Cysteine cathepsin proteases play critical roles in cardiovascular disease progression and are implicated in extracellular matrix (ECM) degradation. Patients with pulmonary arterial hypertension (PAH) exhibit increased elastase production by pulmonary arterial smooth muscle cells (PASMCs), which is related to the degradation of elastic fibers and pulmonary vascular remodeling. However, the mechanism by which cathepsins regulate the ECM and PASMC proliferation in PAH remains unclear. We hypothesized that cathepsin proteases in PASMCs promote the development of PAH. Here, we show overexpression of cathepsin S (Cat S) and degradation of elastic laminae in the lungs of patients with idiopathic PAH and in the PASMCs of monocrotaline-induced PAH model (MCT-PAH) rats. In addition, pulmonary hypertension can be treated in MCT-PAH rats by administering a selective Cat S inhibitor, Millipore-219393, which stimulates peroxisome proliferator-activated receptor-γ (PPARγ) to inhibit the expression of Cat S, thus suppressing the proliferation and migration of MCT-PAH PASMCs. We then reduced Cat S or PPARγ expression by using small interfering RNA in human PASMCs to demonstrate a mechanistic link between Cat S signaling and PPARγ protein, and the results suggest that PPARγ is upstream of Cat S signaling. In conclusion, the activity of Cat S in pulmonary vascular remodeling and degradation of elastin fibers through the disruption of PPARγ is pathophysiologically significant in PAH.

An inherent concern for a wireless sensor network (WSN)

Two-tiered wireless sensor and actor networks (WSANs) have been proposed to enhance network capabilities, where a set of resource-rich mobile nodes (termed actors ) form a connected backbone to relay sensing data from static sensors to the sink and sometimes are requested by sensors to perform a particular action. Such a two-tiered WSAN facilitates scalability and can efficiently reduce the energy consumption incurred by conventional hop-by-hop relaying via only sensors. However, relocating actors to achieve both connectivity and load balance is a challenge, especially when there is no location information of the nodes. Connectivity ensures that the actors are connected, whereas load balance ensures that actors collect and originate a similar amount of sensory data from the sensors. In this article, we formulate the Connected and Balanced Mobile Actor Relocation (CBMAR) optimization problem to address both connectivity and load balance and prove that the problem is NP-hard. We thus propose a dual-mode distributed actor relocation protocol that does not rely on any location information of nodes to relocate actors. The idea is to locally form virtual Voronoi cells of actors (termed covering cells ) based on the lower-tiered topology, where each actor locally recruits its own sensor members to form its own covering cell. By maintaining the covering cell, each actor locally relocates itself toward a sensor along the lower-tiered topology. Extensive simulation results show that the protocol can achieve both objectives of connectivity and load balance with low moving and communication overheads.

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