A Generalized Allosteric Mechanism for cis-Regulated Cyclic Nucleotide Binding Domains

Cyclic nucleotides (cAMP and cGMP) regulate multiple intracellular processes and are thus of a great general interest for molecular and structural biologists. To study the allosteric mechanism of different cyclic nucleotide binding (CNB) domains, we compared cAMP-bound and cAMP-free structures (PKA, Epac, and two ionic channels) using a new bioinformatics method: local spatial pattern alignment. Our analysis highlights four major conserved structural motifs: 1) the phosphate binding cassette (PBC), which binds the cAMP ribose-phosphate, 2) the “hinge,” a flexible helix, which contacts the PBC, 3) the β2,3 loop, which provides precise positioning of an invariant arginine from the PBC, and 4) a conserved structural element consisting of an N-terminal helix, an eight residue loop and the A-helix (N3A-motif). The PBC and the hinge were included in the previously reported allosteric model, whereas the definition of the β2,3 loop and the N3A-motif as conserved elements is novel. The N3A-motif is found in all cis-regulated CNB domains, and we present a model for an allosteric mechanism in these domains. Catabolite gene activator protein (CAP) represents a trans-regulated CNB domain family: it does not contain the N3A-motif, and its long range allosteric interactions are substantially different from the cis-regulated CNB domains

Health System Resource Gaps and Associated Mortality from Pandemic Influenza across Six Asian Territories

BACKGROUND: Southeast Asia has been the focus of considerable investment in pandemic influenza preparedness. Given the wide variation in socio-economic conditions, health system capacity across the region is likely to impact to varying degrees on pandemic mitigation operations. We aimed to estimate and compare the resource gaps, and potential mortalities associated with those gaps, for responding to pandemic influenza within and between six territories in Asia. METHODS AND FINDINGS: We collected health system resource data from Cambodia, Indonesia (Jakarta and Bali), Lao PDR, Taiwan, Thailand and Vietnam. We applied a mathematical transmission model to simulate a "mild-to-moderate" pandemic influenza scenario to estimate resource needs, gaps, and attributable mortalities at province level within each territory. The results show that wide variations exist in resource capacities between and within the six territories, with substantial mortalities predicted as a result of resource gaps (referred to here as "avoidable" mortalities), particularly in poorer areas. Severe nationwide shortages of mechanical ventilators were estimated to be a major cause of avoidable mortalities in all territories except Taiwan. Other resources (oseltamivir, hospital beds and human resources) are inequitably distributed within countries. Estimates of resource gaps and avoidable mortalities were highly sensitive to model parameters defining the transmissibility and clinical severity of the pandemic scenario. However, geographic patterns observed within and across territories remained similar for the range of parameter values explored. CONCLUSIONS: The findings have important implications for where (both geographically and in terms of which resource types) investment is most needed, and the potential impact of resource mobilization for mitigating the disease burden of an influenza pandemic. Effective mobilization of resources across administrative boundaries could go some way towards minimizing avoidable deaths

Ontogeny of central serotonergic neurons in the directly developing frog, Eleutherodactylus coqui

Embryonic development of the central serotonergic neurons in the directly developing frog, Eleutherodactylus coqui , was determined by using immunocytochemistry. The majority of anuran amphibians (frogs) possess a larval stage (tadpole) that undergoes metamorphosis, a dramatic post-embryonic event, whereby the tadpole transforms into the adult phenotype. Directly developing frogs have evolved a derived life-history mode where the tadpole stage has been deleted and embryos develop directly into the adult bauplan. Embryonic development in E. coqui is classified into 15 stages (TS 1–15; 1 = oviposition / 15 = hatching). Serotonergic immunoreactivity was initially detected at TS 6 in the raphe nuclei in the developing rhombencephalon. At TS 7, immunopositive perikarya were observed in the paraventricular organ in the hypothalamus and reticular nuclei in the hindbrain. Development of the serotonergic system was steady and gradual during mid-embryogenesis. However, starting at TS 13 there was a substantial increase in the number of serotonergic neurons in the paraventricular, raphe, and reticular nuclei, a large increase in the number of varicose fibers, and a differentiation of the reticular nuclei in the hindbrain. Consequentially, E. coqui displayed a well-developed central serotonergic system prior to hatching (TS 15). In comparison, the serotonergic system in metamorphic frogs typically starts to develop earlier but the surge of development that transpires in this system occurs post-embryonically, during metamorphosis, and not in the latter stages of embryogenesis, as it does in E. coqui . Overall, the serotonergic development in E. coqui is similar to the other vertebrates.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47526/1/429_2005_Article_22.pd

Requirements and Design of the PROSPER Protocol for Implementation of Information Infrastructures Supporting Pandemic Response: A Nominal Group Study

Background: Advanced technical systems and analytic methods promise to provide policy makers with information to help them recognize the consequences of alternative courses of action during pandemics. Evaluations still show that response programs are insufficiently supported by information systems. This paper sets out to derive a protocol for implementation of integrated information infrastructures supporting regional and local pandemic response programs at the stage(s) when the outbreak no longer can be contained at its source. Methods: Nominal group methods for reaching consensus on complex problems were used to transform requirements data obtained from international experts into an implementation protocol. The analysis was performed in a cyclical process in which the experts first individually provided input to working documents and then discussed them in conferences calls. Argument-based representation in design patterns was used to define the protocol at technical, system, and pandemic evidence levels. Results: The Protocol for a Standardized information infrastructure for Pandemic and Emerging infectious disease Response (PROSPER) outlines the implementation of information infrastructure aligned with pandemic response programs. The protocol covers analyses of the community at risk, the response processes, and response impacts. For each of these, the protocol outlines the implementation of a supporting information infrastructure in hierarchical patterns ranging from technical components and system functions to pandemic evidence production. Conclusions: The PROSPER protocol provides guidelines for implementation of an information infrastructure for pandemic response programs both in settings where sophisticated health information systems already are used and in developing communities where there is limited access to financial and technical resources. The protocol is based on a generic health service model and its functions are adjusted for community-level analyses of outbreak detection and progress, and response program effectiveness. Scientifically grounded reporting principles need to be established for interpretation of information derived from outbreak detection algorithms and predictive modeling.Original Publication:Toomas Timpka, Henrik Eriksson, Elin A Gursky, Magnus Stromgren, Einar Holm, Joakim Ekberg, Olle Eriksson, Anders Grimvall, Lars Valter and James M Nyce, Requirements and Design of the PROSPER Protocol for Implementation of Information Infrastructures Supporting Pandemic Response: A Nominal Group Study, 2011, PLOS ONE, (6), 3, 0017941.http://dx.doi.org/10.1371/journal.pone.0017941Copyright: Public Library of Science (PLoS)http://www.plos.org