Prevalence of metabolic syndrome among patients with hepatocellular carcinoma of different etiologies: a retrospective study.

AIMS: This study compared the prevalences of metabolic syndrome and of cardiac or kidney comorbidities among patients with hepatocellular carcinoma (HCC) associated with metabolic dysfunction-related fatty liver disease (MAFLD), chronic infection with hepatitis B or C virus (HBV or HCV), or the combination of MAFLD and chronic HBV infection. METHODS: Medical records were retrospectively analyzed for patients with HCC who underwent hepatectomy between March 2013 and March 2023. Patients with HCC of different etiologies were compared in terms of their clinicodemographic characteristics and laboratory data before surgery. RESULTS: Of the 2422 patients, 1,822 (75.2%) were chronically infected with HBV without MAFLD and HCV, 415 (17.2%) had concurrent MAFLD and chronic HBV infection but no HCV infection, 121 (5.0%) had MAFLD without hepatitis virus infection, and 64 (2.6%) were chronically infected with HCV in the presence or absence of MAFLD and HBV infection. Compared to patients chronically infected with HBV without MAFLD and HCV, those with MAFLD but no hepatitis virus infection showed significantly lower prevalence of cirrhosis, ascites, portal hypertension, alpha-fetoprotein concentration ≥ 400 ng/mL, tumor size > 5 cm, multinodular tumors and microvascular invasion. Conversely, they showed significantly higher prevalence of metabolic syndrome, hypertension, type 2 diabetes, abdominal obesity, history of cardiovascular disease, T-wave alterations, hypertriglyceridemia and hyperuricemia, as well as higher risk of arteriosclerotic cardiovascular disease. Compared to patients with MAFLD but no hepatitis virus infection, those with concurrent MAFLD and chronic infection with HBV showed significantly higher prevalence of cirrhosis, ascites and portal hypertension, but significantly lower prevalence of hypertension and history of cardiovascular disease. Compared to patients with other etiologies, those chronically infected with HCV in the presence or absence of MAFLD and HBV infection, showed significantly higher prevalence of cirrhosis, portal hypertension, ascites, and esophagogastric varices. CONCLUSION: Patients with HCC associated with MAFLD tend to have a background of less severe liver disease than those with HCC of other etiologies, but they may be more likely to suffer metabolic syndrome or comorbidities affecting the heart or kidneys.

Adjuvant Therapy for Hepatocellular Carcinoma After Curative Treatment: Several Unanswered Questions.

Most patients with hepatocellular carcinoma (HCC) have a poor prognosis. Hepatectomy and local ablation are the main curative treatments for HCC. Nevertheless, the recurrence rate after hepatectomy or ablation is up to 70%, which seriously affects patient prognosis. Several adjuvant therapies have been explored to reduce postoperative recurrence. However, although a variety of adjuvant therapies have been shown to reduce the recurrence rate and improve overall survival, a standard consensus of national HCC guidelines for adjuvant treatment is lacking. Therefore, there are significant differences in the recommendations for adjuvant therapy for HCC between the Eastern and Western guidelines. A variety of adjuvant treatment methods, such as antiviral therapy, transarterial chemoembolization or traditional Chinese medicine, are recommended by the Chinese HCC guidelines. However, Western guidelines make few recommendations other than antiviral therapy. Adjuvant immune checkpoint inhibitors are recommended only in the recently updated American Association for the Study of Liver Diseases guidelines. This review summarized the existing adjuvant therapy options after curative hepatectomy or ablation and discusses several important dilemmas of adjuvant treatments.

Adrenomedullin improved endothelial dysfunction via receptor-Akt pathway in rats with obesity-related hypertension.

Obesity-related hypertension (OH) is accompanied by obvious endothelial dysfunction, which contributes to increased peripheral vascular resistance and hypertension. Adrenomedullin (ADM), a multifunctional active peptide, is elevated in obese humans. The OH rats induced by high fat diet (HFD) for 28 weeks and the human umbilical vein endothelial cells (HUVECs)-treated by palmitic acid (PA) were used to investigate the effects of ADM on endothelial dysfunction and the underlying mechanisms. Vascular reactivity was assessed using mesenteric arteriole rings, and the protein expression levels were examined by Western blot analysis. Compared with the control rats, OH rats exhibited hypertension and endothelial dysfunction, along with reduced eNOS protein expression and Akt activation, and increased protein expression of proinflammatory cytokines and ROS levels. Four-week ADM administration improved hypertension and endothelial function, increased eNOS protein expression and Akt activation, and attenuated endothelial inflammation and oxidative stress in OH rats. In vitro experiment, the antagonism of ADM receptors with ADM22-52 and the suppression of Akt signaling with A6730 significantly blocked ADM-caused increase of NO content and activation of eNOS and Akt, and inhibited the anti-inflammatory and anti-oxidant effect of ADM in PA-stimulated HUVECs. These data indicate that endothelial dysfunction in OH rats is partially attributable to the decreased NO level, and the increased inflammation and oxidative stress. ADM improves endothelial function and exerts hypotensive effect depending on the increase of NO, and its anti-inflammatory and anti-oxidant effect via receptor-Akt pathway.

Transcranial alternating current stimulation improves quality of life in Parkinson's disease: study protocol for a randomized, double-blind, controlled trial.

BACKGROUND: The neural cells in the brains of patients with Parkinson's disease (PWP) display aberrant synchronized oscillatory activity within the beta frequency range. Additionally, enhanced gamma oscillations may serve as a compensatory mechanism for motor inhibition mediated by beta activity and also reinstate plasticity in the primary motor cortex affected by Parkinson's disease. Transcranial alternating current stimulation (tACS) can synchronize endogenous oscillations with exogenous rhythms, thereby modulating cortical activity. The objective of this study is to investigate whether the addition of tACS to multidisciplinary intensive rehabilitation treatment (MIRT) can improve symptoms of PWP so as to enhance the quality of life in individuals with Parkinson's disease based on the central-peripheral-central theory. METHODS: The present study was a randomized, double-blind trial that enrolled 60 individuals with Parkinson's disease aged between 45 and 70 years, who had Hoehn-Yahr scale scores ranging from 1 to 3. Participants were randomly assigned in a 1:1 ratio to either the tACS + MIRT group or the sham-tACS + MIRT group. The trial consisted of a two-week double-blind treatment period followed by a 24-week follow-up period, resulting in a total duration of twenty-six weeks. The primary outcome measured the change in PDQ-39 scores from baseline (T0) to 4 weeks (T2), 12 weeks (T3), and 24 weeks (T4) after completion of the intervention. The secondary outcome assessed changes in MDS-UPDRS III scores at T0, the end of intervention (T1), T2, T3, and T4. Additional clinical assessments and mechanistic studies were conducted as tertiary outcomes. DISCUSSION: The objective of this study is to demonstrate that tACS can enhance overall functionality and improve quality of life in PWP, based on the framework of MIRT. Additionally, it seeks to establish a potential correlation between these therapeutic effects and neuroplasticity alterations in relevant brain regions. The efficacy of tACS will be assessed during the follow-up period in order to optimize neuroplasticity and enhance its potential impact on rehabilitation efficiency for PWP. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300071969. Registered on 30 May 2023.

Exploring Female Relatives of Patients with Hemophilia' Awareness, Attitudes, and Understanding Towards Genetic Testing.

Purpose: A better understanding of the factors that influence engagement is needed to provide a reference for conducting genetic testing in female relatives of patients with hemophilia (PWH). We therefore determined the perceptions and understanding of genetic testing among female relatives of PWH in China. Methods: We carried out a qualitative study using in-depth, semi-structured interviews with 11 female relatives of PWH in Shanxi Province, China. The resulting data were analyzed using thematic analyses. Results: This study extracted four topics: uncertainty about carrier genetic status; limited understanding of genetic testing; coexistence of positive and negative coping; and multi-aspect demands. Conclusion: Healthcare professionals should provide personalized and multidimensional health education and comprehensive decision-making support to female relatives of PWH, to enhance their motivation and willingness to undergo genetic testing. It is also important to actively improve relevant policies, strengthen the genetic testing service system, and promote the popularization of genetic testing in female relatives of PWH.

A machine learning approach to differentiate wide QRS tachycardia: distinguishing ventricular tachycardia from supraventricular tachycardia.

BACKGROUND: Differential diagnosis of wide QRS tachycardia (WQCT) has been a challenging issue. Published algorithms to distinguish ventricular tachycardia (VT) and supraventricular tachycardia (SVT) have limited diagnostic capabilities. METHODS: A total of 278 patients with WQCT from January 2010 to March 2022 were enrolled. The electrophysiological study confirmed SVT in 154 patients and VT in 65 ones. Two hundred nineteen WQCT 12-lead ECGs were randomly divided into development cohort (n = 165) and testing cohort (n = 54) data sets. The development cohort was split into a training group (n = 115) and an internal validation group (n = 50). Forty ECG features extracted from the 219 WQCT ECGs are fed into 9 iteratively trained ML algorithms. This novel ML algorithm was also compared with four published algorithms. RESULTS: In the development cohort, the Gradient Boosting Machine (GBM) model displayed the maximum area under curve (AUC) (0.91, 95% confidence interval (CI) 0.81-1.00). In the testing cohort, the GBM model had a higher AUC of 0.97 compared to 4 validated ECG algorithms, namely, Brugada (0.68), avR (0.62), RWPTII (0.72), and LLA algorithms (0.70). Accuracy, sensitivity, specificity, negative predictive value, and positive predictive value of the GBM model were 0.94, 0.97, 0.90, 0.94, and 0.95, respectively. CONCLUSIONS: A GBM ML model contributes to distinguishing SVT from VT based on surface ECG features. In addition, we were able to identify important indicators for distinguishing WQCT.

Single Nucleotide Polymorphisms Mutation of Tropoelastin Gene Affects Tropoelastin mRNA and Elastin Expressions in Human Aortic Smooth Muscle Cells.

We aimed to explore the effects of single nucleotide polymorphisms (SNPs) in tropoelastin gene on tropoelastin mRNA and elastin expressions in human aortic smooth muscle cells (HASMCs). Two SNP loci, rs2071307 (G/A) and rs1785598 (G/C), were selected to construct recombinant lentivirus vectors carrying wild-type and mutant tropoelastin gene. Recombinant plasmids including pWSLV-02-ELN, pWSLV-02-ELN-mut1, and pWSLV-02-ELN-mut2 were constructed, before being amplified by polymerase chain reaction (PCR) and sequenced. The prepared plasmids and the packaging plasmids (pVSV-G and psPAX2) were cotransfected into HEK293T cells to obtain recombinant lentiviruses carrying tropoelastin gene. Afterward, HASMCs were infected with recombinant lentiviruses, and the positive cells sorted by flow cytometry were amplified. Four stable HASMCs cell lines including pWSLV-02-ELN, pWSLV-02-ELN-mut1, pWSLV-02-ELN-mut2, and pWSLV-02 vector were constructed. The expressions of tropoelastin mRNA and elastin in HASMCs were detected by real-time quantitative reverse transcription-PCR and western blot, respectively. Recombinant plasmids including pWSLV-02-ELN-mut1, pWSLV-02-ELN-mut2, and pWSLV-02-ELN were successfully constructed. Recombinant lentiviruses carrying tropoelastin gene were obtained via lentivirus packaging. After infection for 24 h, 3 days and 5 days in HASMCs, tropoelastin mRNA expressions in pWSLV-02-ELN-mut1 and pWSLV-02-ELN-mut2 groups were significantly lower than that of pWSLV-02-ELN group. Besides, after infection for 24 h, 3 days, and 5 days, elastin levels in pWSLV-02-ELN-mut1 and pWSLV-02-ELN-mut2 groups were significantly lower than that in pWSLV-02-ELN group. In conclusion, SNPs mutation of tropoelastin gene affected the expression of tropoelastin mRNA and elastin, suggesting that the polymorphisms of rs2071307 and rs17855988 in tropoelastin gene might be important factors for AD development.

Cingulate cGMP-dependent protein kinase I facilitates chronic pain and pain-related anxiety and depression.

ABSTRACT: Patients with chronic pain often experience exaggerated pain response and aversive emotion, such as anxiety and depression. Central plasticity in the anterior cingulate cortex (ACC) is assumed to be a critical interface for pain perception and emotion, which has been reported to involve activation of NMDA receptors. Numerous studies have documented the key significance of cGMP-dependent protein kinase I (PKG-I) as a crucial downstream target for the NMDA receptor-NO-cGMP signaling cascade in regulating neuronal plasticity and pain hypersensitivity in specific regions of pain pathway, ie, dorsal root ganglion or spinal dorsal horn. Despite this, whether and how PKG-I in the ACC contributes to cingulate plasticity and comorbidity of chronic pain and aversive emotion has remained elusive. Here, we uncovered a crucial role of cingulate PKG-I in chronic pain and comorbid anxiety and depression. Chronic pain caused by tissue inflammation or nerve injury led to upregulation of PKG-I expression at both mRNA and protein levels in the ACC. Knockdown of ACC-PKG-I relieved pain hypersensitivity as well as pain-associated anxiety and depression. Further mechanistic analysis revealed that PKG-I might act to phosphorylate TRPC3 and TRPC6, leading to enhancement of calcium influx and neuronal hyperexcitability as well as synaptic potentiation, which results in the exaggerated pain response and comorbid anxiety and depression. We believe this study sheds new light on the functional capability of ACC-PKG-I in modulating chronic pain as well as pain-associated anxiety and depression. Hence, cingulate PKG-I may represent a new therapeutic target against chronic pain and pain-related anxiety and depression.

JMJD6 protects against isoproterenol-induced cardiac hypertrophy via inhibition of NF-κB activation by demethylating R149 of the p65 subunit.

Histone modification plays an important role in pathological cardiac hypertrophy and heart failure. In this study we investigated the role of a histone arginine demethylase, Jumonji C domain-containing protein 6 (JMJD6) in pathological cardiac hypertrophy. Cardiac hypertrophy was induced in rats by subcutaneous injection of isoproterenol (ISO, 1.2 mg·kg-1·d-1) for a week. At the end of the experiment, the rats underwent echocardiography, followed by euthanasia and heart collection. We found that JMJD6 levels were compensatorily increased in ISO-induced hypertrophic cardiac tissues, but reduced in patients with heart failure with reduced ejection fraction (HFrEF). Furthermore, we demonstrated that JMJD6 overexpression significantly attenuated ISO-induced hypertrophy in neonatal rat cardiomyocytes (NRCMs) evidenced by the decreased cardiomyocyte surface area and hypertrophic genes expression. Cardiac-specific JMJD6 overexpression in rats protected the hearts against ISO-induced cardiac hypertrophy and fibrosis, and rescued cardiac function. Conversely, depletion of JMJD6 by single-guide RNA (sgRNA) exacerbated ISO-induced hypertrophic responses in NRCMs. We revealed that JMJD6 interacted with NF-κB p65 in cytoplasm and reduced nuclear levels of p65 under hypertrophic stimulation in vivo and in vitro. Mechanistically, JMJD6 bound to p65 and demethylated p65 at the R149 residue to inhibit the nuclear translocation of p65, thus inactivating NF-κB signaling and protecting against pathological cardiac hypertrophy. In addition, we found that JMJD6 demethylated histone H3R8, which might be a new histone substrate of JMJD6. These results suggest that JMJD6 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.

Structural insights into the substrate binding sites of O-carbamoyltransferase VtdB from Streptomyces sp. NO1W98.

The O-carbamoyltransferase VtdB catalyzes the carbamoylation of venturicidin B, which is essential for the biosynthesis of the antibiotic venturicidin A. Here, the crystal structures of VtdB and VtdB in complex with the intermediate carbamoyladenylate (VtdBCAO) were determined at resolutions of 2.99 Å and 2.90 Å, respectively. The structures resemble the conserved YrdC-like and specific Kae1-like domains. A magnesium ion and the intermediate carbamoyladenylate were also observed in the Kae1-like domain of VtdB. The structure of VtdBCAO in complex with the substrate venturicidin B was modeled by a molecular docking method to better understand the substrate binding mode, revealing a novel venturicidin B binding pocket.

Shared Decision-Making in Hemophilic Arthropathy Rehabilitation: A Qualitative Study.

Purpose: To probe into the needs and barriers underlying patients' participation in shared decision-making related to rehabilitation nursing for hemophilic arthropathy. Patients and Methods: The phenomenological research approach was adopted to conduct a series of semi-structured, in-depth interviews with 15 patients with hemophilic arthropathy undergoing rehabilitative treatments, 10 caregivers, and 7 healthcare providers from a hemophilia treatment center in Shanxi province, China. Colaizzi's seven-step method of data analysis was applied to organize, analyze, and extract the themes from the interview materials. Results: Three main themes emerged from the analysis: the status quo of the healthcare system (insufficient decision support systems and mismatch between healthcare providers' and patients' resources), circumstances of provider-patient interactions (lack of information exchange and unbalanced power structure between healthcare providers and patients), and patient-related factors influencing participation in decision-making (lack of self-efficacy, personal characteristics, family and social decision support, and attitude toward participation in decision-making). Conclusion: Participation in rehabilitation decision-making among patients with hemophilic arthropathy is affected by multiple barriers. Healthcare professionals should improve their understanding of shared decision-making, offer patients active guidance on participating in the decision-making process, prioritize their affective needs, and formulate professional and effective solutions to support shared decision-making as early as possible.

A case of congenital left ventricular diverticulum in an adult patient.

Congenital left ventricular diverticulum (CL.koVD) refers to a localized cystic protrusion of the ventricular wall that interacts with the heart cavities through a narrow channel and is a rare heart malformation. In recent years, many cases of this disease involving infants and children have been reported, while few cases involving adults have been described. The case of an adult with CLVD who underwent successful surgery was retrospectively evaluated. The echocardiography examination indicated that the apical myocardium of the left ventricle was thin and bulging outward and that the contractile movement was significantly reduced. During the surgery, it was observed that the left ventricle was enlarged, and a left ventricular diverticulum structure was observed on the left side of the apex. A bovine pericardial patch of the corresponding size was used to continuously suture and repair the internal orifice of the diverticulum. The postoperative pathology revealed that the resected sample was composed of full myocardial tissue. This report focused on the imaging characteristics of left ventricular diverticula to improve the understanding of CLVD. With its simple, economical, and noninvasive characteristics, echocardiography presents the best option for diagnosing a ventricular diverticulum.

Knowledge of Chinese Pediatric Professionals Regarding Pediatric Pain Management.

Many healthcare professionals base their perceptions of pediatric pain on their knowledge of the subject. Therefore, knowledge deficits in this area may yield negative attitudes toward pain management and add to the complexity of pain management in hospitalized children. This study evaluated the knowledge of pediatric clinicians in China regarding pediatric pain management. Adopting a cross-sectional descriptive comparative design, we surveyed pediatric clinicians using a structured questionnaire. Inclusive criteria were pediatric clinicians, both pediatricians and nurses, with professional pediatric experience of over one year. A total of 507 pediatric clinicians participated. Most were aware of the importance of pain management in sick children but misunderstood pediatric pain, lacked knowledge for performing pediatric pain assessments and lacked knowledge for providing pain relief interventions. Background factors including differing professions (pediatricians and nurses; p = 0.012), age (p < 0.05) and hospital setting of employment (p = 0.003) were significantly related to clinicians' knowledge regarding pain management. Participating pediatricians had higher levels of knowledge of pediatric pain management than nurses. Research revealed four barriers affecting clinicians' knowledge, including misconception of pain in children, lack of professional knowledge and confidence in the practice of pediatric pain assessment, lack of professional knowledge to provide pain relief interventions, and a significant knowledge gap between pediatricians and nurses. The results point out a crucial need for multidisciplinary education to remedy these deficiencies. Further study is needed to explore strategies to strengthen clinicians' knowledge of this vital area of practice.

CRISPR FISHer enables high-sensitivity imaging of nonrepetitive DNA in living cells through phase separation-mediated signal amplification.

The dynamic three-dimensional structures of chromatin and extrachromosomal DNA molecules regulate fundamental cellular processes and beyond. However, the visualization of specific DNA sequences in live cells, especially nonrepetitive sequences accounting for most of the genome, is still vastly challenging. Here, we introduce a robust CRISPR-mediated fluorescence in situ hybridization amplifier (CRISPR FISHer) system, which exploits engineered sgRNA and protein trimerization domain-mediated, phase separation-based exponential assembly of fluorescent proteins in the CRISPR-targeting locus, conferring enhancements in both local brightness and signal-to-background ratio and thus achieving single sgRNA-directed visualization of native nonrepetitive DNA loci in live cells. In one application, by labeling and tracking the broken ends of chromosomal fragments, CRISPR FISHer enables real-time visualization of the entire process of chromosome breakage, separation, and subsequent intra- or inter-chromosomal ends rejoining in a single live cell. Furthermore, CRISPR FISHer allows the movement of small extrachromosomal circular DNAs (eccDNAs) and invading DNAs to be recorded, revealing substantial differences in dynamic behaviors between chromosomal and extrachromosomal loci. With the potential to track any specified self or non-self DNA sequences, CRISPR FISHer dramatically broadens the scope of live-cell imaging in biological events and for biomedical diagnoses.

A New Discovery of Unique 13-(Benzimidazolylmethyl)berberines as Promising Broad-Spectrum Antibacterial Agents.

A new hybridization of berberine and benzimidazoles was performed to produce 13-(benzimidazolylmethyl)berberines (BMB) as potentially broad-spectrum antibacterial agents with the hope of confronting multidrug-resistant bacterial infections in the livestock industry. Some of the newly prepared hybrids showed obvious antibacterial effects against tested strains. Particularly, 13-((1-octyl-benzimidazolyl)methyl)berberine 6f (OBMB-6f) was found to be the most promising compound that not only exerted a strong activity (MIC = 0.25-2 µg/mL) and low cytotoxicity but also possessed a fast bactericidal capacity and low propensity to develop resistance toward Staphylococcus aureus and Escherichia coli even after 26 serial passages. Moreover, OBMB-6f displayed the ability to prevent bacterial biofilm formation at low and high temperatures. The mechanistic exploration revealed that OBMB-6f could significantly disintegrate bacterial membranes, markedly facilitate intracellular ROS generation, and efficiently intercalate into DNA. These results provided a profound insight into BMB against multidrug-resistant bacterial infections in the livestock industry.

GDH promotes isoprenaline-induced cardiac hypertrophy by activating mTOR signaling via elevation of α-ketoglutarate level.

Numerous studies reveal that metabolism dysfunction contributes to the development of pathological cardiac hypertrophy. While the abnormal lipid and glucose utilization in cardiomyocytes responding to hypertrophic stimuli have been extensively studied, the alteration and implication of glutaminolysis are rarely discussed. In the present work, we provide the first evidence that glutamate dehydrogenase (GDH), an enzyme that catalyzes conversion of glutamate into ɑ-ketoglutarate (AKG), participates in isoprenaline (ISO)-induced cardiac hypertrophy through activating mammalian target of rapamycin (mTOR) signaling. The expression and activity of GDH were enhanced in cultured cardiomyocytes and rat hearts following ISO treatment. Overexpression of GDH, but not its enzymatically inactive mutant, provoked cardiac hypertrophy. In contrast, GDH knockdown could relieve ISO-triggered hypertrophic responses. The intracellular AKG level was elevated by ISO or GDH overexpression, which led to increased phosphorylation of mTOR and downstream effector ribosomal protein S6 kinase (S6K). Exogenous supplement of AKG also resulted in mTOR activation and cardiomyocyte hypertrophy. However, incubation with rapamycin, an mTOR inhibitor, attenuated hypertrophic responses in cardiomyocytes. Furthermore, GDH silencing protected rats from ISO-induced cardiac hypertrophy. These findings give a further insight into the role of GDH in cardiac hypertrophy and suggest it as a potential target for hypertrophy-related cardiomyopathy.

CircHIPK3 Regulates Vascular Smooth Muscle Cell Calcification Via the miR-106a-5p/MFN2 Axis.

Atherosclerosis is the most common arterial disease and is closely related to vascular calcification. CircHIPK3 has been implicated in atherosclerosis development, but the possible downstream regulatory mechanisms remain unclear. The levels of circHIPK3, miR-106a and MFN2 in tissues and blood samples of patients with atherosclerosis were detected by RT-qPCR. The levels of circHIPK3, miR-106a and MFN2 were detected by RT-qPCR and the expression levels of MFN2, osteogenic and cartilage differentiation marker proteins were detected by western blot in vitro. ALP staining, Alizarin Red staining, and calcium content detection evaluated the degree of osteogenic differentiation of cells. Alcian blue staining detected the level of cell cartilage differentiation. Luciferase detected the targeting relationship between circHIPK3 and miR-106a-5p, as well as miR-106a-5p and MFN2. CircHIPK3 and MFN2 were low expressed and miR-106a-5p was highly expressed in tissues and blood samples of patients with atherosclerosis, as well as vascular smooth muscle cell (VSMC) with osteogenic and cartilage differentiation. Overexpression of circHIPK3 reduced the cell mineralization and calcium content. Overexpression of circHIPK3 inhibited osteogenic differentiation by decreasing ALP activity, RUNX2, and OPG expression, and increasing SM22α and SMA level. What's more, overexpression of circHIPK3 decreased the chondrogenic differentiation by inhibiting the protein level of SOX9, aggrecan, and collagen II. CircHIPK3 targeted miR-106a-5p and miR-106a-5p targeted MFN2. MiR-106a-5p overexpression or MFN2 depletion repressed the effect of circHIPK3 overexpression on VSMC calcification. CircHIPK3 regulated osteogenic and cartilage differentiation of VSMC via miR-106a-5p/MFN2 axis, indicating a target for treating vascular calcification.

Identification of potential target endoribonuclease NSP15 inhibitors of SARS-COV-2 from natural products through high-throughput virtual screening and molecular dynamics simulation.

SARS-CoV-2 wreaks havoc around the world, triggering the COVID-19 pandemic. It has been confirmed that the endoribonuclease NSP15 is crucial to the viral replication, and thus identified as a potential drug target against COVID-19. The NSP15 protein was used as the target to conduct high-throughput virtual screening on 30,926 natural products from the NPASS database to identify potential NSP15 inhibitors. And 100 ns molecular dynamics simulations were performed on the NSP15 and NSP15-NPC198199 system. In all, 10 natural products with high docking scores with NSP15 protein were obtained, among which compound NPC198199 scored the highest. The analysis of the binding mode between NPC198199 and NSP15 found that NPC198199 would form H-bond interactions with multiple key residues at the catalytic site. Subsequently, a series of post-dynamics simulation analyses (including RMSD, RMSF, PCA, DCCM, RIN, binding free energy, and H-bond occupancy) were performed to further explore inhibitory mechanism of compound NPC198199 on NSP15 protein at the molecular level. The research strongly indicates that the 10 natural compounds screened can be used as potential inhibitors of NSP15, and provides valuable information for the subsequent drug discovery of anti-SARS-CoV-2. PRACTICAL APPLICATIONS: Natural products play an important role in the treatment of many difficult diseases. In this study, high-throughput virtual screening technology was used to screen the natural product database to obtain potential inhibitors against endoribonuclease NSP15. The binding mechanism between natural products and NSP15 was investigated at the molecular level by molecular dynamics technology so that it is expected to become candidate drugs for the treatment of SARS-CoV-2. We hope that our research can provide new clue to combat COVID-19 and overcome the epidemic situation as soon as possible.

Barriers to and Facilitators of Neonatal Palliative Care Among Neonatal Professionals in China.

OBJECTIVES: This study investigated institutional and personal barriers to and facilitators of neonatal palliative care facing neonatal professionals in China. METHODS: A cross-sectional questionnaire surveyed 231 neonatal clinicians employed in 5 neonatal intensive care units from 2 children's hospitals and 3 medical centers in China. MEASUREMENTS: The translated modified version of the Neonatal Palliative Care Attitude Scale was used to survey neonatal clinicians' attitudes and beliefs regarding neonatal palliative care. RESULTS: Findings highlight 4 facilitators and 5 barriers among participating clinicians. Participants gave contradictory responses regarding the relative importance of curative treatment versus palliative care in the NICU. Negatively traumatic feelings, cultural issues and moral distress may impact this contradictory response and discourage clinicians from providing neonatal palliative care. Additionally, neonatologists and nurses held differing attitudes on several topics (p < 0.05). CONCLUSION: Further research should address strategies to improve knowledge and attitudes and relieve moral distress in NICU clinicians. Neonatal clinicians providing neonatal palliative care should receive regular palliative care training addressing culture-specific issues and communication skills. PRACTICE IMPLICATIONS: Study findings will be beneficial to inform clinical education and practice. Regular interdisciplinary team training is needed to enhance support for palliative care and decrease clinicians' moral distress during end-of-life care.