Leptin and mucosal immunity Mackey-Lawrence, N M; Petri, Jr, W A
Mucosal immunology,
09/2012, Letnik:
5, Številka:
5
Journal Article
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Enhanced susceptibility to infection has long been recognized in children with congenital deficiency of leptin or its receptor. Studies in mice have demonstrated that leptin deficiency affects both ...the innate and acquired immune systems. Here, we review recent studies that demonstrate the impact on immunity of a common non-synonomous polymorphism of the leptin receptor. In a Bangladesh cohort of children, the presence of two copies of the ancestral Q223 allele was significantly associated with resistance to amebiasis. Children and mice with at least one copy of the leptin receptor 223R mutation were more susceptible to amebic colitis. Leptin signaling in the intestinal epithelium and downstream STAT3 (signal transducer and activator of transcription 3) and SHP2 (Src homology phosphatase 2) signaling were required for protection in the murine model of amebic colitis. Murine models have also implicated leptin in protection from other infections, including Mycobacterium tuberculosis, Klebsiella pneumoniae, and Streptococcus pneumoniae. Thus, the role of leptin signaling in infectious disease and specifically leptin-mediated protection of the intestinal epithelium will be the focus of this review.
The Bremen Optimal Estimation differential optical absorption spectroscopy (DOAS) (BESD) algorithm for satellite based retrievals of XCO2 (the column‐average dry‐air mole fraction of atmospheric CO2) ...has been applied to Scanning Imaging Absorption Spectrometer for Atmospheric Cartography (SCIAMACHY) data. It uses measurements in the O2‐A absorption band to correct for scattering of undetected clouds and aerosols. Comparisons with precise and accurate ground‐based Fourier transform spectrometer (FTS) measurements at four Total Carbon Column Observing Network (TCCON) sites have been used to quantify the quality of the new SCIAMACHY XCO2 data set. Additionally, the results have been compared to NOAA's assimilation system CarbonTracker. The comparisons show that the new retrieval meets the expectations from earlier theoretical studies. We find no statistically significant regional XCO2 biases between SCIAMACHY and the FTS instruments. However, the standard error of the systematic differences is in the range of 0.2 ppm and 0.8 ppm. The XCO2 single‐measurement precision of 2.5 ppm is similar to theoretical estimates driven by instrumental noise. There are no significant differences found for the year‐to‐year increase as well as for the average seasonal amplitude between SCIAMACHY XCO2 and the collocated FTS measurements. Comparison of the year‐to‐year increase and also of the seasonal amplitude of CarbonTracker exhibit significant differences with the corresponding FTS values at Darwin. Here the differences between SCIAMACHY and CarbonTracker are larger than the standard error of the SCIAMACHY values. The difference of the seasonal amplitude exceeds the significance level of 2 standard errors. Therefore, our results suggest that SCIAMACHY may provide valuable additional information about XCO2, at least in regions with a low density of in situ measurements.
Consistent and accurate long-term data sets of global atmospheric concentrations of carbon dioxide (CO2) are required for carbon cycle and climate-related research. However, global data sets based on ...satellite observations may suffer from inconsistencies originating from the use of products derived from different satellites as needed to cover a long enough time period. One reason for inconsistencies can be the use of different retrieval algorithms. We address this potential issue by applying the same algorithm, the Bremen Optimal Estimation DOAS (BESD) algorithm, to different satellite instruments, SCIAMACHY on-board ENVISAT (March 2002–April 2012) and TANSO-FTS on-board GOSAT (launched in January 2009), to retrieve XCO2, the column-averaged dry-air mole fraction of CO2. BESD has been initially developed for SCIAMACHY XCO2 retrievals. Here, we present the first detailed assessment of the new GOSAT BESD XCO2 product. GOSAT BESD XCO2 is a product generated and delivered to the MACC project for assimilation into ECMWF's Integrated Forecasting System. We describe the modifications of the BESD algorithm needed in order to retrieve XCO2 from GOSAT and present detailed comparisons with ground-based observations of XCO2 from the Total Carbon Column Observing Network (TCCON). We discuss detailed comparison results between all three XCO2 data sets (SCIAMACHY, GOSAT and TCCON). The comparison results demonstrate the good consistency between SCIAMACHY and GOSAT XCO2. For example, we found a mean difference for daily averages of -0.60±1.56 ppm (mean difference ± standard deviation) for GOSAT–SCIAMACHY (linear correlation coefficient r=0.82), -0.34±1.37 ppm (r=0.86) for GOSAT–TCCON and 0.10±1.79 ppm (r=0.75) for SCIAMACHY–TCCON. The remaining differences between GOSAT and SCIAMACHY are likely due to non-perfect collocation (± 2 h,10∘×10∘ around TCCON sites), i.e. the observed air masses are not exactly identical but likely also due to a still non-perfect BESD retrieval algorithm, which will be continuously improved in the future. Our overarching goal is to generate a satellite-derived XCO2 data set appropriate for climate and carbon cycle research covering the longest possible time period. We therefore also plan to extend the existing SCIAMACHY and GOSAT data set discussed here by also using data from other missions (e.g. OCO-2, GOSAT-2, CarbonSat) in the future.
Commercial PIN photodiodes, repurposed as particle detectors, have received a lot of attention along the past decades because they can offer a low-cost solution suitable for several applications. The ...BPX-65 photodiode has been chosen because of its interesting features for measuring electrons in a harsh radiation environment close to the beam of an accelerator. Its electrical characterisation and its application to photon spectrometry have been presented in the companion paper I. Here, its response function (RF) to electrons is investigated using the beam from an electron accelerator with a small energy spread. The empirical expressions for the RF available in the literature have been improved, simplified, and combined to obtain a final form with 7 free parameters: 4 non-linear and 3 linear. A special fitting procedure, which takes advantage of the presence of the linear parameters, is described. The behaviour of these parameters with beam energy and bias is investigated to uncover the physical origin of the three components included in the proposed RF. The interpretation of the features of the spectra is confirmed by Monte Carlo simulations carried out employing the general-purpose PENELOPE/penEasy package. To take into account the charge-collection properties of the device, a simple model has been implemented and is compared to data. It has then been possible to estimate the thickness of the partially dead layer from the experiment.
This work presents the latest release (v9.0) of the University of Leicester GOSAT Proxy XCH4 dataset. Since the launch of the GOSAT satellite in 2009, these data have been produced by the UK National ...Centre for Earth Observation (NCEO) as part of the ESA Greenhouse Gas Climate Change Initiative (GHG-CCI) and Copernicus Climate Change Services (C3S) projects. With now over a decade of observations, we outline the many scientific studies achieved using past versions of these data in order to highlight how this latest version may be used in the future.We describe in detail how the data are generated, providing information and statistics for the entire processing chain from the L1B spectral data through to the final quality-filtered column-averaged dry-air mole fraction (XCH4) data. We show that out of the 19.5 million observations made between April 2009 and December 2019, we determine that 7.3 million of these are sufficiently cloud-free (37.6 %) to process further and ultimately obtain 4.6 million (23.5 %) high-quality XCH4 observations. We separate these totals by observation mode (land and ocean sun glint) and by month, to provide data users with the expected data coverage, including highlighting periods with reduced observations due to instrumental issues.We perform extensive validation of the data against the Total Carbon Column Observing Network (TCCON), comparing to ground-based observations at 22 locations worldwide. We find excellent agreement with TCCON, with an overall correlation coefficient of 0.92 for the 88 345 co-located measurements. The single-measurement precision is found to be 13.72 ppb, and an overall global bias of 9.06 ppb is determined and removed from the Proxy XCH4 data. Additionally, we validate the separate components of the Proxy (namely the modelled XCO2 and the XCH4/XCO2 ratio) and find these to be in excellent agreement with TCCON.In order to show the utility of the data for future studies, we compare against simulated XCH4 from the TM5 model. We find a high degree of consistency between the model and observations throughout both space and time. When focusing on specific regions, we find average differences ranging from just 3.9 to 15.4 ppb. We find the phase and magnitude of the seasonal cycle to be in excellent agreement, with an average correlation coefficient of 0.93 and a mean seasonal cycle amplitude difference across all regions of -0.84 ppb.These data are available at 10.5285/18ef8247f52a4cb6a14013f8235cc1eb .
Top‐down estimates of CO2 fluxes are typically constrained by either surface‐based or space‐based CO2 observations. Both of these measurement types have spatial and temporal gaps in observational ...coverage that can lead to differences in inferred fluxes. Assimilating both surface‐based and space‐based measurements concurrently in a flux inversion framework improves observational coverage and reduces sampling related artifacts. This study examines the consistency of flux constraints provided by these different observations and the potential to combine them by performing a series of 6‐year (2010–2015) CO2 flux inversions. Flux inversions are performed assimilating surface‐based measurements from the in situ and flask network, measurements from the Total Carbon Column Observing Network (TCCON), and space‐based measurements from the Greenhouse Gases Observing Satellite (GOSAT), or all three data sets combined. Combining the data sets results in more precise flux estimates for subcontinental regions relative to any of the data sets alone. Combining the data sets also improves the accuracy of the posterior fluxes, based on reduced root‐mean‐square differences between posterior flux‐simulated CO2 and aircraft‐based CO2 over midlatitude regions (0.33–0.56 ppm) in comparison to GOSAT (0.37–0.61 ppm), TCCON (0.50–0.68 ppm), or in situ and flask measurements (0.46–0.56 ppm) alone. These results suggest that surface‐based and GOSAT measurements give complementary constraints on CO2 fluxes in the northern extratropics and can be combined in flux inversions to improve constraints on regional fluxes. This stands in contrast with many earlier attempts to combine these data sets and suggests that improvements in the NASA Atmospheric CO2 Observations from Space (ACOS) retrieval algorithm have significantly improved the consistency of space‐based and surface‐based flux constraints.
Key Points
Consistent flux constraints are provided by surface in situ and flask, TCCON, and GOSAT measurements of atmospheric CO2
Combining data sets improves agreement between modeled and measured aircraft‐based CO2 measurements
Improvements in NASA ACOS retrieval explain improved consistency of space‐based and surface‐based CO2
Summary Background Few effective treatments exist for patients with advanced urothelial carcinoma that has progressed after platinum-based chemotherapy. We assessed the activity and safety of ...nivolumab in patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after previous platinum-based chemotherapy. Methods In this phase 1/2, multicentre, open-label study, we enrolled patients (age ≥18 years) with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra at 16 sites in Finland, Germany, Spain, the UK, and the USA. Patients were not selected by PD-L1 expression, but tumour PD-L1 membrane expression was assessed retrospectively. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or treatment discontinuation because of unacceptable toxicity or other protocol-defined reasons, whichever occurred later. The primary endpoint was objective response by investigator assessment. All patients who received at least one dose of the study drug were included in the analyses. We report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov , NCT01928394. Findings Between June 5, 2014, and April 24, 2015, 86 patients with metastatic urothelial carcinoma were enrolled in the nivolumab monotherapy group and 78 received at least one dose of treatment. At data cutoff (March 24, 2016), the minimum follow-up was 9 months (median 15·2 months, IQR 12·9–16·8). A confirmed investigator-assessed objective response was achieved in 19 (24·4%, 95% CI 15·3–35·4) of 78 patients. Grade 3–4 treatment-related adverse events occurred in 17 (22%) of 78 patients; the most common were elevated lipase (four 5%), elevated amylase (three 4%), and fatigue, maculopapular rash, dyspnoea, decreased lymphocyte count, and decreased neutrophil count (two 3% each). Serious adverse events were reported in 36 (46%) of 78 patients and eight (10%) had a serious adverse event judged to be treatment related. Two (3%) of 78 patients discontinued because of treatment-related adverse events (grade 4 pneumonitis and grade 4 thrombocytopenia) and subsequently died. Interpretation Nivolumab monotherapy was associated with a substantial and durable clinical response and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data support further investigation of nivolumab monotherapy in advanced urothelial carcinoma. Funding Bristol-Myers Squibb.
Silicon PIN (p-type-intrinsic-n-type) photodiodes are well suited as particle detectors. Here the interest is on a low-cost solution by repurposing a commercial device meant to be used as a light ...sensor. The intended application is to measure the energy spectra of electrons scattered by thin metallic foils covering small angles close to the beam of the accelerator. The main requirements for a suitable device are: 1) a low-cost solution to allow frequent replacements; 2) a small size to avoid as much as possible an unused area that contributes with unnecessary capacitance; 3) a good energy resolution; and 4) an easy repurposing as a charged-particle detector. The photodiode type BPX 65 manufactured by Osram® fulfils well these requirements. Four samples of these commercial devices have been electrically characterised with respect to reverse current and depleted-region capacitance. At the selected working point of 18 V, comfortably below the maximum rating of 20 V recommended by the manufacturer for continuous operation, the total thickness of the depleted and intrinsic regions is estimated to be (60±3) μm. For the four samples considered, the measured reverse currents for a reverse bias of 18 V are around 0.1 nA, well below the typical value specified by the manufacturer (1 nA). To evaluate the performance of the device as a detector, energy spectra have been acquired for γ-rays with energies from 10 to 140 keV using 241Am, 133Ba, and 57Co radioactive sources. The resolution of the BPX 65 encountered with the γ-rays emitted by 241Am at 59.5-keV is ≈2.5 keV (FWHM - Full Width at Half Maximum), which is close to the value obtained with a pulser, showing that its main limitation is the electronic chain employed in the setup. The response function to monoenergetic electrons in the same energy range is studied in the companion paper.
•A commercial PIN photodiode type BPX 65 has been repurposed as a particle detector.•An electrical characterisation of the device has been done.•The thickness of the depleted and intrinsic regions has been determined.•Spectra from radioactive sources have been acquired and analysed.•The energy resolution is 2.5 keV (FWHM) dominated by electronic noise.
Abstract Adrenal medullary hyperplasias (AMHs) are adrenal medullary proliferations with a size < 1 cm, while larger lesions are considered as pheochromocytoma (PCC). This arbitrary distinction has ...been proposed decades ago, although the biological relationship between AMH and PCC has never been investigated. Both lesions are frequently diagnosed in multiple endocrine neoplasia type 2 (MEN2) patients in whom they are considered as two unrelated clinical entities. In this study, we investigated the molecular relationship between AMH and PCC in MEN2 patients. Molecular aberrations of 19 AMHs and 13 PCCs from 18 MEN2 patients were determined by rearranged during transfection (RET) proto-oncogene mutation analysis and loss of heterozygosity (LOH) analysis for chromosomal regions 1p13, 1p36, 3p, and 3q, genomic areas covering commonly altered regions in RET-related PCC. Identical molecular aberrations were found in all AMHs and PCCs, at similar frequencies. LOH was seen for chromosomes 1p13 in 8 of 18 (44%), 1p36 in 9 of 15 (60%), 3p12-13 in 12 of 18 (67%), and 3q23-24 in 10 of 16 (63%) of AMHs, and for chromosome 1p13 in 13 of 13 (100%), 1p36 in 7 of 11 (64%), 3p12-13 in 4 of 11 (36%), and 3q23-24 in 11 of 12 (92%) of PCCs. Our results indicate that AMHs are not hyperplasias and, in clinical practice, should be regarded as PCCs, which has an impact on diagnosis and treatment of MEN2 patients. We therefore propose to replace the term AMH by micro-PCC to indicate adrenal medullary proliferations of less than 1 cm.
NASA's Orbiting Carbon Observatory-2 (OCO-2) has been measuring carbon dioxide column-averaged dry-air mole fraction, XCO2, in the Earth's atmosphere for over 2 years. In this paper, we describe the ...comparisons between the first major release of the OCO-2 retrieval algorithm (B7r) and XCO2 from OCO-2's primary ground-based validation network: the Total Carbon Column Observing Network (TCCON). The OCO-2 XCO2 retrievals, after filtering and bias correction, agree well when aggregated around and coincident with TCCON data in nadir, glint, and target observation modes, with absolute median differences less than 0.4 ppm and RMS differences less than 1.5 ppm. After bias correction, residual biases remain. These biases appear to depend on latitude, surface properties, and scattering by aerosols. It is thus crucial to continue measurement comparisons with TCCON to monitor and evaluate the OCO-2 XCO2 data quality throughout its mission.
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