Subretinal fibrosis secondary to neovascular age-related macular degeneration: mechanisms and potential therapeutic targets.

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration. It causes local damage to photoreceptors, retinal pigment epithelium, and choroidal vessels, which leads to permanent central vision loss of patients with neovascular age-related macular degeneration. The pathogenesis of subretinal fibrosis is complex, and the underlying mechanisms are largely unknown. Therefore, there are no effective treatment options. A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments. The current article reviews several aspects of subretinal fibrosis, including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis; multimodal imaging techniques for subretinal fibrosis; animal models for studying subretinal fibrosis; cellular and non-cellular constituents of subretinal fibrosis; pathophysiological mechanisms involved in subretinal fibrosis, such as aging, infiltration of macrophages, different sources of mesenchymal transition to myofibroblast, and activation of complement system and immune cells; and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis, such as vascular endothelial growth factor, connective tissue growth factor, fibroblast growth factor 2, platelet-derived growth factor and platelet-derived growth factor receptor-ß, transforming growth factor-ß signaling pathway, Wnt signaling pathway, and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10. This review will improve the understanding of the pathogenesis of subretinal fibrosis, allow the discovery of molecular targets, and explore potential treatments for the management of subretinal fibrosis.

Novel MRI signs of the atlantodental space in patients with atlantoaxial dislocation.

OBJECTIVES: The type of atlantodental space tissue in patients with atlantoaxial dislocation (AAD) can help doctors understand the possibility of reduction before surgery. However, relevant research on this topic is lacking. In this study, we aimed to summarise the atlantodental space classification of patients with AAD using magnetic resonance imaging (MRI) and explore their clinical characteristics. MATERIALS AND METHODS: Preoperative 3T cervical MR images of patients who underwent posterior reduction and fixation surgery for non-traumatic AAD between 1 September 2012 and 31 July 2023 were collected. Two radiologists read and recorded the MRI results based on the standard protocol. The kappa value was used to evaluate intra- and inter-observer agreements. The patient's age, sex, body mass index, clinical symptoms, Japanese Orthopaedic Association (JOA) score, and visual analogue scale information were obtained from medical records. RESULTS: A total of 135 patients with AAD (mean age, 51.3 ± 14.0 years, 52 men) were included in the analysis. The inter-observer agreement between the two readers was 0.818 (P < 0.0001). The intra-observer consistencies were 0.882 (P < 0.0001) and 0.896 (P < 0.0001). Patients with inflexible tissue signs exhibit more irreducible in hyperextension position, and their range of motion of ADI is smaller. These patients were older and had a higher incidence of abnormal spinal cord signals and JOA scores. CONCLUSIONS: Novel MRI signs exhibited high inter- and intra-observer consistency and were associated with patient age, abnormal spinal cord signals, reducibility, range of motion of ADI, and symptoms.

Computing high-degree polynomial gradients in memory.

Specialized function gradient computing hardware could greatly improve the performance of state-of-the-art optimization algorithms. Prior work on such hardware, performed in the context of Ising Machines and related concepts, is limited to quadratic polynomials and not scalable to commonly used higher-order functions. Here, we propose an approach for massively parallel gradient calculations of high-degree polynomials, which is conducive to efficient mixed-signal in-memory computing circuit implementations and whose area scales proportionally with the product of the number of variables and terms in the function and, most importantly, independent of its degree. Two flavors of such an approach are proposed. The first is limited to binary-variable polynomials typical in combinatorial optimization problems, while the second type is broader at the cost of a more complex periphery. To validate the former approach, we experimentally demonstrated solving a small-scale third-order Boolean satisfiability problem based on integrated metal-oxide memristor crossbar circuits, with competitive heuristics algorithm. Simulation results for larger-scale, more practical problems show orders of magnitude improvements in area, speed and energy efficiency compared to the state-of-the-art. We discuss how our work could enable even higher-performance systems after co-designing algorithms to exploit massively parallel gradient computation.

Does the Angulation of the Screws in the Zero-P Implant Affect the Clinical and Radiological Outcomes of Patients?

OBJECTIVE: When implanting the Zero-P device, the screws of Zero-P form a bone wedge with a 40 ± 5° cranial and caudal angle (CCA). However, no study has been performed in the optimal CCA of the Zero-P implant. To investigate whether the cranial/caudal angles (CCA) of the screws affect the clinical and radiological outcomes in patients undergoing ACDF with the Zero-P implant. METHODS: From January 2016 to December 2023, we retrospectively analyzed 186 patients who underwent 1-level ACDF with the Zero-P device. The patients were divided into four groups: group A (cranial angle ≤40°, caudal angle ≤40°); group B (cranial angle ≤40°, caudal angle >40°); group C (cranial angle >40°, caudal angle ≤40°); and group D (cranial angle >40°, caudal angle >40°). The clinical outcomes, including Japanese Orthopaedic Association (JOA), neck disability index (NDI), and visual analogue scale (VAS) scores, the radiological parameters, including cervical lordosis (CL), cervical lordosis of operated segments (OPCL), intervertebral space height (ISH) and fusion rate (FR), and the complications, were evaluated and compared. Parametric tests, non-parametric tests, and chi-square tests were conducted to analyze the data. RESULTS: The OPCL of group A was significantly less than that of the other groups at the final follow-up (p < 0.05). The ISH of group D was significantly less than that of group A at the final follow-up (p < 0.05). The subsidence rate of group A was significantly less than that of group D at the final follow-up (p < 0.05). At the final follow-up, the upper adjacent-level degeneration (ASD) of group D was significantly less severe than that of groups A and B (p < 0.05). The clinical outcomes do not differ among groups (p > 0.05). CONCLUSION: A larger CCA of the screws (cranial angle >40°, caudal angle >40°) was better for maintaining OPCL and reducing the incidence of ASD. A smaller CCA of the screws (cranial angle ≤40°, caudal angle ≤40°) was better for maintaining ISH and reducing the rate of subsidence.

Transition-Metal-Free Radical Relay Cascade Annulation of Amides: Access to Antitumor Active Benzo[b]azepine and Oxindole Derivatives.

Efficient metal-free synthesis of benzo[b]azepines and oxindoles is achieved via a radical relay cascade strategy employing halogen atom transfer (XAT) for aryl radical generation followed by intramolecular hydrogen atom transfer (HAT). Optimization yielded moderate to substantial yields under visible light irradiation. Preliminary biological assessments revealed promising anti-tumor activity for select compounds. This study underscores the potential of XAT-mediated radical relay cascades in medicinal chemistry and anticancer drug discovery.

[Relative Quantification for Obtaining the IgG Blood Group Antibodies in Plasma by the Absorption and Elution Test].

OBJECTIVE: To establish the absorption and elution test for relatively quantitive obtaining anti-A and anti-B blood group IgG antibodies in the plasma of O-type RhD-positive pregnant women. METHODS: 95 cases of the O-type RhD-positive pregnant women plasma samples were randomly selected for obtaining the IgG antibodies of anti-A and anti-B blood group, with absorption test under 37 ℃ and elution test under 56 ℃, and the IgG anti-A and anti-B antibody titers of plasma and elution were determined by the microcolumn gel anti-human globulin test. The differences and correlation between the titers of IgG antibodies in the eluent and plasma were compared and analyzed. RESULTS: After a logarithmic transformation (Log2), there was no statistically difference between IgG antibody anti-A difference value and anti-B difference value in the eluent and plasma (P >0.05). The titer of IgG antibody in the eluent was positively correlated with the titer of IgG antibody in the plasma (r =0.914). The linear equation for IgG antibody titers fitted by a scatter plot between the eluent and plasma was Y=-3.55+0.96X. CONCLUSION: The absorption and elution test can be used to obtain the anti-A and anti-B IgG antibodies in the plasma of O-type RhD-positive pregnant women, whose plasma origin IgG titer is greater than 8. Meanwhile, the acquisition of anti-A antibodies was as effective as anti-B antibodies at the same time, and the antibodies obtained are positive proportional to their respective concentrations in the plasma.

Analysis of factors influencing the recurrence of diabetic foot ulcers.

OBJECTIVE: The aim of this study is to investigate the factors influencing the recurrence of diabetic foot ulcers (DFU) and provide guidance for reducing the recurrence rate. METHODS: A total of 211 patients diagnosed with DFU who were hospitalized and discharged from the hospital from October 2015 to January 2020 were included as the study cohort. Participants were divided into two groups according to whether the foot ulcer recurred during the 2-year follow-up period: a recurrence group (n = 84) and a non-recurrence group (n = 127). The following data were collected and analyzed for the two groups of patients: general information, foot information, laboratory indicators, diabetes comorbidities, and complications. RESULTS: (1) The overall recurrence rate of diabetic foot ulcers (DFU) within 2 years was 39.8%, indicating a high recurrence rate. (2) Significant differences were observed between the two patient groups in terms of BMI, HbA1c, TBIL, CRP, financial situation, foot deformity, first ulcer on the sole of the foot, previous amputation history, Wagner grade of the first ulcer, osteomyelitis, DFU duration (>60 days), lower limb vascular reconstruction, peripheral arterial disease (PAD), and diabetic peripheral neuropathy (DPN) (t = 2.455; Z = -1.988, -3.731, -3.618; χ2 = 7.88, 5.004, 3.906, 17.178, 16.237, 5.007, 24.642, 4.782, 29.334, 10.253). No significant differences were found for the other indicators. (3) Logistic regression analysis revealed that TBIL (OR = 0.886, p = 0.036) was a protective factor against ulcer recurrence. In contrast, PAD, previous amputation history, DPN, and the first ulcer on the sole of the foot (OR = 3.987, 6.758, 4.681, 2.405; p < 0.05 or p < 0.01) were identified as risk factors for ulcer recurrence. CONCLUSION: Early screening and preventive education targeting high-risk factors such as DPN, PAD and the initial ulcer location on the sole of the foot are essential to mitigate the high long-term recurrence rate of DFU. Furthermore, the protective role of TBIL in preventing ulcer recurrence underscores the importance of monitoring bilirubin levels as part of a comprehensive management strategy for DFU patients.

Cross-species single-cell RNA sequencing reveals divergent phenotypes and activation states of adaptive immunity in human carotid and experimental murine atherosclerosis.

BACKGROUND AND AIMS: The distinct functions of immune cells in atherosclerosis have been mostly defined by preclinical mouse studies. Contrastingly, the immune cell composition of human atherosclerotic plaques and their contribution to disease progression is only poorly understood. It remains uncertain whether genetic animal models allow for valuable translational approaches. METHODS AND RESULTS: Single cell RNA-sequencing (scRNA-seq) was performed to define the immune cell landscape in human carotid atherosclerotic plaques. The human immune cell repertoire demonstrated an unexpectedly high heterogeneity and was dominated by cells of the T-cell lineage, a finding confirmed by immunohistochemistry. Bioinformatical integration with 7 mouse scRNA-seq data sets from adventitial and atherosclerotic vascular tissue revealed a total of 51 identities of cell types and differentiation states, of which some were only poorly conserved between species and exclusively found in humans. Locations, frequencies, and transcriptional programs of immune cells in mouse models did not resemble the immune cell landscape in human carotid atherosclerosis. In contrast to standard mouse models of atherosclerosis, human plaque leukocytes were dominated by several T-cell phenotypes with transcriptional hallmarks of T-cell activation and memory formation, T-cell receptor-, and pro-inflammatory signaling. Only mice at the age of 22 months partially resembled the activated T-cell phenotype. In a validation cohort of 43 patients undergoing carotid endarterectomy, the abundance of activated immune cell subsets in the plaque defined by multi-color flow cytometry associated with the extend of clinical atherosclerosis. CONCLUSIONS: Integrative scRNA-seq reveals a substantial difference in the immune cell composition of murine and human carotid atherosclerosis - a finding that questions the translational value of standard mouse models for adaptive immune cell studies. Clinical associations suggest a specific role for T-cell driven (auto-) immunity in human plaque formation and -instability.

Sagittal slope angle of lateral atlantoaxial articulation is associated with the severity of basilar invagination with atlantoaxial dislocation and predicts reduction degree after surgery.

OBJECTIVE: To investigate (1) lateral atlantoaxial articulation (LAA) morphology in patients with basilar invagination (BI) with atlantoaxial dislocation (AAD) and healthy individuals and its relationship with the severity of dislocation and (2) the effect of the LAA morphology on reduction degree (RD) after surgery. METHODS: In this retrospective propensity score matching case-control study, imaging and baseline data of 62 patients with BI and AAD from 2011 to 2022 were collected. Six hundred thirteen  participants without occipitocervical junctional deformity served as controls. Logistic regression and receiver operating characteristic (ROC) curve were used for analysis. RESULTS: The age, BMI and sex did not differ significantly between the two groups after propensity score matching. Sagittal slope angle (SSA) and coronal slope angle (CSA) was lower and greater, respectively, in the patient group than in the control group. A negative SSA value usually indicates anteverted LAA. Regression analysis revealed a significant negative correlation between SSA and severity of dislocation. However, no relationship was found between CSA and the severity of dislocation. The multivariate logistic regression analysis revealed that minimum-SSA emerged as an independent predictor of satisfactory reduction (RD ≥ 90%). The ROC curve demonstrated an area under the curve of 0.844, with a cut-off value set at -40.2. CONCLUSION: SSA in patients group was significantly smaller and more asymmetric than that in the control group. Dislocation severity was related to SSA but not to CSA. Minimum-SSA can be used as a predictor of horizontal RD after surgery.

Photoinduced copper catalyzed nitrogen-to-alkyl radical relay Sonogashira-type coupling of o-alkylbenzamides with alkynes.

This report describes a copper-catalyzed, photoinduced N-to-alkyl radical relay Sonogashira-type reactions at benzylic sites in o-alkylbenzamides with alkynes. The process employs an N-to-alkyl radical mechanism, initiated through the copper-catalyzed reductive generation of nitrogen radicals. Radical translocation is facilitated by a 1,5-hydrogen atom transfer (1,5-HAT), leading to the formation of translocated carbon radicals. These radicals are then subjected to copper-catalyzed alkynylation. The methodology exhibits broad sub-strate scope and applicability to the synthesis of complex natural products.

In silico off-target profiling for enhanced drug safety assessment.

Ensuring drug safety in the early stages of drug development is crucial to avoid costly failures in subsequent phases. However, the economic burden associated with detecting drug off-targets and potential side effects through in vitro safety screening and animal testing is substantial. Drug off-target interactions, along with the adverse drug reactions they induce, are significant factors affecting drug safety. To assess the liability of candidate drugs, we developed an artificial intelligence model for the precise prediction of compound off-target interactions, leveraging multi-task graph neural networks. The outcomes of off-target predictions can serve as representations for compounds, enabling the differentiation of drugs under various ATC codes and the classification of compound toxicity. Furthermore, the predicted off-target profiles are employed in adverse drug reaction (ADR) enrichment analysis, facilitating the inference of potential ADRs for a drug. Using the withdrawn drug Pergolide as an example, we elucidate the mechanisms underlying ADRs at the target level, contributing to the exploration of the potential clinical relevance of newly predicted off-target interactions. Overall, our work facilitates the early assessment of compound safety/toxicity based on off-target identification, deduces potential ADRs of drugs, and ultimately promotes the secure development of drugs.

Cognitive dysfunction in schizophrenia patients caused by down-regulation of γ-aminobutyric acid receptor subunits.

BACKGROUND: The expression pattern of gamma aminobutyric acid (GABA) receptor subunits are commonly altered in patients with schizophrenia, which may lead to nerve excitation/inhibition problems, affecting cognition, emotion, and behavior. AIM: To explore GABA receptor expression and its relationship with schizophrenia and to provide insights into more effective treatments. METHODS: This case-control study enrolled 126 patients with schizophrenia treated at our hospital and 126 healthy volunteers who underwent physical examinations at our hospital during the same period. The expression levels of the GABA receptor subunits were detected using 1H-magnetic resonance spectroscopy. The recognized cognitive battery tool, the MATRICS Consensus Cognitive Battery, was used to evaluate the scores for various dimensions of cognitive function. The correlation between GABA receptor subunit downregulation and schizophrenia was also analyzed. RESULTS: Significant differences in GABA receptor subunit levels were found between the case and control groups (P < 0.05). A significant difference was also found between the case and control groups in terms of cognitive function measures, including attention/alertness and learning ability (P < 0.05). Specifically, as the expression levels of GABRA1 (α1 subunit gene), GABRB2 (ß2 subunit gene), GABRD (δ subunit), and GABRE (ε subunit) decreased, the severity of the patients' condition increased gradually, indicating a positive correlation between the downregulation of these 4 receptor subunits and schizophrenia (P < 0.05). However, the expression levels of GABRA5 (α5 subunit gene) and GABRA6 (α6 subunit gene) showed no significant correlation with schizophrenia (P > 0.05). CONCLUSION: Downregulation of the GABA receptor subunits is positively correlated with schizophrenia. In other words, when GABA receptor subunits are downregulated in patients, cognitive impairment becomes more severe.

FGFR2 fusion/rearrangement is associated with favorable prognosis and immunoactivation in patients with intrahepatic cholangiocarcinoma.

Increasing evidence highlights that fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement shows important therapeutic value for patients with intrahepatic cholangiocarcinoma (ICC). This study aims to explore the association of FGFR2 status with the prognosis and immune cell infiltration profiles of patients with ICC. A total of 226 ICC tissue samples from patients who received surgery at the Department of Liver Surgery at Zhongshan Hospital, Fudan University, were collected retrospectively and assigned to a primary cohort (n = 152) and validation cohort (n = 74) group. Fluorescence in situ hybridization was performed to determine FGFR2 status. Multiplex immunofluorescence (mIF) staining and immunohistochemistry were performed to identify immune cells. Thirty-two (14.2%) ICC tissues presented with FGFR2 fusion/rearrangement. FGFR2 fusion/rearrangement was associated with low levels of carcinoembryonic antigen (CEA, P = .026) and gamma glutamyl transferase (γ-GGT, P = .003), low TNM (P = .012), CNLC (P = .008) staging as well as low tumor cell differentiation (P = .016). Multivariate COX regression analyses revealed that FGFR2 fusion/rearrangement was an independent protective factor for both overall survival (OS) and relapse-free survival in patients with ICC. Furthermore, correlation analysis revealed that an FGFR2 fusion/rearrangement was associated with low levels of Tregs and N2 neutrophils and high levels of N1 neutrophils infiltrating into tumors but not with CD8+ T-cell or macrophage tumor infiltration. FGFR2 fusion/rearrangement may exert a profound impact on the prognosis of ICC patients and reprogram the tumor microenvironment to be an immune-activated state. FGFR2 status may be used for ICC prognostic stratification and as an immunotherapeutic target in patients with ICC.

Comparative study on emotional behavior and parental job stress of only-child and non-only-child preschool children.

BACKGROUND: Studies have revealed that Children's psychological, behavioral, and emotional problems are easily influenced by the family environment. In recent years, the family structure in China has undergone significant changes, with more families having two or three children. AIM: To explore the relationship between emotional behavior and parental job stress in only preschool and non-only preschool children. METHODS: Children aged 3-6 in kindergartens in four main urban areas of Shijiazhuang were selected by stratified sampling for a questionnaire and divided into only and non-only child groups. Their emotional behaviors and parental pressure were compared. Only and non-only children were paired in a 1:1 ratio by class and age (difference less than or equal to 6 months), and the matched data were compared. The relationship between children's emotional behavior and parents' job stress before and after matching was analyzed. RESULTS: Before matching, the mother's occupation, children's personality characteristics, and children's rearing patterns differed between the groups (P < 0.05). After matching 550 pairs, differences in the children's parenting styles remained. There were significant differences in children's gender and parents' attitudes toward children between the two groups. The Strengths and Difficulties Questionnaire (SDQ) scores of children in the only child group and the Parenting Stress Index-Short Form (PSI-SF) scores of parents were significantly lower than those in the non-only child group (P < 0.05). Pearson's correlation analysis showed that after matching, there was a positive correlation between children's parenting style and parents' attitudes toward their children (r = 0.096, P < 0.01), and the PSI-SF score was positively correlated with children's gender, parents' attitudes toward their children, and SDQ scores (r = 0.077, 0.193, 0.172, 0.222). CONCLUSION: Preschool children's emotional behavior and parental pressure were significantly higher in multi-child families. Parental pressure in differently structured families was associated with many factors, and preschool children's emotional behavior was positively correlated with parental pressure.

Microvascular destabilization and intricated network of the cytokines in diabetic retinopathy: from the perspective of cellular and molecular components.

Microvascular destabilization is the primary cause of the inner blood-retinal barrier (iBRB) breakdown and increased vascular leakage in diabetic retinopathy (DR). Microvascular destabilization results from the combinational effects of increased levels of growth factors and cytokines, involvement of inflammation, and the changed cell-to-cell interactions, especially the loss of endothelial cells and pericytes, due to hyperglycemia and hypoxia. As the manifestation of microvascular destabilization, the fluid transports via paracellular and transcellular routes increase due to the disruption of endothelial intercellular junctional complexes and/or the altered caveolar transcellular transport across the retinal vascular endothelium. With diabetes progression, the functional and the structural changes of the iBRB components, including the cellular and noncellular components, further facilitate and aggravate microvascular destabilization, resulting in macular edema, the neuroretinal damage and the dysfunction of retinal inner neurovascular unit (iNVU). Although there have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying the microvascular destabilization, some still remain to be fully elucidated. Recent data indicate that targeting the intricate signaling pathways may allow to against the microvascular destabilization. Therefore, efforts have been made to better clarify the cellular and molecular mechanisms that are involved in the microvascular destabilization in DR. In this review, we discuss: (1) the brief introduction of DR and microvascular destabilization; (2) the cellular and molecular components of iBRB and iNVU, and the breakdown of iBRB; (3) the matrix and cell-to-cell contacts to maintain microvascular stabilization, including the endothelial glycocalyx, basement membrane, and various cell-cell interactions; (4) the molecular mechanisms mediated cell-cell contacts and vascular cell death; (5) the altered cytokines and signaling pathways as well as the intricate network of the cytokines involved in microvascular destabilization. This comprehensive review aimed to provide the insights for microvascular destabilization by targeting the key molecules or specific iBRB cells, thus restoring the function and structure of iBRB and iNVU, to treat DR.

Environmental monobutyl phthalate exposure promotes liver cancer via reprogrammed cholesterol metabolism and activation of the IRE1α-XBP1s pathway.

Humans are widely exposed to phthalates, a major chemical plasticizer that accumulates in the liver. However, little is known about the impact of chronic phthalate exposure on liver cancer development. In this study, we applied a long-term cell culture model by treating the liver cancer cell HepG2 and normal hepatocyte L02 to environmental dosage of monobutyl phthalate (MBP), the main metabolite of phthalates. Interestingly, we found that long-term MBP exposure significantly accelerated the growth of HepG2 cells in vitro and in vivo, but barely altered the function of L02 cells. MBP exposure triggered reprogramming of lipid metabolism in HepG2 cells, where cholesterol accumulation subsequently activated the IRE1α-XBP1s axis of the unfolded protein response. As a result, the XBP1s-regulated gene sets and pathways contributed to the increased aggressiveness of HepG2 cells. In addition, we also showed that MBP-induced cholesterol accumulation fostered an immunosuppressive microenvironment by promoting tumor-associated macrophage polarization toward the M2 type. Together, these results suggest that environmental phthalates exposure may facilitate liver cancer progression, and alerts phthalates exposure to patients who already harbor liver tumors.

Histone acetyltransferase Kat2a regulates ferroptosis via enhancing Tfrc and Hmox1 expression in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a prevalent myocardial microvascular complication of the myocardium with a complex pathogenesis. Investigating the pathogenesis of DCM can significantly contribute to enhancing its prevention and treatment strategies. Our study revealed an upregulation of lysine acetyltransferase 2 A (Kat2a) expression in DCM, accompanied by a decrease in N6-methyladenosine (m6A) modified Kat2a mRNA levels. Our study revealed an upregulation of lysine acetyltransferase 2 A (Kat2a) expression in DCM, accompanied by a decrease in N6-methyladenosine (m6A) modified Kat2a mRNA levels. Functionally, inhibition of Kat2a effectively ameliorated high glucose-induced cardiomyocyte injury both in vitro and in vivo by suppressing ferroptosis. Mechanistically, Demethylase alkB homolog 5 (Alkbh5) was found to reduce m6A methylation levels on Kat2a mRNA, leading to its upregulation. YTH domain family 2 (Ythdf2) played a crucial role as an m6A reader protein mediating the degradation of Kat2a mRNA. Furthermore, Kat2a promoted ferroptosis by increasing Tfrc and Hmox1 expression via enhancing the enrichment of H3K27ac and H3K9ac on their promoter regions. In conclusion, our findings unveil a novel role for the Kat2a-ferroptosis axis in DCM pathogenesis, providing valuable insights for potential clinical interventions.

Advancing Automatic Gastritis Diagnosis: An Interpretable Multilabel Deep Learning Framework for the Simultaneous Assessment of Multiple Indicators.

The evaluation of morphologic features, such as inflammation, gastric atrophy, and intestinal metaplasia, is crucial for diagnosing gastritis. However, artificial intelligence analysis for nontumor diseases like gastritis is limited. Previous deep learning models have omitted important morphologic indicators and cannot simultaneously diagnose gastritis indicators or provide interpretable labels. To address this, an attention-based multi-instance multilabel learning network (AMMNet) was developed to simultaneously achieve the multilabel diagnosis of activity, atrophy, and intestinal metaplasia with only slide-level weak labels. To evaluate AMMNet's real-world performance, a diagnostic test was designed to observe improvements in junior pathologists' diagnostic accuracy and efficiency with and without AMMNet assistance. In this study of 1096 patients from seven independent medical centers, AMMNet performed well in assessing activity [area under the curve (AUC), 0.93], atrophy (AUC, 0.97), and intestinal metaplasia (AUC, 0.93). The false-negative rates of these indicators were only 0.04, 0.08, and 0.18, respectively, and junior pathologists had lower false-negative rates with model assistance (0.15 versus 0.10). Furthermore, AMMNet reduced the time required per whole slide image from 5.46 to 2.85 minutes, enhancing diagnostic efficiency. In block-level clustering analysis, AMMNet effectively visualized task-related patches within whole slide images, improving interpretability. These findings highlight AMMNet's effectiveness in accurately evaluating gastritis morphologic indicators on multicenter data sets. Using multi-instance multilabel learning strategies to support routine diagnostic pathology deserves further evaluation.