DDIT4 promotes erythroid differentiation and coordinates with SIPA1 to regulate erythroid proliferation in bone marrow of high altitude erythrocytosis.

Erythrocytosis moderately enhances the oxygen-carrying capacity of the blood and is considered a characteristic response of individuals adapting from low-altitude regions to high-altitude regions. Nevertheless, erythrocytosis can also turn excessive and result in maladaptive syndromes, such as high altitude polycythemia (HAPC). The increased differentiation or proliferation of erythroid cells in the bone marrow may be a crucial factor leading to accumulation of peripheral erythroid cells. However, the mechanism of erythroid regulation within the bone marrow of high-altitude erythrocytosis remains insufficiently systematically observed. We utilized single-cell transcription sequencing to characterize bone marrow cells following chronic hypoxic exposure and found that bone marrow erythrocytosis is associated with the accumulation of Baso-E, Poly-E, and Ortho-E cells at the terminal stage of erythroid lineage differentiation. Through analysis of differential gene expression and localization in differentiated cells within the erythroid lineage, we confirmed that DDIT4 expression was localized in advanced differentiated erythroblast including Baso-E, Poly-E and Ortho-E, its expression was significantly enhanced by hypoxia exposure. We demonstrated that overexpression of DDIT4 could promote K562 cell differentiation, and through the IP pull-down interaction protein profile, we found that DDIT4 might participate in regulating the cell cycle by interacting with SIPA1 to promote the proliferation of erythroid cells and may be involved in HAPC.

Data encryption/decryption and medical image reconstruction based on a sustainable biomemristor designed logic gate circuit.

Memristors are considered one of the most promising new-generation memory technologies due to their high integration density, fast read/write speeds, and ultra-low power consumption. Natural biomaterials have attracted interest in integrated circuits and electronics because of their environmental friendliness, sustainability, low cost, and excellent biocompatibility. In this study, a sustainable biomemristor with Ag/mugwort:PVDF/ITO structure was prepared using spin-coating and magnetron sputtering methods, which exhibited excellent durability, significant resistance switching (RS) behavior and unidirectional conduction properties when three metals were used as top electrode. By studying the conductivity mechanism of the device, a charge conduction model was established by the combination of F-N tunneling, redox, and complexation reaction. Finally, the novel logic gate circuits were constructed using the as-prepared memristor, and further memristor based encryption circuit using 3-8 decoder was innovatively designed, which can realize uniform rule encryption and decryption of medical information for data and medical images. Therefore, this work realizes the integration of memristor with traditional electronic technology and expands the applications of sustainable biomemristors in digital circuits, data encryption, and medical image security.

Development and validation of a machine-learning model for preoperative risk of gastric gastrointestinal stromal tumors.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) have malignant potential, and treatment varies according to risk. However, no specific protocols exist to preoperatively assess the malignant potential of gastric stromal tumors (gGISTs). This study aimed to use machine learning (ML) to develop and validate clinically relevant preoperative models to predict the malignant potential of gGISTs. METHODS: We screened patients diagnosed with gGISTs at the Affiliated Hospital of North Sichuan Medical College. We employed the Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression to identify risk factors. Subsequently, an ensemble of ML models was deployed to determine the optimal classifier. Additionally, we harnessed SHapley Additive exPlanations (SHAP) for tailored risk profiling. RESULTS: We enrolled 318 patients with gGISTs. Utilizing LASSO regression and multifactorial logistic regression, we analyzed the training dataset, revealing that the presence of endoscopic ultrasound (EUS) high-risk features, tumor border clarity, tumor diameter, and monocyte-to-lymphocyte ratio (MLR) were significant predictors of high malignancy risk in gGIST. As determined by our ML approach, the logistic classification model demonstrated optimal performance, with an area under the receiver operating characteristic curve of 0.919 and 0.925 for the training and test sets, respectively. Furthermore, decision curve analysis substantiated the clinical relevance of the model. CONCLUSION: High-risk EUS features, ill-defined tumor margins, larger tumor diameters, and elevated MLR independently predicted heightened malignant potential in gGIST. We developed logistic regression models based on these factors, which were further interpreted using the SHAP methodology. This analytical approach facilitated personalized therapeutic decision-making for diverse patient populations.

Early Neurological Deterioration and Time to Start Dual Antiplatelet Therapy in Patients With Acute Mild-to-Moderate Ischemic Stroke: A Pre-Specified Post Hoc Analysis of the ATAMIS Trial.

BACKGROUND AND PURPOSE: This study comprised a post hoc analysis of the Antiplatelet Therapy in Acute Mild to Moderate Ischemic Stroke (ATAMIS) trial aiming to determine whether the effect of dual antiplatelet therapy compared with that of monotherapy on preventing early neurological deterioration (END) differed according to the time from stroke onset to antiplatelet therapy (OTT). METHODS: In the ATAMIS trial, patients were divided into two subgroups: OTT from 0 to 24 hours (0-24 h group) and OTT from 24 to 48 hours (24-48 h group). We conducted multivariate regression analysis with continuous and categorical OTT to detect the effect of antiplatelet therapy. The primary outcome was END at 7 days, defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) score of more than two points compared with the baseline. The safety outcomes were bleeding events and intracranial hemorrhage within 90 days. RESULTS: A total of 2,915 patients were included. With respect to END at 7 days, clopidogrel plus aspirin showed a lower proportion than aspirin alone across continuous OTT (4.8% vs. 6.7%; adjusted risk difference, -1.9%; 95% confidence interval [CI], -3.6% to -0.2%; P=0.03), and was lower in the 0-24 hours group (5.7% vs. 9.2%; adjusted risk difference, -3.7%; 95% CI, -5.5% to -2.0%; P<0.01), but similar in the 24-48 hours group (3.5% vs. 2.9%; adjusted risk difference, 0.6%; 95% CI, -0.8% to 2.0%; P=0.40). We identified a significant interaction between the treatment effect and time subgroup with respect to the primary outcome (P=0.03). The occurrence of bleeding events and intracranial hemorrhage was similar in the time subgroup. CONCLUSION: For patients with acute mild-to-moderate ischemic stroke, clopidogrel plus aspirin was associated with a lower risk of END at 7 days than aspirin alone when it was started within 24 hours of symptom onset.

Structure-Stability Relation of Single-Atom Catalysts under Operating Conditions of CO2 Reduction.

Single-atom catalysts (SACs) have exhibited exceptional atomic efficiency and catalytic performance in various reactions but suffer poor stability. Understanding the structure-stability relation is the prerequisite for stability optimization but has been rarely explored due to complexity of the degradation process and reaction environments. Herein, we successfully established the structure-stability relation of N-doped carbon-supports SACs (MN4 SACs) under working conditions of CO2 reduction, by using advanced constant-potential density functional theory calculations. Systematic mechanism investigation that considered different factors identifies the key role of initial hydrogen adsorption on the coordination N atom in catalytic stability, where the feasibility of the adsorption eventually determines the leaching of the metal atom. On this basis, a simple descriptor consisting of electron number and electronegativity is constructed, realizing accurate and rapid prediction of the stability of SACs. Furthermore, strategies via modifying the local geometric structure to improve the stability without changing the active centers are proposed accordingly, which are supported by related experiments. These findings fill the current void in understanding SAC stability under practical working conditions, potentially advancing the widespread application of SACs in sustainable energy conversion systems.

Incidence and risk factors of prolonged recovery during procedural sedation in pediatrics.

Background: Sedation-related adverse events not only referred to a cause for morbidity and mortality but also included events that could disrupt routine procedures and thus lead to reduced procedural efficiency or quality. To date, no literature is available to predict the risk factors associated with prolonged recovery in pediatric patients during procedural sedation. Thus, we retrospectively analyzed the two-year sedation data to explore the above questions. Methods: Pediatric patients who underwent procedural sedation between January 2022 and January 2024 were retrospectively analyzed. The patients were divided into two groups according to sedation duration <120 min (Non-prolonged recovery group); or ≧ 120 min (Prolonged recovery group). The primary outcome was the incidence of prolonged recovery. Risk factors associated with prolonged recovery were assessed. Results: A total of 30,003 patients were identified; 854 (2.8%) developed prolonged recovery during procedural sedation. By multivariate regression, a higher body weight (OR 1.03, 95%CI 1.01-1.05), outpatients (OR 1.31, 95%CI 1.07-1.59), patients with sedation history (OR 1.25, 95%CI 1.07-1.44), and patients received chloral hydrate (OR 1.47, 95%CI 1.06-2.03), were associated with increased odds of the prolonged recovery with the initial sedative(s). Conclusion: Monitoring time needs to be extended in patients with sedation history, those with heavier weights, outpatients, and those who received chloral hydrate.

A clinical study on robot navigationassisted intramedullary nail treatment for humeral shaft fractures.

BACKGROUND: The purpose of this study was to evaluate the advantages of robot navigation system-assisted intramedullary nail treatment for humeral shaft fractures and compare it's efficacy with that of traditional surgical intramedullary nail treatment. MATERIALS AND METHODS: This was a retrospective analysis of patients with humeral shaft fractures who received intramedullary nail treatment at our centre from March 2020 to September 2022. The analysis was divided into a robot group and a traditional surgical group on the basis of whether the surgery involved a robot navigation system. We compared the baseline data (age, sex, cause of injury, fracture AO classification, and time of injury-induced surgery), intraoperative conditions (surgery time, length of main nail insertion incision, postoperative fluoroscopy frequency, intraoperative bleeding), fracture healing time, and shoulder joint function at 1 year postsurgery (ASES score and Constant-Murley score) between the two groups of patients. RESULTS: There was no statistically significant difference in the baseline data or average fracture healing time between the two groups of patients. However, the robotic group had significantly shorter surgical times, longer main nail incisions, fewer intraoperative fluoroscopies, and less intraoperative blood loss than did the traditional surgery group (P < 0.001). CONCLUSION: Robot navigation system-assisted intramedullary nail fixation for humeral shaft fractures is a reasonable and effective surgical plan. It can help surgeons determine the insertion point and proximal opening direction faster and more easily, shorten the surgical time, reduce bleeding, avoid more intraoperative fluoroscopy, and enable patients to achieve better shoulder functional outcomes.

Dual Antiplatelet Versus Alteplase for Early Neurologic Deterioration in Minor Stroke With Versus Without Large Vessel Occlusion: Prespecified Post Hoc Analysis of the ARAMIS Trial.

BACKGROUND: Dual antiplatelet therapy (DAPT) was noninferior to alteplase in minor nondisabling strokes in the ARAMIS trial (Antiplatelet Versus R-tPA for Acute Mild Ischemic Stroke); however, early neurological deterioration (END) associated with vessel stenosis may benefit from DAPT. We investigated whether the efficacy of DAPT was greater than alteplase in minor strokes with no large vessel occlusion (LVO). METHODS: This study was a prespecified post hoc analysis of the ARAMIS trial and included patients with responsible vessel examination in the as-treated analysis set of the ARAMIS trial who were divided into LVO group and non-LVO group. In each group, patients were further classified into DAPT and intravenous alteplase treatments. Primary outcome was END at 24 hours defined as more than or equal to 4-point National Institutes of Health Stroke Scale score increase compared with baseline, and safety outcomes were symptomatic intracerebral hemorrhage and bleeding events during study. The primary analysis was estimated with a risk difference calculated by a generalized linear model including adjusted different baseline characteristics between treatments. RESULTS: Of 723 patients from the ARAMIS trial, 480 patients were included: 36 were categorized into LVO group and 444 into non-LVO group, of whom 20 patients had END. Compared with intravenous alteplase, a lower proportion of END was found after DAPT treatment in the non-LVO group (adjusted risk difference, -4.8% [95% CI, -6.9% to -2.6%]; P<0.001), but not in the LVO group (adjusted risk difference, 2.3% [95% CI, -17.6% to 22.3%]; P=0.82). The interaction was marginally significant between groups (P=0.06). In the non-LVO group, a lower proportion of bleeding events was found after DAPT treatment than intravenous alteplase (adjusted risk difference, -6.4% [95% CI, -8.9% to -3.9%]; P<0.001). Other safety outcomes were similar between the 2 treatments. CONCLUSIONS: Among minor nondisabling acute ischemic stroke without LVO, DAPT may be superior to intravenous alteplase regarding preventing END with a better safety profile. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03661411.

Psychological stress impact neurotrophic factor levels in patients with androgenetic alopecia and correlated with disease progression.

BACKGROUND: Androgenetic alopecia (AGA) is a common form of hair loss that can be influenced by psychological factors. AIM: To investigate the impact of mental stress on neurotrophic factors in patients with AGA and correlate the findings with the progression of AGA. METHODS: A total of 120 patients with AGA were analyzed in this study, which were divided into a non-stress group (n = 30) and a stress group (n = 90) on the basis of the presence or absence of psychological stress confirmed by Depression Anxiety Stress Scale-21 scale. The baseline demographic characteristics, serum cortisol levels, hair growth parameters, neurotrophic factors, and AGA progression scores between the non-stress and stress groups were compared. Correlation analyses were conducted to assess the relationships among stress, neurotrophic factors, hair loss progression, and AGA progression. RESULTS: This study revealed significantly higher cortisol levels throughout the day in the stress group than in the non-stress group. The stress group exhibited lower levels of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor and higher expression levels of neurotrophin (NT)-3 and NT-4 than the non-stress group. Hair parameters indicated lower hair diameter, decreased hair density, and more severe AGA grading in the stress group, whereas follicle count and terminal/vellus hair ratio showed no significant differences between the two groups. After 1 year of treatment with 5% minoxidil, efficacy was observed to be lower but AGA progression was notably more pronounced in the stress group than in the non-stress group. Disease progression was positively correlated with high stress and NT-4 levels. CONCLUSION: This study provides compelling evidence of the influence of mental stress on neurotrophic factors and its correlation with the progression of AGA. The findings underscore the need for a comprehensive approach to the management of AGA that considers the physiological and psychosocial aspects. Further research is warranted to validate the findings and explore targeted therapeutic interventions for individuals with stress-related AGA.

Effect of remote ischemic preconditioning on cerebral circulation time in severe carotid artery stenosis: Results from the RIC-CCT trial.

In patients with severe internal carotid artery stenosis (sICAS), cerebral circulation time (CCT) is associated with cerebral hyperperfusion syndrome. This study aims to investigate the effect of remote ischemic preconditioning (RIC) on CCT in patients with sICAS. Patients are randomly assigned to the RIC group (RIC twice daily, for 2-4 days before carotid artery stenting [CAS] as an adjunct to standard medical therapy) and the control group. The results show that RIC produces a significant decrease in CCT of the stenosis side (sCCT) from baseline to pre-CAS, and the occurrence of contrast staining on brain computed tomography (CT) is lower in RIC versus control group after CAS. In addition, significant changes in some serum biomarkers suggest that anti-neuroinflammation, anti-oxidative stress, protecting endothelial injury, and improving cerebral autoregulation may be associated with the effect of RIC. These findings provide supporting evidence that RIC can modulate cerebral circulation in patients with sICAS. This study was registered at ClinicalTrials.gov (NCT05451030).

Factors influencing the turnover intention for disease control and prevention workers in Northeast China: an empirical analysis based on logistic-ISM model.

PURPOSE: This study aimed to determine the current turnover intention among workers at Centers for Disease Control and Prevention (CDCs) in Northeast China and to investigate the factors contributing to this phenomenon. MATERIALS AND METHODS: The cross-sectional study was conducted in May 2023 across four northeastern provinces of China. The study included a total of 11,912 valid participants who were CDC workers selected using a stratified cluster sampling method. The study assessed demographics, turnover intention, work resources, work perceptions, and psychological support through online questionnaires. The binary logistic regression analysis identified the factors associated with turnover intention for CDC workers, while the Interpretative Structural Modelling (ISM) revealed the hierarchical relationship between the influencing factors. RESULTS: The study found that 28.8% of the respondents reported high turnover intention. The binary logistic regression suggested that the risk factors of turnover intention among employees included gender, age, education, and several work-related, organizational, and psychological factors. The work-related factors were daily working hours, job burnout, and role overload. The organizational factor was unit support for training, unit's infrastructure conditions, leadership style, remuneration package and performance appraisal and promotion system. The psychological support factors were family support, professional identity, and organizational commitment. The ISM analysis results showed that the primary factors influencing CDC workers' intention to leave were internally connected and grouped into four categories according to their level of impact: surface, transition, deep, and essential factors. Notably, the essential factors were professional identity and organizational commitment. CONCLUSION: Nearly one-third of the respondents expressed a strong desire to resign from their employment. Turnover intention among CDC workers was subject to diverse influences. Early identification, detection, and targeted multidisciplinary interventions should be introduced to address the array of factors that affect staff, with particular emphasis on boosting the professional identity and organizational commitment of CDC workers.

Systematic review of ultrasound-guided central venous catheter placement-related complications in neonates and infants aged <12 months.

OBJECTIVE: Although ultrasound can be considered an assistant method, successful placement of a central venous catheter (CVC) in infants is still challenging. The incidence of CVC placement-related complications is still high. Therefore, this systematic review aimed to synthesize evidence to assess the effects of ultrasound-guided CVC placement on adverse outcomes in infants and neonates aged <12 months. METHODS: PubMed, Ovid, EMBASE, and the Cochrane Library were searched to identify potentially relevant studies. The main outcome was the incidence of adverse events, which included inadvertent arterial puncture, hematoma, pneumothorax and hemothorax, catheter kinking, threading, and malpositioning problems, venous thrombosis, catheter-related infection, phlebitis, and cardiac tamponade. RESULTS: Eleven studies involving 2097 patients were included in the final analysis. The odds of inadvertent arterial puncture, and catheter kinking, threading, and malpositioning problems were lower in the ultrasound group than in the control group. No significant difference was detected in the incidence of hematoma or venous thrombosis between the control and ultrasound groups. Other complications, such as pneumothorax, hemothorax, phlebitis, and cardiac tamponade, rarely occurred. CONCLUSION: Ultrasound-guided CVC placement can improve the safety of punctures in neonates and infants. CVC punctures should be guided in real-time by ultrasound.

Risk Factor Analysis in Patients Exhibiting Cerebral Microbleeds and the Correlation with Cognitive Impairment.

Objective: To identify the risk factors contributing to cerebral microbleeds (CMBs), analyze the correlation between the quantity and distribution of CMBs and overall cognitive performance, including specific cognitive domains in patients, and investigate the underlying mechanisms by which CMBs impact cognitive function. Methods: Patients diagnosed with cerebral small vessel disease were recruited between September 2022 and September 2023. Clinical baseline data were systematically gathered. The Montreal Cognitive Assessment (MoCA) was employed to evaluate patients' cognitive status. CMBs were identified via susceptibility-weighted imaging (SWI), noting their locations and quantities. Patients were categorized into two cohorts: those without CMBs and those with CMBs. This division facilitated the comparison of basic clinical data and laboratory indicators, aiming to elucidate the risk factors associated with CMBs. Within the CMBs cohort, patients were further classified based on the number of CMBs into mild, moderate, and severe groups, and according to CMBs' locations into deep, cortical-subcortical, and mixed groups. Spearman correlation analysis and ANOVA were utilized to compare the total MoCA scores, as well as scores in specific cognitive domains, across these groups. This approach enabled the analysis of the relationship between the quantity and location of CMBs and cognitive impairment. Results: Statistically significant differences were noted between patients with and without cerebral microbleeds (CMBs) regarding gender, age, hypertension, diabetes, history of cerebral infarction, history of alcohol consumption, glycosylated hemoglobin levels, low-density lipoprotein cholesterol, and homocysteine levels (p < .05). Multifactorial logistic regression analysis identified age, hypertension, diabetes, history of alcohol consumption, and elevated homocysteine as independent risk factors for the development of CMBs. Spearman correlation analysis revealed a linear correlation between the presence of CMBs and the total score of the MoCA (r = -.837, p < .001). The group with CMBs demonstrated a significant decline in visuospatial execution function and delayed recall abilities compared to the group without CMBs (p < .05). Specifically, deep CMBs were linked to impairments in visuospatial execution function, naming, attention, computational ability, language, delayed recall, and orientation (p < .05). Cortical-subcortical CMBs affected visuospatial execution function, attention, computational ability, and delayed recall ability(p < .05). Mixed CMBs impacted visuospatial execution function and naming (p < .05). Conclusion: Age, hypertension, diabetes, history of alcohol consumption, and elevated homocysteine levels are key independent risk factors for CMBs. There exists a linear relationship between the severity of CMBs and the extent of cognitive impairment. Patients with CMBs show notable deterioration in visuospatial execution function and delayed recall abilities. Furthermore, the location of CMBs influences various specific cognitive domains.

Investigating the efficacy of acupuncture in treating patients with metabolic-associated fatty liver disease: a protocol for a randomised controlled clinical trial.

INTRODUCTION: Acupuncture is widely used for metabolic-associated fatty liver disease (MAFLD) treatment; however, the clinical efficacy has not been confirmed due to the lack of high-level evidence-based clinical practice. The purpose of this study is to design a research protocol that will be used to determine the efficacy of acupuncture versus sham acupuncture (SHA) for MAFLD treatment. METHODS AND ANALYSIS: This will be a multicentre, randomised and sham-controlled trial. Ninety-eight participants with MAFLD will be enrolled in this trial. Participants will be randomly assigned in a 1:1 ratio to receive acupuncture or SHA for 12 weeks. The primary outcome is the rate of patients with a 30% relative decline in liver fat after 12 weeks of treatment in MRI-proton density fat fraction (MRI-PDFF), which will be obtained by quantitative chemical shift imaging such as the multipoint Dixon method at 0, 12 and 24 weeks. Secondary outcomes include the changes in the relative liver fat content measured by MRI-PDFF, magnetic resonance elastography, liver function, lipid metabolism, homeostatic model assessment for insulin resistance (HOMA-IR) and serum high sensitivity C reactive protein, which will be obtained at 0, 6, 12 and 24 weeks. Body measurement indicators (body mass index, waist circumference, hip circumference and waist-to-hip ratio) will be obtained at 0, 3, 6, 9, 12 and 24 weeks. The alteration in the gut microbiota composition and its metabolism will be assessed by 16S ribosomal RNA sequencing and liquid chromatography-mass spectrometry at 0 and 12 weeks. ETHICS AND DISSEMINATION: This study protocol has been approved by the ethics committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (2023-1347-114-01). The results of this study will be published in a peer-reviewed journal and presented at academic conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300075701.

Osteogenic-Like Microenvironment of Renal Interstitium Induced by Osteomodulin Contributes to Randall's Plaque Formation.

Calcium oxalate (CaOx) kidney stones are common and recurrent, lacking pharmacological prevention. Randall's plaques (RPs), calcium deposits in renal papillae, serve as niduses for some CaOx stones. This study explores the role of osteogenic-like cells in RP formation resembling ossification. CaP crystals deposit around renal tubules, interstitium, and blood vessels in RP tissues. Human renal interstitial fibroblasts (hRIFs) exhibit the highest osteogenic-like differentiation potential compared to chloride voltage-gated channel Ka positive tubular epithelial cells, aquaporin 2 positive collecting duct cells, and vascular endothelial cells, echoing the upregulated osteogenic markers primarily in hRIFs within RP tissues. Utilizing RNA-seq, osteomodulin (OMD) is found to be upregulated in hRIFs within RP tissues and hRIFs following osteogenic induction. Furthermore, OMD colocalizes with CaP crystals and calcium vesicles within RP tissues. OMD can enhance osteogenic-like differentiation of hRIFs in vitro and in vivo. Additionally, crystal deposits are attenuated in mice with Omd deletion in renal interstitial fibroblasts following CaOx nephrocalcinosis induction. Mechanically, a positive feedback loop of OMD/BMP2/BMPR1A/RUNX2/OMD drives hRIFs to adopt osteogenic-like fates, by which OMD induces osteogenic-like microenvironment of renal interstitium to participate in RP formation. We identify OMD upregulation as a pathological feature of RP, paving the way for preventing CaOx stones.

Mendelian randomization analysis of the causal relationship between serum metabolites and thoracic aortic aneurysm.

Thoracic aortic aneurysm (TAA) is associated with changes in the levels of metabolites; however, the exact causal relationships remain unclear. Identifying this complex relationship may provide new insights into the pathogenesis of TAA. We used genome-wide association studies to investigate the relationship between metabolites and TAA in this study. A total of 1400 serum metabolites were investigated for their potential causal effects on the risk of TAA. We performed bidirectional and 2-sample Mendelian randomization (MR) analysis using 5 MR tests: MR-Egger, weighted mode, weighted median, inverse variance weighted (IVW), and simple mode. We also performed sensitivity analysis to verify our findings, including heterogeneity analysis using IVW and MR-Egger tests and pleiotropy analysis using the MR-Egger test. Multiple metabolites were identified as having a causal effect on the risk of TAA, particularly those related to lipid metabolites; the top 2 risk factors identified using the IVW test were 3-carboxy-4-methyl-5-pentyl-2-furanpropionate (P = .019) and 5alpha-androstan-3alpha,17alpha-diol (P = .021), whereas the 2 top protective factors were 1-stearoyl-2-docosahexaenoyl-gpc (P = .023) and 1-oleoyl-2-docosahexaenoyl-GPC (P = .005). Sensitivity analysis verified the lack of heterogeneity (P = .499, .584, .232, and .624, respectively; IVW test) or pleiotropy (P = .621, .483, .598, and .916, respectively; Egger test). Our study provides new evidence of a causal relationship between metabolites and the risk of TAA, thus providing new insights into the pathogenesis of this disease. These findings suggest a promising approach for metabolite-based therapeutic interventions.

Highly selective fluorescent probe for cysteine via a tandem reaction and its bioimaging application in HeLa cells.

Cysteine, as a vital endogenous small molecule mercaptan, plays a crucial role in various physiological processes. The high sensitivity and selectivity of fluorescent probes provide a method to monitor cysteine, which is helpful to understand the mechanism of cysteine in physiological processes more comprehensively. However, the detection of cysteine can be interfered by other small molecule biothiols. Therefore, the design of fluorescent probe based on the structural characteristics and reactivity of cysteine has become research focus currently. Given the biological compatibilities, biological targets, the metabolic pathway of 3-hydoxythalidomide, and its unique fluorescent properties, herein, we have designed a chemodosimeter, 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl acrylate, for the detection of cysteine based on a tandem reaction of thiol-ene click chemistry and aminolysis involving 3-hydroxythalidomide as a parent compound. Experimental data exhibited that the probe showed unique selectivity and sensitivity for cysteine over other amino acid and biothiols. In addition, the fluorescent intensity at 511 nm increased linearly as a function of cysteine concentration in the range of 0-6 × 10-7 M (regression factor, R2 = 0.999), with a limit of detection of 6.1 nM. The sensing mechanism was confirmed through 1H NMR titration and density functional theory calculations. Additionally, the probe was also successfully utilized for the detection of cysteine in sewage and for bioimaging in HeLa cells.

Dual Antiplatelet Therapy and Outcomes in Acute Mild to Moderate Stroke With Versus Without Large-Artery Atherosclerosis Post Hoc Analysis of ATAMIS.

BACKGROUND: We conducted a post hoc analysis of the ATAMIS (Antiplatelet Therapy in Acute Mild to Moderate Ischemic Stroke) trial to investigate whether the priority of clopidogrel plus aspirin to aspirin alone was consistent between patients with and without stroke pathogenesis of large-artery atherosclerosis (LAA). METHODS AND RESULTS: Patients with stroke classification randomized to a clopidogrel-plus-aspirin group and aspirin-alone group in a modified intention-to-treat analysis set of ATAMIS were classified into LAA and non-LAA subtypes. The primary outcome was early neurologic deterioration at 7 days, defined as a >2-point increase in National Institutes of Health Stroke Scale score compared with baseline, and safety outcomes were bleeding events and intracranial hemorrhage. We compared treatment effects in each stroke subtype and investigated the interaction. Among 2910 patients, 225 were assigned into the LAA subtype (119 in the clopidogrel-plus-aspirin group and 106 in the aspirin-alone group) and 2685 into the non-LAA subtype (1380 in the clopidogrel-plus-aspirin group and 1305 in the aspirin-alone group). Median age was 66 years, and 35% were women. A lower proportion of early neurologic deterioration was found to be associated with dual antiplatelet therapy in the LAA subtype (adjusted risk difference, -10.4% [95% CI, -16.2% to -4.7%]; P=0.001) but not in the non-LAA subtype (adjusted risk difference, -1.4% [95% CI, -2.6% to 0.1%]; P=0.06). No significant interaction was found (P=0.11). CONCLUSIONS: Compared with the non-LAA subtype, patients with stroke of the LAA subtype may get more benefit from dual antiplatelet therapy with clopidogrel plus aspirin with respect to early neurologic deterioration at 7 days. REGISTRATION: URL: clinicaltrials.gov; UnIque identifier: NCT02869009.

Anisomycin alleviates cognitive impairments and pathological features in 3xTg-AD mice.

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Anisomycin is a pyrrolidine antibiotic isolated from Streptomyces griseolus, which is an efficient anti-inflammatory agent that functions both in vivo and in vitro. However, it is not clear whether anisomycin can exert neuroprotective effect in AD. In the present study, anisomycin was intragastrically administrated to female triple-transgenic AD (3xTg-AD) model mice, then Morris water maze test was used to observe the long-term spatial memory of mice, the in vivo hippocampal field potential recording was performed to evaluate the synaptic plasticity, the Western blot and immunofluorescence were employed to detect pathological changes, and the bioinformatics analysis was used to predict the potential target of anisomycin exerting effects in AD. The results showed that anisomycin ameliorated the long-term spatial memory deficits, improved LTP depression and increased the expression of PSD-95, reduced the Aß and tau pathologies, and alleviated the activation of microglia and astrocytes in the brains of 3xTg-AD mice. In addition, the results from bioinformatics analysis showed that the potential target of anisomycin focused on inflammatory pathway. These results indicated that anisomycin exerts neuroprotective effects in 3xTg-AD mice by alleviating neuroinflammation, but the potential mechanism of anisomycin exerting neuroprotective effects needs to be further investigated.

OTUD6B promotes cholangiocarcinoma growth by regulating STAT3 phosphorylation through deubiquitination of PTK2.

Cholangiocarcinoma (CCA) is a hepatobiliary carcinoma with uncontrolled cell proliferation, poor prognosis, and high mortality. The ovarian tumor structural domain (OTU) containing protein 6B (OTUD6B) belongs to the OTU deubiquitin family and is vital in tumor development. However, its expression and biological function in CCA remain unknown. The expression of OTUD6B in CCA was analyzed using TIMER2.0, UALCAN, and GEO databases. MTT, clonal formation assay, immunofluorescence staining, immunohistochemistry staining, and flow cytometry examined the regulation of OTUD6B on cell proliferation, cycle, and apoptosis. The effects of OTUD6B on tumor volume and weight were assessed using the xenograft tumor model. The activities of PTK2 and STAT3 were detected by western blot and CO-IP. The biological database identified that OTUD6B was upregulated in CCA. In CCA cells, OTUD6B knockdown reduced CCA cell proliferation and promoted apoptosis. Cell cycle analysis indicated that the cycle stopped at the G0/G1 phase after OTU6B downregulation. Furthermore, OTUD6B knockdown resulted in a decrease in tumor volume and weight in xenograft tumor models. Mechanistically, OTUD6B is involved in the deubiquitination of PTK2. PTK2 further affected the phosphorylation of STAT3 thereby regulating the CCA process. Our study demonstrates that OTUD6B knockdown participates in the ubiquitination of PTK2 and phosphorylation of STAT3 to alleviate the process of CCA. These results suggest that OTUD6B may be a potential new strategy for CCA treatment.