Gallium nitride high-electron-mobility transistors (GaN-HEMTs) suffer from trapping effects that increases device on-state resistance (RDS(on)) above its theoretical value. This increase is a ...function of the applied dc bias when the device is in its off state, and the time which the device is biased for. Thus, dynamic RDS(on) of different commercial GaN-HEMTs are characterised at different bias voltages in the paper by a proposed new measurement circuit. The time-constants associated with trapping and detrapping effects in the device are extracted using the proposed circuit and it is shown that variations in RDS(on) can be predicted using a series of RC circuit networks. A new methodology for integrating these RDS(on) predictions into existing gallium nitride-high-electron-mobility transistors models in standard SPICE simulators to improve model accuracy is then presented. Finally, device dynamic RDS(on) values of the model is compared and validated with the measurement when it switches in a power converter with different duty cycles and switching voltages.
Conservation practitioners have long recognized ecological connectivity as a global priority for preserving biodiversity and ecosystem function. In the early years of conservation science, ecologists ...extended principles of island biogeography to assess connectivity based on source patch proximity and other metrics derived from binary maps of habitat. From 2006 to 2008, the late Brad McRae introduced circuit theory as an alternative approach to model gene flow and the dispersal or movement routes of organisms. He posited concepts and metrics from electrical circuit theory as a robust way to quantify movement across multiple possible paths in a landscape, not just a single least‐cost path or corridor. Circuit theory offers many theoretical, conceptual, and practical linkages to conservation science. We reviewed 459 recent studies citing circuit theory or the open‐source software Circuitscape. We focused on applications of circuit theory to the science and practice of connectivity conservation, including topics in landscape and population genetics, movement and dispersal paths of organisms, anthropogenic barriers to connectivity, fire behavior, water flow, and ecosystem services. Circuit theory is likely to have an effect on conservation science and practitioners through improved insights into landscape dynamics, animal movement, and habitat‐use studies and through the development of new software tools for data analysis and visualization. The influence of circuit theory on conservation comes from the theoretical basis and elegance of the approach and the powerful collaborations and active user community that have emerged. Circuit theory provides a springboard for ecological understanding and will remain an important conservation tool for researchers and practitioners around the globe.
Aplicaciones de la Teoría de Circuitos a la Conservación y a la Ciencia de la Conectividad
Resumen
Quienes practican la conservación han reconocido durante mucho tiempo que la conectividad ecológica es una prioridad mundial para la preservación de la biodiversidad y el funcionamiento del ecosistema. Durante los primeros años de la ciencia de la conservación los ecólogos difundieron los principios de la biografía de islas para evaluar la conectividad con base en la proximidad entre el origen y el fragmento, así como otras medidas derivadas de los mapas binarios de los hábitats. Entre 2006 y 2008 el fallecido Brad McRae introdujo la teoría de circuitos como una estrategia alternativa para modelar el flujo génico y la dispersión o las rutas de movimiento de los organismos. McRae propuso conceptos y medidas de la teoría de circuitos eléctricos como una manera robusta para cuantificar el movimiento a lo largo de múltiples caminos posibles en un paisaje, no solamente a lo largo de un camino o corredor de menor costo. La teoría de circuitos ofrece muchos enlaces teóricos, conceptuales y prácticos con la ciencia de la conservación. Revisamos 459 estudios recientes que citan la teoría de circuitos o el software de fuente abierta Circuitscape. Nos enfocamos en las aplicaciones de la teoría de circuitos a la ciencia y a la práctica de la conservación de la conectividad, incluyendo temas como la genética poblacional y del paisaje, movimiento y caminos de dispersión de los organismos, barreras antropogénicas de la conectividad, comportamiento ante incendios, flujo del agua, y servicios ambientales. La teoría de circuitos probablemente tenga un efecto sobre la ciencia de la conservación y quienes la practican por medio de una percepción mejorada de las dinámicas del paisaje, el movimiento animal, y los estudios de uso de hábitat, y por medio del desarrollo de nuevas herramientas de software para el análisis de datos y su visualización. La influencia de la teoría de circuitos sobre la conservación viene de la base teórica y la elegancia de la estrategia y de las colaboraciones fuertes y la comunidad activa de usuarios que han surgido recientemente. La teoría de circuitos proporciona un trampolín para el entendimiento ecológico y seguirá siendo una importante herramienta de conservación para los investigadores y practicantes en todo el mundo.
摘要
保护实践者长期以来一直将生态连接度视为保护生物多样性和生态系统功能的当务之急。在保护科学发展早期, 生态学家将岛屿生物地理学的原理进行扩展, 基于源斑块邻近度和其它来自二元生境图的指标来评估连接度。2006 年到2008 年, 已故的Brad McRae 引入了电路理论, 作为模拟基因流和生物体扩散或移动路径的新方法。他用电路理论中的概念和指标开发了一种稳健的方法来量化景观中多种可能的移动路径, 而这不只是一条最低成本的路径或廊道。电路理论为保护科学提供了许多理论、概念和实践方面的联系。我们综述了近期引用电路理论或是开源软件Circuitscape的459 项研究, 重点关注电路理论在连接度保护科学与实践中的应用, 包括景观和种群遗传学、生物体运动和扩散路径、连接度的人为障碍、火灾、水流和生态系统服务等问题。电路理论通过帮助理解景观动力学、动物移动和生境利用研究, 以及开发新的数据分析和可视化软件工具, 影响着保护科学和实践者。电路理论对保护的影响来自于该方法的理论基础和优雅性, 以及现已出现的强大的合作队伍和活跃的用户群体。电路理论为生态学理解提供了跳板, 并将继续作为全球研究人员和实践者的重要保护工具。翻译: 胡怡思; 审校: 聂永刚
Article impact statement: Uses of circuit theory to understand connectivity have had a durable and global impact on conservation science and practice.
•Overview of traditional antibody screening methods & introduction to single cell screening.•Description of a selection of single cell analysis (SCA) tools for antibody discovery.•Discussion on ...advantages and disadvantages of each of the SCA tools described.•Brief discussion on the other application areas for SCA.•Future directions and potential for SCA in antibody discovery.
Microtools that have been developed to allow in depth interrogation of individual cells in high throughput are improving our understanding of biological processes at the single cell level and are opening up new possibilities for biological research. In relation to antibody discovery, these tools are now helping to maximise the full potential of well-established methodologies for antibody generation. Being complementary to both recombinant and native antibody secreting cells, some of these tools are finding widespread use in the field. In this review, we discuss how microtools for single cell analysis are addressing some of the limitations of traditional approaches for antibody screening. We describe the main classes of microtools for antibody discovery along with a comparison of each technology and an outlook for the future utility of some of these microtools for discovery and research.
Conservation decisions should be evaluated for how they meet conservation goals at multiple spatial extents. Conservation easements are land use decisions resulting from a combination of social and ...environmental conditions. An emerging area of research is the evaluation of spatial distribution of easements and their spatial correlates. We tested the relative influence of interacting social and environmental variables on the spatial distribution of conservation easements by ownership category and conservation status. For the Appalachian region of the United States, an area with a long history of human occupation and complex land uses including public-private conservation, we found that settlement, economic, topographic, and environmental data associated with spatial distribution of easements (N = 4813). Compared to random locations, easements were more likely to be found in lower elevations, in areas of greater agricultural productivity, farther from public protected areas, and nearer other human features. Analysis of ownership and conservation status revealed sources of variation, with important differences between local and state government ownerships relative to non-governmental organizations (NGOs), and among U.S. Geological Survey (USGS) GAP program status levels. NGOs were more likely to have easements nearer protected areas, and higher conservation status, while local governments held easements closer to settlement, and on lands of greater agricultural potential. Logistic interactions revealed environmental variables having effects modified by social correlates, and the strongest predictors overall were social (distance to urban area, median household income, housing density, distance to land trust office). Spatial distribution of conservation lands may be affected by geographic area of influence of conservation groups, suggesting that multi-scale conservation planning strategies may be necessary to satisfy local and regional needs for reserve networks. Our results support previous findings and provide an ecoregion-scale view that conservation easements may provide, at local scales, conservation functions on productive, more developable lands. Conservation easements may complement functions of public protected areas but more research should examine relative landscape-level ecological functions of both forms of protection.
Bromodomain-containing protein 4 (BRD4) represents a promising drug target for anti-inflammatory therapeutics. Herein, we report the design, synthesis, and pharmacological evaluation of novel ...chromone derivatives via scaffold hopping to discover a new class of orally bioavailable BRD4-selective inhibitors. Two potent BRD4 bromodomain 1 (BD1)-selective inhibitors 44 (ZL0513) and 45 (ZL0516) have been discovered with high binding affinity (IC50 values of 67–84 nM) and good selectivity over other BRD family proteins and distant BD-containing proteins. Both compounds significantly inhibited the expression of Toll-like receptor-induced inflammatory genes in vitro and airway inflammation in murine models. The cocrystal structure of 45 in complex with human BRD4 BD1 at a high resolution of 2.0 Å has been solved, offering a solid structural basis for its binding validation and further structure-based optimization. These BRD4 BD1 inhibitors demonstrated impressive in vivo efficacy and overall promising pharmacokinetic properties, indicating their therapeutic potential for the treatment of inflammatory diseases.
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), ...was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907). PARP1 pY907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. The combination of c-Met and PARP1 inhibitors synergized to suppress the growth of breast cancer cells in vitro and xenograft tumor models, and we observed similar synergistic effects in a lung cancer xenograft tumor model. These results suggest that the abundance of PARP1 pY907 may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients whose tumors show high c-Met expression and who do not respond to PARP inhibition alone.
The histone-like nucleoid structuring (H-NS) protein plays a fundamental role in DNA condensation and is a key regulator of enterobacterial gene expression in response to changes in osmolarity, pH, ...and temperature. The protein is capable of high-order self-association via interactions of its oligomerization domain. Using crystallography, we have solved the structure of this complete domain in an oligomerized state. The observed superhelical structure establishes a mechanism for the self-association of H-NS via both an N-terminal antiparallel coiled-coil and a second, hitherto unidentified, helix-turn-helix dimerization interface at the C-terminal end of the oligomerization domain. The helical scaffold suggests the formation of a H-NS:plectonemic DNA nucleoprotein complex that is capable of explaining published biophysical and functional data, and establishes a unifying structural basis for coordinating the DNA packaging and transcription repression functions of H-NS.
Cardiovascular disease (CVD) is the single greatest cause of adult mortality in the western world and, consequently, places a massive burden on healthcare services and the economy. Lifestyles, lack ...of clearly defined risk assessment criteria, consistently high incidences of misdiagnosis and inappropriate referrals, all contribute significantly to this problem. It also correlates directly with inefficient or non-accessible early detection systems. Over the last decade much research has focused on the identification of cardiac biomarkers that can be used for the detection of cardiac distress and that add value to current risk stratification criteria. An exposition of some of the most consistently cited biomarkers is provided and their current status and potential value as early CVD risk predictors, more accurate diagnostic markers of acute myocardial damage and as reliable prognostic indicators, is evaluated. The particular importance of early prediction and the integral role that point-of-care (POC) testing is expected to play in the future of cardiac care is critically discussed.
Staphylococcus aureus VraR, a vancomycin-resistance-associated response regulator, activates a cell-wall-stress stimulon in response to antibiotics that inhibit cell wall formation. X-ray crystal ...structures of VraR in both unphosphorylated and beryllofluoride-activated states have been determined, revealing a mechanism of phosphorylation-induced dimerization that features a deep hydrophobic pocket at the center of the receiver domain interface. Unphosphorylated VraR exists in a closed conformation that inhibits dimer formation. Phosphorylation at the active site promotes conformational changes that are propagated throughout the receiver domain, promoting the opening of a hydrophobic pocket that is essential for homodimer formation and enhanced DNA-binding activity. This prominent feature in the VraR dimer can potentially be exploited for the development of novel therapeutics to counteract antibiotic resistance in this important pathogen.
Systematic conservation planning has been used extensively throughout the world to identify important areas for maintaining biodiversity and functional ecosystems, and is well suited to address ...large-scale biodiversity conservation challenges of the twenty-first century. Systematic planning is necessary to bridge implementation, scale, and data gaps in a collaborative effort that recognizes competing land uses. Here, we developed a conservation planning process to identify and unify conservation priorities around the central and southern Appalachian Mountains as part of the Appalachian Landscape Conservation Cooperative (App LCC). Through a participatory framework and sequential, cross-realm integration in spatial optimization modeling we highlight lands and waters that together achieve joint conservation goals from LCC partners for the least cost. This process was driven by a synthesis of 26 multi-scaled conservation targets and optimized for simultaneous representation inside the program Marxan to account for roughly 25% of the LCC geography. We identify five conservation design elements covering critical ecological processes and patterns including interconnected regions as well as the broad landscapes between them. Elements were then subjected to a cumulative threats index for possible prioritization. The evaluation of these elements supports multi-scaled decision making within the LCC planning community through a participatory, dynamic, and iterative process.
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