Characterization of reduced astrocyte creatine kinase levels in Alzheimer's disease.

The creatine-phosphocreatine cycle serves as a crucial temporary energy buffering system in the brain, regulated by brain creatine kinase (CKB), in maintaining Adenosine triphosphate (ATP) levels. Alzheimer's disease (AD) has been linked to increased CKB oxidation and loss of its regulatory function, although specific pathological processes and affected cell types remain unclear. In our study, cerebral cortex samples from individuals with AD, dementia with Lewy bodies (DLB), and age-matched controls were analyzed using antibody-based methods to quantify CKB levels and assess alterations associated with disease processes. Two independently validated antibodies exclusively labeled astrocytes in the human cerebral cortex. Combining immunofluorescence (IF) and mass spectrometry (MS), we explored CKB availability in AD and DLB cases. IF and Western blot analysis demonstrated a loss of CKB immunoreactivity correlated with increased plaque load, severity of tau pathology, and Lewy body pathology. However, transcriptomics data and targeted MS demonstrated unaltered total CKB levels, suggesting posttranslational modifications (PTMs) affecting antibody binding. This aligns with altered efficiency at proteolytic cleavage sites indicated in the targeted MS experiment. These findings highlight that the proper function of astrocytes, understudied in the brain compared with neurons, is highly affected by PTMs. Reduction in ATP levels within astrocytes can disrupt ATP-dependent processes, such as the glutamate-glutamine cycle. As CKB and the creatine-phosphocreatine cycle are important in securing constant ATP availability, PTMs in CKB, and astrocyte dysfunction may disturb homeostasis, driving excitotoxicity in the AD brain. CKB and its activity could be promising biomarkers for monitoring early-stage energy deficits in AD.

FeSA­Ir/Metallene Nanozymes Induce Sequential Ferroptosis­Pyroptosis for Multi­Immunogenic Responses Against Lung Metastasis.

For cancer metastasis inhibition, the combining of nanozymes with immune checkpoint blockade (ICB) therapy remains the major challenge in controllable reactive oxygen species (ROS) generation for creating effective immunogenicity. Herein, new nanozymes with light-controlled ROS production in terms of quantity and variety are developed by conjugating supramolecular-wrapped Fe single atom on iridium metallene with lattice-strained nanoislands (FeSA-Ir@PF NSs). The Fenton-like catalysis of FeSA-Ir@PF NSs effectively produced •OH radicals in dark, which induced ferroptosis and apoptosis of cancer cells. While under second near-infrared (NIR-II) light irradiation, FeSA-Ir@PF NSs showed ultrahigh photothermal conversion efficiency (𝜂, 75.29%), cooperative robust •OH generation, photocatalytic O2 and 1O2 generation, and caused significant pyroptosis of cancer cells. The controllable ROS generation, sequential cancer cells ferroptosis and pyroptosis, led 99.1% primary tumor inhibition and multi-immunogenic responses in vivo. Most importantly, the inhibition of cancer lung metastasis is completely achieved by FeSA-Ir@PF NSs with immune checkpoint inhibitors, as demonstrated in different mice lung metastasis models, including circulating tumor cells (CTCs) model. This work provided new inspiration for developing nanozymes for cancer treatments and metastasis inhibition.

Nanostructurally Engineering Covalent Organic Frameworks for Boosting CO2 Photoreduction.

Herein, a series of imine-linked covalent organic frameworks (COFs) are developed with advanced ordered mesoporous hollow spherical nanomorphology and ultra-large mesopores (4.6 nm in size), named OMHS-COF-M (M = H, Co, and Ni). The ordered mesoporous hollow spherical nanomorphology is revealed to be formed via an Ostwald ripening mechanism based on a one-step self-templated strategy. Encouraged by its unique structural features and outstanding photoelectrical property, the OMHS-COF-Co material is applied as the photocatalyst for CO2-to-CO reduction. Remarkably, it delivers an impressive CO production rate as high as 15 874 µmol g-1 h-1, a large selectivity of 92.4%, and a preeminent cycling stability. From in/ex situ experiments and density functional theory (DFT) calculations, the excellent CO2 photoreduction performance is ascribed to the desirable cooperation of unique ordered mesoporous hollow spherical host and abundant isolated Co active sites, enhancing CO2 activation, and improving electron transfer kinetics as well as reducing the energy barriers for intermediates *COOH generation and CO desorption.

Identification of large yellow croakers (Larimichthys crocea) scavenger receptor genes: Involvement in immune response to Pseudomonas plecoglossicida infection and hypoxia-exposure experiments.

Scavenger receptors (SRs) are pattern recognition receptors involved in the innate immune defense against pathogen infection in fish. However, there has not been much research done on teleosts. In this study, 18 members of the SR gene family were found in large yellow croaker. The identification of the SR gene family showed that the protein length of SR members in large yellow croaker were quite different, and most SR genes were distributed in nuclear and endoplasmic. The evolutionary relationship, exon/intron structure and motif analysis revealed that members of the SR gene family were highly conserved. The results of the expression profiles after Pseudomonas plecoglossicida infection and hypoxia-exposure demonstrated that SR members were involved in inflammatory reactions. Especially, COLEC12 and SCARF1 exhibited substantial changes in response to both P. plecoglossicida and hypoxia stress, indicating their possible immunological functions. The result of this study revealed that SR genes played a vital part in the innate immune response of large yellow croaker, and would give important details for a deeper comprehension of the SR gene family's regulation mechanism under various conditions in large yellow croaker.

Research on the outdoor thermal comfort of children in Hangzhou and Its influence on the underlying surface reflectance.

The outdoor thermal comfort (OTC) of children is more specific than that of adults, and the complex influence of outdoor activity spaces on children's thermal comfort warrants further investigation. To investigate the outdoor thermal comfort baseline (OTCB) of children in Hangzhou and explore the thermal impact of outdoor surfaces on children, a survey was conducted in six typical outdoor activity spaces in Hangzhou, China, during spring and summer utilizing physical measurements, questionnaire surveys, and the universal thermal climate index (UTCI). This study analyzed the differences in thermal perception among children in Hangzhou in different seasons, their OTCB, and the impact of surface reflectance (Rs) on children's OTC. The results indicated the following: 1) In spring, children in Hangzhou generally felt comfortable, but their discomfort with heat noticeably increased in summer. 2) The neutral UTCIs (NUTCIs) for Hangzhou children were 11.6 °C (spring) and 27.7 °C (summer), and the NUTCI ranges (NUTCIRs) were 9.7-17.5 °C (spring) and 25.7-30.0 °C (summer); additionally, the thermal acceptability ranges (TARs) were 13.2-25.2 °C (spring) and 11.8-34.8 °C (summer). 3) A high Rs made children feel more uncomfortable with heat, which was primarily due to the space's total shortwave and longwave radiation, which peaked between 14:00 and 15:00. 4) Based on the research findings, corresponding bioclimatic design strategies were proposed. Recommendations include using high Rs underlays with shading, composite underlays, or the future adoption of thermochromic coatings. Keeping permeable underlays moist is essential for activating their cooling mechanisms. Fundamental safety measures are imperative. This study provides valuable data for urban planners and landscape designers to create public spaces suitable for children's outdoor activities, contributing to a harmonious and unified living environment.

[Application of electrical impedance tomography imaging technology combined with generative adversarial network in pulmonary ventilation monitoring].

Electrical impedance tomography (EIT) plays a crucial role in the monitoring of pulmonary ventilation and regional pulmonary function test. However, the inherent ill-posed nature of EIT algorithms results in significant deviations in the reconstructed conductivity obtained from voltage data contaminated with noise, making it challenging to obtain accurate distribution images of conductivity change as well as clear boundary contours. In order to enhance the image quality of EIT in lung ventilation monitoring, a novel approach integrating the EIT with deep learning algorithm was proposed. Firstly, an optimized operator was introduced to enhance the Kalman filter algorithm, and Tikhonov regularization was incorporated into the state-space expression of the algorithm to obtain the initial lung image reconstructed. Following that, the imaging outcomes were fed into a generative adversarial network model in order to reconstruct accurate lung contours. The simulation experiment results indicate that the proposed method produces pulmonary images with clear boundaries, demonstrating increased robustness against noise interference. This methodology effectively achieves a satisfactory level of visualization and holds potential significance as a reference for the diagnostic purposes of imaging modalities such as computed tomography.

Deep Learning-Based 6-DoF Object Pose Estimation Considering Synthetic Dataset.

Due to the difficulty in generating a 6-Degree-of-Freedom (6-DoF) object pose estimation dataset, and the existence of domain gaps between synthetic and real data, existing pose estimation methods face challenges in improving accuracy and generalization. This paper proposes a methodology that employs higher quality datasets and deep learning-based methods to reduce the problem of domain gaps between synthetic and real data and enhance the accuracy of pose estimation. The high-quality dataset is obtained from Blenderproc and it is innovatively processed using bilateral filtering to reduce the gap. A novel attention-based mask region-based convolutional neural network (R-CNN) is proposed to reduce the computation cost and improve the model detection accuracy. Meanwhile, an improved feature pyramidal network (iFPN) is achieved by adding a layer of bottom-up paths to extract the internalization of features of the underlying layer. Consequently, a novel convolutional block attention module-convolutional denoising autoencoder (CBAM-CDAE) network is proposed by presenting channel attention and spatial attention mechanisms to improve the ability of AE to extract images' features. Finally, an accurate 6-DoF object pose is obtained through pose refinement. The proposed approach is compared to other models using the T-LESS and LineMOD datasets. Comparison results demonstrate the proposed approach outperforms the other estimation models.

Atomically Dispersed NiN3 Sites on Highly Defective Micro-Mesoporous Carbon for Superior CO2 Electroreduction.

Direct electrochemical conversion of CO2 to CO product powered by renewable electricity is widely advocated as an emerging strategy for alleviating CO2 emissions while addressing global energy issues. However, the development of low-cost and efficient electrocatalysts with high Faradaic efficiency for CO production (FECO ) and high current density remains a grand challenge. Herein, a robust single nickel atomic site electrocatalyst, which features isolated and dense single atomic NiN3 sites anchored on highly defective hierarchically micro-mesoporous carbon (Ni-SAs/HMMNC-800), to enable enhanced charge transport and more exposed active sites for catalyzing electrochemical CO2 -to-CO conversion, is reported. The Ni-SAs/HMMNC-800 catalyst achieves excellent activity and selectivity with high FECO values of >90% throughout a wide potential range (the FECO reaches 99.5% at -0.7 V vs reversible hydrogen electrode) and a CO partial current density as high as 13.0 mA cm-2 at -0.7 V versus reversible hydrogen electrode, as well as a far outstanding durability during long-term continuous operation, indicating a superior CO2 electroreduction performance than that of other reference samples and most of previously reported carbon-based single atom electrocatalysts. Experimental and density functional theory calculations reveal that atomic NiN3 coordination sites coupled adjacent defects are favorable to significantly enhancing the formation of COOH* reaction intermediates while suppressing the competing hydrogen evolution reaction, thereby enhancing the electrocatalytic activity for CO2 -to-CO reduction. Notably, this work provides a valuable new prospect for designing and synthesizing efficient and cost-effective single atom CO2 electroreduction catalysts for practical applications.

Associations between anterior segment biometry and high axial myopia in 3438 cataractous eyes in the Chinese population.

BACKGROUND: To investigate the associations between anterior segment biometry and high axial myopia in cataractous eyes in the Chinese population. METHODS: Data on 3438 eyes from 3438 subjects were analyzed in this cross-sectional study. Anterior segment biometry, axial length measurements, and intraocular pressure evaluation were implemented using an Oculus Pentacam HR, a Zeiss IOLMaster 500, and a Nidek TonoRef II, respectively. A multivariate-adjusted logistic model and a multivariate-adjusted linear model were used for statistical analysis. RESULTS: The mean age of the subjects was 62.2 ± 10.6 years, and 56.4% were female. There were 2665 subjects with high axial myopia (axial length, ≥26.50 mm) and 773 without (axial length, < 26.50 mm). The characteristics independently associated with high axial myopia included lower total corneal refractive power, a more negative Q value, greater total corneal astigmatism, greater white-to-white corneal diameter, greater anterior chamber depth, and higher intraocular pressure (all P <  0.05). In addition, greater axial length correlated with a thicker temporal cornea and a thinner nasal cornea (both P <  0.001). CONCLUSIONS: For cataractous eyes, high axial myopia was associated with corneal flattening, increased total corneal astigmatism, anterior segment enlargement, and intraocular pressure elevation. The findings may inform the choice of intraocular lenses and the calculation of their power, help improve the surgical practice of refractive cataract procedures, and provide useful information on the centration and stability of intraocular lenses.

Haplotyping by CRISPR-mediated DNA circularization (CRISPR-hapC) broadens allele-specific gene editing.

Allele-specific protospacer adjacent motif (asPAM)-positioning SNPs and CRISPRs are valuable resources for gene therapy of dominant disorders. However, one technical hurdle is to identify the haplotype comprising the disease-causing allele and the distal asPAM SNPs. Here, we describe a novel CRISPR-based method (CRISPR-hapC) for haplotyping. Based on the generation (with a pair of CRISPRs) of extrachromosomal circular DNA in cells, the CRISPR-hapC can map haplotypes from a few hundred bases to over 200 Mb. To streamline and demonstrate the applicability of the CRISPR-hapC and asPAM CRISPR for allele-specific gene editing, we reanalyzed the 1000 human pan-genome and generated a high frequency asPAM SNP and CRISPR database (www.crispratlas.com/knockout) for four CRISPR systems (SaCas9, SpCas9, xCas9 and Cas12a). Using the huntingtin (HTT) CAG expansion and transthyretin (TTR) exon 2 mutation as examples, we showed that the asPAM CRISPRs can specifically discriminate active and dead PAMs for all 23 loci tested. Combination of the CRISPR-hapC and asPAM CRISPRs further demonstrated the capability for achieving highly accurate and haplotype-specific deletion of the HTT CAG expansion allele and TTR exon 2 mutation in human cells. Taken together, our study provides a new approach and an important resource for genome research and allele-specific (haplotype-specific) gene therapy.

Characteristics of Nursing Home Resident Movement Patterns: Results from the TEAM-UP Trial.

OBJECTIVE: To determine movement patterns of nursing home residents, specifically those with dementia or obesity, to improve repositioning approaches to pressure injury (PrI) prevention. METHODS: A descriptive exploratory study was conducted using secondary data from the Turn Everyone And Move for Ulcer Prevention (TEAM-UP) clinical trial examining PrI prevention repositioning intervals. K-means cluster analysis used the average of each resident's multiple days' observations of four summary mean daily variables to create homogeneous movement pattern clusters. Growth mixture models examined movement pattern changes over time. Logistic regression analyses predicted resident and nursing home cluster group membership. RESULTS: Three optimal clusters partitioned 913 residents into mutually exclusive groups with significantly different upright and lying patterns. The models indicated stable movement pattern trajectories across the 28-day intervention period. Cluster profiles were not differentiated by residents with dementia (n = 450) or obesity (n = 285) diagnosis; significant cluster differences were associated with age and Braden Scale total scores or risk categories. Within clusters 2 and 3, residents with dementia were older (P < .0001) and, in cluster 2, were also at greater PrI risk (P < .0001) compared with residents with obesity; neither group differed in cluster 1. CONCLUSIONS: Study results determined three movement pattern clusters and advanced understanding of the effects of dementia and obesity on movement with the potential to improve repositioning protocols for more effective PrI prevention. Lying and upright position frequencies and durations provide foundational knowledge to support tailoring of PrI prevention interventions despite few significant differences in repositioning patterns for residents with dementia or obesity.

Effect of Varying Repositioning Frequency on Pressure Injury Prevention in Nursing Home Residents: TEAM-UP Trial Results.

OBJECTIVE: To investigate the clinical effectiveness of three nursing-home-wide repositioning intervals (2-, 3-, or 4-hour) without compromising pressure injury (PrI) incidence in 4 weeks. METHODS: An embedded pragmatic cluster randomized controlled trial was conducted in nine nursing homes (NHs) that were randomly assigned to one of three repositioning intervals. Baseline (12 months) and 4-week intervention data were provided during the TEAM-UP (Turn Everyone And Move for Ulcer Prevention) study. Intervention residents were without current PrIs, had PrI risk (Braden Scale score) ≥10 (not severe risk), and used viable 7-inch high-density foam mattresses. Each arm includes three NHs with an assigned single repositioning interval (2-, 3-, or 4-hour) as standard care during the intervention. A wireless patient monitoring system, using wearable single-use patient sensors, cued nursing staff by displaying resident repositioning needs on conveniently placed monitors. The primary outcome was PrI incidence; the secondary outcome was staff repositioning compliance fidelity. RESULTS: From May 2017 to October 2019, 1,100 residents from nine NHs were fitted with sensors; 108 of these were ineligible for some analyses because of missing baseline data. The effective sample size included 992 residents (mean age, 78 ± 13 years; 63% women). The PrI incidence during the intervention was 0.0% compared with 5.24% at baseline, even though intervention resident clinical risk scores were significantly higher (P < .001). Repositioning compliance for the 4-hour repositioning interval (95%) was significantly better than for the 2-hour (80%) or 3-hour (90%) intervals (P < .001). CONCLUSIONS: Findings suggest that current 2-hour protocols can be relaxed for many NH residents without compromising PrI prevention. A causal link was not established between repositioning interval treatments and PrI outcome; however, no new PrIs developed. Compliance improved as repositioning interval lengthened.

para-Selective C-H Borylation of Aromatic Quaternary Ammonium and Phosphonium Salts.

Aromatic ammonium and phosphonium salts are important synthetic intermediates and multifunctional materials, but para-selective functionalization of the aromatic salts remains a challenge. Here we develop an ionic ligand based on our newly designed "biphenyl-phenanthroline" skeleton and realize the Ir-catalyzed para-selective C-H borylation of seven types of aromatic quaternary ammonium and phosphonium salts. Gram-scale transformation, late-stage elaboration for drug molecule, and diversification of borylated products demonstrate the potential utility of this reaction. The mechanistic studies and computational analysis elucidate the origin of para-selectivity.

Hydrogen-Bonded Organic Framework Ultrathin Nanosheets for Efficient Visible-Light Photocatalytic CO2 Reduction.

Post-modification of robust guanine-quadruplex-linked 2,2'-pyridine-containing HOF-25 with Ni(ClO4 )2 ⋅ 6 H2 O followed by exfoliation using sonication method affords hydrogen-bonded organic framework (HOF) nanosheets (NSs) of HOF-25-Ni in the yield of 56 %. TEM and AFM technologies disclose the ultrathin nature of HOF-25-Ni NSs with thickness of 4.4 nm. STM observation determines the presence of sql segments assembled from HOF-25-Ni building blocks at the heptanoic acid/highly oriented pyrolytic graphite interface, supporting the simulated 2D supramolecular framework. ICP-MS, XAS, and XPS data prove the successful immobilization of atomic nickel sites on the 20 % total 2,2'-pyridine moieties in crystalline HOF-25-Ni. With the aid of [Ru(bpy)3 ]2+ and triisopropanolamine, 10 wt% HOF-25-Ni NSs dispersed on graphene oxide efficiently promotes visible-light-driven CO2 reduction, showing a 96.3 % CO selectivity with a prominent conversion rate up to 24 323 µmol g-1 h-1 .

County-level Predictors of Growth in Community-based Primary Care Use Among Veterans.

BACKGROUND: The 2014 Choice Act expanded the Veterans Health Administration's (VA) capacity to purchase services for VA enrollees from community providers, yet little is known regarding the growth of Veterans' primary care use in community settings. OBJECTIVES: The aim was to measure county-level growth in VA community-based primary care (CBPC) penetration following the Choice Act and to assess whether CBPC penetration increased in rural counties with limited access to VA facilities. DATA AND SAMPLE: A total of 3132 counties from VA administrative data from 2015 to 2018, Area Health Resources Files, and County Health Rankings. ANALYSIS: We defined the county-level CBPC penetration rate as the proportion of VA-purchased primary care out of all VA-purchased primary care (ie, within and outside VA). We estimated county-level multivariate linear regression models to assess whether rurality and supply of primary care providers and health care facilities were significantly associated with CBPC growth. RESULTS: Nationally, CBPC penetration rates increased from 2.7% in 2015 to 7.3% in 2018. The rurality of the county was associated with a 2-3 percentage point (pp) increase in CBPC penetration growth (P<0.001). The presence of a VA facility was associated with a 1.7 pp decrease in CBPC penetration growth (P<0.001), while lower primary care provider supply was associated with a 0.6 pp increase in CBPC growth (P<0.001). CONCLUSION: CBPC as a proportion of all VA-purchased primary care was small but increased nearly 3-fold between 2015 and 2018. Greater increases in CBPC penetration were concentrated in rural counties and counties without a VA facility, suggesting that community care may enhance primary care access in rural areas with less VA presence.

Identification of glycolysis related pathways in pancreatic adenocarcinoma and liver hepatocellular carcinoma based on TCGA and GEO datasets.

BACKGROUND: Abnormal energy metabolism is one of the characteristics of tumor cells, and it is also a research hotspot in recent years. Due to the complexity of digestive system structure, the frequency of tumor is relatively high. We aim to clarify the prognostic significance of energy metabolism in digestive system tumors and the underlying mechanisms. METHODS: Gene set variance analysis (GSVA) R package was used to establish the metabolic score, and the score was used to represent the metabolic level. The relationship between the metabolism and prognosis of digestive system tumors was explored using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Volcano plots and gene ontology (GO) analyze were used to show different genes and different functions enriched between different glycolysis levels, and GSEA was used to analyze the pathway enrichment. Nomogram was constructed by R package based on gene characteristics and clinical parameters. qPCR and Western Blot were applied to analyze gene expression. All statistical analyses were conducted using SPSS, GraphPad Prism 7, and R software. All validated experiments were performed three times independently. RESULTS: High glycolysis metabolism score was significantly associated with poor prognosis in pancreatic adenocarcinoma (PAAD) and liver hepatocellular carcinoma (LIHC). The STAT3 (signal transducer and activator of transcription 3) and YAP1 (Yes1-associated transcriptional regulator) pathways were the most critical signaling pathways in glycolysis modulation in PAAD and LIHC, respectively. Interestingly, elevated glycolysis levels could also enhance STAT3 and YAP1 activity in PAAD and LIHC cells, respectively, forming a positive feedback loop. CONCLUSIONS: Our results may provide new insights into the indispensable role of glycolysis metabolism in digestive system tumors and guide the direction of future metabolism-signaling target combined therapy.

Systematical analysis reveals a strong cancer relevance of CREB1-regulated genes.

The transcription factor cyclic-AMP response element-binding protein 1 (CREB1) responds to cAMP level and controls the expression of target genes, which regulates nutrition partitioning. The promoters of CREB1-targeted genes responsive to cAMP have been extensively investigated and characterized with the presence of both cAMP response element and TATA box. Compelling evidence demonstrates that CREB1 also plays an essential role in promoting tumor development. However, only very few genes required for cell survival, proliferation and migration are known to be constitutively regulated by CREB1 in tumors. Their promoters mostly do not harbor any cAMP response element. Thus, it is very likely that CREB1 regulates the expressions of distinct sets of target genes in normal tissues and tumors. The whole gene network constitutively regulated by CREB1 in tumors has remained unrevealed. Here, we employ a systematical and integrative approach to decipher this gene network in the context of both tissue cultured cancer cells and patient samples. We combine transcriptomic, Rank-Rank Hypergeometric Overlap, and Chipseq analysis, to define and characterize CREB1-regulated genes in a multidimensional fashion. A strong cancer relevance of those top-ranked targets, which meet the most stringent criteria, is eventually verified by overall survival analysis of cancer patients. These findings strongly suggest the importance of genes constitutively regulated by CREB1 for their implicative involvement in promoting tumorigenesis.

Endothelial Scaffolding Protein ENH (Enigma Homolog Protein) Promotes PHLPP2 (Pleckstrin Homology Domain and Leucine-Rich Repeat Protein Phosphatase 2)-Mediated Dephosphorylation of AKT1 and eNOS (Endothelial NO Synthase) Promoting Vascular Remodeling.

OBJECTIVE: A decrease in nitric oxide, leading to vascular smooth muscle cell proliferation, is a common pathological feature of vascular proliferative diseases. Nitric oxide synthesis by eNOS (endothelial nitric oxide synthase) is precisely regulated by protein kinases including AKT1. ENH (enigma homolog protein) is a scaffolding protein for multiple protein kinases, but whether it regulates eNOS activation and vascular remodeling remains unknown. Approach and Results: ENH was upregulated in injured mouse arteries and human atherosclerotic plaques and was associated with coronary artery disease. Neointima formation in carotid arteries, induced by ligation or wire injury, was greatly decreased in endothelium-specific ENH-knockout mice. Vascular ligation reduced AKT and eNOS phosphorylation and nitric oxide production in the endothelium of control but not ENH-knockout mice. ENH was found to interact with AKT1 and its phosphatase PHLPP2 (pleckstrin homology domain and leucine-rich repeat protein phosphatase 2). AKT and eNOS activation were prolonged in VEGF (vascular endothelial growth factor)-induced ENH- or PHLPP2-deficient endothelial cells. Inhibitors of either AKT or eNOS effectively restored ligation-induced neointima formation in ENH-knockout mice. Moreover, endothelium-specific PHLPP2-knockout mice displayed reduced ligation-induced neointima formation. Finally, PHLPP2 was increased in the endothelia of human atherosclerotic plaques and blood cells from patients with coronary artery disease. CONCLUSIONS: ENH forms a complex with AKT1 and its phosphatase PHLPP2 to negatively regulate AKT1 activation in the artery endothelium. AKT1 deactivation, a decrease in nitric oxide generation, and subsequent neointima formation induced by vascular injury are mediated by ENH and PHLPP2. ENH and PHLPP2 are thus new proatherosclerotic factors that could be therapeutically targeted.

Engineering of Coordination Environment and Multiscale Structure in Single-Site Copper Catalyst for Superior Electrocatalytic Oxygen Reduction.

Herein, we report efficient single copper atom catalysts that consist of dense atomic Cu sites dispersed on a three-dimensional carbon matrix with highly enhanced mesoporous structures and improved active site accessibility (Cu-SA/NC(meso)). The ratio of +1 to +2 oxidation state of the Cu sites in the Cu-SA/NC(meso) catalysts can be controlled by varying the urea content in the adsorption precursor, and the activity for ORR increases with the addition of Cu1+ sites. The optimal Cu1+-SA/NC(meso)-7 catalyst with highly accessible Cu1+ sites exhibits superior ORR activity in alkaline media with a half-wave potential (E1/2) of 0.898 V vs RHE, significantly exceeding the commercial Pt/C, along with high durability and enhanced methanol tolerance. Control experiments and theoretical calculations demonstrate that the superior ORR catalytic performance of Cu1+-SA/NC(meso)-7 catalyst is attributed to the atomically dispersed Cu1+ sites in catalyzing the reaction and the advantage of the introduced mesoporous structure in enhancing the mass transport.

Identification and functional characterization of mutations in LPL gene causing severe hypertriglyceridaemia and acute pancreatitis.

Hypertriglyceridaemia is a very rare disorder caused by the mutations of LPL gene, with an autosomal recessive mode of inheritance. Here, we identified two unrelated Chinese patients manifested with severe hypertriglyceridaemia and acute pancreatitis. The clinical symptoms of proband 1 are more severe than proband 2. Whole exome sequencing and Sanger sequencing were performed. Functional analysis of the identified mutations has been done. Whole exome sequencing identified two pairs of variants in LPL gene in the proband 1 (c.162C>A and c.1322+1G>A) and proband 2 (c.835C>G and c.1322+1G>A). The substitution (c.162C>A) leads to the formation of a truncated (p.Cys54*) LPL protein. The substitution (c.835C>G) leads to the replacement of leucine to valine (p.Leu279Val). The splice donor site mutation (c.1322+1G>A) leads to the formation of alternative transcripts with the loss of 134 bp in exon 8 of the LPL gene. The proband 1 and his younger son also harbouring a heterozygous variant (c.553G>T; p.Gly185Cys) in APOA5 gene. The relative expression level of the mutated LPL mRNA (c.162C>A, c.835C>G and c.1322+1G>A) showed significant differences compared to wild-type LPL mRNA, suggesting that all these three mutations affect the transcription of LPL mRNA. These three mutations (c.162C>A, c.835C>G and c.1322+1G>A) showed noticeably decreased LPL activity in cell culture medium but not in cell lysates. Here, we identified three mutations in LPL gene which causes severe hypertriglyceridaemia with acute pancreatitis in Chinese patients. We also described the significance of whole exome sequencing for identifying the candidate gene and disease-causing mutation in patients with severe hypertriglyceridaemia and acute pancreatitis.