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AIM: To evaluate the application effectiveness of the 3D surgical video system and intraoperative optical coherence tomography(OCT)in idiopathic epiretinal membrane vitrectomy.METHODS: A retrospective analysis was conducted on 61 patients(61 eyes)with idiopathic epiretinal membrane at our hospital from January 2023 to October 2023. The patients were divided into two groups based on the surgical methods: with 31 patients(31 eyes)who underwent surgery using the 3D surgical video system and intraoperative OCT technology in 3D group, and 30 patients(30 eyes)underwent surgery using the Resight non-contact wide-angle lens system in traditional surgery group. Surgical time, membrane peeling time were recorded, followed-up for 6 mo, post-operative best-corrected visual acuity(BCVA), intraocular pressure(IOP), central macular thickness(CMT), and complications were analyzed for the two groups.RESULTS:All patients successfully underwent surgery without experiencing serious intraoperative complications such as major retinal hemorrhage, retinal tears, or retinal detachment. Additionally, no postoperative complications such as endophthalmitis or secondary glaucoma occurred. The surgical duration and membrane peeling time in the 3D group were significantly shorter than those in the traditional surgery group(20.13±1.59 vs 25.97±2.09 min; 3.74±0.89 vs 8.13±1.72 min, respectively; both P0.008). However, both BCVA and CMT improved significantly at 3 and 6 mo postoperatively compared to preoperative levels(both P0.05).CONCLUSION: Both the 3D surgical video system and the traditional surgical group can treat idiopathic epiretinal membrane, but the 3D surgical video system has advantages in shortening the surgical time, improving surgical efficiency, and enhancing the precision of surgical steps during surgery with the assistance of intraoperative OCT.

Abstract Quantum walks provide a speed-up in computational power for various quantum algorithms and serve as inspiration for the construction of complex graph representations. Many pioneering works have been dedicated to expanding the experimental state space and the complexity of graphs. However, these experiments are mostly limited to small experimental scale, which do not reach a many-body level and fail to reflect the multi-particle quantum interference effects among non-adjacent modes. Here, we present a quantum walk with three photons on a two-dimensional triangular lattice, which is mapped to a 19 × 19 × 19 high-dimensional state space and constructs a complex graph with 6859 nodes and 45,486 edges. By utilizing the statistical signatures of the output combinations and incorporating machine learning techniques, we successfully validate the nonclassical properties of the experiment. Our implementation provides a paradigm for exponentially expanding the state space and graph complexity of quantum walks, paving the way for surmounting the classical regime in large-scale quantum simulations.

Abstract Objective To investigate pantothenate kinases 1 (PANK1) expression in kidney renal clear cell carcinoma (KIRC) tissues, analyze its correlation with clinicopathological features and prognosis, and explore its impact on invasion, migration, and apoptosis in KIRC cells. Methods GEPIA (gene expression profiling interactive analysis), UALCAN and LinkedOmics, were employed to analyze PANK1 expression in KIRC tissues and its correlation with clinical characteristics. Comparative analyses were performed between KIRC (Caki-1 and 786-O) and noncancerous renal cells (HK-2 and RPTEC). Transfection with PANK1 activation particles was conducted, followed by Wound healing, Transwell assay, Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) staining, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and Western blotting. Results PANK1 was down-regulated in KIRC tissues and cells compared to normal tissues and noncancerous cells. Correlation analyses linked PANK1 expression with clinicopathological features in KIRC, with high PANK1 expression associated with a favorable outcome. High PANK1 expression correlated positively with E-cadherin (CDH1), tight junction protein 1 (TJP1), Fas cell surface death receptor (FAS), caspase-8 (CASP8), and CASP9, while showing a negative correlation with vimentin (VIM), snail family transcriptional repressor 1 (SNAIL1), twist family BHLH transcription factor 1 (TWIST1), and TWIST2. PANK1 overexpression increased CDH1, TJP1, FAS, CASP8, and CASP9 while downregulating SNAIL1, VIM, TWIST1, and TWIST2, inhibiting invasion and migration, and promoting apoptosis in KIRC cells. Conclusion PANK1 down-regulation in KIRC tissues correlated with clinicopathological features and prognosis. Its overexpression modulated epithelial-mesenchymal transition (EMT)-related gene, inhibited invasion, promoted apoptosis in KIRC cells, highlighting its role in disease progression and therapeutic potential.

Abstract Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.

Abstract Background Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer’s disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified. Methods The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test. Results The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits. Conclusions DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders. Graphical Abstract Scheme depicting the possible mechanism by which DNase II deficiency induces cognitive impairment in mice. DNase II deficiency induces tau phosphorylation by regulating kinases CDK5 and CaMKII as well as phosphatase PP2A through accumulation of undigested damaged DNA in the cytoplasm of neurons. Then phosphorylated tau induces synaptic loss, neuroinflammation, and neuronal apoptosis, eventually rendering cognitive impairment in mice.

Summary: We previously described that the KDM5B histone H3 lysine 4 demethylase is an oncogene in estrogen-receptor-positive breast cancer. Here, we report that KDM5A is amplified and overexpressed in basal breast tumors, and KDM5 inhibition (KDM5i) suppresses the growth of KDM5-amplified breast cancer cell lines. Using CRISPR knockout screens in a basal breast cancer cell line with or without KDM5i, we found that deletion of the ZBTB7A transcription factor and core SAGA complex sensitizes cells to KDM5i, whereas deletion of RHO-GTPases leads to resistance. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed co-localization of ZBTB7A and KDM5A/B at promoters with high histone H3K4me3 and dependence of KDM5A chromatin binding on ZBTB7A. ZBTB7A knockout altered the transcriptional response to KDM5i at NF-κB targets and mitochondrion-related pathways. High expression of ZBTB7A in triple-negative breast cancer is significantly associated with poor response to neoadjuvant chemotherapy. Our work furthers the understanding of KDM5-mediated gene regulation and identifies mediators of sensitivity to KDM5i.

ObjectiveThis study aimed to assess the efficacy of innovative Chemiluminescence Immunoassay (CLIA) in testing Cryptococcal Antigen (CrAg) across two medical centers, employing the FDA-approved CrAg Lateral Flow Assay (LFA) by IMMY as a reference standard.MethodsThe study encompassed patients diagnosed with cryptococcosis at West China Hospital of Sichuan University (HX) between July 2022 and May 2023, and Suzhou Fifth People’s Hospital (SZ) from September 2020 to September 2023. All specimens underwent simultaneous detection using the LFA (IMMY, Norman, USA) and CLIA (Chuanglan, Suzhou, China).ResultsA total of 628 patients were enrolled, revealing a remarkable 99.20% concordance between LFA and CLIA (623/628, 99.20%). The LFA exhibited a sensitivity of 96.83% (244/252) and specificity of 98.35% (179/182). Among the 42 patients with unaltered CrAg titers, the changes of Signal-to-Cut-Off ratio (ΔS/CO) results exhibited a noteworthy discrepancy, with 71.43% (30/42) demonstrating a decreasing trend in ΔS/CO of at least 10%.ConclusionsThe CLIA method demonstrated commendable specificity and sensitivity, exhibiting a high level of agreement with the FDA-approved LFA method. Additionally, CLIA demonstrated superior utility for treatment monitoring compared to LFA, offering continuous insight into the fluctuation of CrAg concentrations.

BackgroundColorectal cancer (CRC) poses a significant global health burden, with high incidence and mortality rates. Despite advances in diagnostic and therapeutic modalities, early diagnosis remains critical for improved outcomes. Recent research has realized the important role of gut microbiota in CRC development, highlighting the need to elucidate potential relationships.MethodsIn this study, we employed Mendelian randomization (MR) to establish a robust potential link between gut microbial genera and CRC. Data from the MiBioGen database provided curated genome-wide association study (GWAS) summary datasets for microbial genera, while the Finngen database provided CRC outcome data. Instrumental variables (IVs) were identified based on genetic variants associated with gut microbiota. Various MR methods, including Inverse Variance Weighted (IVW), Weighted Median, Weighted Mode, Simple Mode, and MR-Egger, were employed to estimate potential effects. Functional analysis of genes near single nucleotide polymorphisms (SNPs) was performed to unravel potential pathways.ResultsAnalysis of microbial genera identified five potentially associated with CRC: Eubacterium fissicatena group, Anaerofilum, Defluviitaleaceae UCG011, Ruminococcus 2, and Sutterella. Notably, Defluviitaleaceae UCG011 emerged as the only risk factor. Gene analysis revealed hub genes PTPRD and DSCAM near Defluviitaleaceae UCG011 associated SNPs. Expression analysis showed that PTPRD decreased in colon cancer and DSCAM decreased in rectal cancer. The methylation status of the PTPRD gene promoter region indicated potential regulatory alterations.ConclusionThis study establishes a potential relationship between five specific gut microbial genera, particularly Defluviitaleaceae UCG011, and CRC. Hub genes PTPRD and DSCAM provide insights into potential molecular mechanisms, suggesting the potential role of Defluviitaleaceae UCG011 in modulating the initiation and progression of CRC. Further research is essential to validate these associations and delve deeper into therapeutic implications.

ABSTRACT Objectives Whether to perform local radiotherapy on metastatic bone for primary bone‐only oligometastatic nasopharyngeal carcinoma (NPC) patients remains unclear. Therefore, we analyzed the treatment methods and their survival and developed a prognostic model to predict outcomes and guide personalized treatment. Materials and Methods We studied 308 primary bone‐only oligometastatic NPC patients who were treated with either palliative chemotherapy (PCT) alone, PCT combined with locoregional radiotherapy (LRRT), or PCT, LRRT, and radiotherapy to metastatic bones (bRT). The primary endpoint was overall survival (OS). Cox regression was utilized to identify independent prognostic factors, leading to the construction of a nomogram model. Patients were stratified into two risk groups based on median prognostic scores, and treatment modalities were compared using log‐rank test while employing the inverse probability of treatment weighting (IPTW) to balance baseline characteristics and adjust for sample size differences between risk groups. Results The best OS was observed in the group treated with PCT, LRRT, and bRT (HR = 0.60, 95% CI: 0.45–0.81, p = 0.002). Multivariable analysis revealed that age, N stage, pre‐treatment levels of LDH, and EBV DNA were independent prognostic factors for OS. In total, 155 patients were in low‐risk group while 153 were in high‐risk group. Before and after IPTW, the high‐risk group benefited from the PCT, LRRT, and bRT regimen (adjusted HR = 0.53, 95% CI: 0.42–0.67, p

The aim of this study is to assess the impact of serum magnesium (Mg) levels on prognostic outcomes in patients with non-small cell lung cancer (NSCLC) undergoing treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). A cohort comprising 91 patients with NSCLC with epidermal growth factor receptor mutations received EGFR-TKI therapy. Assessments of liver and kidney function and electrolyte levels were conducted before treatment initiation and after completing two cycles of EGFR-TKI therapy. Data on variables such as age, gender, presence of distant metastasis, smoking history, other therapeutic interventions, and the specific TKI used were collected for analysis. Cox regression analysis revealed that patients with higher Mg levels prior to EGFR-TKI therapy had significantly longer progression-free survival (PFS) and overall survival (OS). Elevated Mg levels remained predictive of PFS and OS after two cycles of EGFR-TKI therapy. Multiple regression analysis confirmed these findings. Additionally, it was observed that smokers might represent a unique population, demonstrating a correlation between OS and Mg levels. Our findings indicate that serum Mg level is a prognostic factor in patients with NSCLC undergoing EGFR-TKI therapy. This may provide new insights into the underlying mechanisms of EGFR-TKI therapy related to electrolyte balance.

Objective Bone marrow mesenchymal stem cells (BMSCs) show significant potential for osteogenic differentiation. However, the underlying mechanisms of osteogenic capability in osteoporosis‐derived BMSCs (OP‐BMSCs) remain unclear. This study aims to explore the impact of YTHDF3 (YTH N6‐methyladenosine RNA binding protein 3) on the osteogenic traits of OP‐BMSCs and identify potential therapeutic targets to boost their bone formation ability. Methods We examined microarray datasets (GSE35956 and GSE35958) from the Gene Expression Omnibus (GEO) to identify potential m6A regulators in osteoporosis (OP). Employing differential, protein interaction, and machine learning analyses, we pinpointed critical hub genes linked to OP. We further probed the relationship between these genes and OP using single‐cell analysis, immune infiltration assessment, and Mendelian randomization. Our in vivo and in vitro experiments validated the expression and functionality of the key hub gene. Results Differential analysis revealed seven key hub genes related to OP, with YTHDF3 as a central player, supported by protein interaction analysis and machine learning methodologies. Subsequent single‐cell, immune infiltration, and Mendelian randomization studies consistently validated YTHDF3's significant link to osteoporosis. YTHDF3 levels are significantly reduced in femoral head tissue from postmenopausal osteoporosis (PMOP) patients and femoral bone tissue from PMOP mice. Additionally, silencing YTHDF3 in OP‐BMSCs substantially impedes their proliferation and differentiation. Conclusion YTHDF3 may be implicated in the pathogenesis of OP by regulating the proliferation and osteogenic differentiation of OP‐BMSCs.

BackgroundCurrently, there is a lack of global or even country/regional level data on adolescent non-alcoholic fatty liver disease (NAFLD) prevalence. However, an evidenced dose-dependent relationship exists between body mass index (BMI) and the risk of NAFLD. We aim to estimate the global and regional prevalence of adolescent NAFLD and related non-alcoholic steatohepatitis (NASH) based on BMI.MethodsSigmoidal fitting curves were generated between BMI and the risk of NAFLD/NASH using the data extracted from the NHANES database. With global and regional BMI data from the NCD-RisC database, adolescent NAFLD/NASH prevalence was estimated at the international, regional, and country levels from 1975 to 2016. The prevalence of adolescent NAFLD/NASH from 2017 to 2030 was also forecasted.ResultsThe mean NAFLD prevalence was 15.31, and 12.68%, while the mean NASH prevalence was 2.50, and 2.47%, in boys, and girls aged 12–18, respectively. For both boys and girls, NAFLD/NASH prevalence increased with increasing BMI, and age. The global prevalence of adolescent NAFLD/NASH has gradually increased in the period from 1975 to 2016 and will maintain a similar trend between 2017 and 2030. High-income Western Countries had higher adolescent NAFLD/NASH whereas South Asia and Sub-Saharan Africa exhibited relatively lower adolescent NAFLD/NASH prevalence. The estimated annual percentage change (EAPC) of NAFLD prevalence in boys ranged from 0.72% (age 18) to 1.16% (age 12) while that in girls ranged from 0.69% (age 18) to 0.92% (age 12). EAPC of NASH prevalence in boys ranged from 1.65% (age 18) to 1.77% (age 12), and in girls from 1.48% (age 18) to 1.68% (age 12).ConclusionThe adolescent NAFLD/NASH prevalence increases year by year, and its burden varies significantly among different countries and regions. BMI is a precise predictor of NAFLD/NASH prevalence.

The coral reefs along Pakistan’s coastline are of ecological and economic significance. However, they are increasingly threatened by anthropogenic threats and climate change. These vulnerable ecosystems are declining due to various factors such as sedimentation, climate change, overfishing, destructive fishing practices, marine pollution, and tourism development. We found that 29%, 24%, 26%, 16% and 18% of the studies exceeding, marine pollution, overfishing/destructive fishing, coastal tourism, climate change and sedimentation, respectively; thus, indicating inadequate water quality status in part of Pakistan coastal water. These influences lead to several negative impacts, such as jeopardized coral health, decline in biodiversity, and the simplification of reef structures. In response to these threats, conservation efforts are imperative. This literature review provides an in-depth analysis of anthropogenic threats, climate change and the conservation of coral reefs in Pakistan. This review provides suggestions on how the country could better conserve its coral reef ecosystem. These include (1) initiatives such as establishing marine protected areas (MPAs), (2) encouraging sustainable fishing practices and reducing pollution, (3) developing the country as an ecotourism destination and implementing climate change adaptation measures, and (4) community engagement through awareness campaigns and fostering collaboration among, governmental organizations, non-governmental organizations (NGOs) and scientists. These comprehensive conservation policies address human-caused and other challenges, safeguarding their ecological, economic, and cultural relevance for future generations.

Background: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is significantly influenced by intestinal flora. Understanding the genetic and microbiotic interplay is crucial for IBD prediction and treatment. Methods: We used Mendelian randomization (MR), transcriptomic analysis, and machine learning techniques, integrating data from the MiBioGen Consortium and various GWAS datasets. SNPs associated with intestinal flora were mapped to genes, with LASSO regression refining gene selection. Differentially expressed genes (DEGs) and immune infiltration patterns were identified through transcriptomic analysis. Six machine learning models were used for predictive modeling. Findings: MR analysis identified 25 gut microbiota classifications causally related to IBD. SNP mapping and gene expression analysis highlighted 24 significant genes. Drug target MR and colocalization validated these genes' causal relationships with IBD. Key pathways identified included the PI3K-Akt signaling pathway and epithelial-mesenchymal transition. Immune infiltration analysis revealed distinct patterns between high and low LASSO score groups. Machine learning models demonstrated high predictive value, with soft voting enhancing reliability. Interpretation: By integrating MR, transcriptomic analysis, and sophisticated machine learning approaches, this study elucidates the causal relationships between intestinal flora and IBD. The application of machine learning not only enhanced predictive modeling but also offered new insights into IBD pathogenesis, highlighted potential therapeutic targets, and established a robust framework for predicting IBD onset.

BackgroundIt is challenging for clinicians to distinguish adrenocortical carcinoma (ACC) from benign adrenocortical adenomas (ACA) in their early stages. This study explored the value of serum steroid profiling as a complementary biomarker for malignancy diagnosis of ACC other than diameter and explored the influence of sex and functional status.MethodsIn this retrospective study, a matched cohort of patients diagnosed with either ACC or ACA based on histopathology was meticulously paired in a 1:1 ratio according to sex, age, and functional status. Eight serum steroids including 11-deoxycortisol, 11-deoxycorticosterone, progesterone, androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone, and estradiol, were quantified by liquid chromatography tandem mass spectrometry. We conducted a comparative analysis of the clinical characteristics and serum steroid profiles of patients with ACC and ACA, with further subgroup analysis.ResultsThe study included 31 patients with ACC and 31 matched patients with ACA. Patients with ACC exhibited significantly larger tumor diameters, lower body mass index (BMI), and higher levels of 11-deoxycortisol, progesterone, and androstenedione than those with ACA. 11-deoxycortisol was the only valuable index for discriminating ACC from ACA, regardless of functional status and sex. Progesterone, DHEA, and DHEAS levels were higher in the functional ACC group than in the non-functional ACC group. Female ACC patients, especially in postmenopausal female exhibited higher levels of androstenedione than male patients. The area under the curve of tumor diameter, 11-deoxycortisol, and BMI was 0.947 (95% CI 0.889–1.000), with a sensitivity of 96.8% and specificity of 90.3%.ConclusionSerum steroid profiling serves as a helpful discriminative marker for ACC and ACA, with 11-deoxycortisol being the most valuable marker. For other steroid hormones, consideration of sex differences and functional status is crucial.

Objective: The purpose of this study is to investigate the role of PMMA-induced biofilm in nerve regeneration compared with silicone-induced biofilm involved in the mechanism. Methods: PMMA or silicon rods were placed next to the sciatic nerve to induce a biological membrane which was assayed by PCR, Western blot, immunohistochemistry, immunofluorescence and proteomics. A 10 mm sciatic nerve gaps were repaired with the autologous nerve wrapped in an induced biological membrane. The repair effects were observed through general observation, functional evaluation of nerve regeneration, ultrasound examination, neural electrophysiology, the wet weight ratio of bilateral pretibial muscle and histological evaluation. Cell proliferation and migration of Schwann cells co-cultured with EGF-treated fibroblasts combined with siRNA were investigated. Results: The results indicated that expression of GDNF, NGF and VEGF along with neovascularization was similar in the silicone and PMMA group and as the highest at 6 weeks after operation. Nerve injury repair mediated by toluidine blue and S100β/NF200 expression, the sensory and motor function evaluation, ultrasound, target organ muscle wet-weight ratio, percentage of collagen fiber, electromyography and histochemical staining were not different between the two groups and better than blank group. EGF-treated fibroblasts promoted proliferation and migration may be Tnc expression dependently. Conclusion: Our study suggested that PMMA similar to silicon induced biofilm may promote autogenous nerve transplantation to repair nerve defects through EGF/Tnc/FN1 to increase Schwann cells proliferation and migration.

IntroductionThe morbidity and mortality rates of coronary heart disease are significant, with PCI being the primary treatment. The high incidence of ISR following PCI poses a challenge to its effectiveness. Currently, there are numerous studies on ISR risk prediction models after PCI, but the quality varies and there is still a lack of systematic evaluation and analysis.MethodsTo systematically retrieve and evaluate the risk prediction models for ISR after PCI. A comprehensive search was conducted across 9 databases from inception to March 1, 2024. The screening of literature and extraction of data were independently carried out by two investigators, utilizing the checklist for critical appraisal and data extraction for systematic reviews of prediction modeling studies (CHARMS). Additionally, the risk of bias and applicability were evaluated using the Prediction Model Risk of Bias Assessment Tool (PROBAST).ResultsA total of 17 studies with 29 models were included, with a sample size of 175–10,004 cases, and the incidence of outcome events was 5.79%–58.86%. The area under the receiver operating characteristic curve was 0.530–0.953. The top 5 predictors with high frequency were diabetes, number of diseased vessels, age, LDL-C and stent diameter. Bias risk assessment into the research of the risk of higher bias the applicability of the four study better.DiscussionThe overall risk of bias in the current ISR risk prediction model post-PCI is deemed high. Moving forward, it is imperative to enhance study design and specify the reporting process, optimize and validate the model, and enhance its performance.

Most Oxalis are highly ornamentally valuable, but their taxonomy is difficult, which greatly limits the landscape application of this genus. The pollen morphology and exine ornamentation of 14 species of the Oxalis were observed using scanning electron microscopy, and their pollen morphology was clustered and analyzed to explore their interspecific relationship based on the results of palynological clustering. The results were as follows: (1) The pollens of the 14 species observed were subspheroidal or oblatesphere, and in polar view they were all 3-colpate, of which 96.3% were medium-sized and 3.7% were small, with different style types showing the largest grains were produced in stamens with long filaments and the smallest ones in stamens with short filaments; most pollen grains were 3-colpate, sparsely 2-colpate and 4-colpate, O. stellata and O. pes-caprae, respectively; exine ornamentation could be divided into two categories: supra-areolate and reticulate. (2) For the first time, three species with aberrant pollen grains were observed, namely O. glabra, O. simplex and O. pes-caprae. The aberrant pollens exhibited as abnormal number and arrangement of the colpi, but normal exine structure. There were 2-zonocolpate grains in O. glabra, spiralaperturate grains in O. simplex, and 4-zonocolpate grains and spiralaperturate grains in O. pes-caprae. (3) The 14 species could be divided into two categories according to the exine ornamentation, one included O. massonorum and O. nidulans with supra-areolate pollen. The other category included 12 species with reticulate pollen. Species in the latter category could be further divided into four types: O. glabra, O. versicolor, and O. tenuifolia were more closely related; O. compressa, O. pes-caprae, O. namaquana, and O. fabaefolia were more closely related; O. bowiei, O. stellata, and O. perdicaria were more closely related; O. zeekoevleyensis and O. simplex were relatively distantly related to other Oxalis. The results of this study show that species with similar pollen morphology have certain similarity in plant morphology, and the pollen morphology characteristics can be used as the basis for the study of phylogenetic relationship and taxonomic classification, which can further provide a theoretical basis for the selection of parents in Oxalis cross-breeding.

Abstract This study evaluated the impacts of sulfamethoxazole (SMX) on antioxidant, immune, histopathological dynamic changes, and gut microbiota of zebrafish. SMX was carried out five groups: 0 (C), 3 mg/L (T3), 6 mg/L (T6), 12 mg/L (T12), and 24 mg/L (T24), with 5 replicates per group for an 8-weeks chronic toxicity test. It was found that SMX is considered to have low toxicity to adult zebrafish. SMX with the concentration not higher than 24 mg/L has no obvious inhibitory effect on the growth of fish. Under different concentrations of SMX stress, oxidative damage and immune system disorder were caused to the liver and gill, with the 12 and 24 mg/L concentration being the most significant. At the same time, it also causes varying degrees of pathological changes in both intestinal and liver tissues. As the concentration of SMX increases, the composition and abundance of the gut microbiota in zebrafish significantly decrease.

Abstract The elderly frequently present impaired blood–brain barrier which is closely associated with various neurodegenerative diseases. However, how the albumin, the most abundant protein in the plasma, leaking through the disrupted BBB, contributes to the neuropathology remains poorly understood. We here demonstrated that mouse serum albumin-activated microglia induced astrocytes to A1 phenotype to remarkably increase levels of Elovl1, an astrocytic synthase for very long-chain saturated fatty acids, significantly promoting VLSFAs secretion and causing neuronal lippoapoptosis through endoplasmic reticulum stress response pathway. Moreover, MSA-activated microglia triggered remarkable tau phosphorylation at multiple sites through NLRP3 inflammasome pathway. Intracerebroventricular injection of MSA into the brains of C57BL/6J mice to a similar concentration as in patient brains induced neuronal apoptosis, neuroinflammation, increased tau phosphorylation, and decreased the spatial learning and memory abilities, while Elovl1 knockdown significantly prevented the deleterious effect of MSA. Overall, our study here revealed that MSA induced tau phosphorylation and neuron apoptosis based on MSA-activated microglia and astrocytes, respectively, showing the critical roles of MSA in initiating the occurrence of tauopathies and cognitive decline, and providing potential therapeutic targets for MSA-induced neuropathology in multiple neurodegenerative disorders.

Abstract The neurotoxic α-synuclein (α-syn) oligomers play an important role in the occurrence and development of Parkinson’s disease (PD), but the factors affecting α-syn generation and neurotoxicity remain unclear. We here first found that thrombomodulin (TM) significantly decreased in the plasma of PD patients and brains of A53T α-syn mice, and the increased TM in primary neurons reduced α-syn generation by inhibiting transcription factor p-c-jun production through Erk1/2 signaling pathway. Moreover, TM decreased α-syn neurotoxicity by reducing the levels of oxidative stress and inhibiting PAR1-p53-Bax signaling pathway. In contrast, TM downregulation increased the expression and neurotoxicity of α-syn in primary neurons. When TM plasmids were specifically delivered to neurons in the brains of A53T α-syn mice by adeno-associated virus (AAV), TM significantly reduced α-syn expression and deposition, and ameliorated the neuronal apoptosis, oxidative stress, gliosis and motor deficits in the mouse models, whereas TM knockdown exacerbated these neuropathology and motor dysfunction. Our present findings demonstrate that TM plays a neuroprotective role in PD pathology and symptoms, and it could be a novel therapeutic target in efforts to combat PD. Schematic representation of signaling pathways of TM involved in the expression and neurotoxicity of α-syn. A TM decreased RAGE, and resulting in the lowered production of p-Erk1/2 and p-c-Jun, and finally reduce α-syn generation. α-syn oligomers which formed from monomers increase the expression of p-p38, p53, C-caspase9, C-caspase3 and Bax, decrease the level of Bcl-2, cause mitochondrial damage and lead to oxidative stress, thus inducing neuronal apoptosis. TM can reduce intracellular oxidative stress and inhibit p53-Bax signaling by activating APC and PAR-1. B The binding of α-syn oligomers to TLR4 may induce the expression of IL-1β, which is subsequently secreted into the extracellular space. This secreted IL-1β then binds to its receptor, prompting p65 to translocate from the cytoplasm into the nucleus. This translocation downregulates the expression of KLF2, ultimately leading to the suppression of TM expression. By Figdraw.

Abstract Introduction The impact of immunosuppression on prognosis of carbapenem-resistant organism (CRO) bloodstream infection (BSI) remains unclear. The aim of this study was to clarify the relationship between immunosuppression and mortality of CRO-BSI and to identify the risk factors associated with mortality in immunosuppressed patients. Methods This retrospective study included 279 patients with CRO-BSI from January 2018 to March 2023. Clinical characteristics and outcomes were compared between the immunosuppressed and immunocompetent patients. The relationship between immunosuppression and 30-day mortality after BSI onset was assessed through logistic-regression analysis, propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Factors associated with mortality in immunosuppressed patients were analyzed using multivariable logistic regression analysis. Results A total of 88 immunocompetent and 191 immunosuppressed patients were included, with 30-day all-cause mortality of 58.8%. Although the 30-day mortality in immunosuppressed patients was significantly higher than in immunocompetent patients (46.6% vs. 64.4%, P = 0.007), immunosuppression was not an independent risk factor for mortality in multivariate logistic regression analysis (odds ratio [OR] 3.53, 95% confidence interval [CI] 0.74–18.89; P = 0.123), PSM (OR 1.38, 95% CI 0.60–3.18; P = 0.449,) or IPTW (OR 1.40, 95% CI 0.58–3.36; P = 0.447). For patients with CRO-BSI, regardless of immune status, appropriate antibiotic therapy was associated with decreased 30-day mortality, while Charlson comorbidity index (CCI), intensive care unit (ICU)-acquired infection and thrombocytopenia at CRO-BSI onset were associated with increased mortality. Conclusion Despite the high mortality rate of CRO-BSI, immunosuppression did not affect the mortality. Appropriate antibiotic therapy is crucial for improving the prognosis of CRO-BSI, regardless of the immune status.

Abstract Due to a rapidly aging global population, osteoporosis and the associated risk of bone fractures have become a wide-spread public health problem. However, osteoporosis is very heterogeneous, and the existing standard diagnostic measure is not sufficient to accurately identify all patients at risk of osteoporotic fractures and to guide therapy. Here, we constructed the first prospective multi-omics atlas of the largest osteoporosis cohort to date (longitudinal data from 366 participants at three time points), and also implemented an explainable data-intensive analysis framework (DLSF: Deep Latent Space Fusion) for an omnigenic model based on a multi-modal approach that can capture the multi-modal molecular signatures (M3S) as explicit functional representations of hidden genotypes. Accordingly, through DLSF, we identified two subtypes of the osteoporosis population in Chinese individuals with corresponding molecular phenotypes, i.e., clinical intervention relevant subtypes (CISs), in which bone mineral density benefits response to calcium supplements in 2-year follow-up samples. Many snpGenes associated with these molecular phenotypes reveal diverse candidate biological mechanisms underlying osteoporosis, with xQTL preferences of osteoporosis and its subtypes indicating an omnigenic effect on different biological domains. Finally, these two subtypes were found to have different relevance to prior fracture and different fracture risk according to 4-year follow-up data. Thus, in clinical application, M3S could help us further develop improved diagnostic and treatment strategies for osteoporosis and identify a new composite index for fracture prediction, which were remarkably validated in an independent cohort (166 participants).

Abstract Quantum effects in photosynthetic energy transport in nature, especially for the typical Fenna-Matthews-Olson (FMO) complexes, are extensively studied in quantum biology. Such energy transport processes can be investigated as open quantum systems that blend the quantum coherence and environmental noise, and have been experimentally simulated on a few quantum devices. However, the existing experiments always lack a solid quantum simulation for the FMO energy transport due to their constraints to map a variety of issues in actual FMO complexes that have rich biological meanings. Here we successfully map the full coupling profile of the seven-site FMO structure by comprehensive characterisation and precise control of the evanescent coupling of the three-dimensional waveguide array. By applying a stochastic dynamical modulation on each waveguide, we introduce the base site energy and the dephasing term in coloured noise to faithfully simulate the power spectral density of the FMO complexes. We show our photonic model well interprets the phenomena including reorganisation energy, vibrational assistance, exciton transfer and energy localisation. We further experimentally demonstrate the existence of an optimal transport efficiency at certain dephasing strength, providing a window to closely investigate environment-assisted quantum transport.

Highlights A strategy based on metal-organic decomposition is proposed to enhance the tube-tube interactions of carbon nanotubes (CNTs). The robust tube-tube interactions of CNTs enhance both EMI shielding performance and mechanical properties of CNT film. This innovative approach provides an effective way to obtain high-performance CNT film.

Abstract Background Sinus of Valsalva aneurysm (SVA) is an extremely rare condition, and its rupture causes acute symptoms such as chest pain and dyspnea. Ruptured SVA is frequently associated with other congenital defects. Case presentation A 37-year-old male presented with SVA originating from the left coronary sinus that ruptured into the interventricular septum. SVA was diagnosed by echocardiography, cardiac computed tomography and magnetic resonance imaging, and confirmed during the operation. Conclusions SVA is a rare cardiac abnormality which can lead to severe clinical symptoms upon rupture. Immediate surgery is necessary to repair the ruptured SVA.

IntroductionKinesiophobia denotes an excessive and irrational apprehension towards physical activity or exercise among patients, stemming from a perception of susceptibility to painful injury or re-injury. Cardiac rehabilitation stands pivotal in the secondary prevention spectrum for individuals with cardiovascular ailments, with exercise constituting a cornerstone of this regimen. However, the emergence of kinesiophobia poses a formidable challenge, diminishing patient adherence to cardiac rehabilitation protocols, particularly among those grappling with chronic heart failure. To bolster exercise-based rehabilitation initiatives in this cohort, a thorough comprehension of the multifaceted factors precipitating kinesiophobia is imperative. This review endeavors to delineate prevailing evidence and prevalence concerning kinesiophobia triggers in chronic heart failure patients, while pinpointing research lacunae for future exploration.MethodsEmploying a scoping review methodology, our investigation culled data from diverse scholarly databases, including Embase, PubMed, Scopus, CINAHL, Web of Science, Medline, Sinomed, CNKI, Wangfan, and VIP.ResultsAfter thorough evaluation, 9 studies that met the inclusion criteria were ultimately incorporated.DiscussionOur findings underscore a notable prevalence of kinesiophobia in chronic heart failure patients, predominantly influenced by socio-demographic factors, psychological and cognitive factors, disease and treatment factors, as well as lifestyle and behavior. Armed with these insights, future interventions can be tailored to mitigate kinesiophobia levels, fostering enhanced engagement in exercise-centric cardiac rehabilitation endeavors among patients grappling with chronic heart failure.

Orthocarbonate Sr2CO4 is a recently discovered Sr-carbonate that plays a crucial role in understanding the global long-term carbon cycle. In this work, the structure, equation of state, elasticity, and thermal conductivity of Sr2CO4 were studied by first-principles calculations. The results show that the surfaces of the SrO9 and SrO11 polyhedrons, which make up Sr2CO4, are composed of triangles and quadrangles. By comparison with other alkaline earth metal orthocarbonates, SrCO3 polymorphs, and the Preliminary Reference Earth Model (PREM), Sr2CO4 is found to be a carbonate with high density, low wave velocity, low anisotropy, and low thermal conductivity in the entire Earth’s mantle. This study may help to understand the high-pressure behavior of alkaline earth metal orthocarbonates in the Earth’s interior.

The present study was aimed to investigate the effects of Phaeodactylum tricornutum oil (PO) and Laminaria japonica oil (LO) against obesity and other metabolic disorders in a high-fat diet (HFD) induced obese mouse model. The results revealed that PO or LO supplementation significantly reduced HFD-induced body weight gain, hyperlipemia, and fat accumulation in mice. PO or LO supplementation also inhibited SREBP-1-mediated de novo lipogenesis and PPARγ-mediated adipogenesis, as well as enhanced PPARα-mediated fatty acid β-oxidation in the WAT and liver of HFD-fed mice. Moreover, PO or LO supplementation attenuated low-grade chronic inflammation, hyperglycemia and insulin resistance in obese mice. Furthermore, Dietary PO or LO also modulated HFD-induced gut microbiota dysbiosis and increased the SCFAs production. More importantly, our results also manifested that the ameliorative effect of PO and LO against HFD-induced obesity, IR and gut microbiota dysbiosis was comparable, but was superior than that of krill oil and fish oil.

Cancer is a heavy human burden worldwide, with high morbidity and mortality. Identification of novel cancer diagnostic and prognostic biomarkers is important for developing cancer treatment strategies and reducing mortality. Transcription factors, including SRY associated high mobility group box (SOX) proteins, are thought to be involved in the regulation of specific biological processes. There is growing evidence that SOX transcription factors play an important role in cancer progression, including tumorigenesis, changes in the tumor microenvironment, and metastasis. SOX5 is a member of SOX Group D of Sox family. SOX5 is expressed in various tissues of human body and participates in various physiological and pathological processes and various cellular processes. However, the abnormal expression of SOX5 is associated with cancer of various systems, and the abnormal expression of SOX5 acts as a tumor promoter to promote cancer cell viability, proliferation, invasion, migration and EMT through multiple mechanisms. In addition, the expression pattern of SOX5 is closely related to cancer type, stage and adverse clinical outcome. Therefore, SOX5 is considered as a potential biomarker for cancer diagnosis and prognosis. In this review, the expression of SOX5 in various human cancers, the mechanism of action and potential clinical significance of SOX5 in tumor, and the therapeutic significance of Sox5 targeting in cancer were reviewed. In order to provide a new theoretical basis for cancer clinical molecular diagnosis, molecular targeted therapy and scientific research.

Extrarenal rhabdoid tumor of the greater omentum is extremely rare, with only sporadic reports and limited documentation of its ultrasonographic findings. Here, we report a case of an extrarenal rhabdoid tumor of the greater omentum in a 16-year-old girl and review the relevant literature. It was found that the disease mainly occurred in female children and adolescents, and mainly manifested as lower abdominal pain and a large abdominal cystic or solid hemorrhagic mass. The clinical characteristics include a high degree of malignancy and mortality. Ultrasound shows some malignant features, but it is not specific; thus, it is easy to be misdiagnosed in the clinic.

Abstract Background Magnesium (Mg) is both an essential macro-element and a known catalyst, and it plays a vital role in various physiological activities and mechanisms in relation to chronic kidney disease (CKD). However, epidemiological evidence involving this is limited and not entirely consistent. This study aims to explore the association of serum Mg concentrations with the risk of CKD among general Chinese adults. Methods A total of 8,277 Chinese adults were included in the wave of 2009 from the China Health and Nutrition Survey (CHNS). The primary outcome was the risk of CKD, which was defined as the estimated glomerular filtration rate (eGFR)

Abstract Sepsis‐induced myocardial injury is one of the most difficult complications of sepsis in intensive care units. Annexin A1 (ANXA1) short peptide (ANXA1sp) protects organs during the perioperative period. However, the protective effect of ANXA1sp against sepsis‐induced myocardial injury remains unclear. We aimed to explore the protective effects and mechanisms of ANXA1sp against sepsis‐induced myocardial injury both in vitro and in vivo. Cellular and animal models of myocardial injury in sepsis were established with lipopolysaccharide. The cardiac function of mice was assessed by high‐frequency echocardiography. Elisa assay detected changes in inflammatory mediators and markers of myocardial injury. Western blotting detected autophagy and mitochondrial biosynthesis‐related proteins. Autophagic flux changes were observed by confocal microscopy, and autophagosomes were evaluated by TEM. ATP, SOD, ROS, and MDA levels were also detected.ANXA1sp pretreatment enhanced the 7‐day survival rate, improved cardiac function, and reduced TNF‐α, IL‐6, IL‐1β, CK‐MB, cTnI, and LDH levels. ANXA1sp significantly increased the expression of sirtuin‐3 (SIRT3), mitochondrial biosynthesis‐related proteins peroxisome proliferator‐activated receptor γ co‐activator 1α (PGC‐1α), and mitochondrial transcription factor A (TFAM). ANXA1sp increased mitochondrial membrane potential (△Ψm), ATP, and SOD, and decreased ROS, autophagy flux, the production of autophagosomes per unit area, and MDA levels. The protective effect of ANXA1sp decreased significantly after SIRT3 silencing in vitro and in vivo, indicating that the key factor in ANXA1sp's protective role is the upregulation of SIRT3. In summary, ANXA1sp attenuated sepsis‐induced myocardial injury by upregulating SIRT3 to promote mitochondrial biosynthesis and inhibit oxidative stress and autophagy.

Objective To investigate the relationship between triglyceride glucose (TyG) index and the total load of cerebral small vessel disease (CSVD) and its different imaging markers. Methods A total of 202 patients with CSVD admitted to The Third Hospital of Hebei Medical University from January 2020 to May 2022 were selected. The clinical data of all patients were collected and TyG index was calculated. The lacunes, cerebral microbleeds (CMBs), white matter hyperintensity (WMH) and enlarged perivascular space (EPVS) were evaluated by MRI, and total load of CSVD score was calculated. Results 1) TyG index and total load of CSVD score: Logistic regression analysis showed the male (OR = 2.245, 95%CI: 1.017-4.957; P = 0.045), increase of age (OR = 1.084, 95%CI: 1.046-1.124; P = 0.000), hypertension (OR = 2.457, 95%CI: 1.189-5.078; P = 0.015) and increase of TyG index (OR = 2.657, 95%CI: 1.353-5.216; P = 0.005) were risk factors for moderate and severe total load of CSVD. 2) TyG index and imaging markers of CSVD: Logistic regression analysis showed the increase of TyG index was the risk factor of moderate and severe WMH (OR = 2.313, 95%CI: 1.095-4.885; P = 0.028), CMBs (OR = 1.690, 95%CI: 1.011-2.824; P = 0.045), lacunes (OR = 2.087, 95%CI: 1.235-3.525; P = 0.006), moderate and severe EPVS in basal ganglia (OR = 2.005, 95%CI: 1.190-3.378; P = 0.009). Conclusions TyG index is associated with the total load and various imaging markers of CSVD, which can be used as a valuable biomarker to evaluate CSVD and its severity.

Abstract Altered DNA methylation is a crucial epigenetic event in hepatocellular carcinoma (HCC) development and progression. Through methylation-transcriptomic analysis, we identified a set of sixty potential DNA methylation-based epidriver genes. In this set of genes, we focused on the hypermethylation of EMX1, which is frequently observed in hepatobiliary tumors. Despite of its frequent occurrence, the function of EMX1 remains largely unknown. By utilizing bisulfite-next-generation sequencing, we have detected EMX1 DNA hypermethylation on the gene body, which is positively correlated with EMX1 mRNA expression. Further analysis revealed that EMX1 mRNA terminal exon splicing in HCC generated two protein isoforms: EMX1 full length (EMX1-FL) and alternative terminal exon splicing isoform (EMX1-X1). Cellular functional assays demonstrated that gain-of-function EMX1-FL, but not EMX1-X1, induced HCC cells migration and invasion while silencing EMX1-FL inhibited HCC cells motility. This result was further validated by in vivo tumor metastasis models. Mechanistically, EMX1-FL bound to EGFR promoter, promoting EGFR transcription and activating EGFR-ERK signaling to trigger tumor metastasis. Therefore, EGFR may be a potential therapeutic target for EMX1-high expression HCC. Our work illuminated the crucial role of gene body hypermethylation-activated EMX1-FL in promoting tumorigenesis and metastasis in HCC. These findings pave the way for targeting the EMX1-EGFR axis in HCC tumorigenicity and metastasis.

Sound is an important medium of communication among insects. Some longhorn beetles produce sounds during their daily activities, and these sounds play a role in courtship, predation, and defense. However, whether there are differences in the sounds emitted by longhorn beetles and how to distinguish and recognize these sounds have not been investigated in detail. Here, the sounds of Glenea cantor (Fabricius), Moechotypa diphysis (Pascoe), and Psacothea hilaris (Pascoe) were collected, and the differences in their stridulatory organs were observed and compared using scanning electron microscopy (SEM). The characteristics of their sounds were analyzed using MATLAB. Linear prediction cepstral coefficients (LPCC) and Mel frequency cepstral coefficients (MFCC) were used to extract the sound features, and the support vector machine (SVM) model was used to identify the sounds of three species. The results showed that the stridulatory organs of three species of longhorn beetles differed in morphology and time domain, and the combination of MFCC and SVM had a better recognition ability. The difference in the stridulatory organs of longhorn beetles may be an important reason for the differences in the sounds they produce, and we discussed the application of insect sounds in insect classification.

Abstract Necrotizing enterocolitis (NEC) is a life-threatening, inflammatory disease affecting premature infants with intestinal necrosis, but the mechanism remains unclear. Neonatal macrophages are thought to play an important role in the pathogenesis of NEC through the production of proinflammatory cytokines. Restriction of cytokine expression in macrophages of NEC tissues may be beneficial. In adult macrophages, interfering with Rac1 has been shown to influence the expression of cytokines. Here, we investigated whether interfering with Rac1 in neonatal macrophages affects their inflammatory responses. First, we found that Rac1-activation was upregulated in the macrophages of rats with NEC model induction compared to controls. The M1 macrophages derived from human neonatal monocytes showed greater Rac1-activation than the M2 macrophages derived from the same monocytes. Inhibition of Rac1-activation by NSC23766 potently reduced the production of proinflammatory cytokines in these M1 macrophages. While neonatal monocytes differentiated into M1 macrophages in vitro, NSC23766 significantly altered cell function during the first six days of incubation with GM-CSF rather than during the subsequent stimulation phase. However, the same effect of NSC23766 was not observed in adult macrophages. Using mass spectrometry, Y-box binding protein 1 (YB1) was identified as being downregulated upon inhibition of Rac1-activation in the neonatal macrophages. Moreover, we found that inhibition of Rac1-activation shortens the poly A tail of PABPC1 mRNA, thereby reducing the translation of PABPC1 mRNA. Consequently, the downregulation of PABPC1 resulted in a reduced translation of YB1 mRNA. Furthermore, we found that TLR4 expression was downregulated in neonatal macrophages, while YB1 expression was reduced. Adding resatorvid (TLR4 signaling inhibitor) to the macrophages treated with NSC23766 did not further reduce the cytokine expression. These findings reveal a novel Rac1-mediated pathway to inhibit cytokine expression in neonatal M1 macrophages and suggest potential targets for the prevention or treatment of NEC.

Abstract Background Managing multidrug-resistant (MDR) HIV infections in children is particularly challenging due to the lack of experience with new drugs in the pediatric setting. Second-line albuvirtide (ABT) with an optimized antiretroviral background therapy was approved for adults and adolescents after first-line treatment failure. This paper describes the treatment outcomes and adverse effects of an ABT-based dual-active antiretroviral treatment regimen in a child with MDR HIV strains. Case presentation A 13 year-old Chinese female patient infected with MDR HIV strains showed a decrease in viral load (from 4.48 log10 to 1.73 log10) and an increase in CD4 + T cells (from 15 to 308 cells/µl) after 12 months of treatment with an ABT-based antiretroviral regimen. The child showed no relevant drug-related adverse reactions. Conclusions The case reported here could suggest that an ABT-based antiretroviral therapy might be beneficial and without relevant toxicity in children with MDR HIV. Infectiologists specializing in managing HIV should be prepared to manage an increasing number of children with MDR HIV. ABT might be a new treatment option for MDR HIV infection in children.

Abstract The visceral hybrid procedure combining retrograde visceral bypass grafting and completion endovascular stent grafting is a feasible alternative to conventional open surgical or wholly endovascular repairs of thoracoabdominal aneurysms (TAAA). However, the wide variability in visceral hybrid configurations means that a priori prediction of surgical outcome based on haemodynamic flow profiles such as velocity pattern and wall shear stress post repair remain challenging. We sought to appraise the clinical relevance of computational fluid dynamics (CFD) analyses in the setting of visceral hybrid TAAA repairs. Two patients, one with a type III and the other with a type V TAAA, underwent successful elective and emergency visceral hybrid repairs, respectively. Flow patterns and haemodynamic parameters were analysed using reconstructed pre- and post-operative CT scans. Both type III and type V TAAAs showed highly disturbed flow patterns with varying helicity values preoperatively within their respective aneurysms. Low time-averaged wall shear stress (TAWSS) and high endothelial cell action potential (ECAP) and relative residence time (RRT) associated with thrombogenic susceptibility was observed in the posterior aspect of both TAAAs preoperatively. Despite differing bypass configurations in the elective and emergency repairs, both treatment options appear to improve haemodynamic performance compared to preoperative study. However, we observed reduced TAWSS in the right iliac artery (portending a theoretical risk of future graft and possibly limb thrombosis), after the elective type III visceral hybrid repair, but not the emergency type V repair. We surmise that this difference may be attributed to the higher neo-bifurcation of the aortic stent graft in the type III as compared to the type V repair. Our results demonstrate that CFD can be used in complicated visceral hybrid repair to yield potentially actionable predictive insights with implications on surveillance and enhanced post-operative management, even in patients with complicated geometrical bypass configurations.

Abstract Immunotherapy combined with antiangiogenic targeted therapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for refractory recurrent/metastatic nasopharyngeal carcinoma (RM-NPC). We conducted a phase 2 trial to evaluate the safety and activity of camrelizumab plus apatinib in platinum-resistant (cohort 1, NCT04547088) and PD-1 inhibitor resistant NPC (cohort 2, NCT04548271). Here we report on the primary outcome of objective response rate (ORR) and secondary endpoints of safety, duration of response, disease control rate, progression-free survival, and overall survival. The primary endpoint of ORR was met for cohort 1 (65%, 95% CI, 49.6–80.4, n = 40) and cohort 2 (34.3%; 95% CI, 17.0–51.8, n = 32). Grade ≥ 3 treatment-related adverse events (TRAE) were reported in 47 (65.3%) of 72 patients. Results of our predefined exploratory investigation of predictive biomarkers show: B cell markers are the most differentially expressed genes in the tumors of responders versus non-responders in cohort 1 and that tertiary lymphoid structure is associated with higher ORR; Angiogenesis gene expression signatures are strongly associated with ORR in cohort 2. Camrelizumab plus apatinib combination effectiveness is associated with high expression of PD-L1, VEGF Receptor 2 and B-cell-related genes signatures. Camrelizumab plus apatinib shows promising efficacy with a measurable safety profile in RM-NPC patients.

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.

Background: Patients with initially unresectable colorectal cancer liver metastases (IU-CRLM) might benefit from using an effective systemic treatment followed by resection of liver metastases but the curative success rate is quite low. Indeed, nearly one-third of patients exhibit early recurrence within the first 6 months after surgery, and these individuals often have poor overall survival. Objectives: This study aims to clarify the application value of serial circulating tumor DNA (ctDNA) analysis in predicting the clinical outcome of IU-CRLM patients following liver metastasectomy. Design: A retrospective study was conducted on a cohort of patients with IU-CRLM between February 2018 and April 2021. Methods: Plasma samples at different time points during CRLM treatment [baseline (BL), preoperation (PRE), postoperation (POST), end-of-treatment (EOT), and progressive disease (PD)] were retrospectively collected from patients with initially unresectable CRLM enrolled at the Sun Yat-sen University Cancer Center. Dynamic changes of SEPTIN 9 (SEPT9) and Neuropeptide Y (NPY) methylated circulating tumor DNA (MetctDNA) levels in serial plasma samples were detected using droplet-digital PCR (ddPCR). Results: SEPT9 and NPY genes were hypermethylated in colon cancer cell lines and tissues while no difference was observed between primary and metastatic tumors. Patients with MetctDNA positive at POST or EOT had significantly lower recurrence-free survival (RFS) compared to patients with MetctDNA negative at these time points [POST: Hazard ratio (HR) 9.44, 95% confidence interval (CI) 5.15–17.30, p < 0.001; EOT: HR 11.48, 95% CI 3.27–40.31, p < 0.001]. Multivariate analysis demonstrated that POST (OR 33.96, 95% CI 4.03–286.10, p = 0.001) and EOT (OR 18.36, 95% CI 1.14–295.71, p = 0.04) MetctDNA was an independent risk factor for early recurrence. Time-dependent receiver operating characteristic curve (T-ROC) analysis revealed that area under the curve (AUC) value was greatest at the relapse time point of 6 months post-intervention, with POST-AUC and EOT-AUC values of 0.74 (95% CI 0.66–0.81) and 0.73 (95% CI 0.53–0.94), respectively. Serial MetctDNA analysis showed that RFS was significantly lower in patients with no MetctDNA clearance compared with those with MetctDNA clearance (HR 26.05, 95% CI 4.92–137.81, p < 0.001). Conclusion: Our study confirmed that serial ctDNA analysis of NPY and SEPT9 gene methylation could effectively predict early recurrence in IU-CRLM patients, especially at POST and EOT.

The intestinal bacteria of longhorn beetles would be ideal targets for pest control and lignocellulosic resources by destroying or exploiting their cellulose-degrading function. This article aims to investigate the diversity and community structure of intestinal bacteria the oligophagous longhorn beetle Glenea cantor. Additionally, it seeks to identify the presence of lignocellulose-degrading bacteria in the gut, and explore their role in consuming host kapok trees Bombax malabaricum. In this study, the bacterial community from G. cantor was examined by Illumina sequencing of 16S ribosomal RNA (rRNA) targeting the V3 and V4 regions. A total of 563,201 valid sequences and 814 OTUs were obtained. The dominant phyla were Proteobacteria, and the dominant genera were Acinetobacter and Lactococcus. The analysis of microbial diversity revealed a high bacterial diversity in the samples, with the gut bacteria playing a crucial role in the physiological activities of the host, particularly, 9 genera of intestinal bacteria with cellulose degradation function were found, highlighting their vital role in cellulose degradation. Five strains of cellulose-degrading bacteria, belonging to the genus Pseudomonas, were obtained from the intestinal tract of G. cantor larvae using traditional isolation and culture techniques as well as 16S rDNA sequencing. Among these strains, A4 exhibited a cellulase activity of 94.42 ± 0.42 U/mL, while A5 displayed the highest filter paper enzyme activity of 127.46 ± 3.54 U/mL. These results offered valuable insights into potential targets for pest control through internal attack digestion and cellulose-degrading bacteria in longhorn beetles.

Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%–15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.

Taq DNA polymerase is a thermostable enzyme and widely used in PCR technology. In order to improve the production of Taq DNA polymerase by recombinant Escherichia coli, in this study the enzyme yield and specific activity of the enzyme were taken as the inspection indicators. The single factors producing Taq DNA polymerase content were optimized through single factor test: fermentation temperature, pH, amount of IPTG inducer, induction time, and inoculation amount. The results showed that fermentation temperature, pH, concentration of IPTG inducer had a significant impact on the specific enzyme activity of Taq DNA polymerase produced by the genetic engineering strain, while induction culture time and inoculation amount had no significant impact on the specific enzyme activity of Taq DNA polymerase produced by the genetic engineering strain. So fermentation temperature, pH and IPTG inducer concentration were selected as three factors of response surface to optimize the fermentation process of recombinant Escherichia coli for Taq DNA polymerase production. The response surface analysis results showed and that the order of significance for the specific activity of enzymes were: IPTG inducer concentration>fermentation temperature>pH, and the optimal fermentation process parameters were: fermentation temperature 37.2 ℃, pH 7.5, IPTG inducer concentration 0.800 mmol/L. Under this condition, the specific activity of Taq DNA polymerase reached (43.822±0.878) kU/mg.

Abstract Stent graft-induced new entry tear (SINE) is a serious complication in aortic dissection patients caused by the stent-graft itself after thoracic endovascular aortic repair (TEVAR). The stability of SINE is a key indicator for the need and timing of reinterventions. This study aimed to understand the role of hemodynamics in SINE stability by means of computational fluid dynamics (CFD) analysis based on patient-specific anatomical information. Four patients treated with TEVAR who developed a distal SINE (dSINE) were included; two patients had a stable dSINE and two patients experienced expansion of the dSINE upon follow-up examinations. CFD simulations were performed on geometries reconstructed from computed tomography scans acquired upon early detection of dSINE in these patients. Computational results showed that stable dSINEs presented larger regions with low time-averaged wall shear stress (TAWSS) and high relative residence time (RRT), and partial thrombosis was observed at subsequent follow-ups. Furthermore, significant systolic antegrade flow was observed in the unstable dSINE which also had a larger retrograde flow fraction (RFF) on the SINE plane. In conclusion, this pilot study suggested that high RRT and low TAWSS may indicate stable dSINE by promoting thrombosis, whereas larger RFF and antegrade flows inside dSINE might be associated with its expansion.

Cattle are central to the lives and diverse cultures of African people. It has played a crucial role in providing valuable protein for billions of households and sources of income and employment for producers and other actors in the livestock value chains. The long-term natural selection of African cattle typically signals signatures in the genome, contributes to high genetic differentiations across breeds. This has enabled them to develop unique adaptive traits to cope with inadequate feed supply, high temperatures, high internal and external parasites, and diseases. However, these unique cattle genetic resources are threatened by indiscriminate cross-breeding, breed replacements with exotic cosmopolitan breeds, and climate change pressures. Although there are no functional genomics studies, recent advancements in genotyping and sequencing technologies have identified and annotated limited functional genes and causal variants associated with unique adaptive and economical traits of African cattle populations. These genome-wide variants serve as candidates for breed improvement and support conservation efforts for endangered cattle breeds against future climate changes. Therefore, this review plans to collate comprehensive information on the identified selection footprints to support genomic studies in African cattle to confirm the validity of the results and provide a framework for further genetic association and QTL fine mapping studies.

Abstract The incidence of rheumatoid arthritis (RA) is increasing with age. DNA fragments is known to accumulate in certain autoimmune diseases, but the mechanistic relationship among ageing, DNA fragments and RA pathogenesis remain unexplored. Here we show that the accumulation of DNA fragments, increasing with age and regulated by the exonuclease TREX1, promotes abnormal activation of the immune system in an adjuvant‐induced arthritis (AIA) rat model. Local overexpression of TREX1 suppresses synovial inflammation in rats, while conditional genomic deletion of TREX1 in AIA rats result in higher levels of circulating free (cf) DNA and hence abnormal immune activation, leading to more severe symptoms. The dysregulation of the heterodimeric transcription factor AP-1, formed by c-Jun and c-Fos, appear to regulate both TREX1 expression and SASP induction. Thus, our results confirm that DNA fragments are inflammatory mediators, and TREX1, downstream of AP-1, may serve as regulator of cellular immunity in health and in RA.