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Abstract GWASs have linked the 3p21.1 locus, which is associated with the expression levels of NEK4, to bipolar disorder. Here, we use integrative analyses of GWAS statistics and eQTL annotations to establish that elevated NEK4 expression in the hippocampus is associated with an increased risk of bipolar disorder. To further study this association, we generate transgenic male mice that conditionally overexpress NEK4 in the pyramidal neurons of the adult forebrain, or use AAV to overexpress NEK4 in the dorsal hippocampus. Compared to the control mice, male mice of both strains exhibit a shift from a diurnal anxiety state to a nocturnal normal or anxiolytic-like state. Overexpression of NEK4 also affects the circadian fluctuations in dendritic spine morphology and synaptic structure. Furthermore, we show that treatment with lithium ameliorates the effects of NEK4 overexpression in male mice. We then perform phosphoproteomic analyses to demonstrate that the diurnal and nocturnal phosphoproteomic profiles of male control and NEK4 overexpressing mice are different. These results suggest that male mice with different NEK4 expression levels may recapitulate some of the core features observed in patients with bipolar disorder, indicating that interruption of the homeostatic dynamics of synapses may underlie the emotional swings in bipolar disorder.

Abstract Objective Early identification of modifiable risk factors is crucial for the prevention of constipation. This study systematically investigated the relationship between genetically predicted modifiable risk factors and constipation. Methods The inverse variance weighting (IVW) method was employed as the primary analytical approach. For similar exposure indicators, the multivariate Mendelian randomization (MVMR) method was used to adjust for potential biases in univariate MR analysis. The robustness of the results was further evaluated using the MR-Egger intercept test, Cochran’s Q test, and leave-one-out analysis. Bonferroni correction was applied to reduce the false positive rate in the results. Results The IVW analysis indicated a significant causal association between genetically predicted gastroesophageal reflux disease [OR (95% CI) = 1.192 (1.079–1.315), P = 0.0005], atorvastatin use [OR (95% CI) = 16.995 (3.327–86.816), P = 0.0007], and constipation. Additionally, there was a potential causal association between education level [OR (95% CI) = 0.859 (0.767–0.964), P = 0.009], major depressive disorder [OR (95% CI) = 1.206 (1.041–1.399), P = 0.013], hypothyroidism [OR (95% CI) = 2.299 (1.327–3.985), P = 0.003], and aspirin use [OR (95% CI) = 4.872 (1.174–20.221), P = 0.029] with constipation. No causal associations were found for the other included indicators. Sensitivity analysis demonstrated the absence of evidence for heterogeneity and pleiotropy in any positive results. Conclusion This study identified several risk factors that could be targeted for the prevention of constipation, offering valuable insights for public health policies.

AbstractThe main purpose of this study was to explore the changes of biomarkers in different developmental stages of bleomycin-induced pulmonary fibrosis (PF) in rats via comprehensive pathophysiology, UPLC-QTOF/MS metabonomic technology, and 16S rRNA gene sequencing of intestinal microbiota. The rats were randomly divided into normal control and 1-, 2- and 4-week model group. The rat model of PF was established by one-time intratracheal instillation of bleomycin. The levels of inflammatory and fibrosis-related factors such as hydroxyproline (HYP), type III procollagen (COL-III), type IV collagen (COL-IV), hyaluronidase (HA), laminin (LN), interleukin (IL)-1β, IL-6, malondialdehyde (MDA) increased and superoxide dismutase (SOD) decreased as the PF cycle progressed. In the 1-, 2- and 4-week model group, 2, 19 and 18 potential metabolic biomarkers and 3, 16 and 12 potential microbial biomarkers were detected, respectively, which were significantly correlated. Glycerophospholipid metabolism pathway was observed to be an important pathway affecting PF at 1, 2 and 4 weeks; arginine and proline metabolism pathways significantly affected PF at 2 weeks. Linoleic acid metabolism pathway exhibited clear metabolic abnormalities at 2 and 4 weeks of PF, and alpha-linolenic acid metabolism pathway significantly affected PF at 4 weeks.

Aims: The metabolic variations between the cartilage of osteoarthritis (OA) and Kashin-Beck disease (KBD) remain largely unknown. Our study aimed to address this by conducting a comparative analysis of the metabolic profiles present in the cartilage of KBD and OA. Methods: Cartilage samples from patients with KBD (n = 10) and patients with OA (n = 10) were collected during total knee arthroplasty surgery. An untargeted metabolomics approach using liquid chromatography coupled with mass spectrometry (LC-MS) was conducted to investigate the metabolomics profiles of KBD and OA. LC-MS raw data files were converted into mzXML format and then processed by the XCMS, CAMERA, and metaX toolbox implemented with R software. The online Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to annotate the metabolites by matching the exact molecular mass data of samples with those from the database. Results: A total of 807 ion features were identified for KBD and OA, including 577 positive (240 for upregulated and 337 for downregulated) and 230 negative (107 for upregulated and 123 for downregulated) ions. After annotation, LC-MS identified significant expressions of ten upregulated and eight downregulated second-level metabolites, and 183 upregulated and 162 downregulated first-level metabolites between KBD and OA. We identified differentially expressed second-level metabolites that are highly associated with cartilage damage, including dimethyl sulfoxide, uric acid, and betaine. These metabolites exist in sulphur metabolism, purine metabolism, and glycine, serine, and threonine metabolism. Conclusion: This comprehensive comparative analysis of metabolism in OA and KBD cartilage provides new evidence of differences in the pathogenetic mechanisms underlying cartilage damage in these two conditions. Cite this article: Bone Joint Res 2024;13(7):362–371.

This paper presents a selective review of statistical computation methods for massive data analysis. A huge amount of statistical methods for massive data computation have been rapidly developed in the past decades. In this work, we focus on three categories of statistical computation methods: (1) distributed computing, (2) subsampling methods, and (3) minibatch gradient techniques. The first class of literature is about distributed computing and focuses on the situation, where the dataset size is too huge to be comfortably handled by one single computer. In this case, a distributed computation system with multiple computers has to be utilized. The second class of literature is about subsampling methods and concerns about the situation, where the blacksample size of dataset is small enough to be placed on one single computer but too large to be easily processed by its memory as a whole. The last class of literature studies those minibatch gradient related optimization techniques, which have been extensively used for optimizing various deep learning models.

The classification of Mortise and Tenon (MT) joints is vital, as it enables standardized terminology, facilitates comparative analysis, and enhances understanding of construction techniques across a variety of applications including the design, manufacturing, and management of wood products. Although the classification of MT joints is crucial, current research in this area lacks a systematic approach. The study adopts a morphological composition paradigm to investigate MT joints. This study introduces a 6-level classification index hierarchy for MT morphology, employing methods from biological classification and arithmetic cross-method coding. By encoding joint features and morphological composition, the study delineates 352 possible joint types and 1056 theoretical compositions across dimensions, elucidating diverse structural logics and aiding comprehension. Next, a feasibility typicality assessment identifies 198 typical and 310 atypical morphological types, presented clearly in graphical form. Validations are conducted through analysis of 2654 research cases, which are encoded according to the index hierarchy, thereby affirming the scientific validity and practical utility of the classification system.

Abstract Diabetic corneal neuropathy (DCN) is a common diabetic ocular complication with limited treatment options. In this study, we investigated the effects of topical and oral fenofibrate, a peroxisome proliferator-activated receptor-α agonist, on the amelioration of DCN using diabetic mice (n = 120). Ocular surface assessments, corneal nerve and cell imaging analysis, tear proteomics and its associated biological pathways, immuno-histochemistry and western blot on PPARα expression, were studied before and 12 weeks after treatment. At 12 weeks, PPARα expression markedly restored after topical and oral fenofibrate. Topical fenofibrate significantly improved corneal nerve fibre density (CNFD) and tortuosity coefficient. Likewise, oral fenofibrate significantly improved CNFD. Both topical and oral forms significantly improved corneal sensitivity. Additionally, topical and oral fenofibrate significantly alleviated diabetic keratopathy, with fenofibrate eye drops demonstrating earlier therapeutic effects. Both topical and oral fenofibrate significantly increased corneal β-III tubulin expression. Topical fenofibrate reduced neuroinflammation by significantly increasing the levels of nerve growth factor and substance P. It also significantly increased β-III-tubulin and reduced CDC42 mRNA expression in trigeminal ganglions. Proteomic analysis showed that neurotrophin signalling and anti-inflammation reactions were significantly up-regulated after fenofibrate treatment, whether applied topically or orally. This study concluded that both topical and oral fenofibrate ameliorate DCN, while topical fenofibrate significantly reduces neuroinflammation.

Summary: Strains from the Cryptococcus gattii species complex (CGSC) have caused the Pacific Northwest cryptococcosis outbreak, the largest cluster of life-threatening fungal infections in otherwise healthy human hosts known to date. In this study, we utilized a pan-phenome-based method to assess the fitness outcomes of CGSC strains under 31 stress conditions, providing a comprehensive overview of 2,821 phenotype-strain associations within this pathogenic clade. Phenotypic clustering analysis revealed a strong correlation between distinct types of stress phenotypes in a subset of CGSC strains, suggesting that shared determinants coordinate their adaptations to various stresses. Notably, a specific group of strains, including the outbreak isolates, exhibited a remarkable ability to adapt to all three of the most commonly used antifungal drugs for treating cryptococcosis (amphotericin B, 5-fluorocytosine, and fluconazole). By integrating pan-genomic and pan-transcriptomic analyses, we identified previously unrecognized genes that play crucial roles in conferring multidrug resistance in an outbreak strain with high multidrug adaptation. From these genes, we identified biomarkers that enable the accurate prediction of highly multidrug-adapted CGSC strains, achieving maximum accuracy and area under the curve (AUC) of 0.79 and 0.86, respectively, using machine learning algorithms. Overall, we developed a pan-omic approach to identify cryptococcal multidrug resistance determinants and predict highly multidrug-adapted CGSC strains that may pose significant clinical concern.

Background: Considerable studies show that ETS variant 4 (ETV4) plays an important roles in multitudinous tumor. This study investigated its function in cholangiocarcinoma (CCA) progression and revealed the underlying mechanisms. Methods: The expression of ETV4 in CCA was evaluated using TCGA database and the single-cell analysis based on GSE189903 dataset. ETV4 expression in CCA human specimens was detected by reverse transcription-quantitative PCR, immunohistochemistry, and western blot. Cell Counting Kit-8, EdU, colony formation, wound healing, and Transwell assays were used to analyze the effects of ETV4. Extracellular acidification rate, oxygen consumption rate, glucose uptake, and lactate production were used to measure glycolysis in CAA cells. Western blot was performed to explore glycolysis-related proteins. Tumor growth was evaluated in mice xenograft tumors. Results: ETV4 was up-regulated in CCA epithelial cells. The high-expression of ETV4 was associated with poor prognosis of patients with CCA. ETV4 overexpression enhanced the proliferation, migration, invasion, and glycolysis of CCA cells; ETV4 silencing led to the contrary effects. Mechanistically, ETV4 activates TGF-β/Smad2/3 signaling pathway. In mice xenograft mode, ETV4 silencing inhibits the tumor growth, the expression of glycolysis-related proteins and TGF-β/Smad2/3 pathway proteins. Conclusions: ETV4 functions as an essential factor in the roles of TGF-β1 in CCA cells, and may be a promising target for TGF-β1-mediated CCA progression.

Aims: To assess the alterations in cell-specific DNA methylation associated with chondroitin sulphate response using peripheral blood collected from Kashin-Beck disease (KBD) patients before initiation of chondroitin sulphate treatment. Methods: Peripheral blood samples were collected from KBD patients at baseline of chondroitin sulphate treatment. Methylation profiles were generated using reduced representation bisulphite sequencing (RRBS) from peripheral blood. Differentially methylated regions (DMRs) were identified using MethylKit, while DMR-related genes were defined as those annotated to the gene body or 2.2-kilobase upstream regions of DMRs. Selected DMR-related genes were further validated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to assess expression levels. Tensor composition analysis was performed to identify cell-specific differential DNA methylation from bulk tissue. Results: This study revealed 21,060 hypermethylated and 44,472 hypomethylated DMRs, and 13,194 hypermethylated and 22,448 hypomethylated CpG islands for differential global methylation for chondroitin sulphate treatment response. A total of 12,666 DMR-related genes containing DMRs were identified in their promoter regions, such as CHL1 (false discovery rate (FDR) = 2.11 × 10-11), RIC8A (FDR = 7.05 × 10-4), and SOX12 (FDR = 1.43 × 10-3). Additionally, RIC8A and CHL1 were hypermethylated in responders, while SOX12 was hypomethylated in responders, all showing decreased gene expression. The patterns of cell-specific differential global methylation associated with chondroitin sulphate response were observed. Specifically, we found that DMRs located in TESPA1 and ATP11A exhibited differential DNA methylation between responders and non-responders in granulocytes, monocytes, and B cells. Conclusion: Our study identified cell-specific changes in DNA methylation associated with chondroitin sulphate response in KBD patients. Cite this article: Bone Joint Res 2024;13(5):237–246.

Five common watermelon varieties in the Beijing region, namely ‘L600’ ‘Guanghui L1000’ ‘Jingmei 2K’ ‘Chaoyue Mengxiang’ and ‘Xiaotianwang’ were investigated to compare quality indicators such as soluble solids, hardness, organic acids, soluble sugars, sweetness, and vitamin C. The aim was to provide a basis for the selection of high-quality watermelon varieties in Beijing. The results indicated that different watermelon varieties exhibited certain variations in quality characteristics. Specifically, ‘Xiaotianwang’ displayed significantly higher hardness and vitamin C content than other varieties (P

[Introduction] With the large-scale application of new energy, the challenges faced by the grid connection of new energy power generation are growing, and the importance of energy storage system is increasing. carbon dioxide energy storage (CES) technology is a kind of compressed gas energy storage technology emerging in recent years, with the advantages of high energy storage density, long service life and high design flexibility. For liquid carbon dioxide energy storage (LCES) technology, CO2 is stored as liquid phase in both HP and LP sides of the system, which has high energy storage density and strong operation stability. [Method] Firstly, the operation principle and key technical indicators of the LCES system was introduced and the importance of carbon dioxide liquefaction and common liquefaction processes were clarified. Then, the research status of CO2 liquefaction on the LP side of the LCES system was introduced, including the use of mixed energy storage working medium, self-condensation, the LNG cold energy, and the regenerator. The characteristics of each method were analyzed in detail. [Result] The research indicates that the application of regenerator is the most effective method. It is necessary to further analyze the challenges faced by current cold storage liquefaction technology and its development direction. [Conclusion] The research could provide guidance for the further development of CO2 liquefaction technology for the LCES system.

ABSTRACT Metagenomic next-generation sequencing (mNGS) is an unbiased and rapid method for detecting pathogens. This study enrolled 145 suspected severe pneumonia patients who were admitted to the Affiliated Hospital of Jining Medical University. This study primarily aimed to determine the diagnostic performance of mNGS and conventional microbiological tests (CMTs) using bronchoalveolar lavage fluid samples for detecting pathogens. Our findings indicated that mNGS performed significantly higher sensitivity (97.54% vs 28.68%, P < 0.001), coincidence (90.34% vs 35.17%, P < 0.001), and negative predictive value (80.00% vs 13.21%, P < 0.001) but performed lower specificity than CMTs (52.17% vs 87.5%, P < 0.001). Streptococcus pneumoniae as the most common bacterial pathogen had the largest proportion (22.90%, 30/131) in this study. In addition to bacteria, fungi, and virus, mNGS can detect a variety of atypical pathogens such as Mycobacterium tuberculosis and non-tuberculous. Mixed infections were common in patients with severe pneumonia, and bacterial-fungal-viral-atypical pathogens were the most complicated infection. After adjustments of antibiotics based on mNGS and CMTs, the clinical manifestation improved in 139 (95.86%, 139/145) patients. Our data demonstrated that mNGS had significant advantage in diagnosing respiratory tract infections, especially atypical pathogens and fungal infections. Pathogens were detected timely and comprehensively, contributing to the adjustments of antibiotic treatments timely and accurately, improving patient prognosis and decreasing mortality potentially.IMPORTANCEMetagenomic next-generation sequencing using bronchoalveolar lavage fluid can provide more comprehensive and accurate pathogens for respiratory tract infections, especially when considering the previous usage of empirical antibiotics before admission or complicated clinical presentation. This technology is expected to play an important role in the precise application of antimicrobial drugs in the future.

Changes in global precipitation patterns and increased nitrogen (N) deposition have important effects on the dynamics of the carbon (C) cycle in grassland ecosystems. Long-term overgrazing caused heavy degradation of grasslands and more than 60 % of China’s natural grasslands experienced moderate to severe degradation. To elucidate the effects of increasing precipitation and N deposition on C fluxes in a desert steppe ecosystem, experiments with nitrogen and water addition were conducted with four treatments, i.e., control (CK), N addition (N), water addition (W), combined addition of N and water (NW), in a Stipa breviflora desert steppe that had been heavily degraded. The ecosystem CO2 fluxes, including gross ecosystem productivity (GEP), net ecosystem CO2 exchange (NEE), and ecosystem respiration (ER), were determined using the closed chamber method during the growing seasons (May–October) of 2019 and 2020. Our results showed that water and nitrogen addition did not change the patterns of the seasonal dynamics of the ecosystem CO2 fluxes, indicating that water is the main limiting factor of CO2 fluxes in the studied desert steppe ecosystem. Precipitation increase (both W and NW treatments) stimulated all three components of the ecosystem CO2 fluxes, but N addition alone enhanced NEE and GEP while had no significant effects on ER, indicating water-induced increase of GEP was caused by both NEE and ER while N-induced increase of GEP was mainly caused by increases of NEE. Water addition can increase the effectiveness of N addition, but there was little interaction between the two factors. Soil moisture was more significantly correlated than soil temperature with ecosystem CO2 fluxes, and water addition could further enhance the correlation of ecosystem CO2 fluxes with soil temperature and moisture. Overall, ecosystem CO2 fluxes are more sensitive to the precipitation increase than to the N addition. These findings indicate that water supply will play more important role in ecosystem productivity of the desert steppe under the predicted scenarios of precipitation increase and increasing N deposition, which also provides scientific evidence for the restoration of those degraded desert steppe induced by overgrazing can not be achieved simply by increasing soil N availability.

BackgroundThe clinical management of type 2 diabetes mellitus (T2DM) presents a significant challenge due to the constantly evolving clinical practice guidelines and growing array of drug classes available. Evidence suggests that artificial intelligence (AI)–enabled clinical decision support systems (CDSSs) have proven to be effective in assisting clinicians with informed decision-making. Despite the merits of AI-driven CDSSs, a significant research gap exists concerning the early-stage implementation and adoption of AI-enabled CDSSs in T2DM management. ObjectiveThis study aimed to explore the perspectives of clinicians on the use and impact of the AI-enabled Prescription Advisory (APA) tool, developed using a multi-institution diabetes registry and implemented in specialist endocrinology clinics, and the challenges to its adoption and application. MethodsWe conducted focus group discussions using a semistructured interview guide with purposively selected endocrinologists from a tertiary hospital. The focus group discussions were audio-recorded and transcribed verbatim. Data were thematically analyzed. ResultsA total of 13 clinicians participated in 4 focus group discussions. Our findings suggest that the APA tool offered several useful features to assist clinicians in effectively managing T2DM. Specifically, clinicians viewed the AI-generated medication alterations as a good knowledge resource in supporting the clinician’s decision-making on drug modifications at the point of care, particularly for patients with comorbidities. The complication risk prediction was seen as positively impacting patient care by facilitating early doctor-patient communication and initiating prompt clinical responses. However, the interpretability of the risk scores, concerns about overreliance and automation bias, and issues surrounding accountability and liability hindered the adoption of the APA tool in clinical practice. ConclusionsAlthough the APA tool holds great potential as a valuable resource for improving patient care, further efforts are required to address clinicians’ concerns and improve the tool’s acceptance and applicability in relevant contexts.

Introduction: Amygdalus mongolica (Maxim.) Ricker is a traditional Chinese medicine known for its ability to relieve cough and expectorate phlegm and is commonly used to treat dry throat, dry cough, and bronchitis. A. mongolica oil and amygdalin were the active components isolated from the seed kernel seeds of A. mongolica. The main objective of this study was to investigate the effects of A. mongolica oil and amygdalin on bleomycin-induced pulmonary fibrosis (PF) in rats by integrating pharmacodynamic, transcriptomics, and bioinformatics, to determine the changes of miRNAs in both against PF, and to explore the underlying mechanisms. Methods: A rat model of PF was induced by administering bleomycin through the trachea. The rats were randomized into several groups: a control group (CON), an untreated model group (MOD), an active control group treated with pirfenidone (PFD), and groups receiving different doses of A. mongolica oil (5 g/kg [OIL-L], 10 g/kg [OIL-M], and 15 g/kg [OIL-H]), or amygdalin (20 mg/kg [AMY-L], 40 mg/kg [AMY-M], and 80 mg/kg [AMY-H]). After 28 days, samples were collected for subsequent pharmacodynamic and transcriptomic analyses. Results: The results demonstrated that A. mongolica oil and amygdalin effectively reduced the abnormally elevated levels of IL-1β, IL-6, HA, LN and COL-IV in PF rats and alleviated bleomycin-induced pulmonary fibrotic changes. Furthermore, compared to the MOD group, the expression levels of 27 miRNAs were up-regulated and 23 miRNAs were down-regulated in the OIL 10 g/kg group. Among the up-regulated miRNAs, two novel differentially expressed miRNAs (DE-miRNAs) were identified. In the AMY 20 mg/kg group, 12 miRNAs were up-regulated and 10 were down-regulated when compared to the MOD group. These DE-miRNAs were found to be enriched in pathways such as the PI3K-Akt signalling pathway, MAPK signalling pathway, and calcium signalling pathway. The microRNAs miR-301b-3p, miR-667-5p, miR-363-3p, and miR-540-3p may be associated with both the anti-PF mechanism of A. mongolica oil and the anti-PF mechanism of amygdalin. Discussion: Numerous studies have demonstrated the significance of various pathways, including PI3K-Akt, MAPK, and calcium signalling pathways, in the mechanism of PF and the development of anti-PF medications. Meanwhile, multiple miRNAs, including miR-301b-3p, miR-667-5p, miR-363-3p, and miR-540-3p, have been found to be associated with lung disease and fibrosis. Conclusions: The present experiments confirmed the effectiveness of A. mongolica oil and amygdalin in reducing inflammation and fibrosis in bleomycin-induced PF rats, with particularly favorable outcomes observed in the A. mongolica oil 10 g/kg versus amygdalin 20 mg/kg. Meanwhile, miRNAs miR-301b-3p, miR-667-5p, miR-363-3p and miR-540-3p were found to be potentially associated with both A. mongolica oil and amygdalin anti-PF mechanisms. Based on our findings, we suggest that these miRNAs might play key roles in the anti-PF mechanism of A. mongolica. The individual miRNAs require further investigation.

Abstract Objective To compare the outcomes of patients undergoing Retroperitoneal laparoscopic Radical nephrectomy (RLRN) and Transperitoneal laparoscopic Radical nephrectomy (TLRN). Methods A total of 120 patients with localized renal cell carcinoma were randomized into either RLRN or TLRN group. Mainly by comparing the patient perioperative related data, surgical specimen integrity, pathological results and tumor results. Results Each group comprised 60 patients. The two group were equivalent in terms of perioperative and pathological outcomes. The mean integrity score was significantly lower in the RLRN group than TLRN group. With a median follow-up of 36.4 months after the operation, Kaplan–Meier survival analysis showed no significant difference between RLRN and TLRN in overall survival (89.8% vs. 88.5%; P = 0.898), recurrence-free survival (77.9% vs. 87.7%; P = 0.180), and cancer-specific survival (91.4% vs. 98.3%; P = 0.153). In clinical T2 subgroup, the recurrence rate and recurrence-free survival in the RLRN group was significantly worse than that in the TLRN group (43.2% vs. 76.7%, P = 0.046). Univariate and multivariate COX regression analysis showed that RLRN (HR: 3.35; 95%CI: 1.12–10.03; P = 0.030), male (HR: 4.01; 95%CI: 1.07–14.99; P = 0.039) and tumor size (HR: 1.23; 95%CI: 1.01–1.51; P = 0.042) were independent risk factor for recurrence-free survival. Conclusions Our study showed that although RLRN versus TLRN had roughly similar efficacy, TLRN outperformed RLRN in terms of surgical specimen integrity. TLRN was also significantly better than RLRN in controlling tumor recurrence for clinical T2 and above cases. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/showproj.html?proj=24400 ), identifier: ChiCTR1800014431, date: 13/01/2018.

Long non-coding RNAs (lncRNAs), a class of important regulatory factors for many biological processes in plants, have received much attention in recent years. To explore the molecular roles of lncRNAs in sweet cherry fruit ripening, we conducted widely targeted metabolome, transcriptome and lncRNA analyses of sweet cherry fruit at three ripening stages (yellow stage, pink stage, and dark red stage). The results show that the ripening of sweet cherry fruit involves substantial metabolic changes, and the rapid accumulation of anthocyanins (cyanidin 3-rutinoside, cyanidin 3-O-galactoside, and cyanidin 3-O-glucoside) is the main cause of fruit coloration. These ripening-related alterations in the metabolic profile are driven by specific enzyme genes related to the synthesis and decomposition of abscisic acid (ABA), cell wall disintegration, and anthocyanin biosynthesis, as well as transcription factor genes, such as MYBs, bHLHs, and WD40s. LncRNAs can target these ripening-related genes to form regulatory modules, incorporated into the sweet cherry fruit ripening regulatory network. Our study reveals that the lncRNA-mRNA module is an important component of the sweet cherry fruit ripening regulatory network. During sweet cherry fruit ripening, the differential expression of lncRNAs will meditate the spatio-temporal specific expression of ripening-related target genes (encoding enzymes and transcription factors related to ABA metabolism, cell wall metabolism and anthocyanin metabolism), thus driving fruit ripening.

Abstract Background The Barcelona Clinic Liver Cancer (BCLC) staging system is an internationally recognized clinical staging system for hepatocellular carcinoma (HCC). However, this staging system does not address the staging and surgical treatment strategies for patients with spontaneous rupture hemorrhage in HCC. In this study, we aimed to investigate the prognosis of patients with BCLC stage A undergoing liver resection for HCC with spontaneous rupture hemorrhage and compare it with the prognosis of patients with BCLC stage A undergoing liver resection without rupture. Methods Clinical data of 99 patients with HCC who underwent curative liver resection surgery were rigorously followed up and treated at Shandong Provincial Hospital from January 2013 to January 2023. A retrospective cohort study design was used to determine whether the presence of ruptured HCC (rHCC) is a risk factor for recurrence and survival after curative liver resection for HCC. Prognostic comparisons were made between patients with ruptured and non‐ruptured BCLC stage A HCC (rHCC and nrHCC, respectively) who underwent curative liver resection. Results rHCC (hazard ratio [HR] = 2.974, [p] = 0.016) and tumor diameter greater than 5 cm (HR = 2.819, p = 0.022) were identified as independent risk factors for overall survival (OS) after curative resection of BCLC stage A HCC. The postoperative OS of the spontaneous rupture in the HCC group (Group I) was shorter than that in the BCLC stage A group (Group II) (p = 0.008). Tumor invasion without penetration of the capsule was determined to be an independent risk factor for recurrence‐free survival (RFS) after liver resection for HCC (HR = 2.584, p = 0.002). Conclusion HCC with concurrent spontaneous rupture hemorrhage is an independent risk factor for postoperative OS after liver resection. The BCLC stage A1 should be added to complement the current BCLC staging system to provide further guidance for the treatment of patients with spontaneous rupture of HCC.

ObjectiveTo explore the clinical characteristics and treatment outcomes of children with central nervous system (CNS) involvement in eosinophilic granulomatosis with polyangiitis (EGPA).MethodsA child who presented with EGPA complicated by CNS involvement was admitted to our hospital in June 2023. The clinical features were analyzed retrospectively, and relevant literatures were reviewed to provide a comprehensive overview of this condition.ResultsA ten-year-old girl, who had a history of recurrent cough and asthma accompanied by peripheral blood eosinophilia for eight months, was admitted to our hospital. On admission, spotted papules were visible on her hands and feet, bilateral pulmonary rales were audible. The laboratory examination revealed that the proportion of eosinophils (EOS) exceeded 10% of white blood cells, the anti-neutrophil cytoplasmic antibody (MPO-ANCA) was positive, the immunoglobulin G level was 15.80g/L, and the immunoglobulin E level was greater than 2500.00IU/mL. The imaging examination showed multiple patchy and nodular high-density shadows in both lungs as well as sinusitis. Pulmonary function tests indicated moderate ventilation and diffusion dysfunction. Bone marrow cytology demonstrated a significant increase in the proportion of eosinophils. Skin pathology confirmed leukocytoclastic vasculitis. During the hospitalization, the child had a convulsion. The magnetic resonance imaging (MRI) scan of the brain showed multiple abnormal signal shadows in the bilateral cerebral cortex and the electroencephalogram (EEG) showed epileptic waves. Following the administration of methylprednisolone pulse therapy in combination with cyclophosphamide treatment, her cough and asthma resolved, the skin rash disappeared without any further convulsions. We found that only a young EGPA patient with CNS involvement had been previously reported. The previously reported case began with long-term fever, weight loss, and purpuric rash. Both patients responded well to treatment with glucocorticoids and cyclophosphamide, experiencing significant improvement in their clinical symptoms and normalization of their peripheral blood eosinophils.ConclusionThe diagnosis of EGPA in children can be challenging. When a child is affected by EGPA, it is essential to remain vigilant for signs of CNS involvement. The treatment with glucocorticoids and cyclophosphamide is effective in managing EGPA in children.

BackgroundGlycine is an integral component of the human detoxification system as it reacts with potentially toxic exogenous and endogenously produced compounds and metabolites via the glycine conjugation pathway for urinary excretion. Because individuals with obesity have reduced glycine availability, this detoxification pathway may be compromised. However, it should be restored after bariatric surgery because of increased glycine production.ObjectiveTo examine the impact of obesity-associated glycine deficiency on the glycine conjugation pathway. We hypothesize that the synthesis rates of acylglycines from endogenous and exogenous sources are significantly reduced in individuals with obesity but increase after bariatric surgery.MethodsWe recruited 21 participants with class III obesity and 21 with healthy weight as controls. At baseline, [1,2-13C2] glycine was infused to study the glycine conjugation pathway by quantifying the synthesis rates of several acylglycines. The same measurements were repeated in participants with obesity six months after bariatric surgery. Data are presented as mean ± standard deviation, and p-value< 0.05 is considered statistically significant.ResultsBaseline data of 20 participants with obesity were first compared to controls. Participants with obesity were significantly heavier than controls (mean BMI 40.5 ± 7.1 vs. 20.8 ± 2.1 kg/m2). They had significantly lower plasma glycine concentration (168 ± 30 vs. 209 ± 50 μmol/L) and slower absolute synthesis rates of acetylglycine, isobutyrylglycine, tigylglycine, isovalerylglycine, and hexanoylglycine. Pre- and post-surgery data were available for 16 participants with obesity. Post-surgery BMI decreased from 40.9 ± 7.3 to 31.6 ± 6.0 kg/m2. Plasma glycine concentration increased from 164 ± 26 to 212 ± 38 μmol/L) and was associated with significantly higher rates of excretion of acetylglycine, isobutyrylglycine, tigylglycine, isovalerylglycine, and hexanoylglycine. Benzoic acid (a xenobiotic dicarboxylic acid) is excreted as benzoylglycine; its synthesis rate was significantly slower in participants with obesity but increased after bariatric surgery.ConclusionObesity-associated glycine deficiency impairs the human body’s ability to eliminate endogenous and exogenous metabolites/compounds via the glycine conjugation pathway. This impairment is ameliorated when glycine supply is restored after bariatric surgery. These findings imply that dietary glycine supplementation could treat obesity-associated metabolic complications due to the accumulation of intramitochondrial toxic metabolites.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT04660513, identifier NCT04660513.

Introduction: Pulmonary fibrosis (PF), a type of interstitial pneumonia with complex etiology and high mortality, is characterized by progressive scarring of the alveolar interstitium and myofibroblastic lesions. In this study, we screened for potential biomarkers in PF and clarified the role of the lncRNA-miRNA-mRNA ceRNA network in the inhibitory effect of SRL-4 on PF.Methods: Healthy male SPF SD rats were randomly divided into three groups, namely, CON, MOD, and SRL-4. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to determine the biological functions of the target genes. A visualized lncRNA-miRNA-mRNA ceRNA network was constructed using Cytoscape, while key genes in the network were identified using the cytoNCA plugin.Results: Seventy-four differentially expressed lncRNAs and 118 differentially expressed mRNAs were identified. Gene Ontology analysis revealed that the target genes were mainly enriched in the cell membrane and in response to organic substances, while Kyoto Encyclopedia of Genes and Genomes analysis showed that the target genes were mainly enriched in the AMPK, PPAR, and cAMP signaling pathways. We elucidated a ceRNA axis, namely, Plcd3-OT1/rno-miR-150-3p/Fkbp5, with potential implications in PF. Key genes, such as AABR07051308.1-201, F2rl2-OT1, and LINC3337, may be important targets for the treatment of PF, while the AMPK, PPAR, and cAMP signaling pathways are potential key targets and important pathways through which SRL-4 mitigates PF.Conclusion: Our findings suggest that SRL-4 improves PF by regulating the lncRNA-miRNA-mRNA network.

Abstract For patients with severe aplastic anemia (SAA) in China who have had an insufficient response to the first-line treatment with hematopoietic stem cell transplantation or immunosuppressive therapy, there is no established standard of care other than transfusion support and treatment of infections. This non-randomized, open-label, Phase II multicenter trial investigated the efficacy and safety of eltrombopag in 20 adult Chinese patients with refractory or relapsed (r/r) SAA. The primary endpoint of hematologic response rate at Week 26, defined as the proportion of patients who met any of the International Working Group criteria, was observed in 70% (14/20) of patients, with more than 50% of these having at least bi-lineage response. Reduced red blood cell and platelet transfusion at Week 26 were observed in 57% (8/14) and 80% (8/10) of patients, respectively. Safety findings were consistent with the established safety profile of eltrombopag and no new safety signals were reported. None of the patients discontinued eltrombopag because of safety concerns. Although the sample size was small, this is the first prospective study to show that eltrombopag is efficacious and has a favorable safety profile in a Chinese patient population with r/r SAA. Trial registration: This trial is registered on ClinicalTrials.gov (NCT03988608); registered 17 June 2019.

Abstract This pilot study explores the relationship between nocturnal hypoglycemia (NH) and subjective sleep quality in people with type 1 diabetes (T1D). Twenty-seven adults with T1D wore a Freestyle Libre Pro CGM and recorded subjective sleep quality daily, as assessed by a single Likert scale question. Frequency, duration, area under the curve (AUC) of NH (00:00–06:00) defined as sensor glucose below threshold (

Abstract The use of machine learning (ML) in predicting disease prognosis has increased, and researchers have adopted different methods for variable selection to optimize early screening for AIS to determine its prognosis as soon as possible. We aimed to improve the understanding of the predictors of poor functional outcome at three months after discharge in AIS patients treated with intravenous thrombolysis and to construct a highly effective prognostic model to improve prediction accuracy. And four ML methods (random forest, support vector machine, naive Bayesian, and logistic regression) were used to screen and recombine the features for construction of an ML prognostic model. A total of 352 patients that had experienced AIS and had been treated with intravenous thrombolysis were recruited. The variables included in the model were NIHSS on admission, age, white blood cell count, percentage of neutrophils and triglyceride after thrombolysis, tirofiban, early neurological deterioration, early neurological improvement, and BP at each time point or period. The model's area under the curve for predicting 30‐day modified Rankin scale was 0.790 with random forest, 0.542 with support vector machine, 0.411 with naive Bayesian, and 0.661 with logistic regression. The random forest model was shown to accurately evaluate the prognosis of AIS patients treated with intravenous thrombolysis, and therefore they may be helpful for accurate and personalized secondary prevention. The model offers improved prediction accuracy that may reduce rates of misdiagnosis and missed diagnosis in patients with AIS.

Starch, a semi-crystalline energy storage form primarily found in plant plastids plays a crucial role in various food or no-food applications. Despite the starch biosynthetic pathway's main enzymes have been characterized, their origin and evolution remained a subject of debate. In this study, we conducted the comprehensive phylogenetic and structural analysis of three types of starch biosynthetic enzymes: starch synthase (SS), starch branching enzyme (SBE) and isoamylase-type debranching enzyme (ISA) from 51,151 annotated genomes. Our findings provide valuable insights into the possible scenario for the origin and evolution of the starch biosynthetic pathway. Initially, the ancestor of SBE can be traced back to an unidentified bacterium that existed before the formation of the last eukaryotic common ancestor (LECA) via horizontal gene transfer (HGT). This transfer event likely provided the eukaryote ancestor with the ability to synthesize glycogen. Furthermore, during the emergence of Archaeplastida, one clade of SS was transferred from Deltaproteobacteria by HGT, while ISA and the other clade of SS originated from Chlamydiae through endosymbiosis gene transfer (EGT). Both these transfer events collectively contributed to the establishment of the original starch biosynthetic pathway. Subsequently, after the divergence of Viridiplantae from Rhodophyta, all three enzymes underwent multiple duplications and N-terminus extension domain modifications, resulting in the formation of functionally specialized isoforms and ultimately leading to the complete starch biosynthetic pathway. By shedding light on the evolutionary origins of key enzymes involved in the starch biosynthetic pathway, this study provides important insights into the evolutionary events of plants.

Glycine is deficient in individuals with obesity but improves following bariatric surgery. Glycine deficiency could impair glutathione (GSH) synthesis and worsen oxidative stress. We examined the impact of obesity-associated glycine deficiency and bariatric surgery on GSH synthesis. Twenty-one participants with severe obesity and twenty-one healthy weight controls were recruited. [1,2-13C2] glycine was infused to measure the erythrocyte (RBC) GSH synthesis rate. Participants with obesity underwent bariatric surgery, and 19 were restudied six months post-surgery. Compared to healthy weight controls, individuals with obesity had significantly lower concentrations of RBC GSH (2.43 ± 0.23 vs. 2.63 ± 0.26 mmol/L, p < 0.01). However, there were no differences in GSH fractional synthesis rate [78.0 (51.4–123.7) vs. 76.9 (49.3–110.1) % pool/day, p = 0.58] or absolute synthesis rate [1.85 (1.25–3.32) vs. 1.92 (1.43–3.03) mmol/L RBC/day, p = 0.97]. Despite a post-surgery increase in glycine concentration, no statistically significant changes in RBC GSH concentration or synthesis rates were detected. Further, the significant correlation between plasma glycine and RBC GSH concentration at baseline (r = 0.46, p < 0.01) was also lost following bariatric surgery. GSH concentration was significantly lower in participants with obesity, but bariatric surgery did not significantly increase GSH concentrations or synthesis rates.

α-Conotoxins, as selective nAChR antagonists, can be valuable tools for targeted drug delivery and fluorescent labeling, while conotoxin-drug or conotoxin-fluorescent conjugates through the disulfide bond are rarely reported. Herein, we demonstrate the [2,4] disulfide bond of α-conotoxin as a feasible new chemical modification site. In this study, analogs of the α-conotoxin LsIA cysteine[2,4] were synthesized by stapling with five linkers, and their inhibitory activities against human α7 and rat α3β2 nAChRs were maintained. To further apply this method in targeted delivery, the alkynylbenzyl bromide linker was synthesized and conjugated with Coumarin 120 (AMC) and Camptothecin (CPT) by copper-catalyzed click chemistry, and then stapled between cysteine[2,4] of the LsIA to construct a fluorescent probe and two peptide-drug conjugates. The maximum emission wavelength of the LsIA fluorescent probe was 402.2 nm, which was essentially unchanged compared with AMC. The cytotoxic activity of the LsIA peptide-drug conjugates on human A549 was maintained in vitro. The results demonstrate that the stapling of cysteine[2,4] with alkynylbenzyl bromide is a simple and feasible strategy for the exploitation and utilization of the α-conotoxin LsIA.

To explore the genes related to anthocyanin accumulation and synthesis during the ripening process of strawberry fruit, qualitative and quantitative analysis of anthocyanin substances was conducted using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) on the fruits of four development stages of 'Benihoppe' strawberry: White (WF), initial ripening (IR), part ripening (PR), and full red fruits (FR). The expression level of structural genes in anthocyanin biosynthesis pathway in different development processes was determined to provide a theoretical basis for anthocyanin metabolism and color quality regulation of strawberry fruit. The results showed 24 anthocyanins and four proanthocyanidins in 'Benihoppe' strawberry. With the ripening of the fruit, the total anthocyanin and proanthocyanidin contents gradually increased and decreased, respectively. Pelargonidin and cyanidin were the main differential metabolites in different developmental stages. Among them, pelargonidin-3-O-glucoside, pelargonidin-3-O-rutinoside and cyanidin-3-O-glucoside were the main substances in anthocyanins, accounting for 79.7%, 14.1% and 3.56% of the total anthocyanins at the full maturity of 'Benihoppe' strawberry, respectively. Real-time PCR analysis showed that the transcription levels of the anthocyanin synthesis pathway genes FaPAL1, FaC4H, FaF3H, FaANS, FaUFGT, and FaMYB10 gradually increased with the fruit development. In summary, the anthocyanin content of 'Benihoppe' strawberry fruit gradually accumulates with fruit maturity, and the substances of anthocyanin differential metabolism include pelargonidin and cyanidin. The expression level of structural genes related to anthocyanin synthesis pathway affects the anthocyanin accumulation of fruit.

Abstract Background Schizophrenia and bipolar disorder (BD) are believed to share clinical symptoms, genetic risk, etiological factors, and pathogenic mechanisms. We previously reported that single nucleotide polymorphisms spanning chromosome 3p21.1 showed significant associations with both schizophrenia and BD, and a risk SNP rs2251219 was in linkage disequilibrium with a human specific Alu polymorphism rs71052682, which showed enhancer effects on transcriptional activities using luciferase reporter assays in U251 and U87MG cells. Methods CRISPR/Cas9-directed genome editing, real-time quantitative PCR, and public Hi-C data were utilized to investigate the correlation between the Alu polymorphism rs71052682 and NISCH. Primary neuronal culture, immunofluorescence staining, co-immunoprecipitation, lentiviral vector production, intracranial stereotaxic injection, behavioral assessment, and drug treatment were used to examine the physiological impacts of Nischarin (encoded by NISCH). Results Deleting the Alu sequence in U251 and U87MG cells reduced mRNA expression of NISCH, the gene locates 180 kb from rs71052682, and Hi-C data in brain tissues confirmed the extensive chromatin contacts. These data suggested that the genetic risk of schizophrenia and BD predicted elevated NISCH expression, which was also consistent with the observed higher NISCH mRNA levels in the brain tissues from psychiatric patients compared with controls. We then found that overexpression of NISCH resulted in a significantly decreased density of mushroom dendritic spines with a simultaneously increased density of thin dendritic spines in primary cultured neurons. Intriguingly, elevated expression of this gene in mice also led to impaired spatial working memory in the Y-maze. Given that Nischarin is the target of anti-hypertensive agents clonidine and tizanidine, which have shown therapeutic effects in patients with schizophrenia and patients with BD in preliminary clinical trials, we demonstrated that treatment with those antihypertensive drugs could reduce NISCH mRNA expression and rescue the impaired working memory in mice. Conclusions We identify a psychiatric risk gene NISCH at 3p21.1 GWAS locus influencing dendritic spine morphogenesis and cognitive function, and Nischarin may have potentials for future therapeutic development.

Abstract Background Genome-wide association studies (GWAS) have reported single-nucleotide polymorphisms (SNPs) in the VRK serine/threonine kinase 2 gene (VRK2) showing genome-wide significant associations with major depression, but the regulation effect of the risk SNPs on VRK2 as well as their roles in the illness are yet to be elucidated. Methods Based on the summary statistics of major depression GWAS, we conducted population genetic analyses, epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to identify the functional SNPs regulating VRK2; we also carried out behavioral assessments, dendritic spine morphological analyses, and phosphorylated 4D-label-free quantitative proteomics analyses in mice with Vrk2 repression. Results We identified a SNP rs2678907 located in the 5’ upstream of VRK2 gene exhibiting large spatial overlap with enhancer regulatory marks in human neural cells and brain tissues. Using luciferase reporter gene assays and eQTL analyses, the depression risk allele of rs2678907 decreased enhancer activities and predicted lower VRK2 mRNA expression, which is consistent with the observations of reduced VRK2 level in the patients with major depression compared with controls. Notably, Vrk2 −/− mice exhibited depressive-like behaviors compared to Vrk2 +/+ mice and specifically repressing Vrk2 in the ventral hippocampus using adeno-associated virus (AAV) lead to consistent and even stronger depressive-like behaviors in mice. Compared with Vrk2 +/+ mice, the density of mushroom and thin spines in the ventral hippocampus was significantly altered in Vrk2 −/− mice, which is in line with the phosphoproteomic analyses showing dysregulated synapse-associated proteins and pathways in Vrk2 −/− mice. Conclusions Vrk2 deficiency mice showed behavioral abnormalities that mimic human depressive phenotypes, which may serve as a useful murine model for studying the pathophysiology of depression.

Abstract Background Several previous studies have shown that dietary patterns are associated with the incidence of depressive symptoms. However, the results have been inconsistent. This study aimed to prospectively investigate the association between dietary patterns and the risk of depressive symptoms in two large cohort studies. Methods The Tianjin Chronic Low-grade Systemic Inflammation and Health (TCLSIH) cohort study included a total of 7,094 participants living in Tianjin, China from 2013 to 2019, and the UK Biobank cohort study includes 96,810 participants who were recruited from 22 assessment centers across the UK taken between 2006 and 2010. All participants were free of a history of cardiovascular disease (CVD), cancer, and depressive symptoms at baseline. Dietary patterns at baseline were identified with factor analysis based on responses to a validated food frequency questionnaire in TCLSIH or Oxford WebQ in UK Biobank. Depressive symptoms were evaluated using the Chinese version of the Zung Self-Rating Depression Scale (SDS) in TCLSIH or hospital inpatient records in UK Biobank. Cox proportional hazards regression models were used to estimate the association between dietary patterns and depressive symptoms. Results A total of 989, and 1,303 participants developed depressive symptoms during 17,410 and 709,931 person-years of follow-up. After adjusting for several potential confounders, the multivariable HRs (95% CIs) of the depressive symptoms were 0.71 (0.57, 0.88) for traditional Chinese dietary pattern, 1.29 (1.07, 1.55) for processed animal offal included animal food dietary pattern, and 1.22 (1.02, 1.46) for sugar rich dietary pattern in TCLSIH (all Q4 vs Q1). In the UK Biobank, the HRs (95% CIs) of depressive symptoms were 1.39 (1.16, 1.68) for processed food dietary pattern (Q4 vs Q1), 0.90 (0.77, 1.00) for healthy dietary pattern (Q3 vs Q1), and 0.89 (0.75, 1.05) for meat dietary pattern (Q4 vs Q1) in the final adjusted model. Conclusion Dietary patterns rich in processed foods were associated with a higher risk of depressive symptoms, and following a traditional Chinese dietary pattern or healthy dietary pattern was associated with a lower risk of depressive symptoms, whereas meat dietary pattern was not associated.

Abstract Deep cement mixing piles are a key technology for treating settlement distress of soft soil subgrade. However, it is very challenging to accurately evaluate the quality of pile construction due to the limitations of pile material, large number of piles and small pile spacing. Here, we propose the idea of transforming defect detection of piles into quality evaluation of ground improvement. Geological models of pile group reinforced subgrade are constructed and their ground-penetrating radar response characteristics are revealed. We have also developed ground-penetrating radar attribute analysis technology and established ground-penetrating radar technical system for evaluating the quality of ground improvement. We further prove that the ground-penetrating radar results integrating single-channel waveform, multi-channel section and attributes can effectively detect the defects and stratum structure after ground improvement. Our research results provide a rapid, efficient and economic technical solution for the quality evaluation of ground improvement in soft soil subgrade reinforcement engineering.

Introduction: Knee osteoarthritis (KOA) is a type of joint disease causing degenerative changes that are challenging to treat. The improved tug-of-war acupuncture (BHZF) can improve joint pain in KOA. However, the associated mechanism has not been validated. Methods: The KOA rabbit model was established. After the surgery, the improved BHZF was provided as an intervention, and the animals were euthanized after 2 weeks. Histopathological changes in the synovium and cartilage were observed on hematoxylin & eosin staining and Safranin O-Fast Green staining. Synovial fluid and serum samples were collected to assess the presence of cytokines using the enzyme-linked immunosorbent assay. The expression of M1 macrophage (CD86) and M2 macrophage (ARG1) markers in the cartilage and synovium was detected via immunohistochemistry and immunofluorescence assays. Results: The improved BHZF could reduce KOA-related pain and inhibit joint swelling. Further, it significantly maintained the morphology of articular chondrocytes in KOA and reduced the decomposition of the cartilage matrix. Then, it significantly reduced the expression of CD86-positive cells (P

Photoelectrochemical water splitting via solar irradiation has garnered significant interest due to its potential in large-scale renewable hydrogen production. Heterostructure materials have emerged as an effective strategy, demonstrating enhanced performance in photoelectrochemical water-splitting applications compared to individual photocatalysts. In this study, to augment the performance of sprayed TiVO4 thin films, a hydrothermally prepared WO3 underlayer was integrated beneath the spray pyrolised TiVO4 film. The consequent heterostructure demonstrated notable enhancements in optical, structural, microstructural attributes, and photocurrent properties. This improvement is attributed to the strategic deposition of WO3 underlayer, forming a heterostructure composite electrode. This led to a marked increase in photocurrent density for the WO3/TiVO4 photoanode, reaching a peak of 740 μA/cm2 at an applied potential of 1.23 V vs RHE, about nine-fold that of standalone TiVO4. Electrochemical impedance spectroscopy revealed a reduced semicircle for the heterostructure, indicating improved charge transfer compared to bare TiVO4. The heterostructure photoelectrode exhibited enhanced charge carrier conductivity at the interface and sustained stability over 3 h. The distinct attributes of heterostructure photoelectrode present significant opportunities for devising highly efficient sunlight-driven water-splitting systems.

Although cytochrome P450 enzymes are the most versatile biocatalysts in nature, there is insufficient comprehension of the molecular mechanism underlying their functional innovation process. Here, by combining ancestral sequence reconstruction, reverse mutation assay, and progressive forward accumulation, we identified 5 founder residues in the catalytic pocket of flavone 6-hydroxylase (F6H) and proposed a “3-point fixation” model to elucidate the functional innovation mechanisms of P450s in nature. According to this design principle of catalytic pocket, we further developed a de novo diffusion model (P450Diffusion) to generate artificial P450s. Ultimately, among the 17 non-natural P450s we generated, 10 designs exhibited significant F6H activity and 6 exhibited a 1.3- to 3.5-fold increase in catalytic capacity compared to the natural CYP706X1. This work not only explores the design principle of catalytic pockets of P450s, but also provides an insight into the artificial design of P450 enzymes with desired functions.

Protein engineering aimed at increasing temperature tolerance through iterative mutagenesis and high-throughput screening is often labor-intensive. Here, we developed a deep evolution (DeepEvo) strategy to engineer protein high-temperature tolerance by generating and selecting functional sequences using deep learning models. Drawing inspiration from the concept of evolution, we constructed a high-temperature tolerance selector based on a protein language model, acting as selective pressure in the high-dimensional latent spaces of protein sequences to enrich those with high-temperature tolerance. Simultaneously, we developed a variant generator using a generative adversarial network to produce protein sequence variants containing the desired function. Afterward, the iterative process involving the generator and selector was executed to accumulate high-temperature tolerance traits. We experimentally tested this approach on the model protein glyceraldehyde 3-phosphate dehydrogenase, obtaining 8 variants with high-temperature tolerance from just 30 generated sequences, achieving a success rate of over 26%, demonstrating the high efficiency of DeepEvo in engineering protein high-temperature tolerance.

Cavitation limits the efficient and stable operation of rotating machinery. The exploration of control methods for hydrofoil cavitation is important for improving the performance of hydraulic machinery. The leading-edge protuberances of the humpback flipper and the spine structure of the tail fin of sailfish are two common bionic structures for cavitation control; however, the control effects of both have limitations. Accordingly, in this study, a passive control method for hydrofoil cavitation was developed by combining the two bionic structures. With the large eddy simulation method, the cavitation processes of wavy leading-edge hydrofoil, bionic fin spine structure hydrofoil, and novel bionic combined structure hydrofoil were studied under a cavitation number of σ = 0.8. The control mechanisms of the three bionic structures for the hydrofoil cavitation were investigated. The results indicated that the novel bionic combined hydrofoil realised the superposition and complementation of the control effects of the two single bionic structures and achieved a better cavitation inhibition effect, reducing the total volume of cavitation by 43 %. In addition, it enhanced the stability of the flow field and reduced the standard deviation of the pressure coefficient on the suction surface by up to 46.55 %. This research provides theoretical support for the optimisation and modification of the blades of hydraulic machinery, such as propellers and pump turbines.

Background and aimsAt present, evidence on the association between high-density lipoprotein cholesterol (HDL-C) levels and aggravation of acute pancreatitis (AP) is limited. This study aimed to investigate the relationship between the lowest HDL-C level during intensive care units (ICU) stay and AP aggravation and to determine the optimum cutoff lowest HDL-C level.MethodsPatients admitted to the ICU of the Shandong Provincial Hospital for AP from 2015 to 2021 were included. The lowest HDL-C level during ICU stay was set as the independent variable, and the progression or non-progression to severe AP (SAP) was set as the dependent variable. Univariate and multivariate analyses were performed to determine the relationship between the two variables, and receiver operating characteristic (ROC) curves were plotted to analyze the predictive ability of the lowest HDL-C level for progression to SAP.ResultsThis study included 115 patients. The difference in the lowest HDL-C level between the SAP and moderately SAP groups was significant (P < 0.05). After adjusting for covariates, the lowest HDL-C level showed a negative correlation with the occurrence of SAP, with a relative risk of 0.897 (95% confidence interval: 0.827–0.973). The area under the ROC curve for prediction of AP aggravation by the lowest HDL-C level was 0.707, and the optimum cutoff lowest HDL-C level was 0.545 mmol/L.ConclusionNo less than 0.545 mmol/L of the HDL-C level during ICU stay may be an independent protective factor for the aggravation of AP.

To further investigate the effects of temperature on the bearing capacity of the energy pile, the influence of soil temperature was considered and the pile top displacement corresponding to the ultimate side friction resistance of the energy pile was obtained. An improved exponential model that accounts for the influence of pile-soil temperature was developed. The feasibility of the model was verified through an indoor model test and numerical simulation. The results indicate that the error between the improved exponential model and the indoor model test was smaller compared with the numerical simulation. The maximum side friction error between the improved exponential model and the model test reached 0.8 % and 4.6 % at the end of the heating and cooling stages, respectively. The maximum additional thermal stress error between the improved model and the model test was 1.3% and 3.9% at the end of the heating and cooling stages, respectively. The error of the traditional and improved exponential model of additional thermal stress was 16 %. It is established that the improved exponential model was proved suitable for thermo-mechanical coupling analysis of energy piles. The temperature effect of the soil should be considered in the investigation of the energy pile.

Objective To analyze the correlations between plasma orexin⁃A and clinical manifestations of dementia with Lewy bodies (DLB). Methods A total of 51 patients with DLB from Beijing Tiantan hospital, Capital Medical University, and 46 sex, age and education matched controls were conducted from January 2019 to December 2021. Overall cognitive function was assessed by Mini⁃Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), dementia severity was assessed by Clinical Dementia Rating Scale (CDR), activities of daily living was assessed by Activities of Daily Living Scale (ADL), depression severity was assessed by Hamilton Depression Rating Scale 17 (HAMD⁃17), neuropsychiatric symptoms was assessed by Neuropsychiatric Inventory (NPI), and plasma orexin⁃A level was measured. The univariate and multivariate Logistic regression analyses were used to screen influencing factors for DLB. Pearson and partial correlation analyses were used to explore the correlation between plasma orexin⁃A and core clinical features of DLB. Multivariate linear stepwise regression analysis was used to analyze the linear correlation between plasma orexin⁃A level and neuropsychological tests. Results The scores of MMSE (Z=⁃ 8.387, P=0.000) and MoCA (Z=⁃8.479, P=0.000) in DLB group were significantly lower than those in control group, while the scores of CDR (Z=⁃9.072, P = 0.000), ADL(Z=⁃8.692, P=0.000), HAMD⁃17 (Z=⁃7.568, P=0.000), NPI (Z=⁃8.270, P=0.000) and plasma orexin⁃A level (Z=⁃2.688, P=0.007) were significantly higher than those in control group. Plasma orexin⁃A level in DLB patients with fluctuating cognition (Z=⁃2.172, P=0.030) and with Parkinsonism (Z=⁃1.981, P=0.048) were lower than those without these symptoms, respectively. Logistic regression analysis showed drinking history was a potentially independent protective factor for DLB (OR=0.278, 95%CI:0.095-0.808; P=0.019), while increased plasma orexin⁃A level was an independent risk factor for DLB (OR=6.878, 95%CI:1.241-38.137; P=0.027). Correlation analysis showed that plasma orexin⁃A level was negatively correlated with the occurrence of Parkinsonism in patients with DLB (r=⁃ 0.322, P=0.043). Multivariate linear stepwise regression analysis showed no statistically significant relationship between the plasma orexin⁃A level and the scores of neuropsychological tests (P>0.05, for all). Conclusions The plasma orexin⁃A level in patients with DLB were higher than controls, and the elevated plasma orexin⁃A level could significantly increase the risk of DLB, while reduce the incidence of Parkinsonism. Dysfunction of orexin⁃A system might be a potential mechanism for the occurrence of DLB.

Background: Adrenal insufficiency (AI) is potentially life-threatening, and accurate diagnosis is crucial. The first-line diagnostic test, the adreno corticotrophic hormone (ACTH) stimulation test, measures serum total cortisol. However , this is affected in states of altered albumin or cortisol-binding globulin levels, limitin g reliability. Salivary cortisol reflects free bioactive cortisol levels and is a promising alter native. However, few studies are available, and heterogenous methodologies limit applicability. Methods: This study prospectively recruited 42 outpatients undergoing ev aluation for AI, excluding participants with altered cortisol-binding states. Serum (immunoassay) and salivary (liquid chromatography tandem mass spectrometry) c ortisol levels were sampled at baseline, 30 min, and 60 min following 250 μg synact hen administration. AI was defined as a peak serum cortisol level

Abstract Conopomorpha sinensis Bradley is a destructive pest that causes severe economic damage to litchi and longan. Previous C. sinensis research has focused on population life tables, oviposition selectivity, pest population prediction, and control technology. However, there are few studies on its mitogenome and phylogenetic evolution. In this study, we sequenced the whole mitogenome of C. sinensis by the third-generation sequencing, and analyzed the characteristics of its mitogenome by comparative genome. The complete mitogenome of C. sinensis is a typical circular and double-stranded structure. The ENC-plot analyses revealed that natural selection could affect the information of codon bias of the protein-coding genes in the mitogenome of C. sinensis in the evolutionary process. Compared with 12 other Tineoidea species, the trnA-trnF gene cluster of tRNA in the C. sinensis mitogenome appears to have a new arrangement pattern. This new arrangement has not been found in other Tineoidea or other Lepidoptera, which needs further exploration. Meanwhile, a long AT repeated sequence was inserted between trnR and trnA, trnE and trnF, ND1 and trnS in the mitogenome of C. sinensis, and the reason for this sequence remains to be further studied. Furthermore, the results of phylogenetic analysis showed that the litchi fruit borer belonged to Gracillariidae, and Gracillariidae was monophyletic. The results will contribute to an improved understanding of the complex mitogenome and phylogeny of C. sinensis. It also will provide a molecular basis for further research on the genetic diversity and population differentiation of C. sinensis.

Abstract Background Acute myeloid leukemia with myelodysplasia‐related changes (AML‐MRC) generally confers poor prognosis, however, patient outcomes are heterogeneous. The impact of TP53 allelic state and variant allele frequency (VAF) in AML‐MRC remains poorly defined. Methods We retrospectively evaluated 266 AML‐MRC patients who had NGS testing at our institution from 2014 to 2020 and analyzed their clinical outcomes based on clinicopathological features. Results TP53 mutations were associated with cytogenetic abnormalities in 5q, 7q, 17p, and complex karyotype. Prognostic evaluation of TP53MUT AML‐MRC revealed no difference in outcome between TP53 double/multi‐hit state and single‐hit state. Patients with high TP53MUT variant allele frequency (VAF) had inferior outcomes compared to patients with low TP53MUT VAF. When compared to TP53WT patients, TP53MUT patients had inferior outcomes regardless of MRC‐defining criteria, TP53 allelic state, or VAF. TP53 mutations and elevated serum LDH were independent predictors for inferior OS and EFS, while PHF6 mutations and transplantation were independent predictors for favorable OS and EFS. NRAS mutation was an independent predictor for favorable EFS. Conclusions Our study suggests that TP53MUT AML‐MRC defines a very‐high‐risk subentity of AML in which novel therapies should be explored.

This paper presents experimental and numerical studies on the mechanical behavior of 5A90 aluminum-lithium alloy under combined tension and shear loading. Extensive experimental tests under tension and combined loading were conducted, and the influence of material direction, notch radius, and load angle were considered. Based on the test results, the yield strength, ultimate strength, fracture displacement, strain-stress curve, and displacement-stress curve were obtained, discussed, and analyzed. The finite element model (FEM) including fracture behavior was developed, and it was found that the established FEM can well predict the mechanical response of 5A90 aluminum-lithium alloy. Parametric studies were also conducted. Finally, by comparing with the results from FEM (and tests) and predictions from available design codes, the calculation method in Eurocode 9 was suggested to predict the combined strength of 5A90 aluminum-lithium alloy.

Optical clocks have been applied to the generation of time scales since they provide superb uncertainty and instability in recent years. This paper presents the simulations about the impact of the optical clock’s operational strategies on the performance of the generated time scale through two distinct steering algorithms. By post-processing the measured frequency difference between the 87Sr optical lattice clock and the hydrogen maser at the National Time Service Center, we realized an “optically steered” time scale TS(Sr), and the variation of the time difference TT(BIPM22)-TS(Sr) is 0.1 ns during the modified Julian date 59794–59819.

Introduction Continuous monitoring of vital signs during and after ischaemic stroke was recommended by the ‘Guidelines for the Early Management of Patients with Acute Ischaemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischaemic Stroke’. Vital sign data can be associated with disease conditions and prognosis, while there is limited evidence regarding continuous monitoring of vital signs during and after acute ischaemic stroke. The wearable intelligent vital sign monitoring device is small and lightweight and constantly monitors the health status during daily activities. However, wearable intelligent vital sign monitoring devices have not been widely used in clinical practice so far. Therefore, we will investigate the effectiveness and safety of wearable intelligent vital sign monitoring devices in early in-hospital management and monitoring programmes for patients with acute ischaemic stroke. This paper presents the study protocol.Methods and design This study is a prospective, multicentre, observational registry study starting from 20 March 2023 to 20 March 2025. A total of 5740 patients with acute ischaemic stroke from 10 Chinese hospitals are planned to be enrolled. Continuous vital sign data, demographics, medical history, medication history, treatments, laboratory tests, imaging scans and follow-up data will be collected. Follow-up time points were 30 days after discharge, 30 days after intravenous thrombolysis, 3 months after intravenous thrombolysis and 12 months after intravenous thrombolysis (until March 2026). The primary outcome included the evaluation of the modified Rankin Scale at 3 months, as well as the assessment of the rate of symptomatic and asymptomatic intracranial haemorrhage throughout the hospitalisation period.Ethics and dissemination This study has been approved by the Medical Ethics Committee of Xuanwu Hospital, Capital Medical University ([2022] 203). We plan to disseminate the research findings through publication in peer-reviewed scientific journals and presentations at international conferences.Trial registration number ChiCTR2300069512.