Oncologic Applications of Artificial Intelligence and Deep Learning Methods in CT Spine Imaging-A Systematic Review.

In spinal oncology, integrating deep learning with computed tomography (CT) imaging has shown promise in enhancing diagnostic accuracy, treatment planning, and patient outcomes. This systematic review synthesizes evidence on artificial intelligence (AI) applications in CT imaging for spinal tumors. A PRISMA-guided search identified 33 studies: 12 (36.4%) focused on detecting spinal malignancies, 11 (33.3%) on classification, 6 (18.2%) on prognostication, 3 (9.1%) on treatment planning, and 1 (3.0%) on both detection and classification. Of the classification studies, 7 (21.2%) used machine learning to distinguish between benign and malignant lesions, 3 (9.1%) evaluated tumor stage or grade, and 2 (6.1%) employed radiomics for biomarker classification. Prognostic studies included three (9.1%) that predicted complications such as pathological fractures and three (9.1%) that predicted treatment outcomes. AI's potential for improving workflow efficiency, aiding decision-making, and reducing complications is discussed, along with its limitations in generalizability, interpretability, and clinical integration. Future directions for AI in spinal oncology are also explored. In conclusion, while AI technologies in CT imaging are promising, further research is necessary to validate their clinical effectiveness and optimize their integration into routine practice.

Extensive Dysregulation of Phenylalanine Metabolism Is Associated With Stress Hyperphenylalaninemia and 30-Day Death in Critically Ill Patients With Acute Decompensated Heart Failure.

BACKGROUND: Stress hyperphenylalaninemia predicts elevated mortality rates in patients with acute decompensated heart failure (ADHF). This study investigated the metabolic pathways underlying this association and identified a unique metabolic phenotype underlying the association between stress hyperphenylalaninemia and adverse outcomes in ADHF. METHODS AND RESULTS: This was a retrospective cohort study. We enrolled 120 patients with ADHF in an intensive care unit (60 with a phenylalanine level ≥112 µM, 60 with a phenylalanine level <112 µM), and 30 controls. Plasma phenylalanine-derived metabolites were measured, and participants were evaluated for 30-day death. Patients with ADHF had extensive activations of the alternative pathways for metabolizing phenylalanine, leading to the levels of phenylalanine-derived downstream metabolites 1.5 to 6.1 times higher in patients with ADHF than in the controls (all P<0.001). Extensive dysregulation of these alternative pathways significantly increased phenylalanine levels and contributed to a distinct metabolic phenotype, characterized by increased phenylalanine, tyrosine, homogentisic acid, and succinylacetone levels but decreased benzoic acid and 3,4-dihydroxyphenylalanine levels. Throughout the 30-day follow-up period, 47 (39.2%) patients died. This distinct metabolic phenotype was associated with an increased mortality rate (odds ratio, 1.59 [95% CI, 1.27-1.99]; P<0.001). A multivariable analysis confirmed the independent association of this metabolic phenotype, in addition to phenylalanine and tyrosine levels, with 30-day death. CONCLUSIONS: In patients with ADHF, extensive dysregulation of the alternative pathways for metabolizing phenylalanine was correlated with stress hyperphenylalaninemia and a distinct metabolic phenotype on the phenylalanine-tyrosine-homogentisic acid-succinylacetone axis. Both stress hyperphenylalaninemia and metabolic dysregulation on this axis were associated with poor outcomes.

Characterization of cross-reactivity of coxsackievirus A2 VP1-specific polyclonal antibodies with enterovirus A71, coxsackievirus A16, and coxsackievirus A6.

Coxsackievirus A2 (CVA2) is associated with multiple diseases in children. Currently, there is limited research on immunological detection methods for CVA2. Herein, the VP1 gene of CVA2 strain 201711, belonging to cluster 2 within genotype D, was analyzed. The structures of VP1 from CVA2 strains 201711, 7-1 and 12-1, enterovirus A71 (EV-A71) strain 201713, coxsackievirus A16 (CVA16) strain 201717, and coxsackievirus A6 (CVA6) strain JLS10 were compared. The Escherichia coli BL21(DE3)/pET vector system was employed to express the recombinant protein containing the entire VP1 of CVA2 strain 201711. Mice were immunized with the purified protein, and the sera were collected and used to specifically identify the VP1 in CVA2-infected RD cells by Western blot and immunofluorescence assay. There was no evident cross-reactivity of the sera with the VP1 of EV-A71, CVA16, and CVA6 strains mentioned above. Therefore, this study provided mouse-specific anti-CVA2 VP1 polyclonal antibodies for CVA2 detection.

Toripalimab plus chemotherapy and radiotherapy for treatment-naive advanced esophageal squamous cell carcinoma: a single-arm phase 2 trial.

This single-arm phase 2 trial (ChiCTR2100046715) examined previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) who received four cycles of paclitaxel with carboplatin every 3 weeks. Toripalimab was infused intravenously every 3 weeks for 12 months, or until disease progression or intolerable toxicity. Radiotherapy that encompassed the primary lesions and metastases commenced in the third cycle. The median progression-free survival time was 9.8 months (95% confidence interval [CI]: 6.8-not estimable) in the intent-to-treat population, failing to meet the pre-specified primary endpoints. Secondary endpoints included an objective response rate of 45.5%, a disease control rate of 57.6%, and a median duration of response of 11.5 months (interquartile range, 6.4-15.0). The 1-year progression-free survival and overall survival rates were 41.9% (95% CI: 27.7-63.5) and 69.7% (95% CI: 55.7-87.3), respectively. Lymphopenia was the most frequent grade ≥3 adverse event (82%), and an esophageal fistula developed in three patients (9.1%). No treatment-related deaths occurred. In prespecified exploratory biomarker analysis, higher densities of CD8 + T cells, CD11c+ dendritic cells, and CD68+ macrophages correlated with improved tumor response and prognosis. Radiotherapy supplementation to first-line chemo-immunotherapy for treatment-naive advanced ESCC demonstrated some antitumor activity and manageable safety profiles, warranting further randomized controlled trials.

Halogen Bonding Initiated Difunctionalization of [1.1.1]Propellane via Photoinduced Polarity Match Additions.

Bicyclo[1.1.1]pentane (BCP), recognized as a bioisostere for para-disubstituted benzene, has gained widespread interest in drug development due to its ability to enhance the physicochemical properties of pharmaceuticals. In this work, we introduce a photoinduced, halogen bonding-initiated, metal-free strategy for synthesizing various BCP derivatives. This method involves the generation of nucleophilic α-aminoalkyl radicals via halogen-bonding adducts. These undergo selective radical addition to [1.1.1]propellane, yielding electrophilic BCP radicals that subsequently participate in polarity-matched additions, culminating in the difunctionalization of bicyclopentane. The versatility and practicality of this metal-free approach are underscored by its broad substrate scope, which includes late-stage functionalization and a series of valuable transformations, all conducted under mild reaction conditions.

Overlapping peri-implantation phenotypes of ZNHIT1 and ZNHIT2 despite distinct functions during early mouse development.

Mammalian preimplantation development culminates in the formation of a blastocyst which undergoes extensive gene expression regulation to successfully implant into the maternal endometrium. Zinc-finger HIT domain-containing (ZNHIT) 1 and 2 are members of a highly conserved family, yet they have been identified as subunits of distinct complexes. Here we report that knockout of either Znhit1 or Znhit2 results in embryonic lethality during peri-implantation stages. Znhit1 and Znhit2 mutant embryos have overlapping phenotypes, including reduced proportion of SOX2-positive ICM cells, a lack of Fgf4 expression and aberrant expression of NANOG and SOX17. Furthermore, we find that the similar phenotypes are caused by distinct mechanisms. Specifically, embryos lacking ZNHIT1 likely fail to incorporate sufficient H2A.Z at the promoter region of Fgf4 and other genes involved in cell projection organization resulting in impaired invasion of trophoblast cells during implantation. In contrast, Znhit2 mutant embryos display a complete lack of nuclear EFTUD2, a key component of U5 spliceosome, indicating a global splicing deficiency. Our findings unveil the indispensable yet distinct roles of ZNHIT1 and ZNHIT2 in early mammalian embryonic development.

Study on the sensitizing effect of SM-1 combined with irradiation on head and neck squamous cell carcinoma.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is globally prevalent with high recurrence, low survival rate, and poor quality of life for patients. Derived from PAC-1, SM-1 can activate procaspase-3 and induce apoptosis in cancer cells to exert anti-tumor effects. However, the inhibitory effect of SM-1 on HNSCC after combination with radiation are unclear. This study aims to investigate the radiosensitizing effect of SM-1 on HNSCC in vitro and in vivo. METHODS: MTT method was used to detect the effect of SM-1 on the viability of HNSCC cell lines (HONE1, HSC-2, and CAL27). The effects of SM-1 combined with radiation on the survival index of HONE1, HSC-2, and CAL27 cell lines were determined by colony formation assay. Flow cytometry was used to investigate the effects of SM-1 and radiation combination on cell apoptosis and cell cycle, and western blot experiments were performed to detect the expression of apoptosis and cell cycle-related proteins. Finally, a xenograft tumor model of CAL27 was established to evaluate the anti-tumor effect of SM-1 combined with radiation in vivo. RESULTS: In vitro, SM-1 effectively inhibited the activity of HNSCC cell lines HONE1, HSC-2, and CAL27 cells, and synergistically showed anti-proliferation activity during combined irradiation. Meanwhile, anti-tumor effect of SM-1 on HNSCC was higher than that of Debio1143, and the radiosensitivity of cells was greatly increased. Flow cytometry and western blot analysis showed that SM-1 induced G2/M phase arrest of head and neck squamous cell carcinoma cells via inhibiting the expression of CyclinB1 and CDC2. Moreover, SM-1 activated caspase-3 activity and up-regulated the cleaved form of PARP1 to induce cell apoptosis. In vivo, SM-1 combined irradiation showed a good anti-tumor effect. CONCLUSION: SM-1 enhances HNSCC cell radiation sensitivity in vitro and in vivo, supporting its potential as a radiosensitizer for clinical trials in combination with radiotherapy.

Fc receptor-like A promotes malignant behavior in renal cell carcinoma and correlates with tumor immune infiltration.

BACKGROUND: Our study aims to investigate the mechanisms through which Fc receptor-like A (FCRLA) promotes renal cell carcinoma (RCC) and to examine its significance in relation to tumor immune infiltration. MATERIALS AND METHODS: The correlation between FCRLA and data clinically related to RCC was explored using The Cancer Genome Atlas (TCGA), then validated using Gene Expression Omnibus (GEO) gene chip data. Enrichment and protein-protein interaction (PPI) network analyses were performed for FCRLA and its co-expressed genes. FCRLA was knocked down in RCC cell lines to evaluate its impact on biological behavior. Then the potential downstream regulators of FCRLA were determined by western blotting, and rescue experiments were performed for verification. The relevance between FCRLA and various immune cells was analyzed through GSEA, TIMER, and GEPIA tools. TIDE and ESTIMATE algorithms were used to predict the effect of FCRLA in immunotherapy. RESULTS: Fc receptor-like A was associated with clinical and T stages and could predict the M stage (AUC = 0.692) and 1-3- and 5-year survival rates (AUC = 0.823, 0.834, and 0.862) of RCC patients. Higher expression of FCLRA predicted an unfavorable overall survival (OS) in TCGA-RCC and GSE167573 datasets (p = 0.03, p = 0.04). FCRLA promoted the malignant biological behavior of RCC cells through the pERK1/2/-MMP2 pathway and was associated with tumor immune microenvironment in RCC. CONCLUSION: Fc receptor-like A is positively correlated with poor outcomes in RCC patients and plays an oncogenic role in RCC through the pERK1/2-MMP2 pathway. Patients with RCC might benefit from immunotherapy targeting FCRLA.

Effectiveness of high-intensity focused ultrasound combined with gonadotropin-releasing hormone agonist or combined with levonorgestrel-releasing intrauterine system for adenomyosis: A systematic review and meta-analysis.

Gonadotropin-Releasing Hormone Agonist (GnRH-a) and levonorgestrel releasing intrauterine system (LNG-IUS) are conventional conservative treatments for adenomyosis, and high-intensity focused ultrasound (HIFU) is a novel ablation technique. This study aimed to investigate the effectiveness of HIFU combined with GnRH-a or LNG-IUS for adenomyosis patients. In this systematic review and meta-analysis, Pubmed, Embase, Cochrane Library and Scopus databases were searched up to December 2021. Published studies comparing HIFU plus GnRH-a with HIFU plus LNG-IUS in adenomyosis patients were assessed for eligibility by two independent authors. Risk of bias tool was utilized for risk evaluation. We selected treatment effective rate of dysmenorrhea (pain during menstruation) as the primary outcome; effective rate of menorrhagia severity and reduction rate of adenomyotic lesion as the secondary outcomes. Adverse effects were assessed. Four studies with a total 729 patients were enrolled in the meta-analysis. HIFU plus LNG-IUS showed lower dysmenorrhea [within 6 months: risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83-0.93, p < 0.00001; over 1 year: RR 0.73, 95% CI 0.65-0.82, p < 0.00001] and less menorrhagia severity (RR 0.63, 95% CI 0.60-0.66, p < 0.00001) than HIFU plus GnRH-a. Both groups demonstrated equal efficacy in adenomyotic lesion reduction rate (RR 1.03, 95% CI 0.97-1.09, p = 0.30). Adverse effects happened equally in both groups. Combination therapy of HIFU and LNG-IUS revealed better effectiveness in treating dysmenorrhea and menorrhagia than that of HIFU and GnRH-a. However, interpreting the conclusion should be approached with caution as a result of significant heterogeneity.

Prognostic Significance of Phenylalanine in Heart Failure: Clinical Insights and Inter-Organ Crosstalk Snapshot.

Background: Heart failure (HF) remains a leading cause of morbidity and mortality globally, necessitating the identification of reliable prognostic biomarkers to guide therapeutic interventions. Recent clinical observations have underscored phenylalanine (PHE) as a prognostic marker in HF, although the mechanisms involving inter-organ crosstalk remain understood. Methods: This study adopted a dull approach, with a retrospective analysis of 550 HF patients to establish the prognostic value of pre-discharge PHE levels and a study on the inter-organ crosstalk of PHE among 24 patients. We analyzed the correlations between PHE concentrations and clinical outcomes, alongside a comprehensive examination of PHE metabolism across the skeletal muscle, liver, heart, kidney, and lung. Results: In the clinical prognostic analysis of 550 patients hospitalized for acute decompensated HF, elevated PHE levels (≥65.6 µM) were significantly and independently associated with increased all-cause mortality during a median follow-up of 4.5 years (log rank = 36.7, p < 0.001), underscoring its value as a prognostic marker in HF. The inter-organic crosstalk study elucidated the mechanism associated with PHE elevation in patients with HF, characterized by an increase in PHE output in skeletal muscle and a decrease in hepatic and cardiac PHE uptakes. Notably, PHE concentration gradients across these organs were correlated with HF severity, such as the NYHA functional class, B-type natriuretic peptide levels, and the presence of acute HF. Conclusions: Our findings confirm the prognostic significance of PHE in patients with HF and unveil the complex metabolic interplay among key organs that contribute to PHE dysregulation. These insights not only reinforce the importance of metabolic monitoring in HF management but also open avenues for therapeutic targets.

Arteriovenous malformation-related headache and seizures in pregnancy masquerading as eclampsia: A case report.

OBJECTIVE: Cerebral arteriovenous malformation during pregnancy is rare but lethal disease that usually present with new-onset seizures and headaches mimicking eclampsia. We report a rare case of cerebral arteriovenous malformation with abrupt seizures in the third trimester. CASE REPORT: A 28-year-old primipara was brought to our emergency department at 32 6/7 weeks of gestation with new-onset acute seizures and hypertension. Owing to neurological deterioration, the patient underwent emergency cesarean delivery. However, 24 h after cesarean delivery and eclampsia treatment, the seizures worsened. Computed tomography and magnetic resonance imaging showed unruptured arteriovenous malformation of the right frontal lobe. Subsequently, intraarterial embolization was performed. The patient was discharged 5 days after surgery without neurological sequelae or obstetric complications. CONCLUSION: This case report highlights the differential diagnoses of sudden new-onset seizures in late pregnancy for obstetricians and emergency medicine physicians. Lethal cerebral diseases, apart from eclampsia, should be considered during pregnancy.

Cervical cancer and risk of dementia: real-world insights from a nationwide cohort study in Taiwan.

OBJECTIVE: Cervical cancer, linked to human papillomavirus (HPV), ranks fourth among women's cancers globally. Several studies have found an association between viral infections or cancer and dementia, which is a major public health concern. This study aimed to provide real-world data on the association between cervical cancer and the risk of dementia. METHODS: This population-based cohort study, utilizing Taiwan's National Health Insurance Research Database, included 53 905 patients, with 10 781 having cervical cancer, matching with 43 124 controls in a 1:4 ratio based on age and indexed date. Incidence density rates were used to calculate the incidence rate of dementia. Adjusting for comorbidities, a multivariable Cox proportional hazards regression model was used to estimate the hazard ratios and 95% confidence intervals. Additionally, the risk of dementia was further verified using the cumulative incidence analyzed by the Kaplan-Meier method. RESULTS: This study indicated a significantly higher dementia risk in the cervical cancer cohort compared with the non-cervical cancer cohort (adjusted HR (aHR)=1.64, 95% CI 1.16 to 2.26; p<0.001), suggesting a 1.64-fold increased risk. Notably, cervical cancer posed a greater risk of dementia (aHR=1.69, 95% CI 1.21 to 2.29; p<0.001) compared with carcinoma in situ of the cervix (p=0.18) and cervical intraepithelial neoplasia (p=0.23). The cumulative incidence of dementia in the cervical cancer group was significantly higher (log-rank test, p<0.001) than the control group. CONCLUSIONS: Cervical cancer (invasive disease) was associated with a significant risk of dementia, unlike carcinoma in situ of the cervix and cervical intraepithelial neoplasia (pre-invasive diseases), suggesting HPV infections may play a role in dementia, particularly oncogenic types. This highlights the importance of further investigation into the underlying mechanisms of the association between cervical cancer and dementia.

Altered Abdominal Muscle Recruitment and Declined Physical Function in Postpartum Individuals With Pregnancy-Related Pelvic Girdle Pain: A Matched Case-Control Study.

INTRODUCTION: The influence of pregnancy-related pelvic girdle pain (PPGP) on lumbopelvic muscles has not been comprehensively examined in postpartum individuals. Previous research also presented self-reported activity limitations without objective measures. METHODS: Thirty postpartum individuals with PPGP (PPGP group) and 30 age-, parity-, and postpartum duration-matched asymptomatic individuals (healthy group) were recruited. Transabdominal ultrasonography was used to measure muscle thickness or activation changes of the external oblique (EO), internal oblique (IO), transverse abdominals, lumbar multifidus, and pelvic floor muscles (PFMs) during rest and while performing the active straight leg raise (ASLR). Muscle changes were compared separately in the painful and nonpainful sides between the PPGP and health control group. Physical function was assessed using the ASLR fatigue (ASLRF), timed up-and-go, and 6-m walking (6MW) tests. RESULTS: The PPGP group had greater thickening changes in the bilateral IO during ASLR compared with the healthy group (nonpainful side, 16.34 vs 3.52 mm; P = .010; painful side, 18.83 vs 6.60 mm; P = .02) but became thinner in the EO (nonpainful side, -2.19 vs 19.97 mm; P < .001; painful side, -5.97 vs 21.43 mm; P < .001). Thicker IO and EO on the nonpainful side (IO, 6.60 vs 5.78 mm; P = .004; EO, 5.37 vs 4.54 mm; P = .011) and a lower bladder base (indication of PFMs) (91.87 vs 78.61 mm; P = .002) during rest were also observed in the PPGP group. Furthermore, the performance of the ASLRF and 6MW tests was poorer in the PPGP than in the healthy group (ASLRF nonpainful side, 82.36 vs 59.09 sec; P = .01; painful side, 75.73 vs 59.26 sec; P = .04; 6MW, 3.48 vs 3.17 sec; P = .02). DISCUSSION: Postpartum individuals with PPGP demonstrated altered abdominal muscle recruitment strategies during loading tasks, with objectively impaired physical functions. These findings are critical for developing effective muscle training interventions for PPGP.

LEUTX regulates porcine embryonic genome activation in somatic cell nuclear transfer embryos.

Emerging evidence highlights the regulatory role of paired-like (PRD-like) homeobox transcription factors (TFs) in embryonic genome activation (EGA). However, the majority of PRD-like genes are lost in rodents, thus prompting an investigation into PRD-like TFs in other mammals. Here, we showed that PRD-like TFs were transiently expressed during EGA in human, monkey, and porcine fertilized embryos, yet they exhibited inadequate expression in their cloned embryos. This study, using pig as the research model, identified LEUTX as a key PRD-like activator of porcine EGA through genomic profiling and found that LEUTX overexpression restored EGA failure and improved preimplantation development and cloning efficiency in porcine cloned embryos. Mechanistically, LEUTX opened EGA-related genomic regions and established histone acetylation via recruiting acetyltransferases p300 and KAT2A. These findings reveal the regulatory mechanism of LEUTX to govern EGA in pigs, which may provide valuable insights into the study of early embryo development for other non-rodent mammals.

Transabdominal ultrasonography-guided biofeedback training for pelvic floor muscles integrated with stabilization exercise improved pregnancy-related pelvic girdle pain and disability: a randomized controlled trial.

OBJECTIVES: Investigate effects of integrated training for pelvic floor muscles (PFM) with and without transabdominal ultrasonography (TAUS) imaging-guided biofeedback in postpartum women with pregnancy-related pelvic girdle pain (PPGP). DESIGN: Three-arm, single-blinded randomized controlled trial SETTING: University laboratory PARTICIPANTS: Fifty-three postpartum women with PPGP randomized into stabilization exercise with TAUS-guided biofeedback (BIO+EXE), exercise (EXE), and control (CON) groups. INTERVENTIONS: The BIO+EXE and EXE groups underwent an 8-week exercise program, with the BIO+EXE group receiving additional TAUS-guided biofeedback for PFM training during the first 4 weeks. The CON group only received a pelvic educational session. MAIN OUTCOME MEASURES: Primary outcomes included self-reported pain (numeric rating scale) and disability (pelvic girdle questionnaire). Secondary outcomes included functional tests (active straight leg raising [ASLR] fatigue, timed up-and-go, and 6-meter walking tests) and muscle contractibility indicated by muscle thickness changes for abdominal muscles and bladder base displacement for PFM (ultrasonographic measures). RESULTS: The BIO+EXE group had lower pain [1.8 (1.5) vs. 4.4 (1.5), mean difference -2.6, 95% confidence interval (CI) -3.9 to -1.2] and disability [14% (10) vs. 28% (21), mean difference -14, 95% CI -25 to -2] and faster walking speed [3.1 seconds (1) vs. 3.3 seconds (1), mean difference -0.2, 95% CI -1.0 to -0.2] than the CON group. The EXE group only had lower pain intensity compared to the CON group [2.7 (2.0) vs. 4.4 (1.5), mean difference -1.7, 95% CI -3.1 to -0.4]. No significant differences were observed among groups in timed up-and-go, ASLR fatigue, or muscle contractibility. CONCLUSIONS: Integrated training for PFM and stabilization with TAUS-guided biofeedback seems to be beneficial for reducing pain and disability in postpartum women with PPGP. CONTRIBUTION OF THE PAPER.

Propofol Mitigates Sepsis-Induced Brain Injury by Inhibiting Ferroptosis Via Activation of the Nrf2/HO-1axis.

BACKGROUND: Sepsis-associated encephalopathy (SAE) develops in 30-70% of hospitalized patients with sepsis. In intensive care units (ICUs), propofol is often administered to ensure an appropriate level of sedation in mechanically ventilated patients. Ferroptosis is a newly identified mode of cellular death characterized by the peroxidation of membrane lipids and excessive iron. This study was conducted to explore the interplay between propofol, sepsis, and ferroptosis. METHODS: An acute systemic inflammatory model was constructed via the intraperitoneal administration of lipopolysaccharide (LPS). Nissl and Fluoro-Jade C (FJC) staining were employed to display neuronal damage and degeneration. Western blotting and immunofluorescence (IF) staining of Bax and Bcl-2 were used to confirm the neural apoptosis. QPCR of cytokines and DHE staining were used to indicate neuroinflammation. To validate ferroptosis, we assessed the content of malondialdehyde (MDA), GSH, and tissue iron, accompanied by transcription level of CHAC1, PTGS2 and GPX4. Additionally, we examined the content of acyl-CoA synthetase long-chain family member 4 (ACSL4), xCT (SLC7A11, solute carrier family 7 member 11), and glutathione peroxidase 4 (GPX4). The IF staining of Iba1-labeled microglia and GFAP-marked astrocytes were used to measure the gliosis. Erastin was pre-pretreated to confirm the anti-ferroptotic capability of propofol. ML385 was preconditioned to explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in propofol-repressed ferroptosis. RESULTS: Propofol dose-dependently inhibited the decrease of Nissl-positive neurons and the increase of FJC-stained neurons in septic hippocampus and cortex. Neural cytokines, oxidative stress, apoptosis and gliosis were reduced by propofol. Propofol repressed the level of MDA, iron, CHAC1, PTGS2, ACLS4 and restored the content of GSH, GPX4, xCT, Nrf2 and HO-1, thus inhibiting sepsis-induced ferroptosis. All protections from propofol could be reversed by eratsin and ML385 pretreatment. CONCLUSION: Propofol protected against sepsis-induced brain damage, neuroinflammation, neuronal apoptosis and gliosis through the activation of the Nrf2/HO-1 axis to combat ferroptosis.

Temporal landscape and translational regulation of A-to-I RNA editing in mouse retina development.

BACKGROUND: The significance of A-to-I RNA editing in nervous system development is widely recognized; however, its influence on retina development remains to be thoroughly understood. RESULTS: In this study, we performed RNA sequencing and ribosome profiling experiments on developing mouse retinas to characterize the temporal landscape of A-to-I editing. Our findings revealed temporal changes in A-to-I editing, with distinct editing patterns observed across different developmental stages. Further analysis showed the interplay between A-to-I editing and alternative splicing, with A-to-I editing influencing splicing efficiency and the quantity of splicing events. A-to-I editing held the potential to enhance translation diversity, but this came at the expense of reduced translational efficiency. When coupled with splicing, it could produce a coordinated effect on gene translation. CONCLUSIONS: Overall, this study presents a temporally resolved atlas of A-to-I editing, connecting its changes with the impact on alternative splicing and gene translation in retina development.

Propofol and Dexmedetomidine Ameliorate Endotoxemia-Associated Encephalopathy via Inhibiting Ferroptosis.

Background: Sepsis is recognized as a multiorgan and systemic damage caused by dysregulated host response to infection. Its acute systemic inflammatory response highly resembles that of lipopolysaccharide (LPS)-induced endotoxemia. Propofol and dexmedetomidine are two commonly used sedatives for mechanical ventilation in critically ill patients and have been reported to alleviate cognitive impairment in many diseases. In this study, we aimed to explore and compare the effects of propofol and dexmedetomidine on the encephalopathy induced by endotoxemia and to investigate whether ferroptosis is involved, finally providing experimental evidence for multi-drug combination in septic sedation. Methods: A total of 218 C57BL/6J male mice (20-25 g, 6-8 weeks) were used. Morris water maze (MWM) tests were performed to evaluate whether propofol and dexmedetomidine attenuated LPS-induced cognitive deficits. Brain injury was evaluated using Nissl and Fluoro-Jade C (FJC) staining. Neuroinflammation was assessed by dihydroethidium (DHE) and DCFH-DA staining and by measuring the levels of three cytokines. The number of Iba1+ and GFAP+ cells was used to detect the activation of microglia and astrocytes. To explore the involvement of ferroptosis, the levels of ptgs2 and chac1; the content of iron, malondialdehyde (MDA), and glutathione (GSH); and the expression of ferroptosis-related proteins were investigated. Conclusion: The single use of propofol and dexmedetomidine mitigated LPS-induced cognitive impairment, while the combination showed poor performance. In alleviating endotoxemic neural loss and degeneration, the united sedative group exhibited the most potent capability. Both propofol and dexmedetomidine inhibited neuroinflammation, while propofol's effect was slightly weaker. All sedative groups reduced the neural apoptosis, inhibited the activation of microglia and astrocytes, and relieved neurologic ferroptosis. The combined group was most prominent in combating genetic and biochemical alterations of ferroptosis. Fpn1 may be at the core of endotoxemia-related ferroptosis activation.