Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology, cognition, and behavior in APP/PS1 mice.

JOURNAL/nrgr/04.03/01300535-202502000-00030/figure1/v/2024-05-28T214302Z/r/image-tiff In patients with Alzheimer's disease, gamma-glutamyl transferase 5 (GGT5) expression has been observed to be downregulated in cerebrovascular endothelial cells. However, the functional role of GGT5 in the development of Alzheimer's disease remains unclear. This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer's disease, as well as the underlying mechanism. We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer's disease (Aß1-42-treated hCMEC/D3 and bEnd.3 cells), as well as in the APP/PS1 mouse model. Additionally, injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits. Interestingly, increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-ß in the brains of APP/PS1 mice. This effect may be attributable to inhibition of the expression of ß-site APP cleaving enzyme 1, which is mediated by nuclear factor-kappa B. Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer's disease pathogenesis, and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice. These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer's disease.

Przewaquinone A inhibits Angiotensin II-induced endothelial diastolic dysfunction activation of AMPK.

BACKGROUND: Endothelial dysfunction (ED), characterized by markedly reduced nitric oxide (NO) bioavailability, vasoconstriction, and a shift toward a proinflammatory and prothrombotic state, is an important contributor to hypertension, atherosclerosis, and other cardiovascular diseases. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is widely involved in cardiovascular development. Przewaquinone A (PA), a lipophilic diterpene quinone extracted from Salvia przewalskii Maxim, inhibits vascular contraction. PURPOSE: Herein, the goal was to explore the protective effect of PA on ED in vivo and in vitro, as well as the underlying mechanisms. METHODS: A human umbilical vein endothelial cell (HUVEC) model of ED induced by angiotensin II (AngII) was used for in vitro observations. Levels of AMPK, endothelial nitric oxide synthase (eNOS), vascular cell adhesion molecule-1 (VCAM-1), nitric oxide (NO), and endothelin-1 (ET-1) were detected by western blotting and ELISA. A mouse model of hypertension was established by continuous infusion of AngII (1000 ng/kg/min) for 4 weeks using osmotic pumps. Following PA and/or valsartan administration, NO and ET-1 levels were measured. The levels of AMPK signaling-related proteins in the thoracic aorta were evaluated by immunohistochemistry. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were measured using the tail cuff method. Isolated aortic vascular tone measurements were used to evaluate the vasodilatory function in mice. Molecular docking, molecular dynamics, and surface plasmon resonance imaging (SPRi) were used to confirm AMPK and PA interactions. RESULTS: PA inhibited AngII-induced vasoconstriction and vascular adhesion as well as activated AMPK signaling in a dose-dependent manner. Moreover, PA markedly suppressed blood pressure, activated vasodilation in mice following AngII stimulation, and promoted the activation of AMPK signaling. Furthermore, molecular simulations and SPRi revealed that PA directly targeted AMPK. AMPK inhibition partly abolished the protective effects of PA against endothelial dysfunction. CONCLUSION: PA activates AMPK and ameliorates endothelial dysfunction during hypertension.

[Prenatal diagnosis of a fetus with Rubinstein-Taybi syndrome].

OBJECTIVE: To explore the clinical characteristics and variant of CREBBP gene in a fetus with Rubinstein-Taybi syndrome (RSTS). METHODS: A fetus with RSTS diagnosed at the Third Affiliated Hospital of Zhengzhou University in August 2022 was selected as the study subject. Clinical data, amniotic fluid sample of the fetus and peripheral blood samples of its parents were collected for whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: Foot malformation, cerebellar vermis agenesis, brain agenesis, polysyndactyly of the big toes and other phenotypes were found by prenatal ultrasound. WES revealed that the fetus has harbored a heterozygous c.4684G>T (p.E1562*) variant in exon 28 of the CREBBP gene (NM_004380.3), which was de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic (PVS1+PS2_Moderate+PM2_Supporting). After genetic counseling, the couple had opted to terminate the pregnancy and refused autopsy of the fetus. CONCLUSION: The c.4684G>T (p.E1562*) variant of the CREBBP gene probably underlay the RSTS in this fetus. The newly discovered variant has enriched the mutational spectrum of the CREBBP gene and illustrated that WES is an efficient tool for the prenatal diagnosis of RSTS.

PROTAC-Mediated HDAC7 Protein Degradation Unveils Its Deacetylase-Independent Proinflammatory Function in Macrophages.

Class IIa histone deacetylases (Class IIa HDACs) play critical roles in regulating essential cellular metabolism and inflammatory pathways. However, dissecting the specific roles of each class IIa HDAC isoform is hindered by the pan-inhibitory effect of current inhibitors and a lack of tools to probe their functions beyond epigenetic regulation. In this study, a novel PROTAC-based compound B4 is developed, which selectively targets and degrades HDAC7, resulting in the effective attenuation of a specific set of proinflammatory cytokines in both lipopolysaccharide (LPS)-stimulated macrophages and a mouse model. By employing B4 as a molecular probe, evidence is found for a previously explored role of HDAC7 that surpasses its deacetylase function, suggesting broader implications in inflammatory processes. Mechanistic investigations reveal the critical involvement of HDAC7 in the Toll-like receptor 4 (TLR4) signaling pathway by directly interacting with the TNF receptor-associated factor 6 and TGFß-activated kinase 1 (TRAF6-TAK1) complex, thereby initiating the activation of the downstream mitogen-activated protein kinase/nuclear factor-κB (MAPK/NF-κB) signaling cascade and subsequent gene transcription. This study expands the insight into HDAC7's role within intricate inflammatory networks and highlights its therapeutic potential as a novel target for anti-inflammatory treatments.

Predicting pre- and post-operative acute kidney injury in elderly patients with coronary artery disease.

Background: Limited evidence exists regarding the clinical baseline characteristics at admission for acute kidney injury (AKI) before and after interventional cardiac procedures (ICP) in elderly patients with coronary artery disease (CAD). Methods: A total of 488 elderly patients were enrolled in this retrospective single-center study conducted from January 2019 to July 2022, and a classification and regression tree (CART) analysis was performed to identify the high-risk population. Results: The AKI incidence was 21.1 % (103/488) in this study, with 27 and 76 individuals developing AKI before and after ICP, respectively. CART analysis revealed that exposure to nephrotoxic drugs and diuretics had the strongest predictive capacities for identifying patients at risk of developing pre-ICP AKI, with the incidence among these high-risk patients ranging from 6.5 % to 13.8 %. Meanwhile, the optimum discriminators for identifying those at high risk of post-ICP AKI were the administration of diuretics, D-value ≤ -860 mL, age >73 years, and administration of nephrotoxic drugs, and the latter model predicted that the AKI incidence among high-risk patients was between 50.0 % and 60.0 %. Conclusions: Elderly patients with CAD exhibited an elevated incidence of AKI. CART models suggested that exposure to nephrotoxic drugs and diuretics, D-value, and age were significantly associated with AKI in the elderly with CAD. Importantly, these baseline characteristics at admission could be utilized to identify elderly patients at high risk of pre- and post-ICP AKI.

Effects of tanshinone IIA on endothelial cell dysfunction in uremic condition.

An arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis in uremic patients, yet its dysfunction poses a significant clinical challenge. Venous stenosis, primarily caused by venous neointimal hyperplasia, is a key factor in the failure of vascular access. During vascular access dysfunction, endothelial cells (ECs) transform mechanical stimuli into intracellular signals and interact with vascular smooth muscle cells. Tanshinone IIA, an important compound derived from Salvia miltiorrhiza, has been widely used to treat cardiovascular diseases. However, its role in modulating ECs under uremic conditions remains incompletely understood. In this research, ECs were exposed to sodium tanshinone IIA sulfonate (STS) and subjected to shear stress and uremic conditions. The results indicate that STS can reduce the suppressive effects on the expression of NF-κB p65, JNK and Collagen I in uremia-induced ECs. Moreover, the downregulation of NF-κB p65, JNK and Collagen I can be enhanced through the inhibition of ERK1/2 and the upregulation of Caveolin-1. These findings suggest that tanshinone IIA may improve EC function under uremic conditions by targeting the Caveolin-1/ERK1/2 pathway, presenting tanshinone IIA as a potential therapeutic agent against AVF immaturity caused by EC dysfunction.

Characterization of typical transuranic nuclides in a reference fallout material using SF-ICP-MS.

For the quality control in determining transuranic nuclides in fallout samples, this work first reported the 237Np activity concentration in a reference fallout material and further calculated the activity ratios of 237Np/239+240Pu and 237Np/241Am, and the atom ratio of 237Np/239Pu in it. The reference fallout material prepared by the Meteorological Research Institute was collected at 14 stations throughout Japan in 1963-1979. The 237Np and Pu isotopes (239Pu and 240Pu) were separated and purified using AG MP-1M anion-exchange resin, quantified using 242Pu as an isotope dilution tracer, and determined by the SF-ICP-MS. The analytical method was validated by the analysis of 4 sediment reference materials. The activity concentrations of 237Np, 239Pu and 240Pu were (25.9 ± 0.6) × 10-3, 4.10 ± 0.01 and 2.89 ± 0.04 Bq/kg, respectively, in the investigated reference fallout material. The activity ratio of 237Np/239+240Pu (3.7 ± 0.1) × 10-3 was consistent with the global fallout evaluation value. The 237Np/239Pu atom ratio of 0.561 ± 0.014 was higher than the average global fallout value of 0.41 ± 0.010, indicating the necessity of establishing regional characteristic global fallout value of 237Np/239Pu atom ratio for assessment of radioactive contamination. Comparison of the 237Np/239+240Pu activity ratios between in the reference fallout material and in soils over several decades indicated that 237Np has stronger migration capability than Pu isotopes in soils because 237Np was depleted compared to reference fallout material.

Rogue curves in the Davey-Stewartson I equation.

We report new rogue wave patterns whose wave crests form closed or open curves in the spatial plane, which we call rogue curves, in the Davey-Stewartson I equation. These rogue curves come in various striking shapes, such as rings, double rings, and many others. They emerge from a uniform background (possibly with a few lumps on it), reach high amplitude in such striking shapes, and then disappear into the same background again. We reveal that these rogue curves would arise when an internal parameter in bilinear expressions of the rogue waves is real and large. Analytically, we show that these rogue curves are predicted by root curves of certain types of double-real-variable polynomials. We compare analytical predictions of rogue curves to true solutions and demonstrate good agreement between them.

Multi-modal fusion and feature enhancement U-Net coupling with stem cell niches proximity estimation for voxel-wise GBM recurrence prediction.

Objective.We aim to develop a Multi-modal Fusion and Feature Enhancement U-Net (MFFE U-Net) coupling with stem cell niche proximity estimation to improve voxel-wise Glioblastoma (GBM) recurrence prediction.Approach.57 patients with pre- and post-surgery magnetic resonance (MR) scans were retrospectively solicited from 4 databases. Post-surgery MR scans included two months before the clinical diagnosis of recurrence and the day of the radiologicaly confirmed recurrence. The recurrences were manually annotated on the T1ce. The high-risk recurrence region was first determined. Then, a sparse multi-modal feature fusion U-Net was developed. The 50 patients from 3 databases were divided into 70% training, 10% validation, and 20% testing. 7 patients from the 4th institution were used as external testing with transfer learning. Model performance was evaluated by recall, precision, F1-score, and Hausdorff Distance at the 95% percentile (HD95). The proposed MFFE U-Net was compared to the support vector machine (SVM) model and two state-of-the-art neural networks. An ablation study was performed.Main results.The MFFE U-Net achieved a precision of 0.79 ± 0.08, a recall of 0.85 ± 0.11, and an F1-score of 0.82 ± 0.09. Statistically significant improvement was observed when comparing MFFE U-Net with proximity estimation couple SVM (SVMPE), mU-Net, and Deeplabv3. The HD95 was 2.75 ± 0.44 mm and 3.91 ± 0.83 mm for the 10 patients used in the model construction and 7 patients used for external testing, respectively. The ablation test showed that all five MR sequences contributed to the performance of the final model, with T1ce contributing the most. Convergence analysis, time efficiency analysis, and visualization of the intermediate results further discovered the characteristics of the proposed method.Significance. We present an advanced MFFE learning framework, MFFE U-Net, for effective voxel-wise GBM recurrence prediction. MFFE U-Net performs significantly better than the state-of-the-art networks and can potentially guide early RT intervention of the disease recurrence.

Feasibility of dose calculation for treatment plans using electron density maps from a novel dual-layer detector spectral CT simulator.

BACKGROUND: Conventional single-energy CT can only provide a raw estimation of electron density (ED) for dose calculation by developing a calibration curve that simply maps the HU values to ED values through their correlations. Spectral CT, also known as dual-energy CT (DECT) or multi-energy CT, can generate a series of quantitative maps, such as ED maps. Using spectral CT for radiotherapy simulations can directly acquire ED information without developing specific calibration curves. The purpose of this study is to assess the feasibility of utilizing electron density (ED) maps generated by a novel dual-layer detector spectral CT simulator for dose calculation in radiotherapy treatment plans. METHODS: 30 patients from head&neck, chest, and pelvic treatment sites were selected retrospectively, and all of them underwent spectral CT simulation. Treatment plans based on conventional CT images were transplanted to ED maps with the same structure set, including planning target volume (PTV) and organs at risk (OARs), and the dose distributions were then recalculated. The differences in dose and volume histogram (DVH) parameters of the PTV and OARs between the two types of plans were analyzed and compared. Besides, gamma analysis between these plans was performed by using MEPHYSTO Navigator software. RESULTS: In terms of PTV, the homogeneity index (HI), gradient index (GI), D2%, D98%, and Dmean showed no significant difference between conventional plans and ED plans. For OARs, statistically significant differences were observed in parotids D50%, brainstem in head&neck plans, spinal cord in chest plans and rectum D50% in pelvic plans, whereas the variance remained minor. For the rest, the DVH parameters exhibited no significant difference between conventional plans and ED plans. All of the mean gamma passing rates (GPRs) of gamma analysis were higher than 90%. CONCLUSION: Compared to conventional treatment plans relying on CT images, plans utilizing ED maps demonstrated similar dosimetric quality. However, the latter approach enables direct utilization in dose calculation without the requirements of establishing and selecting a specific Hounsfield unit (HU) to ED calibration curve, providing an advantage in clinical applications.

Association of thyroid hormone with osteoarthritis: from mendelian randomization and RNA sequencing analysis.

BACKGROUND: The relationship between thyroid hormone (TH) levels in vivo and osteoarthritis (OA) remains inconclusive. This study aims to investigate the association between TH levels and OA, analyze the effect of triiodothyronine on hypertrophic chondrocyte differentiation and OA progression, and identify potential target genes of triiodothyronine in OA to evaluate its diagnostic value. METHODS: Two-sample mendelian randomization method was used to probe the causal links between hyperthyroidism and OA. Differentially expressed genes (DEGs) from two RNA-sequencing data in Gene Expression Omnibus (GSE199847 and GSE114007) and enrichment analysis of DEGs (166 commonly upregulated genes and 71 commonly downregulated genes of GSE199847 and GSE114007) was performed to analyze the effect of triiodothyronine (T3) on hypertrophic chondrocyte differentiation and OA. C28/I2 cells treated with T3 and reverse transcription and quantitative real-time polymerase chain reaction were used to validate T3 targeted genes. The diagnostic performance of target genes was assessed by the receiver operating characteristic (ROC) curve and area under the curve (AUC). RESULTS: There was a positive causal association between hyperthyroidism and OA (IVW result, OR = 1.330, 95% CI 1.136-1.557, P = 0.0004). Weighted median and Weighted mode analysis also demonstrated that hyperthyroidism had a positive causal association with OA (p < 0.05, OR > 1). Bioinformatics analysis indicated T3 can partially induce the emergence of late hypertrophic chondrocyte and promote OA through extracellular matrix organization, blood vessel development, skeletal system development and ossification. Post-T3 treatment, MAFB, C1QTNF1, COL3A1 and ANGPTL2 were significantly elevated in C28/I2 cells. ROC curves in GSE114007 showed that AUC of all above genes were ≥ 0.7. CONCLUSIONS: This study identified that hyperthyroidism has a positive causal association with OA by MR analysis. T3 induced hypertrophic chondrocytes promote OA progression by upregulating genes such as MAFB, C1QTNF1, COL3A1 and ANGPTL2, which can also serve as OA diagnosis.

Application of Emerging Teaching Models in Dental Education: A Systematic Review and Meta-Analysis.

INTRODUCTION AND AIMS: As an experimental teaching method, emerging learning methods including problem-based learning (PBL), case-based learning, team-based learning and flipped classroom (FC) have been widely applied in dental education. This study aims to evaluate the effect of these teaching methods on dental education performance compared to traditional lecture-based learning (LBL). METHODS: The search was carried out in April 2024 in PubMed, EMBASE, Web of Science, and Cochrane Library. All randomized controlled trials were included and the methodological quality assessment was based on the guidelines described in the Cochrane Handbook for Systematic Reviews, followed by a meta-analysis using Stata 14.0 software. Using standard mean deviation (SMD) and 95% confidence interval (95% CI) to determine the effectiveness of emerging teaching methods and LBL in all dental disciplines. Meta-regression was used to analyse sources of heterogeneity. Sensitivity analysis was performed to determine the stability, and Begg's analysis was used to determine whether there is publication bias. RESULTS: A total of 29 randomized controlled trials including 3502 students were included. The results indicate that emerging educational methods have a significantly positive effect on achieving higher scores (SMD = 0.48, 95% CI = 0.34-0.62, P < .001), whether it was theoretical scores (SMD = 0.52, 95% CI = 0.32-0.72, P < .001) or skill scores (SMD = 0.45, 95% CI = 0.15-0.76, P < .001). Compared to LBL, PBL (SMD = 0.33, 95% CI = 0.01-0.65, P = .045) and FC (SMD = 0.50, 95% CI = 0.31-0.69, P < .001) can both significantly improve students' academic performance. CONCLUSION: Compared to LBL, emerging educational methods (PBL, case-based learning, and FC) have significantly improved the learning effectiveness of dental students. These emerging educational methods can be advocated and popularized as routine teaching methods. CLINICAL RELEVANCE: This study is the first meta-analysis of the effects of emerging teaching methods in dental education which shows great impact of emerging teaching methods on students' development.

Identification of 5-Thiocyanatothiazol-2-amines Disrupting WDR5-MYC Protein-Protein Interactions.

MYC amplification is frequently observed in approximately 50% of human cancers, rendering it a highly desired anticancer target. Given the challenge of direct pharmacological inhibiting of MYC, impairing the interaction of MYC and its key cofactor WDR5 has been proposed as a promising strategy for MYC-driven cancer treatment. Herein, we report the discovery of 5-thiocyanatothiazol-2-amines that disrupt the WDR5-MYC interaction. Hit fragments were initially identified in a fluorescence polarization (FP)-based screening of an in-house library, and structural-activity relationship exploration resulted in the lead compounds 4m and 4o with potent inhibitory activities on WDR5-MYC interaction (K i = 2.4 µM for 4m; K i = 1.0 µM for 4o). These compounds were further validated via differential scanning fluorimetry (DSF) and coimmunoprecipitation (Co-IP). Moreover, 4m and 4o exhibited good cellular activities with the IC50 values at the micromolar level (IC50 = 0.71-7.40 µM) against multiple MYC-driven cancer cell lines. Our findings afforded a potential small molecule blocking the WDR5-MYC interaction.

The association between fatty acids and atherosclerotic diseases: A mendelian randomization study.

BACKGROUND: The current observational studies have disputed the relationship between various fatty acids and atherosclerotic diseases, and the causal relationship between the two is still unclear. METHODS: In this study, we utilized the available genome-wide association studies (GWAS) summary data on fatty acids and atherosclerotic diseases from the IEU OpenGWAS project. After identifying the appropriate single nucleotide polymorphisms (SNPs) as instrumental variables, we employed the MR-PRESSO outlier test to remove extreme values. Subsequently, we conducted a two-sample mendelian randomization (MR) analysis and performed sensitivity analyses to ensure the reliability of the results. RESULTS: The results of MR analysis suggest that ratio of saturated fatty acids to total fatty acids is positively correlated with the incidence rate of coronary heart disease (OR = 1.341, 95% CI = 1.016-1.769, P value = 0.038), monounsaturated fatty acid levels is negatively correlated with the incidence of stroke (OR = 0.800, 95% CI = 0.642-0.996, P value = 0.046), and docosahexaenoic acid levels is negatively correlated with the incidence of peripheral artery disease (OR = 0.747, 95% CI = 0.572-0.976, P value = 0.033). All results showed no heterogeneity or pleiotropy, but leave-one-out tests showed that the analysis results of some fatty acids were driven by a single SNP. CONCLUSIONS: This study highlights the existence of causal relationships between fatty acids and atherosclerotic diseases at the genetic level. These findings provide valuable insights for potential prevention measures and therapeutic targets for the three atherosclerotic diseases.

Correlation Between Dynamic Spray Plume and Drug Deposition of Solution-Based Pressurized Metered-Dose Inhalers.

Background: The lack of visual dynamic spray characterization has made the understanding of the physical processes governing atomization and drug particle formation difficult. This study aimed to investigate the changes in the spray plume morphology and aerodynamic particle size of solution-based pressurized metered-dose inhalers (pMDIs) under different conditions to achieve better drug deposition. Methods: Solution-based pMDIs were studied, and the effects of various factors, such as propellant concentration, orifice diameters, and atomization chamber volume, on drug deposition were examined by analyzing the characteristics of spray plume and aerodynamic particle size. Results: Reducing the actuator orifice and spray area led to a concentrated spray plume and increased duration and speed. Moreover, the aerodynamic particle sizes D50 and D90 decreased, whereas D10 remained relatively unchanged. Decreasing the atomization chamber volume of the actuator led to reduced spray area and an increased duration but a decreased plume velocity. D90 exhibited a decreasing trend, whereas D10 and D50 remained relatively unchanged. Reducing the propellant concentration in the prescription, the spray area and the plume velocity first decreased and then increased. The duration initially increased and then decreased. The values of D50 and D90 showed an initial decreasing followed by an increasing trend, whereas D10 remained relatively unchanged. Conclusions: During the development process, attention should be paid to the changes in the spray area, spray angle, duration, and speed of the spray plume. This study recommended analyzing the characteristics of the spray plume and combining the data of two or more aerodynamic particle size detection methods to verify the deposition in vitro to achieve rapid screening and obtain high lung deposition in vivo.

Identification of Distinct, Quantitative Pattern Classes from Emergent Tissue-Scale hiPSC Bioelectric Properties.

Bioelectric signals possess the ability to robustly control and manipulate patterning during embryogenesis and tissue-level regeneration. Endogenous local and global electric fields function as a spatial 'pre-pattern', controlling cell fates and tissue-scale anatomical boundaries; however, the mechanisms facilitating these robust multiscale outcomes are poorly characterized. Computational modeling addresses the need to predict in vitro patterning behavior and further elucidate the roles of cellular bioelectric signaling components in patterning outcomes. Here, we modified a previously designed image pattern recognition algorithm to distinguish unique spatial features of simulated non-excitable bioelectric patterns under distinct cell culture conditions. This algorithm was applied to comparisons between simulated patterns and experimental microscopy images of membrane potential (Vmem) across cultured human iPSC colonies. Furthermore, we extended the prediction to a novel co-culture condition in which cell sub-populations possessing different ionic fluxes were simulated; the defining spatial features were recapitulated in vitro with genetically modified colonies. These results collectively inform strategies for modeling multiscale spatial characteristics that emerge in multicellular systems, characterizing the molecular contributions to heterogeneity of membrane potential in non-excitable cells, and enabling downstream engineered bioelectrical tissue design.

Ualign: pushing the limit of template-free retrosynthesis prediction with unsupervised SMILES alignment.

MOTIVATION: Retrosynthesis planning poses a formidable challenge in the organic chemical industry, particularly in pharmaceuticals. Single-step retrosynthesis prediction, a crucial step in the planning process, has witnessed a surge in interest in recent years due to advancements in AI for science. Various deep learning-based methods have been proposed for this task in recent years, incorporating diverse levels of additional chemical knowledge dependency. RESULTS: This paper introduces UAlign, a template-free graph-to-sequence pipeline for retrosynthesis prediction. By combining graph neural networks and Transformers, our method can more effectively leverage the inherent graph structure of molecules. Based on the fact that the majority of molecule structures remain unchanged during a chemical reaction, we propose a simple yet effective SMILES alignment technique to facilitate the reuse of unchanged structures for reactant generation. Extensive experiments show that our method substantially outperforms state-of-the-art template-free and semi-template-based approaches. Importantly, our template-free method achieves effectiveness comparable to, or even surpasses, established powerful template-based methods. SCIENTIFIC CONTRIBUTION: We present a novel graph-to-sequence template-free retrosynthesis prediction pipeline that overcomes the limitations of Transformer-based methods in molecular representation learning and insufficient utilization of chemical information. We propose an unsupervised learning mechanism for establishing product-atom correspondence with reactant SMILES tokens, achieving even better results than supervised SMILES alignment methods. Extensive experiments demonstrate that UAlign significantly outperforms state-of-the-art template-free methods and rivals or surpasses template-based approaches, with up to 5% (top-5) and 5.4% (top-10) increased accuracy over the strongest baseline.

Liquid-Based Cytology of Small Cell Carcinoma of the Cervix: A Multicenter Retrospective Study.

Background/Aims: There are currently few reports describing the liquid-based cytological characteristics of small cell neuroendocrine carcinoma of the cervix. This study aimed to retrospectively analyze these features to reduce missed or misdiagnosis. Methods: A total of 11 patients with histologically diagnosed small cell carcinoma of the cervix from three hospitals between 2017 and 2023 were included in this study. The cytological morphology of small cell carcinoma of the cervix and causes of missed or misdiagnosis were analyzed and summarized through a review of clinical data, liquid-based cytology, histology, immunohistochemistry, and human papillomaviruses (HPV) test results. Results: In this study, the positivity rate of preliminary cytological screening was 63.6% (7/11); however, no cases were accurately diagnosed as small cell carcinoma of the cervix. A total of 36.4% (4/11) of small cell carcinoma of the cervix cases were cytologically negative; retrospective cytology found that two of these were false negatives. The main cytological features of small cell carcinoma of the cervix were summarized. Most of the liquid-based cytology smear cells were dense, and almost all cases showed clustered and scattered cytoplasm-scanty tumor cells. The tumor cells were all deeply stained and relatively consistent small cells. Most cases showed typical nuclear molding, chromatin stippling, and no obvious nucleoli. Mild nuclear smears, nuclear fragments, and mitotic figures were seen in most cases. Conclusion: Liquid-based cytology has a high rate of missed diagnosis and misdiagnosis in small cell carcinoma of the cervix. This study confirms that reviewing cytology results can effectively reduce this proportion and that increasing understanding of small cell carcinoma of the cervix morphology is conducive to improving the cytology-based diagnosis rate.

Protective effect and mechanism of Xiaoyu Xiezhuo decoction on ischemia-reperfusion induced acute kidney injury based on gut-kidney crosstalk.

This study aimed to explore the mechanism of Xiaoyu Xiezhuo decoction (XXD) on ischemia-reperfusion-induced acute kidney injury (IRI-AKI) using network pharmacology methods and gut microbiota analysis. A total of 1778 AKI-related targets were obtained, including 140 targets possibly regulated by AKI in XXD, indicating that the core targets were mainly enriched in inflammatory-related pathways, such as the IL-17 signaling pathway and TNF signaling pathway. The unilateral IRI-AKI animal model was established and randomly divided into four groups: the sham group, the AKI group, the sham + XXD group, and the AKI + XXD group. Compared with the rats in the AKI group, XXD improved not only renal function, urinary enzymes, and biomarkers of renal damage such as Kim-1, cystatin C, and serum inflammatory factors such as IL-17, TNF-α, IL-6, and IL 1-ß, but also intestinal metabolites including lipopolysaccharides, d-lactic acid, indoxyl sulfate, p-cresyl sulfate, and short-chain fatty acids. XXD ameliorated renal and colonic pathological injury as well as inflammation and chemokine gene abundance, such as IL-17, TNF-α, IL-6, IL-1ß, ICAM-1, and MCP-1, in AKI rats via the TLR4/NF-κB/NLRP3 pathway, reducing the AKI score, renal pathological damage, and improving the intestinal mucosa's inflammatory infiltration. It also repaired markers of the mucosal barrier, including claudin-1, occludin, and ZO-1. Compared with the rats in the AKI group, the α diversity was significantly increased, and the Chao1 index was significantly enhanced after XXD treatment in both the sham group and the AKI group. The treatment group significantly reversed this change in microbiota.