Spatially confined CuFe2O4 nanosphere in N/O-codoped porous carbon mimetics for triple-mode sensing of antibiotics and visual detection of neurotransmitters in biofluids.

BACKGROUND: Carbon-based nanozymes have recently received enormous concern, however, there is still a huge challenge for inexpensive and large-scale synthesis of magnetic carbon-based "Two-in-One" mimics with both peroxidase (POD)-like and laccase-like activities, especially their potential applications in multi-mode sensing of antibiotics and neurotransmitters in biofluids. Although some progresses have been made in this field, the feasibility of biomass-derived carbon materials with both POD-like and laccase-like activities by polyatomic doping strategy is still unclear. In addition, multi-mode sensing platform can provide a more reliable result because of the self-validation, self-correction and mutual agreement. Nevertheless, the use of magnetic carbon-based nanozyme sensors for the multi-mode detection of antibiotics and neurotransmitters have not been investigated. RESULTS: We herein report a shrimp shell-derived N, O-codoped porous carbon confined magnetic CuFe2O4 nanosphere with outstanding laccase-like and POD-like activities for triple-mode sensing of antibiotic d-penicillamine (D-PA) and chloramphenicol (CPL), as well as colorimetric detection of neurotransmitters in biofluids. The magnetic CuFe2O4/N, O-codoped porous carbon (MCNPC) armored mimetics was successfully fabricated using a combined in-situ coordination and high-temperature crystallization method. The synthesized MCNPC composite with superior POD-like activity can be used for colorimetric/temperature/smartphone-based triple-mode detection of D-PA and CPL in goat serum. Importantly, the MCNPC nanozyme can also be used for colorimetric analysis of dopamine and epinephrine in human urine. SIGNIFICANCE: This work not only offered a novel strategy to large-scale, cheap synthesize magnetic carbon-based "Two-in-One" armored mimetics, but also established the highly sensitive and selective platforms for triple-mode monitoring D-PA and CPL, as well as colorimetric analysis of neurotransmitters in biofluids without any tanglesome sample pretreatment.

Arabidopsis PDLP7 modulated plasmodesmata function is related to BG10-dependent glucosidase activity required for callose degradation.

The microdomains of plasmodesmata, specialized cell-wall channels responsible for communications between neighboring cells, are composed of various plasmodesmata-located proteins (PDLPs) and lipids. Here, we found that, among all PDLP or homologous proteins in Arabidopsis thaliana genome, PDLP5 and PDLP7 possessed a C-terminal sphingolipid-binding motif, with the latter being the only member that was significantly upregulated upon turnip mosaic virus and cucumber mosaic virus infections. pdlp7 mutant plants exhibited significantly reduced callose deposition, larger plasmodesmata diameters, and faster viral transmission. These plants exhibited increased glucosidase activity but no change in callose synthase activity. PDLP7 interacted specifically with glucan endo-1,3-ß-glucosidase 10 (BG10). Consistently, higher levels of callose deposition and slower virus transmission in bg10 mutants were observed. The interaction between PDLP7 and BG10 was found to depend on the presence of the Gnk2-homologous 1 (GnK2-1) domain at the N terminus of PDLP7 with Asp-35, Cys-42, Gln-44, and Leu-116 being essential. In vitro supplementation of callose was able to change the conformation of the GnK2-1 domain. Our data suggest that the GnK2-1 domain of PDLP7, in conjunction with callose and BG10, plays a key role in plasmodesmata opening and closure, which is necessary for intercellular movement of various molecules.

NLRX1 Inhibits LPS-Induced Microglial Death via Inducing p62-Dependent HO-1 Expression, Inhibiting MLKL and Activating PARP-1.

The activation of microglia and the production of cytokines are key factors contributing to progressive neurodegeneration. Despite the well-recognized neuronal programmed cell death regulated by microglial activation, the death of microglia themselves is less investigated. Nucleotide-binding oligomerization domain, leucine-rich repeat-containing X1 (NLRX1) functions as a scaffolding protein and is involved in various central nervous system diseases. In this study, we used the SM826 microglial cells to understand the role of NLRX1 in lipopolysaccharide (LPS)-induced cell death. We found LPS-induced cell death is blocked by necrostatin-1 and zVAD. Meanwhile, LPS can activate poly (ADP-ribose) polymerase-1 (PARP-1) to reduce DNA damage and induce heme oxygenase (HO)-1 expression to counteract cell death. NLRX1 silencing and PARP-1 inhibition by olaparib enhance LPS-induced SM826 microglial cell death in an additive manner. Less PARylation and higher DNA damage are observed in NLRX1-silencing cells. Moreover, LPS-induced HO-1 gene and protein expression through the p62-Keap1-Nrf2 axis are attenuated by NLRX1 silencing. In addition, the Nrf2-mediated positive feedback regulation of p62 is accordingly reduced by NLRX1 silencing. Of note, NLRX1 silencing does not affect LPS-induced cellular reactive oxygen species (ROS) production but increases mixed lineage kinase domain-like pseudokinase (MLKL) activation and cell necroptosis. In addition, NLRX1 silencing blocks bafilomycin A1-induced PARP-1 activation. Taken together, for the first time, we demonstrate the role of NLRX1 in protecting microglia from LPS-induced cell death. The underlying protective mechanisms of NLRX1 include upregulating LPS-induced HO-1 expression via Nrf2-dependent p62 expression and downstream Keap1-Nrf2 axis, mediating PARP-1 activation for DNA repair via ROS- and autophagy-independent pathway, and reducing MLKL activation.

[Coordinated Control of Carbon Emission Reduction and Air Quality Improvement in the Industrial Sector in Hunan Province].

Climate warming and air pollution are the main environmental problems in China. This study used China's Carbon Accounting Database, energy economic model, and air quality model to analyze the potential carbon emission peaking path and synergistic air quality improvement gain in the industrial sector in Hunan Province. Based on China's Carbon Accounting Database and the local industry/energy statistical yearbooks in Hunan, the total CO2 emissions in Hunan Province in 2019 were 310.6 Mt, of which the industrial sector accounted for over 70% of the emissions, mainly from the production and supply of electricity, steam, and heat; the production of non-metallic minerals; and the smelting and pressing of ferrous metals. Three potential industrial carbon emission peaking scenarios were analyzed using the LEAP energy economic model, including the business-as-usual scenario (peaking by 2030), moderate emission reduction scenario (peaking by 2028), and aggressive emission reduction scenario (peaking by 2025), by employing different economic growth rates, energy technology progress, and energy structures of the industrial sector. Furthermore, by combining the anthropogenic air pollutant emission inventory and the regional air quality model WRF-Chem, we analyzed the air quality improvement associated with various carbon emission peak paths. The results showed that the annual mean concentrations of major air pollutants had decreased in the three scenarios, especially in the Chang-Zhu-Tan Region. The aggressive emission reduction scenario was the most effective scenario, followed by the moderate emission reduction scenario and the business-as-usual scenario. Manufacturing was the sector with the most significant synergistic effect of pollution and carbon reduction. When carbon emission peaks were achieved, the annual average concentrations of PM2.5 and PM10 in Hunan Province could be synergistically reduced by 0.6-1.8 µg·m-3 and 1.8-8.9 µg·m-3, respectively. Our findings offer important insights into carbon emission peaking and can provide useful information for potential mitigation actions.

CASK Mediates Oxidative Stress-Induced Microglial Apoptosis-Inducing Factor-Independent Parthanatos Cell Death via Promoting PARP-1 Hyperactivation and Mitochondrial Dysfunction.

Calcium/calmodulin-dependent serine protein kinase (CASK) is a scaffold protein and plays critical roles in neuronal synaptic formation and brain development. Previously, CASK was shown to associate with EGFR to maintain the vulval cell differentiation in C. elegans. In this study, we explored the role of CASK in CHME3 microglial cells. We found that CASK silencing protects cells from H2O2-induced cell death by attenuating PARP-1 activation, mitochondrial membrane potential loss, reactive oxygen species production, and mitochondrial fission, but it increases oxidative phosphorylation. The PARP-1 inhibitor olaparib blocks H2O2-induced cell death, suggesting the death mode of parthanatos. CASK silencing also increases AKT activation but decreases AMPK activation under H2O2 treatment. Pharmacological data further indicate that both signaling changes contribute to cell protection. Different from the canonical parthanatos pathway, we did not observe the AIF translocation from mitochondria into the nucleus, suggesting a non-canonical AIF-independent parthanatos in H2O2-treated CHME3 cells. Moreover, we found that CASK silencing upregulates the EGFR gene and protein expression and increases H2O2-induced EGFR phosphorylation in CHME3 microglia. However, EGFR activation does not contribute to cell protection caused by CASK silencing. In conclusion, CASK plays a crucial role in microglial parthanatos upon H2O2 treatment via stimulation of PARP-1 and AMPK but the inhibition of AKT. These findings suggest that CASK might be an ideal therapeutic target for CNS disorders.

[Analysis of the Efficacy and Prognosis Factors of Acute Myeloid Leukemia with a Combination Therapy of Venetoclax].

OBJECTIVE: To explore the efficacy and prognosis factors of acute myeloid leukemia with a combination therapy of venetoclax. METHODS: A retrospective analysis was performed on the clinical data of AML patients treated with a combination therapy of venetoclax from March 2020 to April 2023 in the First Hospital of Lanzhou University. The efficacy, adverse reactions and survival were observed, and the influencing factors were analyzed. RESULTS: A total of 74 AML patients were included in this study, including 43 initially treated AML and 31 relapsed or refractory AML (R/R AML). The median age of 43 initially treated AML patients was 65 years old, the composite complete remission (cCR) rate was 67.4% (29/43), the objective response rate (ORR) was 72.1% (31/43), and the median overall survival (OS) was 17.3 months. The median age of 31 R/R AML patients was 51 years old, with a cCR rate of 38.7% (12/31), an ORR of 58.1% (18/31), and a median OS of 7.1 months. Sex, the blood cell count before VEN, gene mutation and prognosis stratification were related to whether to obtain cCR. Failure to obtain cCR was an independent risk factor for adverse outcomes. CONCLUSION: A combination therapy of venetoclax is safe and efficacious for AML. Its efficacy and survival are affected by molecular biology, cytogenetics and other factors.

[The Correlation of Gene Mutation and Clinical Characteristics in Patients with Myelodysplastic Syndrome and Prognostic Analysis].

OBJECTIVE: To explore the correlation between gene mutations and clinical characteristics, prognosis of myelodysplastic syndromes (MDS). METHODS: Clinical data of 131 patients with MDS were collected from the First Hospital of Lanzhou University from June 2015 to February 2023, which 19 of them developed into secondary acute myeloid leukemia (sAML) during follow-up time. Second generation sequencing technology was used to detect the mutation types of MDS disease-related genes, drawn gene maps, and analyzed their correlation and prognosis based on the clinical data of patients. RESULTS: The median age of 131 MDS patients was 58(17-86) years old. The ratio of male to female was 1.3∶1. A total of 148 gene mutations and 25 types were found in the center. U2AF1 and ASXL1 were often co-mutations with other genes, which were accompanied by 20q- and normal karyotype (NK) respectively. SETBP1 and SRSF2 were more common in patients over 60 years old, while NPM1 and WT1 under 60 years. Older patients had a higher the number of genetic mutations than younger patients. The incidence of SF3B1 and RUNX1 in males was higher than females and DNMT3A in females was higher than males. The number of gene mutations in sAML was higher than MDS (1.8 vs 1.0, P =0.006). The univariate and multivariate analysis showed that IPSS-R prognostic score≥3.5, TP53 were adverse factors for poor prognosis in MDS patients. Patients with monoallelic mutation（ma-TP53）and wild-type（wt-TP53） TP53 had OS better than biallelic mutation（bi-TP53）(P =0.003). The OS of MDS patients was better than sAML(P =0.01) and transplant patients was significantly better than nontransplant patients(P =0.036). CONCLUSION: Gene mutation is closely related to cytogenetic indexes and clinical features (peripheral blood cell count, sex, age). IPSS-R prognostic score and TP53 were risk factors affecting OS in MDS patients.

Perioperative corticosteroids for reducing postoperative complications following esophagectomy: an updated systematic review and meta-analysis.

BACKGROUND: This updated systematic review and meta-analysis aims to evaluate the efficacy and safety of perioperative corticosteroid administration versus placebo for esophageal cancer patients following scheduled esophagectomy. METHODS: We searched databases through June 30, 2023. We included articles on randomized controlled trials (RCTs) comparing perioperative corticosteroid administration with placebo in esophageal cancer patients with esophagectomy. The outcomes were the death rate during hospitalization, length of hospital stay, and short-term complications. Risk ratios (RRs) and corresponding 95% confidence interval (CIs) for each estimated effect size were applied for dichotomous outcomes, and the mean difference (MD) and corresponding 95% CIs for each estimated effect size were applied for continuous outcomes. We used GRADE to evaluate the quality of each of the outcome and the level of recommendations. RESULTS: Nine RCTs with 508 participants were included in this study. Severe outcomes, including the length of hospital stay, leakage, mortality during the hospitalization period in the corticosteroid group was comparable to that in the control group, but positive effects of corticosteroid administration were observed on the length of intensive care unit stay (MD -3.1, 95% CI - 5.43 to - 0.77), cardiovascular disorders (RR 0.44, 95% CI 0.21-0.94) and other general complications (RR 0.49, 95% CI 0.29-0.85). CONCLUSIONS: Peri-operative intravenous corticosteroid administration may reduce cardiovascular disorders, other general complications and the length of ICU stay without carrying severe outcomes. More high quality RCTs are warranted to further investigate the effects of corticosteroids on postoperative mortality and complications for esophageal cancer patients with esophagectomy. SYSTEMATIC REVIEW REGISTRATION: Cochrane, registration number: 196.

Development of A Nomogram for Progression-free Survival in Patients with Stage II/T3N0 Nasopharyngeal Carcinoma to Explore Different Treatment Modalities.

Purpose To explore the prognostic value of clinical and serological risk factors for progression-free survival (PFS) in stage II and T3N0 nasopharyngeal carcinoma (NPC) and construct a nomogram based on these factors. Additionally, to investigate the long-term survival and short-term toxic reactions of patients in different risk stratification under different treatment modalities. Methods The patients were randomly divided into training and validation cohorts in a 7:3 ratio. Independent prognostic factors were identified using Cox regression analysis, and a nomogram was constructed by combining these predictive factors with the TNM staging system. The nomogram was then validated in the validation cohort, and patients were classified into different risk groups based on the nomogram. The PFS, overall survival (OS), and acute toxicities were compared among different treatment modalities after balancing baseline characteristics. Results Multivariate Cox regression analysis indicated that pathological type, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were independent prognostic factors(p<0.05) in this study. The nomogram showed good prognostic accuracy in both the training and validation cohorts (C-index of 0.73 and 0.70, respectively). In the different risk subgroups, there were no statistically significant differences in PFS and OS between radiotherapy and chemoradiotherapy groups(p>0.05). The treatment modality of combined chemotherapy was associated with more acute toxic reactions. Conclusion We established and validated a nomogram for predicting PFS in patients with stage II/T3N0 NPC. Intensity-modulated radiation therapy (IMRT) combined with chemotherapy did not provide additional survival benefits for these patients and was associated with more chemotherapy-related side effects.

Spatiotemporal roles of AMPK in PARP-1- and autophagy-dependent retinal pigment epithelial cell death caused by UVA.

BACKGROUND: Although stimulating autophagy caused by UV has been widely demonstrated in skin cells to exert cell protection, it remains unknown the cellular events in UVA-treated retinal pigment epithelial (RPE) cells. METHODS: Human ARPE-19 cells were used to measure cell viability, mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP), mitochondrial mass and lysosomal mass by flow cytometry. Mitochondrial oxygen consumption rate (OCR) was recorded using Seahorse XF flux analyzer. Confocal microscopic images were performed to indicate the mitochondrial dynamics, LC3 level, and AMPK translocation after UVA irradiation. RESULTS: We confirmed mitochondrial ROS production and DNA damage are two major features caused by UVA. We found the cell death is prevented by autophagy inhibitor 3-methyladenine and gene silencing of ATG5, and UVA induces ROS-dependent LC3II expression, LC3 punctate and TFEB expression, suggesting the autophagic death in the UVA-stressed RPE cells. Although PARP-1 inhibitor olaparib increases DNA damage, ROS production, and cell death, it also blocks AMPK activation caused by UVA. Interestingly we found a dramatic nuclear export of AMPK upon UVA irradiation which is blocked by N-acetylcysteine and olaparib. In addition, UVA exposure gradually decreases lysosomal mass and inhibits cathepsin B activity at late phase due to lysosomal dysfunction. Nevertheless, cathepsin B inhibitor, CA-074Me, reverses the death extent, suggesting the contribution of cathepsin B in the death pathway. When examining the role of EGFR in cellular events caused by UVA, we found that UVA can rapidly transactivate EGFR, and treatment with EGFR TKIs (gefitinib and afatinib) enhances the cell death accompanied by the increased LC3II formation, ROS production, loss of MMP and mass of mitochondria and lysosomes. Although AMPK activation by ROS-PARP-1 mediates autophagic cell death, we surprisingly found that pretreatment of cells with AMPK activators (A769662 and metformin) reverses cell death. Concomitantly, both agents block UVA-induced mitochondrial ROS production, autophagic flux, and mitochondrial fission without changing the inhibition of cathepsin B. CONCLUSION: UVA exposure rapidly induces ROS-PARP-1-AMPK-autophagic flux and late lysosomal dysfunction. Pre-inducing AMPK activation can prevent cellular events caused by UVA and provide a new protective strategy in photo-oxidative stress and photo-retinopathy.

A novel intronic variant in ROBO3 associated with horizontal gaze palsy with progressive scoliosis: case report and literature review.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, autosomal recessive inherited disorder caused by mutations in ROBO3 gene. The clinical features of HGPPS include horizontal gaze palsy, progressive scoliosis, other oculomotor abnormalities such as strabismus and nystagmus. Whole-exome sequencing (WES) is used to diagnose rare Mendelian disorders, when routine standard tests have failed to make a formal pathological diagnosis. However, WES may identify variants of uncertain significance (VUS) that may add further ambiguity to the diagnosis. We report the case of a 4-year-old boy with horizontal gaze palsy, progressive scoliosis, microcephaly, and mild developmental delay. WES identified an intronic VUS in ROBO3 gene. We performed minigene splicing functional analysis to confirm the pathogenicity of this VUS. This report illustrates that WES data analysis with supportive functional analysis provides an effective approach to improve the diagnostic yield for unsolved clinical cases. This case also highlights the phenotypic heterogeneity in patients with HGPPS.

Prognostic estimation for acute ischemic stroke patients undergoing mechanical thrombectomy within an extended therapeutic window using an interpretable machine learning model.

Background: Mechanical thrombectomy (MT) is effective for acute ischemic stroke with large vessel occlusion (AIS-LVO) within an extended therapeutic window. However, successful reperfusion does not guarantee positive prognosis, with around 40-50% of cases yielding favorable outcomes. Preoperative prediction of patient outcomes is essential to identify those who may benefit from MT. Although machine learning (ML) has shown promise in handling variables with non-linear relationships in prediction models, its "black box" nature and the absence of ML models for extended-window MT prognosis remain limitations. Objective: This study aimed to establish and select the optimal model for predicting extended-window MT outcomes, with the Shapley additive explanation (SHAP) approach used to enhance the interpretability of the selected model. Methods: A retrospective analysis was conducted on 260 AIS-LVO patients undergoing extended-window MT. Selected patients were allocated into training and test sets at a 3:1 ratio following inclusion and exclusion criteria. Four ML classifiers and one logistic regression (Logit) model were constructed using pre-treatment variables from the training set. The optimal model was selected through comparative validation, with key features interpreted using the SHAP approach. The effectiveness of the chosen model was further evaluated using the test set. Results: Of the 212 selected patients, 159 comprised the training and 53 the test sets. Extreme gradient boosting (XGBoost) showed the highest discrimination with an area under the curve (AUC) of 0.93 during validation, and maintained an AUC of 0.77 during testing. SHAP analysis identified ischemic core volume, baseline NHISS score, ischemic penumbra volume, ASPECTS, and patient age as the top five determinants of outcome prediction. Conclusion: XGBoost emerged as the most effective for predicting the prognosis of AIS-LVO patients undergoing MT within the extended therapeutic window. SHAP interpretation improved its clinical confidence, paving the way for ML in clinical decision-making.

Electron density effect of aromatic carboxylic acids in naphthalenediimide-based coordination polymers: from thermal electron transfer and charge transfer to photoinduced electron transfer.

Various naphthalenediimide (NDI) based electron donor-acceptor coordination polymers (D-A CPs) have been constructed and used to explore charge transfer (CT) and electron transfer (ET) behaviors. Up to now, significant progress has been made in the interface contact and electron donor-acceptor ability matching mechanism, while the electronic density effect of the electron donors on the CT and ET behaviors is still not known. Herein, two NDI-based D-A CPs, [Cd2(H2NDI)(IPA)2(H2O)2] (1) and [Cd2(H2NDI)(IPA-OH)2(H2O)2] (2), are constructed using an NDI-based ligand and two aromatic carboxylic acid ligands (H2NDI = 2,7-bis(3,5-dimethyl) dipyrazol-1,4,5,8-naphthalene tetracarboxydiimide, H2IPA = isophthalic acid; and H2IPA-OH = 5-hydroxyisophthalic acid). UV-vis and EPR spectroscopy and DFT calculations analyses reveal that the occurrence of themal electron transfer (TET) in 1 and 2 results from the HOMO of the IPA and IPA-OH lying higher than the LUMO of the NDI. Meanwhile, compared to 1, the UV-vis absorption spectrum of 2 exhibits a significant red shift, which suggests higher electron density of the donor and more electron transfer pathways are beneficial for the occurrence of intermolecular CT. After UV light irradiation, the comparison of the photochromic behavior of 1 and 2 confirms the negative effect of the stronger CT on photoinduced electron transfer (PET). The present study illustrates the delicate modulating effect of electron density on the CT and ET behaviors in D-A CPs.

[Effect of Carbon Dioxide Emission Reduction Policy on Air Quality Improvement in Jiangsu Province].

Carbon emission peaking and air quality improvement is an urgent issue in the research of the atmospheric environment. Here, the emission factor method was used to compile the city-level greenhouse gas emission inventory of Jiangsu Province from 2010 to 2019, which was then combined with greenhouse gas-air pollutant synergy analysis and WRF-Chem air quality model simulation to analyze the synergistic gain of air quality improvement under different carbon emission reduction scenarios. The results revealed that the annual mean CO2 emission in Jiangsu Province from 2010 to 2019 was 701.74-897.47 Mt. Suzhou, Xuzhou, and Nanjing had the highest emissions (91.19-182.12 Mt·a-1); Yangzhou, Suqian, and Lianyungang had the lowest emissions (13.19-32.54 Mt·a-1); and majority of the cities had a continuous upward trend in the CO2 emissions. Energy activities were the main source of CO2 emissions, accounting for nearly 90%, whereas industrial production processes contributed to the remaining 10%. This study designed three types of CO2 emission reduction conditions according to different emission reduction priorities, namely, sector-wide collaborative, energy priority, and industrial priority. Each type of emission reduction condition included a different intensity of CO2 emission reduction (10%, 20%, and 40%). The condition-based simulation results demonstrated that, taking 2017 as the base year, the average annual decrease in PM2.5 concentration in sector-wide collaborative, energy priority, and industrial priority emission reduction was 6.7-21.1, 3.1-12.0, and 3.4-14.3 µg·m-3, respectively. Sector-wide collaborative emission reduction had the most notable improvement in PM2.5 pollution. Under the condition of the sector-wide collaborative emission reduction of 40%, the average annual PM2.5 concentration of all cities, excluding Xuzhou and Suqian, met the national Ⅱ standard (35 µg·m-3). The change responses of PM10, SO2, NO2, and CO were similar to that of PM2.5, but O3 pollution increased under the conditions of energy and industrial priorities.

Canadian radiology workforce demographics: Results from a national survey.

Rationale and objective: Demographic data collected about Canadian radiologists and trainees has been limited primarily to binary gender and geographic location. The purpose of this study was to investigate: (1) demographic characteristics of Canadian radiologists and trainees; (2) types of diversity important to radiologists; (3) relationship of radiologist demographics to practice characteristics; and (4) relationship of radiologist demographics to years in practice, (YIP). Materials and methods: French and English surveys were distributed via email through radiology associations and social media. Frequency counts of demographic variables were calculated, and chi-square and Fisher's Exact tests were performed to explore the relationships between demographic characteristics and role. Results: 611 individuals responded to the survey. 573 respondents were included in the analysis. 454 (78.8%) were practicing radiologists and 119 (20.7%) were residents/fellows. Half identified as women (50.4%). English was the primary language for most respondents. There was an association between role and sexual orientation (p = 0.02), visible minority (χ2 = 4.79, p < 0.05), religion (χ2 = 4.11, p < 0.05), and having children (χ2 = 136.65, p < 0.05). For radiologists, being a visible minority (χ2 = 11.59, p < 0.05) and age (χ2 = 56.3, p < 0.05) were associated with academic rank while gender (χ2 = 3.83, p < 0.05) and age (χ2 = 13.74, p < 0.05) were related to part-/full-time status. Less women, visible minorities, and women with children had been in practice for long. Discussion: This study represents a comprehensive analysis of Canadian radiology demographics. Results suggest there is increasing diversity among trainees; however, significant demographic underrepresentation compared to the diversity of Canada exists.

Metformin inhibits methylglyoxal-induced retinal pigment epithelial cell death and retinopathy via AMPK-dependent mechanisms: Reversing mitochondrial dysfunction and upregulating glyoxalase 1.

Diabetic retinopathy (DR) is a major cause of blindness in adult, and the accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is a precursor of AGEs. Although the therapeutic potential of metformin for retinopathy disorders has recently been elucidated, possibly through AMPK activation, it remains unknown how metformin directly affects the MGO-induced stress response in retinal pigment epithelial cells. Therefore, in this study, we compared the effects of metformin and the AMPK activator A769662 on MGO-induced DR in mice, as well as evaluated cytotoxicity, mitochondrial dynamic changes and dysfunction in ARPE-19 cells. We found MGO can induce mitochondrial ROS production and mitochondrial membrane potential loss, but reduce cytosolic ROS level in ARPE-19 cells. Although these effects of MGO can be reversed by both metformin and A769662, we demonstrated that reduction of mitochondrial ROS production rather than restoration of cytosolic ROS level contributes to cell protective effects of metformin and A769662. Moreover, MGO inhibits AMPK activity, reduces LC3II accumulation, and suppresses protein and gene expressions of MFN1, PGC-1α and TFAM, leading to mitochondrial fission, inhibition of mitochondrial biogenesis and autophagy. In contrast, these events of MGO were reversed by metformin in an AMPK-dependent manner as evidenced by the effects of compound C and AMPK silencing. In addition, we observed an AMPK-dependent upregulation of glyoxalase 1, a ubiquitous cellular enzyme that participates in the detoxification of MGO. In intravitreal drug-treated mice, we found that AMPK activators can reverse the MGO-induced cotton wool spots, macular edema and retinal damage. Functional, histological and optical coherence tomography analysis support the protective actions of both agents against MGO-elicited retinal damage. Metformin and A769662 via AMPK activation exert a strong protection against MGO-induced retinal pigment epithelial cell death and retinopathy. Therefore, metformin and AMPK activator can be therapeutic agents for DR.

Disparities in Radiologist Fee-For-Service Payments by Gender in Canada.

Objective: To examine differences in fee-for-service (FFS) payments to men and women radiologists in Canada and evaluate potential contributors. Methods: Publicly available FFS radiology billing data was analyzed from British Columbia (BC), Ontario (ON), Prince-Edward Island (PEI) and Nova Scotia (NS) between 2017 and 2021. Data was analyzed by gender on a per-province and national level. Variables evaluated included year, province, procedure billings, and days worked (BC and ON only). The gender pay gap was expressed as the difference in mean billing payments between men and women divided by mean payments to men. Results: Data points from 8478 radiologist years were included (2474 [29%] women and 6004 [71%] men). The unadjusted difference in annual FFS billings between men and women was $126,657. Overall, payments to women were 81% of payments to men with a 19% gender pay gap. The difference in billings between men and women did not change significantly between 2017 and 2021 (range in gender pay gap, 17-21%) but did vary by province (highest gap NS). Compared to men, women worked fewer days per year (weighted mean 218 ± 29 vs 236 ± 25 days/year, P < .001, 8% difference). Conclusion: In an analysis of fee-for-service payments to radiologists in 4 Canadian provinces between 2017 and 2021, payments to women were 81% of payments to men with a 19% gender pay gap. Payments were lower to women across all years evaluated. Women worked 8% fewer days per year on average than men, which did not fully account for the difference in FFS billing payments between men and women. Summary Statement: In an analysis of fee-for-service payments to Canadian radiologists between 2017 and 2021, payments to women were 81% of payments to men with a 19% gender pay gap which is not fully accounted for by time spent working.

Epigenetic upregulation of spleen tyrosine kinase in cancer cells through p53-dependent downregulation of DNA methyltransferase.

Syk is a tumor suppressor gene in some solid tumors. Currently, it remains unknown how Syk gene hypermethylation is controlled by DNA methyltransferase (DNMT) and p53. In colorectal cancer HCT116 cells, we found that protein and mRNA levels of Syk were much higher in WT than in p53-/- cells. Both p53 inhibitor PFT-α and p53 silencing can reduce the protein and mRNA expression of Syk in WT cells, while DNMT inhibitor 5-Aza-2'-dC can increase Syk expression in p53-/- cells. Interestingly, the DNMT expression in p53-/- HCT116 cells was higher than that in WT cells. PFT-α can not only enhance Syk gene methylation but also increase DNMT1 protein and mRNA levels in WT HCT116 cells. In metastatic lung cancer cell lines A549 and PC9, which express WT p53 and gain function of p53, respectively, PFT-α can also downregulate Syk mRNA and protein expression. However, the Syk methylation level was increased by PFT-α in A549 but not in PC9 cells. Likewise, 5-Aza-2'-dC transcriptionally increased Syk gene expression in A549 cells, but not in PC9 cells. In summary methylation of Syk promoter requires DNMT1, and p53 can upregulate Syk expression via downregulation of DNMT1 at the transcriptional level.

Base-Promoted Decarboxylative Annulation of Methyl 2-(2-Bromophenyl)acetates and Ynones to Access Benzoxepines.

A simple and efficient base-mediated decarboxylative annulation of ynones with methyl 2-(2-bromophenyl)acetates has been developed. A broad range of benzoxepines were prepared with a broad substrate scope and high regioselectivity in moderate to excellent yields under transition-metal-free conditions. This method proceeds through a tandem [2 + 4] annulation, ring-opening decarboxylative reaction, and the intramolecular nucleophilic aromatic substitution reaction. Additionally, the key intermediates were successfully obtained and characterized unambiguously by single-crystal X-ray crystallography, which could favorably support a decarboxylative annulation mechanism. Furthermore, gram-scale reaction and synthetic applications for the further functionalization are also studied.

P2X7 Is Involved in the Mouse Retinal Degeneration via the Coordinated Actions in Different Retinal Cell Types.

Adenosine triphosphate (ATP) released from dying cells with high concentrations is sensed as a danger signal by the P2X7 receptor. Sodium iodate (NaIO3) is an oxidative toxic agent, and its retinal toxicity has been used as the model of dry age-related macular degeneration (AMD). In this study, we used NaIO3-treated mice and cultured retinal cells, including BV-2 microglia, 661W photoreceptors, rMC1 Müller cells and ARPE-19 retinal epithelial cells, to understand the pathological action of P2X7 in retinal degeneration. We found that NaIO3 can significantly decrease the photoreceptor function by reducing a-wave and b-wave amplitudes in electroretinogram (ERG) analysis. Optical coherence tomography (OCT) analysis revealed the degeneration of retinal epithelium and ganglion cell layers. Interestingly, P2X7-/- mice were protected from the NaIO3-induced retinopathy and inflammatory NLRP3, IL-1ß and IL-6 gene expression in the retina. Hematoxylin and eosin staining indicated that the retinal epithelium was less deteriorated in P2X7-/- mice compared to the WT group. Although P2X7 was barely detected in 661W, rMC1 and ARPE-19 cells, its gene and protein levels can be increased after NaIO3 treatment, leading to a synergistic cytotoxicity of BzATP [2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate tri(triethyleneammonium)salt] and NaIO3 administration in ARPE-19 cells. In conclusion, the paracrine action of the ATP/P2X7 axis via cell-cell communication is involved in NaIO3-induced retinal injury. Our results show that P2X7 antagonist might be a potential therapy in inflammation-related retinal degeneration.