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This study is a comparison of CFC-12 (CCl2F2) measurements in firn air and ice core samples from three Antarctic sites: South Pole, West Antarctic Ice Sheet Divide (79.46°S, 112.13°W), and Siple Dome (81.65°S, 148.81°W). CFC-12 is a synthetic chlorofluorocarbon manufactured during the mid-late 20th century for use as a refrigerant and an aerosol spray propellant. Its atmospheric history is well established with agreement among instrumental time series measurements and industry-reported production data [Walker et al., 2000], the distribution of dissolved CFC-12 in the oceans [e.g. Weiss et al., 1985], and firn air measurements [Butler et al., 1999]. The atmospheric history indicates that there was no measureable CFC-12 in the atmosphere prior to the 1940’s. The firn air CFC-12 profiles are consistent with the known atmospheric history of this gas. In contrast, the air in ice core samples collected near the close-off depth exhibit anomalously high CFC-12 levels. We propose that this is due to entrapment of modern air in open pores that close after drilling, resulting in elevated CFC-12 mixing ratios. These results demonstrate how the composition of air trapped in shallow ice cores can be altered during the post-drilling period through purely physical processes. Comparison of firn air and ice core bubble composition is one of the commonly used tools for studying the bubble close-off process. The post-drilling entrapment process detected in this study represents a potential complication for such investigations.

Air and water concentrations of methyl bromide (CH3Br) and methyl chloride CHCl) were measured in the Southern Ocean (latitudes 45°-67°S, longitudes 144°-139°E) from late October through mid-December 2001. CH3Br and CH3Cl were undersaturated with mean saturation anomalies of -39 ± 11% and -37 ± 11% between 45° and 65°S. The minimum degradation rate constants needed to maintain these saturation anomalies are consistent with the observed total degradation rate constants, suggesting that there is no significant production of these gases in this region. Near the Antarctic coast (south of 65°S) the saturation anomalies for both gases decreased to approximately -80%, although CFC-11 measurements suggest these extreme anomalies are associated with enhanced vertical mixing rather than with degradation in the surface waters. Copyright 2004 by the American Geophysical Union.

We conducted a detailed investigation of the evolution of methyl bromide concentrations, degradation rates, and ventilation rates for 26 days in a naturally contained, warm-core eddy of the North Atlantic Ocean. This is the first study of the oceanic cycling of methyl bromide in a natural, contained system with a complete suite of supporting measurements of physical and chemical variables. Methyl bromide concentrations in the mixed layer ranged from 2.3 to 4.2 nmol m-3, degradation rates ranged from 0.1 to 0.9 nmol m-3 d-1, net sea-to-air exchange rates ranged from 0 to 0.5 nmol m-3 d-1, and net loss rates through the thermocline were less than 0.1 nmol m-3 d-1. From a mass balance for methyl bromide in the mixed layer, we calculated production rates ranging from

[1] We simulate the oceanic and atmospheric distribution of methyl iodide (CH3I) with a global 3-D model driven by assimilated meteorological observations from the Goddard Earth Observing System of the NASA Data Assimilation Office and coupled to an oceanic mixed layer model. A global compilation of atmospheric and oceanic observations is used to constrain and evaluate the simulation. Seawater CH3I(aq) in the model is produced photochemically from dissolved organic carbon, and is removed by reaction with Cl- and emission to the atmosphere. The net oceanic emission to the atmosphere is 214 Gg yr-1. Small terrestrial emissions from rice paddies, wetlands, and biomass burning are also included in the model. The model captures 40% of the variance in the observed seawater CH3I(aq) concentrations. Simulated concentrations at midlatitudes in summer are too high, perhaps because of a missing biological sink of CH3I(aq). We define a marine convection index (MCI) as the ratio of upper tropospheric (8-12 km) to lower tropospheric (0-2.5 km) CH3I concentrations averaged over coherent oceanic regions. The MCI in the observations ranges from 0.11 over strongly subsiding regions (southeastern subtropical Pacific) to 0.40 over strongly upwelling regions (western equatorial Pacific). The model reproduces the observed MCI with no significant global bias (offset of only +11%) but accounts for only 15% of its spatial and seasonal variance. The MCI can be used to test marine convection in global models, complementing the use of radon-222 as a test of continental convection. Copyright 2002 by the American Geophysical Union.

Measurements of trace gases in air trapped in polar firn (unconsolidated snow) demonstrate that natural sources of chlorofluorocarbons, halons, persistent chlorocarbon solvents and sulphur hexafluoride to the atmosphere are minimal or non-existent. Atmospheric concentrations of these gases, reconstructed back to the late nineteenth century, are consistent with atmospheric histories derived from anthropogenic emission rates and known atmospheric lifetimes. The measurements confirm the predominance of human activity in the atmospheric budget of organic chlorine, and allow the estimation of atmospheric histories of halogenated gases of combined anthropogenic and natural origin. The pre-twentieth-century burden of methyl chloride was close to that at present, while the burden of methyl bromide was probably over half of today's value.

Half the world's population is at risk of developing a malaria infection, which is caused by parasites of the genus Plasmodium . Currently, resistance has been identified to all clinically available antimalarials, highlighting an urgent need to develop novel compounds and better understand common mechanisms of resistance. We previously identified a novel tetrahydro-β-carboline compound, PRC1590, which potently kills the malaria parasite. To better understand its mechanism of action, we selected for and characterized resistance to PRC1590 in Plasmodium falciparum . Through in vitro selection of resistance to PRC1590, we have identified that a single-nucleotide polymorphism on the parasite's multidrug resistance protein 1 (PfMDR1 G293V) mediates resistance to PRC1590. This mutation results in stereospecific resistance and sensitizes parasites to other antimalarials, such as mefloquine, quinine, and MMV019017. Intraerythrocytic asexual stage specificity assays have revealed that PRC1590 is most potent during the trophozoite stage when the parasite forms a single digestive vacuole (DV) and actively digests hemoglobin. Moreover, fluorescence microscopy revealed that PRC1590 disrupts the function of the DV, indicating a potential molecular target associated with this organelle. Our findings mark a significant step in understanding the mechanism of resistance and the mode of action of this emerging class of antimalarials. In addition, our results suggest a potential link between resistance mediated by PfMDR1 and PRC1590's molecular target. This research underscores the pressing need for future research aimed at investigating the intricate relationship between a compound's chemical scaffold, molecular target, and resistance mutations associated with PfMDR1.

Calophyllum tomentosum belonging to Clusiaceae family is an Indian medicinal plant used as folklore medicine to cure various kinds of diseases reported in Ayurveda, and the leaves of the plant are also used as an active ingredient for the preparation of a botanical medicine known as 'Punnaga', 'Surapunnaga' and 'Tamoil' among other common names. Chemical profiling of the methanol extract of the defatted leaf revealed the presence of amentoflavone (1) as one of the constituents along with coumarins, terpenoids, steroids, and apetalic acids. Structural determination of amentoflavone (1) has been conducted by chemical, spectral, and spectrometric methods in comparison with spectral values available in the literature and confirmed by a single crystal X-ray diffraction study. Amentoflavone (1) and its derivative (2-5) tested to check the efficacy of anti-malarial activity against Plasmodium falciparum. Amongst them, only tetra methoxy amentoflavone, (2) exhibited moderate anti-malarial activity with IC 50 value 1.99±0.42 μM against Plasmodium falciparum in comparison with artemisinin as control, whereas the other products possessed almost negligible activity although their structural skeletons are identical with little variation of number and nature of substituents. The structure activity relationship (SAR) of the active constituent and its derivatives is reported herein., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The development of parasite resistance to both artemisinin derivatives and their partner drugs jeopardizes the effectiveness of the artemisinin combination therapy. Thus, the discovery of new antimalarial drugs, with new mechanisms of action, is urgently needed. We recently disclosed that β-carboline 1a was orally efficacious in Plasmodium berghei -infected mice and that it showed low cross-resistance between susceptible Plasmodium falciparum and four different drug-resistant strains. In this report, we describe the synthesis and in vitro antimalarial evaluation of 91 new derivatives of 1a . The asexual blood stage growth inhibition data show a clear preference for a 3,4-dihalogenated, 3,5-dihalogenated, 3,4,5-trichloro-, or 4-trifluoromethyphenyl ring at the C1-position. The most potent compound, 3,4,5-trichlorophenyl-substituted 42a , is twice as potent as 1a . Six potent analogues were assessed for their drug-like properties, and four of these were subjected to in vitro barcoded cross-resistance profiling. Compounds 1a , 1m , 42a , and 42m showed no cross-resistance to 32 resistance mutations on the Dd2 genetic background and 10 resistance mutations on the 3D7 genetic background. These data suggest that compounds in this scaffold possess a novel mechanism of antimalarial action.

Dolichols are isoprenoid end-products of the mevalonate and 2 C -methyl-D-erythritol-4-phosphate pathways. The synthesis of dolichols is initiated with the addition of several molecules of isopentenyl diphosphate to farnesyl diphosphate. This reaction is catalyzed by a cis -prenyltransferase and leads to the formation of polyprenyl diphosphate. Subsequent steps involve the dephosphorylation and reduction of the α-isoprene unit by a polyprenol reductase, resulting in the generation of dolichol. The size of the dolichol varies, depending on the number of isoprene units incorporated. In eukaryotes, dolichols are synthesized as a mixture of four or more different lengths. Their biosynthesis is predicted to occur in the endoplasmic reticulum, where dolichols play an essential role in protein glycosylation. In this study, we have developed a selection of aptamers targeting dolichols and enhanced their specificity by incorporating fatty acids for negative selection. One aptamer showed high enrichment and specificity for linear polyisoprenoids containing at least one oxygen atom, such as an alcohol or aldehyde, in the α-isoprene unit. The selected aptamer proved to be a valuable tool for the subcellular localization of polyisoprenoids in the malaria parasite. To the best of our knowledge, this is the first time that polyisoprenoids have been localized within a cell using aptamer-based imaging techniques.

Cripowellins from Crinum erubescens are known pesticidal and have potent antiplasmodial activity. To gain mechanistic insights to this class of natural products, studies to determine the timing of action of cripowellins within the asexual intraerythrocytic cycle of Plasmodium falciparum were performed and led to the observation that this class of natural products induced reversible cytostasis in the ring stage within the first 24 h of treatment. The transcriptional program necessary for P. falciparum to progress through the asexual intraerythrocytic life cycle is well characterized. Whole transcriptome abundance analysis showed that cripowellin B "pauses" the transcriptional program necessary to progress through the intraerythrocytic life cycle coinciding with the lack of morphological progression of drug treated parasites. In addition, cripowellin B-treated parasites re-enter transcriptional progression after treatment was removed. This study highlights the use of cripowellins as chemical probes to reveal new aspects of cell cycle progression of the asexual ring stage of P. falciparum which could be leveraged for the generation of future antimalarial therapeutics.

The tetrahydro-β-carboline scaffold has proven fertile ground for the discovery of antimalarial agents (e.g., MMV008138 ( 1 ) and cipargamin ( 2 )). Similarity searching of a publicly disclosed collection of antimalarial hits for molecules resembling 1 drew our attention to N2-acyl tetrahydro-β-carboline GNF-Pf-5009 ((±)- 3b ). Compound purchase, "analog by catalog", and independent synthesis of hits indicated the benzofuran-2-yl amide portion was required for in vitro efficacy against P. falciparum . Preparation of pure enantiomers demonstrated the pharmacological superiority of ( R )- 3b . Synthesis and evaluation of D- and F-ring substitution variants and benzofuran isosteres indicated a clear structure-activity relationship. Ultimately ( R )- 3b was tested in Plasmodium berghei -infected mice; unfavorable physicochemical properties may be responsible for the lack of oral efficacy., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Virtual ligand screening of a publicly available database of antimalarial hits using a pharmacophore derived from antimalarial MMV008138 identified TCMDC-140230, a tetrahydro-β-carboline amide, as worthy of exploration. All four stereoisomers of this structure were synthesized, but none potently inhibited growth of the malaria parasite Plasmodium falciparum . Interestingly, 7e , a minor byproduct of these syntheses, proved to be potent in vitro against P. falciparum and was orally efficacious (40 mg/kg) in an in vivo mouse model of malaria., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Humans have significantly altered the energy balance of the Earth's climate system mainly not only by extracting and burning fossil fuels but also by altering the biosphere and using halocarbons. The 3rd US National Climate Assessment pointed to a need for a system of indicators of climate and global change based on long-term data that could be used to support assessments and this led to the development of the National Climate Indicators System (NCIS). Here we identify a representative set of key atmospheric indicators of changes in atmospheric radiative forcing due to greenhouse gases (GHGs), and we evaluate atmospheric composition measurements, including non-CO 2 GHGs for use as climate change indicators in support of the US National Climate Assessment. GHG abundances and their changes over time can provide valuable information on the success of climate mitigation policies, as well as insights into possible carbon-climate feedback processes that may ultimately affect the success of those policies. To ensure that reliable information for assessing GHG emission changes can be provided on policy-relevant scales, expanded observational efforts are needed. Furthermore, the ability to detect trends resulting from changing emissions requires a commitment to supporting long-term observations. Long-term measurements of greenhouse gases, aerosols, and clouds and related climate indicators used with a dimming/brightening index could provide a foundation for quantifying forcing and its attribution and reducing error in existing indicators that do not account for complicated cloud processes., Competing Interests: Conflict of interestThe authors declare no competing interests., (© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021.)

The antimalarial candidate MMV008138 (1a) is of particular interest because its target enzyme (IspD) is absent in human. To achieve higher potency, and to probe for steric demand, a series of analogs of 1a were prepared that featured methyl-substitution of the B- and C-rings, as well as ring-chain transformations. X-ray crystallography, NMR spectroscopy and calculation were used to study the effects of these modifications on the conformation of the C-ring and orientation of the D-ring. Unfortunately, all the B- and C-ring analogs explored lost in vitro antimalarial activity. The possible role of steric effects and conformational changes on target engagement are discussed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Unique lindenane sesquiterpenoid dimers from Chloranthecae spp. were recently identified with promising in vitro antiplasmodial activity and potentially novel mechanisms of action. To gain mechanistic insights to this new class of natural products, in vitro selection of Plasmodium falciparum resistance to the most active antiplasmodial compound, chlorajaponilide C, was explored. In all selected resistant clones, the half-maximal effective concentration (EC 50 ) of chlorajaponilide C increased >250-fold, and whole genome sequencing revealed mutations in the recently discovered P. falciparum prodrug activation and resistance esterase (PfPARE). Chlorajaponilide C was highly potent (mean EC 50 = 1.6 nM, n = 34) against fresh Ugandan P. falciparum isolates. The analysis of the structure-resistance relationships revealed that in vitro potency of a subset of lindenane sesquiterpenoid dimers was not mediated by PfPARE mutations. Thus, chlorajaponilide C, but not some related compounds, required parasite esterase activity for in vitro potency, and those compounds serve as the foundation for development of potent and selective antimalarials.

Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2- C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure-activity relationships by probing the ability of MMV008138 analogs to inhibit PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for fosmidomycin (FOS) and 19 previously disclosed analogs and report parasite growth and PfIspD inhibition data for 27 new analogs of MMV008138. In addition, we show that MMV008138 does not target the recently characterized human IspD, reinforcing MMV008138 as a prototype of a new class of species-selective IspD-targeting antimalarial agents.

Pretreatment with ionic liquids (IL) such as 1-ethyl-3-methylimidazolium chloride or acetate is an effective method for aiding deconstruction of lignocellulosic biomass; however, the residual IL remaining in hydrolysates can be inhibitory to growth of ethanologenic or oleaginous yeasts that have been examined in the literature. The aim of this study was to identify oleaginous yeasts that are tolerant of the IL [C 2 C 1 Im][OAc] and [C 2 C 1 Im]Cl using 45 strains belonging to 38 taxonomically diverse species within phyla Ascomycota and Basidiomycota. Yeasts were cultivated in laboratory medium supplemented with 0, 2, or 4% IL in 96-well plates. The eight most tolerant strains were then cultivated in 10-mL media with no IL, 242mM [C 2 C 1 Im][OAc], or 242mM [C 2 C 1 Im]Cl. The effects of [C 2 C 1 Im] + exposure on cell mass production and lipid accumulation varied at the species and strain level. The acetate salt decreased cell biomass and lipid production more severely than did the chloride ion for six strains. Lipid output was not markedly different (2.1 vs. 2.3 g/L) in Yarrowia lipolytica UCDFST 51-30, but decreased from 5 to 65% in other yeasts. An equimolar concentration of the chloride salt resulted in much milder effects, from 25% decrease to 66% increase in lipid output. The highest lipid outputs in this media were 8.3 and 7.9 g/L produced by Vanrija humicola UCDFST 10-1004 and UCDFST 12-717, respectively. These results demonstrated substantial lipid production in the presence of [C 2 C 1 Im]Cl at concentrations found in lignocellulosic hydrolysates, and thus, these two strains are ideal candidates for further investigation.

Antiplasmodial bioassay guided fractionation of a Madagascar collection of Crinum firmifolium led to the isolation of seven compounds. Five of the seven compounds were determined to be 2-alkylquinolin-4(1H)-ones with varying side chains. Compounds 1 and 4 were determined to be known compounds with reported antiplasmodial activities, while 5 was believed to be a new branched 2-alkylquinolin-4(1H)-one, however, it was isolated in limited quantities and in admixture and therefore was synthesized to confirm its structure as a new antiplasmodial compound. Along with 5, two other new and branched compounds 6 and 7 were synthesized as well. Accompanying the five quinolones were two known compounds 2 and 3 which are inactive against Plasmodium falciparum. The isolation, structure elucidation, total synthesis, and biological evaluation of these compounds are discussed in this article., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Ambient levels and variability of major atmospheric halocarbons, i.e. CFC-12, CFC-11, CFC-113, CCl4, CH3CCl3, C2HCl3, and C2Cl4 in a major metropolis (Taipei, Taiwan) were re-investigated after fourteen years by flask sampling in 2012. Our data indicates that the variability expressed as standard deviations (SD) of CFC-113 and CCl4 remained small (2.0 ppt and 1.9 ppt, respectively) for the 10th-90th percentile range in both sampling periods; whereas the variability of CFC-12, CFC-11, C2HCl3, and C2Cl4 measured in 2012 became noticeably smaller than observed in 1998, suggesting their emissions were reduced over time. By comparing with the background data of a global network (NOAA/ESRL/GMD baseline observatories), the ambient levels and distribution of these major halocarbons in Taipei approximated those at a background site (Mauna Loa) in 2012, suggesting that the fingerprint of the major halocarbons in a used-to-be prominent source area has gradually approached to that of the background atmosphere., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

An important ethical and safety concern that geriatricians, primary care providers, and home health professionals need to address is gun ownership by elderly adults. Those aged 65 and older now have the highest rate of gun ownership in America, and they also have a high prevalence of depression and suicide. Dementia can add additional layers of risk. Even older gun owners who are otherwise intellectually intact may benefit from information about gun safety with the increasing numbers of children being cared for by grandparents. Health professionals should ask patients, "Is there a gun in the home?" in the clinic and during home visits. Healthcare professionals must have knowledge and skills to address safe gun ownership in elderly adults. The 5 L's (Locked, Loaded, Little children, feeling Low, Learned owner) will assist professionals in addressing all aspects of safe ownership., (© 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society.)

Earth's climate is warming as a result of anthropogenic emissions of greenhouse gases, particularly carbon dioxide (CO(2)) from fossil fuel combustion. Anthropogenic emissions of non-CO(2) greenhouse gases, such as methane, nitrous oxide and ozone-depleting substances (largely from sources other than fossil fuels), also contribute significantly to warming. Some non-CO(2) greenhouse gases have much shorter lifetimes than CO(2), so reducing their emissions offers an additional opportunity to lessen future climate change. Although it is clear that sustainably reducing the warming influence of greenhouse gases will be possible only with substantial cuts in emissions of CO(2), reducing non-CO(2) greenhouse gas emissions would be a relatively quick way of contributing to this goal.

This work describes the in situ synthesis of oligonucleotide arrays on glass surfaces. These arrays are composed of features defined and separated by differential surface tension (surface tension arrays). Specifically, photolithographic methods were used to create a series of spatially addressable, circular features containing an amino-terminated organosilane coupled to the glass through a siloxane linkage. Each feature is bounded by a perfluorosilanated surface. The differences in surface energies between the features and surrounding zones allow for chemical reactions to be readily localized within a defined site. The aminosilanation process was analyzed using contact angle, X-ray photoelectron spectroscopy (XPS), and time-of-flight/secondary ion mass spectroscopy (TOF-SIMS). The efficiency of phosphoramidite-based oligonucleotide synthesis on these surface tension arrays was measured by two methods. One method, termed step-yields-by-hybridization, indicates an average synthesis efficiency for all four (A,G,C,T) bases of 99.9 +/- 1.1%. Step yields measured for the individual amidite bases showed efficiencies of 98.8% (dT), 98.0% (dA), 97.0% (dC), and 97.6% (dG). The second method for determining the amidite coupling efficiencies was by capillary electrophoresis (CE) analysis. Homopolymers of dT (40- and 60mer), dA (40mer), and dC (40mer) were synthesized on an NH(4)OH labile linkage. After cleavage, the products were analyzed by CE. Synthesis efficiencies were calculated by comparison of the full-length product peak with the failure peaks. The calculated coupling efficiencies were 98.8% (dT), 96.8% (dA), and 96.7% (dC).

Background: Following root planing and scaling many studies have implied an association between a loss of clinical attachment at sites with initially shallow pockets (1 to 3 mm) and gains in attachment level for deeper probing depths. However, these effects are also consistent with a statistical phenomenon referred to as regression towards the mean. This principle suggests that extreme values will moderate the next time they are recorded. The purpose of this report was to estimate the effect that regression towards the mean has on perceived changes in attachment level after root planing and scaling., Methods: During the initial examination, 2 different investigators conducted 2 full-mouth probings. Two quadrants were randomly selected to be root planed and scaled until the root surfaces were smooth by tactile touch of an explorer. The 2 remaining quadrants were not treated. At 4 to 6 weeks after treatment, another full mouth probing was done. An examiner who was blind to the quadrants that had been scaled measured attachment level and probing depth after therapy. This study design provided periodontal measurements before and after root planing and scaling, measurements before and after a period of 4 to 6 weeks of no therapy, and duplicate measurements at the beginning of the study., Results: Using the repeat examination when no true change could occur, shallow sites (< or =3 mm of probing depth) showed average negative differences between repeat attachment level measurements (-0.23 mm), which mimicked loss of periodontal attachment. Deep sites, (>6 mm) showed average positive values (0.40) mimicking gain in attachment level. These results suggest that regression towards the mean is a significant effect in this data set. Both shallow non-scaled and scaled sites had similar differences in repeat measures (-0.28 mm, -0.25 mm) which were also similar to and not statistically different from changes after therapy for both non-scaled (-0.21 mm) and scaled sites (-0.08 mm). Thus not only does this data set exhibit regression towards the mean, but it explains the majority of perceived loss of periodontal attachment after scaling at sites that have minimal probing depth., Conclusions: These results suggest that the majority of perceived loss of attachment due to scaling at sites of minimal probing depth that have been reported in many studies may be due a statistical phenomenon called regression towards the mean.

Background: This cohort study examined the role of smoking during hospitalization, duration of cessation counseling, patient awareness of the hospital's smoke-free policy, belief that smoking is associated with a current symptom or disease, and the presence of withdrawal symptoms with 12-month smoking cessation among inpatients enrolled in a smoking cessation program., Methods: Inpatients in four community hospitals (N = 1,317) participated in a smoking cessation intervention consisting of face-to-face counseling at baseline and four follow-up counseling phone calls. Patients were classified as nonsmokers only if they reported not smoking at both the 6- and the 12-month interviews. All patients lost to follow-up were considered smokers., Results: At 1 year the smoking cessation rate was 22.5%. Cessation was independently associated with reporting no smoking during hospitalization, noting no withdrawal symptoms at baseline, and believing that a current illness or symptom is related to smoking. Length of counseling interview and awareness of the hospital's smoke-free policy were not independently associated with cessation. CONCLUSIONS. Smoking cessation programs and hospital policies that decrease smoking during hospitalization, address withdrawal symptoms during hospitalization, and make clear the connection between a patient's health and cigarette smoking may increase the effectiveness of their smoking cessation efforts.

Dramatic declines in emissions of methyl chloroform (1,1, 1-trichloroethane) resulting from the Montreal Protocol provide an unprecedented opportunity to improve our understanding of the oxidizing power of Earth's atmosphere. Atmospheric observations of this industrial gas during the late 1990s yield new insights into the global burden and distribution of the hydroxyl radical. Our results set firm upper limits on the global and Southern Hemispheric lifetimes of methyl chloroform and confirm the predominance of hydroxyl in the tropics. Our analysis suggests a global lifetime for methyl chloroform of 5.2 (+0.2, -0.3) years, a Southern Hemispheric lifetime of 4.9 (+0.2, -0.3) years, and mean annual concentrations of OH that are 15 +/- 10% higher south of the intertropical convergence zone than those north of this natural mixing boundary between the hemispheres.

The N-1-naphthylphthalamic acid (NPA)-binding protein is part of the auxin efflux carrier, the protein complex that controls polar auxin transport in plant tissues. This study tested the hypothesis that the NPA-binding protein (NBP) is associated with the actin cytoskeleton in vitro and that an intact actin cytoskeleton is required for polar auxin transport in vivo. Cytoskeletal polymerization was altered in extracts of zucchini hypocotyls with reagents that stabilized either the polymeric or monomeric forms of actin or tubulin. Phalloidin treatment altered actin polymerization, as demonstrated by immunoblot analyses following native and denaturing electrophoresis. Phalloidin increased both filamentous actin (F-actin) and NPA-binding activity, while cytochalasin D and Tris decreased both F-actin and NPA-binding activity in cytoskeletal pellets. The microtubule stabilizing drug taxol increased pelletable tubulin, but did not alter either the amount of pelletable actin or NPA-binding activity. Treatment of etiolated zucchini hypocotyls with cytochalasin D decreased the amount of auxin transport and its regulation by NPA. These experimental results are consistent with an in vitro actin cytoskeletal association of the NPA-binding protein and with the requirement of an intact actin cytoskeleton for maximal polar auxin transport in vivo.

A novel, miniaturized high-throughput screening format is described for assay of combinatorial libraries generated on beads. This approach, which is ideally suited to encoded libraries synthesized on beads, utilizes the photolytic cleavage of individual compounds into a high-density well array (>6500 wells within a standard 96-well microtiter plate footprint) with well volumes as low as 0.37 microl. As a model study, an encoded dipeptide library (324 members) acylated with isobutyl succinate was assayed using this format to search for potential inhibitors of matrilysin, a member of the matrix metalloproteinase superfamily. In situ release of compounds from solid support was accomplished by photochemical cleavage after beads and enzyme were distributed to the wells. After the addition of a fluorogenic substrate to the array, the extent of enzyme inhibition and identification of active compounds was quantitated by imaging of the fluorescence emission upon uv irradiation. The structure-activity relationship data generated from the identified inhibitors in this study corroborate previous findings, thus validating the utility of this approach as a means of high-throughput screening of bead-based libraries.

Two families of peptides that specifically bind the extracellular domain of the human type I interleukin I (IL-1) receptor were identified from recombinant peptide display libraries. Peptides from one of these families blocked binding of IL-lalpha to the type I IL-1 receptor with IC50 values of 45-140 microM. Affinity-selective screening of variants of these peptides produced ligands of much higher affinity (IC50 approximately 2 nM). These peptides block IL-1-driven responses in human and monkey cells; they do not bind the human type II IL-1 receptor or the murine type I IL-1 receptor. This is the first example (that we know of) of a high affinity peptide that binds to a cytokine receptor and acts as a cytokine antagonist.

Analyses of air sampled from remote locations across the globe reveal that tropospheric chlorine attributable to anthropogenic halocarbons peaked near the beginning of 1994 and was decreasing at a rate of 25 &plusmn; 5 parts per trillion per year by mid-1995. Although bromine from halons was still increasing in mid-1995, the summed abundance of these halogens in the troposphere is decreasing. To assess the effect of this trend on stratospheric ozone, estimates of the future stratospheric abundance of ozone-depleting gases were made for mid-latitude and polar regions on the basis of these tropospheric measurements. These results suggest that the amount of reactive chlorine and bromine will reach a maximum in the stratosphere between 1997 and 1999 and will decline thereafter if limits outlined in the adjusted and amended Montreal Protocol on Substances That Deplete the Ozone Layer are not exceeded in future years.

Surface waters along a cruise track in the East Pacific Ocean were undersaturated in methyl bromide (CH(3)Br) in most areas except for coastal and upwelling regions, with saturation anomalies ranging from + 100 percent in coastal waters to -50 percent in open ocean areas, representing a regionally weighted mean of -16 (-13 to -20) percent. The partial lifetime of atmospheric CH(3)Br with respect to calculated oceanic degradation along this cruise track is 3.0 (2.9 to 3.6) years. The global, mean dry mole fraction of CH3Br in the atmosphere was 9.8 +/- 0.6 parts per trillion, with an interhemispheric ratio of 1.31 +/- 0.08. These data indicate that approximately 8 percent (0.2 parts per trillion) of the observed interhemispheric difference in atmospheric CH3Br could be attributed to an uneven global distribution of oceanic sources and sinks.

Triazolopyrimidine sulfanilides are a class of highly active herbicides whose primary target is acetolactate synthase. Spontaneous mutants of tobacco (Nicotiana tabacum) (KS-43) and cotton (Gossypium hirsutum) (PS-3 and DO-2) resistant to triazolopyrimidine sulfonanilide were selected in tissue culture. Acetolactate synthase partially purified from the three mutants were 80- to 1000-fold less sensitive to inhibition by the compound compared with the corresponding wild-type enzyme. The mutants also varied in the cross-resistance pattern to other acetolactate synthase inhibiting herbicides in the sulfonylurea, imidazolinone, and pyrimidyl-oxy-benzoate chemical families. Thus, acetolactate synthase from KS-43, PS-3, and DO-2 cultures have different mutations. The affinities for pyruvate, thiamine pyrophosphate, as well as the activity of the mutant enzymes were found to be comparable to the corresponding wild-type enzymes. However, the enzyme from PS-3 was highly resistant to feedback inhibition by valine and leucine. In contrast, acetolactate synthase from KS-43 and DO-2 were inhibited by valine and leucine to nearly the same extent as the wild-type enzymes. Also, PS-3 cultures accumulated much higher levels of the branched chain amino acids compared to the wild-type cotton culture. The mutation in the PS-3 enzyme has therefore rendered it insensitive to feedback regulation by valine and leucine.

The binding of human [125I]GH, ovine [125I]GH, bovine [125I]GH, and ovine [125I]PRL, to hepatic microsomal membranes (100,000 g) prepared from fetal, neonatal, and infant lambs and adult ewes has been examined. The specific binding of hGH increases (P less than 0.01) from 3.4 +/- 0.8% in the fetus (n = 7) to 20.0 +/- 2.1% (n = 6) in lambs at least 6 days postpartum. The binding of oGH is low in the fetus (0.7 +/- 0.2%; n = 13) and neonatal lamb (1.3 +/- 0.5%; n = 5) and increases (P less than 0.01) in older lambs (14.6 +/- 4.7%; n = 6) and adult sheep (14.9 +/- 5.3%; n = 4). Similarly, the binding of bGH is less (P less than 0.05) to fetal tissues. In contrast, the binding of oPRL is similar in fetal and postnatal preparations. Cross-reaction studies suggest that the binding of GHs is to a site with lactogenic characteristics in the fetus. In contrast, in lambs at least 4 days postpartum and in adult sheep, binding is to a site with somatogenic characteristics. The inability to detect somatogenic sites in the fetal liver is not due to saturation by endogenous GH or chorionic somatomammotropin, as the binding characteristics do not change after MgCl2 pretreatment of the membrane fractions. No change in binding is observed 25 days after fetal decapitation at 69 days (n = 3), suggesting that circulating GH does not down-regulate the fetal GH receptor. These observations suggest an immaturity of the somatogenic receptor in the ovine fetal liver and its appearance in the perinatal period. Immaturity of this receptor is likely to be the basis for the lack of a major effect of fetal GH on fetal somatic growth.

A specific radioimmunoassay for insulin-like growth factor I (IGF-I) has been used to study the distribution of circulating IGF-I on its carrier proteins in sheep. Serum or plasma samples obtained from fetal, neonatal and adult sheep were chromatographed at neutral pH on Sephadex G-200 columns. IGF-I eluted primarily in the 20 000-100 000 dalton region and to a lesser extent in the 20 000-100 000 dalton region in the adult. In the fetus, IGF-I eluted primarily in the 20 000-50 000 dalton region. Studies in the neonatal lamb showed IGF-I activity to fluctuate between different size binding proteins but by 7 days after birth the pattern was similar to that of the adult. When labelled IGF-I and IGF-II were added to serum which was chromatographed over Sephadex G-200 at a neutral pH, binding was displayed in the 50 000-100 000 dalton region for both adult and fetus. However in the fetus, but not in the adult, binding of 125I-labelled IGF-II was also found at greater than 200 000 daltons. These studies demonstrate that the distribution of IGF-binding proteins varies between the adult and the fetal lamb. The appearance of the 150 000 dalton binding protein is coincidental with the appearance of the somatogenic receptor in the infant liver and is consistent with the GH-dependent nature of this form of binding protein in other species. The marked developmental changes in the circulating form of IGF-I in the perinatal lamb may be of functional significance and lead to altered biological availability of circulating IGF-I.

Plasma samples taken every 30 min over a 26-h period each month from six 4- to 15-month-old red deer stags were analysed for GH. In addition, two samples taken at 10.00 and 22.00 h were analysed for insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II). A concentrate diet was available ad libitum. Food intake, body weight and antler status were recorded. Concentrations of GH were analysed using the PULSAR peak detection routine. Secretion of GH was pulsatile in every month of sampling, but the pattern of pulsatility differed seasonally. During the autumn and early winter (April-June in the Southern hemisphere) GH pulses were frequent and of low amplitude. In contrast, GH pulses in spring (August-September) were of high amplitude and high frequency resulting in a high mean level of GH circulating in the plasma. In early summer (November) the GH pulse amplitude was much lower and pulse frequency fell. There was a rise in GH pulse frequency not accompanied by an increase in GH pulse amplitude in summer (December-January). GH pulse amplitude seemed to be the main determinant of mean GH plasma level. Secretion of IGF-I was raised 1 month after peak monthly mean GH secretion. There was little consistent relationship between concentrations of IGF-II and mean daily GH. Concentrations of GH correlated positively and significantly with liveweight gain and antler growth rate with a delay of 1 month. Significantly positive correlations between concentrations of IGF-I, liveweight gain and antler growth rate were observed. It is considered that the spring and summer (September-December) seasonal acceleration of liveweight gain and antler development in stags could be a consequence of high winter/early spring (August-September) GH pulse frequency and amplitude resulting in increased concentrations of IGF-I, particularly in October.

The signs and symptoms of 56 patients with myofascial pain-dysfunction syndrome were tabulated. Patients were classified by age, sex, education and professional background, frequency of complaints of pain, occlusal relationships, oral habits, and specific muscles that were tender on palpation. A coincidence of stress and tension and the onset of myofascial pain was observed. It is suggested that myofascial pain may be more common in women than in men. Muscle tenderness was associated particularly with the masseter, temporal, and lateral and medial pterygoid muscles.

Specific radioligand assays for the two somatomedins, insulin-like growth factor (IGF)-I and IGF-II, have been used to study the ontogeny of somatomedin secretion in the perinatal lamb. Plasma samples were obtained from sheep fetuses from 54 days of gestation to term (147 days) and from neonatal lambs. All samples were first extracted in acid-ethanol to remove the somatomedin-binding proteins. Concentrations of IGF-I measured by radioimmunoassay were lower (P less than 0.01) in the fetus than in the adult sheep (0.96 +/- 0.17 (S.D.) units/ml, n = 11). Fetal IGF-I values rose (P less than 0.01) from 0.29 +/- 0.15 units/ml (n = 6) at 50-80 days to 0.79 +/- 0.18 units/ml (n = 13) at 140-150 days. While values were similar 0-2 days after birth, they rose (P less than 0.01) to 2.4 +/- 1.3 units/ml (n = 15) 3-7 days after birth. By 60 days they had fallen to adult values. In contrast, IGF-II levels measured by rat placental membrane radioreceptor assay were higher (P less than 0.001) in the fetus (2.71 +/- 1.06 units/ml, n = 18) than in the adult (1.0 +/- 0.17 units/ml) and showed no gestational trend between 50 and 140 days of gestation. Longitudinal studies showed a fall (P less than 0.01) in IGF-II values starting several days before birth. By 12 h after birth, IGF-II concentrations were similar to the adult and showed no subsequent postnatal change. These results demonstrate that IGF-I and IGF-II are not secreted in parallel in the perinatal lamb. There are major changes in the regulation of both IGF-I and IGF-II in relationship to birth. It is suggested that the high fetal IGF-II concentrations appear to be maintained by a stimulus withdrawn before birth. The postnatal rise in IGF-I may be related to the increase in hepatic somatogenic receptors at this age.

The relationship between plasma GH profiles and circulating concentrations of insulin-like growth factor 1 (IGF-1) at three different planes of nutrition, chosen to represent a high, medium and low level of nutrition (3%, 1.8% and 1% dry matter of liveweight per day) was studied in 15 young Angus steers. All steers were maintained on 3% dry matter for 5 weeks, then on one of the three nutritional planes for 4 weeks and then all were returned to 3% dry matter for 3 weeks. Blood was sampled through jugular catheters at 15-min intervals for 25 h at the end of each phase of the study and additional samples were taken on 2 days each week. Pulsatile release of GH occurred episodically with a diurnal increase during night and morning hours only in steers on high nutritional intakes. Reduced feeding at both the medium and the low plane abolished the diurnal rhythm and significantly increased mean plasma GH concentrations, the amplitude of GH pulses and the area under the GH profiles. Baseline concentrations of GH and pulse frequency did not change through nutritional manipulation. Upon realimentation, plasma GH concentrations decreased in both previously undernourished groups, with those fed 1% dry matter still having increased levels 10 days after refeeding. Plasma IGF-1 concentrations showed no periodicity. With nutritional deprivation, a decrease in IGF-1 concentration was observed only at negative energy balance (1% group). In this group plasma IGF-1 concentrations were progressively restored within 1 week of realimentation.(ABSTRACT TRUNCATED AT 250 WORDS)

This report is an example of tumor metastasis to the temporomandibular joint and its effect on pain, restriction of jaw movement, and the subsequent inability of the patient to function normally. Neoplasm is not the usual etiology of myofascial pain dysfunctionsyndrome and the muscle sparm component of this patient's jaw dysfunction was emphasizedby the relief of symptoms from the use of symptomatic reversible type therapy (tranquilizer, muscle relaxant, and heat). There was an overlay of stress-tension factors in this case history that contributed to the muscle spasm symptoms of the patient. There canbe other etiological factors in jaw dysfunction associated with TMJ pathology such asdevelopmental anomalies, trauma, arthritis, and neoplasm, but as a group they comprise only about 5% of TMJ dysfunction problems (D.M. Laskin, personal communication).

The secretion of thyrotropin (TSH) has been investigated in the chronically catheterized ovine fetus (term 145-150 days). Forty-two random plasma samples from 25 fetuses (86-149 days of gestation) were measured for TSH concentrations by radioimmunoassay. Plasma TSH concentrations were highest in the youngest fetuses [86-110 days, 3.9 +/- (SD) 5.5 microU/ml, n = 13]. Thereafter TSH concentrations declined to 0.4 +/- 0.6 microU/ml (n = 13, p less than 0.05) at 130-150 days of gestation. However, serial sampling at 15-20 min intervals for 180 min from 14 individual fetuses (91-139 days) showed that TSH was secreted in a markedly exaggerated pulsatile manner compared to that observed after birth. The mean amplitude of TSH pulses fell (p less than 0.005) from 5.9 +/- 8.1 microU/ml in the fetuses to 2.1 +/- 1.1 microU/ml in five neonatal lambs (6-22 days) and to 1.5 +/- 0.4 microU/ml in three adult nonpregnant ewes. The mean pulse frequency for the 14 fetuses was 0.7 +/- 0.3 pulses/h and was reduced (p less than 0.001) to 0.3 +/- 0.1 pulses/h in lambs and to 0.3 +/- 0.1 pulses/h in the ewes. In the neonate, hypothermia is a potent stimulus to TSH release. To examine the ontogeny of this response, the temperature of the fetus in utero (106-127 days of gestation) was lowered by circulating water (14-18 degrees C) at either a fast or slow rate through a coil placed either externally around the fetus or internally in the fetal esophagus and stomach.(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated the possibility that IGF-1 may play a role in the regulation of antler development. Plasma IGF-1 concentrations were measured throughout the first period of development of the pedicle and first antler of red deer (Cervus elaphus) to determine whether a relationship existed between growth of antler cartilage (velvet antler) and IGF-1. We report that plasma levels of IGF-1 are significantly elevated during the velvet antler growing phase relative to the other phases of pedicle and first antler development and a strong positive correlation exists between antler growth rate and circulating concentrations of IGF-1. As IGF-1 has been demonstrated to influence cartilage growth, we suggest that IGF-1 is a candidate as an antler stimulating hormone.

An interdisciplinary approach to licensing partially-sighted individuals to drive is presented. The model includes the participation of optometry, special education, and the department of motor vehicles.