moderately affected highlighting a different role of the ECM remodelling in different tissues of obesity. Moreover, we identified a novel association between collagen 24α1 and insulin resistance in the skeletal muscle. Using quantitative gene expression analysis, we extended this association to the white adipose tissue. Importantly, collagen 24α1 mRNA was increased in the visceral adipose tissue, but not the subcutaneous adipose tissue of obese diabetic subjects compared to lean controls, implying a potential pathogenic role of collagen 24α1 in obesity and type 2 diabetes

Achilles Tendon Replacement by a Collagen Fiber Prosthesis: Morphological Evaluation of Neotendon Formation.

Reconstituted type I collagen was processed into fibers which were subsequently severely dehydrated and cyanamide cross-linked. Fibers prepared by this method were stronger and more resistant to degradation than uncrosslinked fibers. When used as a tendon replacement prosthesis, morphological events occurred which were observed by light, scanning, transmission electron microscopy and electron histochemistry. Resorption was the initial host response to the prosthesis and involved gradual biodegradation. Formation of a host-replacement tendon was the second response. Increased collagen fibril diameters and a transition in the proteoglycan/collagen fibril interactions occurred in the newly developing connective tissue between 3 and 10 weeks post-implantation. These extracellular matrix transitions were major events occurring during wound healing and led to the assembly of a mature connective tissue. When used as a tendon prosthesis, these collagen fibers rapidly resorb while allowing simultaneous formation of aligned connective tissue. The fibers may have other applications in the fields of Orthopaedic Surgery, Neurosurgery and Biomaterials Research

Dynamical Masses for Low-Mass Pre-Main Sequence Stars: A Preliminary Physical Orbit for HD 98800 B

We report on Keck Interferometer observations of the double-lined binary (B) component of the quadruple pre-main sequence (PMS) system HD 98800. With these interferometric observations combined with astrometric measurements made by the Hubble Space Telescope Fine Guidance Sensors (FGS), and published radial velocity observations we have estimated preliminary visual and physical orbits of the HD 98800 B subsystem. Our orbit model calls for an inclination of 66.8 $\pm$ 3.2 deg, and allows us to infer the masses and luminosities of the individual components. In particular we find component masses of 0.699 $\pm$ 0.064 and 0.582 $\pm$ 0.051 M_{\sun} for the Ba (primary) and Bb (secondary) components respectively. Modeling of the component SEDs finds temperatures and luminosities in agreement with previous studies, and coupled with the component mass estimates allows for comparison with PMS models in the low-mass regime with few empirical constraints. Solar abundance models seem to under-predict the inferred component temperatures and luminosities, while assuming slightly sub-solar abundances bring the models and observations into better agreement. The present preliminary orbit does not yet place significant constraints on existing pre-main sequence stellar models, but prospects for additional observations improving the orbit model and component parameters are very good.Comment: 20 pages, 6 figures, ApJ in press; tables 2 and 3 to be included in ApJ versio

FGF19 Action in the Brain Induces Insulin-Independent Glucose Lowering

Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving glucose tolerance in these animals. The gut-derived hormone FGF19 has previously been shown to exert potent antidiabetic effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved glucose intolerance within 2 hours. Minimal model analysis of glucose and insulin data obtained during a frequently sampled i.v. glucose tolerance test showed that the antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of glucose to lactate. Together, these findings implicate the brain in the antidiabetic action of systemic FGF19 and establish the brain’s capacity to rapidly, potently, and selectively increase insulin-independent glucose disposal

Limiting Extracellular Matrix Expansion in Diet-Induced Obese Mice Reduces Cardiac Insulin Resistance and Prevents Myocardial Remodelling

Aims/Hypothesis: Obesity increases deposition of extracellular matrix (ECM) components of cardiac tissue. Since obesity aggregates with insulin resistance and heart disease, it is imperative to determine whether the increased ECM deposition contributes to this disease cluster. The hypotheses tested in this study were that in cardiac tissue of obese mice i) increased deposition of ECM components (collagens and hyaluronan) contributes to cardiac insulin resistance and that a reduction in these components improves cardiac insulin action and ii) reducing excess collagens and hyaluronan mitigates obesity-associated cardiac dysfunction.Methods: Genetic and pharmacological approaches that manipulated collagen and hyaluronan contents were employed in obese C57BL/6 mice fed a high fat (HF) diet. Cardiac insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and cardiac function was measured by pressure-volume loop analysis in vivo.Results: We demonstrated a tight association between increased ECM deposition with cardiac insulin resistance. Increased collagen deposition by genetic deletion of matrix metalloproteinase 9 (MMP9) exacerbated cardiac insulin resistance and pirfenidone, a clinically available anti-fibrotic medication which inhibits collagen expression, improved cardiac insulin resistance in obese mice. Furthermore, decreased hyaluronan deposition by treatment with PEGylated human recombinant hyaluronidase PH20 (PEGPH20) improved cardiac insulin resistance in obese mice. These relationships corresponded to functional changes in the heart. Both PEGPH20 and pirfenidone treatment in obese mice ameliorated HF diet-induced abnormal myocardial remodelling.Conclusion: Our results provide important new insights into the role of ECM deposition in the pathogenesis of cardiac insulin resistance and associated dysfunction in obesity of distinct mouse models. These findings support the novel therapeutic potential of targeting early cardiac ECM abnormalities in the prevention and treatment of obesity-related cardiovascular complications.<br/

Limiting Extracellular Matrix Expansion in Diet-Induced Obese Mice Reduces Cardiac Insulin Resistance and Prevents Myocardial Remodelling

Aims/Hypothesis: Obesity increases deposition of extracellular matrix (ECM) components of cardiac tissue. Since obesity aggregates with insulin resistance and heart disease, it is imperative to determine whether the increased ECM deposition contributes to this disease cluster. The hypotheses tested in this study were that in cardiac tissue of obese mice i) increased deposition of ECM components (collagens and hyaluronan) contributes to cardiac insulin resistance and that a reduction in these components improves cardiac insulin action and ii) reducing excess collagens and hyaluronan mitigates obesity-associated cardiac dysfunction.Methods: Genetic and pharmacological approaches that manipulated collagen and hyaluronan contents were employed in obese C57BL/6 mice fed a high fat (HF) diet. Cardiac insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and cardiac function was measured by pressure-volume loop analysis in vivo.Results: We demonstrated a tight association between increased ECM deposition with cardiac insulin resistance. Increased collagen deposition by genetic deletion of matrix metalloproteinase 9 (MMP9) exacerbated cardiac insulin resistance and pirfenidone, a clinically available anti-fibrotic medication which inhibits collagen expression, improved cardiac insulin resistance in obese mice. Furthermore, decreased hyaluronan deposition by treatment with PEGylated human recombinant hyaluronidase PH20 (PEGPH20) improved cardiac insulin resistance in obese mice. These relationships corresponded to functional changes in the heart. Both PEGPH20 and pirfenidone treatment in obese mice ameliorated HF diet-induced abnormal myocardial remodelling.Conclusion: Our results provide important new insights into the role of ECM deposition in the pathogenesis of cardiac insulin resistance and associated dysfunction in obesity of distinct mouse models. These findings support the novel therapeutic potential of targeting early cardiac ECM abnormalities in the prevention and treatment of obesity-related cardiovascular complications.<br/