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Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans.

HCFC‐22 is an ozone‐depleting substance with a greenhouse effect. The atmospheric mole fractions of HCFC‐22 have been increasing since the 1950s. Within the NDACC‐IRWG network, HCFC‐22 mol fractions can be retrieved from solar absorption spectra measured by ground‐based FTIR. However, only a few sites have provided HCFC‐22 data sets. Here, we demonstrate a harmonized FTIR HCFC‐22 retrieval strategy and generate a new global NDACC‐IRWG HCFC‐22 data set at 16 FTIR sites. The systematic and random uncertainties are 5.3%–8.7% and 3.2%–8.0%, respectively. A maximum HCFC‐22 column annual growth rate was observed in 2009 with a mean of 7.65 ± 1.39 ppt/year, and the HCFC‐22 annual growth rate decreased to 3.57 ± 1.39 ppt/year (2016–2020) and 2.15 ± 2.09 ppt/year (2021–2023). The annual growth rates derived from the FTIR measurements are compared to the ones derived from NOAA surface flask samplings and ACE‐FTS satellite measurements, and the three independent data sets show a good agreement. Plain Language Summary: Monitoring the atmospheric HCFC‐22 mol fraction and its long‐term trend is important to the stratospheric ozone layer and climate change. Ground‐based FTIR measurements within the NDACC‐IWRG community provide a powerful technique for observing atmospheric trace gases. However, due to different retrieval software and procedures among the sites, the record was too heterogeneous for monitoring the global evolution of HCFC‐22 over time. In this study, we propose a harmonized FTIR HCFC‐22 retrieval strategy and generate a global NDACC‐IRWG HCFC‐22 data set at 16 FTIR sites. The retrieval uncertainty of the FTIR HCFC‐22 is well presented and discussed. Based on the new FTIR HCFC‐22 measurements, the HCFC‐22 annual growth rates between 1990 and 2023 are evaluated. The results are compared with two independent data sets: NOAA flask samplings and ACE‐FTS satellite measurements. Good agreement among the three data sets is found, with a clear decrease in the growth rate of atmospheric HCFC‐22 in recent years. According to the latest Montreal Protocol, HCFC‐22 should be phased out within the next 5–6 years. The global FTIR observations will assure continuity into the next years and decades when HCFC‐22 mol fractions should start decreasing after the official phase‐out. Key Points: Implemented a harmonized NDACC‐IRWG FTIR HCFC‐22 retrieval strategy and provided a new global long‐term HCFC‐22 data setA decrease in the growth rate of the atmospheric HCFC‐22 column has been observed by FTIR measurements since 2009The FTIR, NOAA flask samplings, and ACE‐FTS satellite observations show a good agreement in the HCFC‐22 trend [ABSTRACT FROM AUTHOR]

BackgroundThere is limited evidence that among HIV-infected patients haemoglobin A1c (HbA1c) values may not accurately reflect glycaemia. We assessed HbA1c discordance (observed HbA1c - expected HbA1c) and associated factors among HIV-infected participants in the Multicenter AIDS Cohort Study (MACS).MethodsFasting glucose (FG) and HbA1c were measured at each semi-annual MACS visit since 1999. All HIV-infected and HIV-uninfected men for whom at least one FG and HbA1c pair measurement was available were evaluated. Univariate median regression determined the association between HbA1c and FG by HIV serostatus. The relationship between HbA1c and FG in HIV-uninfected men was used to determine the expected HbA1c. Generalized estimating equations determined factors associated with the Hb1Ac discordance among HIV-infected men. Clinically significant discordance was defined as observed HbA1c - expected HbA1c ≤-0.5%.ResultsOver 13 years, 1500 HIV-uninfected and 1357 HIV-infected men were included, with a median of 11 visits for each participant. At an FG of 125 mg/dL, the median HbA1c among HIV-infected men was 0.21% lower than among HIV-uninfected men and the magnitude of this effect increased with FG >126 mg/dL. Sixty-three percent of HIV-infected men had at least one visit with clinically significant HbA1c discordance, which was independently associated with: low CD4 cell count (

Alcohol dehydrogenase 1B (ADH1B) is a primate-specific enzyme which, uniquely among the ADH class 1 family, is highly expressed both in adipose tissue and liver. Its expression in adipose tissue is reduced in obesity and increased by insulin stimulation. Interference with ADH1B expression has also been reported to impair adipocyte function. To better understand the role of ADH1B in adipocytes, we used CRISPR/Cas9 to delete ADH1B in human adipose stem cells (ASC). Cells lacking ADH1B failed to differentiate into mature adipocytes manifested by minimal triglyceride accumulation and a marked reduction in expression of established adipocyte markers. As ADH1B is capable of converting retinol to retinoic acid (RA), we conducted rescue experiments. Incubation of ADH1B-deficient preadipocytes with 9-cis-RA, but not with all-transretinol, significantly rescued their ability to accumulate lipids and express markers of adipocyte differentiation. A homozygous missense variant in ADH1B (p.Arg-313Cys) was found in a patient with congenital lipodystrophy of unknown cause. This variant significantly impaired the protein's dimerization, enzymatic activity, and its ability to rescue differentiation in ADH1B-deficient ASC. The allele frequency of this variant in the Middle Eastern population suggests that it is unlikely to be a fully penetrant cause of severe lipodystrophy. In conclusion, ADH1B appears to play an unexpected, crucial and cell-autonomous role in human adipocyte differentiation by serving as a necessary source of endogenous retinoic acid. [ABSTRACT FROM AUTHOR]

The Geostationary Environment Monitoring Spectrometer (GEMS) on board GEO-KOMPSAT-2B was launched in February 2020 and has been monitoring atmospheric chemical compositions over Asia. We present the first evaluation of the operational GEMS formaldehyde (HCHO) vertical column densities (VCDs) during and after the in-orbit test (IOT) period (August–October 2020) by comparing them with the products from the TROPOspheric Monitoring Instrument (TROPOMI) and Fourier-transform infrared (FTIR) and multi-axis differential optical absorption spectroscopy (MAX-DOAS) instruments. During the IOT, the GEMS HCHO VCDs reproduced the observed spatial pattern of TROPOMI VCDs over the entire domain (r= 0.62) with high biases (10 %–16 %). We found that the agreement between GEMS and TROPOMI was substantially higher in Northeast Asia (r= 0.90), encompassing the Korean Peninsula and east China. GEMS HCHO VCDs captured the seasonal variation in HCHO, primarily driven by biogenic emissions and photochemical activities, but showed larger variations than those of TROPOMI over coastal regions (Kuala Lumpur, Singapore, Shanghai, and Busan). In addition, GEMS HCHO VCDs showed consistent hourly variations with MAX-DOAS (r= 0.77) and FTIR (r= 0.86) but were 30–40 % lower than ground-based observations. Different vertical sensitivities of GEMS and ground-based instruments caused these biases. Utilizing the averaging kernel smoothing method reduces the low biases by approximately 10 % to 15 % (normalized mean bias (NMB): - 47.4 % to - 31.5 % and - 38.6 % to - 26.7 % for MAX-DOAS and FTIR, respectively). The remaining discrepancies are due to multiple factors, including spatial collocation and different instrumental sensitivities, requiring further investigation using inter-comparable datasets. [ABSTRACT FROM AUTHOR]

Spaceborne formaldehyde (HCHO) measurements constitute an excellent proxy for the sources of non-methane volatile organic compounds (NMVOCs). Past studies suggested substantial overestimations of NMVOC emissions in state-of-the-art inventories over major source regions. Here, the QA4ECV (Quality Assurance for Essential Climate Variables) retrieval of HCHO columns from OMI (Ozone Monitoring Instrument) is evaluated against (1) FTIR (Fourier-transform infrared) column observations at 26 stations worldwide and (2) aircraft in situ HCHO concentration measurements from campaigns conducted over the USA during 2012–2013. Both validation exercises show that OMI underestimates high columns and overestimates low columns. The linear regression of OMI and aircraft-based columns gives ΩOMI=0.651Ωairc+2.95×1015 molec.cm-2 , with ΩOMI and Ωairc the OMI and aircraft-derived vertical columns, whereas the regression of OMI and FTIR data gives ΩOMI=0.659ΩFTIR+2.02×1015 molec.cm-2. Inverse modelling of NMVOC emissions with a global model based on OMI columns corrected for biases based on those relationships leads to much-improved agreement against FTIR data and HCHO concentrations from 11 aircraft campaigns. The optimized global isoprene emissions (∼445Tgyr-1) are 25% higher than those obtained without bias correction. The optimized isoprene emissions bear both striking similarities and differences with recently published emissions based on spaceborne isoprene columns from the CrIS (Cross-track Infrared Sounder) sensor. Although the interannual variability of OMI HCHO columns is well understood over regions where biogenic emissions are dominant, and the HCHO trends over China and India clearly reflect anthropogenic emission changes, the observed HCHO decline over the southeastern USA remains imperfectly elucidated. [ABSTRACT FROM AUTHOR]

Volatile organic compounds (VOCs) are key precursors of particulate matter and tropospheric ozone. Although the terrestrial biosphere is by far the largest source of VOCs into the atmosphere, the emissions of biogenic VOCs remain poorly constrained at the regional scale. In this work, we derive top-down biogenic emissions over Europe using weekly averaged TROPOMI formaldehyde (HCHO) data from 2018 to 2021. The systematic bias of the TROPOMI HCHO columns is characterized and corrected for based on comparisons with FTIR data at seven European stations. The top-down fluxes of biogenic, pyrogenic, and anthropogenic VOC sources are optimized using an inversion framework based on the MAGRITTEv1.1 chemistry transport model and its adjoint. The inversion leads to strongly increased isoprene emissions with respect to the MEGAN–MOHYCAN inventory over the model domain (from 8.1 to 18.5 Tgyr-1), which is driven by the high observed TROPOMI HCHO columns in southern Europe. The impact of the inversion on biomass burning VOCs (+ 13 %) and anthropogenic VOCs (- 17 %) is moderate. An evaluation of the optimized HCHO distribution against ground-based remote sensing (FTIR and MAX-DOAS) and in situ data provides generally improved agreement at stations below about 50 ∘ N but indicates overestimated emissions in northern Scandinavia. Sensitivity inversions show that the top-down emissions are robust with respect to changes in the inversion settings and in the model chemical mechanism, leading to differences of up to 10 % in the total emissions. However, the top-down emissions are very sensitive to the bias correction of the observed columns, as the biogenic emissions are 3 times lower when the correction is not applied. Furthermore, the use of different a priori biogenic emissions has a significant impact on the inversion results due to large differences among bottom-up inventories. The sensitivity run using CAMS-GLOB-BIOv3.1 as a priori emissions in the inversion results in 30 % lower emissions with respect to the optimization using MEGAN–MOHYCAN. In regions with large temperature and cloud cover variations, there is strong week-to-week variability in the observed HCHO columns. The top-down emissions, which are optimized at weekly increments, have a much improved capability of representing these large fluctuations than an inversion using monthly increments. [ABSTRACT FROM AUTHOR]

Objective Underdiagnosis is an important issue in genetic lipodystrophies, which are rare diseases with metabolic, cardiovascular, gynecological, and psychological complications. We aimed to characterize the diagnostic pathway in these diseases from the patients' perspective. Design Cross-sectional study conducted through a self-reported patient questionnaire. Methods Patients with genetic lipodystrophy were recruited throughout the French national reference network for rare diseases of insulin secretion and insulin sensitivity. Patients completed a self-reported questionnaire on disease symptoms, steps leading to the diagnosis, and healthcare professionals involved. Descriptive analyses were conducted. Results Out of 175 eligible patients, 109 patients (84% women) were included; 93 had partial familial lipodystrophy and 16 congenital generalized lipodystrophy. Metabolic comorbidities (diabetes 68%, hypertriglyceridemia 66%, hepatic steatosis 57%), cardiovascular (hypertension 54%), and gynecologic complications (irregular menstruation 60%) were frequently reported. Median age at diagnosis was 30 years (interquartile range [IQR] 23-47). The overall diagnostic process was perceived as "very difficult" for many patients. It extended over 12 years (IQR 5-25) with more than five different physicians consulted by 36% of respondents, before diagnosis, for lipodystrophy-related symptoms. The endocrinologist made the diagnosis for 77% of the patients. Changes in morphotype were reported as the first symptoms by the majority of respondents. Conclusions Diagnostic pathway in patients with genetic lipodystrophy is rendered difficult by the multisystemic features of the disease and the lack of knowledge of non-specialized physicians. Training physicians to systematically include adipose tissue examination in routine clinical evaluation should improve diagnosis and management of lipodystrophy and lipodystrophy-associated comorbidities. [ABSTRACT FROM AUTHOR]

Long-term ground-based ozone measurements are crucial to study the recovery of stratospheric ozone as well as the trends of tropospheric ozone. This study is performed in the context of the LOTUS (Long-term Ozone Trends and Uncertainties in the Stratosphere) and TOAR-II (Tropospheric Ozone Assessment Report, phase II) initiatives. We perform an intercomparison study of total column ozone and multiple partial ozone columns between the ground-based measurements available at the Lauder station from 2000 to 2022, which are the Fourier transform infrared (FTIR) spectrometer, Dobson Umkehr, ozonesonde, lidar, and the microwave radiometer. We compare partial columns, defined to provide independent information: one tropospheric and three stratospheric columns. The intercomparison is analyzed using the median of relative differences (the bias) of FTIR with each of the other measurements, the scaled Median Absolute deviation (MAD s ), and a trend of these differences (measurement drift). The total column shows a bias and strong scatter well within the combined systematic and random uncertainties respectively. There is however a drift of 0.6±0.5 %/decade if we consider the full time series. In the troposphere we find a low bias of -1.9 % with the ozonesondes. No drift is found between the three instruments in the troposphere, which is good for trend studies within TOAR-II. In both the lower and upper stratosphere, we get a negative bias for all instruments with respect to FTIR (between -1.2 % and -6.8 %), but all are within the range of the systematic uncertainties. In the middle stratosphere we seem to find a negative bias of around -5.2 to -6.6 %, pointing towards too high values for FTIR in this partial column. We find no significant drift in the stratosphere between ozonesonde and FTIR for all partial columns. We do observe drift between the FTIR and Umkehr partial columns in the lower and upper stratospheres (2.6±1.1 %/decade and -3.2±0.9 %/decade), with lidar in the midle and upper stratosphere (2.1±0.8 %/decade and -3.7±1.2 %/decade), and with MWR in the midle stratosphere (3.1±1.7 %/decade). These drifts point to the fact that the different observed trends in LOTUS are not due to different sampling, vertical sensitivity or time periods and gaps. However, the difference in trends in LOTUS is reduced by applying a new FTIR retrieval strategy, which changes inputs such as the choice of microwindows, spectroscopy from HITRAN2008 to HITRAN2020, and the regularization method. [ABSTRACT FROM AUTHOR]

Spaceborne formaldehyde (HCHO) measurements constitute an excellent proxy for the sources of non-methane volatile organic compounds (NMVOCs). Past studies suggested substantial overestimations of NMVOC emission in state-of-the-art inventories over major source regions. Here, the QA4ECV (Quality Assurance for Essential Climate Variables) retrieval of HCHO columns from OMI (Ozone Monitoring Instrument) are evaluated against (1) FTIR (Fourier-transform infrared) column observations at 26 stations worldwide, and (2) aircraft in situ HCHO concentration measurements from campaigns conducted over the U.S. in 2012-2013. Both validation exercises show that OMI underestimates high columns and overestimates low columns. The linear regression of OMI and aircraft-based columns gives OMI = 0.651 airc +2.95 · 1015 molec.cm-2, with OMI and airc the OMI and aircraft-derived vertical columns, whereas the regression of OMI and FTIR data gives OMI = 0.659 FTIR +2.02 · 1015 molec.cm-2. Inverse modelling of NMVOC emissions with a global model based on OMI columns corrected for biases based on those relationships leads to much-improved agreement against FTIR data and HCHO concentrations from 11 aircraft campaigns. The optimized global isoprene emissions (- 445Tg yr-1) are 25% higher than those obtained without bias correction. The optimized isoprene emissions bear both striking similarities and differences with recently published emissions based on spaceborne isoprene columns from the CrIS (Cross-track Infrared Sounder) sensor. Although the interannual variability of OMI HCHO columns is well understood over regions where biogenic emissions are dominant, and the HCHO trends over China and India clearly reflect anthropogenic emission changes, the observed HCHO decline over the Southeastern U.S. remains imperfectly elucidated. [ABSTRACT FROM AUTHOR]