Understanding the drivers of energy and material flows of cities is important for addressing global environmental challenges. Accessing, sharing, and managing energy and material resources is particularly critical for megacities, which face enormous social stresses because of their sheer size and complexity. Here we quantify the energy and material flows through the world’s 27 megacities with populations greater than 10 million people as of 2010. Collectively the resource flows through megacities are largely consistent with scaling laws established in the emerging science of cities. Correlations are established for electricity consumption, heating and industrial fuel use, ground transportation energy use, water consumption, waste generation, and steel production in terms of heating-degree-days, urban form, economic activity, and population growth. The results help identify megacities exhibiting high and low levels of consumption and those making efficient use of resources. The correlation between per capita electricity use and urbanized area per capita is shown to be a consequence of gross building floor area per capita, which is found to increase for lower-density cities. Many of the megacities are growing rapidly in population but are growing even faster in terms of gross domestic product (GDP) and energy use. In the decade from 2001–2011, electricity use and ground transportation fuel use in megacities grew at approximately half the rate of GDP growth.

Objective. Osteoarthritic (OA) chondrocytes behave in an intrinsically deregulated manner, characterized by chronic loss of healthy cartilage and inappropriate differentiation to a hypertrophic-like state. IKK␣ and IKK␤ are essential kinases that activate NF-B transcription factors, which in turn regulate cell differentiation and inflammation. This study was undertaken to investigate the differential roles of each IKK in chondrocyte differentiation and hypertrophy.Methods. Expression of IKK␣ or IKK␤ was ablated in primary human chondrocytes by retrotransduction of specific short-hairpin RNAs. Micromass cultures designed to reproduce chondrogenesis with progression to the terminal hypertrophic stage were established, and anabolism and remodeling of the extracellular matrix (ECM) were investigated in the micromasses using biochemical, immunohistochemical, and ultrastructural techniques. Cellular parameters of hypertrophy (i.e., proliferation, viability, and size) were also analyzed.Results. The processes of ECM remodeling and mineralization, both characteristic of terminally differentiated hypertrophic cells, were defective following the loss of IKK␣ or IKK␤. Silencing of IKK␤ markedly enhanced accumulation of glycosaminoglycan in conjunction with increased SOX9 expression. Ablation of IKK␣ dramatically enhanced type II collagen deposition independent of SOX9 protein levels but in association with suppressed levels of runt-related transcription factor 2. Moreover, IKK␣-deficient cells retained the phenotype of cells in a pre-hypertrophic-like state, as evidenced by the smaller size and faster proliferation of these cells prior to micromass seeding, along with the enhanced viability of their differentiated micromasses.Conclusion. IKK␣ and IKK␤ exert differential roles in ECM remodeling and endochondral ossification, which are events characteristic of hypertrophic chondrocytes and also complicating factors often found in OA. Because the effects of IKK␣ were more profound and pleotrophic in nature, our observations suggest that exacerbated IKK␣ activity may be responsible, at least in part, for the characteristic abnormal phenotypes of OA chondrocytes.

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Objective. To link matrix metalloproteinase 13 (MMP-13) activity and extracellular matrix (ECM) remodeling to alterations in regulatory factors leading to a disruption in chondrocyte homeostasis.Methods. MMP-13 expression was ablated in primary human chondrocytes by stable retrotransduction of short hairpin RNA. The effects of MMP-13 knockdown on key regulators of chondrocyte differentiation (SOX9, runt-related transcription factor 2 [RUNX-2], and ␤-catenin) and angiogenesis (vascular endothelial growth factor [VEGF]) were scored at the protein level (by immunohistochemical or Western blot analysis) and RNA level (by real-time polymerase chain reaction) in high-density monolayer and micromass cultures under mineralizing conditions. Effects on cellular viability in conjunction with chondrocyte progression toward a hypertrophic-like state were assessed in micromass cultures. Alterations in SOX9 subcellular distribution were assessed using confocal microscopy in micromass cultures and also in osteoarthritic cartilage.Results. Differentiation of control chondrocyte micromasses progressed up to a terminal phase, with calcium deposition in conjunction with reduced cell viability and scant ECM. MMP-13 knockdown impaired ECM remodeling and suppressed differentiation in conjunction with reduced levels of RUNX-2, ␤-catenin, and VEGF. MMP-13 levels in vitro and ECM remodeling in vitro and in vivo were linked to changes in SOX9 subcellular localization. SOX9 was largely excluded from the nuclei of chondrocytes with MMP-13-remodeled or -degraded ECM, and exhibited an intranuclear staining pattern in chondrocytes with impaired MMP-13 activity in vitro or with more intact ECM in vivo.Conclusion. MMP-13 loss leads to a breakdown in primary human articular chondrocyte differentiation by altering the expression of multiple regulatory factors.The maturation of chondrocytes is arrested in articular cartilage, which prevents their differentiation toward a more terminal hypertrophic-like phenotype (1). The mechanisms maintaining articular chondrocyte homeostasis are perturbed in osteoarthritis (OA), in which chondrocytes recapitulate aspects of endochon-

Cardiac myocytes undergo apoptosis under condition of ischemia. Little is known, however, about the molecular pathways that mediate this response. We show that serum deprivation and hypoxia, components of ischemia in vivo, resulted in apoptosis of rat ventricular myoblast cells H9c2. Hypoxia alone did not induce signi¢cant apoptosis for at least 48 h, but largely increased the proapoptotic action of serum deprivation. H9c2 cells apoptosis is evidenced by an increase in terminal (TdT)-mediated dUTP nick end-labeling-positive nuclei and by activation of caspases 3, 6, 7 and 9, and loss of mitochondrial functions. In this model of simulated ischemia, represented by serum deprivation plus hypoxia, cardiomyoblasts apoptosis was associated with a p53-independent Bax accumulation and with a down-regulation of Bcl-xL, whereas the levels of cIAP-1, cIAP-2 and X-IAP proteins did not change. Phorbol-12-myristate-13-acetate signi¢cantly reduced the induction of apoptosis, inhibiting caspase 3 cleavage, Bax accumulation, Bcl-xL downregulation as well as restoring cell viability. ß