Self-limited uptake of α-pinene-oxide to acidic aerosol: the effects of liquid-liquid phase separation and implications for the formation of secondary organic aerosol and organosulfates from epoxides

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Atmos. Chem. Phys. Discuss., 13, 7151–7174, 2013 doi:10.5194/acpd-13-7151-2013 © Author(s) 2013. CC Attribution 3.0 License. Atmospheric Chemistry and Physics Discussions This discussion paper is/has been under review for the journal Atmospheric Chemistry and Physics (ACP). Please refer to the corresponding final paper in ACP if available. Self-limited uptake of α-pinene-oxide to acidic aerosol: the effects of liquid-liquid phase separation and implications for the formation of secondary organic aerosol and organosulfates from epoxides G. T. Drozd, J. L. Woo, and V. F. McNeill Department of Chemical EnginGeeeroinsgc,ieCnotilfuicmbia University, New York, NGYe, o1s0c0ie2n7t,ifUicSA Received: 5 March 2013 – Accepted: 8 March 2013 – Published: 18 March 2013 Correspondence to: V. F. McNeill ( Published by Copernicus PubGliceaotiosncsieonntifbicehalf of the European GeosGcieeonscceiseUntnifiiocn. 7151 Discussion Paper | Discussion Paper | Discussion Paper | Discussion Paper | Open Access ACPD 13, 7151–7174, 2013 Self-limited uptake of α -pinene-oxide to acidic aerosol G. T. Drozd et al. Title Page Abstract Introduction Conclusions References Tables Figures ◭◮ ◭◮ Back Close Full Screen / Esc Printer-friendly Version Interactive Discussion Abstract The reactive uptake of α-pinene oxide (αPO) to acidic sulfate aerosol was studied under humid conditions in order to gain insight into the effects of liquid-liquid phase separation on aerosol heterogeneous chemistry and further elucidate the formation 5 of secondary organic aerosol and organosulfates from epoxides. A continuous flow environmental chamber was used to monitor changes in diameter of monodisperse, deliquesced, acidic sulfate particles exposed to αPO at 30 and 50 % RH. In order to induce phase separation and probe potential limits to particle growth from acidic uptake, αPO was introduced over a wide range of concentrations, from 200 ppb to 10 5 ppm. Uptake was observed to be highly dependent on initial aerosol pH. Significant uptake of αPO to aerosol was observed with initial pH < 0. When exposed to 200 ppb αPO, aerosol with pH = −1 doubled in volume, and 6 % volume growth was observed at pH = 0. Aerosol with pH = 1 showed no growth. The extreme acidity required for efficient αPO uptake suggests that this chemistry is typically not a major route to formation of 15 aerosol mass or organosulfates in the atmosphere. Partition coefficients (Kp) ranged from 0.2–1.6 × 10−4 m3 µg−1 and were correlated to initial particle acidity and particle organic content; particles with higher organic content had lower partition coefficients. Effective uptake coefficients (γ) ranged from 0.4 to 4.7 × 10−5 and are much lower than recently reported for uptake to bulk solutions. In experiments in which αPO was 20 added to bulk H2SO4 solutions, phase separation was observed for mass loadings similar to those observed with particles, and product distributions were dependent on acid concentration. Liquid-liquid phase separation in bulk experiments, along with our observations of decreased uptake to particles with the largest growth factors, suggest an organic coating forms upon uptake to particles, limiting reactive uptake. 7152 Discussion Paper | Discussion Paper | Discussion Paper | Discussion Paper | ACPD 13, 7151–7174, 2013 Self-limited uptake of α -pinene-oxide to acidic aerosol G. T. Drozd et al. Title Page Abstract Introduction Conclusions References Tables Figures ◭◮ ◭◮ Back Close Full Screen / Esc Printer-friendly Version Interactive Discussion 1 Introduction The reactive uptake of volatile organic compounds (VOCs) by tropospheric aqueous aerosols has recently gained attention as a potential source of secondary organic aerosol (SOA) and organosulfate species (Ervens et al., 2011; Lim et al., 2010; Mc5 Neill et al., 2012; Volkamer et al., 2009; Sareen et al., 2010; Kroll et al., 2005; Nozie´ re et al., 2010; Galloway et al., 2009; Liggio et al., 2005). Volatile compounds can react in the particle phase (e.g. hydrolyzing or oligomerizing) after uptake to form low-volatility products. Recently, interest has grown in reactive uptake for aerosols with significant water content (McNeill et al., 2012). Aqueous uptake and processing of organic matter 10 may be important in explaining the extreme levels of oxidation (O : C ≥ 1) observed in secondary organic aerosol (Lee et al., 2011; McNeill et al., 2012). The focus of this study is the reactive uptake of epoxides to acidic sulfate aerosol and understanding the effects of particle composition on acid-mediated reactive uptake. Epoxides have been identified as potential SOA precursors in both laboratory studies 15 and thermodynamic calculations, in particular through their ability to form organosul- fates (OS) through acid-catalyzed ring opening (Iinuma et al., 2009; Lal et al., 2012; Minerath and Elrod, 2009; Paulot et al., 2009). Recent observations of OS in ambient samples have led to laboratory studies aimed at determining their formation mechanisms and organic precursors (Surratt et al., 2006, 2007, 2008; Lin et al., 2011; Hatch 20 et al., 2011; Lal et al., 2012; Minerath et al., 2008, 2009; Minerath and Elrod, 2009; Darer et al., 2011; Hu et al., 2011; Perri et al., 2010). OS yields are known to depend on particle acidity and total aerosol volume (Surratt et al., 2007; Iinuma et al., 2009; Lal et al., 2012; Hu et al., 2011). In addition, while initial OS formation may drive uptake to aerosol, less-substituted OS or those with nearby electron-withdrawing groups may 25 readily hydrolyze to diol compounds (Hu et al., 2011). Laboratory experiments have observed monoterpene-derived epoxide uptake to extremely acidic aerosol (pH ∼ 0), but results at acidities above 0 and less than 7 have not been reported. We conducted 7153 Discussion Paper | Discussion Paper | Discussion Paper | Discussion Paper | ACPD 13, 7151–7174, 2013 Self-limited uptake of α -pinene-oxide to acidic aerosol G. T. Drozd et al. Title Page Abstract Introduction Conclusions References Tables Figures ◭◮ ◭◮ Back Close Full Screen / Esc Printer-friendly Version Interactive Discussion experiments over a wide range of aerosol pH and αPO concentrations to explore the importance of epoxide uptake under ambient conditions. Reactive uptake can be strongly affected by particle morphology and phase separation of particle organic and inorganic components. After liquid-liquid phase sepa5 ration, a core-shell morphology with the organic phase coating the outer surface of the particle has been observed (Bertram et al., 2011; Smith et al., 2012; You et al., 2012). Such a morphology change is expected to impact aerosol heterogeneous chemistry by changing the surface composition from aqueous to organic (You et al., 2012). Zuend and Seinfeld also showed via calculations that liquid-liquid phase separation 10 can dramatically impact gas-particle partitioning of semivolatile species (Zuend et al., 2010). Particles with significant water content may exist in several morphologies. These could include a fully mixed aqueous/organic particle, a phase separated aqueous core with an organic shell, and an aqueous phase partially engulfed by an organic phase (Smith et al., 2012). The organic-rich phase of phase-separated acidic particles may be 15 proton-depleted, with the aqueous phase retaining the initial acidity (Reichardt, 1990; Pavia et al., 1999). In addition, uptake studies with bulk phase mimics of acidic sulfate aerosol particles (e.g. sulfuric acid solutions) do not replicate this complicated phase behavior and may only represent initial uptake rates to systems with low levels of organics. By studying uptake to both bulk solutions and particles over a range of organic 20 content and acidities, we begin to elucidate the effects of particle morphology on uptake to acidic aerosol. 2 Experimental methods 2.1 Smog chamber setup All chamber experiments were conducted in a ∼ 3.5 m3 Teflon chamber as shown in 25 Fig. 1. The chamber is run in steady-state operation with a constant gas flow of 13 Lpm for a chamber residence time of about 4 h, and in practice stable conditions were 7154 Discussion Paper | Discussion Paper | Discussion Paper | Discussion Paper | ACPD 13, 7151–7174, 2013 Self-limited uptake of α -pinene-oxide to acidic aerosol G. T. Drozd et al. Title Page Abstract Introduction Conclusions References Tables Figures ◭◮ ◭◮ Back Close Full Screen / Esc Printer-friendly Version Interactive Discussion reached between 3 and 4 h. This is consistent with previous static chamber studies of epoxides and similar aerosol acidity, particle concentration, and αPO concentration that indicate reactive uptake reaches steady state after about 2 h (Lin et al., 2011; Iinuma et al., 2009). Prior to each experiment, the bag was rinsed with de-ionized wa- 5 ter and flushed with dry nitrogen to remove any material present on the chamber walls. All chamber experiments were conducted at approximately 50 % RH and 25 C, except for experiments with a particularly high particle acidity of pH = −1, which were run at 30 % RH. A hygrometer (Vaisala) was used to monitor the humidity and temperature of the chamber. The conditions for each experiment are listed in Table 1; also shown are 10 the results of each experiment to be discussed below. The bag was filled with a combination of three flows: humidified nitrogen, ammo- nium sulfate/sulfuric acid aerosol in nitrogen, and αPO in nitrogen. The final humidity was adjusted by combining a nitrogen flow that passed through a water bubbler filled with de-ionized water and a second flow of dry nitrogen. The total humid-nitrogen flow 15 was 11 Lpm. An atomizer (TSI-3076) produced seed particles by atomizing a 0.2 M (NH4)2SO4 with a nitrogen flow rate of 2 Lpm. Particle acidity was altered by adjusting the ratio of H2SO4 : (NH4)2SO4 in the atomizing solution. In order to achieve precise growth measurements, the atomizer output was size-selected at 150 nm using a DMA operating at a 8 : 0.8 sheath to sample flow (Lpm) ratio. Particle concentrations 20 in the bag were in the range of 1000–3000 cm−3. αPO (Sigma Aldrich, > 97 %) va- por was injected at variable concentrations by passing nitrogen over liquid αPO held at varying temperature, which was controlled using a cold finger setup. To run below ambient temperatures, the cold finger was immersed in a dewar filled with either ice (0 C) or an NaCl/ice bath (−20 C). The concentration of the αPO delivered from the 25 cold finger was calibrated in a separate set of experiments with a custom-built chem- ical ionization mass spectrometer using H3O+·(H2O)n as the reagent ion. See Sareen et al. for a description of the instrument and its operation (Sareen et al., 2010). αPO w(Ca1s0Hde16teOcHte+d Has2Oth)eatpmro/tzon1a7t1e,damndoltehceupleroatot nma/tzed15d3im(Cer10(2H 1C6O10+H1H6O+)+, its water cluster H+) at m/z 205. 7155 Discussion Paper | Discussion Paper | Discussion Paper | Discussion Paper | ACPD 13, 7151–7174, 2013 Self-limited uptake of α -pinene-oxide to acidic aerosol G. T. Drozd et al. Title Page Abstract Introduction Conclusions References Tables Figures ◭◮ ◭◮ Back Close Full Screen / Esc Printer-friendly Version Interactive Discussion 2.2 Chamber operation Data from a typical experiment are shown in Fig. 2. After a stable initial diameter is achieved for the seed particles, in this case ∼ 150 nm pure sulfuric acid particles at 50 % RH, the αPO flow was initiated. After ∼ 30 min lag period, particles are observed 5 at larger diameters. After injecting αPO for roughly 4 h, the particles in the chamber attain a stable output diameter. 2.3 Bulk uptake studies 2.3.1 Gas phase uptake to bulk surfaces The phase behavior and diffusivity of αPO reactive uptake products were observed 10 in additional experiments in which gas-phase αPO was taken up by bulk aqueous sulfuric acid samples. 4 vials with 10 mL of sulfuric acid of varying concentration in water (10, 3, 1, and 0.1 M) and 1 vial with 3 mL of pure αPO were placed beneath a large inverted beaker. This created a sustained exposure of the acid surface to the room temperature vapor pressure of gas-phase αPO (0.819 torr, 25 C). Vials after 15 18 h of αPO exposure are shown in Fig. 3a. In the 10 M acid solution, a light-red layer was formed at the solution surface within several hours and continued to thicken with longer αPO exposure. The 3 M solution became slightly cloudy, and none of the other solutions formed visible products from αPO exposure. The top and bottom layer of the acid solutions were extracted with a pipette, and the UV-Vis absorbance spectra 20 of these fractions were measured. Digital photographs of the 10 M reaction vials were used to monitor the depth of this colored layer with time and estimate the aqueousphase diffusion coefficient of αPO. Control experiments in which the acid solutions were exposed to ambient laboratory air under the trapped beaker in the absence of αPO resulted in no color change. 7156 Discussion Paper | Discussion Paper | Discussion Paper | Discussion Paper | ACPD 13, 7151–7174, 2013 Self-limited uptake of α -pinene-oxide to acidic aerosol G. T. Drozd et al. Title Page Abstract Introduction Conclusions References Tables Figures ◭◮ ◭◮ Back Close Full Screen / Esc Printer-friendly Version Interactive Discussion 2.3.2 Slow addition of liquid αPO to bulk acid solution To deliver a larger volume fraction of αPO, 3 mL of liquid αPO was slowly added at 750µL h−1 to 3 mL of sulfuric acid solutions with a syringe pump to achieve a 50 % volume fraction of αPO after 3 h. For both the 10 M and 3 M acid concentrations, visible 5 phase separation occurred; the vial with 10 M acid is shown in Fig. 3b. 3 Results and discussion 3.1 Uptake of αPO to particles: effect of α PO concentration and particle acidity The volume-growth factor, defined as the ratio between the final and initial volumes (Vf/Vi), increased with the gas-phase αPO concentration. These results are displayed in 10 Fig. 4 and Table 1 for experiments for several particle acidities. High particle acidity and gas-phase αPO concentration resulted in very high growth factors and particle organic content. For particles with pH ∼ −0.5 and 5 ppm αPO, the growth factor is greater than 2 and the organic fraction of the particle, (Vf/Vi − 1)/Vf reaches nearly 50 %. The clear trend of increased uptake with particle acidity indicates that αPO only 15 forms SOA under conditions of reactive uptake. This is consistent with the relatively low aqueous solubility of αPO (219 mg L−1 or roughly 0.02 % by mass). Previous measurements have also shown αPO uptake to be strongly dependent on particle acidity (Surratt et al., 2006, 2007; Lin et al., 2011; Iinuma et al., 2009; Lal et al., 2012). Iinuma et al. ran experiments with acidic (pH = 0) and neutral aerosol, but only observed up20 take at pH = 0 (Lal et al., 2012). Surratt and co-workers also observed a strong pH dependence for the reactive uptake of isoprene-derived epoxides, with greater uptake at low pH, consistent with acid-catalyzed reactions driving uptake to aerosol (Lin et al., 2011). 7157 Discussion Paper | Discussion Paper | Discussion Paper | Discussion Paper | ACPD 13, 7151–7174, 2013 Self-limited uptake of α -pinene-oxide to acidic aerosol G. T. Drozd et al. Title Page Abstract Introduction Conclusions References Tables Figures ◭◮ ◭◮ Back Close Full Screen / Esc Printer-friendly Version Interactive Discussion 3.2 Partitioning coefficients To quantify the partitioning of a gas-phase component to the aqueous aerosol, we use an effective partitioning coefficient, Kp,eff (µg m−3): Kp,eff = ∆Cp,tot Cg × Cp,tot (1) 5 where ∆Cp,tot is the increase in total particle mass concentration from gas uptake, Cg is the mass concentration of organic precursor in the gas phase, and Cp,tot is the total particle mass concentration, all expressed in (µg m−3). The partitioning coefficient is shown as a function of particle growth factor in Fig. 5. A value of 2.8 × 10−4 m3 µ−1 g−1 was measured by Iinuma et al. under conditions of 50 ppb αPO, 4 × 10−6 cm3 m−3 seed 10 concentration, and particles with pH = 0 (Iinuma et al., 2009). We measured Kp,eff under similar conditions and 200 ppb αPO to be between 0.4–1 × 10−4 m3 µ−1 g−1. This is good agreement given measurement uncertainty and the observed increase in uptake coefficient with lower αPO concentration. As shown in Fig. 5, the partitioning coefficient decreases with increasing growth 15 factor. In other words, as the organic fraction of the particle becomes greater, the affinity of αPO for the particle decreases. The trend of uptake with growth factor suggests that changes in particle composition and/or morphology upon αPO uptake play a major role in determining αPO partitioning to acidic particles. 3.3 Uptake of αPO to bulk solutions 20 The uptake of αPO to bulk sulfuric acid solutions was strongly pH-dependent. The reactive uptake of αPO by the 10 M H2SO4 solution was made evident by the formation of a red layer at the top of the solution. When left to sit over 48 h, this layer darkened and grew thicker. UV-Vis spectrophotometry confirms the formation of strongly lightabsorbing products at high solution acidities and that this chemistry is reversible upon 7158 Discussion Paper | Discussion Paper | Discussion Paper | Discussion Paper | ACPD 13, 7151–7174, 2013 Self-limited uptake of α -pinene-oxide to acidic aerosol G. T. Drozd et al. Title Page equilibrium value of MeCpG steps (,+14 deg.) [31,44]. In comparison, methylation has a significantly lower stability cost when happening at major groove positions, such as 211 and 21 base pair from dyad (mutations 9 and 12), where the roll of the nucleosome bound conformation (+10 deg.) is more compatible with the equilibrium geometry of MeCpG steps. The nucleosome destabilizing effect of cytosine methylation increases with the number of methylated cytosines, following the same position dependence as the single methylations. The multiple-methylation case reveals that each major groove meth- PLOS Computational Biology | 3 November 2013 | Volume 9 | Issue 11 | e1003354 DNA Methylation and Nucleosome Positioning ylation destabilizes the nucleosome by around 1 kJ/mol (close to the average estimate of 2 kJ/mol obtained for from individual methylation studies), while each minor groove methylation destabilizes it by up to 5 kJ/mol (average free energy as single mutation is around 6 kJ/mol). This energetic position-dependence is the reverse of what was observed in a recent FRET/SAXS study [30]. The differences can be attributed to the use of different ionic conditions and different sequences: a modified Widom-601 sequence of 157 bp, which already contains multiple CpG steps in mixed orientations, and which could assume different positioning due to the introduction of new CpG steps and by effect of the methylation. The analysis of our trajectories reveals a larger root mean square deviation (RMSD) and fluctuation (RMSF; see Figures S2– S3 in Text S1) for the methylated nucleosomes, but failed to detect any systematic change in DNA geometry or in intermolecular DNA-histone energy related to methylation (Fig. S1B, S1C, S4–S6 in Text S1). The hydrophobic effect should favor orientation of the methyl group out from the solvent but this effect alone is not likely to justify the positional dependent stability changes in Figure 2, as the differential solvation of the methyl groups in the bound and unbound states is only in the order of a fraction of a water molecule (Figure S5 in Text S1). We find however, a reasonable correlation between methylation-induced changes in hydrogen bond and stacking interactions of the bases and the change in nucleosome stability (see Figure S6 in Text S1). This finding suggests that methylation-induced nucleosome destabilization is related to the poorer ability of methylated DNA to fit into the required conformation for DNA in a nucleosome. Changes in the elastic deformation energy between methylated and un-methylated DNA correlate with nucleosomal differential binding free energies To further analyze the idea that methylation-induced nucleosome destabilization is connected to a worse fit of methylated DNA into the required nucleosome-bound conformation, we computed the elastic energy of the nucleosomal DNA using a harmonic deformation method [36,37,44]. This method provides a rough estimate of the energy required to deform a DNA fiber to adopt the super helical conformation in the nucleosome (full details in Suppl. Information Text S1). As shown in Figure 2, there is an evident correlation between the increase that methylation produces in the elastic deformation energy (DDE def.) and the free energy variation (DDG bind.) computed from MD/TI calculations. Clearly, methylation increases the stiffness of the CpG step [31], raising the energy cost required to wrap DNA around the histone octamers. This extra energy cost will be smaller in regions of high positive roll (naked DNA MeCpG steps have a higher roll than CpG steps [31]) than in regions of high negative roll. Thus, simple elastic considerations explain why methylation is better tolerated when the DNA faces the histones through the major groove (where positive roll is required) that when it faces histones through the minor groove (where negative roll is required). Nucleosome methylation can give rise to nucleosome repositioning We have established that methylation affects the wrapping of DNA in nucleosomes, but how does this translate into chromatin structure? As noted above, accumulation of minor groove methylations strongly destabilizes the nucleosome, and could trigger nucleosome unfolding, or notable changes in positioning or phasing of DNA around the histone core. While accumulation of methylations might be well tolerated if placed in favorable positions, accumulation in unfavorable positions would destabilize the nucleosome, which might trigger changes in chromatin structure. Chromatin could in fact react in two different ways in response to significant levels of methylation in unfavorable positions: i) the DNA could either detach from the histone core, leading to nucleosome eviction or nucleosome repositioning, or ii) the DNA could rotate around the histone core, changing its phase to place MeCpG steps in favorable positions. Both effects are anticipated to alter DNA accessibility and impact gene expression regulation. The sub-microsecond time scale of our MD trajectories of methylated DNAs bound to nucleosomes is not large enough to capture these effects, but clear trends are visible in cases of multiple mutations occurring in unfavorable positions, where unmethylated and methylated DNA sequences are out of phase by around 28 degrees (Figure S7 in Text S1). Due to this repositioning, large or small, DNA could move and the nucleosome structure could assume a more compact and distorted conformation, as detected by Lee and Lee [29], or a slightly open conformation as found in Jimenez-Useche et al. [30]. Using the harmonic deformation method, we additionally predicted the change in stability induced by cytosine methylation for millions of different nucleosomal DNA sequences. Consistently with our calculations, we used two extreme scenarios to prepare our DNA sequences (see Fig. 3): i) all positions where the minor grooves contact the histone core are occupied by CpG steps, and ii) all positions where the major grooves contact the histone core are occupied by CpG steps. We then computed the elastic energy required to wrap the DNA around the histone proteins in unmethylated and methylated states, and, as expected, observed that methylation disfavors DNA wrapping (Figure 3A). We have rescaled the elastic energy differences with a factor of 0.23 to match the DDG prediction in figure 2B. In agreement with the rest of our results, our analysis confirms that the effect of methylation is position-dependent. In fact, the overall difference between the two extreme methylation scenarios (all-in-minor vs all-in-major) is larger than 60 kJ/mol, the average difference being around 15 kJ/ mol. We have also computed the elastic energy differences for a million sequences with CpG/MeCpG steps positioned at all possible intermediate locations with respect to the position (figure 3B). The large differences between the extreme cases can induce rotations of DNA around the histone core, shifting its phase to allow the placement of the methylated CpG steps facing the histones through the major groove. It is illustrative to compare the magnitude of CpG methylation penalty with sequence dependent differences. Since there are roughly 1.5e88 possible 147 base pairs long sequence combinations (i.e., (4n+4(n/2))/2, n = 147), it is unfeasible to calculate all the possible sequence effects. However, using our elastic model we can provide a range of values based on a reasonably large number of samples. If we consider all possible nucleosomal sequences in the yeast genome (around 12 Mbp), the energy difference between the best and the worst sequence that could form a nucleosome is 0.7 kj/mol per base (a minimum of 1 kJ/mol and maximum of around 1.7 kJ/mol per base, the first best and the last worst sequences are displayed in Table S3 in Text S1). We repeated the same calculation for one million random sequences and we obtained equivalent results. Placing one CpG step every helical turn gives an average energetic difference between minor groove and major groove methylation of 15 kJ/ mol, which translates into ,0.5 kJ/mol per methyl group, 2 kJ/ mol per base for the largest effects. Considering that not all nucleosome base pair steps are likely to be CpG steps, we can conclude that the balance between the destabilization due to CpG methylation and sequence repositioning will depend on the PLOS Computational Biology | 4 November 2013 | Volume 9 | Issue 11 | e1003354 DNA Methylation and Nucleosome Positioning Figure 3. Methylated and non-methylated DNA elastic deformation energies. (A) Distribution of deformation energies for 147 bplong random DNA sequences with CpG steps positioned every 10 base steps (one helical turn) in minor (red and dark red) and major (light and dark blue) grooves respectively. The energy values were rescaled by the slope of a best-fit straight line of figure 2, which is 0.23, to source of circulating FGF-21. The lack of association between circulating and muscle-expressed FGF-21 also suggests that muscle FGF-21 primarily works in a local manner regulating glucose metabolism in the muscle and/or signals to the adipose tissue in close contact to the muscle. Our study has some limitations. The number of subjects is small and some correlations could have been significant with greater statistical power. Another aspect is that protein levels of FGF-21 were not determined in the muscles extracts, consequently we cannot be sure the increase in FGF-21 mRNA is followed by increased protein expression. In conclusion, we show that FGF-21 mRNA is increased in skeletal muscle in HIV patients and that FGF-21 mRNA in muscle correlates to whole-body (primarily reflecting muscle) insulin resistance. These findings add to the evidence that FGF-21 is a myokine and that muscle FGF-21 might primarily work in an autocrine manner. Acknowledgments We thank the subjects for their participation in this study. 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