P2X2 Dominant Deafness Mutations Have No Negative Effect on Wild-Type Isoform: Implications for Functional Rescue and in Deafness Mechanism

The P2X2 receptor is an ATP-gated ion channel, assembled by three subunits. Recently, it has been found that heterozygous mutations of P2X2 V60L and G353R can cause autosomal dominant nonsyndromic hearing loss. However, the underlying mechanism remains unclear. The fact that heterozygous mutations cause deafness suggests that the mutations may have dominant-negative effect (DNE) on wild-type (WT) P2X2 isoforms and/or other partners leading to hearing loss. In this study, the effect of these dominant deafness P2X2 mutations on WT P2X2 was investigated. We found that sole transfection of both V60L and G353R deafness mutants could efficiently target to the plasma membrane, like WT P2X2, but exhibit a significantly reduced response to ATP stimulation. Both mutants reduced the channel conductance, but G353R mutation also altered the voltage dependency. Co-expression with WT P2X2 could restore the response to ATP. As the ratio of WT P2X2 vs. mutants increased, the response to ATP was also increased. Computer modeling confirmed that both V60L and G353R dominant-deafness mutant subunits do not have any negative effect on WT P2X2 subunit, when assembled as a heterotrimer. Improper docking or defective gating is the more likely mechanism for impaired channel function by these P2X2 deafness mutations. These results suggest that P2X2 dominant deafness mutations do not have negative effects on WT P2X2 isoforms, and that adding additional WT P2X2 could rescue the lost channel function caused by the deafness mutations. These P2X2 dominant deafness mutations may have negative-effects on other partners leading to hearing loss

Background CO₂ levels and error analysis from ground-based solar absorption IR measurements in central Mexico

In this investigation we analyze two common optical configurations to retrieve CO₂ total column amounts from solar absorption infrared spectra. The noise errors using either a KBr or a CaF₂ beam splitter, a main component of a Fourier transform infrared spectrometer (FTIR), are quantified in order to assess the relative precisions of the measurements. The configuration using a CaF₂ beam splitter, as deployed by the instruments which contribute to the Total Carbon Column Observing Network (TCCON), shows a slightly better precision. However, we show that the precisions in X$_{CO2}$ ( =  0.2095  ⋅  $\frac{Total Column CO₂}{Total Column O₂}$) retrieved from  >  96 % of the spectra measured with a KBr beam splitter fall well below 0.2 %. A bias in X$_{CO2}$ (KBr − CaF₂) of +0.56 ± 0.25 ppm was found when using an independent data set as reference. This value, which corresponds to +0.14 ± 0.064 %, is slightly larger than the mean precisions obtained. A 3-year X$_{CO2}$ time series from FTIR measurements at the high-altitude site of Altzomoni in central Mexico presents clear annual and diurnal cycles, and a trend of +2.2 ppm yr⁻¹ could be determined

First detection of ammonia (NH₃) in the Asian summer monsoon upper troposphere

Ammonia (NH3) has been detected in the upper troposphere by the analysis of averaged MIPAS (Michelson Interferometer for Passive Atmospheric Sounding) infrared limb-emission spectra. We have found enhanced amounts of NH3 within the region of the Asian summer monsoon at 12–15 km altitude. Three-monthly, 10° longitude  ×  10° latitude average profiles reaching maximum mixing ratios of around 30 pptv in this altitude range have been retrieved, with a vertical resolution of 3–8 km and estimated errors of about 5 pptv. These observations show that loss processes during transport from the boundary layer to the upper troposphere within the Asian monsoon do not deplete the air entirely of NH3. Thus, ammonia might contribute to the so-called Asian tropopause aerosol layer by the formation of ammonium aerosol particles. On a global scale, outside the monsoon area and during different seasons, we could not detect enhanced values of NH3 above the actual detection limit of about 3–5 pptv. This upper bound helps to constrain global model simulations

Combined direct-sun ultraviolet and infrared spectroscopies at Popocatépetl volcano (Mexico)

Volcanic plume composition is strongly influenced by both changes in magmatic systems and plume-atmosphere interactions. Understanding the degassing mechanisms controlling the type of volcanic activity implies deciphering the contributions of magmatic gases reaching the surface and their posterior chemical transformations in contact with the atmosphere. Remote sensing techniques based on direct solar absorption spectroscopy provide valuable information about most of the emitted magmatic gases but also on gas species formed and converted within the plumes. In this study, we explore the procedures, performances and benefits of combining two direct solar absorption techniques, high resolution Fourier Transform Infrared Spectroscopy (FTIR) and Ultraviolet Differential Optical Absorption Spectroscopy (UV-DOAS), to observe the composition changes in the Popocatépetl’s plume with high temporal resolution. The SO2 vertical columns obtained from three instruments (DOAS, high resolution FTIR and Pandora) were found similar (median difference <12%) after their intercalibration. We combined them to determine with high temporal resolution the different hydrogen halide and halogen species to sulfur ratios (HF/SO2, BrO/SO2, HCl/SO2, SiF4/SO2, detection limit of HBr/SO2) and HCl/BrO in the Popocatépetl’s plume over a 2.5-years period (2017 to mid-2019). BrO/SO2, BrO/HCl, and HCl/SO2 ratios were found in the range of (0.63 ± 0.06 to 1.14 ± 0.20) × 10−4, (2.6 ± 0.5 to 6.9 ± 2.6) × 10−4, and 0.08 ± 0.01 to 0.21 ± 0.01 respectively, while the SiF4/SO2 and HF/SO2 ratios were found fairly constant at (1.56 ± 0.25) × 10−3 and 0.049 ± 0.001. We especially focused on the full growth/destruction cycle of the most voluminous lava dome of the period that took place between February and April 2019. A decrease of the HCl/SO2 ratio was observed with the decrease of the extrusive activity. Furthermore, the short-term variability of BrO/SO2 is measured for the first time at Popocatépetl volcano together with HCl/SO2, revealing different behaviors with respect to the volcanic activity. More generally, providing such temporally resolved and near-real-time time series of both primary and secondary volcanic gaseous species is critical for the management of volcanic emergencies, as well as for the understanding of the volcanic degassing processes and their impact on the atmospheric chemistry.We acknowledge financial support from grants UNAM-PAPIIT IA101620 and IN111521. NT and TBo also thank the stipend given by the Mexican Foreign Affairs Department (Secretaría de Relaciones Exteriores) and its AMEXCID program. Financial support from Conacyt-AEM through grant No. 275239 is acknowledged

New Insights Into Permeation of Large Cations Through ATP-Gated P2X Receptors

The permeability of large cations through the P2X pore has remained arguably the most controversial and complicated topic in P2X-related research, with the emergence of conflicting studies on the existence, mechanism and physiological relevance of a so-called “dilated” state. Due to the important role of several “dilating” P2X subtypes in numerous diseases, a clear and detailed understanding of this phenomenon represents a research priority. Recent advances, however, have challenged the existence of a progressive, ATP-induced pore dilation, by demonstrating that this phenomenon is an artifact of the method employed. Here, we discuss briefly the history of this controversial and enigmatic dilated state, from its initial discovery to its recent reconsideration. We will discuss the literature in which mechanistic pathways to a large cation-permeable state are proposed, as well as important advances in the methodology employed to study this elusive state. Considering recent literature, we will also open the discussion as to whether an intrinsically dilating P2X pore exists, as well as the physiological relevance of such a large cation-permeable pore and its potential use as therapeutic pathway

Direct solar FTIR measurements of CO2_2 and HCl in the plume of Popocatépetl Volcano, Mexico

Volcanic CO$_2$ emissions inventories have great importance in the understanding of the geological carbon cycle. Volcanoes provide the primary pathway for solid-earth volatiles to reach the Earth’s atmosphere and have the potential to significantly contribute to the carbon-climate feedback. Volcanic carbon emissions (both passive and eruptive degassing) included in inventories, largely stem from patchy surface measurements that suffer from difficulties in removing the atmospheric background. With a 27-year-long ongoing open-vent eruption, Popocatépetl ranks as one of the highest permanent volcanic CO$_2$ emitters worldwide and provides an excellent natural laboratory to design and experiment with new remote sensing methods for volcanic gas emission measurements. Since October 2012, infrared spectra at different spectral regions have been recorded with a solar occultation FTIR spectrometer. The near-infrared spectra allow for high precision measurements of CO$_2$ and HCl columns. Under favorable conditions, the continuous observations during sunrise allow the reconstruction of a plume cross-section of HCl and the estimation of the emission flux using wind data. Despite that the detection of CO$_2$ is more challenging, on April 26th, 2015 we captured a volcanic plume under favourable wind conditions which allowed us to reconstruct from this particular event a CO$_2$ emission rate of 116.10 ± 17.2 kg/s. The volcanic HCl emission on this event was the highest detected during the 2012-2016 period. An annual average CO$_2$ emission estimate of (41.2 ± 16.7) kg/s ((1.30 ± 0.53) Tg/yr) could be determined from a statistical treatment of the detected CO$_2$ and HCl columns in the IR spectra, and their corresponding molecular ratios, during this period. A total of 25 events were used to derive a mean CO$_2$/HCl molecule ratio of 11.4 ± 4.4 and an average HCl emission rate of (3.0 ± 0.3) kg/s could be determined. The CO$_2$ emissions of Popocatépetl were found to be around 0.32% of the total anthropogenic CO$_2$ emissions reported in the country and 3.6% of those corresponding to the Mexico City Metropolitan Area (MCMA). CO$_2$ emissions from the Popocatépetl volcano can be considered to play a negligible role in the global CO$_2$ budget, but should be taken into account

Formaldehyde total column densities over Mexico City: comparison between multi-axis differential optical absorption spectroscopy and solar-absorption Fourier transform infrared measurements

Formaldehyde (HCHO) total column densities over the Mexico City metropolitan area (MCMA) were retrieved using two independent measurement techniques: multi-axis differential optical absorption spectroscopy (MAX-DOAS) and Fourier transform infrared (FTIR) spectroscopy. For the MAX-DOAS measurements, the software QDOAS was used to calculate differential slant column densities (dSCDs) from the measured spectra and subsequently the Mexican MAX-DOAS fit (MMF) retrieval code to convert from dSCDs to vertical column densities (VCDs). The direct solar-absorption spectra measured with FTIR were analyzed using the PROFFIT (PROFile FIT) retrieval code. Typically the MAX-DOAS instrument reports higher VCDs than those measured with FTIR, in part due to differences found in the ground-level sensitivities as revealed from the retrieval diagnostics from both instruments, as the FTIR and the MAX-DOAS information do not refer exactly to the same altitudes of the atmosphere. Three MAX-DOAS datasets using measurements conducted towards the east, west or both sides of the measurement plane were evaluated with respect to the FTIR results. The retrieved MAX-DOAS HCHO VCDs where 6 %, 8 % and 28 % larger than the FTIR measurements which, supported with satellite data, indicates a large horizontal inhomogeneity in the HCHO abundances. The temporal change in the vertical distribution of this pollutant, guided by the evolution of the mixing-layer height, affects the comparison of the two retrievals with different sensitivities (total column averaging kernels). In addition to the reported seasonal and diurnal variability of HCHO columns within the urban site, background data from measurements at a high-altitude station, located only 60 km away, are presented

Measurement report: Evolution and distribution of NH3_3 over Mexico City from ground-based and satellite infrared spectroscopic measurements

Ammonia (NH$_3$) is the most abundant alkaline compound in the atmosphere, with consequences for the environment, human health, and radiative forcing. In urban environments, it is known to play a key role in the formation of secondary aerosols through its reactions with nitric and sulfuric acids. However, there are only a few studies about NH$_3$ in Mexico City. In this work, atmospheric NH$_3$ was measured over Mexico City between 2012 and 2020 by means of ground based solar absorption spectroscopy using Fourier transform infrared (FTIR) spectrometers at two sites (urban and remote). Total columns of NH$_3$ were retrieved from the FTIR spectra and compared with data obtained from the Infrared Atmospheric Sounding Interferometer (IASI) satellite instrument. The diurnal variability of NH$_3$ differs between the two FTIR stations and is strongly influenced by the urban sources. Most of the NH$_3$ measured at the urban station is from local sources, while the NH$_3$ observed at the remote site is most likely transported from the city and surrounding areas. The evolution of the boundary layer and the temperature play a significant role in the recorded seasonal and diurnal patterns of NH$_3$. Although the vertical columns of NH$_3$ are much larger at the urban station, the observed annual cycles are similar for both stations, with the largest values in the warm months, such as April and May. The IASI measurements underestimate the FTIR NH$_3$ total columns by an average of 32.2 ± 27.5 % but exhibit similar temporal variability. The NH$_3$ spatial distribution from IASI shows the largest columns in the northeast part of the city. In general, NH$_3$ total columns over Mexico City measured at the FTIR stations exhibited an average annual increase of 92 ± 3.9 × 10$^{13}$ molecules cm$^{−2}$ yr$^{−1}$ (urban, from 2012 to 2019) and 8.4 ± 1.4 × 10$^{13}$ molecules cm$^{−2}$ yr$^{−1}$ (re- mote, from 2012 to 2020), while IASI data within 20 km of the urban station exhibited an average annual increase of 38 ± 7.6 × 10$^{13}$ molecules cm$^{−2}$ yr$^{−1}$ from 2008 to 2018

Ground-based remote sensing of O₃ by high- and medium-resolution FTIR spectrometers over the Mexico City basin

We present atmospheric ozone (O₃) profiles measured over central Mexico between November 2012 and February 2014 from two different ground-based FTIR (Fourier transform infrared) solar absorption experiments. The first instrument offers very high-resolution spectra and contributes to NDACC (Network for the Detection of Atmospheric Composition Change). It is located at a mountain observatory about 1700 m above the Mexico City basin. The second instrument has a medium spectral resolution and is located inside Mexico City at a horizontal distance of about 60 km from the mountain observatory. It is documented that the retrieval with the high- and medium-resolution experiments provides O₃ variations for four and three independent atmospheric altitude ranges, respectively, and the theoretically estimated errors of these profile data are mostly within 10 %. The good quality of the data is empirically demonstrated above the tropopause by intercomparing the two FTIR O₃ data, and for the boundary layer by comparing the Mexico City FTIR O₃ data with in situ O₃ surface data. Furthermore, we develop a combined boundary layer O₃ remote sensing product that uses the retrieval results of both FTIR experiments, and we use theoretical and empirical evaluations to document the improvements that can be achieved by such a combination

Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

The known seven mammalian receptor subunits (P2X1–7) form cationic channels gated by ATP. Three subunits compose a receptor channel. Each subunit is a polypeptide consisting of two transmembrane regions (TM1 and TM2), intracellular N- and C-termini, and a bulky extracellular loop. Crystallization allowed the identification of the 3D structure and gating cycle of P2X receptors. The agonist-binding pocket is located at the intersection of two neighbouring subunits. In addition to the mammalian P2X receptors, their primitive ligand-gated counterparts with little structural similarity have also been cloned. Selective agonists for P2X receptor subtypes are not available, but medicinal chemistry supplied a range of subtype-selective antagonists, as well as positive and negative allosteric modulators. Knockout mice and selective antagonists helped to identify pathological functions due to defective P2X receptors, such as male infertility (P2X1), hearing loss (P2X2), pain/cough (P2X3), neuropathic pain (P2X4), inflammatory bone loss (P2X5), and faulty immune reactions (P2X7)