Acetyl-CoA synthetase 2 induces pyroptosis and inflammation of renal epithelial tubular cells in sepsis-induced acute kidney injury by upregulating the KLF5/NF-κB pathway.

BACKGROUND: Pyroptosis of the renal tubular epithelial cells (RTECs) and interstitial inflammation are central pathological characteristics of acute kidney injury (AKI). Pyroptosis acts as a pro-inflammatory form of programmed cell death and is mainly dependent on activation of the NLRP3 inflammasome. Previous studies revealed that acetyl-CoA synthetase 2 (ACSS2) promotes inflammation during metabolic stress suggesting that ACSS2 might regulate pyroptosis and inflammatory responses of RTECs in AKI. METHODS AND RESULTS: The expression of ACSS2 was found to be significantly increased in the renal epithelial cells of mice with lipopolysaccharide (LPS)-induced AKI. Pharmacological and genetic strategies demonstrated that ACSS2 regulated NLRP3-mediated caspase-1 activation and pyroptosis through the stimulation of the KLF5/NF-κB pathway in RTECs. The deletion of ACSS2 attenuated renal tubular pathological injury and inflammatory cell infiltration in an LPS-induced mouse model, and ACSS2-deficient mice displayed impaired NLRP3 activation-mediated pyroptosis and decreased IL-1ß production in response to the LPS challenge. In HK-2 cells, ACSS2 deficiency suppressed NLRP3-mediated caspase-1 activation and pyroptosis through the downregulation of the KLF5/NF-κB pathway. The KLF5 inhibitor ML264 suppressed NF-κB activity and NLRP3-mediated caspase-1 activation, thus protecting HK-2 cells from LPS-induced pyroptosis. CONCLUSION: Our results suggested that ACSS2 regulates activation of the NLRP3 inflammasome and pyroptosis by inducing the KLF5/NF-κB pathway in RTECs. These results identified ACSS2 as a potential therapeutic target in AKI.

Comparison of the Watson formula and bioimpedance spectroscopy for measuring body volume and calculating kt/V in patients with peritoneal dialysis.

CONCLUSION: There were significant differences between Vwat and Vbis and between Kt/Vwat and Kt/Vbis. Kt/Vwat may underestimate small-solute dialysis adequacy in most cases. Kt/Vbis instead of Kt/Vwat could be accounted for in creating individualized dialysis prescriptions if the patient has no obvious clinical symptoms.

Prognosis of Peritoneal Dialysis Patients with Different Peritoneal Transport Characteristics: A Retrospective Cohort Study.

INTRODUCTION: We aimed to examine the clinical characteristics of peritoneal dialysis (PD) patients with different baseline peritoneal transport characteristics and the effect of peritoneal transport characteristics on the prognosis of PD patients. METHODS: Patients who received PD for more than 3 months were included. Clinical characteristics, risk factors for high peritoneal transport, and risk factors for death and technique failure were examined. All patients were treated with glucose-containing peritoneal dialysis solution, and the peritoneal dialysis protocol was either day ambulatory peritoneal dialysis (DAPD) or continuous ambulatory peritoneal dialysis (CAPD). RESULTS: A total of 351 patients were enrolled, comprising 70 in the low transport group, 149 in the low average transport group, 88 in the high average transport group, and 44 in the high transport group. Multivariate logistic regression analysis showed that a high Charlson's comorbidity index (CCI) and low albumin were risk factors for a high baseline transport status. In the nonhigh transport group, the proportion of patients with albumin less than 30 g/L, who developed high transport status, was higher than those with albumin more than 30 g/L (P = .029). The survival rate in the high transport group was significantly lower than that in the other three groups (P < .001). Multivariate Cox regression analysis showed that age, systolic blood pressure, CCI, C-reactive protein (CRP) and high transport were independent risk factors for all-cause mortality. Male sex, triglycerides and CRP were independent risk factors for technique failure. CONCLUSION: High peritoneal transport status is an independent risk factor for death. High CCI and low albumin are determinants of baseline high peritoneal transport. To avoid development of a high transport state, serum albumin should be increased to more than 30 g/L.  DOI: 10.52547/ijkd.7617.

A landscape of metabolic variation among clinical outcomes of peritoneal dialysis in end-stage renal disease.

BACKGROUND: Peritoneal dialysis (PD) helps prevent lethal complications of end-stage renal disease (ESRD). However, the clinical outcomes are affected by PD-related complications. We investigated metabolic biomarkers to estimate the clinical outcomes of PD and identify patients at high risk of downstream complications and recurrent/relapsing infections. METHODS: Metabolites of normal control and ESRD patient were compared via an untargeted metabolomic analysis. Potential metabolic biomarkers were selected and quantified using a multiple reaction monitoring-based target metabolite detection method. A nomogram was built to predict the clinical outcomes of PD patients using clinical features and potential metabolic biomarkers with the least absolute shrinkage and selection operator Cox regression model. RESULTS: Twenty-five endogenous metabolites were identified and analyzed. ESRD-poor clinical outcome-related metabolic modules were constructed. Adenine, isoleucine, tyramine, xanthosine, phenylacetyl-L-glutamine, and cholic acid were investigated using the weighted gene correlation network analysis blue module. Potential metabolic biomarkers were differentially expressed between the NC and ESRD groups and the poor and good clinical outcomes of PD groups. A 3-metabolite fingerprint classifier of isoleucine, cholic acid, and adenine was included in a nomogram predicting the clinical outcomes of PD. CONCLUSION: Metabolic variations can predict the clinical outcomes of PD in ESRD patients.

Acetyl-CoA synthetase 2 promotes diabetic renal tubular injury in mice by rewiring fatty acid metabolism through SIRT1/ChREBP pathway.

Diabetic nephropathy (DN) is characterized by chronic low-grade renal inflammatory responses, which greatly contribute to disease progression. Abnormal glucose metabolism disrupts renal lipid metabolism, leading to lipid accumulation, nephrotoxicity, and subsequent aseptic renal interstitial inflammation. In this study, we investigated the mechanisms underlying the renal inflammation in diabetes, driven by glucose-lipid metabolic rearrangement with a focus on the role of acetyl-CoA synthetase 2 (ACSS2) in lipid accumulation and renal tubular injury. Diabetic models were established in mice by the injection of streptozotocin and in human renal tubular epithelial HK-2 cells cultured under a high glucose (HG, 30 mmol/L) condition. We showed that the expression levels of ACSS2 were significantly increased in renal tubular epithelial cells (RTECs) from the diabetic mice and human diabetic kidney biopsy samples, and ACSS2 was co-localized with the pro-inflammatory cytokine IL-1ß in RTECs. Diabetic ACSS2-deficient mice exhibited reduced renal tubular injury and inflammatory responses. Similarly, ACSS2 knockdown or inhibition of ACSS2 by ACSS2i (10 µmol/L) in HK-2 cells significantly ameliorated HG-induced inflammation, mitochondrial stress, and fatty acid synthesis. Molecular docking revealed that ACSS2 interacted with Sirtuin 1 (SIRT1). In HG-treated HK-2 cells, we demonstrated that ACSS2 suppressed SIRT1 expression and activated fatty acid synthesis by modulating SIRT1-carbohydrate responsive element binding protein (ChREBP) activity, leading to mitochondrial oxidative stress and inflammation. We conclude that ACSS2 promotes mitochondrial oxidative stress and renal tubular inflammation in DN by regulating the SIRT1-ChREBP pathway. This highlights the potential therapeutic value of pharmacological inhibition of ACSS2 for alleviating renal inflammation and dysregulation of fatty acid metabolic homeostasis in DN. Metabolic inflammation in the renal region, driven by lipid metabolism disorder, is a key factor in renal injury in diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is abundantly expressed in renal tubular epithelial cells (RTECs) and highly upregulated in diabetic kidneys. Deleting ACSS2 reduces renal fatty acid accumulation and markers of renal tubular injury in diabetic mice. We demonstrate that ACSS2 deletion inhibits ChREBP-mediated fatty acid lipogenesis, mitochondrial oxidative stress, and inflammatory response in RTECs, which play a major role in the progression of diabetic renal tubular injury in the kidney. These findings support the potential use of ACSS2 inhibitors in treating patients with DN.

Trends in bronchopulmonary dysplasia and respiratory support among extremely preterm infants in China over a decade.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is one of the most serious complications affecting extremely preterm infants. We aimed to evaluate temporal trends in BPD and administration of respiratory support among extremely preterm infants in China over a decade. METHODS: This was a retrospective study using data from a multicenter database, which included infants born less than 28 weeks' gestation discharged from 68 tertiary neonatal care centers in China between 2010 and 2019. Changes in rates and severity of BPD, as well as modalities and duration of respiratory support, were evaluated. RESULTS: Among 4808 eligible infants with gestational age (GA) of 21+6/7  to 27+6/7 weeks and a mean (SD) birth weight of 980 (177) g, no significant change of median GA was found over time. Overall, 780 (16.2%) infants died before 36 weeks' postmenstrual age, 2415 (50.2%) were classified as having no BPD, 917 (19.1%) developed Grade 1 BPD, 578 (12.0%) developed Grade 2 BPD, and 118 (2.5%) developed Grade 3 BPD. The rate of BPD increased from 20.8% in 2010 to 40.7% in 2019 (aRR for trend, 1.081; 95% confidence interval, 1.062-1.099), especially for Grade 1 and Grade 2. Although survival to discharge improved over the decade, the overall survival without BPD did not change during the study period. The use of invasive mechanical ventilation (IMV) remained unchanged. However, the use of noninvasive ventilation (NIV) increased from 71.5% in 2010 to 89.8% in 2019. Moreover, the median duration of NIV increased over time, from 17.0 (4.8, 34.0) days in 2010 to 33.0 (21.0, 44.0) days in 2019, without significant change in the duration of IMV. CONCLUSIONS: Although survival increased over the decade and respiratory support practices changed significantly between 2010 and 2019 in China, with increased use and duration of NIV, there was an increased rate of BPD and survival without BPD has not improved.

Long noncoding RNA MEG8 induces an imbalance of Th17/Treg cells through the miR-107/STAT3 axis in Henoch-Schonlein purpura rats.

T-helper (Th) 17/ T-regulatory (Treg) cell dysregulation underlies the pathogenesis of Henoch-Schonlein purpura (HSP). This research focused on the implication/s of the long noncoding RNA (lncRNAs) maternally expressed gene 8 (MEG8) in Th17 and Treg cell differentiation in HSP rats. MEG8, miR-107, signal transducer and activator of transcription-3 (STAT3), receptor-related orphan receptor γt (RORγt), and the transcription factor forkhead box P3 (Foxp3) expression levels were detected using real-time quantitative polymerase chain reaction and Western blot analyses. Flow cytometry was employed for measuring Th17 and Treg cells within the CD4+ T cell population. The interaction between miR-107 and MEG8 or STAT3 was examined. A low proportion of MEG8 and Treg cells together with Th17 cells were denoted within HSP rats. Moreover, MEG8 overexpression altered the Th17/Treg imbalance in peripheral blood CD4+ T-cell population, and the miR-107 mimic and STAT3 silencing reversed this effect. Thus, MEG8 served as a sponge for miR-107, lowering binding activity to STAT3 and thus overexpressing the molecule. Taken together, MEG8 induces an imbalance of Th17/Treg cells through the miR-107/STAT3 axis in HSP rats.

The role of murine M1 macrophages from different sources in unilateral ureteral obstruction.

Introduction: The unilateral ureteral obstruction (UUO) model is the most extensively used model to investigate chronic renal fibrosis. Macrophages play a critical role in the UUO model. We aimed to analyze the phenotype of macrophages from different sources activated in vitro and explore the role of M1 macrophages from various sources in UUO. Material and methods: C57BL/6 mice were randomly allocated to five different groups (n = 5 per group): the sham-operated control group, PBS-treated (UUO + PBS) group, bone marrow-derived M1 macrophage-treated (UUO + BM1) group, peritoneal M1 macrophage-treated (UUO + PM1) group, and splenic M1 macrophage-treated (UUO + SPM1) group. After M1 macrophages were injected into the tail vein of UUO-treated mice, renal fibrosis indexes were determined using HE, Masson staining, and α-SMA. Results: Compared to those in the UUO + PBS group, the pathological changes were much more severe in the UUO + BM1, UUO + PM1, and UUO + SPM1 groups. Compared to that in the UUO + PBS group, UUO + BM1 group, and UUO + SPM1 group, the collagen area in the UUO + PM1 group was higher at post-UUO day 5 (p < 0.01). The expression of α-SMA in the UUO + PM1 group was higher than that in the UUO + PBS group, UUO + BM1 group, and UUO + SPM1group (p < 0.001). Conclusions: The M1 macrophages cultured in vitro were reinjected into mice and aggravated kidney injury and fibrosis. Compared with BM1 and SPM1, PM1 demonstrated a stronger effect on inducing renal injury and fibrosis.

Calcium-Sensitive Receptors Alters Intestinal Microbiota Metabolites Especially SCFAs and Ameliorates Intestinal Barrier Damage in Neonatal Rat Endotoxemia.

Purpose: The calcium-sensing receptor (CaSR) acts as a major modulator of tissue responses related to calcium homeostasis and expresses highly in the mammalian intestine. Endotoxemia tends to impair intestinal barrier function and poses significant obstacles in clinical treatment. This work is designed to decipher whether CaSR can protect lipopolysaccharide (LPS)-induced intestinal barrier dysfunction in neonatal rats by targeting intestinal metabolites. Patient and Methods: In this study, we utilized gas chromatography (GC) combined with liquid chromatography-mass spectrometry (LC-MS) to quantitatively analyze SCFAs and metabolites in fecal samples of 24 neonatal rats with LPS induced endotoxemia. Results: Our results showed that CaSR alleviated endotoxin damage to the intestinal tight junction structure and upregulated the levels of butyric acid, propionic acid, valeric acid, and isovaleric acid in short-chain fatty acids (SCFAs). Non-targeted metabolomics analysis indicated that CaSR improved intestinal metabolic disorders by regulating glycerophospholipid metabolism, α-linolenic acid metabolism, as well as sphingolipids metabolism. Conclusion: CaSR can alter intestinal microbiota metabolites, especially SCFAs, and improve intestinal barrier damage in neonatal rat endotoxemia.

A Noise-Based Novel Strategy for Faster SNN Training.

Spiking neural networks (SNNs) are receiving increasing attention due to their low power consumption and strong bioplausibility. Optimization of SNNs is a challenging task. Two main methods, artificial neural network (ANN)-to-SNN conversion and spike-based backpropagation (BP), both have advantages and limitations. ANN-to-SNN conversion requires a long inference time to approximate the accuracy of ANN, thus diminishing the benefits of SNN. With spike-based BP, training high-precision SNNs typically consumes dozens of times more computational resources and time than their ANN counterparts. In this letter, we propose a novel SNN training approach that combines the benefits of the two methods. We first train a single-step SNN(T = 1) by approximating the neural potential distribution with random noise, then convert the single-step SNN(T = 1) to a multistep SNN(T = N) losslessly. The introduction of gaussian distributed noise leads to a significant gain in accuracy after conversion. The results show that our method considerably reduces the training and inference times of SNNs while maintaining their high accuracy. Compared to the previous two methods, ours can reduce training time by 65% to 75% and achieves more than 100 times faster inference speed. We also argue that the neuron model augmented with noise makes it more bioplausible.

Kunxian capsule alleviates podocyte injury and proteinuria by inactivating ß-catenin in db/db mice.

Background: Diabetic kidney disease (DKD) remains the primary cause of end-stage renal disease (ESRD) globally, but treatment options are limited. Kunxian capsule (KXC) has been utilized for the treatment of autoimmune diseases and IgA nephropathy in China. However, its effect on DKD remains poorly investigated. Therefore, this study aimed to explore the protective effect of KXC in db/db mice and elucidate its underlying mechanism. Methods: The renoprotective effects of KXC were assessed in a DKD mouse model using male BKS db/db diabetic mice. After 8 weeks of treatment, the urinary albumin-to-creatinine ratio (UACR), blood biochemical parameters, renal histopathological manifestation, and podocyte ultrastructural changes were evaluated. Additionally, the expression of podocyte epithelial-to-mesenchymal transition (EMT) markers [WT1, ZO-1, and collogen I (Col1a1)] was quantitatively analyzed. Furthermore, we explored the role of KXC in the ß-catenin signaling pathway to elucidate the underlying mechanism of KXC's renoprotective effect. Results: KXC treatment effectively reduced albuminuria and attenuated renal structural abnormalities in db/db mice. Additionally, KXC restored the protein and mRNA expression of WT1 and ZO-1 while suppressing the expression of Col1a1 in db/db mice, indicating its ability to alleviate podocyte EMT. Mechanistically, KXC exerted a significant suppressive effect on the activation of ß-catenin signaling in diabetic kidneys. Conclusion: KXC has the potential to protect podocytes during DKD by alleviating podocyte EMT through inactivating ß-catenin signaling.

LncRNA CRNDE is involved in the pathogenesis of renal fibrosis by regulating renal epithelial cell mesenchymal-epithelial transition via targeting miR-29a-3p.

Results of previous studies suggested that renal fibrosis and epithelial-mesenchymal transition (EMT) plays an important role in the process of renal fibrosis, but the underlying mechanism remains unclear. Long coding RNA (lncRNA) CRNDE has emerged as potent regulators of EMT programs, therefore, in present work, we examined the roles of LncRNA CRNDE/miR-29a-3p axis in renal fibrosis and the underlying mechanism. We found that in both renal fibrosis animal and cell models, lncRNA CRNDE was dynamically upregulated in animal models or cells by the treatment of TGF-ß. Furthermore, knockdown of CRNDE to rat significantly inhibited EMT, prevented renal fibrosis. Finally, CRNDE regulates renal fibrosis through suppression of miR-29a-3p expression. Together, our results demonstrated that CRNDE acted as a regulator of renal fibrosis via targeting miR-29a-3p. Our findings may provide a potential therapeutic target for the treatment of renal fibrosis.

Knockdown of AK142426 suppresses M2 macrophage polarization and inflammation in peritoneal fibrosis via binding to c-Jun.

BACKGROUND: Peritoneal fibrosis is a common complication of peritoneal dialysis, which may lead to ultrafiltration failure and ultimately treatment discontinuation. LncRNAs participate in many biological processes during tumorigenesis. We investigated the role of AK142426 in peritoneal fibrosis. METHODS: The AK142426 level in peritoneal dialysis (PD) fluid was detected by quantitative real-time-PCR assay. The M2 macrophage distribution was determined by flow cytometry. The inflammatory cytokines of TNF-α and TGF-ß1 were measured by ELISA assay. The direct interaction between AK142426 and c-Jun was evaluated by RNA pull-down assay. In addition, the c-Jun and fibrosis related proteins were assessed by western blot analysis. RESULTS: The PD-induced peritoneal fibrosis mouse model was successfully established. More importantly, PD treatment induced M2 macrophage polarization and the inflammation in PD fluid, which might be associated with exosome transmission. Fortunately, AK142426 was observed to be upregulated in PD fluid. Mechanically, knockdown of AK142426 suppressed M2 macrophage polarization and inflammation. Furthermore, AK142426 could upregulate c-Jun through binding c-Jun protein. In rescue experiments, overexpression of c-Jun could partially abolish the inhibitory effect of sh-AK142426 on the activation of M2 macrophages and inflammation. Consistently, knockdown of AK142426 alleviated peritoneal fibrosis in vivo. CONCLUSIONS: This study demonstrated that knockdown of AK142426 suppressed M2 macrophage polarization and inflammation in peritoneal fibrosis via binding to c-Jun, suggesting that AK142426 might be a promising therapeutic target for patients of peritoneal fibrosis.

Case Report: A case of multisystem inflammatory syndrome in an 11-year-old female after COVID-19 inactivated vaccine.

Background: Multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory, multisystem syndrome temporally associated with SARS-CoV-2, is a rare but serious complication of SARS-CoV-2 infection in children that typically occurs 2-6 weeks after SARS-CoV-2 infection. The pathophysiology of MIS-C is unknown. MIS-C, first recognized in April 2020, is characterized by fever, systemic inflammation, and multi-system organ involvement. Post-vaccination adverse effects have increased with COVID-19 vaccinations, and MIS linked to immunization with COVID-19 vaccines has also been observed. Case Report: An 11-year-old Chinese girl presented with a high-grade fever, rash, and dry cough for 2 days. She had her 2nd SARS-CoV-2 inactivated vaccination dose five days before hospital admission. On day 3 & 4, she experienced bilateral conjunctivitis, hypotension (66/47 mmHg), and a high CRP level. She was diagnosed with MIS-C. The patient's condition deteriorated rapidly, necessitating intensive care unit admission. The patient's symptoms improved after intravenous immunoglobulin, methylprednisolone, and oral aspirin therapy. She was discharged from the hospital after 16 days as her general condition, and laboratory biomarkers returned to normal. Conclusion: Inactivated Covid-19 vaccination might trigger MIS-C. Further research is needed to evaluate whether a correlation exists between COVID-19 vaccination and MIS-C development.

Functional Characterization of Renal Tubular Epithelial Cells in Optimized Coculture Systems.

BACKGROUND: Obtaining sufficient renal tubular epithelial cells (RTCs) and maintaining the functions of RTCs are vital for developing a bioartificial renal tubule-assisted device for continuous renal replacement therapy. METHODS: We established an optimal Transwell coculture system using human primary renal proximal tubule epithelial cells (RPTECs) and bone marrow mesenchymal stem cells at different cell ratios to investigate morphological and functional changes in RTCs. Changes in cell proliferation, megalin expression, cell cycle, apoptosis, and levels of insulin-like growth factor-1 (IGF-1) and bone morphogenetic protein-7 (BMP-7) after cell culture were investigated. RESULTS: RPTEC/BMMSC coculture at a cell ratio of 3:1 resulted in optimal morphology, function, and growth of RPTECs, in which, viability, proliferation, cytochrome P450 activity, and megalin expression in RPTECs were significantly increased compared to those in other cocultures or RPTECs alone. Additionally, IGF-1 and BMP-7 levels were significantly higher in the 3:1 RPTEC/BMMSC coculture than in the RPTECs alone. CONCLUSION: Our results demonstrate that coculture with RPTECs has great potential for use in renal replacement therapy, thereby providing fundamental information for manufacturing a bioartificial kidney.

Gut microbiota involved in myocardial dysfunction induced by sepsis.

Myocardial dysfunction is an important complication of sepsis and an important cause of death in sepsis patients. Sepsis will significantly change the composition of gut microbiota, and the destruction of gut microbiota also creates conditions for the occurrence and progression of sepsis. Gut microbiota is an important player in myocardial injury in sepsis. This review elaborates on the possible mechanisms of gut microbiota affecting myocardial injury in sepsis, including short-chain fatty acids, trimethylamine and trimethylamine oxides, various cytokines, and mitochondrial dysfunction. A better understanding of the mechanism could help improve the treatment of sepsis and get a better prognosis for sepsis patients.

Calcium-sensing receptor alleviates gut damage caused by endotoxemia by regulating gut microbiota.

Background: Growing evidence points to an association between the gut microbiota and neonatal diseases. Calcium-sensing receptor (CaSR) is a major modulator of tissue responses associated with calcium homeostasis and is highly expressed in the mammalian gut. CaSR may affect the composition and balance of the intestinal microenvironment. Methods: Neonatal rats were randomized to the control, lipopolysaccharide (LPS), CaSR agonist, and CaSR inhibitor groups. The intestinal contents of neonatal rats were collected within 24 hours or 7 days after intervention. Then, 16S rRNA short amplicon sequencing was used to analyze biological information and the richness and diversity of individual taxa. Results: LPS aggravated intestinal injury. The CaSR agonist alleviated injury, and the inhibitor further enhance intestinal injury. Activation of CaSR enhanced the diversity of the gut microbiota and the abundance of Lactobacillus. The lowest abundance of Firmicutes and the highest abundance of Bacteroidetes were found in the agonist group. CaSR impacted the bacterial species in rats with endotoxemia, and Akkermansia had the greatest effect on the differences among groups. Conclusions: Activation of CaSRs could enhance the species richness and ß-diversity of the gut microbiota and alter the abundance of many taxa. This could attenuate LPS-induced gut injury by modulating the gut microbiota.

The identification of the key residues E829 and R845 involved in transient receptor potential melastatin 2 channel gating.

Transient receptor potential melastatin 2 (TRPM2), a non-selective cation channel, is involved in many physiological and pathological processes, including temperature sensing, synaptic plasticity regulation, and neurodegenerative diseases. However, the gating mechanism of TRPM2 channel is complex, which hinders its functional research. With the discovery of the Ca2+ binding site in the S2-S3 domain of TRPM2 channel, more and more attention has been drawn to the role of the transmembrane segments in channel gating. In this study, we focused on the D820-F867 segment around the S2 domain, and identified the key residues on it. Functional assays of the deletion mutants displayed that the deletions of D820-W835 and L836-P851 destroyed channel function totally, indicating the importance of these two segments. Sequence alignments on them found three polar and charged residues with high conservation (D820, E829, and R845). D820A, E829A, and R845A which removed the charge and the side chain of the residues were tested by 500 µM adenosine diphosphate-ribose (ADPR) or 50 mM Ca2+. E829A and R845A affected the characteristic of channel currents, while D820A behaved similarly to WT, indicating the participations of E829 and R845 in channel gating. The charge reversing mutants, E829K and R845D were then constructed and the electrophysiological tests showed that E829A and E829K made the channel lose function. Interestingly, R845A and R845D exhibited an inactivation process when using 500 µM ADPR, but activated normally by 50 mM Ca2+. Our data suggested that the negative charge at E829 took a vital part in channel activation, and R845 increased the stability of the Ca2+ combination in S2-S3 domain, thus guaranteeing the opening of TRPM2 channel. In summary, our identification of the key residues E829 and R845 in the transmembrane segments of TRPM2. By exploring the gating process of TRPM2 channel, our work helps us better understand the mechanism of TRPM2 as a potential biomarker in neurodegenerative diseases, and provides a new approach for the prediction, diagnosis, and prognosis of neurodegenerative diseases.

Suppressing the polarization aberrations by combining reflection and refraction optical groups.

Polarization remote sensing technology expands the dimensions of the target and enriches its basic information over traditional remote sensing methods. During the imaging process, polarization imaging changes the polarization information of the target by the modulation of the optical system, affecting the detection accuracy. We term the modulation of the polarization state of light by an optical system as polarization aberration, and we found that a lens group combined with mirrors is beneficial in suppressing polarization aberrations. This study analyzed the principles of suppression and the polarization aberration of the optical system before and after suppression. Simulation results show that the diattenuation's average value is reduced by 51.1% and the retardance's average value is reduced by 26.3% after suppression. The corrected polarization cross-coupled energy is reduced by 73.18% in the central field of view and by 69.80% in the fringe field of view. Adding a lens group also effectively suppresses traditional aberrations and expands the field of view.