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AIM: To compare the short-term effectiveness of intelligent navigated laser photocoagulation and 577-nm subthreshold micropulse laser (SML) treatment in patients with chronic central serous chorioretinopathy (cCSC). METHODS: This observational retrospective cohort study included 60 consecutive patients who underwent intelligent navigated laser photocoagulation (n=30) or 577-nm SML treatment (n=30) for cCSC between Jan. 2021 and Oct. 2022. During 3mo follow-up, all patients underwent assessments of best correct visual acuity (BCVA) and optical coherence tomography (OCT). RESULTS: The operation of laser treatment was successful in all cases. At 1mo, BCVA improved significantly more in the intelligent navigated laser photocoagulation group compared to the SML group (P0.05). Central macular thickness (CMT) in the intelligent navigated laser photocoagulation group was lower than in the SML group at 1mo (P0.05). CONCLUSION: Intelligent navigated laser photocoagulation is superior to SML for treating cCSC, leading to better improvements in vision and CMT for short term.

In ophthalmology, the quality of fundus images is critical for accurate diagnosis, both in clinical practice and in artificial intelligence (AI)-assisted diagnostics. Despite the broad view provided by ultrawide-field (UWF) imaging, pseudocolor images may conceal critical lesions necessary for precise diagnosis. To address this, we introduce UWF-Net, a sophisticated image enhancement algorithm that takes disease characteristics into consideration. Using the Fudan University ultra-wide-field image (FDUWI) dataset, which includes 11 294 Optos pseudocolor and 2415 Zeiss true-color UWF images, each of which is rigorously annotated, UWF-Net combines global style modeling with feature-level lesion enhancement. Pathological consistency loss is also applied to maintain fundus feature integrity, significantly improving image quality. Quantitative and qualitative evaluations demonstrated that UWF-Net outperforms existing methods such as contrast limited adaptive histogram equalization (CLAHE) and structure and illumination constrained generative adversarial network (StillGAN), delivering superior retinal image quality, higher quality scores, and preserved feature details after enhancement. In disease classification tasks, images enhanced by UWF-Net showed notable improvements when processed with existing classification systems over those enhanced by StillGAN, demonstrating a 4.62% increase in sensitivity (SEN) and a 3.97% increase in accuracy (ACC). In a multicenter clinical setting, UWF-Net-enhanced images were preferred by ophthalmologic technicians and doctors, and yielded a significant reduction in diagnostic time ((13.17 ± 8.40) s for UWF-Net enhanced images vs (19.54 ± 12.40) s for original images) and an increase in diagnostic accuracy (87.71% for UWF-Net enhanced images vs 80.40% for original images). Our research verifies that UWF-Net markedly improves the quality of UWF imaging, facilitating better clinical outcomes and more reliable AI-assisted disease classification. The clinical integration of UWF-Net holds great promise for enhancing diagnostic processes and patient care in ophthalmology.

Abstract Background Pericardiectomy due to constrictive pericarditis is usually safe procedure. There was a rare event of thrombosis after pericardiectomy, which was mainly accounted by low-cardiac-output syndrome. Case presentation Here, we report the case undergoing pericardiectomy after constrictive pericarditis, with fatal cerebral thrombosis after pericardiectomy confirmed by endovascular mechanical thrombectomy. Even though recanalization was completed and suggestive decompressive craniectomy was in preparation, the patient still died for cerebral hernia due to severe edema. The causes of cerebral thrombosis after pericardiectomy in this case was accounted by the persistence of nonpliable pericardium encasing the left ventricular wall limited local myocardium motor, pro-coagulable state due to thermal transmission during decortication like radiofrequency ablation under the condition of postoperative atrial fibrillation and rapid ventricular rates precipitated the information of mural thrombus in cardiac cavity and migration into the main branch of the aortic arch. Conclusion The protocol of prompt aggressive anticoagulation prophylaxis would be vigilantly recommended for the patients undergoing pericardiectomy.

Abstract DNA methylation (DNAm) has been implicated in acute coronary syndrome (ACS), but the causality remains unclear in cross-sectional studies. Here, we conduct a prospective epigenome-wide association study of incident ACS in two Chinese cohorts (discovery: 751 nested case-control pairs; replication: 476 nested case-control pairs). We identified and validated 26 differentially methylated positions (DMPs, false discovery rate [FDR]

Abstract Introduction To assess the safety and efficacy of repeated intravitreal injections of RC28-E, a novel bispecific antibody that simultaneously binds vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with neovascular age-related macular degeneration (AMD). This was a prospective, multicenter, open-label clinical trial; 37 patients with choroidal neovascularization secondary to AMD and best-corrected visual acuity (BCVA) letter scores between 73 and 34 were enrolled. Methods Treatment regimens consisted of a 3-month loading phase and a pro re nata (PRN) maintenance phase. This study included three treatment groups: the 0.5, 1.0, and 2.0 mg RC28-E groups, with escalating doses ranging from 0.5 to 2.0 mg. Patients were evaluated monthly for 48 weeks. Safety was assessed based on ocular and systemic adverse events (AEs), pharmacokinetic characteristics, and the presence of anti-RC28-E antibodies. Efficacy was assessed using the mean change in BCVA and central subfield thickness (CST) from baseline to week 48. Results Most AEs were mild or moderate. The most common AE was a minor injection-related subconjunctival hemorrhage (16.2%). The AEs did not increase with dose or repeated injections. At week 48, mean improvements in BCVA from baseline in the 0.5, 1.0, and 2.0 mg groups were 6.1 ± 8.3, 9.9 ± 10.7, and 7.6 ± 9.38 letters, respectively; mean reductions in CST in the three groups were 112.1 ± 160.5, 175.1 ± 212.4, and 128.7 ± 145.8 μm, respectively. The serum RC28-E concentrations in 95% of the patients were below the quantification limit of the assay. No significant change from baseline was observed in the mean plasma concentrations of VEGF or FGF over the 48 weeks of treatment. Pre-treatment antibodies to RC28-E were detected in 1 of the 37 patients. Antibodies to RC28-E were detected in two patients after dosing with RC28-E for 48 weeks. Conclusion RC28-E was well tolerated and exhibited an overall favorable safety profile with evidence of improvements in BCVA and anatomical parameters.

Abstract Round-shoulder posture (RSP) is a common postural condition, characterized by protraction, downward rotation, anterior tilting and internal rotation of the scapula. RSP can lead to shoulder dysfunction. Different methods have been proposed for rehabilitating and correcting the altered posture in RSP including stretching, strengthening exercises, and shoulder brace or taping. However, the findings are controversial and studies are ongoing to develop more effective method. The present study is aimed at investigating the effects of scapular posterior tilting (SPT) exercise in different support positions on scapular muscle activities in men and women with RSP. In a prospective observational clinical study, we assessed demographic, basic clinical parameters and study variables of the subjects with RSP (n = 20) (men/women = 9/11) attending Daegu University in Gyeongsan, South Korea. To do so, we compared electromyographic (EMG) activities of lower trapezius and serratus anterior muscles between men and women with RSP during SPT exercise on four different support surfaces to determine any difference in the EMG activities. The results revealed that women showed significant differences in EMG activities in the lower and left upper trapezius and serratus anterior muscles, while men showed significant differences in EMG activity only in the lower trapezius muscle during SPT exercise on four different surfaces (P 0.0125).

Abstract Feed efficiency (FE) is essential for pig production, has been reported to be partially explained by gut microbiota. Despite an extensive body of research literature to this topic, studies regarding the regulation of feed efficiency by gut microbiota remain fragmented and mostly confined to disorganized or semi-structured unrestricted texts. Meanwhile, structured databases for microbiota analysis are available, yet they often lack a comprehensive understanding of the associated biological processes. Therefore, we have devised an approach to construct a comprehensive knowledge graph by combining unstructured textual intelligence with structured database information and applied it to investigate the relationship between pig gut microbes and FE. Firstly, we created the pgmReading knowledge base and the domain ontology of pig gut microbiota by annotating, extracting, and integrating semantic information from 157 scientific publications. Secondly, we created the pgmPubtator by utilizing PubTator to expand the semantic information related to microbiota. Thirdly, we created the pgmDatabase by mapping and combining the ADDAGMA, gutMGene, and KEGG databases based on the ontology. These three knowledge bases were integrated to form the Pig Gut Microbial Knowledge Graph (PGMKG). Additionally, we created five biological query cases to validate the performance of PGMKG. These cases not only allow us to identify microbes with the most significant impact on FE but also provide insights into the metabolites produced by these microbes and the associated metabolic pathways. This study introduces PGMKG, mapping key microbes in pig feed efficiency and guiding microbiota-targeted optimization.

Abstract Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that acid-sensing ion channel 3 (ASIC3) exacerbates psoriatic inflammation through a sensory neurogenic pathway. Global or nociceptor-specific Asic3 knockout (KO) in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation to the same extent as nociceptor ablation. However, ASIC3 is dispensable for IL-23-induced psoriatic inflammation that bypasses the need for nociceptors. Mechanistically, ASIC3 activation induces the activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons to promote neurogenic inflammation. Botulinum neurotoxin A and CGRP antagonists prevent sensory neuron-mediated exacerbation of psoriatic inflammation to similar extents as Asic3 KO. In contrast, replenishing CGRP in the skin of Asic3 KO mice restores the inflammatory response. These findings establish sensory ASIC3 as a critical constituent in psoriatic inflammation, and a promising target for neurogenic inflammation management.

Abstract Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating mitochondrial transcription and oxidative phosphorylation. In our study, we examined the impact of POLRMT on angiogenesis and found that its silencing or knockout (KO) in human umbilical vein endothelial cells (HUVECs) and other endothelial cells resulted in robust anti-angiogenic effects, impeding cell proliferation, migration, and capillary tube formation. Depletion of POLRMT led to impaired mitochondrial function, characterized by mitochondrial depolarization, oxidative stress, lipid oxidation, DNA damage, and reduced ATP production, along with significant apoptosis activation. Conversely, overexpressing POLRMT promoted angiogenic activity in the endothelial cells. In vivo experiments demonstrated that endothelial knockdown of POLRMT, by intravitreous injection of endothelial specific POLRMT shRNA adeno-associated virus, inhibited retinal angiogenesis. In addition, inhibiting POLRMT with a first-in-class inhibitor IMT1 exerted significant anti-angiogenic impact in vitro and in vivo. Significantly elevated expression of POLRMT was observed in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. POLRMT endothelial knockdown inhibited pathological retinal angiogenesis and mitigated retinal ganglion cell (RGC) degeneration in DR mice. At last, POLRMT expression exhibited a substantial increase in the retinal proliferative membrane tissues of human DR patients. These findings collectively establish the indispensable role of POLRMT in angiogenesis, both in vitro and in vivo.

Abstract Background Intravitreal injections of angiogenesis inhibitors have proved efficacious in the majority of patients with ocular angiogenesis. However, one-fourth of all treated patients fail to derive benefits from intravitreal injections. tRNA-derived small RNA (tsRNA) emerges as a crucial class of non-coding RNA molecules, orchestrating key roles in the progression of human diseases by modulating multiple targets. Through our prior sequencing analyses and bioinformatics predictions, tRNA-Cys-5-0007 has shown as a potential regulator of ocular angiogenesis. This study endeavors to elucidate the precise role of tRNA-Cys-5-0007 in the context of ocular angiogenesis. Methods Quantitative reverse transcription PCR (qRT-PCR) assays were employed to detect tRNA-Cys-5-0007expression. EdU assays, sprouting assays, transwell assays, and Matrigel assays were conducted to elucidate the involvement of tRNA-Cys-5-0007 in endothelial angiogenic effects. STZ-induced diabetic model, OIR model, and laser-induced CNV model were utilized to replicate the pivotal features of ocular vascular diseases and evaluate the influence of tRNA-Cys-5-0007 on ocular angiogenesis and inflammatory responses. Bioinformatics analysis, luciferase activity assays, RNA pull-down assays, and in vitro studies were employed to elucidate the anti-angiogenic mechanism of tRNA-Cys-5-0007. Exosomal formulation was employed to enhance the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007. Results tRNA-Cys-5-0007 expression was down-regulated under angiogenic conditions. Conversely, tRNA-Cys-5-0007 overexpression exhibited anti-angiogenic effects in retinal endothelial cells, as evidenced by reduced proliferation, sprouting, migration, and tube formation abilities. In diabetic, laser-induced CNV, and OIR models, tRNA-Cys-5-0007 overexpression led to decreased ocular vessel leakage, inhibited angiogenesis, and reduced ocular inflammation. Mechanistically, these effects were attributed to the targeting of vascular endothelial growth factor A (VEGFA) and TGF-β1 by tRNA-Cys-5-0007. The utilization of an exosomal formulation further potentiated the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007. Conclusions Concurrent targeting of tRNA-Cys-5-0007 for anti-angiogenic and anti-inflammatory therapy holds promise for enhancing the effectiveness of current anti-angiogenic therapy.

Abstract Implantable neural probes, essential for brain electrophysiological research, have advanced with ultra-flexible designs to mitigate immune responses and postoperative complications. Strategies of shuttle-assisted implantation and temporary stiffening address issues in penetrating these probes into the target region, avoiding undesired bending. However, the risk of intraoperative bleeding remains due to these implants’ necessary rigidity during insertion. Here, we describe a neural probe with mechanical compliance accompanying self-implantation along the principal axis in the absence of bleeding. Crucial to the behavior is its anisotropic relaxation, which is dominated by the cross-sectional in-plane deformation inhibition due to interchain interactions between the parallel backbones in the globally aligned polymer system. We observed the ensured upright insertion of the probe into the brain while avoiding angiorrhexis with a two-photon microscope and a high-speed camera. The probes permit electrophysiological studies with minimal foreign body responses and imageological compatibility, underscoring their clinical potential.

Abstract Mangrove‐saltmarsh ecotones are experiencing rapid alterations due to climate change and human activities, however, the ecological and morphological implications of these shifts remain largely unknown. This study systematically explores how interspecific interactions and herbivory influence the dominant wetland species, as well as the resultant morphological evolution and landscape configuration. To achieve this, we develop a new eco‐morphodynamic model that integrates hydrodynamics, sediment transport, bed‐level change, and vegetation dynamics. The novelty of the current model lies in newly incorporated modules to simulate biotic interactions between mangroves and saltmarshes, enabling exploration of eco‐morphodynamic feedback in mangrove‐saltmarsh ecotones in response to tidal flows and species interactions. Our results show that vertical growth rates of coexisting vegetation species are dominant factors in determining wetland dominance. When mangroves and saltmarshes exhibit comparable growth rates, mangroves typically become the dominant wetland species. Conversely, if mangroves grow more slowly than saltmarshes, they are unable to outcompete saltmarshes. Additionally, herbivory can fundamentally alter wetland dominance depending on herbivore food preferences. Our simulations further underline that saltmarsh‐dominated wetlands develop channel networks more extensively and rapidly than mangrove‐dominated systems. This pattern is also observed during species invasions, with invading saltmarshes extending channel networks, while invading mangroves inhibit ongoing network expansion. This study highlights the pivotal roles of relative growth properties and herbivory in driving ecotone development in respect to wetland dominance and channel network development at the intertidal scale.

Abstract Background Although RANK‐LRANK interaction is essential for osteoclastogenesis, the mechanisms by which cancer cells invade bone tissues and initiate osteolytic metastasis remain unclear. Here, we show that the hyperactivation of RelB fosters prostate cancer (PCa) osteolytic metastasis by coordinating interleukin‐8 (IL‐8) and calcium‐binging protein A4 (S100A4). Methods The factors promoting PCa bone metastasis were investigated in sera from PCa patients and tumour tissues derived from nude mice using immunohistochemical analysis and enzyme‐linked immunosorbent assays (ELISA). Cell mobility and mineralization were quantified using BioStation CT and Osteolmage assay. The relative cistrome was investigated in advanced PCa cells by standard transcriptional analyses, including the luciferase reporter response, site‐directed mutagenesis, and chromatin immunoprecipitation (ChIP) assay. PCa cell‐initiated tumour formation, expansion, and bone metastasis were validated in mice using multiple approaches, including orthotopic, intraskeletal, and caudal arterial implantation models. Results IL‐8 and S100A4 correlated with patient Gleason scores and bone metastasis. RelB upregulated IL‐8, facilitating androgen receptor (AR)‐independent growth. RelB‐Sp1 interaction enhanced epithelial‐mesenchymal transition (EMT) by activating Snail and Twist. RelB‐NFAT1c super‐enhancer upregulated S100A4 in the organization of the cytoskeleton and bone metastasis. The RelB‐IL‐8‐S100A4 signalling axis was confirmed to promote osteolytic metastasis in nude mice. Conclusion RelB‐IL‐8 reciprocally promoted EMT by activating inflammatory signalling and inactivating AR signalling. IL‐8 is essential for provoking PCa metastasis but insufficient to drive bone metastasis. IL‐8‐S100A4 cooperation was necessary for metastatic cells to target the bone. Highlights RelB activates inflammatory signalling by upregulating IL‐8 and suppressing AR. RelB upregulates S100A4 by cooperating with NFATC1. IL‐8 boosts EMT by activating Snail 1 and Twist 1, and S100A4 exacerbates osteolytic metastasis via calcium consumption. RelB harnesses IL‐8 and S100A4 to drive PCa osteolytic metastasis.

Abstract Lymphangiogenesis plays a pivotal role in the pathogenesis of various vascular disorders, including ocular vascular diseases and cancers. Deregulation of N6‐methyladenosine (m6A) modification has been identified as a key contributor to human diseases. However, the specific involvement of m6A modification in lymphatic remodeling remains poorly understood. In this study, we demonstrate that inflammatory stimulation and corneal sutures induce elevated levels of methyltransferase‐like 3 (METTL3)‐mediated m6A modification. METTL3 knockdown inhibits lymphatic endothelial viability, proliferation, migration, and tube formation in vitro. METTL3 knockdown attenuates corneal sutures‐induced lymphangiogenesis and intratumoral lymphangiogenesis initiated by subcutaneous grafts, consequently restraining corneal neovascularization, tumor growth, and tumor neovascularization in vivo. Mechanistically, METTL3 knockdown upregulates prostaglandin–endoperoxide synthase 2 expression through an m6A–YTHDF2‐dependent pathway, enhancing the synthesis of cyclopentenone prostaglandins (CyPGs). Aberrant CyPG production in lymphatic endothelial cells impairs mitochondrial oxidative phosphorylation, contributing to pathological lymphangiogenesis. Moreover, selective inhibition of METTL3 with STM2457 reduces m6A levels in lymphatic endothelial cells, effectively suppressing pathological lymphangiogenesis. This study provides compelling evidence that lymphatic‐specific METTL3 plays a critical role in vascular patterning through prostaglandin metabolism reprogramming. Thus, METTL3 emerges as a promising target for treating lymphangiogenesis‐related diseases.

With the use of metagenomic next-generation sequencing, patients diagnosed with Whipple pneumonia are being increasingly correctly diagnosed. We report a series of 3 cases in China that showed a novel pattern of movable infiltrates and upper lung micronodules. After treatment, the 3 patients recovered, and lung infiltrates resolved.

Abstract Uveal melanoma (UVM), an uncommon yet potentially life-threatening ocular cancer, arises from melanocytes in the uveal tract of the eye. The exploration of novel oncotargets for UVM is of paramount importance. In this study, we show that PCK1 (phosphoenolpyruvate carboxykinase 1) expression is upregulated in various UVM tissues as well as in primary UVM cells and immortalized lines. Furthermore, bioinformatics studies reveal that PCK1 overexpression in UVM correlates with advanced disease stages and poor patient survival. Genetic silencing (utilizing viral shRNA) or knockout (via CRISPR/Cas9) of PCK1 significantly curtailed cell viability, proliferation, cell cycle progression, and motility, while provoking apoptosis in primary and immortalized UVM cells. Conversely, ectopic overexpression of PCK1, achieved through a viral construct, bolstered UVM cell proliferation and migration. Gαi3 expression and Akt phosphorylation were reduced following PCK1 silencing or knockout, but increased after PCK1 overexpression in UVM cells. Restoring Akt phosphorylation through a constitutively active mutant Akt1 (S473D) ameliorated the growth inhibition, migration suppression, and apoptosis induced by PCK1 silencing in UVM cells. Additionally, ectopic expression of Gαi3 restored Akt activation and counteracted the anti-UVM cell effects by PCK1 silencing. In vivo, the growth of subcutaneous xenografts of primary human UVM cells was significantly inhibited following intratumoral injection of adeno-associated virus (aav) expressing PCK1 shRNA. PCK1 depletion, Gαi3 downregulation, Akt inhibition, proliferation arrest, and apoptosis were detected in PCK1-silenced UVM xenografts. Collectively, our findings demonstrate that PCK1 promotes UVM cell growth possibly by modulating the Gαi3-Akt signaling pathway.

Background This study aimed to explore the effect of a P2Y12 inhibitor regimen on the occurrence of postoperative atrial fibrillation (POAF) after off‐pump coronary artery bypass graft surgery in carriers with the cytochrome P450 family 2 subfamily C member19 loss‐of‐function allele. Methods and Results From May 2019 to November 2023, patients containing the cytochrome P450 family 2 subfamily C member19*2 or *3 allele undergoing elective first‐time off‐pump coronary artery bypass graft surgery including aspirin 100 mg/d and ticagrelor 180 mg/d (AT group; n=95) versus clopidogrel 75 mg/d (aspirin and clopidogrel group; n=95) were prospectively followed. The primary end point was the cumulative incidence of POAF in a week. The secondary end points were POAF burden, platelet aggregability, systemic immune‐inflammation index and heart rate variability. The incidence of POAF was 21.1% in the AT group versus 41.1% in the aspirin and clopidogrel group (hazard ratio, 0.46 [95% CI, 0.27–0.76]; P=0.003). POAF burden, ADP‐induced platelet aggregation and systemic immune‐inflammation index was notably lower in the AT group than the aspirin and clopidogrel group. Heart rate variability data showed an increase in both high‐frequency and SD of normal‐to‐normal RR intervals in the AT group with a decreased low‐frequency/high‐frequency ratio, suggesting that the sympathetic/parasympathetic activation was balanced. Conclusions In patients carrying the cytochrome P450 family 2 subfamily C member19 loss‐of‐function allele, an AT regimen after off‐pump coronary artery bypass grafting was associated with a lower incidence of POAF, paralleled by lower atrial fibrillation burden, ADP‐induced platelet aggregation, lower systemic immune‐inflammation index reaction, and a balanced automatic nerve system compared with an aspirin and clopidogrel regimen. Inhibiting the systemic immune‐inflammation response and sustaining automatic nerve balance may underlie the therapeutic effect of POAF by a potent antiplatelet combination.

Background: Lipid accumulation and redox imbalance, resulting from dysregulation of hepatic fatty acids oxidation, contribute to the development of steatohepatitis and insulin resistance. Recently, dysregulated RNA N6-methyladenosine (m6A) methylation modification has been found involving fatty liver. However, the role of methyltransferase-like 14 (METTL14), the core component of m6A methylation, in the development of steatohepatitis is unknown. Herein, we aimed to explore the role of METTL14 on steatohepatitis and insulin resistance in mice with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: The liver tissues of mice and patients with MASLD were collected to detect the expression of METTL14. METTL14 overexpression and METTL14 silence were used to investigate the effect of METTL14 on lipid metabolism disorder in vivo and in vitro. Knockout of METTL14 in primary hepatocytes was used to investigate the role of Sirtuin 1 (SIRT1) on lipid accumulation induced by METTL14. Results: METTL14 was dramatically up-regulated in the livers of db/db mice, high-fat diet (HFD)-fed mice, and patients with MASLD. METTL14 overexpression exacerbated MASLD and promoted lipid metabolism disorder and insulin resistance in mice. Conversely, METTL14 knockout ameliorated lipid deposition and insulin resistance in HFD-fed mice. Furthermore, METTL14 overexpression facilitated lipid accumulation, while METTL14 knockout reduced lipid accumulation in HepG2 cells and primary hepatocytes. In addition, METTL14 lost up-regulated SIRT1 expression in hepatocytes. SIRT1 deficiency abrogated the ameliorating effects of METTL14 downregulation in MASLD mice. Conclusions: These findings suggest that dysfunction of the METTL14-SIRT1 pathway might promote hepatic steatosis and insulin resistance.

BackgroundAs one of the serious complications of sepsis in children, sepsis-associated encephalopathy (SAE) is associated with significantly poor prognosis and increased mortality. However, predictors of outcomes for pediatric SAE patients have yet to be identified. The aim of this study was to develop nomograms to predict the 14-day and 90-day mortality of children with SAE, providing early warning to take effective measures to improve prognosis and reduce mortality.MethodsIn this multicenter, retrospective study, we screened 291 patients with SAE admitted to the PICU between January 2017 and September 2022 in Shandong Province. A least absolute shrinkage and selector operation (LASSO) method was used to identify the optimal prognostic factors predicting the outcomes in pediatric patients with SAE. Then, multivariable logistic regression analysis was performed based on these variables, and two nomograms were built for visualization. We used the area under the curve (AUC), calibration curves and decision curves to test the accuracy and discrimination of the nomograms in predicting outcomes.ResultsThere were 129 patients with SAE in the training cohort, and there were 103 and 59 patients in the two independent validation cohorts, respectively. Vasopressor use, procalcitonin (PCT), lactate and pediatric critical illness score (PCIS) were independent predictive factors for 14-day mortality, and vasopressor use, PCT, lactate, PCIS and albumin were independent predictive factors for 90-day mortality. Based on the variables, we generated two nomograms for the early identification of 14-day mortality (AUC 0.853, 95% CI 0.787–0.919, sensitivity 72.4%, specificity 84.5%) and 90-day mortality (AUC 0.857, 95% CI 0.792–0.923, sensitivity 72.3%, specificity 90.6%), respectively. The calibration plots for nomograms showed excellent agreement of mortality probabilities between the observed and predicted values in both training and validation cohorts. Decision curve analyses (DCA) indicated that nomograms conferred high clinical net benefit.ConclusionThe nomograms in this study revealed optimal prognostic factors for the mortality of pediatric patients with SAE, and individualized quantitative risk evaluation by the models would be practical for treatment management.

Abstract This cohort study aims to assess the connection between cytochrome P450 family 2 subfamily C member 19 (CYP2C19) genotyping, platelet aggregability following oral clopidogrel administration, and the occurrence of postoperative atrial fibrillation (POAF) after off‐pump coronary artery bypass graft (CABG) surgery. From May 2017 to November 2022, a total of 258 patients undergoing elective first‐time CABG surgery, receiving 100 mg/day oral aspirin and 75 mg/day oral clopidogrel postoperatively, was included for analysis. These patients were categorized based on CYP2C19 genotyping. Platelet aggregability was assessed serially using multiple‐electrode aggregometry before CABG, 1 and 5 days after the procedure, and before discharge. The incidences of POAF were compared using the log‐rank test for cumulative risk. CYP2C19 genotyping led to categorization into CYP2C19*1*1 (WT group, n = 123) and CYP2C19*2 or *3 (LOF group, n = 135). Baseline characteristics and operative data showed no significant differences between the two groups. The incidence of POAF after CABG was 42.2% in the LOF group, contrasting with 22.8% in the WT group (hazard risk [HR]: 2.061; 95% confidence interval [CI]: 1.347, 3.153; p = 0.0013). Adenosine diphosphate‐stimulated platelet aggregation was notably higher in the LOF group compared to the WT group 5 days after CABG (30.4% ± 6.5% vs. 17.9% ± 4.1%, p

IntroductionMicroaneurysms serve as early signs of diabetic retinopathy, and their accurate detection is critical for effective treatment. Due to their low contrast and similarity to retinal vessels, distinguishing microaneurysms from background noise and retinal vessels in fluorescein fundus angiography (FFA) images poses a significant challenge.MethodsWe present a model for automatic detection of microaneurysms. FFA images were pre-processed using Top-hat transformation, Gray-stretching, and Gaussian filter techniques to eliminate noise. The candidate microaneurysms were coarsely segmented using an improved matched filter algorithm. Real microaneurysms were segmented by a morphological strategy. To evaluate the segmentation performance, our proposed model was compared against other models, including Otsu's method, Region Growing, Global Threshold, Matched Filter, Fuzzy c-means, and K-means, using both self-constructed and publicly available datasets. Performance metrics such as accuracy, sensitivity, specificity, positive predictive value, and intersection-over-union were calculated.ResultsThe proposed model outperforms other models in terms of accuracy, sensitivity, specificity, positive predictive value, and intersection-over-union. The segmentation results obtained with our model closely align with benchmark standard. Our model demonstrates significant advantages for microaneurysm segmentation in FFA images and holds promise for clinical application in the diagnosis of diabetic retinopathy.ConclusionThe proposed model offers a robust and accurate approach to microaneurysm detection, outperforming existing methods and demonstrating potential for clinical application in the effective treatment of diabetic retinopathy.

ABSTRACT The gut microbiota contributes to skeletal muscle energy metabolism and is an indirect factor affecting meat quality. However, the role of specific gut microbes in energy metabolism and fiber size of skeletal muscle in chickens remains largely unknown. In this study, we first performed cecal microbiota transplantation from Chinese indigenous Jingyuan chickens (JY) to Arbor Acres chickens (AA), to determine the effects of microbiota on skeletal muscle fiber and energy metabolism. Then, we used metagenomics, gas chromatography, and metabolomics analysis to identify functional microbes. Finally, we validated the role of these functional microbes in regulating the fiber size via glucose metabolism in the skeletal muscle of chickens through feeding experiments. The results showed that the skeletal muscle characteristics of AA after microbiota transplantation tended to be consistent with that of JY, as the fiber diameter was significantly increased, and glucose metabolism level was significantly enhanced in the pectoralis muscle. L. plantarum, L. ingluviei, L. salivarius, and their mixture could increase the production of the microbial metabolites protoporphyrin IX and short-chain fatty acids, therefore increasing the expression levels of genes related to the oxidative fiber type (MyHC SM and MyHC FRM), mitochondrial function (Tfam and CoxVa), and glucose metabolism (PFK, PK, PDH, IDH, and SDH), thereby increasing the fiber diameter and density. These three Lactobacillus species could be promising probiotics to improve the meat quality of chicken.IMPORTANCEThis study revealed that the L. plantarum, L. ingluviei, and L. salivarius could enhance the production of protoporphyrin IX and short-chain fatty acids in the cecum of chickens, improving glucose metabolism, and finally cause the increase in fiber diameter and density of skeletal muscle. These three microbes could be potential probiotic candidates to regulate glucose metabolism in skeletal muscle to improve the meat quality of chicken in broiler production.

Abstract Background Patients with sepsis-associated encephalopathy (SAE) have higher mortality rates and longer ICU stays. Predictors of SAE are yet to be identified. We aimed to establish an effective and simple-to-use nomogram for the individual prediction of SAE in patients with sepsis admitted to pediatric intensive care unit (PICU) in order to prevent early onset of SAE. Methods In this retrospective multicenter study, we screened 790 patients with sepsis admitted to the PICU of three hospitals in Shandong, China. Least absolute shrinkage and selection operator regression was used for variable selection and regularization in the training cohort. The selected variables were used to construct a nomogram to predict the risk of SAE in patients with sepsis in the PICU. The nomogram performance was assessed using discrimination and calibration. Results From January 2017 to May 2022, 613 patients with sepsis from three centers were eligible for inclusion in the final study. The training cohort consisted of 251 patients, and the two independent validation cohorts consisted of 193 and 169 patients. Overall, 237 (38.7%) patients developed SAE. The morbidity of SAE in patients with sepsis is associated with the respiratory rate, blood urea nitrogen, activated partial thromboplastin time, arterial partial pressure of carbon dioxide, and pediatric critical illness score. We generated a nomogram for the early identification of SAE in the training cohort (area under curve [AUC] 0.82, 95% confidence interval [CI] 0.76–0.88, sensitivity 65.6%, specificity 88.8%) and validation cohort (validation cohort 1: AUC 0.80, 95% CI 0.74–0.86, sensitivity 75.0%, specificity 74.3%; validation cohort 2: AUC 0.81, 95% CI 0.73–0.88, sensitivity 69.1%, specificity 83.3%). Calibration plots for the nomogram showed excellent agreement between SAE probabilities of the observed and predicted values. Decision curve analysis indicated that the nomogram conferred a high net clinical benefit. Conclusions The novel nomogram and online calculator showed performance in predicting the morbidity of SAE in patients with sepsis admitted to the PICU, thereby potentially assisting clinicians in the early detection and intervention of SAE.

Abstract Large scale human genome wide association studies (GWAS) have identified a growing pool of genes associated with cigarette smoking. One of the most prominent, phosphodiesterase-4B (PDE4B), has been associated with multiple smoking phenotypes. Although PDE4B modulates the half-life of neuronal cAMP, its precise role in smoking behaviors is unknown. To address this knowledge gap, we used a reverse translational approach. We inactivated PDE4B in bilateral medial nucleus accumbens shell (NAcs) neurons by injecting AAV containing a specific gRNA in female transgenic Cas9+ Long Evans rats. These rats then were given 23-h chronic access to nicotine intravenous self-administration (IVSA) under a schedule of increasing fixed ratios (FR). With the increased effort required at FR7, nicotine SA (i.e. active presses and drug infusions) declined significantly in controls, whereas it was maintained in the mutagenized group. A progressive ratio (PR) study also showed significantly greater cumulative nicotine infusions in the PDE4B-edited group. Hence, we hypothesized that enhanced PDE4B protein activity would reduce nicotine IVSA. A positive allosteric modulator, 2-(3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl)-N-(3,5-dichlorobenzyl)acetamide (MR-L2), was microinfused into NAcs bilaterally at FR3 or FR5; in both cohorts, MR-L2 acutely reduced nicotine IVSA. In summary, these studies show that the activity of PDE4B regulates the capacity of NAcs to maintain nicotine IVSA in face of the cost of increasing work. This finding and the results of the PR study indicate that PDE4B affects the motivation to obtain nicotine. These reverse translational studies in rats provide insight into the motivational effects of NAcs PDE4B that advance our understanding of the smoking behaviors mapped in human GWAS.

In order to analyze the impact of power flow transfer of the DC grid on safe operation, this paper studies the calculation methods of power flow transfer of the DC grid under master–slave control and droop control, including the calculation of power flow transfer in line disconnection situation and converter power changing situation. Through the proposed calculation methods, by considering the safety boundary constraints of the converter station based on the PQ power domain, the impact on the safe operation of a complex DC grid when power flow transferring is analyzed. Finally, to solve instability caused by the power flow transfer, a virtual impedance-based method is introduced to increase the safety boundary and enhances the stable operation ability of the system. Finally, the simulations of an 11-terminal CIGRE DC system established in PSCAD/EMTDC software verify the correctness of the proposed method. 11 This work is supported by Cloud energy storage framework-based AI dispatching strategy of renewable energy integration and contingency response (5100-202199274A-0-0-00).

Recent research on traditional Chinese medicine (TCM) saponin pharmacokinetics has revealed transformative breakthroughs and challenges. The multicomponent nature of TCM makes it difficult to select representative indicators for pharmacokinetic studies. The clinical application of saponins is limited by their low bioavailability and short half-life, resulting in fluctuating plasma concentrations. Future directions should focus on novel saponin compounds utilizing colon-specific delivery and osmotic pump systems to enhance oral bioavailability. Optimizing drug combinations, such as ginsenosides with aspirin, shows therapeutic potential. Rigorous clinical validation is essential for practical applications. This review emphasizes a transformative era in saponin research, highlighting the need for clinical validation. TCM saponin pharmacokinetics, guided by traditional principles, are in development, utilizing multidisciplinary approaches for a comprehensive understanding. This research provides a theoretical basis for new clinical drugs and supports rational clinical medication.

BackgroundDiabetic retinopathy (DR) is a microvascular complication of diabetes, severely affecting patients’ vision and even leading to blindness. The development of DR is influenced by metabolic disturbance and genetic factors, including gene polymorphisms. The research aimed to uncover the causal relationships between blood metabolites and DR.MethodsThe two-sample mendelian randomization (MR) analysis was employed to estimate the causality of blood metabolites on DR. The genetic variables for exposure were obtained from the genome-wide association study (GWAS) dataset of 486 blood metabolites, while the genetic predictors for outcomes including all-stage DR (All DR), non-proliferative DR (NPDR) and proliferative DR (PDR) were derived from the FinnGen database. The primary analysis employed inverse variance weighted (IVW) method, and supplementary analyses were performed using MR-Egger, weighted median (WM), simple mode and weighted mode methods. Additionally, MR-Egger intercept test, Cochran’s Q test, and leave-one-out analysis were also conducted to guarantee the accuracy and robustness of the results. Subsequently, we replicated the MR analysis using three additional datasets from the FinnGen database and conducted a meta-analysis to determine blood metabolites associated with DR. Finally, reverse MR analysis and metabolic pathway analysis were performed.ResultsThe study identified 13 blood metabolites associated with All DR, 9 blood metabolites associated with NPDR and 12 blood metabolites associated with PDR. In summary, a total of 21 blood metabolites were identified as having potential causal relationships with DR. Additionally, we identified 4 metabolic pathways that are related to DR.ConclusionThe research revealed a number of blood metabolites and metabolic pathways that are causally associated with DR, which holds significant importance for screening and prevention of DR. However, it is noteworthy that these causal relationships should be validated in larger cohorts and experiments.

Despite growing evidence suggesting an important contribution of Tumor Protein P53 Inducible Protein 11 (TP53I11) in cancer progression, the role of TP53I11 remains unclear. Our first pan-cancer analysis of TP53I11 showed some tumor tissues displayed reduced TP53I11 expression compared to normal tissues, while others exhibited high TP53I11 expression. Meanwhile, TP53I11 expression carries a particular pan-cancer risk, as high TP53I11 expression levels are detrimental to survival for BRCA, KIRP, MESO, and UVM, but to beneficial survival for KIRC. We demonstrated that TP53I11 expression negatively correlates with DNA methylation in most cancers, and the S14 residue of TP53I11 is phosphorylated in several cancer types. Additionally, TP53I11 was found to be associated with endothelial cells in pan-cancer, and functional enrichment analysis provided strong evidence for its role in tumor angiogenesis. In vitro angiogenesis assays confirmed that TP53I11 can promote angiogenic function of human umbilical vein endothelial cells (HUVECs) in vitro. Mechanistic investigations reveal that TP53I11 is transcriptionally up-regulated by HIF2A under hypoxia.

Background and aimsMost pancreatic insulinomas can be treated by minimally invasive modalities. The aim of this meta-analysis was to assess the clinical outcomes of endoscopic ultrasound (EUS)-guided ablation and minimally invasive surgery (MIS) in the treatment of pancreatic insulinoma.Materials and methodsOnline databases were searched for relevant studies. The primary aim was to compare the rates of adverse events (AEs) and the secondary aims were to compare the clinical and technical success rates, length of hospital stays, and symptom recurrence rates between EUS and MIS approaches.ResultsEight studies with 150 patients were identified that reported EUS-guided ablation outcomes, forming the EUS group, and 9 studies with 236 patients reported MIS outcomes, forming the MIS group. The pooled median age of the included patients in the EUS group was greater than that of the MIS group (64.06 vs. 44.98 years old, p < 0.001). Also, the technical success rate was significantly higher in the EUS group (100% vs. 96.6%, p = 0.025), while the clinical success was significantly higher (6%) in the MIS group (94% vs. 98.7%, p = 0.021). The AE rates (18.7% vs. 31.1%, p = 0.012) and severe AE rates (1.3% vs. 7.9%, p = 0.011) were significantly lower in the EUS group. The median length of hospital stay in the EUS group (2.68 days, 95% CI: 1.88–3.48, I2 = 60.3%) was significantly shorter than in the MIS group (7.40 days, 95% CI: 6.22–8.58, I2 = 42.2%, p < 0.001). The recurrence rate was significantly higher in the EUS group (15.3% vs. 1.3%, p < 0.001).ConclusionsEUS-guided ablation is associated with a lower AE rate and a shorter length of hospital stay, but a higher recurrence rate for the treatment of insulinoma compared with MIS. The EUS approach may be an alternative, even first-line, treatment for poor surgery candidates.

IntroductionExtreme environments such as prolonged high temperatures and droughts can cause vulnerability of vegetation ecosystems. The dry-hot valleys of Southwestern China, known for their extremely high annual temperature, lack of water, and unique non-zonal “hot island” habitat in the global temperate zone, provide exceptional sites for studying how plant adapts to the prolonged dry and hot environment. However, the specific local biotic-environment relationships in these regions remain incompletely elucidated. The study aims to evaluate how valley-type Savanna vegetation species and their communities adapt to long-term drought and high-temperature stress environments.MethodsThe study investigated the changes in species diversity and communities’ aboveground biomass of a valley-type Savanna vegetation along an elevation gradient of Yuanmou dry-hot valley in Jinsha River basin, southwest China. Subsequently, a general linear model was utilized to simulate the distribution pattern of species diversities and their constituent biomass along the elevation gradient. Finally, the RDA and VPH mothed were used to evaluate the impacts and contributions of environmental factors or variables on the patterns.Results and discussionThe field survey reveals an altitudinal gradient effect on the valley-type Savanna, with a dominant species of shrubs and herbs plants distribution below an elevation of 1700m, and a significant positive relationship between the SR, Shannon-Wiener, Simpson, and Pielou indices and altitudes. Relatively, the community aboveground biomass did not increase significantly with elevation, which was mainly due to a decreased biomass of herbaceous plants along the elevation. Different regulators of shrub-herbaceous plant species and their functional groups made different elevation patterns of species diversity and aboveground biomass in valley-type Savannas. Herbaceous plants are responsible for maintaining species diversity and ensuring stability in the aboveground biomass of the vegetation. However, the influence of shrubs on aboveground biomass became more pronounced as environmental conditions varied along the altitudinal gradient. Furthermore, species diversity was mainly influenced by soil and climatic environmental factors, whereas community biomass was mainly regulated by plant species or functional groups. The study demonstrates that the spatial pattern of valley-type Savanna was formed as a result of different environmental responses and the productive capacity of retained plant species or functional groups to climate-soil factors, highlighting the value of the Yuanmou dry-hot Valley as a microcosm for exploring the intricate interactions between vegetation evolution and changes in environmental factors.

Background: CLEC4E has been reported to promote lung cancer progression. Tumor-associated macrophages (TAMs) play an important role in tumorigenesis. Whether the expression of CLEC4E in TAMs is associated with gastric carcinogenesis remains unclear. Methods: The TIMER, UALCAN, UCSC Xena, and KM plotter databases are used to examine the expression of CLEC4E and its prognostic significance in gastric cancer (GC). Additionally, GO, KEGG, and GSEA analysis were conducted, and single-cell RNA-seq (scRNA-seq) datasets were utilized. The Coremine medical database was used to predict therapeutic drugs, and molecular docking was performed. Human GC samples were obtained, and co-culture models were constructed to evaluate the effects of CLEC4E in TAMs on tumor growth, migration, and invasion in vitro. Results: CLEC4E was significantly upregulated in GC, and high CLEC4E expression was associated with poor prognosis. Western blotting and immunostaining showed increased protein levels of CLEC4E in GC. GO, KEGG, and GSEA results indicated that CLEC4E is involved in immune response. Immune infiltration analysis demonstrated that CLEC4E expression positively correlated with multiple immune cell types. scRNA-seq analyses revealed that CLEC4E was predominantly expressed in myeloid cells specifically TAMs, in GC. In vitro experiments confirmed that MFC induced CLEC4E expression in TAMs to mediate tumor progression. Specifically targeting CLEC4E by si-CLEC4E or stigmasterol inhibited cancer cell migration and invasion. Conclusion: CLEC4E is a potential prognostic biomarker and new therapeutic target for GC that can be specifically targeted by stigmasterol.

Abstract Sepsis is a life-threatening multiple-organ injury caused by disordered host immune response to microbial infection. However, the correlation between gut microbiota dysbiosis and immune indicators remains unexplored. To address this gap in knowledge, we carried out 16 S rDNA sequencing, analyzed clinical fecal samples from children with sepsis (n = 30) and control children (n = 25), and obtained immune indicators, including T cell subtypes (CD3+, CD3+CD4+, CD3+CD8+, and CD4/CD8), NK cells, cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ), and immunoglobulin indices (IgA, IgE, IgM and IgG). In addition, we analyzed the correlation between gut microbiota dysbiosis and immune indicators, and evaluated the clinical discriminatory power of discovered bacterial biomarkers. We found that children with sepsis exhibited gut bacterial dysbiosis and low alpha diversity. The Spearman’s rank correlation coefficient suggested that Rhodococcus erythropolis had a significantly positive correlation with IFN-γ and CD3 + T cells. Klebsiella pneumoniae and Streptococcus mitis were significantly correlated with NK cells. Bacteroides uniformis was significantly positively correlated with IgM and erythrocyte sedimentation rate, and Eubacterium eligens was significantly positively correlated with IL-4 and CD3+CD8+ T cells. The biomarkers discovered in this study had strong discriminatory power. These changes in the gut microbiome may be closely related to immunologic dysfunction and to the development or exacerbation of sepsis. However, a large sample size is required for verification.

Abstract The ability of the adult mammalian heart to regenerate can save the cardiac muscle from a loss of function caused by injury. Cardiomyocyte regeneration is a key aspect of research for the treatment of cardiovascular diseases. The mouse heart shows temporary regeneration in the first week after birth; thus, the newborn mouse heart is an ideal model to study heart muscle regeneration. In this study, proteomic analysis was used to investigate the differences in protein expression in the hearts of neonatal mice at days 1 (P1 group), 4 (P4 group), and 7 (P7 group). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed changes in several groups of proteins, including the protein kinase A (PKA) signaling pathway. Moreover, it was found that PKA inhibitors and agonists regulated cardiomyocyte replication in neonatal mouse hearts. These findings suggest that PKA may be a target for the regulation of the cardiomyocyte cell cycle.

Abstract The current study explores the potential function and the underlying mechanisms of endothelial cell-derived R-spondin 3 (RSPO3) neuroprotection against ischemia/reperfusion-induced neuronal cell injury. In both neuronal cells (Neuro-2a) and primary murine cortical neurons, pretreatment with RSPO3 ameliorated oxygen and glucose deprivation (OGD)/re-oxygenation (OGD/R)-induced neuronal cell death and oxidative injury. In neurons RSPO3 activated the Akt, Erk and β-Catenin signaling cascade, but only Erk inhibitors reversed RSPO3-induced neuroprotection against OGD/R. In mouse embryonic fibroblasts (MEFs) and neuronal cells, RSPO3-induced LGR4-Gab1-Gαi1/3 association was required for Erk activation, and either silencing or knockout of Gαi1 and Gαi3 abolished RSPO3-induced neuroprotection. In mice, middle cerebral artery occlusion (MCAO) increased RSPO3 expression and Erk activation in ischemic penumbra brain tissues. Endothelial knockdown or knockout of RSPO3 inhibited Erk activation in the ischemic penumbra brain tissues and increased MCAO-induced cerebral ischemic injury in mice. Conversely, endothelial overexpression of RSPO3 ameliorated MCAO-induced cerebral ischemic injury. We conclude that RSPO3 activates Gαi1/3-Erk signaling to protect neuronal cells from ischemia/reperfusion injury.

Multi-source data-fusion approaches have been developed for estimating regional precipitation. However, studies considering the specific upper limits of the improved gridded rainfall data for different fusion approaches are limited. Here, the potential ranges of accuracy improvement for satellite and reanalysis rainfall products were addressed using various machine learning fusion approaches, including multivariate linear regression (MLR), feedforward neural network (FNN), random forest (RF), and long short-term memory (LSTM), over the Chinese mainland. All four fusion methods reduce errors in the original precipitation products. The upper limits of accuracy improvement in terms of correlation coefficient (CC) and root mean square error (RMSE) were 30.65 and 15.27%, respectively. M-RF showed the best average CC (0.828) and RMSE (4.62 mm/day) in the four seasons. LSTM performed the best under light rainfall events, whereas MLR and RF exhibited better performance under moderate and heavy rainfall events, respectively. Overall, these results serve as a basis for the fusion approach and technique selection, based on the comprehensive validation in different climate zones, altitudes, and seasons over the Chinese mainland. HIGHLIGHTS Machine learning fusion approaches were used for precipitation product estimation.; Four different models were used: MLR, feedforward neural network, RF, and LSTM.; All four fusion methods reduced errors in the original precipitation products.; LSTM showed the best performance for light rainfall events.; MLR and RF performed better for moderate and heavy rainfall events.;

Abstract Background Pathological neovascularization plays a pivotal role in the onset and progression of tumors and neovascular eye diseases. Despite notable advancements in the development of anti-angiogenic medications that target vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), the occurrence of adverse reactions and drug resistance has somewhat impeded the widespread application of these drugs. Therefore, additional investigations are warranted to explore alternative therapeutic targets. In recent years, owing to the swift advancement of high-throughput sequencing technology, pan-cancer analysis and single-cell sequencing analysis have emerged as pivotal methodologies and focal areas within the domain of omics research, which is of great significance for us to find potential targets related to the regulation of pathological neovascularization. Methods Pan-cancer analysis and scRNA-seq data analysis were employed to forecast the association between Actin filament-associated protein 1 like 1 (AFAP1L1) and the development of tumors and endothelial cells. Tumor xenograft model and ocular pathological neovascularization model were constructed as well as Isolectin B4 (IsoB4) staining and immunofluorescence staining were used to assess the effects of AFAP1L1 on the progression of neoplasms and neovascular eye diseases in vivo. Transwell assay, wound scratch assay, tube forming assay, three-dimensional germination assay, and rhodamine-phalloidin staining were used to evaluate the impact of AFAP1L1 on human umbilical vein endothelial cells (HUVECs) function in vitro; Dual luciferase reporting, qRT-PCR and western blot were used to investigate the upstream and downstream mechanisms of pathological neovascularization mediated by AFAP1L1. Results Our investigation revealed that AFAP1L1 plays a crucial role in promoting the development of various tumors and demonstrates a strong correlation with endothelial cells. Targeted suppression of AFAP1L1 specifically in endothelial cells in vivo proves effective in inhibiting tumor formation and ocular pathological neovascularization. Mechanistically, AFAP1L1 functions as a hypoxia-related regulatory protein that can be activated by HIF-1α. In vitro experiments demonstrated that reducing AFAP1L1 levels can reverse hypoxia-induced excessive angiogenic capacity in HUVECs. The principal mechanism of angiogenesis inhibition entails the regulation of tip cell behavior through the YAP-DLL4-NOTCH axis. Conclusion In conclusion, AFAP1L1, a newly identified hypoxia-related regulatory protein, can be activated by HIF-1α. Inhibiting AFAP1L1 results in the inhibition of angiogenesis by suppressing the germination of endothelial tip cells through the YAP-DLL4-NOTCH axis. This presents a promising therapeutic target to halt the progression of tumors and neovascular eye disease.

Abstract Background Ocular neovascularization is a leading cause of blindness and visual impairment. While intravitreal anti-VEGF agents can be effective, they do have several drawbacks, such as endophthalmitis and drug resistance. Additional studies are necessary to explore alternative therapeutic targets. Methods Bioinformatics analysis and quantitative RT-PCR were used to detect and verify the FSCN1 expression levels in oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) mice model. Transwell, wound scratching, tube formation, three-dimensional bead sprouting assay, rhodamine-phalloidin staining, Isolectin B4 staining and immunofluorescent staining were conducted to detect the role of FSCN1 and its oral inhibitor NP-G2-044 in vivo and vitro. HPLC–MS/MS analysis, cell apoptosis assay, MTT assay, H&E and tunnel staining, visual electrophysiology testing, visual cliff test and light/dark transition test were conducted to assess the pharmacokinetic and security of NP-G2-044 in vivo and vitro. Co-Immunoprecipitation, qRT-PCR and western blot were conducted to reveal the mechanism of FSCN1 and NP-G2-044 mediated pathological ocular neovascularization. Results We discovered that Fascin homologue 1 (FSCN1) is vital for angiogenesis both in vitro and in vivo, and that it is highly expressed in oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV). We found that NP-G2-044, a small-molecule inhibitor of FSCN1 with oral activity, can impede the sprouting, migration, and filopodia formation of cultured endothelial cells. Oral NP-G2-044 can effectively and safely curb the development of OIR and CNV, and increase efficacy while overcoming anti-VEGF resistance in combination with intravitreal aflibercept (Eylea) injection. Conclusion Collectively, FSCN1 inhibition could serve as a promising therapeutic approach to block ocular neovascularization.

Plant species loss, driven by global changes and human activities, can have cascading effects on other trophic levels, such as arthropods, and alter the multitrophic structure of ecosystems. While the relationship between plant diversity and arthropod communities has been well-documented, few studies have explored the effects of species composition variation or plant functional groups. In this study, we conducted a long-term plant removal experiment to investigate the impact of plant functional group loss (specifically targeting tall grasses and sedges, as well as tall or short forbs) on arthropod diversity and their functional groups. Our findings revealed that the removal of plant functional groups resulted in increased arthropod richness, abundance and the exponential of Shannon entropy, contrary to the commonly observed positive correlation between plant diversity and consumer diversity. Furthermore, the removal of different plant groups had varying impacts on arthropod trophic levels. The removal of forbs had a more pronounced impact on herbivores compared to graminoids, but this impact did not consistently cascade to higher-trophic arthropods. Notably, the removal of short forbs had a more significant impact on predators, as evidenced by the increased richness, abundance, the exponential of Shannon entropy, inverse Simpson index and inverse Berger-Parker index of carnivores and abundance of omnivores, likely attributable to distinct underlying mechanisms. Our results highlight the importance of plant species identity in shaping arthropod communities in alpine grasslands. This study emphasizes the crucial role of high plant species diversity in controlling arthropods in natural grasslands, particularly in the context of plant diversity loss caused by global changes and human activities.

The minimum average variance estimation (MAVE) method has proven to be an effective approach to sufficient dimension reduction. In this study, we apply the computationally efficient optimization algorithm named alternating direction method of multipliers (ADMM) to a particular approach (MAVE or minimum average variance estimation) to the problem of sufficient dimension reduction (SDR). Under some assumptions, we prove that the iterative sequence generated by ADMM converges to some point of the associated augmented Lagrangian function. Moreover, that point is stationary. It also presents some numerical simulations on synthetic data to demonstrate the computational efficiency of the algorithm.

Tamoxifen (TAM) resistance remains a major obstacle in the treatment of advanced breast cancer (BCa). In addition to the competitive inhibition of the estrogen receptor (ER) signaling pathway, damping of mitochondrial function by increasing reactive oxygen species (ROS) is critical for enhancing TAM pharmacodynamics. Here, we showed that RelB contributes to TAM resistance by inhibiting TAM-provoked ferroptosis. TAM-induced ROS level promoted ferroptosis in TAM-sensitive cells, but the effect was alleviated in TAM-resistant cells with high constitutive levels of RelB. Mechanistically, RelB inhibited ferroptosis by transcriptional upregulating glutathione peroxidase 4 (GPX4). Consequently, elevating RelB and GPX4 in sensitive cells increased TAM resistance, and conversely, depriving RelB and GPX4 in resistant cells decreased TAM resistance. Furthermore, suppression of RelB transcriptional activation resensitized TAM-resistant cells by enhancing ferroptosis in vitro and in vivo. The inactivation of GPX4 in TAM-resistant cells consistently resensitized TAM by increasing ferroptosis-mediated cell death. Together, this study uncovered that inhibition of ferroptosis contributes to TAM resistance of BCa via RelB-upregulated GPX4.

IntroductionArtificial intelligence (AI) technology has made rapid progress for disease diagnosis and triage. In the field of ophthalmic diseases, image-based diagnosis has achieved high accuracy but still encounters limitations due to the lack of medical history. The emergence of ChatGPT enables human-computer interaction, allowing for the development of a multimodal AI system that integrates interactive text and image information.ObjectiveTo develop a multimodal AI system using ChatGPT and anterior segment images for diagnosing and triaging ophthalmic diseases. To assess the AI system's performance through a two-stage cross-sectional study, starting with silent evaluation and followed by early clinical evaluation in outpatient clinics.Methods and analysisOur study will be conducted across three distinct centers in Shanghai, Nanjing, and Suqian. The development of the smartphone-based multimodal AI system will take place in Shanghai with the goal of achieving ≥90% sensitivity and ≥95% specificity for diagnosing and triaging ophthalmic diseases. The first stage of the cross-sectional study will explore the system's performance in Shanghai's outpatient clinics. Medical histories will be collected without patient interaction, and anterior segment images will be captured using slit lamp equipment. This stage aims for ≥85% sensitivity and ≥95% specificity with a sample size of 100 patients. The second stage will take place at three locations, with Shanghai serving as the internal validation dataset, and Nanjing and Suqian as the external validation dataset. Medical history will be collected through patient interviews, and anterior segment images will be captured via smartphone devices. An expert panel will establish reference standards and assess AI accuracy for diagnosis and triage throughout all stages. A one-vs.-rest strategy will be used for data analysis, and a post-hoc power calculation will be performed to evaluate the impact of disease types on AI performance.DiscussionOur study may provide a user-friendly smartphone-based multimodal AI system for diagnosis and triage of ophthalmic diseases. This innovative system may support early detection of ocular abnormalities, facilitate establishment of a tiered healthcare system, and reduce the burdens on tertiary facilities.Trial registrationThe study was registered in ClinicalTrials.gov on June 25th, 2023 (NCT 05930444).

AIM: To investigate the expression level of inflammatory factors of aqueous humor before trabeculectomy in binocular chronic primary angle-closure glaucoma(CPACG)and its correlation with postoperative filtration bleb and intraocular pressure.METHODS: A total of 15 cases(30 eyes)with binocular CPACG who admitted to the Affiliated Eye Hospital of Nanjing Medical University from September to December 2021 and received trabeculectomy were selected. The surgery interval between two eyes was 7d, and the preoperative expression levels of monocyte chemoattractant protein-1(MCP-1), interleukin-17(IL-17), transforming growth factor-β(TGF-β), and interferon-γ(IFN-γ)of the aqueous humor in both eyes were respectively detected by enzyme-linked immunosorbent assay(ELISA). Furthermore, the intraocular pressure(IOP)and the morphology of filtering blebs at 1mo after surgery were measured.RESULTS: The concentrations of MCP-1, IL-17, TGF-β, and IFN-γ in aqueous humor from the first eye before surgery were 330.4±46.2, 357.3±46.9, 2347.5±363.8 and 527.7±101.6pg/mL respectively, and those concentrations in aqueous humor from the fellow eye were 298.2±40.7, 309.1±53.5, 1938.3±426.0 and 628.2±104.9pg/mL respectively. The preoperative expression levels of inflammatory factors of aqueous humor in both eyes were statistically significant(P≤0.05). Furthermore, the expression levels of IL-17 and TGF-β in the aqueous humor of patients with CPACG correlated with IOP and the height of filtering blebs at 1mo after surgery(P

The incidence of myopia is gradually on the rise worldwide, which seriously affects the eye health of teenagers and children, causing enormous loss of socioeconomic benefits. As a result, the prevention and control of myopia is crucial and urgent. In recent years, orthokeratology lens have gradually demonstrated its superiority in the field of myopia prevention and control. At present, the principle of controlling the development of myopia by orthokeratology lens is mainly based on the theory of retinal hyperopia optical defocus, which promotes the shift of hyperopic defocus to myopic defocus in myopic patients to curb the growth of the axial length. The effect of controlling the development of myopia is related to various factors, including the total amount of defocusing, pupil diameter, optical zone design, and lens decentration. The widespread use of orthokeratology lenses will effectively reduce the incidence of myopia in teenagers and children. This paper discusses the principle of controlling the development of myopia by the defocus technique of orthokeratology lenses, and the relationship between the amount of defocusing and the position of the defocusing circle and the effect of myopia prevention and control. A specific review was conducted to clarify the research progress on defocus technique of orthokeratology lens in the prevention and control of myopia.

Feed efficiency is one of the most important issues for sustainable pig production. Daily-phase feeding (DPF) is a form of precision feeding that could improve feed efficiency in pigs. Gut microbiota can regulate host nutrient digestion, absorption, and metabolism. However, which key microbes may play a vital role in improving the feed efficiency during DPF remains unclear. In the present study, we used a DPF program compared to a three-phase feeding (TPF) program in growing-finishing pigs to investigate the effects of gut microbiota on feed efficiency. A total of 204 Landrace × Yorkshire pigs (75 d) were randomly assigned into 2 treatments. Each treatment was replicated 8 times with 13 to 15 pigs per replicate pen. Pigs in the TPF group were fed with a commercial feeding program that supplied fixed feed for phases I, II, and III, starting at 81, 101, and 132 d of age, respectively, and pigs in the DPF group were fed a blend of adjacent phase feed from 81 to 155 d at a gradual daily ratio and phase III feed from 155 to 180 d of age. Daily feed intake and body weight were recorded by a computerized device in the feeders. Feces and blood samples were collected from 1 pig per replicate at 155 and 180 d of age. The results showed that the DPF program remarkably improved the feed efficiency at 155 d (P

Totally video-guided thorascopic cardiac surgery (TVTCS) represents one of the most minimally invasive access routes to the heart. Its feasibility and safety can be guaranteed by an experienced surgeon with skilled operative techniques under the guidance of a video signal via thoracoscopy and the imaging from transesophageal echocardiography. At present, this surgical approach has been applied for atrioventricular valve disease, atrial septum defects plus and partial anomalous pulmonary venous drainage, cardiac tumors, hypertrophic obstructive cardiomyopathy, aortic valve disease, and atrial fibrillation. Multimodality cardiovascular imaging, including echocardiography, X-ray, computed tomography (CT), magnetic resonance imaging (MRI) and cardiac catheterization, provides morphologic characteristics and function status of the cardiovascular system and a comprehensive view of the target anatomy. In this review, the benefits of multimodality cardiovascular imaging are summarized for the clinical practice of TVTCS, including the preoperative preparation, intraoperative guidance and postoperative supervision. The disease categories are also individually reviewed on the basis of multimodality cardiovascular imaging, to ensure the feasibility and safety for TVTCS. Cardiovascular imaging technologies not only confirm who is a candidate for this surgical technique, but also provide technical support during the procedure and for postop follow to assess the clinical outcomes. Multimodality cardiovascular imaging is instrumental to provide the requirements to solve the problems for conduction of TVTCS; and to provide individualized protocols with high-resolution and real-time dynamic imaging fusion.

Ocular neovascularization can impair vision and threaten patients’ quality of life. However, the underlying mechanism is far from transparent. In all mammals, macrophages are a population of cells playing pivotal roles in the innate immune system and the first line of defense against pathogens. Therefore, it has been speculated that the disfunction of macrophage homeostasis is involved in the development of ocular vascular diseases. Moreover, various studies have found that non-coding RNAs (ncRNAs) regulate macrophage homeostasis. This study reviewed past studies of the regulatory roles of ncRNAs in macrophage homeostasis in ocular vascular diseases.

Summary: Depletion of CD8+ T cells is a major obstacle in immunotherapy; however, the relevant mechanisms remain largely unknown. Here, we showed that prostate cancer (PCa) cell-derived exosomes hamper CD8+ T cell function by transporting interleukin-8 (IL-8). Compared to the low IL-8 levels detected in immune cells, PCa cells secreted the abundance of IL-8 and further accumulated in exosomes. The delivery of PCa cell-derived exosomes into CD8+ T cells exhausted the cells through enhanced starvation. Mechanistically, exosomal IL-8 overactivated PPARα in recipient cells, thereby decreasing glucose utilization by downregulating GLUT1 and HK2 but increasing fatty acid catabolism via upregulation of CPT1A and ACOX1. PPARα further activates uncoupling protein 1 (UCP1), leading to fatty acid catabolism for thermogenesis rather than ATP synthesis. Consequently, inhibition of PPARα and UCP1 restores CD8+ T cell proliferation by counteracting the effect of exosomal IL-8. This study revealed that the tumor exosome-activated IL-8-PPARα-UCP1 axis harms tumor-infiltrating CD8+ T cells by interfering with energy metabolism.

Macrophages/microglia are immune system defense and homeostatic cells that develop from bone marrow progenitor cells. According to the different phenotypes and immune responses of macrophages (Th1 and Th2), the two primary categories of polarized macrophages/microglia are those conventionally activated (M1) and alternatively activated (M2). Macrophage/microglial polarization is a key regulating factor in the development of inflammatory disorders, cancers, metabolic disturbances, and neural degeneration. Macrophage/microglial polarization is involved in inflammation, oxidative stress, pathological angiogenesis, and tissue healing processes in ocular diseases, particularly in diabetic retinopathy (DR). The functional phenotypes of macrophages/microglia affect disease progression and prognosis, and thus regulate the polarization or functional phenotype of microglia at different DR stages, which may offer new concepts for individualized therapy of DR. This review summarizes the involvement of macrophage/microglia polarization in physiological situations and in the pathological process of DR, and discusses the promising role of polarization in personalized treatment of DR.