The Role of Introgression During the Radiation of Endemic Fishes Adapted to Living at Extreme Altitudes in the Tibetan Plateau.

Recent genomic analyses of evolutionary radiations suggest that ancient introgression may facilitate rapid diversification and adaptive radiation. The loach genus Triplophysa, a genus with most species endemic to Tibetan Plateau, shows ecological diversity and rapid evolution and represents a potential example of adaptive radiation linked to the uplift of the Tibetan Plateau. Here, we interrogate the complex evolutionary history of Triplophysa fishes through the analysis of whole-genome sequences. By reconstructing the phylogeny of Triplophysa, quantifying introgression across this clade, and simulating speciation and migration processes, we confirm that extensive gene flow events occurred across disparate Triplophysa species. Our results suggest that introgression plays a more substantial role than incomplete lineage sorting in underpinning phylogenetic discordance in Triplophysa. The results also indicate that genomic regions affected by ancient gene flow exhibit characteristics of lower recombination rates and nucleotide diversity and may associate with selection. Simulation analysis of Triplophysa tibetana suggests that the species may have been affected by the Gonghe Movement in the third uplift of the Tibetan Plateau, resulting in founder effects and a subsequent reduction in Ne.

The impact of PET/CT and brain MRI for metastasis detection among patients with clinical T1-category lung cancer: Findings from a large-scale cohort study.

PURPOSE: [18F]-FDG PET/CT and brain MRI are common approaches to detect metastasis in patients of lung cancer. Current guidelines for the use of PET/CT and MRI in clinical T1-category lung cancer lack risk-based stratification and require optimization. This study stratified patients based on metastatic risk in terms of the lesions' size and morphological characteristics. METHODS: The detection rate of metastasis was measured in different sizes and morphological characteristics (solid and sub-solid) of tumors. To confirm the cut-off value for discriminating metastasis and overall survival (OS) prediction, the receiver operating characteristic (ROC) analysis was performed based on PET/CT metabolic parameters (SUVmax/SUVmean/SULpeak/MTV/TLG), followed by Kaplan-Meier analysis for survival in post-operation patients with and without PET/CT plus MRI. RESULTS: 2,298 patients were included. No metastasis was observed in patients with solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm. The cut-off of PET/CT metabolic parameters on discriminating metastasis were 1.09 (SUVmax), 0.26 (SUVmean), 0.31 (SULpeak), 0.55 (MTV), and 0.81 (TLG), respectively. Patients undergoing PET/CT plus MRI exhibited longer OS compared to those who did not receive it in solid nodules ≥ 8.0 mm & sub-solid nodules ≥ 10.0 mm (HR, 0.44; p < 0.001); in solid nodules ≥ 8.0 mm (HR, 0.12; p<0.001) and in sub-solid nodules ≥ 10.0 mm (HR; 0.61; p=0.075), respectively. Compared to patients with metabolic parameters lower than cut-off values, patients with higher metabolic parameters displayed shorter OS: SUVmax (HR, 12.94; p < 0.001), SUVmean (HR, 11.33; p <0.001), SULpeak (HR, 9.65; p < 0.001), MTV (HR, 9.16; p = 0.031), and TLG (HR, 12.06; p < 0.001). CONCLUSION: The necessity of PET/CT and MRI should be cautiously evaluated in patients with solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm, however, these examinations remained essential and beneficial for patients with solid nodules ≥ 8.0 mm and sub-solid nodules ≥ 10.0 mm.

Identification of 10 differentially expressed and cuproptosis-related genes in immune infiltration and prognosis of thyroid carcinoma.

The association between the cuproptosis-related genes and the immune infiltration and their prognostic value in thyroid carcinoma is still unexplored. Bioinformatics analyses were performed with data obtained from the TCGA dataset. The aberrantly expressed genes were selected. KEGG and GO analyses were conducted to explore the enriched pathways of the up-regulated or down-regulated genes in thyroid carcinoma. Totally 1495 genes were differentially expressed (691 up-regulated, 804 down-regulated) in thyroid carcinoma (p<0.05). The 10 cuproptosis-related RNAs (DLD, LIAS, LIPT1, FDX1, DLAT, MTF1, PDHA1, CDKN2A, GLS and PDHB) were also demonstrated to be aberrantly expressed in thyroid carcinoma patients tissues. FDX1 expression was correlated with the overall survival in thyroid carcinoma patients (HR=0.4995, 95% CI: 0.2688-0.9285, p=0.0282). Further multivariate cox regression analysis revealed that DLD (HR=24.8869, 95% CI: 4.48772-138.01181, p=0.00024), and LIAS (HR=7.74092, 95% CI: 1.12194-53.40898, p=0.03783) were associated with the survival of thyroid carcinoma patients. The immune infiltration analysis demonstrated that significant correlation between the 10 cuproptosis-related genes and immune infiltration in thyroid carcinoma (p<0.01). We presented the expression profiles of dysregulated genes in thyroid carcinoma. The findings of our study highlighted the potential of cuproptosis-related genes as prognostic biomarkers for thyroid carcinoma.

Repetitive Transcranial Magnetic Stimulation and Non-convulsive Electric Shock in the Treatment of Depression: A Meta-analysis.

Background: Depression is an affective mental disorder that seriously endangers the physical and psychological health of human beings. This study attempted to systematically evaluate and compare the clinical efficacy and onset time of repetitive transcranial magnetic stimulation and non-convulsive electroshock in the treatment of Depression through the method of evidence-based medicine. Methods: As of December 2022, we have selectively searched domestic and foreign databases by computer, including English databases PubMed, ScienceDir ETC (Elsevier), Embase, wiley, and Chinese databases HowNet (CNKI), Wanfang (WanFang), VIP (VIP), Chinese Medical Association, CBM (sinomed) Chinese biomedical literature database, etc., collected randomized controlled studies on repetitive transcranial magnetic stimulation and non-convulsive electric shock in the treatment of Depression, and included 21 documents in total. Two researchers independently screened the literature, comprehensively evaluated the retrieved literature according to the established inclusion and exclusion criteria, extracted valid data, and used Review Manager 5.4 software for quantitative statistical analysis. The clinical effective rate and Hamilton depression Rating scale (Hamilton depression scale, HAMD) and onset time were used as outcome indicators for evaluation. Results: A total of 12 literatures were included in this study for Meta-analysis, involving a total of 678 subjects. The results of Meta-analysis showed that the HAMD score of the study group was higher than that of the control group after treatment, MD=2.01, 95%CI (0.59-3.68), P < .05; there was no statistically significant difference in clinical efficacy between the study group and the control group, OR = 0.88, 95%CI (0.31-1.92), Z = 1.16, P = .29; the onset time of the study group was shorter than that of the control group, MD = 2.01, 95%CI (0.59-3.68), Z = 3.31, P = .001. Conclusion: Repetitive transcranial magnetic stimulation is superior to non-convulsive electroconvulsive shock in the treatment of Depression. However, further research is needed to verify its long-term efficacy in the treatment of such diseases. Future studies could focus on investigating the sustainability of treatment effects, exploring potential predictors of treatment response, and comparing the cost-effectiveness of rTMS and NCES in clinical practice. Such research would provide valuable insights for optimizing treatment strategies for depression.

APT1-Mediated Depalmitoylation Regulates Hippocampal Synaptic Plasticity.

Palmitoylation may be relevant to the processes of learning and memory, and even disorders, such as post-traumatic stress disorder and aging-related cognitive decline. However, underlying mechanisms of palmitoylation in these processes remain unclear. Herein, we used acyl-biotin exchange, coimmunoprecipitation and biotinylation assays, and behavioral and electrophysiological methods, to explore whether palmitoylation is required for hippocampal synaptic transmission and fear memory formation, and involved in functional modification of synaptic proteins, such as postsynapse density-95 (PSD-95) and glutamate receptors, and detected if depalmitoylation by specific enzymes has influence on glutamatergic synaptic plasticity. Our results showed that global palmitoylation level, palmitoylation of PSD-95 and glutamate receptors, postsynapse density localization of PSD-95, surface expression of AMPARs, and synaptic strength of cultured hippocampal neurons were all enhanced by TTX pretreatment, and these can be reversed by inhibition of palmitoylation with palmitoyl acyl transferases inhibitors, 2-bromopalmitate and N-(tert-butyl) hydroxylamine hydrochloride. Importantly, we also found that acyl-protein thioesterase 1 (APT1)-mediated depalmitoylation is involved in palmitoylation of PSD-95 and glutamatergic synaptic transmission. Knockdown of APT1, not protein palmitoyl thioesterase 1, with shRNA, or selective inhibition, significantly increased AMPAR-mediated synaptic strength, palmitoylation levels, and synaptic or surface expression of PSD-95 and AMPARs. Results from hippocampal tissues and fear-conditioned rats showed that palmitoylation is required for synaptic strengthening and fear memory formation. These results suggest that palmitoylation and APT1-mediated depalmitoylation have critical effects on the regulation of glutamatergic synaptic plasticity, and it may serve as a potential target for learning and memory-associated disorders.SIGNIFICANCE STATEMENT Fear-related anxiety disorders, including post-traumatic stress disorder, are prevalent psychiatric conditions, and fear memory is associated with hyperexcitability in the hippocampal CA1 region. Palmitoylation is involved in learning and memory, but mechanisms coupling palmitoylation with fear memory acquisition remain poorly understood. This study demonstrated that palmitoylation is essential for postsynapse density-95 clustering and hippocampal glutamatergic synaptic transmission, and APT1-mediated depalmitoylation plays critical roles in the regulation of synaptic plasticity. Our study revealed that molecular mechanism about downregulation of APT1 leads to enhancement of AMPAR-mediated synaptic transmission, and that palmitoylation cycling is implicated in fear conditioning-induced synaptic strengthening and fear memory formation.

Identification of T-cell exhaustion-related gene signature for predicting prognosis in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a highly malignant primary brain tumour with a poor prognosis in adults. Identifying biomarkers that can aid in the molecular classification and risk stratification of GBM is critical. Here, we conducted a transcriptional profiling analysis of T-cell immunity in the tumour microenvironment of GBM patients and identified two novel T cell exhaustion (TEX)-related GBM subtypes (termed TEX-C1 and TEX-C2) using the consensus clustering. Our multi-omics analysis revealed distinct immunological, molecular and clinical characteristics for these two subtypes. Specifically, the TEX-C1 subtype had higher infiltration levels of immune cells and expressed higher levels of immune checkpoint molecules than the TEX-C2 subtype. Functional analysis revealed that upregulated genes in the TEX-C1 subtype were significantly enriched in immune response and signal transduction pathways, and upregulated genes in the TEX-C2 subtype were predominantly associated with cell fate and nervous system development pathways. Notably, patients with activated T-cell activity status in the TEX-C1 subgroup demonstrated a significantly worse prognosis than those with severe T cell exhaustion status in the TEX-C2 subgroup. Finally, we proposed a machine-learning-derived novel gene signature comprising 12 TEX-related genes (12TexSig) to indicate tumour subtyping. In the TCGA cohort, the 12TexSig demonstrated the ability to accurately predict the prognosis of GBM patients, and this prognostic value was further confirmed in two independent external cohorts. Taken together, our results suggest that the TEX-derived subtyping and gene signature has the potential to serve as a clinically helpful biomarker for guiding the management of GBM patients, pending further prospective validation.

Electrolyte Engineering on Performance Enhancement of NiCo2 S4 Anode for Sodium Storage.

NiCo2 S4 is an attractive anode for sodium-ion batteries (SIBs) due to its high capacity and excellent redox reversibility. Practical deployment of NiCo2 S4 electrode in SIBs, however, is still hindered by the inferior capacity and unsatisfactory cycling performance, which result from the mismatch between the electrolyte chemistry and electrode. Herein, a functional electrolyte containing 1.0 m NaCF3 SO3 in diethylene glycol dimethyl ether (DEGDME) (1.0 m NaCF3 SO3 -DEGDME) is developed, which can be readily used for NiCo2 S4 anode with high initial coulomb efficiency (96.2%), enhanced cycling performance, and boosted capacities (341.7 mA h g-1 after 250 continuous cycles at the current density of 200 mA g-1 ). The electrochemical tests and related phase characterization combined with density functional theory (DFT) calculation indicate the ether-based electrolyte is more suitable for the NiCo2 S4 anode in SIBs due to the formation of a stable electrode-electrolyte interface. Additionally, the importance of the voltage window is also demonstrated to further optimize the electrochemical performance of the NiCo2 S4 electrode. The formation of sulfide intermediates during charging and discharging is predicted by combining DFT and verified by in situ XRD and HRTEM. The findings indicate that electrolyte engineering would be an effective way of performance enhancement for sulfides in practical SIBs.

A high-efficiency gene silencing in plants using two-hit asymmetrical artificial MicroRNAs.

MicroRNAs (miRNAs) are small non-coding RNA molecules that play a crucial role in gene regulation. They are produced through an enzyme-guided process called dicing and have an asymmetrical structure with two nucleotide overhangs at the 3' ends. Artificial microRNAs (amiRNAs or amiRs) are designed to mimic the structure of miRNAs and can be used to silence specific genes of interest. Traditionally, amiRNAs are designed based on an endogenous miRNA precursor with certain mismatches at specific positions to increase their efficiency. In this study, the authors modified the highly expressed miR168a in Arabidopsis thaliana by replacing the single miR168 stem-loop/duplex with tandem asymmetrical amiRNA duplexes that follow the statistical rules of miRNA secondary structures. These tandem amiRNA duplexes, called "two-hit" amiRNAs, were shown to have a higher efficiency in silencing GFP and endogenous PDS reporter genes compared to traditional "one-hit" amiRNAs. The authors also demonstrated the effectiveness of "two-hit" amiRNAs in silencing genes involved in miRNA, tasiRNA, and hormone signalling pathways, individually or in families. Importantly, "two-hit" amiRNAs were also able to over-express endogenous miRNAs for their functions. The authors compare "two-hit" amiRNA technology with CRISPR/Cas9 and provide a web-based amiRNA designer for easy design and wide application in plants and even animals.

The transcription factor CEBP homolog of Penaeus vannamei contributes to WSSV replication.

The cellular transcription factors are known to play important roles in virus infection. The present study cloned and characterized a transcription factor CCAAT/Enhancer-binding protein homolog from the shrimp Penaeus vannamei (designates as PvCEBP), and explored its potential functions in white spot syndrome virus (WSSV) infection. PvCEBP has an open reading frame (ORF) of 864 bp encoding a putative protein of 287 amino acids, which contained a highly C-terminal conserved bZIP domain. Phylogenetic tree analysis showed that PvCEBP was evolutionarily clustered with invertebrate CEBPs and closely related to the CEBP of Homarus americanus. Quantitative real-time PCR (qPCR) analysis revealed that PvCEBP was expressed in all examined shrimp tissues, with transcript levels increased in shrimp hemocytes and gill upon WSSV challenge. Furthermore, knockdown of PvCEBP mediated by RNA interference significantly decreased the expression of WSSV genes and viral loads, while enhanced the shrimp survival rate under WSSV challenge. In silico prediction and reporter gene assays demonstrated that PvCEBP could activate the promoter activity of the viral immediate-early gene ie1. Collectively, our findings suggest that PvCEBP is annexed by WSSV to promote its propagation by enhancing the expression of viral immediate-early genes.

A novel clinical diagnostic marker predicting the relationship between visceral adiposity and renal function evaluated by estimated glomerular filtration rate (eGFR) in the Chinese physical examination population.

BACKGROUND AND AIMS: The effect of body fat deposition on the kidney has received increasing attention. The Chinese visceral adiposity index (CVAI) is an important indicator of recent research. The purpose of this study was to explore the predictive value of CVAI and other organ obesity indicators in predicting CKD in Chinese residents. METHODS: A retrospective cross-sectional study of 5355 subjects was performed. First, the study utilized locally estimated scatterplot smoothing to describe the dose-response relationship between the estimated glomerular filtration rate (eGFR) and CVAI. The L1-penalized least absolute shrinkage and selection operator (LASSO) regression algorithm was used for covariation screening, and the correlation between CVAI and eGFR was quantified using multiple logistic regression. At the same time, the diagnostic efficiency of CVAI and other obesity indicators was evaluated by ROC curve analysis. RESULTS: CVAI and eGFR were negatively correlated. Using group one as the control, an odds ratio (OR) was calculated to quantify CVAI quartiles (ORs of Q2, Q3, and Q4 were 2.21, 2.99, and 4.42, respectively; P for trend < 0.001). CVAI had the maximum area under the ROC curve compared with other obesity indicators, especially in the female population (AUC: 0.74, 95% CI: 0.71-0.76). CONCLUSIONS: CVAI is closely linked to renal function decline and has certain reference value for the screening of CKD patients, particularly in women.

Learning styles of medical students from a university in China.

BACKGROUND: Investigating students' learning styles can generate useful information that can improve curriculum design. This study adopts diverse measures to identify the learning styles of students despite limited literature related to clinical medical students in China. We utilized Felder's Index of Learning Styles to examine the learning style characteristics of clinical medical students at Inner Mongolia Minzu University. METHODS: Cluster sampling (probability sampling) was used. This cross-sectional study investigated clinical medicine students with regard to their learning style preference and the difference across genders. This study also analysed data collected from other published studies. A total of 411 students from the medical school at Inner Mongolia Minzu University completed the Index of Learning Styles Questionnaire. The questionnaire assessed the learning styles of students in four dimensions: visual-verbal learning, sequential-global learning, active-reflective leaning, and sensing-intuitive learning. RESULTS: The analysis results show that clinical medicine students choose to receive visual information (73.97% of the student sample) instead of verbal information. These students prioritize sensory information (67.15%) rather than intuitive information and process reflective information (51.82%) rather than active information. They prefer to process information sequentially (59.85%) instead of globally. Our results also show that male students present a higher preference for an active learning style over a reflective learning style, while female students seem to present a higher preference for a reflective learning style over an active learning style. These preferences vary between cohorts (gender), but the difference is not statistically significant. Compared to data collected from other published studies, active, visual, sensing, and sequential are the most popular styles of learning adopted by medical science students. CONCLUSIONS: The identification of medical students' learning style in China provides information that medical educators and others can use to make informed choices about modification, development and strengthening of medical educational programs. Our outcomes may potentially improve motivation, engagement and deep learning in medical education when used as a supplement to teaching/learning activities.

Ubiquitination of GRK2 Is Required for the ß-Arrestin-Biased Signaling Pathway of Dopamine D2 Receptors to Activate ERK Kinases.

A class-A GPCR dopamine D2 receptor (D2R) plays a critical role in the proper functioning of neuronal circuits through the downstream activation of both G-protein- and ß-arrestin-dependent signaling pathways. Understanding the signaling pathways downstream of D2R is critical for developing effective therapies with which to treat dopamine (DA)-related disorders such as Parkinson's disease and schizophrenia. Extensive studies have focused on the regulation of D2R-mediated extracellular-signal-regulated kinase (ERK) 1/2 signaling; however, the manner in which ERKs are activated upon the stimulation of a specific signaling pathway of D2R remains unclear. The present study conducted a variety of experimental techniques, including loss-of-function experiments, site-directed mutagenesis, and the determination of protein interactions, in order to investigate the mechanisms underlying ß-arrestin-biased signaling-pathway-mediated ERK activation. We found that the stimulation of the D2R ß-arrestin signaling pathway caused Mdm2, an E3 ubiquitin ligase, to move from the nucleus to the cytoplasm and interact with tyrosine phosphorylated G-protein-coupled receptor kinase 2 (GRK2), which was facilitated by Src, a non-receptor tyrosine kinase. This interaction led to the ubiquitination of GRK2, which then moved to the plasma membrane and interacted with activated D2R, followed by the phosphorylation of D2R as well as the mediation of ERK activation. In conclusion, Mdm2-mediated GRK2 ubiquitination, which is selectively triggered by the stimulation of the D2R ß-arrestin signaling pathway, is necessary for GRK2 membrane translocation and its interaction with D2R, which in turn mediates downstream ERK signaling. This study is primarily novel and provides essential information with which to better understand the detailed mechanisms of D2R-dependent signaling.

Hypobaric hypoxia triggers pyroptosis in the retina via NLRP3 inflammasome activation.

Hypobaric hypoxia initiates multiple impairment to the retina and is the major cause contributing to retinal function deficits such as high altitude retinopathy. However, the underlying molecular mechanism has not been clearly defined so far and remains to be clarified. In the present study, we have undertaken an approach to mimic 5000 m altitude with a low-pressure oxygen cabin and evaluated if pyroptosis is involved in the mechanisms by which hypobaric hypoxia triggers retinal impairment. We also used Radix Astragali seu Hedysari Compound (RAHC) to determine whether RAHC is capable of exerting protective effects on the hypobaric hypoxia-induced retinal dysfunction. We found that hypobaric hypoxia stress activated inflammasome complex through increasing NOD-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) protein levels. The protein expression of gasdermin-D, a master executor of pyroptosis, and NADPH oxidase 4, which is regarded as a main generator of reactive oxygen species (ROS), also elevated upon hypobaric hypoxia exposure. In addition, hypobaric hypoxia induced a significant increase in pro-inflammatory cytokines expression including interleukin-1ß and interleukin-18 in the rat retina. Our results indicate that hypobaric hypoxia initiates pyroptosis in the rat retina. RAHC attenuates hypobaric hypoxia-triggered retinal pyroptosis via inhibiting NLRP3 inflammasome activation and release of pro-inflammatory cytokines. The involvement of pyroptosis pathway in the retina in response to hypobaric hypoxia supports a novel insight to clarify the pathogenesis of hypobaric hypoxia-induced retinal impairment and provides a feasibility of inflammasome modulation for preserving retinal function.

Crystal structure of 5-Aminolevulinate synthase HemA from Rhodopseudomonas palustris presents multiple conformations.

5-ALA is the precursor of all tetrapyrroles. 5-Aminolevulinate synthase (ALAS) catalyzes the production of 5-aminolevulinic acid (5-ALA) from glycine and succinyl-CoA. HemA from Rhodopseudomonas palustris (Rp-HemA) was reported to be a highly active ALAS. To understand the catalytic mechanism of Rp-HemA, the 2.05 Å resolution crystal structure of Rp-HemA was solved. Open, half close and close conformations were observed in the substrate-free structures. Structure comparison and sequence alignment suggest the newly observed half close conformation may also be conserved in ALAS family. The pre-existed close and half close conformations in Rp-HemA may play a key role for its high activity.

The tyrosine phosphorylation of GRK2 is responsible for activated D2R-mediated insulin resistance.

Dopamine D2 receptor (D2R) plays a key role in the regulation of glucose homeostasis by stimulating the secretion of many glucoregulatory hormones. Insulin resistance (IR) is associated with the pathogenesis of metabolic disorders which occurs when PI3K/Akt signaling pathway is downregulated. However, the potential involvement of D2R in insulin resistance remains unclear. In the present study, we investigated the regulation of glucose transport by D2-like receptors and discovered that activation of D2R, but not D3R or D4R, suppressed insulin-induced 2-DOG uptake and Glut4 membrane translocation in a GRK2- and Src-dependent manner. Further study revealed that activation of D2R inhibits insulin-induced phosphorylation of Akt at Thr308 and Ser473, which are hallmarks of its kinase activity, by increasing the interaction of tyrosine phosphorylated GRK2 with Akt and then preventing Akt from interacting with PDK1. Thus, this study demonstrates that Src mediated GRK2 tyrosine phosphorylation is an essential physiological event that mediates the roles of D2R in insulin resistance.

Prediction of residual ischemic risk in ticagrelor-treated patients with acute coronary syndrome.

BACKGROUND: Despite strong antiplatelet therapy with ticagrelor, serious ischemic events still occur in patients with acute coronary syndrome (ACS). The predictability of platelet reactivity to the residual risk of ischemic events during ticagrelor treatment remains uncertain. OBJECTIVES: We aimed to investigate the predictability of the thromboelastography (TEG)-measured adenosine disphosphate (ADP)-induced platelet inhibition rate (ADP%) to the ischemic events in ticagrelor-treated patients with ACS. METHODS: A cohort of ticagrelor-treated patients with ACS were consecutively recruited. ADP% was measured by TEG after 3 days of ticagrelor maintenance treatment. The primary ischemic event was defined as rehospitalization for unstable angina (UA) within 1 year, and the secondary ischemic event was a composite of the primary ischemic event plus all-cause death, nonfatal myocardial infarction (MI), stent thrombosis, stroke, and unplanned revascularization within 1 year. RESULTS: A total of 751 eligible patients with ACS were included in the analysis, with 336 patients randomly assigned to the derivation group and 415 to the validation group. The overall rates of primary and secondary ischemic events were 14.51% (n = 109) and 16.91% (n = 127), respectively. Compared to the patients without ischemic events, those with ischemic events had a significantly lower ADP% both in the derivation group (for primary ischemic events: 66.05% vs. 92.80%, p < 0.001; for secondary ischemic events: 66.05% vs. 93.20%, p < 0.001) and in the validation group (for primary ischemic events: 66.40% vs. 89.20%, p < 0.001; for secondary ischemic events: 66.90% vs. 89.20%, p < 0.001). Receiver operating characteristic curve (ROC) analysis showed that an ADP% < 76% was the optimal cut-off value for predicting 1-year primary ischemic events, with an area under the curve (AUC) of 0.80 (95% CI: 0.72-0.86, p < 0.001) in the derivation group and 0.77 (95% CI: 0.69-0.85, p < 0.001) in the validation group. The multivariate Cox regression hazard analysis consistently identified an ADP% < 76% as an independent predictor of primary ischemic events in the derivation group (HR: 8.21, 95% CI: 4.82-13.99, p < 0.001) and in the validation group (HR: 6.34 95% CI: 3.32-12.11, p < 0.001). There was also a strong association between an ADP% < 76 and the occurrence of secondary ischemic events in the derivation group (HR: 7.33, 95% CI: 4.47-12.00, p < 0.001) and in the validation group (HR: 4.76, 95% CI: 2.73-8.32, p < 0.001). CONCLUSION: The ADP-induced platelet inhibition rate measured by TEG could predict ischemic events in ticagrelor-treated patients with ACS.

Efficacy and safety of oral anticoagulants in elderly patients with stable coronary artery disease and atrial fibrillation.

BACKGROUND: This study aimed to evaluate the efficacy and safety of oral anticoagulants (OACs) in real-world elderly patients with comorbidities of stable coronary artery disease (SCAD) and atrial fibrillation (AF). METHODS: Elderly patients (aged ≥ 65 years old) diagnosed with SCAD and AF were consecutively recruited and grouped into patients with or without oral anticoagulant (OAC) treatment. Follow-up was performed for 5 years. Major adverse cardiac events (MACEs) were defined as a composite of all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke, and systemic embolism. Major bleeding outcomes were defined as events that were type ≥ 3 based on the Bleeding Academic Research Consortium (BARC) criteria. The net clinical outcomes were defined as the combination of MACEs and bleeding of BARC type ≥ 3. RESULTS: A cohort of 832 eligible patients (78 ± 6.70 years) was included. Compared to the patients without OAC treatment (n = 531, 63.82%), the patients treated with OAC (n = 301, 36.18%) were much younger, had higher body mass index (BMI), and had lower prevalence of heart failure, chronic obstructive pulmonary disease (COPD), renal insufficiency, and previous myocardial infarction. During the follow-up of 5 years, compared to the patients without OAC treatment, patients with OAC had a significantly lower risk of MACEs (20.60% vs. 58.95%, adjusted HR: 0.21, 95% CI: 0.15-0.30, p < 0.001) but a higher risk of BARC ≥ 3 bleeding events (4.65% vs. 1.32%, adjusted HR: 4.71, 95% CI: 1.75-12.64, p = 0.002). In combination, a lower risk of net clinical outcomes could be observed in the patients with OACs (23.26% vs. 58.96%, adjusted HR: 0.27, 95% CI: 0.19-0.38, p < 0.001). Among the patients with OAC treatment, no significant difference was found for MACEs or BARC ≥ 3 bleeding events between the patients with or without comedications of oral antiplatelet agents. CONCLUSIONS: A net clinical benefit of efficacy and safety could be observed in OAC-treated elderly patients with SCAD and AF. This benefit is independent of the comedications of oral antiplatelet treatment.

The causal and independent effect of ozone exposure during pregnancy on the risk of preterm birth: Evidence from northern China.

The concentration of ozone (O3) in the environment is gradually increasing, but there are limited reports on the exposure to O3 during pregnancy on the risk of adverse birth outcomes. Our study aimed to examine the causal and independent effect of O3 exposure during pregnancy on the risk of preterm birth (PTB) and to identify the critical window. Based on the baseline population of the birth cohort in Jinan, northern China, we obtained the individual exposure for each subject during pregnancy of ambient 8-h moving average O3 through the inverse distance weighting model. The effect of O3 exposure during pregnancy on PTB was evaluated through the time-dependent Cox proportional-hazard models. And we assessed the causal relationship by controlling unknown confounding factors using the instrumental variable (IV) analysis, estimated the independent effect by principal component analysis, and identified the critical window period of exposure through the distributed lag model. Among 6501 subjects, 285 mothers delivered prematurely. The median (IQR) of O3 concentration during pregnancy was 109.51 (23.54) µg/m3. The high level of O3 exposure (>173.64 µg/m³) increased the risk of PTB, with HR of 1.92 (95% CI: 1.38-2.66). Furthermore, the HR (95% CI) of the O3 estimated value calculated by the IV (wind speed) on the risk of PTB was 2.63 (1.41-4.88). In addition, the high level of O3 exposure was associated with the risk of PTB in the 13th-18th gestational weeks. Therefore, the high level of O3 exposure during pregnancy may independently increase the risk of PTB, which may be a causal effect. The 13th to 18th week of gestation is a critical window for preventing this risk.

The Dynamic Target Motion Perception Mechanism of Tactile-Assisted Vision in MR Environments.

In the mixed reality (MR) environment, the task of target motion perception is usually undertaken by vision. This approach suffers from poor discrimination and high cognitive load when the tasks are complex. This cannot meet the needs of the air traffic control field for rapid capture and precise positioning of the dynamic targets in the air. Based on this problem, we conducted a multimodal optimization study on target motion perception judgment by controlling the hand tactile sensor to achieve the use of tactile sensation to assist vision in MR environment. This allows it to adapt to the requirements of future development-led interactive tasks under the mixed reality holographic aviation tower. Motion perception tasks are usually divided into urgency sensing for multiple targets and precise position tracking for single targets according to the number of targets and task division. Therefore, in this paper, we designed experiments to investigate the correlation between tactile intensity-velocity correspondence and target urgency, and the correlation between the PRS (position, rhythm, sequence) tactile indication scheme and position tracking. We also evaluated it through comprehensive experiment. We obtained the following conclusions: (1) high, higher, medium, lower, and low tactile intensities would bias human visual cognitive induction to fast, faster, medium, slower, and slow motion targets. Additionally, this correspondence can significantly improve the efficiency of the participants' judgment of target urgency; (2) under the PRS tactile indication scheme, position-based rhythm and sequence cues can improve the judgment effect of human tracking target dynamic position, and the effect of adding rhythm cues is better. However, when adding rhythm and sequence cues at the same time, it can cause clutter; (3) tactile assisted vision has a good improvement effect on the comprehensive perception of dynamic target movement. The above findings are useful for the study of target motion perception in MR environments and provide a theoretical basis for subsequent research on the cognitive mechanism and quantitative of tactile indication in MR environment.

CircRNF121 knockdown suppresses the progression of cervical cancer by regulating miR-153-3p/ATF2 axis and wnt/ß-catenin pathway.

Cervical cancer (CC) is a common malignancy in gynecology. Emerging evidence has demonstrated that circular RNAs (circRNAs) act as vital mediators in CC. However, the roles of circRNA ring finger protein 121 (circRNF121) in CC are largely unknown. Herein, we focused on the exact function and underlying mechanism of circRNF121 in CC development. Our results showed that circRNF121 was highly expressed in CC tissues and cells. Knockdown of circRNF121 suppressed cell growth, metastasis, epithelial-mesenchymal transition (EMT), autophagy, and wnt/ß-catenin pathway in CC cells in vitro and blocked tumor formation in vivo. For mechanism investigation, circRNF121 could affect activating transcription factor 2 (ATF2) expression by decoying miR-153-3p, thereby accelerating CC cell development. In conclusion, circRNF121 exerted the tumor-suppressive role in CC progression by altering miR-153-3p/ATF2 axis. These results suggested that circRNF121 might be a possible circ-targeted therapy for patients with CC.