Orphan Nuclear Receptor NR4A3 Promotes Vascular Calcification via Histone Lactylation.

BACKGROUND: Medial arterial calcification is a chronic systemic vascular disorder distinct from atherosclerosis and is commonly observed in patients with chronic kidney disease, diabetes, and aging individuals. We previously showed that NR4A3 (nuclear receptor subfamily 4 group A member 3), an orphan nuclear receptor, is a key regulator in apo (apolipoprotein) A-IV-induced atherosclerosis progression; however, its role in vascular calcification is poorly understood. METHODS: We generated NR4A3-/- mice and 2 different types of medial arterial calcification models to investigate the biological roles of NR4A3 in vascular calcification. RNA-seq was performed to determine the transcriptional profile of NR4A3-/- vascular smooth muscle cells under ß-glycerophosphate treatment. We integrated Cleavage Under Targets and Tagmentation analysis and RNA-seq data to further investigate the gene regulatory mechanisms of NR4A3 in arterial calcification and target genes regulated by histone lactylation. RESULTS: NR4A3 expression was upregulated in calcified aortic tissues from chronic kidney disease mice, 1,25(OH)2VitD3 overload-induced mice, and human calcified aorta. NR4A3 deficiency preserved the vascular smooth muscle cell contractile phenotype, inhibited osteoblast differentiation-related gene expression, and reduced calcium deposition in the vasculature. Further, NR4A3 deficiency lowered the glycolytic rate and lactate production during the calcification process and decreased histone lactylation. Mechanistic studies further showed that NR4A3 enhanced glycolysis activity by directly binding to the promoter regions of the 2 glycolysis genes ALDOA and PFKL and driving their transcriptional initiation. Furthermore, histone lactylation promoted medial calcification both in vivo and in vitro. NR4A3 deficiency inhibited the transcription activation and expression of Phospho1 (phosphatase orphan 1). Consistently, pharmacological inhibition of Phospho1 attenuated calcium deposition in NR4A3-overexpressed vascular smooth muscle cells, whereas overexpression of Phospho1 reversed the anticalcific effect of NR4A3 deficiency in vascular smooth muscle cells. CONCLUSIONS: Taken together, our findings reveal that NR4A3-mediated histone lactylation is a novel metabolome-epigenome signaling cascade mechanism that participates in the pathogenesis of medial arterial calcification.

Variability, asymmetry and bilateral coordination of gait during single- and dual-task walking of patients with cerebral small vessel disease.

OBJECTIVE: We investigated coefficient of variation (CV), gait asymmetry (GA) and phase coordination index (PCI) in cerebral small vessel disease (CSVD) patients during single-task walking (STW) and dual-task walking (DTW) and explored the relationship between above parameters with disease severity and cognitive function. METHODS: This cross-sectional study collected cognitive function indices and gait parameters from 23 healthy controls and 94 patients with CSVD during STW and DTW. According to the Fazekas scales, the severity of CSVD valued by white matter hyperintensity (WMH) were divided into control, mild, moderate, severe and control group. MRIs were analyzed for WMHs, CMB, lacunes, etc. RESULTS: The control group showed lower PCI than CSVD patients during STW; no differences were detected among the disease severity groups. During DTW, all four groups exhibited significant differences in PCI and CV. For the moderate and severe groups, coordination and variation significantly differed between the two walking methods. There were correlations between the PCI and GA in the moderate and severe groups (R = 0.376, R = 0.573 during DTW; R = 0.414, R = 0.643 during STW) and no correlations in the control group and mild CSVD group. CONCLUSION: PCI and CV may be vital for detecting the symptoms in the early stage of CSVD disease. We also verified that the PCI could become the bridge across the cognition and motor disorder in CSVD, which was helpful for evaluating clinical symptoms comprehensively.

DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics.

BACKGROUND: Heart failure is a global public health issue that is associated with increasing morbidity and mortality. Previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure; however, the underlying mechanisms remain unclear. Because kinases have been reported to modulate mitochondrial function, we investigated the effects of DYRK1B (dual-specificity tyrosine-regulated kinase 1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure. METHODS: We engineered DYRK1B transgenic and knockout mice and used transverse aortic constriction to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-sequencing analysis and mitochondrial functional analysis. RESULTS: We found that DYRK1B expression was clearly upregulated in failing human myocardium and in hypertrophic murine hearts, as well. Cardiac-specific DYRK1B overexpression resulted in cardiac dysfunction accompanied by a decline in the left ventricular ejection fraction, fraction shortening, and increased cardiac fibrosis. In striking contrast to DYRK1B overexpression, the deletion of DYRK1B mitigated transverse aortic constriction-induced cardiac hypertrophy and heart failure. Mechanistically, DYRK1B was positively associated with impaired mitochondrial bioenergetics by directly binding with STAT3 to increase its phosphorylation and nuclear accumulation, ultimately contributing toward the downregulation of PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α). Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. CONCLUSIONS: Taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1B in mitochondrial bioenergetics and the progression of cardiac hypertrophy and heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.

UBP43 promotes epithelial ovarian carcinogenesis via activation of ß-catenin signaling pathway.

Dysregulation of the deubiquitinating protease, UBP43, has been implicated in many human diseases, including cancer. Here, we evaluated the functional significance and mechanism of action of UBP43 in epithelial ovarian cancer. We found that UBP43 was significantly upregulated in the tumor tissues of patients with epithelial ovarian cancer. Similar results were observed in OVCAR-3, Caov-3, TOV-112D, A2780, and SK-OV-3 cells. Furthermore, in vitro functional assays of A2780 and TOV-112D cells demonstrated that UBP43 overexpression promoted cell proliferation, migration, and invasion. Upregulation of UBP43 might result in epithelial-mesenchymal transition by inducing the nuclear transport of ß-catenin, which was accompanied by enhanced N-cadherin but decreased E-cadherin expression. These malignant phenotypes were reversed by UBP43 silencing. Further investigation revealed that the knockdown of UBP43 inhibited cell proliferation by inducing a cell cycle arrest at the G2/M phase. The oncogenic characteristics of UBP43 were validated in a subcutaneous xenograft mouse model. In vivo, tumor growth was delayed in the UBP43-silenced group but accelerated after UBP43 overexpression. Finally, we demonstrated that ß-catenin is a key protein in the UBP43-mediated malignant development of epithelial ovarian cancer. Specifically, overexpression of UBP43 decreased the ubiquitination degradation of ß-catenin and enhanced its protein stability. Also, we observed that the downstream genes of beta-catenin such as cyclin D1, MMP2, and MMP9 were upregulated due to UBP43 overexpression. Thus, we concluded that UBP43 promoted epithelial ovarian cancer tumorigenesis and metastasis through activation of the ß-catenin pathway, suggesting that UBP43 may be a potential therapeutic target for this intractable disease.

Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair.

RATIONALE: Macrophages are critically involved in wound healing following myocardial infarction (MI). Lgr4, a member of LGR (leucine-rich repeat-containing G protein-coupled receptor) family, is emerging as a regulator of macrophage-associated immune responses. However, the contribution of Lgr4 to macrophage phenotype and function in the context of MI remains unclear. OBJECTIVE: To determine the role of macrophage Lgr4 in MI and to dissect the underlying mechanisms. METHODS AND RESULTS: During early inflammatory phase of MI, infarct macrophages rather than neutrophils expressed high level of Lgr4. Macrophage-specific Lgr4 knockout mice had no baseline cardiovascular defects but manifested improved heart function, modestly reduced infarct size, decreased early mortality due to cardiac rupture, and ameliorated adverse remodeling after MI. Improved outcomes in macrophage-specific Lgr4 knockout mice subjected to MI were associated with mitigated ischemic injury and optimal infarct healing, as determined by reduction of cardiac apoptosis in the peri-infarct zone, attenuation of local myocardial inflammatory response, decrease of matrix metalloproteinase expression in the infarct, enhancement of angiogenesis, myofibroblast proliferation, and collagen I deposition in reparative granulation tissue as well as formation of collagen-rich scar. More importantly, macrophage-specific Lgr4 knockout infarcts had reduced numbers of infiltrating leukocytes and inflammatory macrophages but harbored abundant reparative macrophage subsets. Lgr4-null infarct macrophages exhibited a less inflammatory transcriptional signature. These findings were further supported by transcriptomic profiling data showing repression of multiple pathways and broad-spectrum genes associated with proinflammatory responses in macrophage-specific Lgr4 knockout infarcts. Notably, we discovered that Lgr4-mediated functional phenotype programing in infarct macrophages was at least partly attributed to regulation of AP (activator protein)-1 activity. We further demonstrated that the synergistic effects of Lgr4 on AP-1 activation in inflammatory macrophages occurred via enhancing CREB (cAMP response element-binding protein)-mediated c-Fos, Fosl1, and Fosb transactivation. CONCLUSIONS: Together, our data highlight the significance of Lgr4 in governing proinflammatory phenotype of infarct macrophages and postinfarction repair.

Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration.

BACKGROUND: Macrophage-associated immune response plays an important role in myocardial ischemia/reperfusion (IR) injury. Dectin-1, expressed mainly on activated myeloid cells, is crucial for the regulation of immune homeostasis as a pattern recognition receptor. However, its effects and roles during the myocardial IR injury remain unknown. METHODS: Genetic ablation, antibody blockade, or Dectin-1 activation, along with the adoptive bone marrow transfer chimeric model, was used to determine the functional significance of Dectin-1 in myocardial IR injury. Immune cell filtration and inflammation were examined by flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Moreover, Dectin-1+ cells were analyzed by flow cytometry in the blood of patients with ST-segment-elevation myocardial infarction and stable patients with normal coronary artery (control). RESULTS: We demonstrated that Dectin-1 expression observed on the bone marrow-derived macrophages is increased in the heart during the early phase after IR injury. Dectin-1 deficiency and antibody-mediated Dectin-1 inhibition led to a considerable improvement in cardiac function, accompanied by a reduction in cardiomyocyte apoptosis, which was associated with a decrease in M1 macrophage polarization and Ly-6C+ monocyte and neutrophil infiltration. Activation of Dectin-1 with its agonist had the opposite effects. Furthermore, Dectin-1 contributed to neutrophil recruitment through the regulation of Cxcl1 and granulocyte colony-stimulating factor expression. In addition, Dectin-1-dependent interleukin-23/interleukin-1ß production was shown to be essential for interleukin-17A expression by γδT cells, leading to neutrophil recruitment and myocardial IR injury. Furthermore, we demonstrated that circulating Dectin-1+CD14++CD16- and Dectin-1+CD14++CD16+ monocyte levels were significantly higher in patients with ST-segment-elevation myocardial infarction than in controls and positively correlated with the severity of cardiac dysfunction. CONCLUSIONS: Our results reveal a crucial role of Dectin-1 in the process of mouse myocardial IR injury and provide a new, clinically significant therapeutic target.

Interleukin-34 Levels Were Associated with Prognosis in Patients with Acute Myocardial Infarction.

Inflammatory factors have specific value in acute myocardial infarction (AMI). Our previous studies have identified the prognostic value of interleukin (IL)-34 during chronic heart failure. However, the potential impact of IL-34 on AMI remains unknown.Serum IL-34 was measured in 287 AMI patients, and they were followed up for the composite endpoint, including cardiovascular death, heart failure hospitalization, recurrent nonfatal myocardial infarction (MI), and nonfatal stroke.IL-34 levels were significantly associated with the presence of heart failure at baseline and its aggravation after a year. During the five-year follow-up, there was a significant increase in the risk of the composite endpoint (hazard ratio [HR] 1.38 [95% confidence intervals (CI) 1.12-1.70], P < 0.01) and cardiovascular death (HR 1.48 [95%CI 1.03-2.27], P = 0.03) after full adjustment as IL-34 levels increased.Higher IL-34 levels in the acute phase were associated with an increased risk of heart failure after MI and poor prognosis.

Tubular epithelial C1orf54 mediates protection and recovery from acute kidney injury.

Acute kidney injury (AKI) incidence among hospitalized patients is increasing steadily. Despite progress in prevention strategies and support measures, AKI remains correlated with high mortality, particularly among ICU patients, and no effective AKI therapy exists. Here, we investigated the function in kidney ischaemia-reperfusion injury (IRI) of C1orf54, a newly identified protein encoded by an open reading frame on chromosome 1. C1orf54 expression was high in kidney and low in heart, liver, spleen, lung and skeletal muscle in healthy mice, and in the kidney, C1orf54 was expressed in tubular epithelial cells (TECs), but not in glomeruli. C1orf54 expression was markedly decreased on Day 1 after kidney IRI and then gradually recovered to baseline levels by Day 7. Notably, relative to wild-type mice, C1orf54-knockout mice exhibited impaired TEC proliferation and delayed recovery after kidney IRI, which led to deteriorated renal function and increased mortality. Conversely, adenovirus-mediated C1orf54 overexpression promoted TEC proliferation and ameliorated kidney pathology, which resulted in accelerated renal repair and improved renal function. Mechanistically, C1orf54 was found to promote TEC proliferation through PI3K/AKT signalling. Thus, C1orf54 holds considerable potential as a therapeutic target in kidney IRI.

Experimental measurement of a multi-pole magnetorheological fluid clutch under air cooling.

Thermal characteristics have a profound effect on the allowable slip power and torque transmission stability of magnetorheological (MR) fluid devices. This paper investigates the thermal properties of a multi-pole MR clutch under different heat dissipation methods. First, the structure of the clutch is described, and heat generation and heat dissipation of the designed clutch are studied theoretically. Then, a numerical model is established, and several simulations are conducted on steady-state and transient temperatures under various operation conditions. After that, a temperature testing platform for the MR clutch is built, and several temperature experiments are carried out. The results show that the allowable steady-state slip power of the clutch under natural air cooling is about 147 W. Under forced air cooling, the allowable steady-state slip powers are 1.295, 1.555, and 1.790 kW, respectively, when the wind speeds are 3.5, 7.0, and 10.5 m/s. Furthermore, it turned out that the transmission torque of the MR clutch decreases with the increase in temperature. The experimental and simulated values of temperature are in good agreement in terms of numerical values and trends, indicating that the established temperature field simulation model can better reflect the temperature characteristics of the actual operation of the proposed multi-pole MR clutch. This research achievement can provide support for research on heat dissipation technology for MR devices with multiple excitation sources.

The clinical characteristics of cerebral small vessel disease patients with motoric cognitive risk syndrome during single- and dual-task walking.

Objective: We aimed to (1) identify neuroimaging biomarkers of distinguishing motoric cognitive risk syndrome (MCRS) risk among older Chinese adults with cerebral small vessel disease (CSVD) and (2) detect differences in gait parameters and neuroimaging biomarkers between CSVD individual with and without MCRS, especially during dual-task walking (DTW). Methods: We enrolled 126 inpatients with CSVD who were divided into two groups according to MCRS status. Data on basic parameters, variability, asymmetry, and coordination were collected during single-task walking (STW) and DTW. Neuroimaging features (white matter hyperintensities, lacunes, and microbleeds) and total disease burden were calculated. Analysis of variance and logistic regression analyses were applied to assess the role of STW, DTW, and neuroimaging biomarkers in MCRS. Results: In total, 126 consecutive inpatients with CSVD were included (84 and 42 patients were classified as MCRS-negative and MCRS-positive, respectively). The MCRS-positive group showed poorer performance for nearly all gait parameters compared with the MCRS-negative group during cognitive DTW. Meanwhile, all gait parameters except asymmetry were assessed in participants with MCRS for significant deterioration during cognitive DTW compared with that during STW. However, only basic parameters differed between STW and cognitive DTW in participants without MCRS. A significant independent association between total CSVD scores and MCRS was also detected. Conclusions: For CSVD patients, with higher total CSVD burden rather than any single neuroimaging marker, was linked to a greater risk of MCRS. In addition, CSVD individuals with MCRS had higher variability and phase coordination index (PCI), especially in cognitive DTW. Thus, they should concentrate more on their gait variability or coordination and reduce secondary task loads while walking in daily life, especially in cognitive secondary tasks.

Relationship between Body Composition and Gait Characteristics in Patients with Cerebral Small Vessel Disease.

BACKGROUND: This study aims to explore the correlation between body composition, encompassing factors such as muscle mass and fat distribution, and gait performance during both single-task walking (STW) and dual-task walking (DTW) in patients diagnosed with cerebral small vessel disease (CSVD). METHODS: The data of hospitalized patients diagnosed with CSVD, including cadence, stride time, velocity and stride length, as well as information on variability, asymmetry and coordination during both STW and DTW, were assessed. The number of falls reported by each participant was also assessed. RESULTS: A total of 95 CSVD patients were assessed, and the results showed that individuals with low appendicular skeletal muscle mass (ASM), which includes both the low ASM group and the combination of low ASM and high body fat (BF) group, had reduced velocity or cadence, shortened stride length, and prolonged stride time across all walking modalities compared to the control group. Only the combination of the low ASM and high BF group exhibited a deterioration in the coefficient of variation (CV) for all basic parameters and the Phase Coordination Index (PCI) compared to the control group across all walking patterns. Conversely, patients in the high BF group displayed a decline in basic parameters, primarily during cognitive DTW. Concurrently, the high BF group showed a significant increase in the CV and the PCI compared to the control group only during cognitive DTW. Furthermore, regardless of gender, both ASM and BF independently correlated with the occurrence of falls. CONCLUSIONS: CSVD patients with varying.

Motoric Cognitive Risk Syndrome Among Chinese Older Adults with White Matter Lesions: A Cross-Sectional Observational Study.

Brain aging is characterized by the declines in motor and cognitive features. The present study is to detect motor cognitive risk syndrome (MCRS) in older adults with white matter lesions (WML). 134 WML aged patients were recruited and diagnosed with the criteria for MCRS. Numerous cognitive function tests and walking tests were performed. The frequency of MCRS is 28.35%. Verbal fluency test, Mini-Mental State Examination, and dual-task walking speed were independent risk factor of MCRS. These findings indicated that MCRS was common in WML seniors. MCRS was associated with the pathologies of WML in older adults.

Spatiotemporal gait characteristics during single- and dual-task walking are associated with the burden of cerebral small vessel disease.

Introduction: Gait impairment is a common symptom among individuals with cerebral small vessel disease (CSVD). However, performance differences between single-task walking (STW) and dual-task walking (DTW) among individuals with CSVD remain unclear. Therefore, we aimed to examine differences in gait characteristics during STW and DTW as well as the association between gait performance and neuroimaging markers. Methods: We enrolled 126 older individuals with CSVD. The speed, cadence, stride length, stride time, and their dual-task cost (DTC) or variability were measured under the STW, motor-cognitive DTW (cognitive DTW), and motor-motor DTW (motor DTW) conditions. We examined neuroimaging features such as white matter hyperintensities (WMHs), lacunes, microbleeds, and total burden. Further, we analysed the association of neuroimaging markers with gait performance, including gait variability and DTC. Results: Almost all spatiotemporal characteristics, as well as their DTCs or variabilities, showed significant among-group differences according to disease severity in the cognitive DTW condition; however, relatively lesser differences were observed in the STW and motor DTW conditions. The total CSVD burden score was moderately correlated with all the spatial parameters, as well as their DTCs or variabilities, in the cognitive DTW condition. Moreover, WMHs showed a correlation with speed, stride time, and cadence, as well as their DTCs, in the cognitive DTW condition. Furthermore, lacunes showed a moderate correlation with speed, stride length, and the DTC of speed, whilst microbleeds were only related to the DTC of stride length in the cognitive DTW condition. Neuroimaging biomarkers were not correlated with spatiotemporal parameters in STW and motor DTW conditions after Bonferroni correction. Moreover, the correlation coefficient between the total CSVD burden score and gait parameters was greater than those of other biomarkers. Discussion: Parameters in the cognitive DTW condition are more appropriate than those in the motor DTW condition for the evaluation of gait abnormalities in patients with CSVD. Moreover, the total CSVD burden score might have better predictive utility than any single neuroimaging marker. Patients with CSVD, especially those with moderate-to-severe disease, should concentrate more on their gait patterns and reduce the load of secondary cognitive tasks whilst walking in daily life.

A water-soluble fluorescent probe for the determination of γ-glutamyltransferase activity and its application in tumor imaging.

γ-glutamyltransferase (GGT), an important tumor marker, is highly expressed in tumor tissues, and precise detection of its activity provides a vital indicator for the diagnosis and treatment. In this work, a "lighting-on" probe (TCF-GGT) was elaborated to detect endogenous GGT with high selectivity and sensitivity. Dicyanomethyldifuranyl (TCF-OH) was employed as the fluorescence reporter and short peptide glutathione (GSH) worked as the GGT-active trigger, the introduction of which prevented the initial proton transfer of TCF-OH contributing to a blank sensing background. A bright red fluorescence could be switched on upon GGT catalytic hydrolysis, avoiding the potential interference from background. There displayed an excellent water-solubility, and little organic solvent was required during the exploration, which otherwise avoided the potential damage to enzyme and organism. TCF-GGT has been proved to be workable at cellular and organism level with highly effective imaging and a short metabolic cycle, which is expected to offer an alternative solution or reference to the early diagnosis and treatment of tumor.

A turn on fluorescent assay for γ-glutamyltransferase activity and its application in biological imaging.

γ-glutamyltransferase (GGT) is widely presented in living cells and overexpressed in many tumor tissues. Therefore, it is generally considered as an important biomarker for the detection of tumor, especially for liver cancer. Accurate determination of its activity is helpful for early diagnosis and treatment of related diseases. In this work, a "turn on" fluorescent probe NSA-GGT for the detection of GGT activity based on glutamine bond was designed and synthesized by employing dansylamino as fluorophore. The probe shows good water solubility and can be well dispersed in aqueous buffer. After incubated with GGT in phosphate buffer, the fluorescence of NSA-GGT centered at ∼523 nm increased over 25-fold. This sensing pattern exhibits an intriguing sensing sensitivity for GGT, and has good performance on intracellular GGT staining, serving as a promising candidate for GGT measurement. Subsequent biological experiments showed that probe NSA-GGT could also be used for fluorescent imaging of GGT activity in living cells and animal tissues.

Global Characteristics and Dynamics of Single Immune Cells After Myocardial Infarction.

Background Myocardial infarction (MI) is characterized by the emergence of dead or dying cardiomyocytes and excessive immune cell infiltration after coronary vessel occlusion. However, the complex transcriptional profile, pathways, cellular interactome, and transcriptional regulators of immune subpopulations after MI remain elusive. Methods and Results Here, male C57BL/6 mice were subjected to MI surgery and monitored for 1 day and 7 days, or sham surgery for 7 days, then cardiac CD45-positive immune cells were collected for single-cell RNA sequencing to determine immune heterogeneity. A total of 30 135 CD45+ immune cells were partitioned into macrophages, monocytes, neutrophils, dendritic cells, and T or B cells for further analysis. We showed that macrophages enriched for Olr1 and differentially expressed Gpnmb represented 2 crucial ischemia-associated macrophages with distinct proinflammatory and prophagocytic capabilities. In contrast to the proinflammatory subset of macrophages enriched for Olr1, Gpnmb-positive macrophages exhibited higher phagocytosis and fatty acid oxidation preference, which could be abolished by etomoxir treatment. In addition to macrophages, MI triggered prompt recruitment of neutrophils into murine hearts, which constituted the sequential cell-fate from naïve S100a4-positive, to activated Sell-high, to aging Icam1-high neutrophils. In silico tools predicted that the excessively expanded neutrophils at 1 day were attributed to chemokine C-C motif ligand/chemokine C-X-C motif ligand pathways, whereas CD80/inducible T-cell costimulator (ICOS) signaling was responsible for the immunosuppressive response at day 7 after MI. Finally, the Fos/AP-1 (activator protein 1) regulon was identified as the critical regulator of proinflammatory responses, which was significantly activated in patients with dilated cardiomyopathy and ischemic cardiomyopathy. We showed the enriched Fos/AP-1 target gene loci in genome-wide association study signals for coronary artery diseases and MI. Targeting Fos/AP-1 with the selective inhibitor T5224 blunted leukocyte infiltration and alleviated cardiac dysfunction in the preclinical murine MI model. Conclusions Taken together, this single-cell RNA sequencing data lay the groundwork for the understanding of immune cell heterogeneity and dynamics in murine ischemic hearts. Moreover, Fos/AP-1 inhibition mitigates inflammatory responses and cardiac dysfunction, which might provide potential therapeutic benefits for heart failure intervention after MI.

Designed Co-DNA-Locker and Ratiometric SERS Sensing for Accurate Detection of Exosomes Based on Gold Nanorod Arrays.

Exosomes, which can transfer and deliver information about the original cell, are considered to be ideal candidates for early cancer diagnosis and evaluation of therapeutic efficacy due to their high abundance and stability. However, the highly expressed proteins on the surface of exosomes are usually associated with a variety of cancers; it is difficult to distinguish them by a single marker. Herein, a controlled self-assembly of gold nanorod (AuNR) arrays was prepared to construct a surface-enhanced Raman spectroscopy (SERS) sensor for the specific detection of exosomes secreted by SK-Br-3 cells based on a designed colocalization-dependent system (Co-DNA-Locker) and ratiometric strategy. After the exosomes are captured in the sensing array by the EpCAM aptamer modified on the surface of AuNRs, the DNA logic process occurs because the other two proteins, CD63 and HER2, are expressed simultaneously on the surface of exosomes secreted by SK-Br-3 cells, and the SERS signal intensity of the Rhodamine 6G (R6G) tagged on the terminal of DNA TE increased with an increase in the concentration of the exosomes, while the SERS signal intensity of Cy5 linked on the terminal of the EpCAM aptamer, which acts as an internal standard, remains stable. The AuNRs are uniformly arranged in a hexagonal shape, and the dense "hot spots" produce "hot surfaces," which greatly improve the sensitivity and uniformity of detection. In the presence of target exosomes, the DNA colocalization three-signal input switch and the ratiometric strategy realize the specific and accurate detection of exosomes. This sensing strategy achieves a wide detection range (1.0 × 104-5.0 × 106 particles/mL) and a lower detection limit (5.3 × 103 particles/mL), without using any signal amplification mechanism, demonstrating promising applications in health care monitoring and clinical diagnostics.

Diagnosis and Assessment of Apathy in Elderly Chinese Patients With Cerebral Small Vessel Disease.

Objective: The study aimed to estimate the frequency of apathy in Chinese patients with cerebral small vessel disease (CSVD) and investigate the relationship between apathy and neuroimaging markers of CSVD. Methods: A total of 150 CSVD aged patients were recruited for a cross-sectional observational study. Following the new revised version of diagnostic criteria for apathy (DCA), each patient was evaluated successively by the neuropsychiatric inventory (NPI-apathy), geriatric depression scale (GDS), and caregiver burden scale (CBS). The MRI presence of lacunes, white matter hyperintensities, cerebral microbleeds, and perivascular spaces were rated independently. Furthermore, presence of all these MRI markers were summed in a score of 0-4 representing all CSVD features combined. Results: According to the DCA, we found that the frequency of apathy in Chinese Alzheimer's disease patients reached 37.33%, with lack of and diminished goal-directed activities in the dimension of behavior/cognition. We did not find a close relationship between apathy and depression. Caregiver burden was positively correlated with apathy severity. Apathy, but not depression, was positively associated with total CSVD burden, rather than a separate MRI marker of CSVD. Conclusion: As a key component of neuropsychiatric symptoms, apathy was common in Chinese elderly with CSVD, more attention should be paid to apathy in clinical practice of CSVD.

Soluble ST2 levels for predicting the presence and severity of metabolic syndrome.

To explore the relationship between soluble ST2 (sST2) and metabolic syndrome (MetS) and determine whether sST2 levels can predict the presence and severity of MetS. We evaluated 550 consecutive subjects (58.91 ± 9.69 years, 50% male) with or without MetS from the Department of Vascular & Cardiology, Shanghai Jiao Tong University-Affiliated Ruijin Hospital. Serum sST2 concentrations were measured. The participants were divided into three groups according to the sST2 tertiles. Univariate and multivariable logistic regression models were used to evaluate the association between serum sST2 concentrations and the presence of MetS. Serum sST2 concentrations were significantly higher in the MetS group than in those in the no MetS group (14.80 ± 7.01 vs 11.58 ± 6.41 ng/mL, P < 0.01). Subjects with more MetS components showed higher levels of sST2. sST2 was associated with the occurrence of MetS after multivariable adjustment as a continuous log-transformed variable (per 1 SD, odds ratio (OR): 1.42, 95% CI: 1.13-1.80, P < 0.01). Subgroup analysis showed that individuals with MetS have significantly higher levels of sST2 than those without MetS regardless of sex and age. High serum sST2 levels were significantly and independently associated with the presence and severity of MetS. Thus, sST2 levels may be a novel biomarker and clinical predictor of MetS.

Efficient adsorption of methylene blue by xanthan gum derivative modified hydroxyapatite.

In this work, hydroxyapatite modified by xanthan gum (XG) derivative material (XMH) was prepared and applied to remove methylene blue (MB) from water. The physicochemical properties of XMH were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, X-Ray spectroscopy and thermogravimetric analysis. Results showed the operating variables (pH, ionic strength and adsorbent dosage) were related to the MB removal efficiency. Adsorption kinetic and adsorption isotherm were well fitted by the pseudo-second-order model and the Langmuir isotherm model, respectively. It indicated that the adsorption process was a monolayer layer adsorption and chemisorption process. Besides, the result of intra-particle diffusion model demonstrated that the intra-particle diffusion was not the only rate determining step. The maximum adsorption capability on MB was 769 mg/g. Thermodynamic parameters (ΔG0, ΔH0, and ΔS0) showed that the adsorption was a spontaneous and endothermic process. Adsorption mechanisms of MB on XMH might be governed by electrostatic attraction and hydrogen-bonding. Furthermore, XMH could be regenerated well and retained MB removal efficiency of 81% after five cycles of adsorption and desorption. Therefore, XMH is a promising adsorbent for the efficient removal of MB from aqueous solution due to its low cost, good thermal stability and excellent adsorption performance.