Tripedal DNA Walker as a Signal Amplifier Combined with a Potential-Resolved Multicolor Electrochemiluminescence Strategy for Ultrasensitive Detection of Prostate Cancer Staging Indicators.

A multicolor electrochemiluminescence (ECL) biosensor based on a closed bipolar electrode (BPE) array was proposed for the rapid and intuitive analysis of three prostate cancer staging indicators. First, [Irpic-OMe], [Ir(ppy)2(acac)], and [Ru(bpy)3]2+ were applied as blue, green, and red ECL emitters, respectively, whose mixed ECL emission colors covered the whole visible region by varying the applied voltages. Afterward, we designed a simple Mg2+-dependent DNAzyme (MNAzyme)-driven tripedal DNA walker (TD walker) to release three output DNAs. Immediately after, three output DNAs were added to the cathodic reservoirs of the BPE for incubation. After that, we found that the emission colors from the anode of the BPE changed as a driving voltage of 8.0 V was applied, mainly due to changes in the interfacial potential and faradaic currents at the two poles of the BPE. Via optimization of the experimental parameters, cutoff values of such three indicators at different clinical stages could be identified instantly with the naked eye, and standard precision swatches with multiple indicators could be prepared. Finally, in order to precisely determine the prostate cancer stage, the multicolor ECL device was used for clinical analysis, and the resulting images were then compared with standard swatches, laying the way for accurate prostate cancer therapy.

Dual "on-off" signal conversion strategy based on surface plasmon coupling and resonance energy transfer for visual electrochemiluminescence ratiometric analysis of MiRNA-141.

An electrochemiluminescence (ECL) biosensor with a pair of new ECL emitters and a novel sensing mechanism was designed for the high-sensitivity detection of microRNA-141 (miRNA-141). Sulfur-doped boron nitrogen quantum dots (S-BN QDs) were initially employed to modify the cathode of the bipolar electrode (BPE), while the anode reservoir was [Ir(dfppy)2(bpy)]PF6/TPrA system. The next step involved attaching H1-bound ultra-small WO3-x nanodots (WO3-x NDs) to the S-BN QDs-modified BPE cathode via DNA hybridization. A strong surface plasmon coupling (SPC) effect was observed between S-BN QDs and WO3-x NDs, which allowed for the enhancement of the red and visible ECL emission from S-BN QDs. After target-induced cyclic amplification to produce abundant Zn2+ and Au NPs-DNA3-Au NPs (Au NPs-S3-Au NPs), Zn2+ could cleave DNA at a nucleotide sequence-specific recognition site to release the WO3-x NDs, resulting in the first diminution of cathode ECL signal and the first enhancement of anode ECL signal. Moreover, the ECL signal at cathode decreased for the second time and the emission of [Ir(dfppy)2(bpy)]PF6 was continuously enhanced after the introduction of Au nanoparticles-S3-Au nanoparticles on the cathode surface. Our sensing mode with a dual "on-off" signal conversion strategy shows a good detection capability for miRNAs ranging from 10-17 to 10-10 M, with a limit of detection (LOD) as low as 10-17 M, which has great application potential in biomedical research and clinical diagnosis.

H3K4 Trimethylation Mediate Hyperhomocysteinemia Induced Neurodegeneration via Suppressing Histone Acetylation by ANP32A.

Homocysteine (Hcy) is an independent and serious risk factor for dementia, including Alzheimer's disease (AD), but the precise mechanisms are still poorly understood. In the current study, we observed that the permissive histone mark trimethyl histone H3 lysine 4 (H3K4me3) and its methyltransferase KMT2B were significantly elevated in hyperhomocysteinemia (HHcy) rats, with impairment of synaptic plasticity and cognitive function. Further research found that histone methylation inhibited synapse-associated protein expression, by suppressing histone acetylation. Inhibiting H3K4me3 by downregulating KMT2B could effectively restore Hcy-inhibited H3K14ace in N2a cells. Moreover, chromatin immunoprecipitation revealed that Hcy-induced H3K4me3 resulted in ANP32A mRNA and protein overexpression in the hippocampus, which was regulated by increased transcription Factor c-fos and inhibited histone acetylation and synapse-associated protein expression, and downregulating ANP32A could reverse these changes in Hcy-treated N2a cells. Additionally, the knockdown of KMT2B restored histone acetylation and synapse-associated proteins in Hcy-treated primary hippocampal neurons. These data have revealed a novel crosstalk mechanism between KMT2B-H3K4me3-ANP32A-H3K14ace, shedding light on its role in Hcy-related neurogenerative disorders.

Corrigendum: Comparison of cardiac function between single left ventricle and tricuspid atresia: assessment using echocardiography combined with computational fluid dynamics.

[This corrects the article DOI: 10.3389/fped.2023.1159342.].

Metagenomic insights into the dynamic degradation of brown algal polysaccharides by kelp-associated microbiota.

Marine bacteria play important roles in the degradation and cycling of algal polysaccharides. However, the dynamics of epiphytic bacterial communities and their roles in algal polysaccharide degradation during kelp decay are still unclear. Here, we performed metagenomic analyses to investigate the identities and predicted metabolic abilities of epiphytic bacterial communities during the early and late decay stages of the kelp Saccharina japonica. During kelp decay, the dominant epiphytic bacterial communities shifted from Gammaproteobacteria to Verrucomicrobia and Bacteroidetes. In the early decay stage of S. japonica, epiphytic bacteria primarily targeted kelp-derived labile alginate for degradation, among which the gammaproteobacterial Vibrionaceae (particularly Vibrio) and Psychromonadaceae (particularly Psychromonas), abundant in alginate lyases belonging to the polysaccharide lyase (PL) families PL6, PL7, and PL17, were key alginate degraders. More complex fucoidan was preferred to be degraded in the late decay stage of S. japonica by epiphytic bacteria, predominantly from Verrucomicrobia (particularly Lentimonas), Pirellulaceae of Planctomycetes (particularly Rhodopirellula), Pontiellaceae of Kiritimatiellota, and Flavobacteriaceae of Bacteroidetes, which depended on using glycoside hydrolases (GHs) from the GH29, GH95, and GH141 families and sulfatases from the S1_15, S1_16, S1_17, and S1_25 families to depolymerize fucoidan. The pathways for algal polysaccharide degradation in dominant epiphytic bacterial groups were reconstructed based on analyses of metagenome-assembled genomes. This study sheds light on the roles of different epiphytic bacteria in the degradation of brown algal polysaccharides.IMPORTANCEKelps are important primary producers in coastal marine ecosystems. Polysaccharides, as major components of brown algal biomass, constitute a large fraction of organic carbon in the ocean. However, knowledge of the identities and pathways of epiphytic bacteria involved in the degradation process of brown algal polysaccharides during kelp decay is still elusive. Here, based on metagenomic analyses, the succession of epiphytic bacterial communities and their metabolic potential were investigated during the early and late decay stages of Saccharina japonica. Our study revealed a transition in algal polysaccharide-degrading bacteria during kelp decay, shifting from alginate-degrading Gammaproteobacteria to fucoidan-degrading Verrucomicrobia, Planctomycetes, Kiritimatiellota, and Bacteroidetes. A model for the dynamic degradation of algal cell wall polysaccharides, a complex organic carbon, by epiphytic microbiota during kelp decay was proposed. This study deepens our understanding of the role of epiphytic bacteria in marine algal carbon cycling as well as pathogen control in algal culture.

Design, Synthesis, Nematicidal, and Fungicidal Activities of Novel Azo and Azoxy Compounds.

Bursaphelenchus xylophilus (B. xylophilus) and Meloidogyne are parasitic nematodes that have caused severe ecological and economic damage in pinewood and crops, respectively. Jietacins (jietacin A and B) were found to have excellent biological activity against B. xylophilus. Based on our tremendous demand for chemicals against B. xylophilus, a novel scaffold based on the azo and azoxy groups was designed, and a series of compounds were synthesized. In the bioassay, Ia, IIa, IIc, IId, and IVa exhibited higher activity against B. xylophilus in vitro than avermectin (LC50 = 2.43 µg·mL-1) with LC50 values of 1.37, 1.12, 0.889, 1.56, and 1.10 µg·mL-1, respectively. Meanwhile, Ib, Ic, IIc, and IVa showed good inhibition effects against Meloidogyne in vivo at the concentrations of 80 and 40 µg·mL-1 with inhibition rates of 89.0% and 81.6%, 95.6% and 75.7%, 96.3% and 41.2%, and 86.8% and 78.7%, respectively. In fungicidal activity in vitro, IIb and IVa exhibited excellent effect against Botryosphaeria dothidea with the inhibition of 82.59% and 85.32% at the concentration of 10 µg·mL-1, while the inhibition of Ia was 83.16% against Rhizoctonia solani at the concentration of 12.5 µg·mL-1. Referring to the biological activity against B. xylophilus, a 3D-QASR model was built in which the electron-donating group and small group at the 4-phenylhydrazine were favorable for the activity. In general, the novel azoxy compounds, especially IIc possess great potential for application in the prevention of B. xylophilus.

A clinical predictive model for pre-transplantation Klebsiella pneumoniae colonization and relevance for clinical outcomes in patients receiving allogeneic hematopoietic stem cell transplantation.

The purpose of this study is to establish a clinical prediction model to discriminate patients at high risk of Klebsiella pneumoniae (KP) colonization before allogeneic hematopoietic stem cell transplantation (allo-HSCT) and evaluate the impact of KP colonization on clinical outcomes after allo-HSCT. We retrospectively collected data from 2,157 consecutive patients receiving allo-HSCT between January 2018 and March 2022. KP colonization was defined as a positive test for KP from a pharyngeal or anal swab before allo-HSCT. Logistic regression was used to build a clinical prediction model. Cox regression analyses were performed to explore the effect of KP colonization on clinical outcomes. Among all the inpatients, 166 patients had KP colonization and 581 with no positive pathogenic finding before transplantation. Seven candidate predictors were entered into the final prediction model. The prediction model had an area under the curve of 0.775 (95% CI 0.723-0.828) in the derivation cohort and 0.846 (95% CI: 0.790-0.902) in the validation cohort. Statistically significantly different incidence rates were observed among patient groups with clinically predicted low, medium, and high risk for KP infection (P < 0.001). The presence of KP colonization delayed platelet engraftment (P < 0.001) and patients with KP colonization were more likely to develop KP bloodstream infections within 100 days after allo-HSCT (P < 0.0001). Patients with KP colonization had higher non-relapse mortality (P = 0.032), worse progression-free survival (P = 0.0027), and worse overall survival within 100 days after allo-HSCT (P = 0.013). Our findings suggest that increased awareness of risks associated with pre-transplantation bacterial colonization is warranted.IMPORTANCESeveral studies have identified that Klebsiella pneumoniae (KP) is among the most common and deadly pathogens for patients in hospital intensive care units and those receiving transplantation. However, there are currently no studies that evaluate the impact of KP colonization to patients undergoing allogeneic hematopoietic stem cell transplantation. Our results confirm that pre-existing KP colonization is relatively common in a hematology transplant ward setting and negatively affects post-transplantation prognosis. Our clinical prediction model for KP colonization can support early intervention in patients at high risk to avoid subsequent bloodstream infections and improve survival outcomes. Altogether, our data suggest that increased awareness of risks associated with pre-transplantation bacterial colonization is warranted. Future studies are needed to confirm these findings and to test early intervention strategies for patients at risk of complications from KP infection.

Ni Single-Atoms Based Memristors with Ultrafast Speed and Ultralong Data Retention.

Memristor with low-power, high density, and scalability fulfills the requirements of the applications of the new computing system beyond Moore's law. However, there are still nonideal device characteristics observed in the memristor to be solved. The important observation is that retention and speed are correlated parameters of memristor with trade off against each other. The delicately modulating distribution and trapping level of defects in electron migration-based memristor is expected to provide a compromise method to address the contradictory issue of improving both switching speed and retention capability. Here, high-performance memristor based on the structure of ITO/Ni single-atoms (NiSAs/N-C)/Polyvinyl pyrrolidone (PVP)/Au is reported. By utilizing well-distributed trapping sites , small tunneling barriers/distance and high charging energy, the memristor with an ultrafast switching speed of 100 ns, ultralong retention capability of 106  s, a low set voltage (Vset ) of ≈0.7 V, a substantial ON/OFF ration of 103 , and low spatial variation in cycle-to-cycle (500 cycles) and device-to-device characteristics (128 devices) is demonstrated. On the premise of preserving the strengths of a fast switching speed, this memristor exhibits ultralong retention capability comparable to the commercialized flash memory. Finally, a memristor ratioed logic-based combinational memristor array to realize the one-bit full adder is further implemented.

Hierarchies in Visual Pathway: Functions and Inspired Artificial Vision.

The development of artificial intelligence has posed a challenge to machine vision based on conventional complementary metal-oxide semiconductor (CMOS) circuits owing to its high latency and inefficient power consumption originating from the data shuffling between memory and computation units. Gaining more insights into the function of every part of the visual pathway for visual perception can bring the capabilities of machine vision in terms of robustness and generality. Hardware acceleration of more energy-efficient and biorealistic artificial vision highly necessitates neuromorphic devices and circuits that are able to mimic the function of each part of the visual pathway. In this paper, we review the structure and function of the entire class of visual neurons from the retina to the primate visual cortex within reach (Chapter 2) are reviewed. Based on the extraction of biological principles, the recent hardware-implemented visual neurons located in different parts of the visual pathway are discussed in detail in Chapters 3 and 4. Furthermore, valuable applications of inspired artificial vision in different scenarios (Chapter 5) are provided. The functional description of the visual pathway and its inspired neuromorphic devices/circuits are expected to provide valuable insights for the design of next-generation artificial visual perception systems.

Aerobic exercise attenuates autophagy-lysosomal flux deficits by ADRB2/ß2-adrenergic receptor-mediated V-ATPase assembly factor VMA21 signaling in APP-PSEN1/PS1 mice.

Growing evidence suggests that macroautophagy/autophagy-lysosomal pathway deficits contribute to the accumulation of amyloid-ß (Aß) in Alzheimer disease (AD). Aerobic exercise (AE) has long been investigated as an approach to delay and treat AD, although the exact role and mechanism are not well known. Here, we revealed that AE could reverse autophagy-lysosomal deficits via activation of ADRB2/ß2-adrenergic receptor, leading to significant attenuation of amyloid-ß pathology in APP-PSEN1/PS1 mice. Molecular mechanism research found that AE could reverse autophagy deficits by upregulating the AMP-activated protein kinase (AMPK)-MTOR (mechanistic target of rapamycin kinase) signaling pathway. Moreover, AE could reverse V-ATPase function by upregulating VMA21 levels. Inhibition of ADRB2 by propranolol (antagonist, 30 µM) blocked AE-attenuated Aß pathology and cognitive deficits by inhibiting autophagy-lysosomal flux. AE may mitigate AD via many pathways, while ADRB2-VMA21-V-ATPase could improve cognition by enhancing the clearance of Aß through the autophagy-lysosomal pathway, which also revealed a novel theoretical basis for AE attenuating pathological progression and cognitive deficits in AD.

Risk Factors for Carbapenem-Resistant Enterobacteriaceae Colonization and the Effect on Clinical Outcomes and Prognosis in Allogeneic Hematopoietic Stem Cell Transplanted Patients.

Purpose: The current study assesses which are the main risk factors, clinical outcome and prognosis following the colonization of CRE in patients that underwent allo-HSCT. Patients and Methods: A total of 343 patients subjected to allo-HSCT in the period comprised between June 2021 and June 2022 were enrolled in this retrospective study. The CRE colonization was diagnosed by clinical history and routine microbial culture of perirectal swab. In this regard, a clinical prediction model was designed based on independent risk factors underlying the pre-transplantation CRE colonization using a backward stepwise logistic regression, followed by the evaluation of its discrimination and calibration efficacies, along with clinical usefulness. Furthermore, univariate and multivariate Cox regression analyses were then conducted to assess the risk factors for post-transplantation clinical outcomes. Results: Out of 343 patients enrolled in this study, 135 (39.3%) reported CRE colonization. The independent risk factor variables for CRE colonization were incorporated into the nomogram to build a prediction model, which showed an area under the curve of 0.767 (95% CI: 0.716-0.818), and well-fitted calibration curves (χ2 = 1.737, P = 0.9788). The patients with CRE colonization reported a significantly lower platelet engraftment rate with a higher risk of post-transplantation BSI when compared with the non-CRE colonization group (P = 0.02 and P < 0.001; respectively). The non-relapse mortality (NRM) value was higher in the CRE patients (P < 0.05), consistently with a survival probability that was thus significantly lower for the same timeframe (P < 0.05). Conclusion: A reliable clinical prediction model for pre-transplantation CRE colonization was developed that demonstrated that the CRE colonization negatively affects platelet engraftment and survival outcomes following allo-HSCT.

Comparison of cardiac function between single left ventricle and tricuspid atresia: assessment using echocardiography combined with computational fluid dynamics.

Patients with single left ventricle (SLV) and tricuspid atresia (TA) have impaired systolic and diastolic function. However, there are few comparative studies among patients with SLV, TA and children without heart disease. The current study includes 15 children in each group. The parameters measured by two-dimensional echocardiography, three-dimensional speckle tracking echocardiography (3DSTE), and vortexes calculated by computational fluid dynamics were compared among these three groups. Twist is best correlated with ejection fraction measured by 3DSTE. Twist, torsion, apical rotation, average radial strain, peak velocity of systolic wave in left lateral wall by tissue Doppler imaging (sL), and myocardial performance index are better in the TA group than those in the SLV group. sL by tissue Doppler imaging in the TA group are even higher than those in the Control group. In patients with SLV, blood flow spreads out in a fan-shaped manner and forms two small vortices. In the TA group, the main vortex is similar to the one in a normal LV chamber, but smaller. The vortex rings during diastolic phase are incomplete in the SLV and TA groups. In summary, patients with SLV or TA have impaired systolic and diastolic function. Patients with SLV had poorer cardiac function than those with TA due to less compensation and more disordered streamline. Twist may be good indicator for LV function.

Danggui Buxue decoction ameliorates mitochondrial biogenesis and cognitive deficits through upregulating histone H4 lysine 12 acetylation in APP/PS1 mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Buxue decoction (DBD) is a classic herbal decoction consisting of Astragali Radix (AR) and Angelica Sinensis Radix (ASR) with a 5:1 wt ratio, which can supplement 'blood' and 'qi' (vital energy) for the treatment of clinical diseases. According to Traditional Chinese Medicine (TCM) theory, dementia is induced by Blood deficiency and Qi weakness, which causes a decline in cognition. However, the underlying mechanisms of DBD improving cognition deficits in neurodegenerative disease are no clear. AIM OF THE STUDY: This study aims at revealing the underlying mechanisms of DBD plays a protective role in the cognitive deficits and pathology process of Alzheimer's disease (AD). MATERIALS AND METHODS: The APP/PS1 (Mo/HuAPP695swe/PS1-dE9) double transgenic mice were adopted as an experimental model of AD. Qualitative and quantitative analysis of 3 compounds in DBT was analyzed by HPLC. Morris water maze test, Golgi staining and electrophysiology assays were used to evaluate the effects of DBD on cognitive function and synaptic plasticity in APP/PS1 mice. Western blot, immunofluorescence and Thioflavin S staining were used for the pathological evaluation of AD. Monitoring the level of ATP, mitochondrial membrane potential, SOD and MDA to evaluate the mitochondrial function, and with the usage of qPCR and CHIP for the changes of histone post-translational modification. RESULTS: In the current study, we found that DBD could effectively attenuate memory impairments and enhance long-term potentiation (LTP) with concurrent increased expression of memory-associated proteins. DBD markedly decreased Aß accumulation in APP/PS1 mice by decreasing the phosphorylation of APP at the Thr668 level but not APP, PS1 or BACE1. Further studies demonstrated that DBD restored mitochondrial biogenesis deficits and mitochondrial dysfunction. Finally, the restored mitochondrial biogenesis and cognitive deficits are under HADC2-mediated histone H4 lysine 12 (H4K12) acetylation at the peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) and N-methyl-D-aspartate receptor type 2B (GluN2B) promoters. CONCLUSIONS: These findings reveal that DBD could ameliorate mitochondrial biogenesis and cognitive deficits by improving H4K12 acetylation. DBD might be a promising complementary drug candidate for AD treatment.

Gate-tunable transport in van der Waals topological insulator Bi4Br4nanobelts.

Bi4Br4is a quasi-one-dimensional van der Waals topological insulator with novel electronic properties. Several efforts have been devoted to the understanding of its bulk form, yet it remains a challenge to explore the transport properties in low-dimensional structures due to the difficulty of device fabrication. Here we report for the first time a gate-tunable transport in exfoliated Bi4Br4nanobelts. Notable two-frequency Shubnikov-de Haas oscillations oscillations are discovered at low temperatures, with the low- and high-frequency parts coming from the three-dimensional bulk state and the two-dimensional surface state, respectively. In addition, ambipolar field effect is realized with a longitudinal resistance peak and a sign reverse in the Hall coefficient. Our successful measurements of quantum oscillations and realization of gate-tunable transport lay a foundation for further investigation of novel topological properties and room-temperature quantum spin Hall states in Bi4Br4.

Ionizable drug delivery systems for efficient and selective gene therapy.

Gene therapy has shown great potential to treat various diseases by repairing the abnormal gene function. However, a great challenge in bringing the nucleic acid formulations to the market is the safe and effective delivery to the specific tissues and cells. To be excited, the development of ionizable drug delivery systems (IDDSs) has promoted a great breakthrough as evidenced by the approval of the BNT162b2 vaccine for prevention of coronavirus disease 2019 (COVID-19) in 2021. Compared with conventional cationic gene vectors, IDDSs can decrease the toxicity of carriers to cell membranes, and increase cellular uptake and endosomal escape of nucleic acids by their unique pH-responsive structures. Despite the progress, there remain necessary requirements for designing more efficient IDDSs for precise gene therapy. Herein, we systematically classify the IDDSs and summarize the characteristics and advantages of IDDSs in order to explore the underlying design mechanisms. The delivery mechanisms and therapeutic applications of IDDSs are comprehensively reviewed for the delivery of pDNA and four kinds of RNA. In particular, organ selecting considerations and high-throughput screening are highlighted to explore efficiently multifunctional ionizable nanomaterials with superior gene delivery capacity. We anticipate providing references for researchers to rationally design more efficient and accurate targeted gene delivery systems in the future, and indicate ideas for developing next generation gene vectors.

Utility of fetal cardiac magnetic resonance imaging in assessing the cardiac axis in fetuses with congenital heart disease.

BACKGROUND: Fetal dedicated echocardiography is the standard to measure the fetal cardiac axis. However, fetal screening ultrasound (US) or fetal dedicated echocardiography may be technically limited. OBJECTIVE: The purpose of this study was to explore the accuracy of fetal cardiac magnetic resonance imaging (MRI) to measure the cardiac axis in fetuses with congenital heart disease as an adjunct to fetal dedicated echocardiography and to assess the predictive value of fetal cardiac MRI measurements in distinguishing healthy fetuses from fetuses with congenital heart disease. MATERIALS AND METHODS: This is a retrospective study of fetuses referred to our hospital for a fetal cardiac MRI from November 2019 to December 2021. Cardiac axes were measured in the 4-chamber view of the fetal heart using fetal cardiac MRI and dedicated echocardiography, or only using fetal cardiac MRI when screening US was technically limited. The fetuses were divided into a congenital heart disease group and a healthy control group. We used Bland-Altman analysis and the intraclass correlation coefficient (ICC) to assess the agreement of cardiac axis measurements in fetuses with congenital heart disease obtained by cardiac MRI and by fetal dedicated echocardiography. Receiver operating characteristic (ROC) curve analysis of the fetal cardiac axes in the congenital heart disease and healthy fetus groups assessed the predictive value of the cardiac axis measurements. RESULTS: This retrospective study included 431 women (162 carrying fetuses with congenital heart disease, 269 carrying healthy fetuses). Cardiac axes were measured in the 162 fetuses with congenital heart disease using fetal cardiac MRI and dedicated echocardiography. Cardiac axes were measured in the 269 healthy control fetuses using fetal cardiac MRI when fetal screening US was technically limited. The interobserver analysis and intraobserver analysis showed that the cardiac axis measured by fetal cardiac MRI and fetal dedicated echocardiography was repeatable (ICC>0.90). In 162 fetuses with congenital heart disease, Bland-Altman analysis showed a strong agreement between cardiac MRI and fetal dedicated echocardiography measurements for the cardiac axis. The ICC for the cardiac axis values between cardiac MRI and fetal dedicated echocardiography measurements was 0.99. In fetuses with congenital heart disease, 64.2% (104/162) had an abnormal cardiac axis. For the fetal cardiac axis in both the 162 fetuses with congenital heart disease and the 269 healthy fetuses, the area under the ROC curve reached 0.85 (95% confidence interval: 0.80-0.89; P<0.0001). CONCLUSION: The cardiac axis can be accurately measured using fetal cardiac MRI when fetal dedicated echocardiography/fetal screening US is technically limited. The cardiac axis measurements by fetal cardiac MRI are consistent with known cardiac axis measurements by fetal dedicated echocardiography. The frequency of abnormal cardiac axis depends on the type of congenital heart disease.

Bioinformatics analysis of sterol O⁃acyltransferase 1 gene related to hepatocellular carcinoma / 中国生物制品学杂志

@#Abstract：Objective To predict the structure and function of sterol O⁃acyltransferase 1（SOAT1）related to hepatocellular carcinoma（HCC）by using bioinformatics tools，in order to understand its mechanism as the marker and therapeutic target of S⁃Ⅲ subtype. Methods The structure，function and protein interaction of SOAT1 were predicted and analyzed by using databases or softwares such as NCBI，STRING，Protscale，SignalP，TMHMM，PSORT，SOPMA，SWISS ⁃ MODEL， NetNGlyc，NetOGlyc，Netphos and ProtParam. Results The protein encoded by SOAT1 was a hydrophobic protein with good stability，which was a nonclassical pathway protein with 8 transmembrane regions，mainly distributed among the cell membrane. SOAT1 was expressed in many tissues，while most of them in the adrenal gland，which showed multiple phosphorylation sites and was mainly involved in the synthesis and catabolism of cholesterol. Conclusion Bioinformatics analysis of structure and function of SOAT1 showed that SOAT1 lipid synthesis and catabolism pathways played an important role，and lipid expression was closely related to the development of cancer，indicating that the treatment of HCC may be achieved by regulating the expression of SOAT1 gene.

Rational design, synthesis and biological evaluation of novel 2-(substituted amino)-[1,2,4]triazolo[1,5-a]pyrimidines as novel tubulin polymerization inhibitors.

Following our previously reported compound 3, we designed and synthesized a series of new 2-(substituted amino)- [1,2,4]triazolo[1,5-a]pyrimidines as potential tubulin polymerization inhibitors. Among them, analogue 4k, having a 3-hydroxy-4-methoxyphenylamino group, was observed to display excellent antiproliferative activity toward HeLa, HCT116, A549, and T47D with the IC50 values of 0.31, 1.28, 3.99 and 10.32 µM, respectively, which were approximately 32, 48, 4, and 5-fold improvement compared with 3. Importantly, 4k possessed significant selectivity in inhibiting cancer cell lines over the normal HEK293 cells. Moreover, futher mechanism analysis demonstrated that 4k caused G2/M arrest, induced cells apoptosis in HeLa cells, and manifested significant tubulin polymerization inhibitory activity with the IC50 value of 4.9 µM, which is comparable to CA-4 (IC50 = 4.2 µM). The observations performed in this study reveal that 2-arylamino- [1,2,4]triazolo[1,5-a]pyrimidines represent a novel class of tubulin polymerization inhibitors with potent antiproliferative efficacy.

Activation of ß2-adrenergic Receptor Ameliorates Amyloid-ß-induced Mitophagy Defects and Tau Pathology in Mice.

Defective mitophagy and mitochondrial dysfunction have been linked to aging and Alzheimer's disease (AD). ß2-Adrenergic receptor (ADRB2) is critical for mitochondrial and cognitive function. However, researchers have not clearly determined whether ADRB2 activation ameliorates defective mitophagy and cognitive deficits in individuals with AD. Here, we observed that the activation of ADRB2 by clenbuterol (Clen, ADRB2 agonist, 2 mg/kg/day) ameliorated amyloid-ß-induced (Aß1-42 bilateral intracerebral infusion, 2 µl, 5 µg/µl) memory deficits. Activation of ADRB2 also attenuated Aß-induced mitochondrial dysfunction, as revealed by increased ATP levels, mitochondrial membrane potential (MMP/Δψm) and complex I activity. Further studies revealed that ADRB2 activation restored mitophagy deficits, as revealed by the increased light chain 3 (LC3)-II/LC3-I ratio, Atg5 levels, and Atg7 levels and decreased p62 levels, along with the upregulation of PTEN-induced putative kinase 1 (PINK1), Parkin and NAD+ levels. Activation of ADRB2 rescued Aß-induced oxidative stress and neuronal death. ADRB2 activation also attenuated Aß-induced tau hyperphosphorylation by regulating glycogen synthase kinase-3ß expression in the hippocampus. Finally, we established that Clen improved mitophagy and attenuated mitochondrial dysfunction, and tau pathology in mice by activating the ADRB2/Akt/PINK1 signaling pathway. Conversely, the inhibition of ADRB2 by propranolol (ßAR antagonist, 10 µM) blocked the Clen-mediated improvements in pathological changes in N2a cells. The results from the present study indicate that ADRB2 activation may be a therapeutic strategy for AD.

Pharmacokinetic Study of Nalbuphine in Surgical Patients Undergoing General Anesthesia with Varying Degrees of Liver Dysfunction.

Purpose: This study aimed to characterize the pharmacokinetics of nalbuphine in patients undergoing general anesthesia with varying degrees of liver dysfunction. Patients and Methods: Twenty-four patients were enrolled and divided into three cohorts based on liver function: normal liver function (n = 13), mild liver dysfunction (n = 5), and moderate/severe liver dysfunction (n = 6). During the induction of anesthesia, they received 15 mg of nalbuphine intravenously. Venous blood samples were collected from each patient. The plasma concentration of nalbuphine was determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of nalbuphine were calculated by non-compartmental analysis (NCA) using Phoenix WinNonlin software. Results: Compared with the normal liver function group, the plasma elimination half-life (T1/2) of nalbuphine was increased by approximately 33% in the moderate/severe liver dysfunction group (2.66 h vs 3.54 h, P<0.05), and the volume of distribution (Vd) increased by approximately 85% (100.08 L vs 184.95 L, P<0.05). Multivariate analysis revealed that weight and platelet were associated with clearance (CL); total bilirubin as an independent factor was associated with T1/2, and weight associated with area under the curve (AUC(0→∞)) independently. Conclusion: The T1/2, mean residence time, and Vd of nalbuphine in patients with moderate/severe liver dysfunction were prolonged or increased significantly compared with those in the normal liver function group. These data suggest that it may need to be used with caution when nalbuphine is administered to patients with moderate or severe liver dysfunction.