Blinded outcomes and angina assessment of coronary bioresorbable scaffolds: 30-day and 1-year results from the ABSORB IV randomised trial.

BACKGROUND: Previous studies showed more adverse events with coronary bioresorbable vascular scaffolds (BVS) than with metallic drug-eluting stents (DES), although in one randomised trial angina was reduced with BVS. However, these early studies were unmasked, lesions smaller than intended for the scaffold were frequently enrolled, implantation technique was suboptimal, and patients with myocardial infarction, in whom BVS might be well suited, were excluded. METHODS: In the active-controlled, blinded, multicentre, randomised ABSORB IV trial, patients with stable coronary artery disease or acute coronary syndromes aged 18 years or older were recruited from 147 hospitals in five countries (the USA, Germany, Australia, Singapore, and Canada). Enrolled patients were randomly assigned (1:1) to receive polymeric everolimus-eluting BVS (Absorb; Abbott Vascular, Santa Clara, CA, USA) with optimised implantation technique or cobalt-chromium everolimus-eluting stents (EES; Xience; Abbott Vascular, Santa Clara, CA, USA). Randomisation was stratified by diabetic status, whether patients would have been eligible for enrolment in the previous ABSORB III trial, and site. Patients and clinical assessors were masked to randomisation. The primary endpoint was target lesion failure (cardiac death, target vessel myocardial infarction, or ischaemia-driven target lesion revascularisation) at 30 days, tested for non-inferiority with a 2·9% margin for the risk difference. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02173379, and is closed to accrual. FINDINGS: Between Aug 15, 2014, and March 31, 2017, we screened 18 722 patients for eligibility, 2604 of whom were enrolled. 1296 patients were assigned to BVS, and 1308 patients were assigned to EES. Follow-up data at 30 days and 1 year, respectively, were available for 1288 and 1254 patients with BVS and for 1303 and 1272 patients with EES. Biomarker-positive acute coronary syndromes were present in 622 (24%) of 2602 patients, and, by angiographic core laboratory analysis, 78 (3%) of 2893 of lesions were in very small vessels. Target lesion failure at 30 days occurred in 64 (5·0%) patients assigned to BVS and 48 (3·7%) patients assigned to EES (difference 1·3%, upper 97·5% confidence limit 2·89; one-sided pnon-inferiority=0·0244). Target lesion failure at 1 year occurred in 98 (7·8%) patients assigned to BVS and 82 (6·4%) patients assigned to EES (difference 1·4%, upper 97·5% confidence limit 3·4; one-sided pnon-inferiority=0·0006). Angina, adjudicated by a central events committee at 1 year, occurred in 270 (20·3%) patients assigned to BVS and 274 (20·5%) patients assigned to EES (difference -0·3%, 95% CI -3·4% to 2·9%; one-sided pnon-inferiority=0·0008; two-sided psuperiority=0·8603). Device thrombosis within 1 year occurred in nine (0·7%) patients assigned to BVS and four (0·3%) patients assigned to EES (p=0·1586). INTERPRETATION: Polymeric BVS implanted with optimised technique in an expanded patient population resulted in non-inferior 30-day and 1-year rates of target lesion failure and angina compared with metallic DES. FUNDING: Abbott Vascular.

Bouncier Particles at Night: Biogenic Secondary Organic Aerosol Chemistry and Sulfate Drive Diel Variations in the Aerosol Phase in a Mixed Forest.

Aerosol phase state is critical for quantifying aerosol effects on climate and air quality. However, significant challenges remain in our ability to predict and quantify phase state during its evolution in the atmosphere. Herein, we demonstrate that aerosol phase (liquid, semisolid, solid) exhibits a diel cycle in a mixed forest environment, oscillating between a viscous, semisolid phase state at night and liquid phase state with phase separation during the day. The viscous nighttime particles existed despite higher relative humidity and were independently confirmed by bounce factor measurements and atomic force microscopy. High-resolution mass spectrometry shows the more viscous phase state at night is impacted by the formation of terpene-derived and higher molecular weight secondary organic aerosol (SOA) and smaller inorganic sulfate mass fractions. Larger daytime particulate sulfate mass fractions, as well as a predominance of lower molecular weight isoprene-derived SOA, lead to the liquid state of the daytime particles and phase separation after greater uptake of liquid water, despite the lower daytime relative humidity. The observed diel cycle of aerosol phase should provoke rethinking of the SOA atmospheric lifecycle, as it suggests diurnal variability in gas-particle partitioning and mixing time scales, which influence aerosol multiphase chemistry, lifetime, and climate impacts.

Late Strut Fracture Within a Partially Resorbed Bioresorbable Vascular Scaffold: A Possible Cause of Late Scaffold Thrombosis and Acute Coronary Syndrome.

The Bioresorbable Vascular Scaffold (BVS, Abbott Vascular, Santa Clara, Cal, USA) is an exciting advance in percutaneous coronary intervention providing a temporary drug eluting scaffold resorbed in two to five years. We present two cases of late scaffold thrombosis associated with strut fracture during the period of resorption, at 20 and 24 months following BVS implantation. We propose luminal migration of malapposed struts following strut fracture during resorption as a potential mechanism for late scaffold thrombosis and acute coronary syndrome.

Source attribution and quantification of benzene event emissions in a Houston ship channel community based on real-time mobile monitoring of ambient air.

UNLABELLED: A mobile laboratory equipped with a proton transfer reaction mass spectrometer (PTR-MS) operated in Galena Park, Texas, near the Houston Ship Channel during the Benzene and other Toxics Exposure Study (BEE-TEX). The mobile laboratory measured transient peaks of benzene of up to 37 ppbv in the afternoon and evening of February 19, 2015. Plume reconstruction and source attribution were performed using the four-dimensional (4D) variational data assimilation technique and a three-dimensional (3D) micro-scale forward and adjoint air quality model based on mobile PTR-MS data and nearby stationary wind measurements at the Galena Park Continuous Air Monitoring Station (CAMS). The results of inverse modeling indicate that significant pipeline emissions of benzene may at least partly explain the ambient concentration peaks observed in Galena Park during BEE-TEX. Total pipeline emissions of benzene inferred within the 16-km(2) model domain exceeded point source emissions by roughly a factor of 2 during the observational episode. Besides pipeline leaks, the model also inferred significant benzene emissions from marine, railcar, and tank truck loading/unloading facilities, consistent with the presence of a tanker and barges in the Kinder Morgan port terminal during the afternoon and evening of February 19. Total domain emissions of benzene exceeded corresponding 2011 National Emissions Inventory (NEI) estimates by a factor of 2-6. IMPLICATIONS: Port operations involving petrochemicals may significantly increase emissions of air toxics from the transfer and storage of materials. Pipeline leaks, in particular, can lead to sporadic emissions greater than in emission inventories, resulting in higher ambient concentrations than are sampled by the existing monitoring network. The use of updated methods for ambient monitoring and source attribution in real time should be encouraged as an alternative to expanding the conventional monitoring network.

Updated methods for assessing the impacts of nearby gas drilling and production on neighborhood air quality and human health.

UNLABELLED: An explosive growth in natural gas production within the last decade has fueled concern over the public health impacts of air pollutant emissions from oil and gas sites in the Barnett and Eagle Ford shale regions of Texas. Commonly acknowledged sources of uncertainty are the lack of sustained monitoring of ambient concentrations of pollutants associated with gas mining, poor quantification of their emissions, and inability to correlate health symptoms with specific emission events. These uncertainties are best addressed not by conventional monitoring and modeling technology, but by increasingly available advanced techniques for real-time mobile monitoring, microscale modeling and source attribution, and real-time broadcasting of air quality and human health data over the World Wide Web. The combination of contemporary scientific and social media approaches can be used to develop a strategy to detect and quantify emission events from oil and gas facilities, alert nearby residents of these events, and collect associated human health data, all in real time or near-real time. The various technical elements of this strategy are demonstrated based on the results of past, current, and planned future monitoring studies in the Barnett and Eagle Ford shale regions. IMPLICATIONS: Resources should not be invested in expanding the conventional air quality monitoring network in the vicinity of oil and gas exploration and production sites. Rather, more contemporary monitoring and data analysis techniques should take the place of older methods to better protect the health of nearby residents and maintain the integrity of the surrounding environment.

Interrupted aorta diagnosed in a 51-year-old woman.

A 51-year-old lady presented with increasing heart failure symptoms and palpitations. She had recently been diagnosed with a congenital ventricular septal defect, bicuspid aortic valve, and Eisenmenger's syndrome. There was clinical evidence of right heart failure and differential clubbing and cyanosis affecting the feet but not hands. A cardiac magnetic resonance imaging demonstrated interruption of the aortic arch beyond the left subclavian artery, with the descending aorta perfused entirely through a large patent ductus arteriosus.

Dorsal hippocampus represents locations to avoid as well as locations to approach during approach-avoidance conflict.

Worrying about perceived threats is a hallmark of multiple psychological disorders including anxiety. This concern about future events is particularly important when an individual is faced with an approach-avoidance conflict. Potential goals to approach are known to be represented in the dorsal hippocampus during theta sweeps. Similarly, important non-local information is represented during hippocampal high synchrony events (HSEs), which are correlated with sharp-wave ripples (SWRs). It is likely that potential future threats may be similarly represented. We examined how threats and rewards were represented within the hippocampus during approach-avoidance conflicts in rats faced with a predator-like robot guarding a food reward. We found representations of the pseudo-predator during HSEs when hesitating in the nest, and during theta prior to retreating as the rats approached the pseudo-predator. After the first attack, we observed new place fields appearing at the location of the robot (not the location the rat was when attacked). The anxiolytic diazepam reduced anxiety-like behavior and altered hippocampal local field potentials, including reducing SWRs, suggesting that one potential mechanism of diazepam's actions may be through altered representations of imagined threat. These results suggest that hippocampal representation of potential threats could be an important mechanism that underlies worry and a potential target for anxiolytics.

Early SGLT2 inhibitor use is associated with improved left atrial strain following acute coronary syndrome.

AIM: Left atrial (LA) strain, a novel marker of LA function, reliably predicts diastolic dysfunction. SGLT2 inhibitors improve heart failure outcomes, but limited data exists regarding their use in the immediate aftermath of acute coronary syndrome (ACS). We studied the effect of empagliflozin on LA strain in patients with type 2 diabetes (T2D) and ACS. METHODS: Patients with ACS and T2D were identified and empagliflozin was initiated in eligible patients prior to discharge. Patients not initiated on empagliflozin were analysed as a comparator group. A blinded investigator assessed LA strain using baseline and 3-6 month follow-up echocardiograms. RESULTS: Forty-four participants (n = 22 each group) were included. Baseline characteristics and LA strain were similar in the two groups. LA reservoir, conduit and contractile strain increased in empagliflozin group (28.0 ± 8.4% to 34.6 ± 12.2% p < 0.001, 14.5 ± 5.4% to 16.7 ± 7.0% p = 0.034, 13.5 ± 5.2% to 17.9 ± 7.2% p = 0.005, respectively) but remained unchanged in comparison group (29.2 ± 6.7% to 28.8 ± 7.0%, 12.8 ± 4.2% to 13.3 ± 4.7%, 16.7 ± 5.3% to 15.5 ± 4.5%, respectively, p = NS). The difference in change between groups was significant for LA reservoir (p = 0.003) and contractile strain (p = 0.005). CONCLUSION: In patients with ACS and T2D, addition of empagliflozin to standard ACS therapy prior to discharge is associated with improved LA function.

Excess nitrate loads to coastal waters reduces nitrate removal efficiency: mechanism and implications for coastal eutrophication.

Terrestrial ecosystems are becoming increasingly nitrogen-saturated due to anthropogenic activities, such as agricultural loading with artificial fertilizer. Thus, more and more reactive nitrogen is entering streams and rivers, primarily as nitrate, where it is eventually transported towards the coastal zone. The assimilation of nitrate by coastal phytoplankton and its conversion into organic matter is an important feature of the aquatic nitrogen cycle. Dissolved reactive nitrogen is converted into a particulate form, which eventually undergoes nitrogen removal via microbial denitrification. High and unbalanced nitrate loads to the coastal zone may alter planktonic nitrate assimilation efficiency, due to the narrow stochiometric requirements for nutrients typically shown by these organisms. This implies a cascade of changes for the cycling of other elements, such as carbon, with unknown consequences at the ecosystem level. Here, we report that the nitrate removal efficiency (NRE) of a natural phytoplankton community decreased under high, unbalanced nitrate loads, due to the enhanced recycling of organic nitrogen and subsequent production and microbial transformation of excess ammonium. NRE was inversely correlated with the amount of nitrate present, and mechanistically controlled by dissolved organic nitrogen (DON), and organic carbon (Corg) availability. These findings have important implications for the management of nutrient runoff to coastal zones.

5-Year Outcomes After Bioresorbable Coronary Scaffolds Implanted With Improved Technique.

BACKGROUND: Bioresorbable vascular scaffolds (BVS) were designed to improve late event-free survival compared with metallic drug-eluting stents. However, initial trials demonstrated worse early outcomes with BVS, in part due to suboptimal technique. In the large-scale, blinded ABSORB IV trial, polymeric everolimus-eluting BVS implanted with improved technique demonstrated noninferior 1-year outcomes compared with cobalt chromium everolimus-eluting stents (CoCr-EES). OBJECTIVES: This study sought to evaluate the long-term outcomes from the ABSORB IV trial. METHODS: We randomized 2,604 patients at 147 sites with stable or acute coronary syndromes to BVS with improved technique vs CoCr-EES. Patients, clinical assessors, and event adjudicators were blinded to randomization. Five-year follow-up was completed. RESULTS: Target lesion failure at 5 years occurred in 216 (17.5%) patients assigned to BVS and 180 (14.5%) patients assigned to CoCr-EES (P = 0.03). Device thrombosis within 5 years occurred in 21 (1.7%) BVS and 13 (1.1%) CoCr-EES patients (P = 0.15). Event rates were slightly greater with BVS than CoCr-EES through 3-year follow-up and were similar between 3 and 5 years. Angina, also centrally adjudicated, recurred within 5 years in 659 patients (cumulative rate 53.0%) assigned to BVS and 674 (53.3%) patients assigned to CoCr-EES (P = 0.63). CONCLUSIONS: In this large-scale, blinded randomized trial, despite the improved implantation technique, the absolute 5-year rate of target lesion failure was 3% greater after BVS compared with CoCr-EES. The risk period for increased events was limited to 3 years, the time point of complete scaffold bioresorption; event rates were similar thereafter. Angina recurrence after intervention was frequent during 5-year follow-up but was comparable with both devices.(Absorb IV Randomized Controlled Trial; NCT02173379).

Early Australian experience with intravascular lithotripsy treatment of severe calcific coronary stenosis: IVL in acute/chronic coronary syndromes.

Aims: Calcified coronary stenoses are a serious impediment to optimal stent expansion and can lead to stent failure and catastrophic adverse outcomes. We hereby present early Australian experience with intravascular lithotripsy for the treatment of calcific lesions in acute and chronic coronary syndromes. Methods and results: This was a single-centre retrospective study of all patients treated with intravascular lithotripsy (IVL) between October 2019 and June 2021. Patient demographics, procedural variables, and treatment safety/efficacy outcomes were evaluated. During this period, there were 40 patients and 41 coronary lesions with IVL-assisted percutaneous coronary intervention (PCI) (70% male; mean age 72.8±9.5 years). Indications for PCI were acute coronary syndromes in 25 patients (62.5%), and stable angina in 15 patients (37.5%). Upfront IVL usage occurred in 5% of cases with the rest being bailout procedures due to suboptimal initial balloon predilatation or stent underexpansion. Angiographic success (<20% residual stenosis) occurred in 37 cases (92.5%), with mean residual stenosis of 8.25%±8.5%. Two patients experienced procedural complications (5%). Conclusions: IVL appears to be a safe and effective modality in modifying coronary calcium to achieve optimal stent expansion in real-world practice. This device obviates the need for more complex lesion preparation strategies such as rotational or orbital atherectomy.

Response of nitrous oxide emissions to individual rain events and future changes in precipitation.

Changing precipitation has the potential to alter nitrous oxide (N2 O) emissions from agricultural regions. In this study, we applied the Coupled Model Intercomparison Project Phase 5 end-of-century RCP 8.5 (business as usual) precipitation projections for the U.S. Upper Midwest and examined the effects of mean precipitation changes, characterized by increased early-season rainfall and decreased mid- to late-season rainfall, on N2 O emissions from a conventionally managed corn (Zea mays L.) cropping system grown in an indoor mesocosm facility over four growing seasons. We also assessed the response of N2 O emissions to over 1,000 individual rain events. Nitrous oxide emissions were most strongly correlated with water-filled pore space (WFPS) and soil nitrogen (N) status. After rain events, the change in N2 O emissions, relative to pre-rain emissions, was more likely to be positive when soil NO3 - was >40 mg N kg-1 soil and soil NH4 + was >10 mg N kg-1 soil and was more likely to be negative when soil NO3 - was >40 mg N kg-1 soil and soil NH4 + was <10 mg N kg-1 soil. Similarly, hourly N2 O emissions remained <5 nmol m- 2 s-1 when combined NH4 + + NO3 - was <20 mg N kg-1 soil or NH4 + and NO3 - were <5 and 20 mg N kg-1 soil, respectively. Rain event magnitude did not substantially affect the change in N2 O flux. Finally, growing-season N2 O emissions, soil moisture, and inorganic N content were not affected by the future precipitation pattern. Near-optimal soil WFPS combined with soil N concentrations above the identified thresholds favor higher N2 O emissions.

Traffic, transport, and vegetation drive VOC concentrations in a major urban area in Texas.

The population of Texas has increased rapidly in the past decade. The San Antonio Field Study (SAFS) was designed to investigate ozone (O3) production and precursors in this rapidly changing, sprawling metropolitan area. There are still many questions regarding the sources and chemistry of volatile organic compounds (VOCs) in urban areas like San Antonio which are affected by a complex mixture of industry, traffic, biogenic sources and transported pollutants. The goal of the SAFS campaign in May 2017 was to measure inorganic trace gases, VOCs, methane (CH4), and ethane (C2H6). The SAFS field design included two sites to better assess air quality across the metro area: an urban site (Traveler's World; TW) and a downwind/suburban site (University of Texas at San Antonio; UTSA). The results indicated that acetone (2.52 ± 1.17 and 2.39 ± 1.27 ppbv), acetaldehyde (1.45 ± 1.02 and 0.93 ± 0.45 ppbv) and isoprene (0.64 ± 0.49 and 1.21 ± 0.85 ppbv; TW and UTSA, respectively) were the VOCs with the highest concentrations. Additionally, positive matrix factorization showed three dominant factors of VOC emissions: biogenic, aged urban mixed source, and acetone. Methyl vinyl ketone and methacrolein (MVK + MACR) exhibited contributions from both secondary photooxidation of isoprene and direct emissions from traffic. The C2H6:CH4 demonstrated potential influence of oil and gas activities in San Antonio. Moreover, the high O3 days during the campaign were in the NOx-limited O3 formation regime and were preceded by evening peaks in select VOCs, NOx and CO. Overall, quantification of the concentration and trends of VOCs and trace gases in a major city in Texas offers vital information for general air quality management and supports strategies for reducing O3 pollution. The SAFS campaign VOC results will also add to the growing body of literature on urban sources and concentrations of VOCs in major urban areas.

Dynamic nuclear polarization system output volume reduction using inert fluids.

PURPOSE: To present a method for significantly increasing the concentration of a hyperpolarized compound produced by a commercial dynamic nuclear polarization (DNP) polarizer, enabling the polarization process to be more suitable for preclinical applications. MATERIALS AND METHODS: Using a HyperSense DNP polarizer, we investigated the combined use of perfluorocarbon and water to warm and dissolve the hyperpolarized material from the polarization temperature of 1.4K to produce material at temperatures suitable for injection. RESULTS: By replacing 75% of the water in the dissolution volume with a chemically and biologically inert liquid that is immiscible with water, the injection volume can be reduced 4-fold. Rapid separation of the water and perfluorocarbon mixture enables the aqueous layer containing polarized material to be easily and rapidly collected. CONCLUSION: The approach provides a significantly increased concentration of compound in a volume for injection that is more appropriate for small animal studies. This is demonstrated for (13) C-labeled pyruvic acid and (13) C-labeled succinate, but may be applied to the majority of nuclei and compounds hyperpolarized by the DNP method.

Lessons from thymic epithelial heterogeneity: FoxN1 and tissue-restricted gene expression by extrathymic, endodermally derived epithelium.

Modeling of thymic epithelial differentiation has been guided by several important underlying assumptions. One is that within epithelial tissues derived from pharyngeal endoderm, FoxN1 expression is signature for the thymic epithelial lineage. Another is that expression of tissue-restricted Ag (TRA) is a unique feature of thymic epithelium. In this murine study, we evaluate the thymic expression of a subset of TRA, parathyroid hormone, calcitonin, and thyroglobulin, as part of an effort to better define the heterogeneity of medullary thymic epithelial cells. In this study, we demonstrate that both conventional and cystic epithelial cells display a history of FoxN1 expression using a cre-lox approach. We also document that extrathymic epithelial tissues that originate from pharyngeal endoderm also have a history of FoxN1 expression, indicating that FoxN1 expression per se is not a signature for the thymic lineage and suggesting that FoxN1 expression, whereas necessary for thymic epithelium, development, is not sufficient for this process to occur. Both cystic and conventional medullary thymic epithelial cells express these TRAs, as do extrathymic epithelial tissues that are not usually considered to be sources of these molecules. This finding supports the proposition that promiscuous gene expression is not unique to the thymus. Furthermore, the pattern of promiscuous gene expression in these extrathymic epithelia is consistent with developmental regulation processes and suggests that it is premature to discard the possibility that some promiscuous gene expression in the thymus reflects normal differentiation programs of epithelia.

Water quality measurements in Buzzards Bay by the Buzzards Bay Coalition Baywatchers Program from 1992 to 2018.

The Buzzards Bay Coalition's Baywatchers Monitoring Program (Baywatchers) collected summertime water quality information at more than 150 stations around Buzzards Bay, Massachusetts from 1992 to 2018. Baywatchers documents nutrient-related water quality and the effects of nitrogen pollution. The large majority of stations are located in sub-estuaries of the main Bay, although stations in central Buzzards Bay and Vineyard Sound were added beginning in 2007. Measurements include temperature, salinity, Secchi depth and concentrations of dissolved oxygen, ammonium, nitrate + nitrite, total dissolved nitrogen, particulate organic nitrogen, particulate organic carbon, ortho-phosphate, chlorophyll a, pheophytin a, and in lower salinity waters, total phosphorus and dissolved organic carbon. The Baywatchers dataset provides a long-term record of the water quality of Buzzards Bay and its sub-estuaries. The data have been used to identify impaired waters, evaluate discharge permits, support the development of nitrogen total maximum daily loads, develop strategies for reducing nitrogen inputs, and increase public awareness and generate support for management actions to control nutrient pollution and improve water quality.

Alterations of the medullary epithelial compartment in the Aire-deficient thymus: implications for programs of thymic epithelial differentiation.

A widely held model of thymic epithelial differentiation is based on patterns of keratin expression, where a K8(+)K5(+) progenitor gives rise to K8(+)K5/K14(-) cortical thymic epithelium (CTEC), and medullary thymic epithelium (MTEC) are K8(-)K5(+)K14(+). The thymic phenotype of p63-deficient mice indicates that p63 is an important regulator of proximal stages of thymic epithelial differentiation. In this study, we have examined several features of the thymic medullary compartment in wild-type and Aire-deficient thymi in an effort to integrate the proapoptotic activity of Aire with these different perspectives of TE differentiation. Patterns of keratin and p63 expression by MTEC described here are difficult to reconcile with postmitotic MTEC that express a K8(-)K14(+) phenotype and suggest that the patterns of p63 and keratin expression reflecting differentiation programs of other epithelial tissues provide a useful framework for revising models of TE differentiation. Alterations of the Aire(-/-) MTEC compartment included reduced expression of p63, increased frequency of MTEC expressing truncated Aire protein, and shifts in the pattern of keratin expression and epithelial morphology. These data suggest a scenario where cellular targets of Aire-mediated apoptosis are postmitotic MTEC that have not yet completed their terminal differentiation program. According to this view, the minor population of globular K8(+)K14(-/low) MTEC observed in the Aire(+/+) thymus and significantly expanded in the Aire(-/-) thymic medulla represent end-stage, terminally differentiated MTEC. These Aire-dependent alterations of the MTEC compartment suggest that the activity of Aire is not neutral with respect to the program of MTEC differentiation.

Avoid-approach conflict behaviors differentially affected by anxiolytics: implications for a computational model of risky decision-making.

Whether fear or anxiety is expressed is thought to depend on an animal's proximity to threat. In general, fear is elicited when threat is proximal, while anxiety is a response to threat that is distal and uncertain. This threat gradient model suggests that fear and anxiety involve non-overlapping neural circuitry, yet few behavioral paradigms exist that elicit both states. We studied avoid-approach conflict in rats that were behaving in a predator-inhabited foraging arena task that involved tangible threat and reward incentives. In the task, rats exhibited a variety of both fearful and anxious behaviors corresponding to proximal and distal threat, respectively. We then administered ethanol or diazepam to the rats in order to study how anxiolytics affected these fear and anxiety behaviors. We discovered that both ethanol and diazepam attenuated proximal-threat fear-like behaviors. Furthermore, we found that diazepam, but not ethanol, increased distal-threat anxiety-like behavior but also made rats less risk-averse. Finally, we describe how decisional conflict can be modeled as a partially observable Markov decision process and characterize a potential relationship between anxious behavior, diazepam's ability to suppress hippocampal theta oscillations, and hippocampal representations of the future.

Screening for compounds that affect the interaction between bacterial two-component signal transduction response regulator protein and cognate promoter DNA.

Bacterial signal transduction systems can be used as drug targets. The signal transduction targets fall into two groups--sensor kinases and response regulators. Previously reported studies describe hits that were thought to inactivate sensor kinases but on closer examination were found to act elsewhere instead; a possible reason for this is that full-length sensor kinases are integral membrane proteins whose activity might reflect interaction with the cell membrane or with membrane components. We describe a model system that instead is based on the interaction between a test compound and a response regulator in a homogeneous phase reaction. In this system, response regulator-DNA complex formation and its inhibition by a test compound are measured by fluorescence polarization. The model system should be readily adaptable to drug discovery based on other bacterial two-component s transduction systems.

Bidirectional Ecosystem-Atmosphere Fluxes of Volatile Organic Compounds Across the Mass Spectrum: How Many Matter?

Terrestrial ecosystems are simultaneously the largest source and a major sink of volatile organic compounds (VOCs) to the global atmosphere, and these two-way fluxes are an important source of uncertainty in current models. Here, we apply high-resolution mass spectrometry (proton transfer reaction-quadrupole interface time-of-flight; PTR-QiTOF) to measure ecosystem-atmosphere VOC fluxes across the entire detected mass range (m/z 0-335) over a mixed temperate forest and use the results to test how well a state-of-science chemical transport model (GEOS-Chem CTM) is able to represent the observed reactive carbon exchange. We show that ambient humidity fluctuations can give rise to spurious VOC fluxes with PTR-based techniques and present a method to screen for such effects. After doing so, 377 of the 636 detected ions exhibited detectable gross fluxes during the study, implying a large number of species with active ecosystem-atmosphere exchange. We introduce the reactivity flux as a measure of how Earth-atmosphere fluxes influence ambient OH reactivity and show that the upward total VOC (∑VOC) carbon and reactivity fluxes are carried by a far smaller number of species than the downward fluxes. The model underpredicts the ∑VOC carbon and reactivity fluxes by 40-60% on average. However, the observed net fluxes are dominated (90% on a carbon basis, 95% on a reactivity basis) by known VOCs explicitly included in the CTM. As a result, the largest CTM uncertainties in simulating VOC carbon and reactivity exchange for this environment are associated with known rather than unrepresented species. This conclusion pertains to the set of species detectable by PTR-TOF techniques, which likely represents the majority in terms of carbon mass and OH reactivity, but not necessarily in terms of aerosol formation potential. In the case of oxygenated VOCs, the model severely underpredicts the gross fluxes and the net exchange. Here, unrepresented VOCs play a larger role, accounting for ~30% of the carbon flux and ~50% of the reactivity flux. The resulting CTM biases, however, are still smaller than those that arise from uncertainties for known and represented compounds.