Deficiency of IKKα in Macrophages Mitigates Fibrosis Progression in the Kidney after Renal Ischemia-Reperfusion Injury

Aims. Acute kidney injury (AKI) can lead to chronic kidney disease (CKD), and macrophages play a key role in this process. The aim of this study was to discover the role of IκB kinase α (IKKα) in macrophages in the process of AKI-to-CKD transition. Main Methods. We crossed lyz2-Cre mice with IKKα-floxed mice to generate mice with IKKα ablation in macrophages (Mac IKKα-/-). A mouse renal ischemia/reperfusion injury (IRI) model was induced by clamping the renal artery for 45 minutes. Treated mice were evaluated for blood biochemistry, tissue histopathology, and fibrosis markers. Macrophages were isolated from the peritoneal cavity for coculturing with tubular epithelial cells (TECs) and flow cytometry analysis. Key Findings. We found that fibrosis and kidney function loss after IRI were significantly alleviated in Mac IKKα-/- mice compared with wild-type (WT) mice. The expression of fibrosis markers and the infiltration of M2 macrophages were decreased in the kidneys of Mac IKKα-/- mice after IRI. The in vitro experiment showed that the IRI TECs cocultured with IKKα-/- macrophages (KO MΦs) downregulated the fibrosis markers accompanied by a downregulation of Wnt/β-catenin signaling. Significance. These data support the hypothesis that IKKα is involved in mediating macrophage polarization and increasing the expression of fibrosis-promoting inflammatory factors in macrophages. Therefore, knockdown of IKKα in macrophages may be a potential method that can be used to alleviate the AKI-to-CKD transition after IRI.

foF2 Seasonal Prediction With IRI-2016 Over Quiet Activity at Dakar Station

This study deals with comparison between Dakar station ionospheric F2 layer critical frequency (foF2) data and both subroutines (CCIR and URSI) of IRI-2016 model predictions. Dakar station is located near the crest of the African Equatorial Ionization Anomaly (EIA) region. Comparisons are made for very quiet activity during the four seasons (spring, summer, autumn and winter) over both solar cycles 21 and 22. The quietest days per season are determined by taking the five days with the lowest aa. The relative standard deviation of modeled foF2 values is used to assess the quality of IRI model prediction. Model predictions are suitable with observed data by day than by night. The accuracy is better during spring season and poor during winter season. During all seasons, both model subroutines don’t express the signature of the observed vertical drift E×B. But they express an intense counter electrojet at the place of mean intensity or high electrojet.

Cyclophilin D Regulates the Nuclear Translocation of AIF, Cardiac Endothelial Cell Necroptosis and Murine Cardiac Transplant Injury

Ischemia-reperfusion injury (IRI) is an inevitable consequence of organ transplant procedure and associated with acute and chronic organ rejection in transplantation. IRI leads to various forms of programmed cell death, which worsens tissue damage and accelerates transplant rejection. We recently demonstrated that necroptosis participates in murine cardiac microvascular endothelial cell (MVEC) death and murine cardiac transplant rejection. However, MVEC death under a more complex IRI model has not been studied. In this study, we found that simulating IRI conditions in vitro by hypoxia, reoxygenation and treatment with inflammatory cytokines induced necroptosis in MVECs. Interestingly, the apoptosis-inducing factor (AIF) translocated to the nucleus during MVEC necroptosis, which is regulated by the mitochondrial permeability molecule cyclophilin D (CypD). Furthermore, CypD deficiency in donor cardiac grafts inhibited AIF translocation and mitigated graft IRI and rejection (n = 7; p = 0.002). Our studies indicate that CypD and AIF play significant roles in MVEC necroptosis and cardiac transplant rejection following IRI. Targeting CypD and its downstream AIF may be a plausible approach to inhibit IRI-caused cardiac damage and improve transplant survival.

On the Electron Temperature in the Topside Ionosphere as Seen by Swarm Satellites, Incoherent Scatter Radars, and the International Reference Ionosphere Model

The global statistical median behavior of the electron temperature (Te) in the topside ionosphere was investigated through in-situ data collected by Langmuir Probes on-board the European Space Agency Swarm satellites constellation from the beginning of 2014 to the end of 2020. This is the first time that such an analysis, based on such a large time window, has been carried out globally, encompassing more than half a solar cycle, from the activity peak of 2014 to the minimum of 2020. The results show that Swarm data can help in understanding the main features of Te in the topside ionosphere in a way never achieved before. Te data measured by Swarm satellites were also compared to data modeled by the empirical climatological International Reference Ionosphere (IRI) model and data measured by Jicamarca (12.0°S, 76.8°W), Arecibo (18.2°N, 66.4°W), and Millstone Hill (42.6°N, 71.5°W) Incoherent Scatter Radars (ISRs). Moreover, the correction of Swarm Te data recently proposed by Lomidze was applied and evaluated. These analyses were performed for two main reasons: (1) to understand how the IRI model deviates from the measurements; and (2) to test the reliability of the Swarm dataset as a new possible dataset to be included in the underlying empirical dataset layer of the IRI model. The results show that the application of the Lomidze correction improved the agreement with ISR data above all at mid latitudes and during daytime, and it was effective in reducing the mismatch between Swarm and IRI Te values. This suggests that future developments of the IRI Te model should include the Swarm dataset with the Lomidze correction. However, the existence of a quasi-linear relation between measured and modeled Te values was well verified only below about 2200 K, while for higher values it was completely lost. This is an important result that IRI Te model developers should properly consider when using the Swarm dataset.

Algorithm Research Using GNSS-TEC Data to Calibrate TEC Calculated by the IRI-2016 Model over China

The International Reference Ionosphere (IRI) is an empirical model widely used to describe ionospheric characteristics. In the previous research, high-precision total ionospheric electron content (TEC) data derived from global navigation satellite system (GNSS) data were used to adjust the ionospheric global index IG12 used as a driving parameter in the standard IRI model; thus, the errors between IRI-TEC and GNSS-TEC were minimized, and IRI-TEC was calibrated by modifying IRI with the updated IG12 index (IG-up). This paper investigates various interpolation strategies for IG-up values calculated from GNSS reference stations and the calibrated TEC accuracy achieved using the modified IRI-2016 model with the interpolated IG-up values as driving parameters. Experimental results from 2015 and 2019 show that interpolating IG-up with a 2.5° × 5° spatial grid and a 1-h time resolution drives IRI-2016 to generate ionospheric TEC values consistent with GNSS-TEC. For 2015 and 2019, the mean absolute error (MAE) of the modified IRI-TEC is improved by 78.57% and 77.42%, respectively, and the root mean square error (RMSE) is improved by 78.79% and 77.14%, respectively. The corresponding correlations of the linear regression between GNSS-TEC and the modified IRI-TEC are 0.986 and 0.966, more than 0.2 higher than with the standard IRI-TEC.

Ginsenoside Rg1 Alleviates Hepatic Ischemia-Reperfusion Injury in Mice via Activating ERα-Regulating YAP Expression

Objective. To verify whether ginsenoside Rg1 alleviates liver hepatic ischemia-reperfusion injury (IRI) in mice by upregulating the expression of Yes-associated protein (YAP) through estrogen receptor alpha pathway. Methods. The whole hepatic IRI model and the local (70%) hepatic IRI model were established, respectively. The whole hepatic IRI model was used to observe the survival curve of mice, and the mouse models with 70% hepatic IRI were used to explore the mechanism of liver injury about Rg1 in hepatic IRI. Wild-type C57BL/6 mice were randomly divided into some groups: (1) the whole hepatic IRI model group: the survival rate of mice was observed at 0, 30, 60, 90, and 120 min after ischemia and Rg1 intervention (90 min after ischemia), with 10 mice in each group, and (2) the 70% hepatic IRI model group: sham operation group, I/R model group, verteporfin (VP) group, doxycycline (Doxy) group, 17β-estradiol (E2) group, clomiphene (Clom) group, and Rg1 group with 6 mice in each group. The level of serum alanine aminotransferase (ALT) was measured by enzyme labeling instrument, the degree of liver injury was analyzed after hematoxylin-eosin (HE) staining, and the function of mitochondria was detected in fresh liver tissue, including mitochondrial membrane potential with JC-1 (5,5′,6,6′-tetrachloro1,1′,3,3′-tetramethylbenzimidazolylcarbocyanine iodide), adenosine triphosphate (ATP), and mitochondrial reactive oxygen species (ROS), and the expression of YAP and estrogen receptor alpha (ERα) genes and proteins were detected by real‐time reverse‐transcriptase polymerase chain reaction (RT-PCR) and Western blot. Results. The whole hepatic IRI model showed that the survival rate of mice decreased with the prolongation of ischemia time. IRI model mice showed mitochondrial damage, JC-1 red/green fluorescence value and ATP significantly decreased, and ROS production increased; in comparison, in the Doxy and E2 intervention group, JC-1 red/green fluorescence value and ATP production increased and ROS downregulated, indicating that mitochondrial function returned to normal. The level of serum ALT showed that the liver enzyme increased with the time of reperfusion and decreased gradually after 6 hours. The results of Western blot and PCR showed that the expression of YAP and ERα showed the same trend. The IRI model mice were observed after 90 minutes of ischemia and 6 hours of reperfusion. Compared with the corresponding sham group, the expression of YAP in the liver tissue of the Doxy group, E2 group, and Rg1 intervention group increased, and the expression of ERα in the E2 group and Rg1 group increased. HE staining showed that a large number of inflammatory cell infiltration could be seen in the liver tissue of the model group, but it decreased in the Doxy and E2 intervention groups. Conclusion. Ginsenoside Rg1 exerts an estrogenic effect by activating ERα, upregulating the expression of YAP, reducing liver oxidative stress injury, and inhibiting mitochondrial injury to protect the liver from ischemia-reperfusion injury in mice.

Evaluating the Performance of IRI-2016 Using GPS-TEC Measurements over the Equatorial Region

Total electron content (TEC) is an important parameter in the ionosphere that is extensively used to study the variability of the ionosphere as it significantly affects radio wave propagations, causing delays on GPS signals. Therefore, evaluating the performance of ionospheric models is crucial to reveal the variety of ionospheric behaviour in different solar activity periods during geomagnetically quiet and disturbed periods for further improvements of the IRI model performance over the equatorial region. This research aimed to investigate the variations of ionospheric VTEC and observe the improvement in the performance of the IRI-2016 (IRI-2001, IRI01-corr, and NeQuick). The IRI-2016 was evaluated with the IRI-2012 using NeQuick, IRI-2001, and IRI01-corr topside electron density options. The data were obtained using a dual-frequency GPS receiver installed at the Universiti Utara Malaysia Kedah (UUMK) (geographic coordinates 4.62° N–103.21° E, geomagnetic coordinates 5.64° N–174.98° E), Mukhtafibillah (MUKH) (geographic coordinates 6.46° N–100.50° E, geomagnetic coordinates 3.32° S–172.99° E), and Tanjung Pengerang (TGPG) (geographic coordinates 1.36° N–104.10°E, geomagnetic coordinates 8.43° S–176.53° E) stations, during ascending to high solar activity at the geomagnetically quiet and disturbed periods in October 2011, March 2012, and March 2013. The maximum hourly ionospheric VTEC was observed during the post-noon time, while the minimum was during the early morning time. The ionospheric VTEC modelled by IRI-2016 had a slight improvement from the IRI-2012. However, the differences were observed during the post-noon and night-time, while the modelled VTEC from both IRI models were almost similar during the early morning time. Regarding the daily quiet and disturbed period’s prediction capability of the IRI-2016 and IRI-2012, IRI-2016 gave better agreement with the measured VTEC. The overall results showed that the model’s prediction performance during the high solar activity period in 2013 was better than the one during the ascending solar activity period. The results of the comparison between IRI-2016 and IRI-2012 in high solar activity exhibited that during quiet periods, all the IRI models showed better agreement with the measured VTEC compared to the disturbed periods.

Abstract MP58: Tissue And Sex Specific Effects Of Gstm1 Deletion In Mouse Models

The glutathione S-transferase ( Gst ) gene family encodes antioxidant enzymes. In humans, a common null allele deletion variant of GST μ-1 ( GSTM1 ) is highly prevalent across populations and is associated with increased risk and progression of various diseases. Using a Gstm1 knockout (KO) mouse model, we previously showed that KO mice with angiotensin II-induced hypertension (HTN) have increased kidney injury compared to wild-type (WT) controls, mediated by elevated oxidative stress. In the same mouse model, we have recently reported that in a Langendorff-perfused cardiac ischemia-reperfusion injury (IRI) model, where damage is also mediated by oxidative stress, male KO hearts are protected while females are not. Here, we investigated the molecular mechanisms for this difference in male hearts. WT and KO mice of both sexes were studied at 12-20 weeks of age. Hearts were snap frozen at baseline and after 25 min of global ischemia, and kidneys were collected at baseline and 4 weeks following HTN induction. A panel of 18 Gst genes were probed by qPCR from baseline hearts and kidneys of both sexes. Global metabolites were assayed using Metabolon, Inc. from hearts of both sexes and kidneys of males, at both baseline and diseased states. Analysis by qPCR (n = 3/group) showed that male, but not female, KO hearts had upregulation of other Gst s. In contrast, no significant differences between were found in male kidneys. Metabolomics (n = 6/group) detected 695 metabolites in hearts and 926 in kidneys. There were increases in several metabolites in KO vs. WT hearts including those with antioxidant properties. Notably, increases in carnosine and anserine were observed in KO male hearts but not in female hearts, while that of other antioxidant-related metabolites were observed in hearts of both sexes, but not in kidneys. HTN induced significant increases in metabolites in KO vs. WT kidneys in the pathways related to and linking methionine, cysteine, and glutathione, which were not observed in hearts. In this study, gene expression and metabolites suggest that the mechanisms compensating for the loss of GSTM1 are both tissue and sex specific. The resulting differences in antioxidant enzymes and metabolites may explain the unexpected protection for male Gstm1 KO hearts in IRI.

MODELING CRITICAL FREQUENCY OF IONOSPHERE D-LAYER AT MINIMUM AND MAXIMUM OF THE SOLAR CYCLE 22WITH IRI-2016

One of the interests of the study of the ionosphere lies in its importance for the transmission of radio waves in telecommunications. The ionospherebehaves as an obstacle to the passage of waves. Thus, the signals of short wavelengths are reflected by the F layer or the upper part of the sublayer E, while theD-layeris the seat of the reflection of low-frequencywaves. The presentstudyinvestigates the temporal variability of the criticalfrequency of the D-layer (for) using the 2016 version of the International Reference Ionosphere (IRI) model under quiet day conditions during at maximum and minimum phase of solar cycle 22. The workisconductedat the Ouagadougou station, located in West Africa. The methodology of the workadopted for the determination of the parameter foDisbased on the calculation of the monthlyhourlyaverages of this variable obtainedwith the help of the model during the monthsthatcharacterize the seasons. The resultsobtained for the parameter for as a function of time during the minimum and maximum of the solar cycle 22 have been presented. The seasonal and temporal variations of the criticalfrequency of the ionosphereD-layer show that the foD values are lower during a minimum of the solar cycle and present maximum values at the Zenith (1200 TL) at a minimum and maximum. Theseresultsalsorevealthatthisparameter varies with time, season, and geographical position. The results of thisstudy show a criticalfrequencybelow 1 MHz during both phases of the solar cycle.

A Global Empirical Model of the Ion Temperature in the Ionosphere for the International Reference Ionosphere

This study presents a suggestion for improvement of the ion temperature (Ti) model in the International Reference Ionosphere (IRI). We have re-examined ion temperature data (primarily available from NASA’s Space Physics Data Facility (SPDF)from older satellites and combined them with newly available data from the Defense Meteorological Satellite Program (DMSP), the Communication Navigation Outage Forecasting System (C/NOFS), and from the recently launched Ionospheric Connection Explorer (ICON). We have compiled these data into a unified database comprising in total Ti data from 18 satellites. By comparisons with long term records of ion temperature from the three incoherent scatter radars (ISRs) (Jicamarca, Arecibo, and Millstone Hill), it was found that an intercalibration is needed to achieve consistency with the ISR data and among individual satellite data sets. This database with thus corrected data has been used for the development of a new global empirical model of Ti with inclusion of solar activity variation. This solar activity dependence is represented by an additive correction term to the Ti global pattern. Due to the limited data coverage at altitudes above 1000 km, the altitude range described by the model ranges from 350 km to 850 km covering only the region where generally Ti is higher than the neutral temperature (Tn) and lower than the electron temperature (Te). This approach is consistent with the current description of Ti in the IRI model. However, instead of one anchor point at 430 km altitude as in the current IRI, our approach includes anchor points at 350, 430, 600, and 850 km. At altitudes above 850 km Ti is merged using a gradient derived from the model at 600 and 850 km, with the electron temperature described by the IRI-2016/TBT-2012 option. Comparisons with the ISR data (Jicamarca, Arecibo, Millstone Hill, and Kharkiv) for high and low solar activity and equinox show that the proposed Ti model captures local time variation of Ti at different altitudes and latitudes better than the current IRI-2016 Ti model.