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This paper addresses two key parallelization challenges the unstructured mesh-based ocean modeling code, MPAS-Ocean, which uses a mesh based on Voronoi tessellations: (1) load imbalance across processes, and (2) unstructured data access patterns, that inhibit intra- and inter-node performance. Our work analyzes the load imbalance due to naive partitioning of the mesh, and develops methods to generate mesh partitioning with better load balance and reduced communication. Furthermore, we present methods that minimize both inter- and intranode data movement and maximize data reuse. Our techniques include predictive ordering of data elements for higher cache efficiency, as well as communication reduction approaches. We present detailed performance data when running on thousands of cores using the Cray XC30 supercomputer and show that our optimization strategies can exceed the original performance by over 2×. Additionally, many of these solutions can be broadly applied to a wide variety of unstructured grid-based computations.

Primary open-angle glaucoma (POAG) is often caused by elevated intraocular pressure (IOP), which arises due to increased resistance to aqueous humor outflow (AHO). Aqueous humor flows through Schlemm's canal (SC), a lymphatic-like vessel encircling the cornea, and via intercellular spaces of ciliary muscle cells. However, the mechanisms underlying increased AHO resistance are poorly understood. Here, we demonstrate that signaling between angiopoietin (Angpt) and the Angpt receptor Tie2, which is critical for SC formation, is also indispensable for maintaining SC integrity during adulthood. Deletion of Angpt1/Angpt2 or Tie2 in adult mice severely impaired SC integrity and transcytosis, leading to elevated IOP, retinal neuron damage, and impairment of retinal ganglion cell function, all hallmarks of POAG in humans. We found that SC integrity is maintained by interconnected and coordinated functions of Angpt-Tie2 signaling, AHO, and Prox1 activity. These functions diminish in the SC during aging, leading to impaired integrity and transcytosis. Intriguingly, Tie2 reactivation using a Tie2 agonistic antibody rescued the POAG phenotype in Angpt1/Angpt2-deficient mice and rejuvenated the SC in aged mice. These results indicate that the Angpt-Tie2 system is essential for SC integrity. The impairment of this system underlies POAGassociated pathogenesis, supporting the possibility that Tie2 agonists could be a therapeutic option for glaucoma., Introduction Glaucoma is a leading cause of irreversible blindness, affecting 3.5% of the population aged 40 to 80 years worldwide (1). It involves cupping of the optic nerve head and [...]

Schlemm's canal (SC) is a specialized vascular structure in the eye that functions to drain aqueous humor from the intraocular chamber into systemic circulation. Dysfunction of SC has been proposed to underlie increased aqueous humor outflow (AHO) resistance, which leads to elevated ocular pressure, a factor for glaucoma development in humans. Here, using lymphatic and blood vasculature reporter mice, we determined that SC, which originates from blood vessels during the postnatal period, acquires lymphatic identity through upregulation of prospero homeobox protein 1 (PROX1), the master regulator of lymphatic development. SC expressed lymphatic valve markers FOXC2 and integrin [α.sub.9] and exhibited continuous vascular endothelialcadherin (VE-cadherin) junctions and basement membrane, similar to collecting lymphatics. SC notably lacked luminal valves and expression of the lymphatic endothelial cell markers podoplanin and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Using an ocular puncture model, we determined that reduced AHO altered the fate of SC both during development and under pathologic conditions; however, alteration of VEGF-C/VEGFR3 signaling did not modulate SC integrity and identity. Intriguingly, PROX1 expression levels linearly correlated with SC functionality. For example, PROX1 expression was reduced or undetectable under pathogenic conditions and in deteriorated SCs. Collectively, our data indicate that PROX1 is an accurate and reliable biosensor of SC integrity and identity., Introduction Schlemm's canal (SC) is an endothelium-lined vascular channel that encircles the margin of the cornea and drains aqueous humor, which is produced in the ciliary body and supplies the [...]

Isolating actively proliferating cardioblasts is the first crucial step for cardiac regeneration through cell implantation. However, the origin and identity of putative cardioblasts are still unclear. Here, we uncover a novel class of cardiac lineage cells, PDGFRα+Flk1− cardioblasts (PCBs), from mouse and human pluripotent stem cells induced using CsAYTE, a combination of the small molecules Cyclosporin A, the rho-associated coiled-coil kinase inhibitor Y27632, the antioxidant Trolox, and the ALK5 inhibitor EW7197. This novel population of actively proliferating cells is cardiac lineage-committed but in a morphologically and functionally immature state compared to mature cardiomyocytes. Most important, most of CsAYTE-induced PCBs spontaneously differentiated into functional αMHC+ cardiomyocytes (M+CMs) and could be a potential cellular resource for cardiac regeneration. [ABSTRACT FROM AUTHOR]

Successful differentiation and expansion of endothelial cells (ECs) from embryonic stem cell (ESC)-derived Flk1+ mesoder-mal precursor cells (MPCs) requires supplementation of vascular endothelial growth factor-A (VEGF-A). While analyz-ing VEGF-AA/EGFR2 downstream signal-ing pathway that underlies the VEGF-A-induced differentiation and expansion of ECs, we fortuitously found that Rho-assoclated protein kinase (ROCK) inhibi-tor Y27632 profoundly promoted the dif-ferentiation and expansion of ECs from Flk1+ MPCs while reducing the differentia-tion and expansion of mural cells. The ROCK suppression-Induced expansion of ECs appears to have resulted from promo-tion of proliferation of ECs via activation of PI3-kinase-Akt signaling. The ECs ob-tained by the combination of ROCK sup-pression and VEGF-A supplementation faithfully expressed most pan-EC surface makers, and phenotyplc analyses re-vealed that they were differentiated to-ward arterial EC. Further incubation of the ICAM2+ ECs with Y27632 and VEGF-A for 2 days promoted expansion of ECs by 6.5-fold compared with those incubated with only VEGF-A. Importantly, the ROCK suppression-Induced ECs displayed neo-vasculogenic abilities in vitro and in vivo. Thus, supplementation of ROCK inhibitor Y27632 along with VEGF-A in 2D Matrigel culture system provides a simple, effi-cient, and versatile method for obtaining ample amount of ESC-derlved ECs at high purity suitable for use in therapeutic neovascularization. (Blood. 2012;120(13): 2733-2744). [ABSTRACT FROM AUTHOR]

Background: Pluripotent stem cell-derived cardiomyocytes (CMs) have become one of the most attractive cellular resources for cell-based therapy to rescue damaged cardiac tissue., Aim: We investigated the regenerative potential of mouse embryonic stem cell (ESC)-derived platelet-derived growth factor receptor-α (DGFRα) + cardiac lineage-committed cells (CLCs), which have a proliferative capacity but are in a morphologically and functionally immature state compared with differentiated CMs., Methods: We induced mouse ESCs into PDGFRα + CLCs and αMHC + CMs using a combination of the small molecule cyclosporin A, the rho-associated coiled-coil kinase inhibitor Y27632, the antioxidant Trolox, and the ALK5 inhibitor EW7197. We implanted PDGFRα + CLCs and differentiated αMHC + CMs into a myocardial infarction (MI) murine model and performed functional analysis using transthoracic echocardiography (TTE) and histologic analysis., Results: Compared with the untreated MI hearts, the anterior and septal regional wall motion and systolic functional parameters were notably and similarly improved in the MI hearts implanted with PDGFRα + CLCs and αMHC + CMs based on TTE. In histologic analysis, the untreated MI hearts contained a thinner ventricular wall than did the controls, while the ventricular walls of MI hearts implanted with PDGFRα + CLCs and αMHC + CMs were similarly thicker compared with that of the untreated MI hearts. Furthermore, implanted PDGFRα + CLCs aligned and integrated with host CMs and were mostly differentiated into α-actinin + CMs, and they did not convert into CD31 + endothelial cells or αSMA + mural cells., Conclusion: PDGFRα + CLCs from mouse ESCs exhibiting proliferative capacity showed a regenerative effect in infarcted myocardium. Therefore, mouse ESC-derived PDGFRα + CLCs may represent a potential cellular resource for cardiac regeneration., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.

Isolating actively proliferating cardioblasts is the first crucial step for cardiac regeneration through cell implantation. However, the origin and identity of putative cardioblasts are still unclear. Here, we uncover a novel class of cardiac lineage cells, PDGFRα + Flk1 - cardioblasts (PCBs), from mouse and human pluripotent stem cells induced using CsAYTE, a combination of the small molecules Cyclosporin A, the rho-associated coiled-coil kinase inhibitor Y27632, the antioxidant Trolox, and the ALK5 inhibitor EW7197. This novel population of actively proliferating cells is cardiac lineage-committed but in a morphologically and functionally immature state compared to mature cardiomyocytes. Most important, most of CsAYTE-induced PCBs spontaneously differentiated into functional αMHC + cardiomyocytes (M + CMs) and could be a potential cellular resource for cardiac regeneration., Competing Interests: The authors declare no competing financial interests.

Vascular endothelial cell migration, which plays an important role in vascular remodeling, is known to be regulated by hemodynamic forces in the blood vessels. When shear stress is applied on mouse microvessel endothelial cells (bEnd.3) in vitro, cells exhibit upstream migration behavior with respect to the direction of the flow. To determine how shear stress magnitude influences mechanotaxis of the cells, endothelial cells were exposed to different magnitudes of unidirectional shear stress. While a higher flow rate reduces the speed of the motility, the horizontal component of the velocity parallel to the flow increases with the flow rate, indicating the higher alignment of cells in the direction parallel to the flow at a higher level of shear stress. In addition, cells seeded on softer substrate, whose elastic modulus is comparable to that of the blood vessels, show enhanced directional persistence when compared to those seeded on a stiffer substrate. The higher directionality accompanies increased stress fiber formation and focal adhesion turn-over, exhibiting higher mechanotaxis behavior. Therefore, the increased stiffness in the vessel may hinder the mechano-sensing mechanism of the endothelial cells, resulting in reduced mechanotaxis in response to hemodynamic shear stress. This substrate stiffness-dependent migration behavior can further elucidate the endothelial cell remodeling and wound healing in pathologically hardened vessels as well as re-endothelialization of vascular stents and grafted tissues.