Identification and characterization of novel genetic variants in the first Chinese family of mucopolysaccharidosis IIIC (Sanfilippo C syndrome).

Mucopolysaccharidosis type IIIC (MPS IIIC) is one of inherited lysosomal storage disorders, caused by deficiencies in lysosomal hydrolases degrading acidic mucopolysaccharides. The gene responsible for MPS IIIC is HGSNAT, which encodes an enzyme that catalyses the acetylation of the terminal glucosamine residues of heparan sulfate. So far, few studies have focused on the genetic landscape of MPS IIIC in China, where IIIA and IIIB were the major subtypes. In this study, we utilized whole-exome sequencing (WES) to identify novel compound heterozygous variants in the HGSNAT gene from a Chinese patient with typical MPS IIIC symptoms: c.743G>A; p.Gly248Glu and c.1030C>T; p.Arg344Cys. We performed in silico analysis and experimental validation, which confirmed the deleterious pathogenic nature of both variants, as evidenced by the loss of HGSNAT activity and failure of lysosomal localization. To the best of our knowledge, the MPS IIIC is first confirmed by clinical, biochemical and molecular genetic findings in China. Our study thus expands the spectrum of MPS IIIC pathogenic variants, which is of importance to dissect the pathogenesis and to carry out clinical diagnosis of MPS IIIC. Moreover, this study helps to depict the natural history of Chinese MPS IIIC populations.

Near-full-length genome analysis of two novel HIV second recombinant forms in Hebei, China.

The number of individuals infected with HIV-1 among men who have sex with men (MSM) has risen rapidly in recent years in China, and the subtypes CRF01_AE, CRF07_BC, and B, as well as many novel unique recombinant forms (URFs) are prevalent among them. Co-circulation of strains among MSM populations allows the generation of circulating recombinant forms (CRFs) and URFs. In this study, we identified two new URFs from two HIV-1-positive subjects who were infected through homosexual contact in Hebei, China. Analysis of near-full-length genome sequences, using phylogenetic and recombination analysis showed that the two URFs originated from CRF01_AE, CRF07_BC, and B, and CRF01_AE segments in the backbone of the URFs were derived from cluster 4 of CRF01_AE. The CRF07_BC segments of two URFs were clustered with 07BC_N in a phylogenetic tree. The identification of novel URFs with complex genomic structures shows that it is necessary to strengthen surveillance of HIV-1 variants in MSM populations in this region.

EPAC inhibitor suppresses angiogenesis and tumor growth of triple-negative breast cancer.

AIMS: Exchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and regulates angiogenesis in the retina. High intratumor microvascular densities (MVD) resulting from angiogenesis is responsible for breast cancer development. Downregulation of EPAC1 in tumor cell reduces triple-negative breast cancer (TNBC)-induced angiogenesis. However, whether Epac1 expressed in vascular endothelial cells contributes to angiogenesis and tumor development of TNBC remains elusive. MAIN METHODS: We employed NY0123, a previously identified potent EPAC inhibitor, to explore the anti-angiogenic biological role of EPAC1 in vitro and in vivo through vascular endothelial cells, rat aortic ring, Matrigel plug, and chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) assays, as well as the in vivo xenograft tumor models of TNBC in both chick embryo and mice. KEY FINDINGS: Inhibiting EPAC1 in vascular endothelial cells by NY0123 significantly suppresses angiogenesis and tumor growth of TNBC. In addition, NY0123 possesses a better inhibitory efficacy than ESI-09, a reported specific EPAC inhibitor tool compound. Importantly, inhibiting EPAC1 in vascular endothelia cells regulates the typical angiogenic signaling network, which is associated with not only vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) signaling, but also PI3K/AKT, MEK/ERK and Notch pathway. CONCLUSIONS: Our findings support that EPAC1 may serve as an effective anti-angiogenic therapeutic target of TNBC, and EPAC inhibitor NY0123 has the therapeutic potential to be developed for the treatment of TNBC.

Relationships between Motor Skills and Academic Achievement in School-Aged Children and Adolescents: A Systematic Review.

PURPOSE: This review systematically summarizes the studies of the relationship between primary-to-secondary school students' motor skills and academic achievement, and analyzes the relationship between gross and fine motor skills and performance in different subjects. METHOD: Five electronic databases, Web Of Science, PubMed, PsycINFO, SPORTDiscus, and Academic Search Premier, were searched in March 2023. Semi-quantitative assessment methods were used to analyze the results of the included studies. RESULTS: Seventy-eight articles were included in this systematic review. The semi-quantitative assessment results showed that gross (+, 65.0/62.5%) and fine motor skills (+, 83.3/80%) were positively correlated with overall performance and language performance, with ≥60% of the associations in the same direction. For different subjects, fine motor skills were positively correlated with students' mathematics (+, 75.0%), reading (+, 72.7%), writing (+, 66.7%), and spelling (+, 60.0%) scores. However, the association between gross motor skills and students' mathematics achievement (?, 52.8%), reading (?, 53.8%), and spelling (?, 50.0%) is uncertain, with <60% of the associations in the same direction. CONCLUSIONS: It is wise to direct our gaze toward the evolution of motor skills among students, especially primary school students. Different motor skill intervention modes should be selected in a targeted manner according to different subject achievements.

Sleep-dependent engram reactivation during hippocampal memory consolidation associated with subregion-specific biosynthetic changes.

Post-learning sleep is essential for hippocampal memory processing, including contextual fear memory consolidation. We labeled context-encoding engram neurons in the hippocampal dentate gyrus (DG) and assessed reactivation of these neurons after fear learning. Post-learning sleep deprivation (SD) selectively disrupted reactivation of inferior blade DG engram neurons, linked to SD-induced suppression of neuronal activity in the inferior, but not superior DG blade. Subregion-specific spatial profiling of transcripts revealed that transcriptomic responses to SD differed greatly between hippocampal CA1, CA3, and DG inferior blade, superior blade, and hilus. Activity-driven transcripts, and those associated with cytoskeletal remodeling, were selectively suppressed in the inferior blade. Critically, learning-driven transcriptomic changes differed dramatically between the DG blades and were absent from all other regions. Together, these data suggest that the DG is critical for sleep-dependent memory consolidation, and that the effects of sleep loss on the hippocampus are highly subregion-specific.

COVID-19 vaccination willingness among people living with HIV in Shijiazhuang, China: a cross-sectional survey.

Objectives: The COVID-19 pandemic imposed an enormous disease and economic burden worldwide. SARS-CoV-2 vaccination is essential to containing the pandemic. People living with HIV (PLWH) may be more vulnerable to severe COVID-19 outcomes; thus, understanding their vaccination willingness and influencing factors is helpful in developing targeted vaccination strategies. Methods: A cross-sectional study was conducted between 15 June and 30 August 2022 in Shijiazhuang, China. Variables included socio-demographic characteristics, health status characteristics, HIV-related characteristics, knowledge, and attitudes toward COVID-19 vaccination and COVID-19 vaccination status. Multivariable logistic regression was used to confirm factors associated with COVID-19 vaccination willingness among PLWH. Results: A total of 1,428 PLWH were included, with a 90.48% willingness to receive the COVID-19 vaccination. PLWH were more unwilling to receive COVID-19 vaccination for those who were female or had a fair/poor health status, had an allergic history and comorbidities, were unconvinced and unsure about the effectiveness of vaccines, were unconvinced and unsure about the safety of vaccines, were convinced and unsure about whether COVID-19 vaccination would affect ART efficacy, or did not know at least a type of domestic COVID-19 vaccine. Approximately 93.00% of PLWH have received at least one dose of the COVID-19 vaccine among PLWH, and 213 PLWH (14.92%) reported at least one adverse reaction within 7 days. Conclusion: In conclusion, our study reported a relatively high willingness to receive the COVID-19 vaccination among PLWH in Shijiazhuang. However, a small number of PLWH still held hesitancy; thus, more tailored policies or guidelines from the government should be performed to enhance the COVID-19 vaccination rate among PLWH.

The research of touch screen usability in civil aircraft cockpit.

With the advancement of touch screen technology, the application of touch screens in civil aircraft cockpits has become increasingly popular. However, further analysis and research are required to fully promote its applications. The paper researched the usability of touch screens in aircraft cockpit considering the operation performance and subjective NASA-TLX workload evaluation, conducted experimental research on three touch gestures: click, drag, and zoom. Additionally, a comparative analysis was conducted on the touch performance under different layouts, positions, touch sizes, dragging direction angles, and zoom multiples. The touch performance indicators include operation time, error rate, operation speed, and workload. The experimental results show that the 21 mm size has the minimum operation time and workload, and 18 mm size has the lowest error rate in the clicking tasks. Additionally, the performance and workload of the captain's layout are better than those of the co-pilot's layout, and the performance of the center console position is best. The operation speed of the dragging tasks is faster when performed at position R3 compared to other positions. The dragging moving angles with better operation speed are 80°-190° and 250°-290°. The operation performance and workload of the zooming tasks vary depending on the zoom multiples. As the multiple increases, the operation time and workload also increase. There is no difference in operation performance or workload between zooming in and zooming out. The paper provides experimental support and suggestions based on human operation and subjective NASA-TLX workload evaluation for the application of touch screens in civil aircraft cockpits.

Omicron BA.4/5 neutralization and cell-mediated immune responses in relation to baseline immune status and breakthrough infection among PLWH: A follow-up cohort study.

There is a paucity of data on hybrid immunity (vaccination plus breakthrough infection [BI]), especially cell-mediated responses to Omicron among immunosuppressed patients. We aim to investigate humoral and cellular responses to Omicron BA.4/5 among people living with HIV (PLWH) with/without BIs, the most prevalent variant of concern after the reopening of China. Based on our previous study, we enrolled 77 PLWH with baseline immune status of severe acute respiratory syndrome coronavirus 2 specific antibodies after inactivated vaccination. "Correlates of protection," including serological immunoassays, T cell phenotypes and memory B cells (MBC) were determined in PLWH without and with BI, together with 16 PLWH with reinfections. Higher inhibition rate of neutralizing antibodies (NAb) against BA.4/5 was elicited among PLWH with BI than those without. Omicron-reactive IL4+ CD8+ T cells were significantly elevated in PLWH experienced postvaccine infection contrasting with those did not. NAb towards wild type at baseline was associated with prolonged negative conversion time for PLWH whereas intermediate MBCs serve as protecting effectors. We uncovered that hybrid immunity intensified more protection on BA.4/5 than vaccination did. Strengthened surveillance on immunological parameters and timely clinical intervention on PLWH deficient in protection would reduce the severity and mortality in the context of coexistence with new Omicron subvariants.

Modifying Surface Termination by Bidentate Chelating Strategy Enables 13.77% Efficient Kesterite Solar Cells.

Surfaces display discontinuities in the kesterite-based polycrystalline films can produce large defect densities, including strained and dangling bonds. These physical defects tend to introduce electronic defects and surface states, which can greatly promote nonradiative recombination of electron-hole pairs and damage device performance. Here, an effective chelation strategy is reported to suppress these harmful physical defects related to unterminated Cu, Zn, and Sn sites by modifying the surface of Cu2ZnSn(S,Se)4 (CZTSSe) films with sodium diethyldithiocarbamate (NaDDTC). The conjoint theoretical calculations and experimental results reveal that the NaDDTC molecules can be coordinate to surface metal sites of CZTSSe films via robust bidentate chelating interactions, effectively reducing surface undercoordinated defects and passivating the electron trap states. Consequently, the solar cell efficiency of the NaDDTC-treated device is increased to as high as 13.77% under 100 mW cm-2 illumination, with significant improvement in fill factor and open-circuit voltage. This surface chelation strategy provides strong surface termination and defect passivation for further development and application of kesterite-based photovoltaics.

Identification of Immune Infiltration and Iron Metabolism-Related Subgroups in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with a broad spectrum of symptoms and prognoses. Effective therapy requires understanding this variability. ASD children's cognitive and immunological development may depend on iron homoeostasis. This study employs a machine learning model that focuses on iron metabolism hub genes to identify ASD subgroups and describe immune infiltration patterns. A total of 97 control and 148 ASD samples were obtained from the GEO database. Differentially expressed genes (DEGs) and an iron metabolism gene collection achieved the intersection of 25 genes. Unsupervised cluster analysis determined molecular subgroups in individuals with ASD based on 25 genes related to iron metabolism. We assessed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, gene set variation analysis (GSVA), and immune infiltration analysis to compare iron metabolism subtype effects. We employed machine learning to identify subtype-predicting hub genes and utilized both training and validation sets to assess gene subtype prediction accuracy. ASD can be classified into two iron-metabolizing molecular clusters. Metabolic enrichment pathways differed between clusters. Immune infiltration showed that clusters differed immunologically. Cluster 2 had better immunological scores and more immune cells, indicating a stronger immune response. Machine learning screening identified SELENBP1 and CAND1 as important genes in ASD's iron metabolism signaling pathway. These genes express in the brain and have AUC values over 0.8, implying significant predictive power. The present study introduces iron metabolism signaling pathway indicators to predict ASD subtypes. ASD is linked to immune cell infiltration and iron metabolism disorders.

Rapid Initiation of Antiretroviral Therapy with Coformulated Bictegravir, Emtricitabine, Tenofovir Alafenamide Versus Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in HIV-positive Men Who Have Sex with Men in China: Week 48 Results of the Multicenter, Randomized Clinical Trial.

BACKGROUND: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with HIV-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400-mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among HIV-positive men who have sex with men (MSM). METHODS: This multicenter, open-label, randomized clinical trial enrolled MSM aged ≥18 years to start ART within 14 days of confirmed HIV diagnosis. The participants were randomly assigned in a 1:1 ratio to receive EFV(400-mg) + 3TC + TDF or BIC/FTC/TAF. The primary end point was viral suppression (<50 copies/ml) at 48 weeks per FDA Snapshot analysis. RESULTS: Between March 2021 and July 2022, 300 participants were enrolled; 154 were assigned to receive EFV + 3TC + TDF (EFV group) and 146 BIC/FTC/TAF (BIC group). At week 48, 118 (79.2%) and 140 (95.9%) participants in the EFV and BIC group, respectively, were retained in care with viral suppression; and 24 (16.1%) and 1 (0.7%) participant in the EFV and BIC group (p < 0.001), respectively, discontinued treatment due to adverse effects, death, or loss to follow-up. The median increase of CD4 count was 181 and 223 cells/µL (p = 0.020), respectively, for the EFV and BIC group, at week 48. The overall incidence of adverse effects was significantly higher for the EFV group (65.8% vs 37.7%, P < 0.001). CONCLUSION: BIC/FTC/TAF was more efficacious and safer than EFV(400-mg) + 3TC + TDF for rapid ART initiation among HIV-positive MSM in China.

Analysis of complete hydatidiform mole in one twin using traditional and molecular techniques.

A pregnant woman with hydatidiform mole in one twin was misdiagnosed as one of the twins with embryonic arrest. She chose to terminate the pregnancy and developed distant lung metastasis. After chemotherapy, she eventually recovered. This article systematically analyzes the diagnosis and treatment of hydatidiform mole in one twin to increase the awareness and reduce misdiagnosis of the disease.

Exploring the measurement of psychological resilience in Chinese civil aviation pilots based on generalizability theory and item response theory.

Understanding and accurately measuring resilience among Chinese civil aviation pilots is imperative, especially concerning the psychological impact of distressing events on their well-being and aviation safety. Despite the necessity, a validated and tailored measurement tool specific to this demographic is absent. Addressing this gap, this study built on the widely used CD-RISC-25 to analyze and modify its applicability to Chinese civil aviation pilots. Utilizing CD-RISC-25 survey data from 231 Chinese pilots, correlational and differential analyses identified items 3 and 20 as incongruent with this population's resilience profile. Subsequently, factor analysis derived a distinct two-factor resilience psychological framework labeled "Decisiveness" and "Adaptability", which diverged from the structure found in American female pilots and the broader Chinese populace. Additionally, to further accurately identify the measurement characteristics of this 2-factor measurement model, this study introduced Generalized Theory and Item Response Theory, two modern measurement analysis theories, to comprehensively analyze the overall reliability of the measurement and issues with individual items. Results showed that the 2-factor model exhibited high reliability, with generalizability coefficient reaching 0.89503 and dependability coefficient reaching 0.88496, indicating the 2-factor measurement questionnaire can be effectively utilized for relative and absolute comparison of Chinese civil aviation pilot resilience. However, items in Factor 2 provided less information and have larger room for optimization than those in Factor 1, implying item option redesign may be beneficial. Consequently, this study culminates in the creation of a more accurate and reliable two-factor psychological resilience measurement tool tailored for Chinese civil aviation pilots, while exploring directions for optimization. By facilitating early identification of individuals with lower resilience and enabling the evaluation of intervention efficacy, this tool aims to positively impact pilot psychological health and aviation safety in the context of grief and trauma following distressing events.

Potential risk factors for mild cognitive impairment among patients with type 2 diabetes experiencing hypoglycemia.

AIMS: This study examined the association between hypoglycemia and mild cognitive impairment (MCI) among patients with type 2 diabetes mellitus (T2DM) and identified risk factors for MCI in patients with hypoglycemia. METHODS: In this retrospective study, 328 patients with T2DM were screened in 2019 and followed up in 2022. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). The diagnosis of MCI was based on established criteria. Risk ratio (RR) with 95 % confidence intervals (CI) was calculated to estimate the risk of MCI. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for MCI in those with hypoglycemia. RESULTS: Patients with hypoglycemia had lower cognitive performance 3 years later. The RR of MCI was 2.221 (95 % CI 1.269-3.885). Multivariate logistic analysis showed that low grip strength, existing diabetic retinopathy (DR), and multiple hypoglycemia episodes were associated with higher odds of MCI in patients with hypoglycemia (adjusted odds ratio [OR] 0.909 [95 % CI 0.859-0.963]), 3.078 [95 % CI 1.158-12.358], and 4.642 [95 % CI 1.284-16.776], respectively, all P < 0.05). CONCLUSIONS: Hypoglycemia increased MCI risk among patients with T2DM. Low grip strength, DR, and multiple hypoglycemia episodes may be potential risk factors for hypoglycemia-associated MCI.

Ecological impacts of the expansion of offshore wind farms on trophic level species of marine food chain.

The global demand for renewable energy has resulted in a rapid expansion of offshore wind farms (OWFs) and increased attention to the ecological impacts of OWFs on the marine ecosystem. Previous reviews mainly focused on the OWFs' impacts on individual species like birds, bats, or mammals. This review collected numerous field-measured data and simulated results to summarize the ecological impacts on phytoplankton, zooplankton, zoobenthos, fishes, and mammals from each trophic level and also analyze their interactions in the marine food chain. Phytoplankton and zooplankton are positively or adversely affected by the 'wave effect', 'shading effect', oxygen depletion and predation pressure, leading to a ± 10% fluctuation of primary production. Although zoobenthos are threatened transiently by habitat destruction with a reduction of around 60% in biomass in the construction stage, their abundance exhibited an over 90% increase, dominated by sessile species, due to the 'reef effect' in the operation stage. Marine fishes and mammals are to endure the interferences of noise and electromagnetic, but they are also aggregated around OWFs by the 'reef effect' and 'reserve effect'. Furthermore, the complexity of marine ecosystem would increase with a promotion of the total system biomass by 40% through trophic cascade effects strengthen and resource partitioning alternation triggered by the proliferation of filter-feeders. The suitable site selection, long-term monitoring, and life-cycle-assessment of ecological impacts of OWFs that are lacking in current literature have been described in this review, as well as the carbon emission and deposition.

Micropollutant rejection by nanofiltration membranes: A mini review dedicated to the critical factors and modelling prediction.

Nanofiltration (NF) membranes, extensively used in advanced wastewater treatment, have broad application prospects for the removal of emerging trace organic micropollutants (MPs). The treatment performance is affected by several factors, such as the properties of NF membranes, characteristics of target MPs, and operating conditions of the NF system concerning MP rejection. However, quantitative studies on different contributors in this context are limited. To fill the knowledge gap, this study aims to assess critical impact factors controlling MP rejection and develop a feasible model for MP removal prediction. The mini-review firstly summarized membrane pore size, membrane zeta potential, and the normalized molecular size (λ = rs/rp), showeing better individual relationships with MP rejection by NF membranes. The Lindeman-Merenda-Gold model was used to quantitatively assess the relative importance of all summarized impact factors. The results showed that membrane pore size and operating pressure were the high impact factors with the highest relative contribution rates to MP rejection of 32.11% and 25.57%, respectively. Moderate impact factors included membrane zeta potential, solution pH, and molecular radius with relative contribution rates of 10.15%, 8.17%, and 7.83%, respectively. The remaining low impact factors, including MP charge, molecular weight, logKow, pKa and crossflow rate, comprised all the remaining contribution rates of 16.19% through the model calculation. Furthermore, based on the results and data availabilities from references, the machine learning-based random forest regression model was trained with a relatively low root mean squared error and mean absolute error of 12.22% and 6.92%, respectively. The developed model was then successfully applied to predict MPs' rejections by NF membranes. These findings provide valuable insights that can be applied in the future to optimize NF membrane designs, operation, and prediction in terms of removing micropollutants.

Fault Feature Extraction Method for Rolling Bearings Based on Complete Ensemble Empirical Mode Decomposition with Adaptive Noise and Variational Mode Decomposition.

Due to the difficulty in dealing with non-stationary and nonlinear vibration signals using the single decomposition method, it is difficult to extract weak fault features from complex noise; therefore, this paper proposes a fault feature extraction method for rolling bearings based on complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) and variational mode decomposition (VMD) methods. CEEMDAN was used to decompose the signal, and the signal was then screened and reconstructed according to the component envelope kurtosis. Based on the kurtosis of the maximum envelope spectrum as the fitness function, the sparrow search algorithm (SSA) was used to perform adaptive parameter optimization for VMD, which decomposed the reconstructed signal into several IMF components. According to the kurtosis value of the envelope spectrum, the optimal component was selected for an envelope demodulation analysis to realize fault feature extraction for rolling bearings. Finally, by using open data sets and experimental data, the accuracy of envelope kurtosis and envelope spectrum kurtosis as a component selection index was verified, and the superiority of the proposed feature extraction method for rolling bearings was confirmed by comparing it with other methods.

From Sheep Track to Motorway: Supramolecular-Mediated 2D Nanofluidic Channels for Ultrafast Water Transport.

Atomic thick 2D materials hold great potential as building blocks to construct highly permeable membranes, yet the permeability of laminar 2D material membranes is still limited by their irregularity sheep track-like interlayer channels. Herein, a supramolecular-mediated strategy to induce the regular assembly of high-throughput 2D nanofluidic channels based on host-guest interactions is proposed. Inspired by the characteristics of motorways, supramolecular-mediated ultrathin 2D membranes with broad and continuous regular water transport channels are successfully constructed using graphene oxide (GO) as an example. The prepared membrane achieves an ultrahigh water permeability (369.94 LMH bar-1 ) more than six times higher than that of the original membranes while maintaining dye rejection above 98.5%, which outperforms the reported 2D membranes. Characterization and simulation results show that the introduction of hyaluronate-grafted ß-cyclodextrin not only expands the interlayer channels of GO membranes but also enables the membranes to operate stably under harsh conditions with the help of host-guest interactions. This universal supramolecular assembly strategy provides new opportunities for the preparation of 2D membranes with high separation performance and reliable and stable nanofluidic channels.

Apelin receptor inhibition in ischemia-reperfused mouse hearts protected by endogenous n-3 polyunsaturated fatty acids.

Background: While the protective effects of n-3 polyunsaturated fatty acids (PUFAs) on cardiac ischemia-reperfusion (IR) injury have been previously reported, limited data are available regarding how these fatty acids affect membrane receptors and their downstream signaling following IR injury. We aimed to identify potential receptors activated by n-3 PUFAs in IR hearts to understand the regulatory mechanisms of these receptors. Methods: We used fat-1 mice, which naturally have elevated levels of n-3 PUFAs, and C57BL/6J mice as a control group to create a myocardial IR injury model through Langendorff perfusion. We assessed the impact of endogenous n-3 PUFAs on left ventricular function, myocardial infarct size, myocardial apoptosis, and ATP production. RNA sequencing (RNA-seq) and bioinformatics analysis were conducted to identify molecular targets affected by n-3 PUFAs. Based on these analyses we then treated IR hearts of WT and fat-1 mice with an antagonist (ML221) or an agonist (apelin-13) for the predicted receptor to assess cardiac contractile function and intracellular signaling pathways. An in vitro hypoxia-reoxygenation (HR) model was also used to confirm the effects of n-3 PUFAs on the examined intracellular signaling pathways. Results: Endogenous n-3 PUFAs protected cardiac structure and function in post-IR hearts, and modulated phosphorylation patterns in the PI3K-AKT-mTOR signaling pathways. RNA-seq analysis revealed that n-3 PUFAs affected multiple biological processes as well as levels of the apelin receptor (APLNR). Consistent with a role for the PLNNR, ML221 synchronized the activation of the PI3K-AKT-mTOR signaling axis, suppressed the expression of PKCδ and phosphorylated p38α, upregulated PKCε expression, upregulated or restored the phosphorylation of myofilaments, and prevented myocardial injury and contractile dysfunction in WT IR hearts. By contrast, apelin-13 disrupted the PI3K-AKT-mTOR signaling axis in post-IR fat-1 hearts. The phosphorylation signaling targeted by APLNR inhibition in post-IR fat-1 hearts was also observed after treating HR cells with eicosatetraenoic acid (EPA). Conclusion: Endogenous n-3 PUFAs protect against post-IR injury and preserve cardiac contractile function possibly through APLNR inhibition. This inhibition synchronizes the PI3K-AKT-mTOR axis, suppresses detrimental phosphorylation signaling, and restores or increases myofilament phosphorylation in post-IR hearts. The beneficial effects observed in fat-1 transgenic mouse hearts can be attributed, at least in part, to elevated EPA levels. This study is the first to demonstrate that n-3 PUFAs protect hearts against IR injury through APLNR inhibition.

GLP-1 Receptor Agonist Improves Mitochondrial Energy Status and Attenuates Nephrotoxicity In Vivo and In Vitro.

High-sugar and high-fat diets cause significant harm to health, especially via metabolic diseases. In this study, the protective effects of the antidiabetic drug exenatide (synthetic exendin-4), a glucagon-like peptide 1 (GLP-1) receptor agonist, on high-fat and high-glucose (HFHG)-induced renal injuries were investigated in vivo and in vitro. In vivo and in vitro renal injury models were established. Metabolomic analysis based on 1H-nuclear magnetic resonance was performed to examine whether exenatide treatment exerts a protective effect against kidney injury in diabetic rats and to explore its potential molecular mechanism. In vivo, 8 weeks of exenatide treatment resulted in the regulation of most metabolites in the diabetes mellitus group. In vitro results showed that exendin-4 restored the mitochondrial functions of mesangial cells, which were perturbed by HFHG. The effects of exendin-4 included the improved antioxidant capacity of mesangial cells, increased the Bcl-2/Bax ratio, and reduced protein expression of cyt-c and caspase-3 activation. In addition, exendin-4 restored mesangial cell energy metabolism by increasing succinate dehydrogenase and phosphofructokinase activities and glucose consumption while inhibiting pyruvate dehydrogenase E1 activity. In conclusion, GLP-1 agonists improve renal injury in diabetic rats by ameliorating metabolic disorders. This mechanism could be partially related to mitochondrial functions and energy metabolism.