Principled Standard Setting Requires Consideration of More Than Science (AEI-Brookings Joint Center for Regulatory Studies, Brief 00-02) Brief Amicus Curiae in Support of Respondents, Browner v. American Trucking Associations, Inc., No. 99-1257, (U.S. September 11, 2000)(with 20 Law Professors, Economists, and Scientists)

Summary of Argument: Throughout this proceeding, EPA has identified no policy or normative criteria to justify its NAAQS standards, thus suggesting that science alone can be used to determine the appropriate air quality standard. Science plays a critical, indeed essential, role in evaluating the risks of possible air quality standards being considered for adoption by EPA. However, science by itself cannot provide the justification for selecting a particular air quality standard. Especially in setting standards for non-threshold pollutants, such as in this case, scientific evidence cannot alone indicate where the standard should be set, since any level above zero will cause some health effects. To provide a principled and consistent basis for justifying the setting of such standards at some level above zero, EPA must articulate other factors -- whether they be costs or other policy criteria -- to guide its decisions on where to set national ambient air quality standards

Calcium Influx: Beyond ‘Current’ Biology

A novel, cell-surface protein essential for Ca2+ release-activated Ca2+ (CRAC) channel function has been identified through independent genome-wide screens. This huge advance will enable molecular dissection of the CRAC channel complex, moving the field beyond Icrac signature to structure

IP3 Receptor Activity Is Differentially Regulated in Endoplasmic Reticulum Subdomains during Oocyte Maturation

SummaryFertilization competency results from hormone-induced remodeling of oocytes into eggs. The signaling pathways that effect this change exemplify bistability, where brief hormone exposure irrevocably switches cell fate. In Xenopus, changes in Ca2+ signaling epitomize such remodeling: The reversible Ca2+ signaling phenotype of oocytes rapidly adapts to support irreversible propagation of the fertilization Ca2+ wave. Here, we simultaneously resolved IP3 receptor (IP3R) activity with endoplasmic reticulum (ER) structure to optically dissect the functional architecture of the Ca2+ release apparatus underpinning this reorganization. We show that changes in Ca2+ signaling correlate with IP3R redistribution from specialized ER substructures called annulate lamellae (AL), where Ca2+ release activity is attenuated, into IP3R-replete patches in the cortical ER of eggs that support the fertilization Ca2+ wave. These data show: first, that IP3R sensitivity is regulated with high spatial acuity even between contiguous ER regions; and second, that drastic reorganization of Ca2+ signaling dynamics can be driven by subcellular redistribution in the absence of changes in channel number or molecular or familial Ca2+ channel diversity. Finally, these results define a novel role for AL in Ca2+ signaling. Because AL are prevalent in other scenarios of rapid cell division, further studies of their impact on Ca2+ signaling are warranted

Timing in Cellular Ca2+ Signaling

SummaryCalcium (Ca2+) signals are generated across a broad time range. Kinetic considerations impact how information is processed to encode and decode Ca2+ signals, the choreography of responses that ensure specific and efficient signaling and the overall temporal amplification such that ephemeral Ca2+ signals have lasting physiological value. The reciprocal importance of timing for Ca2+ signaling, and Ca2+ signaling for timing is exemplified by the altered kinetic profiles of Ca2+ signals in certain diseases and the likely role of basal Ca2+ fluctuations in the perception of time itself

Cooperative activation of IP3 receptors by sequential binding of IP3 and Ca2+ safeguards against spontaneous activity

AbstractBackground: Ca2+ waves allow effective delivery of intracellular Ca2+ signals to cytosolic targets. Propagation of these regenerative Ca2+ signals probably results from the activation of intracellular Ca2+ channels by the increase in cytosolic [Ca2+] that follows the opening of these channels. Such positive feedback is potentially explosive. Mechanisms that limit the spontaneous opening of intracellular Ca2+ channels are therefore likely to have evolved in parallel with the mechanism of Ca2+-induced Ca2+ release.Results: Maximal rates of 45Ca2+ efflux from permeabilised hepatocytes superfused with medium in which the [Ca2+] was clamped were cooperatively stimulated by inositol 1,4,5-trisphosphate (IP3). A minimal interval of ∼400 msec between IP3 addition and the peak rate of Ca2+ mobilisation indicate that channel opening does not immediately follow binding of IP3. Although the absolute latency of Ca2+ release was unaffected by further increasing the IP3 concentration, it was reduced by increased [Ca2+].Conclusions: We propose that the closed conformation of the IP3 receptor is very stable and therefore minimally susceptible to spontaneous activation; at least three (probably four) IP3 molecules may be required to provide enough binding energy to drive the receptor into a stable open conformation. We suggest that a further defence from noise is provided by an extreme form of coincidence detection. Binding of IP3 to each of its four receptor subunits unmasks a site to which Ca2+ must bind before the channel can open. As IP3 binding may also initiate receptor inactivation, there may be only a narrow temporal window during which each receptor subunit must bind both of its agonists if the channel is to open rather than inactivate

REDD+, hype, hope and disappointment : The dynamics of expectations in conservation and development pilot projects

We explore the dynamics of expectations in international forest conservation and development programs, and the impacts and implications of (unfulfilled) expectations for actors involved. Early stages of new international conservation and development programs, often involving pilot projects designed to test intervention concepts at village level, are characterized by large amounts of resources and attention, along with high expectations of success. However, evidence shows that these early expectations are rarely fulfilled. Despite this repeated pattern and growing engagement with expectations in critical conservation and development literature, little is known about the dynamics of expectations in conservation and development pilot projects. We address this knowledge gap first by exploring concepts from the sociology of expectations. We then unpack expectations in a case study of REDD+ pilot projects in Tanzania, using extensive qualitative data reflecting the perspectives and experiences of a wide range of actors involved. Our study finds that expectations play a performative role, mobilizing actors and resources, despite uncertainty identified among policy-makers and practitioners. We also find that once raised, expectations are dynamic and continually mediated by actors and social contexts, which conflicts with attempts to ‘manage’ them. We argue therefore that a trade-off exists between fully piloting new initiatives and raising expectations. We also argue that failure to address this trade-off has implications beyond pilot project objectives and timelines, which are experienced most acutely by village communities. We argue for more critical engagement with expectations and the embedding of accountability for expectations in conservation and development practice. Our findings also challenge the discourse of ‘needing’ to pilot, which prioritizes awareness, impact and innovation without fully considering the potential negative impact of unfulfilled expectations

Localization and socialization: experimental insights into the functional architecture of IP₃ receptors

Inositol 1,4,5-trisphosphate (IP₃)-evoked Ca²⁺ signals display great spatiotemporal malleability. This malleability depends on diversity in both the cellular organization and in situ functionality of IP₃ receptors (IP₃Rs) that regulate Ca²⁺ release from the endoplasmic reticulum (ER). Recent experimental data imply that these considerations are not independent, such that—as with other ion channels—the local organization of IP₃Rs impacts their functionality, and reciprocally IP₃R activity impacts their organization within native ER membranes. Here, we (i) review experimental data that lead to our understanding of the “functional architecture” of IP₃Rs within the ER, (ii) propose an updated terminology to span the organizational hierarchy of IP₃Rs observed in intact cells, and (iii) speculate on the physiological significance of IP₃R socialization in Ca²⁺ dynamics, and consequently the emerging need for modeling studies to move beyond gridded, planar, and static simulations of IP₃R clustering even over short experimental timescales.Centro Regional de Estudios Genómico

Quantifying uncertainty in predictions of groundwater levels using formal likelihood methods

Informal and formal likelihood methods can be used to quantify uncertainty in modelled predictions of groundwater levels (GWLs). Informal methods use a relatively subjective criterion to identify sets of plausible or behavioural parameters of the GWL models. In contrast, formal methods specify a statistical model for the residuals or errors of the GWL model. The formal uncertainty estimates are only reliable when the assumptions of the statistical model are appropriate. We apply the formal approach to historical reconstructions of GWL hydrographs from four UK boreholes. We test whether a model which assumes Gaussian and independent errors is sufficient to represent the residuals or whether a model which includes temporal autocorrelation and a general non-Gaussian distribution is required. Groundwater level hydrographs are often observed at irregular time intervals so we use geostatistical methods to quantify the temporal autocorrelation rather than more standard time series methods such as autoregressive models. According to the Akaike Information Criterion, the more general statistical model better represents the residuals of the GWL model. However, no substantial difference between the accuracy of the GWL predictions and the estimates of their uncertainty is observed when the two statistical models are compared. When the general model is applied, significant temporal correlation over periods ranging from 3 to 20 months is evident for the different boreholes. When the GWL model parameters are sampled using a Markov Chain Monte Carlo approach the distributions based on the general statistical model differ from those of the Gaussian model, particularly for the boreholes with the most autocorrelation. These results suggest that the independent Gaussian model of residuals is sufficient to estimate the uncertainty of a GWL prediction on a single date. However, if realistically autocorrelated simulations of GWL hydrographs for multiple dates are required or if the distributions of the GWL model parameters are of interest, then the more general statistical model should be used