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Objective To establish a scoring system to predict the postoperative delirium in elderly patients with intertrochanteric fracture. Materials and methods We retrospectively reviewed 159 elderly patients with a diagnosis of intertrochanteric fracture and underwent closed reduction and intramedullary nail fixation, and then divided them into two groups including the delirium group (23 cases) or non-delirium group (136 cases) in our hospital from January 2017 to December 2019. The following clinical characteristics were recorded and analyzed: age, gender, fracture classification, body mass index (BMI), history of diabetes mellitus, history of stroke, preoperative albumin, preoperative hemoglobin (Hb), preoperative arterial partial pressure of oxygen (PaO 2 ), time between admission and surgery, lower limb thrombosis, American Society of Anesthesiologists (ASA) grade, operative time, operative blood loss, and intraoperative blood transfusion. The prevalence of these clinical characteristics in delirium group was evaluated, and the scoring system was established using logistic regression analysis. The performance of the scoring system was also prospectively validated. Results The predictive scoring system was based on five clinical characteristics confirmed as significant predictors of postoperative delirium, namely, age > 75 years, history of stroke, preoperative Hb ≤ 100 g/L, preoperative PaO 2  ≤ 60 mmHg, and time between admission to surgery > 3 days. Delirium group showed a significant higher score than non-delirium (6.26 vs. 2.29, P  < 0.001), and the optimal cut-off value for the scoring system was 4 points. The sensitivity and specificity of the scoring system for predicting postoperative delirium were 82.61% and 81.62% in derivation set, respectively, and 72.71% and 75.00% in validation set. Conclusion The predictive scoring system confirmed with achieve satisfactory sensitivity and specificity in predicting postoperative delirium in the elderly with intertrochanteric fracture. The risk of postoperative delirium in patients with the score of 5 to 11 is high, while the score of 0 to 4 is low.

Background Lactobacillus reuteri strains are widely used as probiotics to prevent and treat inflammatory bowel disease by modulating the host’s immune system. However, the underlying mechanisms by which they communicate with the host have not been clearly understood. Bacterial extracellular vesicles (EVs) have been considered as important mediators of host-pathogen interactions, but their potential role in commensals-host crosstalk has not been widely studied. Here, we investigated the regulatory actions of EVs produced by L. reuteri BBC3, a gut-associated commensal bacterium of Black-Bone chicken, in the development of lipopolysaccharide (LPS)-induced intestinal inflammation in a chicken model using both in vivo and in vitro experiments. Results L. reuteri BBC3 produced nano-scale membrane vesicles with the size range of 60–250 nm. Biochemical and proteomic analyses showed that L. reuteri BBC3-derived EVs (LrEVs) carried DNA, RNA and several bioactive proteins previously described as mediators of other probiotics’ beneficial effects such as glucosyltransferase, serine protease and elongation factor Tu. In vivo broiler experiments showed that administration of LrEVs exerted similar effects as L. reuteri BBC3 in attenuating LPS-induced inflammation by improving growth performance, reducing mortality and decreasing intestinal injury. LrEVs suppressed the LPS-induced expression of pro-inflammatory genes ( TNF-α , IL-1β , IL-6 , IL-17 and IL-8 ), and improved the expression of anti-inflammatory genes ( IL-10 and TGF-β ) in the jejunum. LrEVs could be internalized by chicken macrophages. In vitro pretreatment with LrEVs reduced the gene expression of TNF-α , IL-1β and IL-6 by suppressing the NF-κB activity, and enhanced the gene expression of IL-10 and TGF-β in LPS-activated chicken macrophages. Additionally, LrEVs could inhibit Th1- and Th17-mediated inflammatory responses and enhance the immunoregulatory cells-mediated immunosuppression in splenic lymphocytes of LPS-challenged chickens through the activation of macrophages. Finally, we revealed that the reduced content of both vesicular proteins and nucleic acids attenuated the suppression of LrEVs on LPS-induced inflammatory responses in ex vivo experiments, suggesting that they are essential for the LrEVs-mediated immunoregulation. Conclusions We revealed that LrEVs participated in maintaining intestinal immune homeostasis against LPS-induced inflammatory responses in a chicken model. Our findings provide mechanistic insight into how commensal and probiotic Lactobacillu s species modulate the host’s immune system in pathogens-induced inflammation.

Tumour cell phagocytosis by antigen presenting cells (APCs) is critical to the generation of antitumour immunity. However, cancer cells can evade phagocytosis by upregulating anti-phagocytosis molecule CD47. Here, we show that CD47 blockade alone is inefficient in stimulating glioma cell phagocytosis. However, combining CD47 blockade with temozolomide results in a significant pro-phagocytosis effect due to the latter’s ability to induce endoplasmic reticulum stress response. Increased tumour cell phagocytosis subsequently enhances antigen cross-presentation and activation of cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) in APCs, resulting in more efficient T cell priming. This bridging of innate and adaptive responses inhibits glioma growth, but also activates immune checkpoint. Sequential administration of an anti-PD1 antibody overcomes this potential adaptive resistance. Together, these findings reveal a dynamic relationship between innate and adaptive immune regulation in tumours and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses. Professional antigen presenting cells (APCs) are deterred from phagocytosing cancer cells that express CD47. Here, the authors show that in glioblastoma mouse models, temozolomide improves the phagocytosis effect of CD47 blockade in APCs and results in the activation of adaptive anti-tumour responses.

Background METTL3 is the core catalytic enzyme in m6A and is involved in a variety of cardiovascular diseases. However, whether and how METTL3 plays a role during angiotensin II (Ang-II)-induced myocardial hypertrophy is still unknown. Methods Neonatal rat cardiomyocytes (NRCMs) and C57BL/6J mice were treated with Ang-II to induce myocardial hypertrophy. qRT-PCR and western blots were used to detect the expression of RNAs and proteins. Gene function was verified by knockdown and/or overexpression, respectively. Luciferase and RNA immunoprecipitation (RIP) assays were used to verify interactions among multiple genes. Wheat germ agglutinin (WGA), hematoxylin and eosin (H&E), and immunofluorescence were used to examine myocardial size. m6A methylation was detected by a colorimetric kit. Results METTL3 and miR-221/222 expression and m6A levels were significantly increased in response to Ang-II stimulation. Knockdown of METTL3 or miR-221/222 could completely abolish the ability of NRCMs to undergo hypertrophy. The expression of miR-221/222 was positively regulated by METTL3, and the levels of pri-miR-221/222 that bind to DGCR8 or form m6A methylation were promoted by METTL3 in NRCMs. The effect of METTL3 knockdown on hypertrophy was antagonized by miR-221/222 overexpression. Mechanically, Wnt/β-catenin signaling was activated during hypertrophy and restrained by METTL3 or miR-221/222 inhibition. The Wnt/β-catenin antagonist DKK2 was directly targeted by miR-221/222, and the effect of miR-221/222 inhibitor on Wnt/β-catenin was abolished after inhibition of DKK2. Finally, AAV9-mediated cardiac METTL3 knockdown was able to attenuate Ang-II-induced cardiac hypertrophy in mouse model. Conclusions Our findings suggest that METTL3 positively modulates the pri-miR221/222 maturation process in an m6A-dependent manner and subsequently activates Wnt/β-catenin signaling by inhibiting DKK2, thus promoting Ang-II-induced cardiac hypertrophy. AAV9-mediated cardiac METTL3 knockdown could be a therapeutic for pathological myocardial hypertrophy.

Little is known regarding anterior uveitis (AU), the most common ocular disease associated with cytomegalovirus (CMV) infection in immunocompetent populations. CMV AU is highly prevalent in Asia, with a higher incidence in men. Clinically, it manifests mainly as anterior chamber inflammation and elevated intraocular pressure (IOP). Acute CMV AU may resemble Posner–Schlossman syndrome with its recurrent hypertensive iritis, while chronic CMV AU may resemble Fuchs uveitis because of its elevated IOP. Without prompt treatment, it may progress to glaucoma; therefore, early diagnosis is critical to prognosis. Knowledge regarding clinical features and aqueous humor analyses can facilitate accurate diagnoses; so, we compared and summarized these aspects. Early antiviral treatment reduces the risk of a glaucoma surgery requirement, and therapeutic effects vary based on drug delivery. Both oral valganciclovir and topical ganciclovir can produce positive clinical outcomes, and higher concentration and frequency are beneficial in chronic CMV retinitis. An extended antiviral course could prevent relapses, but should be limited to 6 months to prevent drug resistance and side effects. In this review, we have systematically summarized the pathogenesis, clinical features, diagnostic and therapeutic aspects, and immunological mechanisms of CMV AU with the goal of providing a theoretical foundation for early clinical diagnosis and treatment.

This paper presents an optimal water distribution model for canals that focuses on canal flow capacity as a foundational premise. The model aims to optimize the flow rate and timing of irrigation to satisfy the water demands necessary for crop growth. Traditionally, the flow rate in the upper-level canal is viewed as the sum of the flow rates in the lower-level canals, with the distribution of water based solely on this flow rate. However, in practice, the upper-level canal must achieve a certain water level to effectively meet the distribution needs of the lower-level canals. Therefore, this study proposes a new approach to water distribution that takes into account the water level of the upper-level canal. We establish an optimal water distribution model for rotational irrigation, as well as a group model for rotational irrigation, utilizing the NSGA-II algorithm to solve these models. The results demonstrate that distributing water to lower-level canals based on the water level of the upper-level canal aligns more closely with actual water distribution scenarios. This paper presents two types of rotational irrigation models: group-based and random water distribution, each tailored for different levels of canals. These models provide valuable references for optimizing water distribution in irrigation districts.

Extracellular polymeric substances (EPS) are considered crucial components in the formation of microbial aggregates such as biofilms, flocs and granules. However, the role of EPS in sludge aggregation is still unclear. In this study, the differences in EPS characteristics of anammox granular sludge (AG), anammox floc sludge (AF) and activated floc sludge (AS) were investigated to clarify its role in granular aggregation. The results showed that the flocculation ability of EPS extracted from AG (62.8 ± 2.3%) was notably higher than that of EPS extracted from AF (35.7 ± 1.7%) and AS (17.3 ± 1.5%). The zeta potential and hydrophobicity of EPS showed the same tendency. In addition, the PN/PS ratio of AG, AF and AS were 7.66, 4.62 and 3.93, respectively. FTIR, XPS and 3D-EEM fluorescence spectra results revealed that anammox granular sludge has a higher ratio of hydrophobic groups, α-helixs/(β-sheets and random coils), intermolecular hydrogen bonds, and aromatic amino acids, and a lower ratio of electronegative groups. Anammox granular sludge exhibited high aggregation ability, because its EPS had higher zeta potential, hydrophobicity and intermolecular hydrogen bond ratio. This work provides a better understanding of the high aggregation ability of anammox granules and a theoretical basis for improving granules proportion and retention ability of microbes in reactor system.

Cerebral ischemia-reperfusion injury (Cerebral I/R injury) is a critical pathological process following ischemic stroke, closely associated with multiple mechanisms including oxidative stress, neuroinflammation, and neuronal apoptosis. It also involves the alteration and regulation of numerous key genes and non-coding RNAs. Due to its complex regulatory mechanisms, there are currently no Food and Drug Administration (FDA)-approved drugs specifically targeting Cerebral I/R injury. Developing effective therapeutic strategies for Cerebral I/R injury remains a significant challenge in medical research. This review summarizes current treatment approaches for Cerebral I/R injury, which include traditional drugs, antioxidants, neuroprotective agents, exosomes, noncoding RNA therapeutics and combined intervention therapy. Pharmacotherapies exert positive effects on Cerebral I/R injury through antioxidative, anti-inflammatory, and neuroprotective mechanisms. Exosomes and noncoding RNA therapeutics can mitigate brain cell damage and promote neural function recovery by regulating the expression of downstream key genes via miRNAs, demonstrating potential as novel therapeutic options. Emerging evidence indicates that combined therapeutic strategies incorporating nanoparticle-mediated targeting demonstrate efficacy in treating cerebral I/R injury. By exploring the mechanisms of action and clinical application prospects of these different treatment strategies, this review aims to provide new insights and methods for the clinical management of Cerebral I/R injury.

The G‐protein‐coupled receptor 126 (GPR126) may play an important role in tumor development, although its role remains poorly understood. We found that GPR126 had higher expression in most colorectal cancer cell lines than in normal colon epithelial cell lines, and higher expression levels in colorectal cancer tissues than in normal adjacent colon tissues. GPR126 knockdown induced by shRNA inhibited cell viability and colony formation in HT‐29, HCT116, and LoVo cells, decreased BrdU incorporation into newly synthesized proliferating HT‐29 cells, led to an arrest of cell cycle progression at the G1 phase in HCT‐116 and HT‐29 cells, and suppressed tumorigenesis of HT‐29, HCT116, and LoVo cells in nude mouse xenograft models. GPR126 knockdown engendered decreased transcription and translation of histone deacetylase 2 (HDAC2), previously implicated in the activation of GLI1 and GLI2 in the Hedgehog signaling pathway. Ectopic expression of HDAC2 in GPR126‐silenced cells restored cell viability and proliferation, GLI2 luciferase reporter activity, partially recovered GLI2 expression, and reduced the cell cycle arrest. HDAC2 regulated GLI2 expression and, along with GLI2, it bound to the PTCH1 promoter, as evidenced by a chip assay with HT‐29 cells. Purmorphamine, a hedgehog agonist, largely restored the cell viability and expression of GLI2 proteins in GPR126‐silenced HT‐29 cells, whereas GANT61, a hedgehog inhibitor, further enhanced the GPR126 knockdown‐induced inhibitory effects. Our findings demonstrate that GPR126 regulates colorectal cancer cell proliferation by mediating the expression of HDAC2 and GLI2, therefore it may represent a suitable therapeutic target for colorectal cancer treatment. GLI2 binding with HDAC2 to the PTCH1 promoter is regulated by HDAC2 and its expression recovery restores cell viability in GPR126‐silenced cells. A, Western blotting of HDAC2 and GLI2 protein levels in NC‐ and HDAC2‐shRNA‐infected HT‐29 cells. β‐actin was used as a loading control. B, Chromatin from HT‐29 cells was immunoprecipitated with anti‐HDAC2 antibodies and then eluted and immunoprecipitated again with normal mouse IgG(IgG) or anti‐Gli2(GLI2 Ab). Eluted DNA was PCR‐amplified using PTCH1 and GAPDH primers (B1). Quantitative PCR(qPCR) was used to examine the abundance of eluted DNA from B1, with the DNAs from input control as the internal control (B2). C, Ectopic expression of HDAC2 in GPR126‐silenced cells restores transcription activity of GLI2 promoter (Gli2‐Luc). NC or Sh1, cell infected by control virus or GPR126 shRNA virus; pGL3, empty luciferase vector; Gli2‐Luc, luciferase vector with Gli2 promoter; zs‐HDAC2, HDAC2 ectopic expression construct; zs, empty vector for cloning HDAC2 expression vector; ‘‐’, not used in co‐transfection; ‘+’, used in co‐transfection. D‐E, the effect of Purmorphamine (hedgehog agonist) and GANT61 (GLI2 inhibitor), at indicated concentration, on cell viability and GLI2 protein expression in indicate colorectal cancer cells. DMSO, the solvent of Purmorphamine and GANT61. β‐actin was used as a loading control. F, Diagram illustrating the putative mechanisms of GPR126 function in colorectal cancer cells. GPR126 regulates SMO, GLI1, and HDAC2 expression (GSE106696). GLI1 and GLI2, as the downstream components of GPR126 signaling, regulate the expression of hedgehog (HH) target genes, including PTCH1, regulating tumor growth. HDAC2 is regulated by GPR126 regulated HDAC2, mediating GLI2 expression, and binds with GLI2 to the PTCH1 promoter or other promoters of HH target genes. The dotted line indicating ‘Not reported in this article’; solid line indicating ‘Has support in this article’; ‘?’ meaning ‘through unknown mechanism’.

The treatment of osteosarcoma (OS) is still mainly surgery combined with systematic chemotherapy, and gene therapy is expected to improve the survival rate of patients. This study aimed to explore the effect of DEP domain 1 protein (DEPDC1) and kinesin super-family protein 4A (KIF4A) in OS and understand its mechanism. Th expression of DEPDC1 and KIF4A in OS cells was detected by RT-PCR and western blot. The viability, proliferation, invasion and migration of OS cells and tube formation of human umbilical vein endothelial cells (HUVECs) after indicated treatment were in turn detected by CCK-8 assay, EdU staining, wound healing assay, transwell assay and tube formation assay. The interaction between DEPDC1 and KIF4A was predicted by STRING and confirmed by co-immunoprecipitation. The expression of epithelial-mesenchymal transition (EMT)-related proteins, tube formation-related proteins and Hippo signaling pathway proteins was detected by western blot. As a result, the expression of DEPDC1 and KIF4A was all increased in U2OS cells. Down-regulation of DEPDC1 suppressed the viability, proliferation, invasion and migration of U2OS cells and tube formation of HUVECs, accompanied by the increased expression of E-cadherin and decreased expression of N-cadherin, Vimentin and VEGF. DEPDC1 was confirmed to be interacted with KIF4A. Upregulation of KIF4A partially reversed the effect of DEPDC1 interference on the above biological behaviors of U2OS cells. Down-regulation of DEPDC1 promoted the expression of p-LATS1 and p-YAP in Hippo signaling pathway, which was reversed by upregulation of KIF4A. In conclusion, down-regulation of DEPDC1 inhibited the malignant biological behavior of OS cells through the activation of Hippo signaling pathway, which could be reversed by upregulation of KIF4A.