CNP Ameliorates Macrophage Inflammatory Response and Atherosclerosis.

BACKGROUND: CNP (C-type natriuretic peptide), an endogenous short peptide in the natriuretic peptide family, has emerged as an important regulator to govern vascular homeostasis. However, its role in the development of atherosclerosis remains unclear. This study aimed to investigate the impact of CNP on the progression of atherosclerotic plaques and elucidate its underlying mechanisms. METHODS: Plasma CNP levels were measured in patients with acute coronary syndrome. The potential atheroprotective role of CNP was evaluated in apolipoprotein E-deficient (ApoE-/-) mice through CNP supplementation via osmotic pumps, genetic overexpression, or LCZ696 administration. Various functional experiments involving CNP treatment were performed on primary macrophages derived from wild-type and CD36 (cluster of differentiation 36) knockout mice. Proteomics and multiple biochemical analyses were conducted to unravel the underlying mechanism. RESULTS: We observed a negative correlation between plasma CNP concentration and the burden of coronary atherosclerosis in patients. In early atherosclerotic plaques, CNP predominantly accumulated in macrophages but significantly decreased in advanced plaques. Supplementing CNP via osmotic pumps or genetic overexpression ameliorated atherosclerotic plaque formation and enhanced plaque stability in ApoE-/- mice. CNP promoted an anti-inflammatory macrophage phenotype and efferocytosis and reduced foam cell formation and necroptosis. Mechanistically, we found that CNP could accelerate HIF-1α (hypoxia-inducible factor 1-alpha) degradation in macrophages by enhancing the interaction between PHD (prolyl hydroxylase domain-containing protein) 2 and HIF-1α. Furthermore, we observed that CD36 bound to CNP and mediated its endocytosis in macrophages. Moreover, we demonstrated that the administration of LCZ696, an orally bioavailable drug recently approved for treating chronic heart failure with reduced ejection fraction, could amplify the bioactivity of CNP and ameliorate atherosclerotic plaque formation. CONCLUSIONS: Our study reveals that CNP enhanced plaque stability and alleviated macrophage inflammatory responses by promoting HIF-1α degradation, suggesting a novel atheroprotective role of CNP. Enhancing CNP bioactivity may offer a novel pharmacological strategy for treating related diseases.

Creation of an Atherosclerosis Model Using Palmitic Acid and Oleic Acid in the Vascular Smooth Muscle Cells of Rats.

BACKGROUND: Atherosclerosis (AS) is a chronic vascular inflammatory disease resulting from vascular endothelial injury and lipid deposition, closely linked to abnormal lipid metabolism within the body. The critical processes involved in atherosclerosis encompass lipid deposition, oxidation, metabolic disruptions, and inflammatory stimulation within the inner vessel wall. Lipid deposition emerges as a pivotal factor triggering these pathological changes, with vascular smooth muscle cells (VSMCs) playing a significant role in the development of AS. Therefore, the goal was to employ lipids, specifically palmitic acid (PA) and oleic acid (OA) solutions, to stimulate VSMCs and create an in vitro atherosclerosis model. This approach allows for the establishment of a rapid and efficient cell model for simulating atherosclerosis in vitro. METHODS: Primary vascular smooth muscle cells (VSMCs) were isolated and cultured from the thoracic aorta of healthy rats using the tissue-block method. VSMCs were identified through cell climbing slices and immunofluorescence. The growth of VSMCs was observed using light microscopy. The logarithmic growth phase of VSMCs was induced and stimulated by various concentrations of palmitic acid (PA) and oleic acid (OA) ranging from 0 to 650 µmol/L, with a gradient dilution of 50 µmol/L. VSMC activity was assessed using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Intracellular lipid deposition was visualized through Oil Red O staining. The levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) within VSMCs were quantified using commercially available kits. RESULTS: The optimal conditions for VSMC proliferation were determined to be an OA concentration of 500 µmol/L, a PA concentration of 300 µmol/L, and a culture duration of 48 hours. In comparison to the control group, the presence of lipid droplets within VSMCs became significantly evident following treatment with OA or PA. Furthermore, the levels of TC, TG, and LDL-C increased, while the HDL-C content decreased after treatment with OA or PA. CONCLUSIONS: A research model for atherosclerosis (AS) and the early stages of cardiovascular events, specifically lipid deposition, was successfully established through the use of OA and PA solutions. This model has the potential to open up new research avenues for gaining a deeper understanding of the pathogenesis and progression of AS.

Complexities of Coexisting Cardiac Amyloidosis and Coronary Artery Disease: A Contemporary Review of Diagnostic and Treatment Approaches.

Cardiac amyloidosis (CA) represents an emerging challenge in cardiovascular medicine, with notable clinical overlaps and diagnostic complexities when coexisting with coronary artery disease (CAD). This integrative review navigates the intricate terrain of CA and CAD, elucidating epidemiology, clinical presentations, and diagnostic considerations. Examining both immunoglobulin light chain amyloidosis (AL) and transthyretin amyloidosis, we underscore their shared demographic associations, diagnostic intricacies, and potential diagnostic confounders with CAD. Notably, we emphasize the impact of CA on epicardial coronary arteries and the consequential implications for coronary microcirculation. Further exploration reveals the connection between CA and acute myocardial infarction, emphasizing early recognition as pivotal. In terms of differential diagnosis, we underscore the significance of clinical symptoms, electrocardiography, echocardiography, cardiac magnetic resonance, and bone scintigraphy. Additionally, we scrutinize the intricate realm of treatment, encompassing medication selection, antithrombotic strategies, and revascularization modalities. Our review addresses the distinctive challenges posed by CA patients' limited tolerance for conventional therapies. This comprehensive synthesis serves as an invaluable resource for clinicians confronting the intricate intersection of CA and CAD. By offering insights into diagnostic refinement and innovative therapeutic avenues, we aim to enhance patient outcomes and quality of life within this complex clinical landscape.

NAPE-PLD in the ventral tegmental area regulates reward events, feeding and energy homeostasis.

The N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) catalyzes the production of N-acylethanolamines (NAEs), a family of endogenous bioactive lipids, which are involved in various biological processes ranging from neuronal functions to energy homeostasis and feeding behaviors. Reward-dependent behaviors depend on dopamine (DA) transmission between the ventral tegmental area (VTA) and the nucleus accumbens (NAc), which conveys reward-values and scales reinforced behaviors. However, whether and how NAPE-PLD may contribute to the regulation of feeding and reward-dependent behaviors has not yet been investigated. This biological question is of paramount importance since NAEs are altered in obesity and metabolic disorders. Here, we show that transcriptomic meta-analysis highlights a potential role for NAPE-PLD within the VTA→NAc circuit. Using brain-specific invalidation approaches, we report that the integrity of NAPE-PLD is required for the proper homeostasis of NAEs within the midbrain VTA and it affects food-reward behaviors. Moreover, region-specific knock-down of NAPE-PLD in the VTA enhanced food-reward seeking and reinforced behaviors, which were associated with increased in vivo DA release dynamics in response to both food- and non-food-related rewards together with heightened tropism towards food consumption. Furthermore, midbrain knock-down of NAPE-PLD, which increased energy expenditure and adapted nutrient partitioning, elicited a relative protection against high-fat diet-mediated body fat gain and obesity-associated metabolic features. In conclusion, these findings reveal a new key role of VTA NAPE-PLD in shaping DA-dependent events, feeding behaviors and energy homeostasis, thus providing new insights on the regulation of body metabolism.

Risk factors for SARS-CoV-2 pneumonia among renal transplant recipients in Beijing Omicron wave.

The novel coronavirus disease-19 had become an unprecedented global health emergency, quickly expanding worldwide. Omicron (B.1.1.529), as a novel variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was initially identified in South Africa and Botswana. Renal transplant recipients (RTRs) are a special group and are more vulnerable to viral pneumonia. Thus, this study aimed to assess the incidence and risk factors of SARS-CoV-2 pneumonia that occurred in RTRs with Omicron infection. This single-center case-control study enrolled the RTRs who were diagnosed with SARS-CoV-2 infection by the SARS-CoV-2 nucleic acid test, which were divided into two groups according to the imaging features of SARS-CoV-2 pneumonia. The parameters were collected by questionnaires and analyzed using Statistical Product and Service Solutions. A total of 313 RTRs completed the questionnaires, and 131 were enrolled in this study with a mean age of 42.66 years. The incidence of SARS-CoV-2 pneumonia among the enrolled participants was 76.3%. The first symptoms included fever (89.3%), cough (93.1%), and expectoration (81.7%). From the comparison, the parameters such as age, gender, body mass index, lymphocyte count, and the percent of neutrophils and the basic serum creatinine before SARS-CoV-2 infection were significantly different between the two groups (P < 0.05). In multivariate analysis, age and the basic serum creatinine were independent risk factors for developing SARS-CoV-2 pneumonia (P < 0.05). Older RTRs with a high level of serum creatinine before SARS-CoV-2 infection were more at risk of developing SARS-CoV-2 pneumonia. More randomized controlled studies are needed.IMPORTANCEThis study aimed to assess the incidence and the risk factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia that occurred in renal transplant recipients (RTRs) with Omicron infection. In conclusion, older RTRs with a high level of serum creatinine before SARS-CoV-2 infection were more at risk of developing SARS-CoV-2 pneumonia and should be timely treated, in case of severe pneumonia.

The CREB1 inhibitor 666-15 maintains cartilage homeostasis and mitigates osteoarthritis progression.

Aims: cAMP response element binding protein (CREB1) is involved in the progression of osteoarthritis (OA). However, available findings about the role of CREB1 in OA are inconsistent. 666-15 is a potent and selective CREB1 inhibitor, but its role in OA is unclear. This study aimed to investigate the precise role of CREB1 in OA, and whether 666-15 exerts an anti-OA effect. Methods: CREB1 activity and expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) in cells and tissues were measured by immunoblotting and immunohistochemical (IHC) staining. The effect of 666-15 on chondrocyte viability and apoptosis was examined by cell counting kit-8 (CCK-8) assay, JC-10, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining. The effect of 666-15 on the microstructure of subchondral bone, and the synthesis and catabolism of cartilage, in anterior cruciate ligament transection mice were detected by micro-CT, safranin O and fast green (S/F), immunohistochemical staining, and enzyme-linked immunosorbent assay (ELISA). Results: CREB1 was hyperactive in osteoarthritic articular cartilage, interleukin (IL)-1ß-treated cartilage explants, and IL-1ß- or carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-treated chondrocytes. 666-15 enhanced cell viability of OA-like chondrocytes and alleviated IL-1ß- or CCCP-induced chondrocyte injury through inhibition of mitochondrial dysfunction-associated apoptosis. Moreover, inhibition of CREB1 by 666-15 suppressed expression of ADAMTS4. Additionally, 666-15 alleviated joint degeneration in an ACLT mouse model. Conclusion: Hyperactive CREB1 played a critical role in OA development, and 666-15 exerted anti-IL-1ß or anti-CCCP effects in vitro as well as joint-protective effects in vivo. 666-15 may therefore be used as a promising anti-OA drug.

Piezo-enhanced near infrared photocatalytic nanoheterojunction integrated injectable biopolymer hydrogel for anti-osteosarcoma and osteogenesis combination therapy.

Preventing local tumor recurrence while promoting bone tissue regeneration is an urgent need for osteosarcoma treatment. However, the therapeutic efficacy of traditional photosensitizers is limited, and they lack the ability to regenerate bone. Here, a piezo-photo nanoheterostructure is developed based on ultrasmall bismuth/strontium titanate nanocubes (denoted as Bi/SrTiO3), which achieve piezoelectric field-driven fast charge separation coupling with surface plasmon resonance to efficiently generate reactive oxygen species. These hybrid nanotherapeutics are integrated into injectable biopolymer hydrogels, which exhibit outstanding anticancer effects under the combined irradiation of NIR and ultrasound. In vivo studies using patient-derived xenograft models and tibial osteosarcoma models demonstrate that the hydrogels achieve tumor suppression with efficacy rates of 98.6 % and 67.6 % in the respective models. Furthermore, the hydrogel had good filling and retention capabilities in the bone defect region, which exerted bone repair therapeutic efficacy by polarizing and conveying electrical stimuli to the cells under mild ultrasound radiation. This study provides a comprehensive and clinically feasible strategy for the overall treatment and tissue regeneration of osteosarcoma.

The percentage of circulating fibrocytes is associated with increased morbidity of pulmonary hypertension in patients on hemodialysis.

INTRODUCTION: Pulmonary hypertension (PH) is highly prevalent in patients receiving dialysis. The precise mechanisms underlying PH in hemodialysis (HD) patients have not been adequately addressed. Emerging experimental evidence indicates that circulating fibrocytes may contribute significantly to this process. METHODS: We measured the proportion of circulating fibrocytes using flow cytometry analysis and prospectively analyzed patients during HD from February 1, 2017, to February 1, 2022. Then we investigated correlations between circulating fibrocytes, inflammation cytokines, PH, and their affective factors that predict the prognosis of HD patients. RESULTS: The cohort included 192 patients. During a follow-up of 5 years, we registered 66 all-cause deaths, and 11 patients received kidney transplantation. The incidence of PH among HD patients was 30.9%. We found that the circulating fibrocyte level significantly correlated with pulmonary arterial systolic pressure (r = 0.412, p < 0.05). In the multiple logistic regression analysis, the percentage of circulating fibrocytes was an independent predictor of PH (odds ratio [OR]: 2.080, 95% confidence interval [CI]: 1.539-2.812, p < 0.001). Controlling for confounding covariates in the multivariate Cox regression models, the presence of PH conferred an increased risk of all-cause mortality in HD patients [hazard ratio (HR): 2.183, 95% CI:1.257-3.788, p = 0.006]. CONCLUSION: The prevalence of PH was high in HD patients and was associated with higher all-cause mortality. Higher circulating fibrocyte level was an independent predictor of the presence of PH; these fibrocytes may serve as early detection markers and novel therapeutic targets.

Long-term efficacy and safety of cryoballoon ablation of atrial fibrillation: A systematic review and meta-analysis.

BACKGROUND: This meta-analysis evaluated long-term efficacy and safety of cryoballoon ablation (CB) of atrial fibrillation (AF). METHODS: PubMed, Cochrane Library, and Web of Science were searched until July 31, 2023, for published works investigating efficacy and safety of CB of AF in which mean/median follow-up time was not less than 36 months. Safety was assessed by adverse events. Efficacy was assessed by AF recurrence, defined as any atrial arrhythmias lasting more than 30 s. RESULTS: A total of 19 clinical studies were included. After an average of 58.1 months of follow-up, the overall AF recurrence rate was about 37%. The predictors of recurrence were duration of AF (HR 1.00; 95% CI [1.00 ∼ 1.01]), early recurrence of atrial fibrillation (HR 3.96; 95%CI [1.12 ∼ 14.02]), left atrial diameter (HR 1.04; 95%CI [1.02 ∼ 1.06]), and persistent AF (HR1.47; 95% CI [1.19 ∼ 1.82]). In terms of safety, the incidence of transient phrenic paralysis (PNP) was the highest, about 3%; followed by vascular complications (about 2%); pseudoaneurysm, permanent PNP, and all-cause death was (about 1%); and pericardial effusion and stroke / TIA was very low. CONCLUSION: CB is associated with low rates of severe complications and reasonable success rates.

The association between urine ketone and new-onset atrial fibrillation in critically ill patients.

BACKGROUND AND AIMS: New-onset atrial fibrillation (NOAF) is a common manifestation in critically ill patients. There is a paucity of evidence indicating a relationship between urinary ketones and NOAF. METHODS: Critically ill patients with urinary ketone measurements from the Medical Information Mart for Intensive Care (MIMIC-IV) database were included. The primary outcome was NOAF Propensity score matching was performed following by multivariable logistic regression. RESULTS: A total of 24,688 patients with available data of urine ketone were included in this study. The urine ketone of 4014 patients was tested positive. The average age of the included participants was 63.8 years old, and 54.5% of them were male. Result of the fully-adjusted binary logistic regression model showed that patients with positive urinary ketone was associated with a significantly lower risk of NOAF (Odds ratio, 0.79, 95% CI 0.7-0.9), compared with those with negative urinary ketone. In the subgroup analysis according to diabetic status, compared with nondiabetics, patients with diabetes had lower risk of NOAF (p-values for interaction < 0.05). Results of other subgroup analyses according to gender, age, infection, myocardial infarction, and congestive heart failure were consistent with the primary analysis. CONCLUSIONS: Positive urinary ketone body may be associated with reduced risk of NOAF in critically ill patients during intensive care unit hospitalization. Further studies are needed to clarify the underlying mechanisms.

AMFF-Net: An Effective 3D Object Detector Based on Attention and Multi-Scale Feature Fusion.

With the advent of autonomous vehicle applications, the importance of LiDAR point cloud 3D object detection cannot be overstated. Recent studies have demonstrated that methods for aggregating features from voxels can accurately and efficiently detect objects in large, complex 3D detection scenes. Nevertheless, most of these methods do not filter background points well and have inferior detection performance for small objects. To ameliorate this issue, this paper proposes an Attention-based and Multiscale Feature Fusion Network (AMFF-Net), which utilizes a Dual-Attention Voxel Feature Extractor (DA-VFE) and a Multi-scale Feature Fusion (MFF) Module to improve the precision and efficiency of 3D object detection. The DA-VFE considers pointwise and channelwise attention and integrates them into the Voxel Feature Extractor (VFE) to enhance key point cloud information in voxels and refine more-representative voxel features. The MFF Module consists of self-calibrated convolutions, a residual structure, and a coordinate attention mechanism, which acts as a 2D Backbone to expand the receptive domain and capture more contextual information, thus better capturing small object locations, enhancing the feature-extraction capability of the network and reducing the computational overhead. We performed evaluations of the proposed model on the nuScenes dataset with a large number of driving scenarios. The experimental results showed that the AMFF-Net achieved 62.8% in the mAP, which significantly boosted the performance of small object detection compared to the baseline network and significantly reduced the computational overhead, while the inference speed remained essentially the same. AMFF-Net also achieved advanced performance on the KITTI dataset.

The Systemic Immune Inflammatory Response Index Can Predict the Clinical Prognosis of Patients with Initially Diagnosed Coronary Artery Disease.

Background: Recently, the systemic immune inflammatory response index (SIIRI), a novel and expanded inflammatory response marker, has been an independent predictor of lesion severity in patients with acute coronary syndrome (ACS). However, its predictive role in patients with initially diagnosed coronary artery disease (CAD) remains to be explored. Patients and Methods: We evaluated 959 patients with CAD undergoing an initial coronary intervention. Each patient had laboratory measurements, including blood cell counts, taken after admission and before interventional treatment. The primary endpoint was major cardiovascular events (MACEs), defined as cardiovascular death, nonfatal myocardial infarction(MI), and nonfatal stroke. The secondary endpoints included MACEs and readmission for congestive heart failure(HF). Results: During a mean follow-up period of 33.3±9.9 months, 229 (23.9%) MACEs were recorded. ROC curve analysis displayed that the best cut-off value of SIIRI for predicting MACEs was 247.17*1018/L2. Kaplan-Meier survival curve analysis showed that the survival rate of the low SIIRI group was higher than that of the high SIIRI group (P<0.001). Compared with the low SIIRI group, the high SIIRI group had a significantly higher risk of MACEs (187 cases (39.53%) vs.42 patients (8.64%), P<0.001). Univariate and multivariate Cox regression analyses displayed that high SIIRI levels were independently associated with the occurrence of MACEs in patients with initially diagnosed CAD undergoing percutaneous coronary intervention (PCI) (adjusted hazard ratio [HR]: 3.808, 95% confidence interval [CI%]: 2.643-5.486, P<0.001). Adding SIIRI to conventional risk factor models improved the predictive value of MACEs. Conclusion: Elevated SIIRI is associated with adverse cardiovascular prognosis in patients with initially diagnosed CAD. SIIRI can be a simple and practical index to identify high-risk patients with CAD after PCI.

The Systemic Inflammation Index Predicts Poor Clinical Prognosis in Patients with Initially Diagnosed Acute Coronary Syndrome Undergoing Primary Coronary Angiography.

Background: Systemic inflammation index (SII: neutrophil count * platelet count/lymphocyte count) is a new inflammatory marker that can reflect the degree of systemic inflammatory response after coronary artery disease (CAD). However, the predictive value of the SII for clinical prognosis in patients with initially diagnosed acute coronary syndrome (ACS) has yet to be thoroughly studied. Patients and Methods: Patients with initially diagnosed ACS who underwent primary coronary angiography in our hospital from January 2019 to April 2021 were included in this study. 757 patients with ACS who underwent primary coronary angiography were enrolled. According to the baseline SII level, the patients were divided into a high SII group and a low SII group. The primary endpoint was major cardiovascular events (MACEs), defined as cardiac death, non-fatal myocardial infarction (MI), and non-fatal stroke. Results: At a median follow-up of 33.9 months, 140 (18.5%) MACEs were recorded. Receiver operating characteristic (ROC) curve analysis showed that SII's best cut-off value for predicting MACEs was 713.9*109/L. Kaplan-Meier survival curve analysis showed that the survival rate of the low SII group was higher than the high SII group (P<0.001). Compared with the low SII group, the risk of MACEs was significantly increased in the high SII group (89 cases (33.3%) vs.51 patients (10.4%), P<0.001). Univariate and multivariate Cox regression analysis manifested that high SII level was independently associated with the occurrence of MACEs in patients with ACS undergoing primary coronary angiography (adjusted hazard ratio [HR]: 2.915, 95% confidence interval (CI%): 1.830-4.641, P<0.001). Adding SII to the conventional risk factor model improved the predictive value of MACEs. Conclusion: This study showed that elevated SII was associated with adverse cardiovascular prognosis in patients with ACS undergoing primary coronary angiography, making SII a valuable predictor of poor prognosis in patients with ACS undergoing primary coronary angiography.

[Pelvic floor muscle rehabilitation training combined with psychological nursing intervention in the treatment of type â ¢B prostatitis].

OBJECTIVE: To investigate the clinical effect of pelvic floor muscle rehabilitation training combined with psychological nursing intervention in the treatment of intractable type ⅢB prostatitis. METHODS: We retrospectively analyzed the clinical data on 51 cases of intractable type ⅢB prostatitis treated from October 2020 to October 2022, which were randomly assigned to receive Tamsulosin medication (the control group, n = 24) or pelvic floor muscle rehabilitation training and psychological nursing in addition (the intervention group, n = 27), all for 8 weeks. We obtained NIH-CPSI, IIEF-5, Self-Rating Anxiety Scale (SAS) scores, Self-Rating Depression Scale (SDS) scores, the level of lecithin and the count of leukocytes in the prostatic fluid and the incidence of adverse events, and compared them between the two groups of patients before and after treatment. RESULTS: The total effectiveness rate was significantly higher in the intervention than in the control group (88.9% vs 62.5%, P < 0.05). Compared with the baseline, the NIH-CPSI, IIEF-5, SAS and SDS scores and the lecithin level were remarkably increased in both groups after treatment (P < 0.05), even more significantly in the intervention group than in the control (P < 0.05). No statistically significant difference was observed in the count of leukocytes before and after treatment (P > 0.05). CONCLUSION: On the basis of Tamsulosin medication, the application of pelvic floor rehabilitation training combined with psychological care can significantly enhance the therapeutic effect on type IIIB prostatitis, effectively relieve prostatitis pain, improve erectile function, lessen anxiety and depression symptoms, increase the level of lecithosomes and promote the recovery of prostatic function.

NAPE-PLD in the ventral tegmental area regulates reward events, feeding and energy homeostasis.

The N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) catalyzes the production of N-acylethanolamines (NAEs), a family of endogenous bioactive lipids, which are involved in various biological processes ranging from neuronal functions to energy homeostasis and feeding behaviors. Reward-dependent behaviors depend on dopamine (DA) transmission between the ventral tegmental area (VTA) and the nucleus accumbens (NAc), which conveys reward-values and scales reinforced behaviors. However, whether and how NAPE-PLD may contribute to the regulation of feeding and reward-dependent behaviors has not yet been investigated. This biological question is of paramount importance since NAEs are altered in obesity and metabolic disorders. Here, we show that transcriptomic meta-analysis highlights a potential role for NAPE-PLD within the VTA®NAc circuit. Using brain-specific invalidation approaches, we report that the integrity of NAPE-PLD is required for the proper homeostasis of NAEs within the midbrain VTA and it affects food-reward behaviors. Moreover, region-specific knock-down of NAPE-PLD in the VTA enhanced food-reward seeking and reinforced behaviors, which were associated with increased in vivo DA release dynamics in response to both food and non-food-related rewards together with heightened tropism towards food consumption. Furthermore, midbrain knock-down of NAPE-PLD, which increased energy expenditure and adapted nutrient partitioning, elicited a relative protection against high-fat diet-mediated body fat gain and obesity-associated metabolic features. In conclusion, these findings reveal a new key role of VTA NAPE-PLD in shaping DA-dependent events, feeding behaviors and energy homeostasis, thus providing new insights on the regulation of body metabolism.

Carboxypeptidase E is a prognostic biomarker co-expressed with osteoblastic genes in osteosarcoma.

Osteosarcoma (OS) is a rare primary malignant bone tumor in adolescents and children with a poor prognosis. The identification of prognostic genes lags far behind advancements in treatment. In this study, we identified differential genes using mRNA microarray analysis of five paired OS tissues. Hub genes, gene set enrichment analysis, and pathway analysis were performed to gain insight into the pathway alterations of OS. Prognostic genes were screened using the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset, then overlapped with the differential gene dataset. The carboxypeptidase E (CPE) gene, found to be an independent risk factor, was further validated using RT-PCR and Gene Expression Omnibus (GEO) datasets. Additionally, we explored the specific expression of CPE in OS tissues by reanalyzing single-cell genomics. Interestingly, CPE was found to be co-expressed with osteoblast lineage cell clusters that expressed RUNX2, SP7, SPP1, and IBSP marker genes in OS. These results suggest that CPE could serve as a prognostic factor in osteoblastic OS and should be further investigated as a potential therapeutic target.

Dysglycemia and arrhythmias.

Disorders in glucose metabolism can be divided into three separate but interrelated domains, namely hyperglycemia, hypoglycemia, and glycemic variability. Intensive glycemic control in patients with diabetes might increase the risk of hypoglycemic incidents and glucose fluctuations. These three dysglycemic states occur not only amongst patients with diabetes, but are frequently present in other clinical settings, such as during critically ill. A growing body of evidence has focused on the relationships between these dysglycemic domains with cardiac arrhythmias, including supraventricular arrhythmias (primarily atrial fibrillation), ventricular arrhythmias (malignant ventricular arrhythmias and QT interval prolongation), and bradyarrhythmias (bradycardia and heart block). Different mechanisms by which these dysglycemic states might provoke cardiac arr-hythmias have been identified in experimental studies. A customized glycemic control strategy to minimize the risk of hyperglycemia, hypoglycemia and glucose variability is of the utmost importance in order to mitigate the risk of cardiac arrhythmias.

Neutrophil Extracellular Traps: Potential Prothrombotic State Markers and Therapeutic Targets for Atrial Fibrillation.

BACKGROUND: Recently, the mechanism of thrombogenesis has taken a new direction with the involvement of neutrophil extracellular traps (NETs). However, little is known about the relationship between NETs and thrombogenesis in atrial fibrillation (AF). OBJECTIVE: Our study aimed to evaluate NETs in AF patients and their potential association with thrombogenesis. In addition, we studied the effect of NETs on thrombogenesis in rat models. METHODS: A total of 125 AF patients and 172 controls were studied. Spontaneous echo contrast (SEC) was examined using transesophageal echocardiography to assess the prothrombotic state. We used rapid atrial pacing (RAP) rat models to study NETs' formation and their effects on thrombogenesis. The levels of NETs were analyzed by flow cytometry. To deeply understand the regulatory mechanism of NET formation, the transcriptional characteristics of the left atrial appendage (LAA) tissue from RAP rats were analyzed. RESULTS: We found that NETs were increased significantly in AF patients and positively correlated with SEC grades. And inserting the NET level could significantly enhance the predictivity of CHA2DS2-VASc scores for the AF prothrombotic state. In the RAP models, we observed that NET levels increased significantly in the LAA and promoted thrombosis. Meanwhile, we found that these changes could be suppressed by the NET formation inhibitor. Transcriptomic analysis of the LAA tissue from RAP rats suggested that RAP might stimulate the NET formation by promoting the expression of inflammatory cytokine and adhesion genes. CONCLUSION: NETs may constitute useful thrombogenesis risk markers in AF patients and provide a potential therapeutic strategy for AF management.

An RNA-Cleaving DNAzyme That Requires an Organic Solvent to Function.

Engineering functional nucleic acids that are active under unusual conditions will not only reveal their hidden abilities but also lay the groundwork for pursuing them for unique applications. Although many DNAzymes have been derived to catalyze diverse chemical reactions in aqueous solutions, no prior study has been set up to purposely derive DNAzymes that require an organic solvent to function. Herein, we utilized in vitro selection to isolate RNA-cleaving DNAzymes from a random-sequence DNA pool that were "compelled" to accept 35 % dimethyl sulfoxide (DMSO) as a cosolvent, via counter selection in a purely aqueous solution followed by positive selection in the same solution containing 35 % DMSO. This experiment led to the discovery of a new DNAzyme that requires 35 % DMSO for its catalytic activity and exhibits drastically reduced activity without DMSO. This DNAzyme also requires divalent metal ions for catalysis, and its activity is enhanced by monovalent ions. A minimized, more efficient DNAzyme was also derived. This work demonstrates that highly functional, organic solvent-dependent DNAzymes can be isolated from random-sequence DNA libraries via forced in vitro selection, thus expanding the capability and potential utility of catalytic DNA.