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Stratospheric aerosol injection (SAI) comes with a wide range of possible design choices, such as the location and timing of the injection. Different stratospheric aerosol injection strategies can yield different climate responses; therefore, understanding the range of possible climate outcomes is crucial to making informed future decisions on SAI, along with the consideration of other factors. Yet, to date, there has been no systematic exploration of a broad range of SAI strategies. This limits the ability to determine which effects are robust across different strategies and which depend on specific injection choices. This study systematically explores how the choice of SAI strategy affects climate responses in one climate model. Here, we introduce four hemispherically symmetric injection strategies, all of which are designed to maintain the same global mean surface temperature: an annual injection at the Equator (EQ), an annual injection of equal amounts of SO2 at 15° N and 15° S (15N+15S), an annual injection of equal amounts of SO2 at 30° N and 30° S (30N+30S), and a polar injection strategy that injects equal amounts of SO2 at 60° N and 60° S only during spring in each hemisphere (60N+60S). We compare these four hemispherically symmetric SAI strategies with a more complex injection strategy that injects different quantities of SO2 at 30° N, 15° N, 15° S, and 30° S in order to maintain not only the global mean surface temperature but also its large-scale horizontal gradients. All five strategies are simulated using version 2 of the Community Earth System Model with the middle atmosphere version of the Whole Atmosphere Community Climate model, version 6, as the atmospheric component, CESM2(WACCM6-MA), with the global warming scenario, Shared Socioeconomic Pathway (SSP)2-4.5. We find that the choice of SAI strategy affects the spatial distribution of aerosol optical depths, injection efficiency, and various surface climate responses. In addition, injecting in the subtropics produces more global cooling per unit injection, with the EQ and the 60N+60S cases requiring, respectively, 59 % and 50 % more injection than the 30N+30S case to meet the same global mean temperature target. Injecting at higher latitudes results in larger Equator-to-pole temperature gradients. While all five strategies restore Arctic September sea ice, the high-latitude injection strategy is more effective due to the SAI-induced cooling occurring preferentially at higher latitudes. These results suggest trade-offs wherein different strategies appear better or worse, depending on which metrics are deemed important.

Despite offsetting global mean surface temperature, various studies demonstrated that stratospheric aerosol injection (SAI) could influence the recovery of stratospheric ozone and have important impacts on stratospheric and tropospheric circulation, thereby potentially playing an important role in modulating regional and seasonal climate variability. However, so far, most of the assessments of such an approach have come from climate model simulations in which SO2 is injected only in a single location or a set of locations. Here we use CESM2-WACCM6 SAI simulations under a comprehensive set of SAI strategies achieving the same global mean surface temperature with different locations and/or timing of injections, namely an equatorial injection, an annual injection of equal amounts of SO2 at 15∘ N and 15∘ S, an annual injection of equal amounts of SO2 at 30∘ N and 30∘ S, and a polar strategy injecting SO2 at 60∘ N and 60∘ S only in spring in each hemisphere. We demonstrate that despite achieving the same global mean surface temperature, the different strategies result in contrastingly different magnitudes of the aerosol-induced lower stratospheric warming, stratospheric moistening, strengthening of stratospheric polar jets in both hemispheres, and changes in the speed of the residual circulation. These impacts tend to maximise under the equatorial injection strategy and become smaller as the aerosols are injected away from the Equator into the subtropics and higher latitudes. In conjunction with the differences in direct radiative impacts at the surface, these different stratospheric changes drive different impacts on the extratropical modes of variability (Northern and Southern Annular modes), including important consequences on the northern winter surface climate, and on the intensity of tropical tropospheric Walker and Hadley circulations, which drive tropical precipitation patterns. Finally, we demonstrate that the choice of injection strategy also plays a first-order role in the future evolution of stratospheric ozone under SAI throughout the globe. Overall, our results contribute to an increased understanding of the fine interplay of various radiative, dynamical, and chemical processes driving the atmospheric circulation and ozone response to SAI and lay the foundation for designing an optimal SAI strategy that could form a basis of future multi-model intercomparisons.

Depletion of the stratospheric ozone layer remains an ongoing environmental issue, with increasing stratospheric chlorine from very short-lived substances (VSLS) recently emerging as a potential but uncertain threat to its future recovery. Here the impact of chlorinated VSLS (Cl-VSLS) on past ozone is quantified, for the first time, using the UM–UKCA (Unified Model–United Kingdom Chemistry and Aerosol) chemistry-climate model. Model simulations nudged to reanalysis fields show that in the second decade of the 21st century Cl-VSLS reduced total column ozone by, on average, ∼ 2–3 DU (Dobson unit) in the springtime high latitudes and by ∼0.5 DU in the annual mean in the tropics. The largest ozone reductions were simulated in the Arctic in the springs of 2011 and 2020. During the recent cold Arctic winter of 2019/20 Cl-VSLS resulted in local ozone reductions of up to ∼7 % in the lower stratosphere and of ∼7 DU in total column ozone by the end of March. Despite nearly doubling of Cl-VSLS contribution to stratospheric chlorine over the early 21st century, the inclusion of Cl-VSLS in the nudged simulations does not substantially modify the magnitude of the simulated recent ozone trends and, thus, does not help to explain the persistent negative ozone trends that have been observed in the extra-polar lower stratosphere. The free-running simulations, on the other hand, suggest Cl-VSLS-induced amplification of the negative tropical lower-stratospheric ozone trend by ∼20 %, suggesting a potential role of the dynamical feedback from Cl-VSLS-induced chemical ozone loss. Finally, we calculate the ozone depletion potential of dichloromethane, the most abundant Cl-VSLS, at 0.0107. Our results illustrate a so-far modest but nonetheless non-negligible role of Cl-VSLS in contributing to the stratospheric ozone budget over the recent past that if continues could offset some of the gains achieved by the Montreal Protocol.

The paper describes the development and performance of the Double Extended Stratospheric–Tropospheric (DEST vn1.0) chemistry scheme, which forms a part of the Met Office's Unified Model coupled to the United Kingdom Chemistry and Aerosol (UM–UKCA) chemistry–climate model, which is the atmospheric composition model of the United Kingdom Earth System Model (UKESM). The scheme extends the standard Stratospheric–Tropospheric chemistry scheme (StratTrop) by including a range of important updates to the halogen chemistry. These allow process-oriented studies of stratospheric ozone depletion and recovery, including the impacts from both controlled long-lived ozone-depleting substances (ODSs) and emerging issues around uncontrolled very short-lived substances (VSLS). The main updates in DEST are (i) an explicit treatment of 14 of the most important long-lived ODSs; (ii) an inclusion of brominated VSLS (Br-VSLS) emissions and chemistry; and (iii) an inclusion of chlorinated VSLS (Cl-VSLS) emissions/LBCs (lower boundary conditions) and chemistry. We evaluate the scheme's performance by comparing DEST simulations against analogous runs made with the standard StratTrop scheme and against observational and reanalysis datasets. Overall, our scheme addresses some significant shortcomings in the representation of atmospheric halogens in the standard StratTrop scheme and will thus be particularly relevant for studies of ozone layer recovery and processes affecting it, in support of future World Meteorological Organization (WMO) Ozone Assessment Reports.

Abstract Sulfur‐rich volcanic eruptions happen sporadically. If Stratospheric Aerosol Injection (SAI) were to be deployed, it is likely that explosive volcanic eruptions would happen during such a deployment. Here we use an ensemble of Earth System Model simulations to show how changing the injection strategy post‐eruption could be used to reduce the climate risks of a large volcanic eruption; the risks are also modified even without any change to the strategy. For a medium‐size eruption (10 Tg‐SO2) comparable to the SAI injection rate, the volcanic‐induced cooling would be reduced if it occurs under SAI, especially if artificial sulfur dioxide injections were immediately suspended. Alternatively, suspending injection only in the eruption hemisphere and continuing injection in the opposite would reduce shifts in precipitation in the tropical belt and thus mitigate eruption‐induced drought. Finally, we show that for eruptions much larger than the SAI deployment, changes in SAI strategy would have minimal effect.

Abstract Stratospheric Aerosol Injection (SAI) is a proposed method of climate intervention aiming to reduce the impacts of human‐induced global warming by reflecting a portion of incoming solar radiation. Many studies have demonstrated that SAI would successfully reduce global‐mean surface air temperatures; however the vast array of model scenarios and strategies result in a diverse range of climate impacts. Here we compare two SAI strategies—a quasi‐ equatorial injection and a multi‐latitude off‐equatorial injection—simulated with the UK Earth System Model (UKESM1), both aiming to reduce the global‐mean surface temperature from that of a high‐end emissions scenario to that of a moderate emissions scenario. We compare changes in the surface and stratospheric climate under each strategy to determine how the climate response depends on the injection location. In agreement with previous studies, an equatorial injection results in a tropospheric overcooling in the tropics and a residual warming in the polar regions, with substantial changes to stratospheric temperatures, water vapor and circulation. Previous comparisons of equatorial versus off‐equatorial injection strategies are limited to two studies using different versions of the Community Earth System Model. Our study evaluates how the climate responds in UKESM1 under these injection strategies. Our results are broadly consistent with previous findings, concluding that an off‐equatorial injection strategy can minimize regional surface temperature and precipitation changes relative to the target. We also present more in‐depth analysis of the associated changes in Hadley Circulation and regional temperature changes, and call for a new series of inter‐model SAI comparisons using an off‐equatorial strategy.

Solar climate intervention using stratospheric aerosol injection (SAI) has been proposed as a method which could offset some of the adverse effects of global warming. The Assessing Responses and Impacts of Solar climate intervention on the Earth system with Stratospheric Aerosol Injection (ARISE-SAI) set of simulations is based on a moderate-greenhouse-gas-emission scenario and employs injection of sulfur dioxide at four off-equatorial locations using a control algorithm which maintains the global-mean surface temperature at 1.5 K above pre-industrial conditions (ARISE-SAI-1.5), as well as the latitudinal gradient and inter-hemispheric difference in surface temperature. This is the first comparison between two models (CESM2 and UKESM1) applying the same multi-target SAI strategy. CESM2 is successful in reaching its temperature targets, but UKESM1 has considerable residual Arctic warming. This occurs because the pattern of temperature change in a climate with SAI is determined by both the structure of the climate forcing (mainly greenhouse gases and stratospheric aerosols) and the climate models' feedbacks, the latter of which favour a strong Arctic amplification of warming in UKESM1. Therefore, research constraining the level of future Arctic warming would also inform any hypothetical SAI deployment strategy which aims to maintain the inter-hemispheric and Equator-to-pole near-surface temperature differences. Furthermore, despite broad agreement in the precipitation response in the extratropics, precipitation changes over tropical land show important inter-model differences, even under greenhouse gas forcing only. In general, this ensemble comparison is the first step in comparing policy-relevant scenarios of SAI and will help in the design of an experimental protocol which both reduces some known negative side effects of SAI and is simple enough to encourage more climate models to participate.

Abstract The impacts of Stratospheric Aerosol Injection (SAI) on the atmosphere and surface climate depend on when and where the sulfate aerosol precursors are injected, as well as on how much surface cooling is to be achieved. We use a set of CESM2(WACCM6) SAI simulations achieving three different levels of global mean surface cooling and demonstrate that unlike some direct surface climate impacts driven by the reflection of solar radiation by sulfate aerosols, the SAI‐induced changes in the high latitude circulation and ozone are more complex and could be non‐linear. This manifests in our simulations by disproportionally larger Antarctic springtime ozone loss, significantly larger intra‐ensemble spread of the Arctic stratospheric jet and ozone responses, and non‐linear impacts on the extratropical modes of surface climate variability under the strongest‐cooling SAI scenario compared to the weakest one. These potential non‐linearities may add to uncertainties in projections of regional surface impacts under SAI.

Abstract The specifics of the simulated injection choices in the case of stratospheric aerosol injections (SAI) are part of the crucial context necessary for meaningfully discussing the impacts that a deployment of SAI would have on the planet. One of the main choices is the desired amount of cooling that the injections are aiming to achieve. Previous SAI simulations have usually either simulated a fixed amount of injection, resulting in a fixed amount of warming being offset, or have specified one target temperature, so that the amount of cooling is only dependent on the underlying trajectory of greenhouse gases. Here, we use three sets of SAI simulations achieving different amounts of global mean surface cooling while following a middle‐of‐the‐road greenhouse gas emission trajectory: one SAI scenario maintains temperatures at 1.5°C above preindustrial levels (PI), and two other scenarios which achieve additional cooling to 1.0°C and 0.5°C above PI. We demonstrate that various surface impacts scale proportionally with respect to the amount of cooling, such as global mean precipitation changes, changes to the Atlantic Meridional Overturning Circulation and to the Walker Cell. We also highlight the importance of the choice of the baseline period when comparing the SAI responses to one another and to the greenhouse gas emission pathway. This analysis leads to policy‐relevant discussions around the concept of a reference period altogether, and to what constitutes a relevant, or significant, change produced by SAI.

There is now substantial literature on climate model studies of equatorial or tropical stratospheric SO2 injections that aim to counteract the surface warming produced by rising concentrations of greenhouse gases. Here we present the results from the first systematic intercomparison of climate responses in three Earth system models wherein the injection of SO2 occurs at different latitudes in the lower stratosphere: CESM2-WACCM6, UKESM1.0 and GISS-E2.1-G. The first two use a modal aerosol microphysics scheme, while two versions of GISS-E2.1-G use a bulk aerosol (One-Moment Aerosol, OMA) and a two-moment (Multiconfiguration Aerosol TRacker of mIXing state, MATRIX) microphysics approach, respectively. Our aim in this work is to determine commonalities and differences between the climate model responses in terms of the distribution of the optically reflective sulfate aerosols produced from the oxidation of SO2 and in terms of the surface response to the resulting reduction in solar radiation. A focus on understanding the contribution of characteristics of models transport alongside their microphysical and chemical schemes, and on evaluating the resulting stratospheric responses in different models, is given in the companion paper (Bednarz et al., 2023). The goal of this exercise is not to evaluate these single-point injection simulations as stand-alone proposed strategies to counteract global warming; instead we determine sources and areas of agreement and uncertainty in the simulated responses and, ultimately, the possibility of designing a comprehensive intervention strategy capable of managing multiple simultaneous climate goals through the combination of different injection locations. We find large disagreements between GISS-E2.1-G and the CESM2-WACCM6 and UKESM1.0 models regarding the magnitude of cooling per unit of aerosol optical depth (AOD) produced, which varies from 4.7 K per unit of AOD in CESM2-WACCM6 to 16.7 K in the GISS-E2.1-G version with two-moment aerosol microphysics. By normalizing the results with the global mean response in each of the models and thus assuming that the amount of SO2 injected is a free parameter that can be managed independently, we highlight some commonalities in the overall distributions of the aerosols, in the inter-hemispheric surface temperature response and in shifts to the Intertropical Convergence Zone, as well as some areas of disagreement, such as the extent of the aerosol confinement in the equatorial region and the efficiency of the transport to polar latitudes. In conclusion, we demonstrate that it is possible to use these simulations to produce more comprehensive injection strategies in multiple climate models. However, large differences in the injection magnitudes can be expected, potentially increasing inter-model spreads in some stratospheric quantities (such as aerosol distribution) while reducing the spread in the surface response in terms of temperature and precipitation; furthermore, the selection of the injection locations may be dependent on the models' specific stratospheric transport.

The paper constitutes Part 2 of a study performing a first systematic inter-model comparison of the atmospheric responses to stratospheric aerosol injection (SAI) at various single latitudes in the tropics, as simulated by three state-of-the-art Earth system models – CESM2-WACCM6, UKESM1.0, and GISS-E2.1-G. Building on Part 1 (Visioni et al., 2023) we demonstrate the role of biases in the climatological circulation and specific aspects of the model microphysics in driving the inter-model differences in the simulated sulfate distributions. We then characterize the simulated changes in stratospheric and free-tropospheric temperatures, ozone, water vapor, and large-scale circulation, elucidating the role of the above aspects in the surface SAI responses discussed in Part 1. We show that the differences in the aerosol spatial distribution can be explained by the significantly faster shallow branches of the Brewer–Dobson circulation in CESM2, a relatively isolated tropical pipe and older tropical age of air in UKESM, and smaller aerosol sizes and relatively stronger horizontal mixing (thus very young stratospheric age of air) in the two GISS versions used. We also find a large spread in the magnitudes of the tropical lower-stratospheric warming amongst the models, driven by microphysical, chemical, and dynamical differences. These lead to large differences in stratospheric water vapor responses, with significant increases in stratospheric water vapor under SAI in CESM2 and GISS that were largely not reproduced in UKESM. For ozone, good agreement was found in the tropical stratosphere amongst the models with more complex microphysics, with lower stratospheric ozone changes consistent with the SAI-induced modulation of the large-scale circulation and the resulting changes in transport. In contrast, we find a large inter-model spread in the Antarctic ozone responses that can largely be explained by the differences in the simulated latitudinal distributions of aerosols as well as the degree of implementation of heterogeneous halogen chemistry on sulfate in the models. The use of GISS runs with bulk microphysics demonstrates the importance of more detailed treatment of aerosol processes, with contrastingly different stratospheric SAI responses to the models using the two-moment aerosol treatment; however, some problems in halogen chemistry in GISS are also identified that require further attention. Overall, our results contribute to an increased understanding of the underlying physical mechanisms as well as identifying and narrowing the uncertainty in model projections of climate impacts from SAI.

Impacts of chlorinated very short-lived substances (Cl-VSLS) on stratospheric chlorine budget over the first two decades of the 21st century are assessed using the Met Office’s Unified Model coupled to the United Kingdom Chemistry and Aerosol (UM-UKCA) chemistry–climate model; this constitutes the most up-to-date assessment and the first study to simulate Cl-VSLS impacts using a whole atmosphere chemistry–climate model. We examine the Cl-VSLS responses using a small ensemble of free-running simulations and two pairs of integrations where the meteorology was “nudged” to either ERA5 or ERA-Interim reanalysis. The stratospheric chlorine source gas injection due to Cl-VSLS estimated from the free-running integrations doubled from ∼40 ppt Cl injected into the stratosphere in 2000 to ∼80 ppt Cl injected in 2019. Combined with chlorine product gas injection, the integrations showed a total of ∼130 ppt Cl injected into the stratosphere in 2019 due to Cl-VSLS. The use of the nudged model significantly increased the abundance of Cl-VSLS simulated in the lower stratosphere relative to the free-running model. Averaged over 2010–2018, simulations nudged to ERAI-Interim and ERA5 showed 20 ppt (i.e. a factor of 2) and 10 ppt (i.e. ∼50 %) more Cl, respectively, in the tropical lower stratosphere at 20 km in the form of Cl-VSLS source gases compared to the free-running case. These differences can be explained by the corresponding differences in the speed of the large-scale circulation. The results illustrate the strong dependence of the simulated stratospheric Cl-VSLS levels on the model dynamical fields. In UM-UKCA, this corresponds to the choice between free-running versus nudged set-up, and to the reanalysis dataset used for nudging. Temporal changes in Cl-VSLS are found to have significantly impacted recent HCl and COCl2 trends in the model. In the tropical lower stratosphere, the inclusion of Cl-VSLS reduced the magnitude of the negative HCl and COCl2 trends (e.g. from ∼-8%(HCl)/decade and ∼-4 ppt(COCl2)/decade at ∼20 km to ∼-6%(HCl)/decade and ∼ −2 ppt(COCl2)/decade in the free running simulations) and gave rise to positive tropospheric trends in both tracers. In the tropics, both the free-running and nudged integrations with Cl-VSLS included compared much better to the observed trends from the ACE-FTS satellite record than the analogous simulations without Cl-VSLS. Since observed HCl trends provide information on the evolution of total stratospheric chlorine and, thus, the effectiveness of the Montreal Protocol, our results demonstrate that Cl-VSLS are a confounding factor in the interpretation of such data and should be factored into future analysis. Unlike the nudged model runs, the ensemble mean free-running integrations did not reproduce the hemispheric asymmetry in the observed mid-latitude HCl and COCl2 trends related to short-term dynamical variability. The individual ensemble members also showed a considerable spread of the diagnosed tracer trends, illustrating the role of natural interannual variability in modulating the diagnosed responses and the need for caution when interpreting both model and observed tracer trends derived over a relatively short time period.

Abstract Stratospheric aerosol injection (SAI) of reflective sulfate aerosols has been proposed to temporarily reduce the impacts of global warming. In this study, we compare two SAI simulations which inject at different altitudes to provide the same amount of cooling, finding that lower‐altitude SAI requires 64% more injection. SAI at higher altitudes cools the surface more efficiently per unit injection than lower‐altitude SAI through two primary mechanisms: the longer lifetimes of SO2 and SO4 at higher altitudes, and the water vapor feedback, in which lower‐altitude SAI causes more heating in the tropical cold point tropopause region, thereby increasing water vapor transport into the stratosphere and trapping more terrestrial infrared radiation that offsets some of the direct aerosol‐induced cooling. We isolate these individual mechanisms and find that the contribution of lifetime effects to differences in cooling efficiency is approximately five to six times larger than the contribution of the water vapor feedback.

Climate change is a prevalent threat, and it is unlikely that current mitigation efforts will be enough to avoid unwanted impacts. One potential option to reduce climate change impacts is the use of stratospheric aerosol injection (SAI). Even if SAI is ultimately deployed, it might be initiated only after some temperature target is exceeded. The consequences of such a delay are assessed herein. This study compares two cases, with the same target global mean temperature of ∼1.5° C above preindustrial, but start dates of 2035 or a ‘delayed’ start in 2045. We make use of simulations in the Community Earth System Model version 2 with the Whole Atmosphere Coupled Chemistry Model version 6 (CESM2-WACCM6), using SAI under the SSP2-4.5 emissions pathway. We find that delaying the start of deployment (relative to the target temperature) necessitates lower net radiative forcing (−30%) and thus larger sulfur dioxide injection rates (+20%), even after surface temperatures converge, to compensate for the extra energy absorbed by the Earth system. Southern hemisphere ozone is higher from 2035 to 2050 in the delayed start scenario, but converges to the same value later in the century. However, many of the surface climate differences between the 2035 and 2045 start simulations appear to be small during the 10–25 years following the delayed SAI start, although longer simulations would be needed to assess any longer-term impacts in this model. In addition, irreversibilities and tipping points that might be triggered during the period of increased warming may not be adequately represented in the model but could change this conclusion in the real world.

Abstract Objective To identify and descriptively compare medication recommendations among low back pain (LBP) clinical practice guidelines (CPG). Methods We searched PubMed, Cochrane Database of Systematic Review, Index to Chiropractic Literature, AMED, CINAHL, and PEDro to identify CPGs that described the management of mechanical LBP in the prior five years. Two investigators independently screened titles and abstracts and potentially relevant full text were considered for eligibility. Four investigators independently applied the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument for critical appraisal. Data were extracted for pharmaceutical intervention, the strength of recommendation, and appropriateness for the duration of LBP. Results 316 citations were identified, 50 full-text articles were assessed, and nine guidelines with global representation met the eligibility criteria. These CPGs addressed pharmacological treatments with or without non-pharmacological treatments. All CPGS focused on the management of acute, chronic, or unspecified duration of LBP. The mean overall AGREE II score was 89.3% (SD 3.5%). The lowest domain mean score was for applicability, 80.4% (SD 5.2%), and the highest was Scope and Purpose, 94.0% (SD 2.4%). There were ten classifications of medications described in the included CPGs: acetaminophen, antibiotics, anticonvulsants, antidepressants, benzodiazepines, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, oral corticosteroids, skeletal muscle relaxants (SMRs), and atypical opioids. Conclusions Nine CPGs, included ten medication classes for the management of LBP. NSAIDs were the most frequently recommended medication for the treatment of both acute and chronic LBP as a first line pharmacological therapy. Acetaminophen and SMRs were inconsistently recommended for acute LBP. Meanwhile, with less consensus among CPGs, acetaminophen and antidepressants were proposed as second-choice therapies for chronic LBP. There was significant heterogeneity of recommendations within many medication classes, although oral corticosteroids, benzodiazepines, anticonvulsants, and antibiotics were not recommended by any CPGs for acute or chronic LBP.

Abstract Stratospheric aerosol geoengineering has been proposed as a potential solution to reduce climate change and its impacts. Here, we explore the responses of the Hadley circulation (HC) intensity and the intertropical convergence zone (ITCZ) using the strategic stratospheric aerosol geoengineering, in which sulfur dioxide was injected into the stratosphere at four different locations to maintain the global-mean surface temperature and the interhemispheric and equator-to-pole temperature gradients at present-day values (baseline). Simulations show that, relative to the baseline, strategic stratospheric aerosol geoengineering generally maintains northern winter December–January–February (DJF) HC intensity under RCP8.5, while it overcompensates for the greenhouse gas (GHG)-forced southern winter June–July–August (JJA) HC intensity increase, producing a 3.5 ± 0.4% weakening. The residual change of southern HC intensity in JJA is mainly associated with stratospheric heating and tropospheric temperature response due to enhanced stratospheric aerosol concentrations. Geoengineering overcompensates for the GHG-driven northward ITCZ shifts, producing 0.7° ± 0.1° and 0.2° ± 0.1° latitude southward migrations in JJA and DJF, respectively relative to the baseline. These migrations are affected by tropical interhemispheric temperature differences both at the surface and in the free troposphere. Further strategies for reducing the residual change of HC intensity and ITCZ shifts under stratospheric aerosol geoengineering could involve minimizing stratospheric heating and restoring and preserving the present-day tropical tropospheric interhemispheric temperature differences.

This study assesses the impacts of stratospheric aerosol intervention (SAI) and solar dimming on stratospheric ozone based on the G6 Geoengineering Model Intercomparison Project (GeoMIP) experiments, called G6sulfur and G6solar. For G6sulfur, an enhanced stratospheric sulfate aerosol burden reflects some of the incoming solar radiation back into space to cool the surface climate, while for G6solar, the reduction in the global solar constant in the model achieves the same goal. Both experiments use the high emissions scenario of SSP5-8.5 as the baseline experiment and define surface temperature from the medium emission scenario of SSP2-4.5 as the target. In total, six Earth system models (ESMs) performed these experiments, and three out of the six models include interactive stratospheric chemistry. The increase in absorbing sulfate aerosols in the stratosphere results in a heating of the lower tropical stratospheric temperatures by between 5 to 13 K for the six different ESMs, leading to changes in stratospheric transport, water vapor, and other related changes. The increase in the aerosol burden also increases aerosol surface area density, which is important for heterogeneous chemical reactions. The resulting changes in the springtime Antarctic ozone between the G6sulfur and SSP5-8.5, based on the three models with interactive chemistry, include an initial reduction in total column ozone (TCO) of 10 DU (ranging between 0–30 DU for the three models) and up to 20 DU (between 10–40 DU) by the end of the century. The relatively small reduction in TCO for the multi-model mean in the first 2 decades results from variations in the required sulfur injections in the models and differences in the complexity of the chemistry schemes. In contrast, in the Northern Hemisphere (NH) high latitudes, no significant changes can be identified due to the large natural variability in the models, with little change in TCO by the end of the century. However, all three models with interactive chemistry consistently simulate an increase in TCO in the NH mid-latitudes up to 20 DU, compared to SSP5-8.5, in addition to the 20 DU increase resulting from increasing greenhouse gases between SSP2-4.5 and SSP5-8.5. In contrast to G6sulfur, G6solar does not significantly change stratospheric temperatures compared to the baseline simulation. Solar dimming results in little change in TCO compared to SSP5-8.5. Only in the tropics does G6solar result in an increase of TCO of up to 8 DU, compared to SSP2-4.5, which may counteract the projected reduction in SSP5-8.5. This work identifies differences in the response of SAI and solar dimming on ozone for three ESMs with interactive chemistry, which are partly due to the differences and shortcomings in the complexity of aerosol microphysics, chemistry, and the description of ozone photolysis. It also identifies that solar dimming, if viewed as an analog to SAI using a predominantly scattering aerosol, would succeed in reducing tropospheric and surface temperatures, but any stratospheric changes due to the high forcing greenhouse gas scenario, including the potential harmful increase in TCO beyond historical values, would prevail.

Abstract Background Little is known about the preferred treatment strategies of chiropractors in managing low back pain patients with prior lumbar fusions. There are several case reports which describe chiropractic care following surgical intervention, but there are no cohort or experimental studies published. Therefore, we sought to examine self-reported management approaches and practice patterns related to the management of patients with prior surgical lumbar fusion, among United States Veterans Affairs (VA) chiropractors. Methods An electronic survey was administered nationwide to all chiropractors providing clinical care within VA. Questions were informed by a prior survey and piloted on a sample of chiropractors external to VA. Statistical analysis included respondent background information, and quantitative analysis of chiropractic referral patterns and practices. This survey collect information on 1) provider demographics, 2) VA referral patterns, and 3) attitudes, beliefs, practices and interventions utilized by VA chiropractors to manage patients with a history of surgical lumbar fusion. Results The survey response rate was 46.3% (62/134). The respondents were broadly representative of VA chiropractic providers in age, gender, and years in practice. The majority of respondents (90.3%) reported seeing at least 1 post-fusion patient in the past month. The most common therapeutic approaches utilized by VA chiropractors were healthy lifestyle advice (94.9%), pain education (89.8%), exercise prescription (88.1%), stretching (66.1%) and soft tissue manual therapies (62.7%). A relatively smaller proportion described always or frequently incorporating lumbar (16.9%), thoracic (57.6%) or pelvic (39.0%) spinal manipulation. Conclusion This survey provides preliminary data on VA chiropractic services in the management of patients with prior lumbar fusion. These patients are often seen by VA chiropractors, and our findings support the need for further study to advance understanding of interventions utilized by chiropractors in this patient population.

The atmospheric response to the 11-year solar cycle is separated into the contributions from changes in direct radiative heating and photolysis rates using specially designed sensitivity simulations with the UM-UKCA (Unified Model coupled to the United Kingdom Chemistry and Aerosol model) chemistry–climate model. We perform a number of idealised time-slice experiments under perpetual solar maximum (SMAX) and minimum conditions (SMIN), and we find that contributions from changes in direct heating and photolysis rates are both important for determining the stratospheric shortwave heating, temperature and ozone responses to the amplitude of the 11-year solar cycle. The combined effects of the processes are found to be largely additive in the tropics but nonadditive in the Southern Hemisphere (SH) high latitudes during the dynamically active season. Our results indicate that, in contrast to the original mechanism proposed in the literature, the solar-induced changes in the horizontal shortwave heating rate gradients not only in autumn/early winter but throughout the dynamically active season are important for modulating the dynamical response to changes in solar forcing. In spring, these gradients are strongly influenced by the shortwave heating anomalies at higher southern latitudes, which are closely linked to the concurrent changes in ozone. In addition, our simulations indicate differences in the winter SH dynamical responses between the experiments. We suggest a couple of potential drivers of the simulated differences, i.e. the role of enhanced zonally asymmetric ozone heating brought about by the increased solar-induced ozone levels under SMAX and/or sensitivity of the polar dynamical response to the altitude of the anomalous radiative tendencies. All in all, our results suggest that solar-induced changes in ozone, both in the tropics/mid-latitudes and the polar regions, are important for modulating the SH dynamical response to the 11-year solar cycle. In addition, the markedly nonadditive character of the SH polar vortex response simulated in austral spring highlights the need for consistent model implementation of the solar cycle forcing in both the radiative heating and photolysis schemes.

The 11-year solar cycle forcing is recognised as an important atmospheric forcing; however, there remain uncertainties in characterising the effects of solar variability on the atmosphere from observations and models. Here we present the first detailed assessment of the atmospheric response to the 11-year solar cycle in the UM-UKCA (Unified Model coupled to the United Kingdom Chemistry and Aerosol model) chemistry–climate model (CCM) using a three-member ensemble over the recent past (1966–2010). Comparison of the model simulations is made with satellite observations and reanalysis datasets. The UM-UKCA model produces a statistically significant response to the 11-year solar cycle in stratospheric temperatures, ozone and zonal winds. However, there are also differences in magnitude, spatial structure and timing of the signals compared to observational and reanalysis estimates. This could be due to deficiencies in the model performance, and so we include a critical discussion of the model limitations, and/or uncertainties in the current observational estimates of the solar cycle signals. Importantly, in contrast to many previous studies of the solar cycle impacts, we pay particular attention to the role of the chosen analysis method in UM-UKCA by comparing the model composite and a multiple linear regression (MLR) results. We show that the stratospheric solar responses diagnosed using both techniques largely agree with each other within the associated uncertainties; however, the results show that apparently different signals can be identified by the methods in the troposphere and in the tropical lower stratosphere. Lastly, we examine how internal atmospheric variability affects the detection of the 11-year solar responses in the model by comparing the results diagnosed from the three individual ensemble members (as opposed to those diagnosed from the full ensemble). We show overall agreement between the responses diagnosed for the ensemble members in the tropical and mid-latitude mid-stratosphere to lower mesosphere but larger apparent differences at Northern Hemisphere (NH) high latitudes during the dynamically active season. Our UM-UKCA results suggest the need for long data sets for confident detection of solar cycle impacts in the atmosphere, as well as for more research on possible interdependence of the solar cycle forcing with other atmospheric forcings and processes (e.g. Quasi-Biennial Oscillation, QBO; El Niño–Southern Oscillation, ENSO).

>We analyse simulations performed for the Chemistry-Climate Model Initiative (CCMI) to estimate the return dates of the stratospheric ozone layer from depletion caused by anthropogenic stratospheric chlorine and bromine. We consider a total of 155 simulations from 20 models, including a range of sensitivity studies which examine the impact of climate change on ozone recovery. For the control simulations (unconstrained by nudging towards analysed meteorology) there is a large spread (±20 DU in the global average) in the predictions of the absolute ozone column. Therefore, the model results need to be adjusted for biases against historical data. Also, the interannual variability in the model results need to be smoothed in order to provide a reasonably narrow estimate of the range of ozone return dates. Consistent with previous studies, but here for a Representative Concentration Pathway (RCP) of 6.0, these new CCMI simulations project that global total column ozone will return to 1980 values in 2049 (with a 1σ uncertainty of 2043–2055). At Southern Hemisphere mid-latitudes column ozone is projected to return to 1980 values in 2045 (2039–2050), and at Northern Hemisphere mid-latitudes in 2032 (2020–2044). In the polar regions, the return dates are 2060 (2055–2066) in the Antarctic in October and 2034 (2025–2043) in the Arctic in March. The earlier return dates in the Northern Hemisphere reflect the larger sensitivity to dynamical changes. Our estimates of return dates are later than those presented in the 2014 Ozone Assessment by approximately 5–17 years, depending on the region, with the previous best estimates often falling outside of our uncertainty range. In the tropics only around half the models predict a return of ozone to 1980 values, around 2040, while the other half do not reach the 1980 value. All models show a negative trend in tropical total column ozone towards the end of the 21st century. The CCMI models generally agree in their simulation of the time evolution of stratospheric chlorine and bromine, which are the main drivers of ozone loss and recovery. However, there are a few outliers which show that the multi-model mean results for ozone recovery are not as tightly constrained as possible. Throughout the stratosphere the spread of ozone return dates to 1980 values between models tends to correlate with the spread of the return of inorganic chlorine to 1980 values. In the upper stratosphere, greenhouse gas-induced cooling speeds up the return by about 10–20 years. In the lower stratosphere, and for the column, there is a more direct link in the timing of the return dates of ozone and chlorine, especially for the large Antarctic depletion. Comparisons of total column ozone between the models is affected by different predictions of the evolution of tropospheric ozone within the same scenario, presumably due to differing treatment of tropospheric chemistry. Therefore, for many scenarios, clear conclusions can only be drawn for stratospheric ozone columns rather than the total column. As noted by previous studies, the timing of ozone recovery is affected by the evolution of N2O and CH4. However, quantifying the effect in the simulations analysed here is limited by the few realisations available for these experiments compared to internal model variability. The large increase in N2O given in RCP 6.0 extends the ozone return globally by ∼ 15 years relative to N2O fixed at 1960 abundances, mainly because it allows tropical column ozone to be depleted. The effect in extratropical latitudes is much smaller. The large increase in CH4 given in the RCP 8.5 scenario compared to RCP 6.0 also lengthens ozone return by ∼ 15 years, again mainly through its impact in the tropics. Overall, our estimates of ozone return dates are uncertain due to both uncertainties in future scenarios, in particular those of greenhouse gases, and uncertainties in models. The scenario uncertainty is small in the short term but increases with time, and becomes large by the end of the century. There are still some model–model differences related to well-known processes which affect ozone recovery. Efforts need to continue to ensure that models used for assessment purposes accurately represent stratospheric chemistry and the prescribed scenarios of ozone-depleting substances, and only those models are used to calculate return dates. For future assessments of single forcing or combined effects of CO2, CH4, and N2O on the stratospheric column ozone return dates, this work suggests that it is more important to have multi-member (at least three) ensembles for each scenario from every established participating model, rather than a large number of individual models.

Altered sensory processing has been an important feature of the clinical descriptions of autism spectrum disorder (ASD). There is evidence that sensory dysregulation arises early in the progression of ASD and impacts social functioning. This paper reviews behavioral and neurobiological evidence that describes how sensory deficits across multiple modalities (vision, hearing, touch, olfaction, gustation, and multisensory integration) could impact social functions in ASD. Theoretical models of ASD and their implications for the relationship between sensory and social functioning are discussed. Furthermore, neural differences in anatomy, function, and connectivity of different regions underlying sensory and social processing are also discussed. We conclude that there are multiple mechanisms through which early sensory dysregulation in ASD could cascade into social deficits across development. Future research is needed to clarify these mechanisms, and specific focus should be given to distinguish between deficits in primary sensory processing and altered top-down attentional and cognitive processes. Keywords: Autism spectrum disorder, Sensory, Social cognition, Sensory sensitivity

Future trends in Arctic springtime total column ozone, and its chemical and dynamical drivers, are assessed using a seven-member ensemble from the Met Office Unified Model with United Kingdom Chemistry and Aerosols (UM-UKCA) simulating the period 1960–2100. The Arctic mean March total column ozone increases throughout the 21st century at a rate of ∼ 11.5 DU decade−1, and is projected to return to the 1980 level in the late 2030s. However, the integrations show that even past 2060 springtime Arctic ozone can episodically drop by ∼ 50–100 DU below the corresponding long-term ensemble mean for that period, reaching values characteristic of the near-present-day average level. Consistent with the global decline in inorganic chlorine (Cly) over the century, the estimated mean halogen-induced chemical ozone loss in the Arctic lower atmosphere in spring decreases by around a factor of 2 between the periods 2001–2020 and 2061–2080. However, in the presence of a cold and strong polar vortex, elevated halogen-induced ozone losses well above the corresponding long-term mean continue to occur in the simulations into the second part of the century. The ensemble shows a significant cooling trend in the Arctic winter mid- and upper stratosphere, but there is less confidence in the projected temperature trends in the lower stratosphere (100–50 hPa). This is partly due to an increase in downwelling over the Arctic polar cap in winter, which increases transport of ozone into the polar region as well as drives adiabatic warming that partly offsets the radiatively driven stratospheric cooling. However, individual winters characterised by significantly suppressed downwelling, reduced transport and anomalously low temperatures continue to occur in the future. We conclude that, despite the projected long-term recovery of Arctic ozone, the large interannual dynamical variability is expected to continue in the future, thereby facilitating episodic reductions in springtime ozone columns. Whilst our results suggest that the relative role of dynamical processes for determining Arctic springtime ozone will increase in the future, halogen chemistry will remain a smaller but non-negligible contributor for many decades to come.

Wireless Local Area Networks (WLANs) have revolutionized modern communication by providing a user-friendly and cost-efficient solution for Internet access and network resources. However, the increasing popularity of WLANs has also led to a rise in security threats, including jamming, flooding attacks, unfair radio channel access, user disconnection from access points, and injection attacks, among others. In this paper, we propose a machine learning algorithm to detect Layer 2 threats in WLANs through network traffic analysis. Our approach uses a deep neural network to identify malicious activity patterns. We detail the dataset used, including data preparation steps, such as preprocessing and division. We demonstrate the effectiveness of our solution through series of experiments and show that it outperforms other methods in terms of precision. The proposed algorithm can be successfully applied in Wireless Intrusion Detection Systems (WIDS) to enhance the security of WLANs and protect against potential attacks.

The aim of this study was to compare the effectiveness of two diagnostic methods: ultrasonic gingival thickness measurement (UGTM) and cone-beam computed tomography, intraoral scanning by computer-aided design technology with prosthetic-driven implant planning software (CBCT/CAD/PDIP) in determining the gingival phenotype (GP). Thirty periodontally healthy patients were examined. The ultrasonic device Pirop G ® with a frequency of 20 MHz and CBCT/CAD/PDIP were used to measure gingival thickness at upper canines and incisors in three points localized midbuccally, namely free gingival thickness (FGT), supracrestal (SGT) and crestal (CGT). Probing depth (PD), clinical attachment level (CAL) and width of keratinized tissue (WKT) were measured using periodontal probe. Intra-examiner and inter-examiner agreement and agreement between methods were evaluated using Bland-Altman analyses. Comparing both methods in the determination of SGT (bias = 0.17 mm, SD = 0.25 mm, p < 0.000) and CGT (bias = -0.45 mm, SD = 0.32 mm, p < 0.000) 95.0% and 95.6% agreement were found, respectively, and in the FGT range only 93.3% (bias = -0.45 mm, SD = 0.32 mm, p < 0.000). The presence of positive correlations between WKT and SGT was shown. A positive correlation between SGT and WKT confirms the purpose of measuring these parameters for the evaluation of the GP. Both the ultrasonic method and cone-beam computed tomography combined with intraoral scanning and prosthetic-driven implant planning method were useful in determining gingival phenotype, however, the ultrasonic method was more accurate for measuring GT.

The occurrence of microplastic (MP) in food products, such as beverages in plastic bottles, is of high public concern. Existing analytical methods focus on the determination of particle numbers, requiring elaborate sampling tools, laboratory infrastructure and generally time-consuming imaging detection methods. A comprehensive routine analysis of MP in food products is still not possible. In the present work, we present the development of a smart filter crucible as sampling and detection tool. After filtration and drying of the filtered-off solids, a direct determination of the MP mass content from the crucible sample can be done by thermal extraction desorption gas chromatography mass spectroscopy (TED-GC/MS). The new filter crucible allows a filtration of MP down to particle sizes of 5 µm. We determined MP contents below 0.01 µg/L up to 2 µg/L, depending on beverages bottle type. This may be directly related to the bottle type, especially the quality of the plastic material of the screw cap. Dependent on the plastic material, particle formation increases due to opening and closing operations during the use phase. However, we have also found that some individual determinations of samples were subjected to high errors due to random events. A conclusive quantitative evaluation of the products is therefore not possible at present.

BACKGROUND Two clinical parameters, the gingival thickness (GT) and the width of keratinized tissue (WKT), describe the gingival phenotype, which is defined as the 3-dimensional volume of the gingiva. The periodontal phenotype additionally includes the thickness of the labial plate of the alveolar crest (TLPAC). MATERIAL AND METHODS Thirty patients with healthy periodontium on the upper canines and incisors underwent measurements for crestal, supracrestal, free gingival thickness (FGT), the alveolar crest-gingival margin (AC-GM), alveolar crest-cementoenamel junction distance, and the TLPAC at 2, 4, and 8 mm apically from the edge of the alveolar crest using cone-beam computed tomography (CBCT) with computer-aided design and prosthetic-driven implant planning technology. For each tooth, the gingival and periodontal phenotype was evaluated on the basis of the gingival thickness, width of keratinized tissue (WKT), and TLPAC measurements. Each patient's periodontal phenotype was evaluated according to the coronal width/length ratio of both the upper central incisors. RESULTS The dentogingival units had varying average values for the 3 periodontal phenotypes (thin phenotype: FGT 0.65±0.06 mm, WKT 4.85±1.18 mm, AC-GM 3.17±0.64 mm, TLPAC2 0.66±0.28 mm; medium phenotype: FGT 0.87±0.07 mm, WKT 5.49±1.23 mm, AC-GM 3.36±0.65 mm, TLPAC2 0.76±0.37 mm; and thick phenotype: FGT 1.20 mm, WKT 6.00 mm, AC-GM 3.90 mm, TLPAC2 0.90 mm). Positive correlations were seen among WKT, FGT, AC-GM, and TLPAC2. CONCLUSIONS Positive correlations between the FGT and WKT, and the AC-GM distance confirm that measurements using CBCT with computer-aided design and prosthetic-driven implant planning technology can evaluate the gingival phenotype and TLPAC2 for the periodontal phenotype.

Background: The aim of the study was to analyse changes in the size of the corpus callosum (CC) depending on age and sex and to establish the reference values of the morphometric indices of the CC in the Polish population., Materials and Methods: The results of magnetic resonance studies of 1108 patients performed in the years 2010-2014 were analysed. Two independent radiologists evaluated cerebral images to exclude deviations from normal state. In patients divided according to sex and to 10 age groups, measurements of CC and brain dimensions were made and morphometric indices were calculated., Results: The results of measurements related to the following parameters: lengths of longitudinal cross-section of CC (CD), CC thickness in the narrowest place - isthmus (EF), the largest linear dimension of the brain from the frontal pole to the occipital pole (AB), the longitudinal cross-section area of the CC (A1) and cerebral cross-section area (A2) as well as CD/AB and A1/A2 ratios are summarised in 7 figures and 3 tables., Conclusions: It was demonstrated, that in all age groups there are statistically significant differences in the values of the analysed parameters and ratios of CC size. It was indicated, that there are no statistically significant differences between men and women in the CD, EF, and A1 parameters related to CC size, and the profiles of variations of these parameters are very similar. It was proved that the- re are statistical differences between women and men in parameters/indicators concerning of the brain size.

In sodium channelopathies, a severe fixed myopathy caused by a dominant mutation is rare. We describe two unrelated patients with a novel variant, p.Ile1455Thr, with phenotypes of paramyotonia in one case and fixed proximal myopathy with latent myotonia in another. In-vitro whole cell patch-clamp studies show that the mutation slows inactivation and accelerates recovery, in line with other paramyotonia variants with destabilized fast inactivation as pathomechanism. Additionally, p.IleI1455 causes a loss-of-function by reduced membrane insertion, right-shift of activation, and slowed kinetics. Molecular dynamics simulations comparing wild type and mutant Nav1.4 showed that threonine substitution hindered D4S4 mobility in response to membrane depolarization, consistent with effects of the mutation on channel inactivation. The fixed myopathy is likely to be associated to gain-of-function leading to sodium accumulation, regional edema, T-tubular swelling and mitochondrial stress. A possible contribution of the loss-of-function features towards myotonia and myopathy is discussed., (Copyright © 2016. Published by Elsevier B.V.)

Essential tremor (ET) is the most prevalent movement disorder, affecting millions of people in the USA. Although a positive family history is one of the most important risk factors for ET, the genetic causes of ET remain unknown. In an attempt to identify genetic causes for ET, we performed whole-exome sequencing analyses in a large Spanish family with ET, in which two patients also developed epilepsy. To further assess pathogenicity, site-directed mutagenesis, mouse and human brain expression analyses, and patch clamp techniques were performed. A disease-segregating mutation (p.Gly1537Ser) in the SCN4A gene was identified. Posterior functional analyses demonstrated that more rapid kinetics at near-threshold potentials altered ion selectivity and facilitated the conductance of both potassium and ammonium ions, which could contribute to tremor and increase susceptibility to epilepsy, respectively. In this report, for the first time, we associated the genetic variability of SCN4A with the development of essential tremor, which adds ET to the growing list of neurological channelopathies., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The lysis/lysogeny switch of bacteriophage lambda serves as a paradigm for binary cell fate decision, long-term maintenance of cellular state and stimulus-triggered switching between states. In the literature, the system is often referred to as "bistable." However, it remains unclear whether this term provides an accurate description or is instead a misnomer. Here we address this question directly. We first quantify transcriptional regulation governing lysogenic maintenance using a single-cell fluorescence reporter. We then use the single-cell data to derive a stochastic theoretical model for the underlying regulatory network. We use the model to predict the steady states of the system and then validate these predictions experimentally. Specifically, a regime of bistability, and the resulting hysteretic behavior, are observed. Beyond the steady states, the theoretical model successfully predicts the kinetics of switching from lysogeny to lysis. Our results show how the physics-inspired concept of bistability can be reliably used to describe cellular phenotype, and how an experimentally-calibrated theoretical model can have accurate predictive power for cell-state switching.

We studied a two-generation family presenting with conditions that included progressive permanent weakness, myopathic myopathy, exercise-induced contracture before normokalaemic periodic paralysis or, if localized to the tibial anterior muscle group, transient compartment-like syndrome (painful acute oedema with neuronal compression and drop foot). 23Na and 1H magnetic resonance imaging displayed myoplasmic sodium overload, and oedema. We identified a novel familial Ca(v)1.1 calcium channel mutation, R1242G, localized to the third positive charge of the domain IV voltage sensor. Functional expression of R1242G in the muscular dysgenesis mouse cell line GLT revealed a 28% reduced central pore inward current and a -20 mV shift of the steady-state inactivation curve. Both changes may be at least partially explained by an outward omega (gating pore) current at positive potentials. Moreover, this outward omega current of 27.5 nS/nF may cause the reduction of the overshoot by 13 mV and slowing of the upstroke of action potentials by 36% that are associated with muscle hypoexcitability (permanent weakness and myopathic myopathy). In addition to the outward omega current, we identified an inward omega pore current of 95 nS/nF at negative membrane potentials after long depolarizing pulses that shifts the R1242G residue above the omega pore constriction. A simulation reveals that the inward current might depolarize the fibre sufficiently to trigger calcium release in the absence of an action potential and therefore cause an electrically silent depolarization-induced muscle contracture. Additionally, evidence of the inward current can be found in 23Na magnetic resonance imaging-detected sodium accumulation and 1H magnetic resonance imaging-detected oedema. We hypothesize that the episodes are normokalaemic because of depolarization-induced compensatory outward potassium flux through both delayed rectifiers and omega pore. We conclude that the position of the R1242G residue before elicitation of the omega current is decisive for its conductance: if the residue is located below the gating pore as in the resting state then outward currents are observed; if the residue is above the gating pore because of depolarization, as in the inactivated state, then inward currents are observed. This study shows for the first time that functional characterization of omega pore currents is possible using a cultured cell line expressing mutant Ca(v)1.1 channels. Likewise, it is the first calcium channel mutation for complicated normokalaemic periodic paralysis.

Studying the 3D sub-cellular structure of living cells is essential to our understanding of biological function. However, tomographic imaging of live cells is challenging mainly because they are transparent, i.e., weakly scattering structures. Therefore, this type of imaging has been implemented largely using fluorescence techniques. While confocal fluorescence imaging is a common approach to achieve sectioning, it requires fluorescence probes that are often harmful to the living specimen. On the other hand, by using the intrinsic contrast of the structures it is possible to study living cells in a non-invasive manner. One method that provides high-resolution quantitative information about nanoscale structures is a broadband interferometric technique known as Spatial Light Interference Microscopy (SLIM). In addition to rendering quantitative phase information, when combined with a high numerical aperture objective, SLIM also provides excellent depth sectioning capabilities. However, like in all linear optical systems, SLIM's resolution is limited by diffraction. Here we present a novel 3D field deconvolution algorithm that exploits the sparsity of phase images and renders images with resolution beyond the diffraction limit. We employ this label-free method, called deconvolution Spatial Light Interference Tomography (dSLIT), to visualize coiled sub-cellular structures in E. coli cells which are most likely the cytoskeletal MreB protein and the division site regulating MinCDE proteins. Previously these structures have only been observed using specialized strains and plasmids and fluorescence techniques. Our results indicate that dSLIT can be employed to study such structures in a practical and non-invasive manner.

Determining the growth patterns of single cells offers answers to some of the most elusive questions in contemporary cell biology: how cell growth is regulated and how cell size distributions are maintained. For example, a linear growth in time implies that there is no regulation required to maintain homeostasis; an exponential pattern indicates the opposite. Recently, there has been great effort to measure single cells using microelectromechanical systems technology, and several important questions have been explored. However, a unified, easy-to-use methodology to measure the growth rate of individual adherent cells of various sizes has been lacking. Here we demonstrate that a newly developed optical interferometric technique, known as spatial light interference microscopy, can measure the cell dry mass of many individual adherent cells in various conditions, over spatial scales from micrometers to millimeters, temporal scales ranging from seconds to days, and cell types ranging from bacteria to mammalian cells. We found evidence of exponential growth in Escherichia coli, which agrees very well with other recent reports. Perhaps most importantly, combining spatial light interference microscopy with fluorescence imaging provides a unique method for studying cell cycle-dependent growth. Thus, by using a fluorescent reporter for the S phase, we measured single cell growth over each phase of the cell cycle in human osteosarcoma U2OS cells and found that the G2 phase exhibits the highest growth rate, which is mass-dependent and can be approximated by an exponential.

Sphingosine 1-phosphate lyase (S1PL) has been characterized as a novel target for the treatment of autoimmune disorders using genetic and pharmacological methods. Medicinal chemistry efforts targeting S1PL by direct in vivo evaluation of synthetic analogues of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI, 1) led to the discovery of 2 (LX2931) and 4 (LX2932). The immunological phenotypes observed in S1PL deficient mice were recapitulated by oral administration of 2 or 4. Oral dosing of 2 or 4 yielded a dose-dependent decrease in circulating lymphocyte numbers in multiple species and showed a therapeutic effect in rodent models of rheumatoid arthritis (RA). Phase I clinical trials indicated that 2, the first clinically studied inhibitor of S1PL, produced a dose-dependent and reversible reduction of circulating lymphocytes and was well tolerated at dose levels of up to 180 mg daily. Phase II evaluation of 2 in patients with active rheumatoid arthritis is currently underway.

During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.

A 3D quantitative structure-activity relationship study for inhibition of calcium-sensing receptor in the aryloxypropanolamine series predicted that these molecules adopt a U-shaped conformation with pi-stacking between the two aromatic rings. This hypothesis led to the discovery of novel 1-arylmethyl pyrrolidin-2-yl ethanol amines capable of antagonizing the calcium-sensing receptor with potency comparable to that of NPS-2143.

We calculate the temperature dependence of the fluorescence Stokes shift and the fluorescence decay time in linear Frenkel exciton systems resulting from the thermal redistribution of exciton population over the band states. The following factors, relevant to common experimental conditions, are accounted for in our kinetic model: (weak) localization of the exciton states by static disorder, coupling of the localized excitons to vibrations in the host medium, a possible nonequilibrium of the subsystem of localized Frenkel excitons on the time scale of the emission process, and different excitation conditions (resonant or nonresonant). A Pauli master equation, with microscopically calculated transition rates, is used to describe the redistribution of the exciton population over the manifold of localized exciton states. We find a counterintuitive nonmonotonic temperature dependence of the Stokes shift. In addition, we show that depending on experimental conditions, the observed fluorescence decay time may be determined by vibration-induced intraband relaxation, rather than radiative relaxation to the ground state. The model considered has relevance to a wide variety of materials, such as linear molecular aggregates, conjugated polymers, and polysilanes., ((c) 2004 American Institute of Physics.)

We model the optical dynamics in linear Frenkel exciton systems governed by scattering on static disorder and lattice vibrations and calculate the temperature dependent fluorescence spectrum and lifetime. The fluorescence Stokes shift shows a nonmonotonic behavior with temperature, which derives from the interplay of the local band-edge level structure and thermal equilibration. The model yields excellent fits to experiments performed on linear dye aggregates.

Continuing structure-activity studies were performed on the 2,3,4, 5-tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepine farnesyltransferase (FT) inhibitors. These studies demonstrated that a 3(R)-phenylmethyl group, a hydrophilic 7-cyano group, and a 4-sulfonyl group bearing a variety of substituents provide low-nanomolar FT inhibitors with cellular activity at concentrations below 100 nM. Maximal in vivo activity in the mutated K-Ras bearing HCT-116 human colon tumor model was achieved with analogues carrying hydrophobic side chains such as propyl, phenyl, or thienyl attached to the N-4 sulfonyl group. Several such compounds achieved curative efficacy when given orally in this model. On the basis of its excellent preclinical antitumor activity and promising pharmacokinetics, compound 20 (BMS-214662, (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thie nyl sulfonyl)-1H-1,4-benzodiazepine) has been advanced into human clinical trials.