Abstract-Abnormal vascular smooth muscle cell (VSMC) contraction plays an important role in vascular diseases. The RhoA/ROCK signaling pathway is now well recognized to mediate vascular smooth muscle contraction in response to vasoconstrictors by inhibiting myosin phosphatase (MLCP) activity and increasing myosin light chain phosphorylation. Two ROCK isoforms, ROCK1 and ROCK2, are expressed in many tissues, yet the isoform-specific roles of ROCK1 and ROCK2 in vascular smooth muscle and the mechanism of ROCK-mediated regulation of MLCP are not well understood. In this study, ROCK2, but not ROCK1, bound directly to the myosin binding subunit of MLCP, yet both ROCK isoforms regulated MLCP and myosin light chain phosphorylation. Despite that both ROCK1 and ROCK2 regulated MLCP, the ROCK isoforms had distinct and opposing effects on VSMC morphology and ROCK2, but not ROCK1, had a predominant role in VSMC contractility. These data support that although the ROCK isoforms both regulate MLCP and myosin light chain phosphorylation through different mechanisms, they have distinct roles in VSMC function. (Circ Res. 2009;104:531-540.)Key Words: ROCK Ⅲ myosin phosphatase Ⅲ myosin light chain Ⅲ myosin binding subunit I ncreased vascular tone plays an important role in the pathophysiology of vascular diseases including hypertension, atherosclerosis, and myocardial infarction. 1-3 Vascular tone is regulated by the contraction of vascular smooth muscle cells (VSMC) in the blood vessel wall. Vascular smooth muscle contraction is tightly coupled to the phosphorylation of the regulatory myosin light chain, 4 which is regulated by the opposing activities of myosin light chain (MLC) kinase (MLCK) and myosin light chain phosphatase (MLCP) (reviewed elsewhere 5 ). MLCP dephosphorylates MLC, leading to vascular smooth muscle relaxation (reviewed elsewhere 6,7 ). MLCP activity is highly regulated by both vasoconstrictor and vasodilator signaling pathways. Nitrovasodilators stimulate cGMP-dependent protein kinase 1␣, which activates MLCP to cause MLC dephosphorylation and smooth muscle relaxation. 8 -10 Vasoconstrictors, conversely, inhibit MLCP, leading to MLC phosphorylation and smooth muscle contraction (reviewed elsewhere 6 ). Vasoconstrictor-mediated MLCP inhibition occurs by either phosphorylation of the MLCP inhibitory protein CPI-17 11 or by phosphorylation of the myosin binding subunit (MBS) of MLCP at inhibitory sites T696 and T850. [12][13][14] The RhoA/ROCK pathway is the most extensively studied mechanism of MLCP inhibition. Vasoconstrictor G proteincoupled receptor agonists lead to activation of RhoA guanine nucleotide exchange factors and GTP loading of the monomeric GTPase RhoA. 15 GTP-bound RhoA then binds and activates its downstream effector ROCK, 16 -18 which in turn phosphorylates MBS 19 at the 2 phosphorylation sites, 12,13 leading to inhibition of MLCP activity. 14 Phosphorylation at T850 also has been shown to cause dissociation of MBS from myosin. 20 More recently, T850 has been implicated as the major ROCK phosp...

This paper presents a new technique for automatically synthesizing SQL queries from natural language (NL). At the core of our technique is a new NL-based program synthesis methodology that combines semantic parsing techniques from the NLP community with type-directed program synthesis and automated program repair. Starting with a program sketch obtained using standard parsing techniques, our approach involves an iterative refinement loop that alternates between quantitative type inhabitation and automated sketch repair. We use the proposed idea to build an end-to-end system called Sqlizer that can synthesize SQL queries from natural language. Our method is fully automated, works for any database without requiring additional customization, and does not require users to know the underlying database schema. We evaluate our approach on over 450 natural language queries concerning three different databases, namely MAS, IMDB, and YELP. Our experiments show that the desired query is ranked within the top 5 candidates in close to 90% of the cases and that Sqlizer outperforms Nalir, a state-of-the-art tool that won a best paper award at VLDB'14. CCS Concepts: • Human-centered computing → Natural language interfaces; • Software and its engineering → Domain specific languages; • Information systems → Relational database query languages; Database utilities and tools; Extraction, transformation and loading;

Hypertension, a major cardiovascular risk factor and cause of mortality worldwide, is thought to arise from primary renal abnormalities. However, the etiology of most cases of hypertension remains unexplained. Vascular tone, an important determinant of blood pressure, is regulated by nitric oxide, which causes vascular relaxation by increasing intracellular cGMP and activating cGMPdependent protein kinase I (PKGI). Here we show that mice with a selective mutation in the N-terminal protein interaction domain of PKGI␣ display inherited vascular smooth muscle cell abnormalities of contraction, abnormal relaxation of large and resistance blood vessels, and increased systemic blood pressure. Renal function studies and responses to changes in dietary sodium in the PKGI␣ mutant mice are normal. These data reveal that PKGI␣ is required for normal VSMC physiology and support the idea that high blood pressure can arise from a primary abnormality of vascular smooth muscle cell contractile regulation, suggesting a new approach to the diagnosis and therapy of hypertension and cardiovascular diseases.cyclic nucleotides ͉ hypertension ͉ nitric oxide ͉ vascular biology ͉ vascular smooth muscle E levated blood pressure is a major risk factor for cardiovascular diseases and is responsible for widespread morbidity and mortality (1). Blood pressure is regulated by a variety of complex neurohumoral and mechanical signals that together determine systemic vascular tone and resistance (2, 3). The prevailing model for elevated blood pressure states that renal abnormalities of sodium handling cause volume expansion, increased systemic vascular resistance, and hypertension, and a large number of physiologic and genetic studies support this model and the central role of the renal renin-angiotensinaldosterone system in blood pressure regulation (4-8). Changes in vascular morphology and tone can increase vascular resistance and blood pressure (5), but the hypothesis that primary abnormalities of vascular smooth muscle tone can cause hypertension has not been sufficiently tested (6).Vascular smooth muscle contraction is initiated by both calcium-dependent and -independent mechanisms. Increases in intracellular calcium from receptor-or ion channel-activated pathways (2) lead to activation of myosin light chain kinase, which phosphorylates myosin light chains, activating myosin ATPase and increasing vascular smooth muscle cell (VSMC) contraction and vascular tone. The central calcium-independent pathway regulating VSMC tension is mediated by the GTPase RhoA and Rho kinase, which promote VSMC differentiation, stress fiber formation, and contraction, also increasing vascular tone (2, 7). Conversely, VSMC relaxation is mediated by activation of myosin light chain phosphatase (MLCP), which dephosphorylates myosin light chains to cause relaxation. The relative proportion of phosphorylated and dephosphorylated myosin light chains thus determines the state of VSMC tone (reviewed in ref.2). Nitric oxide, the most important endogenous vasodilator, cause...