RESUMEN
Platelet homeostasis is dependent on a tight regulation of both platelet production and clearance. The small GTPase Rap1 mediates platelet adhesion and hemostatic plug formation. However, Rap1 signaling is also critical for platelet homeostasis as both Rap1 deficiency and uninhibited Rap1 signaling lead to marked thrombocytopenia in mice. Here, we investigated the mechanism by which deficiency in Rasa3, a critical negative regulator of Rap1, causes macrothrombocytopenia in mice. Despite marked morphological and ultrastructural abnormalities, megakaryocytes in hypomorphic Rasa3hlb/hlb (R3hlb/hlb) or Rasa3-/- mice demonstrated robust proplatelet formation in vivo, suggesting that defective thrombopoiesis is not the main cause of thrombocytopenia. Rather, we observed that R3hlb/hlb platelets became trapped in the spleen marginal zone/red pulp interface, with evidence of platelet phagocytosis by macrophages. Clearance of mutant platelets was also observed in the liver, especially in splenectomized mice. Platelet count and platelet life span in Rasa3-mutant mice were restored by genetic or pharmacological approaches to inhibit the Rap1/talin1/αIIbß3 integrin axis. A similar pattern of splenic clearance was observed in mice injected with anti-αIIbß3 but not anti-glycoprotein Ibα platelet-depleting antibodies. In summary, we describe a potentially novel, integrin-based mechanism of platelet clearance that could be critical for our understanding of select inherited and acquired thrombocytopenias.
Asunto(s)
Trombocitopenia , Trombopoyesis , Animales , Plaquetas , Proteínas Activadoras de GTPasa/genética , Integrinas , Megacariocitos , RatonesRESUMEN
Sharing low-level functionality between software packages enables more rapid development of new capabilities and reduces the duplication of work among development groups. Using the component approach advocated by the Common Component Architecture Forum, we have designed a flexible interface for sharing integrals between quantum chemistry codes. Implementation of these interfaces has been undertaken within the Massively Parallel Quantum Chemistry package, exposing both the IntV3 and Cints/Libint integrals packages to component applications. Benchmark timings for Hartree-Fock calculations demonstrate that the overhead due to the added interface code varies significantly, from less than 1% for small molecules with large basis sets to nearly 10% for larger molecules with smaller basis sets. Correlated calculations and density functional approaches encounter less severe performance overheads of less than 5%. While these overheads are acceptable, additional performance losses occur when arbitrary implementation details, such as integral ordering within buffers, must be handled. Integral reordering is observed to add an additional overhead as large as 12%; hence, a common standard for such implementation details is desired for optimal performance.
Asunto(s)
Química/métodos , Modelos Químicos , Teoría Cuántica , Diseño de SoftwareRESUMEN
PSI3 is a program system and development platform for ab initio molecular electronic structure computations. The package includes mature programming interfaces for parsing user input, accessing commonly used data such as basis-set information or molecular orbital coefficients, and retrieving and storing binary data (with no software limitations on file sizes or file-system-sizes), especially multi-index quantities such as electron repulsion integrals. This platform is useful for the rapid implementation of both standard quantum chemical methods, as well as the development of new models. Features that have already been implemented include Hartree-Fock, multiconfigurational self-consistent-field, second-order Møller-Plesset perturbation theory, coupled cluster, and configuration interaction wave functions. Distinctive capabilities include the ability to employ Gaussian basis functions with arbitrary angular momentum levels; linear R12 second-order perturbation theory; coupled cluster frequency-dependent response properties, including dipole polarizabilities and optical rotation; and diagonal Born-Oppenheimer corrections with correlated wave functions. This article describes the programming infrastructure and main features of the package. PSI3 is available free of charge through the open-source, GNU General Public License.
RESUMEN
Typical scientific software designs make rigid assumptions regarding programming language and data structures, frustrating software interoperability and scientific collaboration. Component-based software engineering is an emerging approach to managing the increasing complexity of scientific software. Component technology facilitates code interoperability and reuse. Through the adoption of methodology and tools developed by the Common Component Architecture Forum, we have developed a component architecture for molecular structure optimization. Using the NWChem and Massively Parallel Quantum Chemistry packages, we have produced chemistry components that provide capacity for energy and energy derivative evaluation. We have constructed geometry optimization applications by integrating the Toolkit for Advanced Optimization, Portable Extensible Toolkit for Scientific Computation, and Global Arrays packages, which provide optimization and linear algebra capabilities. We present a brief overview of the component development process and a description of abstract interfaces for chemical optimizations. The components conforming to these abstract interfaces allow the construction of applications using different chemistry and mathematics packages interchangeably. Initial numerical results for the component software demonstrate good performance, and highlight potential research enabled by this platform.