Gi- and Gs-coupled GPCRs show different modes of G-protein binding.

More than two decades ago, the activation mechanism for the membrane-bound photoreceptor and prototypical G protein-coupled receptor (GPCR) rhodopsin was uncovered. Upon light-induced changes in ligand-receptor interaction, movement of specific transmembrane helices within the receptor opens a crevice at the cytoplasmic surface, allowing for coupling of heterotrimeric guanine nucleotide-binding proteins (G proteins). The general features of this activation mechanism are conserved across the GPCR superfamily. Nevertheless, GPCRs have selectivity for distinct G-protein family members, but the mechanism of selectivity remains elusive. Structures of GPCRs in complex with the stimulatory G protein, Gs, and an accessory nanobody to stabilize the complex have been reported, providing information on the intermolecular interactions. However, to reveal the structural selectivity filters, it will be necessary to determine GPCR-G protein structures involving other G-protein subtypes. In addition, it is important to obtain structures in the absence of a nanobody that may influence the structure. Here, we present a model for a rhodopsin-G protein complex derived from intermolecular distance constraints between the activated receptor and the inhibitory G protein, Gi, using electron paramagnetic resonance spectroscopy and spin-labeling methodologies. Molecular dynamics simulations demonstrated the overall stability of the modeled complex. In the rhodopsin-Gi complex, Gi engages rhodopsin in a manner distinct from previous GPCR-Gs structures, providing insight into specificity determinants

NONLINEARITIES, SCALE-DEPENDENCE, AND INDIVIDUALISM OF BOREAL FOREST TREES TO CLIMATE FORCING

Changes in climate are affecting tree growth, fire regimes and the geographic ranges of species (Beck et al. 2011; Kelly et al. 2013). Increasing our understanding of how boreal tree species respond to climate warming is critical for predicting the future states of the boreal forest and assessing the global impacts of these changes. Black spruce (Picea mariana [Mill.] B.S.P.) is the most abundant tree species in the Interior Alaskan boreal forest. Although it grows in a variety of community types (Hollingsworth et al. 2006), it is the only tree species found at the coldest, wettest sites on the landscape. Despite its abundance, very little is known about the climate-growth relationships of black spruce, as the majority of dendrochronological studies in Interior Alaska involve white spruce growing at treeline.Funding was provided by a National Science Foundation grant (ARC-0902169), the Scenarios Network for Alaska and Arctic Planning, and the Alaska Climate Science Center (Cooperative Agreement Number G10AC00588 from the U.S. Geological Survey)

DNM1 encephalopathy: A new disease of vesicle fission.

ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention

Prospectus, March 7, 1984

CONGRESS RETURNS TO A \u27MOST IMPORTANT\u27 STUDENT AID DEBATE; News Digest; Four paintings stolen from Parkland; \u27Job Training and Partnership Act\u27: JTPA \u27good opportunity for dedicated\u27; PC Happenings: TV programs for busy parents, Parkland announces registration, Polish folk arts at Parkland; Sargent talks to Lifelong Learners\u27 Club; Yaxley scholarship; Stu-Go News; \u27Planned Parenthood\u27--pro choice organization; In the Library--Paperbacks; Nolen enjoys differences; What is Sadie Hawkins Day?; Did You Know...; Scholarship news for real estate students; Tuexdo styles are changing; What did you thinnk of the Grammy Awards?; Classifieds; \u27Good looking coed\u27 hunt draws lots of photos; Urbana construction will increase; Learning to relax can kill stress; \u27Women\u27s History Week\u27 honored; Parkland Christian Fellowship to sponsor conference; Weather conditions force closing; Math contest at Parkland; Financia; aid for summer and fall; The latest in swimwear; \u27Western look\u27 changing; Creative Corner...Especially for you!!: Believe..., Creed, Dream, The End, Darkness...; All Up to Me, Listening to an old..., Father to Son, How to know just what is real..., For Larry, Hi, I\u27m crazy ...; Bite the Bullet, Answer, Why can\u27t we see?, Love sparked nu the heat of summer...,Keg, A low rumble starts..., Oh, Mothers..., Has the human race forgot to look at a sunset..., I tried to play your game..., You\u27ve let me down...; Jackson leads the way at this year\u27s Grammy awards; Dexter--valuable asset; $50,000 and silence \u27cheap way for MSU to avoid lawsuit\u27; In the Library--; Channel 12 fund drive stresses \u27TV worth paying for\u27; Woody Allen\u27s latest hilarious; \u27Foghat\u27 hits C/U March 18; Predictions for the upcoming Academy Awards; \u27Big Country\u27 to appear; \u27Full Metal Jacket\u27 talent search; \u27The Right Stuff\u27 finally opens in area; Energetic movie should do well; Baseball Schedule; Bank president--NFL referee; High School Notes; Softball Schedule; Cobra baseball to start; Women win tournament; Lake Land advances in sectional; Mens basketball scores; I.M. News; Cobra men advance to sectional; Cobras end up with last year\u27s record; Tae Kwon Do showed display; Cooper remembers 6 good years; First basketball coach tells how it was; NJCAA meethttps://spark.parkland.edu/prospectus_1984/1029/thumbnail.jp

On the Treatment of Airline Travelers in Mathematical Models

The global spread of infectious diseases is facilitated by the ability of infected humans to travel thousands of miles in short time spans, rapidly transporting pathogens to distant locations. Mathematical models of the actual and potential spread of specific pathogens can assist public health planning in the case of such an event. Models should generally be parsimonious, but must consider all potentially important components of the system to the greatest extent possible. We demonstrate and discuss important assumptions relative to the parameterization and structural treatment of airline travel in mathematical models. Among other findings, we show that the most common structural treatment of travelers leads to underestimation of the speed of spread and that connecting travel is critical to a realistic spread pattern. Models involving travelers can be improved significantly by relatively simple structural changes but also may require further attention to details of parameterization

Design and implementation of a generalized laboratory data model

<p>Abstract</p> <p>Background</p> <p>Investigators in the biological sciences continue to exploit laboratory automation methods and have dramatically increased the rates at which they can generate data. In many environments, the methods themselves also evolve in a rapid and fluid manner. These observations point to the importance of robust information management systems in the modern laboratory. Designing and implementing such systems is non-trivial and it appears that in many cases a database project ultimately proves unserviceable.</p> <p>Results</p> <p>We describe a general modeling framework for laboratory data and its implementation as an information management system. The model utilizes several abstraction techniques, focusing especially on the concepts of inheritance and meta-data. Traditional approaches commingle event-oriented data with regular entity data in <it>ad hoc </it>ways. Instead, we define distinct regular entity and event schemas, but fully integrate these via a standardized interface. The design allows straightforward definition of a "processing pipeline" as a sequence of events, obviating the need for separate workflow management systems. A layer above the event-oriented schema integrates events into a workflow by defining "processing directives", which act as automated project managers of items in the system. Directives can be added or modified in an almost trivial fashion, i.e., without the need for schema modification or re-certification of applications. Association between regular entities and events is managed via simple "many-to-many" relationships. We describe the programming interface, as well as techniques for handling input/output, process control, and state transitions.</p> <p>Conclusion</p> <p>The implementation described here has served as the Washington University Genome Sequencing Center's primary information system for several years. It handles all transactions underlying a throughput rate of about 9 million sequencing reactions of various kinds per month and has handily weathered a number of major pipeline reconfigurations. The basic data model can be readily adapted to other high-volume processing environments.</p

Nonprofit governance and accountability : broadening the theoretical perspective

Drawing on comparative case studies, this article critiques the positioning of accountability as a benign and straightforward governance function. From a critical management studies perspective, I offer a conceptualization of the relationship between governance and accountability in which issues of power, beliefs about the nature of organizing, and social relations are integral features. The article clarifies how principal-agent governance assumptions, based on a central logic of unitarism, can drive narrow compliance-based interpretations of accountability. Such an approach appears at odds with the values embedded in the social missions of many nonprofits insofar as they prioritize small sections of powerful stakeholders over sustained periods of time. Conversely, a pluralist logic appears to create space for broad accountability to multiple stakeholders. Here, expressive, values-based accountability is seen as a source of legitimacy and can produce complex relationships, which challenge the instrumental orientation to social relations that principal-agent theories assume

Assessing the Potential Impacts to Riparian Ecosystems Resulting from Hemlock Mortality in Great Smoky Mountains National Park

Hemlock Woolly Adelgid (Adelges tsugae) is spreading across forests in eastern North America, causing mortality of eastern hemlock (Tsuga canadensis [L.] Carr.) and Carolina hemlock (Tsuga caroliniana Engelm.). The loss of hemlock from riparian forests in Great Smoky Mountains National Park (GSMNP) may result in significant physical, chemical, and biological alterations to stream environments. To assess the influence of riparian hemlock stands on stream conditions and estimate possible impacts from hemlock loss in GSMNP, we paired hardwood- and hemlock-dominated streams to examine differences in water temperature, nitrate concentrations, pH, discharge, and available photosynthetic light. We used a Geographic Information System (GIS) to identify stream pairs that were similar in topography, geology, land use, and disturbance history in order to isolate forest type as a variable. Differences between hemlock- and hardwood-dominated streams could not be explained by dominant forest type alone as forest type yields no consistent signal on measured conditions of headwater streams in GSMNP. The variability in the results indicate that other landscape variables, such as the influence of understory Rhododendron species, may exert more control on stream conditions than canopy composition. The results of this study suggest that the replacement of hemlock overstory with hardwood species will have minimal impact on long-term stream conditions, however disturbance during the transition is likely to have significant impacts. Management of riparian forests undergoing hemlock decline should, therefore, focus on facilitating a faster transition to hardwood-dominated stands to minimize long-term effects on water quality