Alphaxalone Binds in Inner Transmembrane ß+-α- Interfaces of α1ß3γ2 γ-Aminobutyric Acid Type A Receptors.

BACKGROUND: Neurosteroids like alphaxalone are potent anxiolytics, anticonvulsants, amnestics, and sedative-hypnotics, with effects linked to enhancement of γ-aminobutyric acid type A (GABAA) receptor gating in the central nervous system. Data locating neurosteroid binding sites on synaptic αßγ GABAA receptors are sparse and inconsistent. Some evidence points to outer transmembrane ß-α interfacial pockets, near sites that bind the anesthetics etomidate and propofol. Other evidence suggests that steroids bind more intracellularly in ß-α interfaces. METHODS: The authors created 12 single-residue ß3 cysteine mutations: ß3T262C and ß3T266C in ß3-M2; and ß3M283C, ß3Y284C, ß3M286C, ß3G287C, ß3F289C, ß3V290C, ß3F293C, ß3L297C, ß3E298C, and ß3F301C in ß3-M3 helices. The authors coexpressed α1 and γ2L with each mutant ß3 subunit in Xenopus oocytes and electrophysiologically tested each mutant for covalent sulfhydryl modification by the water-soluble reagent para-chloromercuribenzenesulfonate. Then, the authors assessed whether receptor-bound alphaxalone, etomidate, or propofol blocked cysteine modification, implying steric hindrance. RESULTS: Eleven mutant ß3 subunits, when coexpressed with α1 and γ2L, formed functional channels that displayed varied sensitivities to the three anesthetics. Exposure to para-chloromercuribenzenesulfonate produced irreversible functional changes in ten mutant receptors. Protection by alphaxalone was observed in receptors with ß3V290C, ß3F293C, ß3L297C, or ß3F301C mutations. Both etomidate and propofol protected receptors with ß3M286C or ß3V290C mutations. Etomidate also protected ß3F289C. In α1ß3γ2L structural homology models, all these protected residues are located in transmembrane ß-α interfaces. CONCLUSIONS: Alphaxalone binds in transmembrane ß-α pockets of synaptic GABAA receptors that are adjacent and intracellular to sites for the potent anesthetics etomidate and propofol.

Future dryness in the southwest US and the hydrology of the early 21st century drought.

Recently the Southwest has experienced a spate of dryness, which presents a challenge to the sustainability of current water use by human and natural systems in the region. In the Colorado River Basin, the early 21st century drought has been the most extreme in over a century of Colorado River flows, and might occur in any given century with probability of only 60%. However, hydrological model runs from downscaled Intergovernmental Panel on Climate Change Fourth Assessment climate change simulations suggest that the region is likely to become drier and experience more severe droughts than this. In the latter half of the 21st century the models produced considerably greater drought activity, particularly in the Colorado River Basin, as judged from soil moisture anomalies and other hydrological measures. As in the historical record, most of the simulated extreme droughts build up and persist over many years. Durations of depleted soil moisture over the historical record ranged from 4 to 10 years, but in the 21st century simulations, some of the dry events persisted for 12 years or more. Summers during the observed early 21st century drought were remarkably warm, a feature also evident in many simulated droughts of the 21st century. These severe future droughts are aggravated by enhanced, globally warmed temperatures that reduce spring snowpack and late spring and summer soil moisture. As the climate continues to warm and soil moisture deficits accumulate beyond historical levels, the model simulations suggest that sustaining water supplies in parts of the Southwest will be a challenge.

Carboetomidate inhibits alpha4/beta2 neuronal nicotinic acetylcholine receptors at concentrations affecting animals.

BACKGROUND: Carboetomidate is an etomidate derivative that produces hypnosis without inhibiting adrenal corticosteroid synthesis. Similar to etomidate, carboetomidate modulates γ-aminobutyric acid type A receptors, but its effects on other ion channel targets of general anesthetics are unknown. METHODS: We compared etomidate and carboetomidate effects on human N-methyl-d-aspartate receptors or neuronal nicotinic acetylcholine receptors (nnAChRs) expressed in Xenopus oocytes, using 2-microelectrode voltage clamp electrophysiology. RESULTS: Etomidate did not affect either type of receptor at clinically relevant concentrations, whereas carboetomidate concentrations near 50% effective concentration for anesthesia significantly inhibited nnAChRs. CONCLUSIONS: Compared with etomidate, carboetomidate's higher hydrophobicity is associated with greater inhibition of nnAChRs.

Sustainable water deliveries from the Colorado River in a changing climate.

The Colorado River supplies water to 27 million users in 7 states and 2 countries and irrigates over 3 million acres of farmland. Global climate models almost unanimously project that human-induced climate change will reduce runoff in this region by 10-30%. This work explores whether currently scheduled future water deliveries from the Colorado River system are sustainable under different climate-change scenarios. If climate change reduces runoff by 10%, scheduled deliveries will be missed approximately 58% of the time by 2050. If runoff reduces 20%, they will be missed approximately 88% of the time. The mean shortfall when full deliveries cannot be met increases from approximately 0.5-0.7 billion cubic meters per year (bcm/yr) in 2025 to approximately 1.2-1.9 bcm/yr by 2050 out of a request of approximately 17.3 bcm/yr. Such values are small enough to be manageable. The chance of a year with deliveries <14.5 bcm/yr increases to 21% by midcentury if runoff reduces 20%, but such low deliveries could be largely avoided by reducing scheduled deliveries. These results are computed by using estimates of Colorado River flow from the 20th century, which was unusually wet; if the river reverts to its long-term mean, shortfalls increase another 1-1.5 bcm/yr. With either climate-change or long-term mean flows, currently scheduled future water deliveries from the Colorado River are not sustainable. However, the ability of the system to mitigate droughts can be maintained if the various users of the river find a way to reduce average deliveries.

Selecting global climate models for regional climate change studies.

Regional or local climate change modeling studies currently require starting with a global climate model, then downscaling to the region of interest. How should global models be chosen for such studies, and what effect do such choices have? This question is addressed in the context of a regional climate detection and attribution (D&A) study of January-February-March (JFM) temperature over the western U.S. Models are often selected for a regional D&A analysis based on the quality of the simulated regional climate. Accordingly, 42 performance metrics based on seasonal temperature and precipitation, the El Nino/Southern Oscillation (ENSO), and the Pacific Decadal Oscillation are constructed and applied to 21 global models. However, no strong relationship is found between the score of the models on the metrics and results of the D&A analysis. Instead, the importance of having ensembles of runs with enough realizations to reduce the effects of natural internal climate variability is emphasized. Also, the superiority of the multimodel ensemble average (MM) to any 1 individual model, already found in global studies examining the mean climate, is true in this regional study that includes measures of variability as well. Evidence is shown that this superiority is largely caused by the cancellation of offsetting errors in the individual global models. Results with both the MM and models picked randomly confirm the original D&A results of anthropogenically forced JFM temperature changes in the western U.S. Future projections of temperature do not depend on model performance until the 2080s, after which the better performing models show warmer temperatures.

Two-frequency injection on a multimode vertical-cavity surface-emitting laser.

We have studied experimentally effects of two-frequency optical injection on a multimode vertical-cavity surface-emitting laser (VCSEL). The injected signal comes from another VCSEL. Polarization switching (PS) with and without frequency locking occurs for relatively small frequency detuning. Outside the regime of polarization switching, the VCSEL demonstrates two types of instabilities. The instability regions and boundaries of PS of each transverse mode are mapped in the parameter plane of frequency detuning versus injected power.

Ignitions explain more than temperature or precipitation in driving Santa Ana wind fires.

Autumn and winter Santa Ana wind (SAW)-driven wildfires play a substantial role in area burned and societal losses in southern California. Temperature during the event and antecedent precipitation in the week or month prior play a minor role in determining area burned. Burning is dependent on wind intensity and number of human-ignited fires. Over 75% of all SAW events generate no fires; rather, fires during a SAW event are dependent on a fire being ignited. Models explained 40 to 50% of area burned, with number of ignitions being the strongest variable. One hundred percent of SAW fires were human caused, and in the past decade, powerline failures have been the dominant cause. Future fire losses can be reduced by greater emphasis on maintenance of utility lines and attention to planning urban growth in ways that reduce the potential for powerline ignitions.

Precipitation regime change in Western North America: The role of Atmospheric Rivers.

Daily precipitation in California has been projected to become less frequent even as precipitation extremes intensify, leading to uncertainty in the overall response to climate warming. Precipitation extremes are historically associated with Atmospheric Rivers (ARs). Sixteen global climate models are evaluated for realism in modeled historical AR behavior and contribution of the resulting daily precipitation to annual total precipitation over Western North America. The five most realistic models display consistent changes in future AR behavior, constraining the spread of the full ensemble. They, moreover, project increasing year-to-year variability of total annual precipitation, particularly over California, where change in total annual precipitation is not projected with confidence. Focusing on three representative river basins along the West Coast, we show that, while the decrease in precipitation frequency is mostly due to non-AR events, the increase in heavy and extreme precipitation is almost entirely due to ARs. This research demonstrates that examining meteorological causes of precipitation regime change can lead to better and more nuanced understanding of climate projections. It highlights the critical role of future changes in ARs to Western water resources, especially over California.

Precipitation in a warming world: Assessing projected hydro-climate changes in California and other Mediterranean climate regions.

In most Mediterranean climate (MedClim) regions around the world, global climate models (GCMs) consistently project drier futures. In California, however, projections of changes in annual precipitation are inconsistent. Analysis of daily precipitation in 30 GCMs reveals patterns in projected hydrometeorology over each of the five MedClm regions globally and helps disentangle their causes. MedClim regions, except California, are expected to dry via decreased frequency of winter precipitation. Frequencies of extreme precipitation, however, are projected to increase over the two MedClim regions of the Northern Hemisphere where projected warming is strongest. The increase in heavy and extreme precipitation is particularly robust over California, where it is only partially offset by projected decreases in low-medium intensity precipitation. Over the Mediterranean Basin, however, losses from decreasing frequency of low-medium-intensity precipitation are projected to dominate gains from intensifying projected extreme precipitation. MedClim regions are projected to become more sub-tropical, i.e. made dryer via pole-ward expanding subtropical subsidence. California's more nuanced hydrological future reflects a precarious balance between the expanding subtropical high from the south and the south-eastward extending Aleutian low from the north-west. These dynamical mechanisms and thermodynamic moistening of the warming atmosphere result in increased horizontal water vapor transport, bolstering extreme precipitation events.

A spatially comprehensive, hydrometeorological data set for Mexico, the U.S., and Southern Canada 1950-2013.

A data set of observed daily precipitation, maximum and minimum temperature, gridded to a 1/16° (~6 km) resolution, is described that spans the entire country of Mexico, the conterminous U.S. (CONUS), and regions of Canada south of 53° N for the period 1950-2013. The dataset improves previous products in spatial extent, orographic precipitation adjustment over Mexico and parts of Canada, and reduction of transboundary discontinuities. The impacts of adjusting gridded precipitation for orographic effects are quantified by scaling precipitation to an elevation-aware 1981-2010 precipitation climatology in Mexico and Canada. Differences are evaluated in terms of total precipitation as well as by hydrologic quantities simulated with a land surface model. Overall, orographic correction impacts total precipitation by up to 50% in mountainous regions outside CONUS. Hydrologic fluxes show sensitivities of similar magnitude, with discharge more sensitive than evapotranspiration and soil moisture. Because of the consistent gridding methodology, the current product reduces transboundary discontinuities as compared with a commonly used reanalysis product, making it suitable for estimating large-scale hydrometeorologic phenomena.

The key role of dry days in changing regional climate and precipitation regimes.

Future changes in the number of dry days per year can either reinforce or counteract projected increases in daily precipitation intensity as the climate warms. We analyze climate model projected changes in the number of dry days using 28 coupled global climate models from the Coupled Model Intercomparison Project, version 5 (CMIP5). We find that the Mediterranean Sea region, parts of Central and South America, and western Indonesia could experience up to 30 more dry days per year by the end of this century. We illustrate how changes in the number of dry days and the precipitation intensity on precipitating days combine to produce changes in annual precipitation, and show that over much of the subtropics the change in number of dry days dominates the annual changes in precipitation and accounts for a large part of the change in interannual precipitation variability.

Mutations at beta N265 in γ-aminobutyric acid type A receptors alter both binding affinity and efficacy of potent anesthetics.

Etomidate and propofol are potent general anesthetics that act via GABAA receptor allosteric co-agonist sites located at transmembrane ß+/α- inter-subunit interfaces. Early experiments in heteromeric receptors identified ßN265 (M2-15') on ß2 and ß3 subunits as an important determinant of sensitivity to these drugs. Mechanistic analyses suggest that substitution with serine, the ß1 residue at this position, primarily reduces etomidate efficacy, while mutation to methionine eliminates etomidate sensitivity and might prevent drug binding. However, the ßN265 residue has not been photolabeled with analogs of either etomidate or propofol. Furthermore, substituted cysteine modification studies find no propofol protection at this locus, while etomidate protection has not been tested. Thus, evidence of contact between ßN265 and potent anesthetics is lacking and it remains uncertain how mutations alter drug sensitivity. In the current study, we first applied heterologous α1ß2N265Cγ2L receptor expression in Xenopus oocytes, thiol-specific aqueous probe modification, and voltage-clamp electrophysiology to test whether etomidate inhibits probe reactions at the ß-265 sidechain. Using up to 300 µM etomidate, we found both an absence of etomidate effects on α1ß2N265Cγ2L receptor activity and no inhibition of thiol modification. To gain further insight into anesthetic insensitive ßN265M mutants, we applied indirect structure-function strategies, exploiting second mutations in α1ß2/3γ2L GABAA receptors. Using α1M236C as a modifiable and anesthetic-protectable site occupancy reporter in ß+/α- interfaces, we found that ßN265M reduced apparent anesthetic affinity for receptors in both resting and GABA-activated states. ßN265M also impaired the transduction of gating effects associated with α1M236W, a mutation that mimics ß+/α- anesthetic site occupancy. Our results show that ßN265M mutations dramatically reduce the efficacy/transduction of anesthetics bound in ß+/α- sites, and also significantly reduce anesthetic affinity for resting state receptors. These findings are consistent with a role for ßN265 in anesthetic binding within the ß+/α- transmembrane sites.

Human-induced changes in the hydrology of the western United States.

Observations have shown that the hydrological cycle of the western United States changed significantly over the last half of the 20th century. We present a regional, multivariable climate change detection and attribution study, using a high-resolution hydrologic model forced by global climate models, focusing on the changes that have already affected this primarily arid region with a large and growing population. The results show that up to 60% of the climate-related trends of river flow, winter air temperature, and snow pack between 1950 and 1999 are human-induced. These results are robust to perturbation of study variates and methods. They portend, in conjunction with previous work, a coming crisis in water supply for the western United States.

Penetration of human-induced warming into the world's oceans.

A warming signal has penetrated into the world's oceans over the past 40 years. The signal is complex, with a vertical structure that varies widely by ocean; it cannot be explained by natural internal climate variability or solar and volcanic forcing, but is well simulated by two anthropogenically forced climate models. We conclude that it is of human origin, a conclusion robust to observational sampling and model differences. Changes in advection combine with surface forcing to give the overall warming pattern. The implications of this study suggest that society needs to seriously consider model predictions of future climate change.