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.

Day-night pattern of acute ST-segment elevation myocardial infarction onset in patients with obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with acute nocturnal hemodynamic and neurohormonal abnormalities that may increase the risk of coronary events, especially during the nighttime. This study sought to investigate the day-night pattern of acute ST-segment elevation myocardial infarction (STEMI) onset in patients with OSA and its impact on cardiovascular adverse events. METHODS: We prospectively enrolled 397 patients with STEMI, for which the time of onset of chest pain was clearly identified. All participants were categorized into non-OSA (n = 280) and OSA (n = 117) groups. The association between STEMI onset time and major adverse cardiovascular and cerebrovascular events was estimated by Cox proportional hazards regression. RESULTS: STEMI onset occurred from midnight to 5:59 am in 33% of patients with OSA, as compared with 15% in non-OSA patients (P < .01). For individuals with OSA, the relative risk of STEMI from midnight to 5:59 am was 2.717 [95% confidence interval (CI) 1.616 - 4.568] compared with non-OSA patients. After a median of 2.89 ± 0.78 years follow-up, symptom onset time was found to be significantly associated with risk of major adverse cardiovascular and cerebrovascular events in patients with OSA, while there was no significant association observed in non-OSA patients. Compared with STEMI presenting during noon to 5:59 pm, the hazard ratios for major adverse cardiovascular and cerebrovascular events in patients with OSA were 4.683 (95% CI 2.024 - 21.409, P = .027) for midnight to 5:59 am and 6.964 (95% CI 1.379 - 35.169, P = .019) for 6 pm to midnight, whereas the hazard ratios for non-OSA patients were 1.053 (95% CI 0.394 - 2.813, P = .917) for midnight to 5:59 am and 0.745 (95% CI 0.278 - 1.995, P = .558) for 6 pm to midnight. CONCLUSIONS: Patients with OSA exhibited a peak incidence of STEMI between midnight and 5:59 am, which showed an independent association with cardiovascular adverse events. CITATION: Wang Y, Buayiximu K, Zhu T, et al. Day-night pattern of acute ST-segment elevation myocardial infarction onset in patients with obstructive sleep apnea. J Clin Sleep Med. 2024;20(5):765-775.

Anti-infection effects of heparin on SARS-CoV-2 in a diabetic mouse model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in more severe syndromes and poorer outcomes in patients with diabetes and obesity. However, the precise mechanisms responsible for the combined impact of corona virus disease 2019 (COVID-19) and diabetes have not yet been elucidated, and effective treatment options for SARS-CoV-2-infected diabetic patients remain limited. To investigate the disease pathogenesis, K18-hACE2 transgenic (hACE2 Tg) mice with a leptin receptor deficiency (hACE2-Lepr -/-) or high-fat diet (hACE2-HFD) background were generated. The two mouse models were intranasally infected with a 5×10 5 median tissue culture infectious dose (TCID 50) of SARS-CoV-2, with serum and lung tissue samples collected at 3 days post-infection. The hACE2-Lepr -/- mice were then administered a combination of low-molecular-weight heparin (LMWH) (1 mg/kg or 5 mg/kg) and insulin via subcutaneous injection prior to intranasal infection with 1×10 4 TCID 50 of SARS-CoV-2. Daily drug administration continued until the euthanasia of the mice. Analyses of viral RNA loads, histopathological changes in lung tissue, and inflammation factors were conducted. Results demonstrated similar SARS-CoV-2 susceptibility in hACE2 Tg mice under both lean (chow diet) and obese (HFD) conditions. However, compared to the hACE2-Lepr +/+ mice, hACE2-Lepr -/- mice exhibited more severe lung injury, enhanced expression of inflammatory cytokines and hypoxia-inducible factor-1α, and increased apoptosis. Moreover, combined LMWH and insulin treatment effectively reduced disease progression and severity, attenuated lung pathological changes, and mitigated inflammatory responses. In conclusion, pre-existing diabetes can lead to more severe lung damage upon SARS-CoV-2 infection, and LMWH may be a valuable therapeutic approach for managing COVID-19 patients with diabetes.

Predictive value of early left ventricular end-diastolic volume changes for late left ventricular remodeling after ST-elevation myocardial infarction.

BACKGROUD: Left ventricular remodeling (LVR) is a major predictor of adverse outcomes in patients with acute ST-elevation myocardial infarction (STEMI). This study aimed to prospectively evaluate LVR in patients with STEMI who were successfully treated with primary percutaneous coronary intervention (PCI) and examine the relationship between early left ventricular dilation and late LVR. METHODS: Overall 301 consecutive patients with STEMI who underwent primary PCI were included. Serial echocardiography was performed on the first day after PCI, on the day of discharge, at 1 month, and 6 months after discharge. RESULTS: Left ventricular remodeling occurred in 57 (18.9%) patients during follow-up. Left ventricular end-diastolic volume (LVEDV) reduced from day 1 postoperative to discharge in the LVR group compared with that in the non-LVR (n-LVR) group. The rates of change in LVEDV (ΔLVEDV%) were -5.24 ± 16.02% and 5.05 ± 16.92%, respectively (p < 0.001). LVEDV increased in patients with LVR compared with n-LVR at 1-month and 6-month follow-ups (ΔLVEDV% 13.05 ± 14.89% vs. -1.9 ± 12.03%; 26.46 ± 14.05% vs. -3.42 ± 10.77%, p < 0.001). Receiver operating characteristic analysis showed that early changes in LVEDV, including ΔLVEDV% at discharge and 1-month postoperative, predicted late LVR with an area under the curve value of 0.80 (95% confidence interval 0.74-0.87, p < 0.0001). CONCLUSIONS: Decreased LVEDV at discharge and increased LVEDV at 1-month follow-up were both associated with late LVR at 6-month. Comprehensive and early monitoring of LVEDV changes may help to predict LVR.

Plasma metabolic fingerprints for large-scale screening and personalized risk stratification of metabolic syndrome.

Direct diagnosis and accurate assessment of metabolic syndrome (MetS) allow for prompt clinical interventions. However, traditional diagnostic strategies overlook the complex heterogeneity of MetS. Here, we perform metabolomic analysis in 13,554 participants from the natural cohort and identify 26 hub plasma metabolic fingerprints (PMFs) associated with MetS and its early identification (pre-MetS). By leveraging machine-learning algorithms, we develop robust diagnostic models for pre-MetS and MetS with convincing performance through independent validation. We utilize these PMFs to assess the relative contributions of the four major MetS risk factors in the general population, ranked as follows: hyperglycemia, hypertension, dyslipidemia, and obesity. Furthermore, we devise a personalized three-dimensional plasma metabolic risk (PMR) stratification, revealing three distinct risk patterns. In summary, our study offers effective screening tools for identifying pre-MetS and MetS patients in the general community, while defining the heterogeneous risk stratification of metabolic phenotypes in real-world settings.

An IL-6/STAT3/MR/FGF21 axis mediates heart-liver cross-talk after myocardial infarction.

The liver plays a protective role in myocardial infarction (MI). However, very little is known about the mechanisms. Here, we identify mineralocorticoid receptor (MR) as a pivotal nexus that conveys communications between the liver and the heart during MI. Hepatocyte MR deficiency and MR antagonist spironolactone both improve cardiac repair after MI through regulation on hepatic fibroblast growth factor 21 (FGF21), illustrating an MR/FGF21 axis that underlies the liver-to-heart protection against MI. In addition, an upstreaming acute interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway transmits the heart-to-liver signal to suppress MR expression after MI. Hepatocyte Il6 receptor deficiency and Stat3 deficiency both aggravate cardiac injury through their regulation on the MR/FGF21 axis. Therefore, we have unveiled an IL-6/STAT3/MR/FGF21 signaling axis that mediates heart-liver cross-talk during MI. Targeting the signaling axis and the cross-talk could provide new strategies to treat MI and heart failure.

Association of Serum BAFF Levels with Cardiovascular Events in ST-Segment Elevation Myocardial Infarction.

OBJECTIVES: The B cell activating factor (BAFF) is a B cell survival factor involved in atherosclerosis and ischemia-reperfusion (IR) injury. This study sought to investigate whether BAFF is a potential predictor of poor outcomes in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: We prospectively enrolled 299 patients with STEMI, and serum levels of BAFF were measured. All subjects were followed for three years. The primary endpoint was major adverse cardiovascular events (MACEs), including cardiovascular death, nonfatal reinfarction, hospitalization for heart failure (HF), and stroke. Multivariable Cox proportional hazards models were constructed to analyze the predictive value of BAFF for MACEs. RESULTS: In multivariate analysis, BAFF was independently associated with risk of MACEs (adjusted HR 1.525, 95% CI 1.085-2.145; p = 0.015) and cardiovascular death (adjusted hazard ratio [HR] 3.632, 95% confidence interval [CI] 1.132-11.650, p = 0.030) after adjustment for traditional risk factors. Kaplan-Meier survival curves demonstrated that patients with BAFF levels above the cut-off value (1.46 ng/mL) were more likely to have MACEs (log-rank p < 0.0001) and cardiovascular death (log-rank p < 0.0001). In subgroup analysis, the impact of high BAFF on MACEs development was stronger in patients without dyslipidemia. Furthermore, the C-statistic and Integrated Discrimination Improvement (IDI) values for MACEs were improved with BAFF as an independent risk factor or when combined with cardiac troponin I. CONCLUSIONS: This study suggests that higher BAFF levels in the acute phase are an independent predictor of the incidence of MACEs in patients with STEMI.

Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1B Inhibition Promotes Megakaryocyte Polyploidization and Platelet Production.

Platelets are produced from mature megakaryocytes which undergo polyploidization and proplatelet formation. Cell-cycle regulation plays a crucial role in megakaryocyte terminal differentiation especially in polyploidization. Dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) controls cell-cycle progression in cancer cells. The objective of this study was to determine DYRK1B function in megakaryocyte maturation and platelet production. A DYRK1B knock-out mouse was generated with increased peripheral platelet count compared with the wild type mouse without affecting megakaryocyte numbers in bone marrow. Polyploidy and proplatelet formations were significantly enhanced when DYRK1B was depleted in vitro. DYRK1B inhibition promoted megakaryocyte maturation by simultaneously upregulating cyclin D1 and downregulating P27. Furthermore, there was platelet restoration in two mice disease models of transient thrombocytopenia. In summary, DYRK1B plays an important role in megakaryocyte maturation and platelet production by interacting with cyclin D1 and P27. DYRK1B inhibition has potential therapeutic value in transient thrombocytopenia treatment. Graphic Abstract.

[68Ga]Ga-DOTA-FAPI-04 PET/MR in patients with acute myocardial infarction: potential role of predicting left ventricular remodeling.

PURPOSE: To assess predictive value of 68Ga-labeled fibroblast activation protein inhibitor-04 ([68Ga]Ga-DOTA-FAPI-04) PET/MR for late left ventricular (LV) remodeling in patients with ST-segment elevated myocardial infarction (STEMI). METHODS: Twenty-six patients with STEMI were included in the study. [68Ga]Ga-DOTA-FAPI-04 PET/MR was performed at baseline and at average 12 months after STEMI. LV remodeling was defined as >10% increase in LV end-systolic volume (LVESV) from baseline to 12 months. RESULTS: The LV remodeling group demonstrated higher [68Ga]Ga-DOTA-FAPI-04 uptake volume (UV) at baseline than the non-LV remodeling group (p < 0.001). [68Ga]Ga-DOTA-FAPI-04 UV at baseline was a significant predictor (OR = 1.048, p = 0.011) for LV remodeling at 12 months after STEMI. Compared to clinical information, MR imaging and cardiac function parameters at baseline, [68Ga]Ga-DOTA-FAPI-04 UV demonstrated better predictive ability (AUC = 0.938, p < 0.001) for late LV remodeling, with sensitivity of 100.0% and specificity of 81.3%. CONCLUSIONS: [68Ga]Ga-DOTA-FAPI-04 PET/MR is an effective tool to non-invasively quantify myocardial fibroblasts activation, and baseline [68Ga]Ga-DOTA-FAPI-04 UV may have potential predictive value for late LV remodeling.

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.

Functional Connectivity Increases in Response to High-Definition Transcranial Direct Current Stimulation in Patients with Chronic Disorder of Consciousness.

High-definition transcranial direct current stimulation (HD-tDCS) has been shown to play an important role in improving consciousness in patients with disorders of consciousness (DOCs), but its neuroelectrophysiological evidence is still lacking. To better explain the electrophysiological mechanisms of the effects of HD-tDCS on patients with DOCs, 22 DOC patients underwent 10 anodal HD-tDCS sessions of the left dorsolateral prefrontal cortex (DLPFC). This study used the Coma Recovery Scale-Revised (CRS-R) to assess the level of consciousness in DOC patients. According to whether the CRS-R score increased before and after stimulation, DOC patients were divided into a responsive group and a non-responsive group. By comparing the differences in resting-state EEG functional connectivity between different frequency bands and brain regions, as well as the relationship between functional connectivity values and clinical scores, the electrophysiological mechanism of the clinical effects of HD-tDCS was further explored. The change of the phase locking value (PLV) on the theta frequency band in the left frontal-parietooccipital region was positively correlated with the change in the CRS-R scores. As the number of interventions increased, we observed that in the responsive group, the change in PLV showed an upward trend, and the increase in the PLV appeared in the left frontal-parietooccipital region at 4-8 Hz and in the intra-bifrontal region at 8-13 Hz. In the non-responsive group, although the CRS-R scores did not change after stimulation, the PLV showed a downward trend, and the decrease in the PLV appeared in the intra-bifrontal region at 8-13 Hz. In addition, at the three-month follow-up, patients with increased PLV in the intra-bifrontal region at 8-13 Hz after repeated HD-tDCS stimulation had better outcomes than those without. Repeated anodal stimulation of the left DLPFC with HD-tDCS resulted in improved consciousness in some patients with DOCs. The increase in functional connectivity in the brain regions may be associated with the improvement of related awareness after HD-tDCS and may be a predictor of better long-term outcomes.

High-Definition Transcranial Direct Current Stimulation of the Dorsolateral Prefrontal Cortex Modulates the Electroencephalography Rhythmic Activity of Parietal Occipital Lobe in Patients With Chronic Disorders of Consciousness.

Background: Disorders of consciousness (DOC) are a spectrum of pathologies affecting one's ability to interact with the external world. At present, High-Definition Transcranial Direct Current Stimulation (HD-tDCS) is used in many patients with DOC as a non-invasive treatment, but electrophysiological research on the effect of HD-tDCS on patients with DOC is limited. Objectives: To explore how HD-tDCS affects the cerebral cortex and examine the possible electrophysiological mechanisms underlying the effects of HD-tDCS on the cerebral cortex. Methods: A total of 19 DOC patients were assigned to HD-tDCS stimulation. Each of them underwent 10 anodal HD-tDCS sessions of the left dorsolateral prefrontal cortex (DLPFC) over 5 consecutive days. Coma Recovery Scale-Revision (CRS-R) scores were recorded to evaluate the consciousness level before and after HD-tDCS, while resting-state electroencephalography (EEG) recordings were obtained immediately before and after single and multiple HD-tDCS stimuli. Depending on whether the CRS-R score increased after stimulation, we classified the subjects into responsive (RE) and non-responsive (N-RE) groups and compared the differences in power spectral density (PSD) between the groups in different frequency bands and brain regions, and also examined the relationship between PSD values and CRS-R scores. Results: For the RE group, the PSD value of the parieto-occipital region increased significantly in the 6-8 Hz frequency band after multiple stimulations by HD-tDCS. After a single stimulation, an increase in PSD was observed at 10-13 and 13-30 Hz. In addition, for all subjects, a positive correlation was observed between the change in PSD value in the parieto-occipital region at 10-13 and 6-8 Hz frequency band and the change in CRS-R score after a single stimulation. Conclusion: Repeated anodal HD-tDCS of the left DLPFC can improve clinical outcomes in patients with DOC, and HD-tDCS-related increased levels of consciousness were associated with increased parieto-occipital PSD.

Autologous Skin Fibroblast-Based PLGA Nanoparticles for Treating Multiorgan Fibrosis.

Fibrotic diseases remain a substantial health burden with few therapeutic approaches. A hallmark of fibrosis is the aberrant activation and accumulation of myofibroblasts, which is caused by excessive profibrotic cytokines. Conventional anticytokine therapies fail to undergo clinical trials, as simply blocking a single or several antifibrotic cytokines cannot abrogate the profibrotic microenvironment. Here, biomimetic nanoparticles based on autologous skin fibroblasts are customized as decoys to neutralize multiple fibroblast-targeted cytokines. By fusing the skin fibroblast membrane onto poly(lactic-co-glycolic) acid cores, these nanoparticles, termed fibroblast membrane-camouflaged nanoparticles (FNPs), are shown to effectively scavenge various profibrotic cytokines, including transforming growth factor-ß, interleukin (IL)-11, IL-13, and IL-17, thereby modulating the profibrotic microenvironment. FNPs are sequentially prepared into multiple formulations for different administration routines. As a proof-of-concept, in three independent animal models with various organ fibrosis (lung fibrosis, liver fibrosis, and heart fibrosis), FNPs effectively reduce the accumulation of myofibroblasts, and the formation of fibrotic tissue, concomitantly restoring organ function and indicating that FNPs are a potential broad-spectrum therapy for fibrosis management.

The validity, reliability and feasibility of four instruments for assessing the consciousness of stroke patients in a neurological intensive care unit compared.

BACKGROUND: Early rehabilitation is the foundation for recovery for those admitted to an intensive care unit. Appropriate assessment of consciousness is needed before any rehabilitative intervention begins. METHODS: This prospective study compared the validity, reliability and applicability of the sedation-agitation scale, the Richmond Agitation-Sedation Scale, the motor activity assessment scale and the Glasgow Coma Scale in a working neurological intensive care unit. Eighty-three stroke patients were assessed with the four scales by the same 3 raters acting independently: a senior physician, a senior therapist and a trainee. That generated 996 assessment records for comparison. RESULTS: Good agreement (r=0.98-0.99) was found among the sedation-agitation scale, the Richmond Agitation-Sedation Scale, the motor activity assessment scale scores, but the Glasgow Coma Scale ratings correlated less well (r=0.72-0.76) with the others. Consistent results were also found among the three raters. After stratification of the ratings by age, gender, level of consciousness and Acute Physiology and Chronic Health Evaluation score, the scales reported significant differences among the levels of consciousness and among those with different Acute Physiology and Chronic Health Evaluation results, but not with different age or gender strata. CONCLUSIONS: The four instruments tested are all reliable enough and feasible for use as a tool for consciousness screening in a neurological intensive care unit.

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.

Automatic pulmonary auscultation grading diagnosis of Coronavirus Disease 2019 in China with artificial intelligence algorithms: A cohort study.

BACKGROUND AND OBJECTIVE: Research on automatic auscultation diagnosis of COVID-19 has not yet been developed. We therefore aimed to engineer a deep learning approach for the automated grading diagnosis of COVID-19 by pulmonary auscultation analysis. METHODS: 172 confirmed cases of COVID-19 in Tongji Hospital were divided into moderate, severe and critical group. Pulmonary auscultation were recorded in 6-10 sites per patient through 3M littmann stethoscope and the data were transferred to computer to construct the dataset. Convolutional neural network (CNN) were designed to generate classifications of the auscultation. F1 score, the area under the curve (AUC) of the receiver operating characteristic curve, sensitivity and specificity were quantified. Another 45 normal patients were served as control group. RESULTS: There are about 56.52%, 59.46% and 78.85% abnormal auscultation in the moderate, severe and critical groups respectively. The model showed promising performance with an averaged F1 scores (0.9938 95% CI 0.9923-0.9952), AUC ROC score (0.9999 95% CI 0.9998-1.0000), sensitivity (0.9938 95% CI 0.9910-0.9965) and specificity (0.9979 95% CI 0.9970-0.9988) in identifying the COVID-19 patients among normal, moderate, severe and critical group. It is capable in identifying crackles, wheezes, phlegm sounds with an averaged F1 scores (0.9475 95% CI 0.9440-0.9508), AUC ROC score (0.9762 95% CI 0.9848-0.9865), sensitivity (0.9482 95% CI 0.9393-0.9578) and specificity (0.9835 95% CI 0.9806-0.9863). CONCLUSIONS: Our model is accurate and efficient in automatically diagnosing COVID-19 according to different categories, laying a promising foundation for AI-enabled auscultation diagnosing systems for lung diseases in clinical applications.

Dynamic Changes of Brain Activity in Different Responsive Groups of Patients with Prolonged Disorders of Consciousness.

As medical technology continues to improve, many patients diagnosed with brain injury survive after treatments but are still in a coma. Further, multiple clinical studies have demonstrated recovery of consciousness after transcranial direct current stimulation. To identify possible neurophysiological mechanisms underlying disorders of consciousness (DOCs) improvement, we examined the changes in multiple resting-state EEG microstate parameters after high-definition transcranial direct current stimulation (HD-tDCS). Because the left dorsolateral prefrontal cortex is closely related to consciousness, it is often chosen as a stimulation target for tDCS treatment of DOCs. A total of 21 patients diagnosed with prolonged DOCs were included in this study, and EEG microstate analysis of resting state EEG datasets was performed on all patients before and after interventions. Each of them underwent 10 anodal tDCS sessions of the left dorsolateral prefrontal cortex over 5 consecutive working days. According to whether the clinical manifestations improved, DOCs patients were divided into the responsive (RE) group and the non-responsive (N-RE) group. The dynamic changes of resting state EEG microstate parameters were also analyzed. After multiple HD-tDCS interventions, the duration and coverage of class C microstates in the RE group were significantly increased. This study also found that the transition between microstates A and C increased, while the transition between microstates B and D decreased in the responsive group. However, these changes in EEG microstate parameters in the N-RE group have not been reported. Our findings suggest that EEG neural signatures have the potential to assess consciousness states and that improvement in the dynamics of brain activity was associated with the recovery of DOCs. This study extends our understanding of the neural mechanism of DOCs patients in consciousness recovery.

Elevated Wnt2 and Wnt4 activate NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 following myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI)-induced excessive myocardial fibrosis exaggerates cardiac dysfunction. However, serum Wnt2 or Wnt4 level in AMI patients, and the roles in cardiac fibrosis are largely unkown. METHODS: AMI and non-AMI patients were enrolled to examine serum Wnt2 and Wnt4 levels by ELISA analysis. The AMI patients were followed-up for one year. MI mouse model was built by ligation of left anterior descending branch (LAD). FINDINGS: Serum Wnt2 or Wnt4 level was increased in patients with AMI, and the elevated Wnt2 and Wnt4 were correlated to adverse outcome of these patients. Knockdown of Wnt2 and Wnt4 significantly attenuated myocardial remodeling and cardiac dysfunction following experimental MI. In vitro, hypoxia enhanced the secretion and expression of Wnt2 and Wnt4 in neonatal rat cardiac myocytes (NRCMs) or fibroblasts (NRCFs). Mechanistically, the elevated Wnt2 or Wnt4 activated ß-catenin /NF-κB signaling to promote pro-fibrotic effects in cultured NRCFs. In addition, Wnt2 or Wnt4 upregulated the expression of these Wnt co-receptors, frizzled (Fzd) 2, Fzd4 and (low-density lipoprotein receptor-related protein 6 (LRP6). Further analysis revealed that Wnt2 or Wnt4 activated ß-catenin /NF-κB by the co-operation of Fzd4 or Fzd2 and LRP6 signaling, respectively. INTERPRETATION: Elevated Wnt2 and Wnt4 activate ß-catenin/NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 in fibroblasts, which contributes to adverse outcome of patients with AMI, suggesting that systemic inhibition of Wnt2 and Wnt4 may improve cardiac dysfunction after MI.

FABP3 Deficiency Exacerbates Metabolic Derangement in Cardiac Hypertrophy and Heart Failure via PPARα Pathway.

Background: Cardiac hypertrophy was accompanied by various cardiovascular diseases (CVDs), and due to the high global incidence and mortality of CVDs, it has become increasingly critical to characterize the pathogenesis of cardiac hypertrophy. We aimed to determine the metabolic roles of fatty acid binding protein 3 (FABP3) on transverse aortic constriction (TAC)-induced cardiac hypertrophy. Methods and Results: Transverse aortic constriction or Ang II treatment markedly upregulated Fabp3 expression. Notably, Fabp3 ablation aggravated TAC-induced cardiac hypertrophy and cardiac dysfunction. Multi-omics analysis revealed that Fabp3-deficient hearts exhibited disrupted metabolic signatures characterized by increased glycolysis, toxic lipid accumulation, and compromised fatty acid oxidation and ATP production under hypertrophic stimuli. Mechanistically, FABP3 mediated metabolic reprogramming by directly interacting with PPARα, which prevented its degradation and synergistically modulated its transcriptional activity on Mlycd and Gck. Finally, treatment with the PPARα agonist, fenofibrate, rescued the pro-hypertrophic effects of Fabp3 deficiency. Conclusions: Collectively, these findings reveal the indispensable roles of the FABP3-PPARα axis on metabolic homeostasis and the development of hypertrophy, which sheds new light on the treatment of hypertrophy.

Roxadustat Does Not Affect Platelet Production, Activation, and Thrombosis Formation.

Objective: Roxadustat is a new medication for the treatment of renal anemia. EPO (erythropoietin)-the current treatment standard-has been reported to enhance platelet activation and production. However, to date, the effect of roxadustat on platelets is unclear. To address this deficiency, herein, we have evaluated the effect of roxadustat on platelet production and function. Approach and Results: We performed several mouse platelet functional assays in the presence/absence of in vitro and in vivo roxadustat treatment. Both healthy and 5/6 nephrectomized mice were utilized. The effect of roxadustat on platelet function of healthy volunteers and chronic kidney disease patients was also evaluated. For platelet production, megakaryocyte maturation and proplatelet formation were assayed in vitro. Peripheral platelet and bone marrow megakaryocyte counts were also determined. We found that roxadustat could not stimulate washed platelets directly, and platelet aggregation, spreading, clot retraction, and P-selectin/JON/A exposure were similar with or without in vitro or in vivo roxadustat treatment among both healthy and 5/6 nephrectomized mice. In vivo mouse thrombosis models were additionally performed, and no differences were detected between the vehicle and roxadustat treatment groups. EPO, which was considered a positive control in the present study, promoted platelet function and production as reported previously. Megakaryocyte maturation and proplatelet formation were also not significantly different between control mice and those treated with roxadustat. After receiving roxadustat for 14 days, no difference in the peripheral platelet count was observed in the mice. Conclusions: Administration of roxadustat has no significant impact on platelet production and function.