Development of a co-culture system for green production of caffeic acid from sugarcane bagasse hydrolysate.

Caffeic acid (CA) is a phenolic acid compound widely used in pharmaceutical and food applications. However, the efficient synthesis of CA is usually limited by the resources of individual microbial platforms. Here, a cross-kingdom microbial consortium was developed to synthesize CA from sugarcane bagasse hydrolysate using Escherichia coli and Candida glycerinogenes as chassis. In the upstream E. coli module, shikimate accumulation was improved by intensifying the shikimate synthesis pathway and blocking shikimate metabolism to provide precursors for the downstream CA synthesis module. In the downstream C. glycerinogenes module, conversion of p-coumaric acid to CA was improved by increasing the supply of the cytoplasmic cofactor FAD(H2). Further, overexpression of ABC transporter-related genes promoted efflux of CA and enhanced strain resistance to CA, significantly increasing CA titer from 103.8 mg/L to 346.5 mg/L. Subsequently, optimization of the inoculation ratio of strains SA-Ec4 and CA-Cg27 in this cross-kingdom microbial consortium resulted in an increase in CA titer to 871.9 mg/L, which was 151.6% higher compared to the monoculture strain CA-Cg27. Ultimately, 2311.6 and 1943.2 mg/L of CA were obtained by optimization of the co-culture system in a 5 L bioreactor using mixed sugar and sugarcane bagasse hydrolysate, respectively, with 17.2-fold and 14.6-fold enhancement compared to the starting strain. The cross-kingdom microbial consortium developed in this study provides a reference for the production of other aromatic compounds from inexpensive raw materials.

Spatiotemporal Regulation and Transport Engineering for Sustainable Production of Geraniol in Candida glycerinogenes.

Geraniol is an attractive natural monoterpene with significant industrial and commercial value in the fields of pharmaceuticals, condiments, cosmetics, and bioenergy. The biosynthesis of monoterpenes suffers from the availability of key intermediates and enzyme-to-substrate accessibility. Here, we addressed these challenges in Candida glycerinogenes by a plasma membrane-anchoring strategy and achieved sustainable biosynthesis of geraniol using bagasse hydrolysate as substrate. On this basis, a remarkable 2.4-fold improvement in geraniol titer was achieved by combining spatial and temporal modulation strategies. In addition, enhanced geraniol transport and modulation of membrane lipid-associated metabolism effectively promoted the exocytosis of toxic monoterpenes, significantly improved the resistance of the engineered strain to monoterpenes and improved the growth of the strains, resulting in geraniol yield up to 1207.4 mg L-1 at shake flask level. Finally, 1835.2 mg L-1 geraniol was obtained in a 5 L bioreactor using undetoxified bagasse hydrolysate. Overall, our study has provided valuable insights into the plasma membrane engineering of C. glycerinogenes for the sustainable and green production of valuable compounds.

Cross-linked α-Ni(OH)2 nanosheets with a Ni3+-rich structure for accelerating electrochemical oxidation of 5-hydroxymethylfurfural.

Electrochemical oxidation of biomass-based 5-hydroxymethylfurfural (HMF) is an effective approach for achieving the high-value products of 2,5-furandicarboxylic acid (FDCA). However, the restricted formation of high-valence metal active species for electrocatalysts results in a sluggish kinetic process of HMF oxidation reaction (HMFOR). Herein, we fabricated the Ni3+-rich cross-linked α-Ni(OH)2 nanosheets for accelerating the HMFOR through an anion-mediated strategy. It is identified that the Cl- ions with strong penetrability replace a portion of lattice oxygen atoms in α-Ni(OH)2 to form Ni-Cl bonds, contributing to breaking the inherent lattice order and generating a special Ni3+-rich structure. Owing to the promoted adsorption and accelerated oxidation of hydroxyl and aldehyde groups by the affluent Ni3+ active species, the large oxidation current density of 116.5 mA cm-2 and HMFOR kinetic constant of 0.067 min-1 has been achieved at 1.45 V (vs. RHE). By analyzing the oxidation products, the FDCA yield and Faradic efficiency are both higher than 99.25 % and 99.36 % for five successive determinations. Therefore, this work provides an insightful anion-mediated strategy for designing high-performance electrocatalysts for biomass conversion application.

Effect of the index of cardiac electrophysiological balance on major adverse cardiovascular events in patients with diabetes complicated with coronary heart disease.

Purpose: To investigate the prognostic value of the index of cardio-electrophysiological balance (ICEB) and its association with major adverse cardiac events (MACE) and cardiovascular death in diabetic patients complicated with coronary heart disease. Methods: A total of 920 diabetic patients were enrolled in this longitudinal study. Participants were categorized into three groups based on their ICEB levels: normal ICEB, low ICEB, and high ICEB. The primary outcome was the occurrence of MACE, and secondary outcomes included cardiovascular death, coronary heart disease (CHD), heart failure (HF), and sudden cardiac arrest (SCA). Patients were followed for a median period of 3.26 years, and the associations between ICEB levels and various outcomes were evaluated. Results: Over the follow-up period, 46 (5.0%) MACE were observed in the normal ICEB group, 57 (6.2%) in the low ICEB group, and 62 (6.8%) in the high ICEB group. Elevated ICEB levels were found to be associated with a higher risk of MACE and cardiovascular death. A significant relationship between ICEB levels and the risk of MACE was observed for both genders. The risk of MACE increased with each unit increment in the ICEB index. However, the two-stage linear regression model did not outperform the single-line linear regression models in determining the threshold effect. Conclusion: This study demonstrates the potential utility of ICEB, derived from a standard non-invasive ECG, as a prognostic tool for predicting MACE and cardiovascular death in diabetic patients complicated with CVD. The associations between ICEB levels and the risk of MACE highlight the importance of understanding cardiac electrophysiological imbalances and their implications in CVD.

Metabolic Engineering of Candida glycerinogenes for Sustainable Production of Geraniol.

Geraniol is a class of natural products that are widely used in the aroma industry due to their unique aroma. Here, to achieve the synthesis of geraniol and alleviate the intense competition from the yeast ergosterol pathway, a transcription factor-mediated ergosterol feedback system was developed in this study to autonomously regulate ergosterol metabolism and redirect carbon flux to geraniol synthesis. In addition, the modification of ergosterol-responsive promoters, the optimization of transcription factor expression intensity, and stepwise metabolic engineering resulted in a geraniol titer of 531.7 mg L-1. For sustainable production of geraniol, we constructed a xylose assimilation pathway in Candida glycerinogenes (C. glycerinogenes). Then, the xylose metabolic capacity was ameliorated and the growth of the engineered strain was rescued by activating the pentose phosphate (PP) pathway. Finally, we obtained 1091.6, 862.4, and 921.8 mg L-1 of geraniol in a 5 L bioreactor by using pure glucose, simulated wheat straw hydrolysates, and simulated sugarcane bagasse hydrolysates, with yields of 47.5, 57.9, and 59.1 mg g-1 DCW, respectively. Our study demonstrated that C. glycerinogenes has the potential to produce geraniol from lignocellulosic biomass, providing a powerful tool for the sustainable synthesis of other valuable monoterpenes.

Balancing Pyruvate Node Based on a Dual-Layered Dynamic Regulation System to Improve the Biosynthesis of Caffeic Acid in Candida glycerinogenes.

Caffeic acid is a phenolic acid compound widely applied in the food and pharmaceutical fields. Currently, one of the reasons for the low yield of caffeic acid biosynthesis is that the carbon flow enters mainly into the TCA cycle via pyruvate, which leads to low concentrations of erythrose 4-phosphate (E4P) and phosphoenolpyruvate (PEP), the precursors of caffeic acid synthesis. Here, we developed a growth-coupled dual-layered dynamic regulation system. This system controls intracellular pyruvate supply in real time by responding to intracellular pyruvate and p-coumaric acid concentrations, autonomously coordinates pathway gene expression, and redirects carbon metabolism to balance cell growth and caffeic acid synthesis. Finally, our constructed engineered strain based on the dual-layered dynamic regulation system achieved a caffeic acid titer of 559.7 mg/L in a 5 L bioreactor. Thus, this study demonstrated the efficiency and potential of this system in boosting the yield of aromatic compounds.

BNP protects against diabetic cardiomyopathy by promoting Opa1-mediated mitochondrial fusion via activating the PKG-STAT3 pathway.

Brain natriuretic peptide (BNP) belongs to the family of natriuretic peptides, which are responsible for a wide range of actions. Diabetic cardiomyopathy (DCM) is often associated with increased BNP levels. This present research intends to explore the role of BNP in the development of DCM and the underlying mechanisms. Diabetes was induced in mice using streptozotocin (STZ). Primary neonatal cardiomyocytes were treated with high glucose. It was found that the levels of plasma BNP started to increase at 8 weeks after diabetes, which preceded the development of DCM. Addition of exogenous BNP promoted Opa1-mediated mitochondrial fusion, inhibited mitochondrial oxidative stress, preserved mitochondrial respiratory capacity and prevented the development of DCM, while knockdown of endogenous BNP exacerbated mitochondrial dysfunction and accelerated DCM. Opa1 knockdown attenuated the aforementioned protective action of BNP both in vivo and in vitro. BNP-induced mitochondrial fusion requires the activation of STAT3, which facilitated Opa1 transcription by binding to its promoter regions. PKG, a crucial signaling biomolecule in the BNP signaling pathway, interacted with STAT3 and induced its activation. Knockdown of NPRA (the receptor of BNP) or PKG blunted the promoting effect of BNP on STAT3 phosphorylation and Opa1-mediated mitochondrial fusion. The results of this study demonstrate for the first time that there is a rise in BNP during the early stages of DCM as a compensatory protection mechanism. BNP is a novel mitochondrial fusion activator in protecting against hyperglycemia-induced mitochondrial oxidative injury and DCM through the activation of NPRA-PKG-STAT3-Opa1 signaling pathway.

The landscape of N6-methyladenosine modification patterns and altered transcript profiles in the cardiac-specific deletion of natriuretic peptide receptor A.

The atrial natriuretic peptide (ANP) and the brain natriuretic peptide (BNP) are critical biological makers and regulators of cardiac functions. Our previous results show that NPRA (natriuretic peptide receptor A)-deficient mice have distinct metabolic patterns and expression profiles compared with the control. Still, the molecular mechanism that could account for this observation remains to be elucidated. Here, methylation alterations were detected by mazF-digestion, and differentially expressed genes of transcriptomes were detected by a Genome Oligo Microarray using the myocardium from NPRA-deficient (NPRA-/-) mice and wild-type (NPRA+/+) mice as the control. Comprehensive analysis of m6A methylation data gave an altered landscape of m6A modification patterns and altered transcript profiles in cardiac-specific NPRA-deficient mice. The m6A "reader" igf2bp3 showed a clear trend of increase, suggesting a function in altered methylation and expression in cardiac-specific NPRA-deficient mice. Intriguingly, differentially m6A-methylated genes were enriched in the metabolic process and insulin resistance pathway, suggesting a regulatory role in cardiac metabolism of m6A modification regulated by NPRA. Notably, it was confirmed that the pyruvate dehydrogenase kinase 4 (Pdk4) gene upregulated the gene expression and the hypermethylation level simultaneously, which may be the key factor for the cardiac metabolic imbalance and insulin resistance caused by natriuretic peptide signal resistance. Taken together, cardiac metabolism might be regulated by natriuretic peptide signaling, with decreased m6A methylation and a decrease of Pdk4.

Tuning Geraniol Biosynthesis via a Novel Decane-Responsive Promoter in Candida glycerinogenes.

Geraniol is a rose-scented monoterpene with significant commercial and industrial value in medicine, condiments, cosmetics, and bioenergy. Here, we first targeted geraniol as a reporter metabolite and explored the suitability and potential of Candida glycerinogenes as a heterologous host for monoterpenoid production. Subsequently, dual-pathway engineering was employed to improve the production of geraniol with a geraniol titer of 858.4 mg/L. We then applied a synthetic hybrid promoter approach to develop a decane-responsive hybrid promoter based on the native promoter PGAP derived from C. glycerinogenes itself. The hybrid promoter was able to be induced by n-decane with 3.6 times higher transcriptional intensity than the natural promoter PGAP. In particular, the hybrid promoter effectively reduces the conflict between cell growth and product formation in the production of geraniol. Ultimately, 1194.6 mg/L geraniol was obtained at the shake flask level. The strong and tunable decane-responsive hybrid promoter developed in this study provides an important tool for fine regulation of toxic terpenoid production in cells.

Production of Caffeic Acid with Co-fermentation of Xylose and Glucose by Multi-modular Engineering in Candida glycerinogenes.

Caffeic acid (CA), a natural phenolic compound, has important medicinal value and market potential. In this study, we report a metabolic engineering strategy for the biosynthesis of CA in Candida glycerinogenes using xylose and glucose. The availability of precursors was increased by optimization of the shikimate (SA) pathway and the aromatic amino acid pathway. Subsequently, the carbon flux into the SA pathway was maximized by introducing a xylose metabolic pathway and optimizing the xylose assimilation pathway. Eventually, a high yielding strain CG19 was obtained, which reached a yield of 4.61 mg/g CA from mixed sugar, which was 1.2-fold higher than that of glucose. The CA titer in the 5 L bioreactor reached 431.45 mg/L with a yield of 8.63 mg/g of mixed sugar. These promising results demonstrate the great advantages of mixed sugar over glucose for high-yield production of CA. This is the first report to produce CA in C. glycerinogenes with xylose and glucose as carbon sources, which developed a promising strategy for the efficient production of high-value aromatic compounds.

Knockdown of hypoxia-inducible factor 1-alpha (HIF1α) interferes with angiopoietin-like protein 2 (ANGPTL2) to attenuate high glucose-triggered hypoxia/reoxygenation injury in cardiomyocytes.

To investigate the role of hypoxia-inducible factor 1-alpha (HIF1A) in hypoxia/reoxygenation (H/R) injury of cardiomyocytes induced by high glucose (HG). The in vitro model of coronary heart disease with diabetes was that H9c2 cells were stimulated by H/R and HG. Quantitative reverse transcription PCR (RT-qPCR) and Western blot analysis were used to detect the expression of HIF1A and angiopoietin-like protein 2 (ANGPTL2) in H9c2 cells. Cell viability and apoptosis were, respectively, estimated by Cell Counting Kit 8 (CCK-8) and TUNEL assays. Lactate dehydrogenase (LDH) activity, inflammation and oxidative stress were in turn detected by their commercial assay kits. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to confirm the association between HIF1A and ANGPTL2 promoter. The expression of nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway-related proteins and apoptosis-related proteins were also detected by Western blot analysis. As a result, ANGPTL2 expression was upregulated in H9c2 cells induced by HG or/and H/R. ANGPTL2 positively modulated HIF1A expression in H9c2 cells. HG or/and H/R suppressed the cell viability and promoted apoptosis, inflammatory response and oxidative stress levels in H9c2 cells. However, the knockdown of ANGPTL2 could reverse the above phenomena in H/R-stimulated-H9c2 cells through activation of Nrf2/HO-1 pathway. HIF1A transcriptionally activated ANGPTL2 expression. The effect of knockdown of ANGPTL2 on H/R triggered-H9c2 cells was weakened by HIF1A overexpression. In conclusion, knockdown of HIF1A downregulated ANGPTL2 to alleviate H/R injury in HG-induced H9c2 cells by activating the Nrf2/HO-1 pathway.

Facile Assembly of Thermosensitive Liposomes for Active Targeting Imaging and Synergetic Chemo-/Magnetic Hyperthermia Therapy.

Cancer stem cells (CSCs) are thought to be responsible for the recurrence of liver cancer, highlighting the urgent need for the development of effective treatment regimens. In this study, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and thermosensitive magnetoliposomes (TMs) conjugated to anti-CD90 (CD90@17-AAG/TMs) were developed for temperature-responsive CD90-targeted synergetic chemo-/magnetic hyperthermia therapy and simultaneous imaging in vivo. The targeting ability of CD90@DiR/TMs was studied with near-infrared (NIR) resonance imaging and magnetic resonance imaging (MRI), and the antitumor effect of CD90@17-AAG/TM-mediated magnetic thermotherapy was evaluated in vivo. After treatment, the tumors were analyzed with Western blotting, hematoxylin and eosin staining, and immunohistochemical (IHC) staining. The relative intensity of fluorescence was approximately twofold higher in the targeted group than in the non-targeted group, while the T 2 relaxation time was significantly lower in the targeted group than in the non-targeted group. The combined treatment of chemotherapy, thermotherapy, and targeting therapy exhibited the most significant antitumor effect as compared to any of the treatments alone. The anti-CD90 monoclonal antibody (mAb)-targeted delivery system, CD90@17-AAG/TMs, exhibited powerful targeting and antitumor efficacies against CD90+ liver cancer stem cells in vivo.

Understanding the lived experiences of medical learners in a narrative medicine course: a phenomenological study.

BACKGROUND: Reflection and various approaches to foster reflection have been regarded as an indispensable element in enhancing professional practice across different disciplines. With its inherent potential to engage learners in reflection and improvement, narrative medicine has been adopted in various settings. However, the relevance and effectiveness of reflection remains underexplored in the context of narrative medicine, specifically in regard to the concern about variability of learner acceptance and the way learners really make sense of these reflective activities. This study aimed to explore what medical learners experience through narrative medicine and the meanings they ascribe to the phenomenon of this narrative-based learning. METHODS: Using a transcendental phenomenology approach, twenty medical learners were interviewed about their lived experiences of taking a narrative medicine course during their internal medicine clerkship rotation. Moustakas' phenomenological analysis procedures were applied to review the interview data. RESULTS: Six themes were identified: feeling hesitation, seeking guidance, shifting roles in narratives, questioning relationships, experiencing transformation, and requesting a safe learning environment. These themes shaped the essence of the phenomenon and illustrated what and how medical learners set out on a reflective journey in narrative medicine. These findings elucidate fundamental elements for educators to consider how narrative approaches can be effectively used to engage learners in reflective learning and practice. CONCLUSION: Adopting Moustakas' transcendental phenomenology approach, a better understanding about the lived experiences of medical learners regarding learning in narrative medicine was identified. Learner hesitancy should be tackled with care by educators so as to support learners with strategies that address guidance, relationship, and learning environment. In so doing, medical learners can be facilitated to develop reflective capabilities for professional and personal growth.

Chitosan oligosaccharide decorated liposomes combined with TH302 for photodynamic therapy in triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive tumor with extremely high mortality that results from its lack of effective therapeutic targets. As an adhesion molecule related to tumorigenesis and tumor metastasis, cluster of differentiation-44 (also known as CD44) is overexpressed in TNBC. Moreover, CD44 can be effectively targeted by a specific hyaluronic acid analog, namely, chitosan oligosaccharide (CO). In this study, a CO-coated liposome was designed, with Photochlor (HPPH) as the 660 nm light mediated photosensitizer and evofosfamide (also known as TH302) as the hypoxia-activated prodrug. The obtained liposomes can help diagnose TNBC by fluorescence imaging and produce antitumor therapy by synergetic photodynamic therapy (PDT) and chemotherapy. RESULTS: Compared with the nontargeted liposomes, the targeted liposomes exhibited good biocompatibility and targeting capability in vitro; in vivo, the targeted liposomes exhibited much better fluorescence imaging capability. Additionally, liposomes loaded with HPPH and TH302 showed significantly better antitumor effects than the other monotherapy groups both in vitro and in vivo. CONCLUSION: The impressive synergistic antitumor effects, together with the superior fluorescence imaging capability, good biocompatibility and minor side effects confers the liposomes with potential for future translational research in the diagnosis and CD44-overexpressing cancer therapy, especially TNBC.

Integrative Proteomic and Metabolomic Analysis Reveals Metabolic Phenotype in Mice With Cardiac-Specific Deletion of Natriuretic Peptide Receptor A.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are important biological markers and cardiac function regulators. Natriuretic peptide receptor A (NPRA) binds to an ANP or BNP ligand and induces transmembrane signal transduction by elevating the intracellular cyclic guanosine monophosphate (cGMP) levels. However, the metabolic phenotype and related mechanisms induced by NPRA deletion remain ambiguous. Here, we constructed myocardial-specific NPRA deletion mice and detected the heart functional and morphological characteristics by histological analysis and explored the altered metabolic pattern and the expression patterns of proteins by liquid chromatography-mass spectrometry (LC-MS)-based omics technology. NPRA deficiency unexpectedly did not result in significant cardiac remodeling or dysfunction. However, compared with the matched littermates, NPRA-deficient mice had significant metabolic differences. Metabolomic analysis showed that the metabolite levels varied in cardiac tissues and plasma. In total, 33 metabolites were identified in cardiac tissues and 54 were identified in plasma. Compared with control mice, NPRA-deficient mice had 20 upregulated and six downregulated metabolites in cardiac tissues and 25 upregulated and 23 downregulated metabolites in plasma. Together, NPRA deficiency resulted in increased nucleotide biosynthesis and histidine metabolism only in heart tissues and decreased creatine metabolism only in plasma. Further proteomic analysis identified 136 differentially abundant proteins in cardiac tissues, including 54 proteins with higher abundance and 82 proteins with lower abundance. Among them, cytochrome c oxidase subunit 7c and 7b (Cox7c, Cox7b), ATP synthase, H+ transporting, mitochondrial Fo complex subunit F2 (ATP5J2), ubiquinol-cytochrome c reductase, complex III subunit X (Uqcr10), and myosin heavy chain 7 (Myh7) were mainly involved in related metabolic pathways. These results revealed the essential role of NPRA in metabolic profiles and may elucidate new underlying pathophysiological mechanisms of NPRA in cardiovascular diseases.

LRP1-mediated pH-sensitive polymersomes facilitate combination therapy of glioblastoma in vitro and in vivo.

BACKGROUND: Glioblastoma (GBM) is the most invasive primary intracranial tumor, and its effective treatment is one of the most daunting challenges in oncology. The blood-brain barrier (BBB) is the main obstacle that prevents the delivery of potentially active therapeutic compounds. In this study, a new type of pH-sensitive polymersomes has been designed for glioblastoma therapy to achieve a combination of radiotherapy and chemotherapy for U87-MG human glioblastoma xenografts in nude mice and significantly increased survival time. RESULTS: The Au-DOX@PO-ANG has a good ability to cross the blood-brain barrier and target tumors. This delivery system has pH-sensitivity and the ability to respond to the tumor microenvironment. Gold nanoparticles and doxorubicin are designed as a complex drug. This type of complex drug improve the radiotherapy (RT) effect of glioblastoma. The mice treated with Au-DOX@PO-ANG NPs have a significant reduction in tumor volume. CONCLUSION: In summary, a new pH-sensitive drug delivery system was fabricated for the treatment of glioblastoma. The new BBB-traversing drug delivery system potentially represents a novel approach to improve the effects of the treatment of intracranial tumors and provides hope for glioblastoma treatment.

Vasonatrin peptide, a synthetic natriuretic peptide, attenuates myocardial injury and oxidative stress in isoprenaline-induced cardiomyocyte hypertrophy.

Isoprenaline-induced cardiac hypertrophy can deteriorate to heart failure, which is a leading cause of mortality. Endogenous vasonatrin peptide (VNP) has been reported to be cardioprotective against myocardial ischemia/reperfusion injury in diabetic rats. However, little is known about the effect of exogenous VNP on cardiac hypertrophy. We further explored whether VNP attenuated isoprenaline-induced cardiomyocyte hypertrophy by examining the levels and activities of cGMP and PKG. In this study, we found that VNP significantly attenuated isoprenaline-induced myocardial hypertrophy and cardiac fibroblast activation in vivo. Moreover, VNP effectively halted the activation of apoptosis and oxidative stress in the isoprenaline-treated myocardium. VNP promoted superoxide dismutase (SOD) activity. Further study revealed that the protective effects of VNP might be mediated by the activity of the cGMP-PKG signaling pathway in vivo or in vitro, while the use of agonists and antagonists confirmed these results. Therefore, we demonstrated that the antiapoptosis and antioxidative stress effects of VNP depends on elevated cGMP-PKG signaling activity both in vivo and in vitro. These results suggest that VNP may be used in the treatment of myocardial hypertrophy.

Cardiac­specific deletion of natriuretic peptide receptor A induces differential myocardial expression of circular RNA and mRNA molecules involved in metabolism in mice.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are important biological markers and regulators of cardiac function. The natriuretic peptide receptor A (NPRA), also known as NPR1 or guanylyl cyclase A, binds ANP and BNP to initiate transmembrane signal transduction by elevating the intracellular levels of cyclic guanosine monophosphate. However, the effects and mechanisms downstream of NPRA are largely unknown. The aim of the present study was to evaluate the changes in the global pattern of mRNA and circular RNA (circRNA) expression in NPRA­/­ and NPRA+/+ myocardium. Differentially expressed mRNA molecules were characterised using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis and were found to be primarily related to metabolic processes. Moreover, circRNA expression was also examined, and a possible competing endogenous RNA network consisting of circRNA, microRNA (miRNA), and mRNA molecules was constructed. The results of this study indicated that NPRA may play a role in cardiac metabolism, which could be mediated by circRNA through endogenous competition mechanisms. These findings may provide insight into future characterisation of various ceRNA network pathways.

Metabonomics Analysis of Myocardial Metabolic Dysfunction in Patients with Cardiac Natriuretic Peptide Resistance.

Brain natriuretic peptide (BNP) is an important biological marker and regulator of cardiac function. BNP resistance is characterized by high concentrations of less functionally effective BNP and common in heart failure (HF) patients. However, the roles and consequences of BNP resistance remain poorly understood. Investigate the effects of cardiac BNP resistance and identify potential metabolic biomarkers for screening and diagnosis. Thirty patients and thirty healthy subjects were enrolled in this study. Cardiac functions were evaluated by echocardiography. The plasma levels of cyclic guanosine monophosphate (cGMP) and BNP were measured by enzyme-linked immunosorbent assay (ELISA) and the cGMP/BNP ratio is calculated to determine cardiac natriuretic peptide resistance. Liquid chromatograph tandem mass spectrometry (LC-MS) based untargeted metabolomics analysis was applied to screen metabolic changes. The cGMP/BNP ratio was markedly lower in HF patients than controls. The cGMP/BNP ratio and ejection fraction (EF) were strongly correlated (R 2 = 0.676, P < 0.05). Importantly, metabolic profiles were substantially different between HF patients and healthy controls. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that the differentially expressed metabolites are involved in signaling pathways that regulate cardiac functions. In HF patients, BNP resistance develops in association with a reduction in heart function and metabolic remodeling. It suggests possible functional roles of BNP resistance in the regulation of cardiac metabolism.

Design Features for Improving Mobile Health Intervention User Engagement: Systematic Review and Thematic Analysis.

BACKGROUND: Well-designed mobile health (mHealth) interventions support a positive user experience; however, a high rate of disengagement has been reported as a common concern regarding mHealth interventions. To address this issue, it is necessary to summarize the design features that improve user engagement based on research over the past 10 years, during which time the popularity of mHealth interventions has rapidly increased due to the use of smartphones. OBJECTIVE: The aim of this review was to answer the question "Which design features improve user engagement with mHealth interventions?" by summarizing published literature with the purpose of guiding the design of future mHealth interventions. METHODS: This review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist. Databases, namely, PubMed, Web of Science, Cochrane Library, Ovid EMBASE, and Ovid PsycINFO, were searched for English and Chinese language papers published from January 2009 to June 2019. Thematic analysis was undertaken to assess the design features in eligible studies. The Mixed Methods Appraisal Tool was used to assess study quality. RESULTS: A total of 35 articles were included. The investigated mHealth interventions were mainly used in unhealthy lifestyle (n=17) and chronic disease (n=10) prevention programs. Mobile phone apps (n=24) were the most common delivery method. Qualitative (n=22) and mixed methods (n=9) designs were widely represented. We identified the following 7 themes that influenced user engagement: personalization (n=29), reinforcement (n=23), communication (n=20), navigation (n=17), credibility (n=16), message presentation (n=16), and interface aesthetics (n=7). A checklist was developed that contained these 7 design features and 29 corresponding specific implementations derived from the studies. CONCLUSIONS: This systematic review and thematic synthesis identified useful design features that make an mHealth intervention more user friendly. We generated a checklist with evidence-based items to enable developers to use our findings easily. Future evaluations should use more robust quantitative approaches to elucidate the relationships between design features and user engagement.