Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3-MAPK Signaling to Trigger Spontaneous Aortic Dissection.

BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS: Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3SMKO and Best3ECKO, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS: Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3SMKO but not Best3ECKO mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3SMKO and ApoE-/- mice. CONCLUSIONS: These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD.

Temporal dynamics of genetic architecture governing leaf development in Populus.

Leaf development is a multifaceted and dynamic process orchestrated by a myriad of genes to shape the proper size and morphology. The dynamic genetic network underlying leaf development remains largely unknown. Utilizing a synergistic genetic approach encompassing dynamic genome-wide association study (GWAS), time-ordered gene co-expression network (TO-GCN) analyses and gene manipulation, we explored the temporal genetic architecture and regulatory network governing leaf development in Populus. We identified 42 time-specific and 18 consecutive genes that displayed different patterns of expression at various time points. We then constructed eight TO-GCNs that covered the cell proliferation, transition, and cell expansion stages of leaf development. Integrating GWAS and TO-GCN, we postulated the functions of 27 causative genes for GWAS and identified PtoGRF9 as a key player in leaf development. Genetic manipulation via overexpression and suppression of PtoGRF9 revealed its primary influence on leaf development by modulating cell proliferation. Furthermore, we elucidated that PtoGRF9 governs leaf development by activating PtoHB21 during the cell proliferation stage and attenuating PtoLD during the transition stage. Our study provides insights into the dynamic genetic underpinnings of leaf development and understanding the regulatory mechanism of PtoGRF9 in this dynamic process.

Genomic insights into selection for heterozygous alleles and woody traits in Populus tomentosa.

Heterozygous alleles are widespread in outcrossing and clonally propagated woody plants. The variation in heterozygosity that underlies population adaptive evolution and phenotypic variation, however, remains largely unknown. Here, we describe a de novo chromosome-level genome assembly of Populus tomentosa, an economic and ecologically important native tree in northern China. By resequencing 302 natural accessions, we determined that the South subpopulation (Pop_S) encompasses the ancestral strains of P. tomentosa, while the Northwest subpopulation (Pop_NW) and Northeast subpopulation (Pop_NE) experienced different selection pressures during population evolution, resulting in significant population differentiation and a decrease in the extent of heterozygosity. Analysis of heterozygous selective sweep regions (HSSR) suggested that selection for lower heterozygosity contributed to the local adaptation of P. tomentosa by dwindling gene expression and genetic load in the Pop_NW and Pop_NE subpopulations. Genome-wide association studies (GWAS) revealed that 88 single nucleotide polymorphisms (SNPs) within 63 genes are associated with nine wood composition traits. Among them, the selection for the homozygous AA allele in PtoARF8 is associated with reductions in cellulose and hemicellulose contents by attenuating PtoARF8 expression, and the increase in lignin content is attributable to the selection for decreases in exon heterozygosity in PtoLOX3 during adaptive evolution of natural populations. This study provides novel insights into allelic variations in heterozygosity associated with adaptive evolution of P. tomentosa in response to the local environment and identifies a series of key genes for wood component traits, thereby facilitating genomic-based breeding of important traits in perennial woody plants.

Solid-liquid transition induced by rigidity disparity in a binary mixture of cell tissues.

The two-dimensional melting of a binary mixture of cell tissues is numerically investigated in the presence of rigidity disparity. We present the full melting phase diagrams of the system by using the Voronoi-based cellular model. It is found that the enhancement of rigidity disparity can induce a solid-liquid transition at both zero temperature and finite temperature. (i) In the case of zero temperature, the system undergoes a continuous solid-hexatic transition followed by a continuous hexatic-liquid transition for zero rigidity disparity, but a discontinuous hexatic-liquid transition for finite rigidity disparity. Remarkably, the solid-hexatic transitions always arise when the soft cells reach the rigidity transition point of monodisperse systems. (ii) In the case of finite temperature, the melting occurs via a continuous solid-hexatic transition followed by a discontinuous hexatic-liquid transition. Our study may contribute to the understanding of solid-liquid transitions in binary mixture systems with rigidity disparity.

New-Onset Fulminant Type 1 Diabetes Following SARS-CoV-2 Protein Subunit Vaccine: A Case Report and Literature Review.

The ravages of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide have sped up the development of relevant vaccines, which is accompanied by public concerns over possible adverse effects. We report a rare case of a 39-year-old woman who suffered from severe hyperglycemia and ketoacidosis with normal hemoglobin A1c four days after SARS-CoV-2 protein subunit vaccine, which is consistent with the diagnosis of fulminant type 1 diabetes (FT1D). She received insulin therapy and recovered after 24 days from onset of the symptoms. This is the first case of new-onset FT1D after SARS-CoV-2 protein subunit vaccination and one of only six that developed after any form of SARS-CoV-2 vaccination. We hope to raise awareness of this potential adverse consequence and recommend careful monitoring after vaccination in patients even without a medical history of diabetes.

Regeneratively mode-locked optoelectronic oscillator.

A regeneratively mode-locked optoelectronic oscillator is proposed to realize multi-mode phase locking in optoelectronic oscillators by coupling a modulating signal generation loop. To verify the feasibility of the scheme, a numerical simulation model is established. In addition, a proof-of-concept experiment is demonstrated in a single-loop optoelectronic oscillator with a 2.2 km polarization-maintaining single-mode fiber, using an electric amplitude modulator/Mach-Zehnder modulator as an active mode-locking device. The generated microwave pulse signal has a center frequency of 10 GHz and a repetition rate of 95 kHz. We believe this scheme can provide a new approach to overcome the problem of detuning between the modulating frequency and the mode spacing during long-term operation.

Lactobacillus rhamnosus GG modifies the metabolome of pathobionts in gnotobiotic mice.

BACKGROUND: Lactobacillus rhamnosus GG (LGG) is the most widely used probiotic, but the mechanisms underlying its beneficial effects remain unresolved. Previous studies typically inoculated LGG in hosts with established gut microbiota, limiting the understanding of specific impacts of LGG on host due to numerous interactions among LGG, commensal microbes, and the host. There has been a scarcity of studies that used gnotobiotic animals to elucidate LGG-host interaction, in particular for gaining specific insights about how it modifies the metabolome. To evaluate whether LGG affects the metabolite output of pathobionts, we inoculated with LGG gnotobiotic mice containing Propionibacterium acnes, Turicibacter sanguinis, and Staphylococcus aureus (PTS). RESULTS: 16S rRNA sequencing of fecal samples by Ion Torrent and MinION platforms showed colonization of germ-free mice by PTS or by PTS plus LGG (LTS). Although the body weights and feeding rates of mice remained similar between PTS and LTS groups, co-associating LGG with PTS led to a pronounced reduction in abundance of P. acnes in the gut. Addition of LGG or its secretome inhibited P. acnes growth in culture. After optimizing procedures for fecal metabolite extraction and metabolomic liquid chromatography-mass spectrometry analysis, unsupervised and supervised multivariate analyses revealed a distinct separation among fecal metabolites of PTS, LTS, and germ-free groups. Variables-important-in-projection scores showed that LGG colonization robustly diminished guanine, ornitihine, and sorbitol while significantly elevating acetylated amino acids, ribitol, indolelactic acid, and histamine. In addition, carnitine, betaine, and glutamate increased while thymidine, quinic acid and biotin were reduced in both PTS and LTS groups. Furthermore, LGG association reduced intestinal mucosal expression levels of inflammatory cytokines, such as IL-1α, IL-1ß and TNF-α. CONCLUSIONS: LGG co-association had a negative impact on colonization of P. acnes, and markedly altered the metabolic output and inflammatory response elicited by pathobionts.

Application of a novel hybrid algorithm of Bayesian network in the study of hyperlipidemia related factors: a cross-sectional study.

BACKGROUND: This article aims to understand the prevalence of hyperlipidemia and its related factors in Shanxi Province. On the basis of multivariate Logistic regression analysis to find out the influencing factors closely related to hyperlipidemia, the complex network connection between various variables was presented through Bayesian networks(BNs). METHODS: Logistic regression was used to screen for hyperlipidemia-related variables, and then the complex network connection between various variables was presented through BNs. Since some drawbacks stand out in the Max-Min Hill-Climbing (MMHC) hybrid algorithm, extra hybrid algorithms are proposed to construct the BN structure: MMPC-Tabu, Fast.iamb-Tabu and Inter.iamb-Tabu. To assess their performance, we made a comparison between these three hybrid algorithms with the widely used MMHC hybrid algorithm on randomly generated datasets. Afterwards, the optimized BN was determined to explore to study related factors for hyperlipidemia. We also make a comparison between the BN model with logistic regression model. RESULTS: The BN constructed by Inter.iamb-Tabu hybrid algorithm had the best fitting degree to the benchmark networks, and was used to construct the BN model of hyperlipidemia. Multivariate logistic regression analysis suggested that gender, smoking, central obesity, daily average salt intake, daily average oil intake, diabetes mellitus, hypertension and physical activity were associated with hyperlipidemia. BNs model of hyperlipidemia further showed that gender, BMI, and physical activity were directly related to the occurrence of hyperlipidemia, hyperlipidemia was directly related to the occurrence of diabetes mellitus and hypertension; the average daily salt intake, daily average oil consumption, smoking, and central obesity were indirectly related to hyperlipidemia. CONCLUSIONS: The BN of hyperlipidemia constructed by the Inter.iamb-Tabu hybrid algorithm is more reasonable, and allows for the overall linking effect between factors and diseases, revealing the direct and indirect factors associated with hyperlipidemia and correlation between related variables, which can provide a new approach to the study of chronic diseases and their associated factors.

Flow and clogging of particles in shaking random obstacles.

Transport of three types of particles (passive particles, active particles, and polar particles) is investigated in a random obstacle array in the presence of a dc drift force. The obstacles are static or synchronously shake along the given direction. When the obstacles are static, the average velocity is a peaked function of the dc drift force (negative differential mobility) for low particle density, while the average velocity monotonically increases with the dc drift force (positive differential mobility) for high particle density. Under the same conditions, passive particles are most likely to pass through the obstacles, while polar particles are easily trapped by the obstacles. The polar alignment can strongly reduce the overall mobility of particles. When the obstacles shake along the given direction, the optimal shaking frequency or amplitude can maximize the average velocity. It is more effective to reduce clogging for the transverse shaking than that for the longitudinal shaking.

Gearbox Fault Diagnosis Based on Hierarchical Instantaneous Energy Density Dispersion Entropy and Dynamic Time Warping.

The accurate fault diagnosis of gearboxes is of great significance for ensuring safe and efficient operation of rotating machinery. This paper develops a novel fault diagnosis method based on hierarchical instantaneous energy density dispersion entropy (HIEDDE) and dynamic time warping (DTW). Specifically, the instantaneous energy density (IED) analysis based on singular spectrum decomposition (SSD) and Hilbert transform (HT) is first applied to the vibration signal of gearbox to acquire the IED signal, which is designed to reinforce the fault feature of the signal. Then, the hierarchical dispersion entropy (HDE) algorithm developed in this paper is used to quantify the complexity of the IED signal to obtain the HIEDDE as fault features. Finally, the DTW algorithm is employed to recognize the fault types automatically. The validity of the two parts that make up the HIEDDE algorithm, i.e., the IED analysis for fault features enhancement and the HDE algorithm for quantifying the information of signals, is numerically verified. The proposed method recognizes the fault patterns of the experimental data of gearbox accurately and exhibits advantages over the existing methods such as multi-scale dispersion entropy (MDE) and refined composite MDE (RCMDE).

A DNA-Azobenzene Nanopump Fueled by Upconversion Luminescence for Controllable Intracellular Drug Release.

Stimulus-responsive drug release possesses considerable significance in cancer therapy. This work reports an upconversion-luminescence-fueled DNA-azobenzene nanopump for rapid and efficient drug release. The nanopump is constructed by assembling the azobenzene-functionalized DNA strands on upconversion nanoparticles (UCNPs). Doxorubicin (DOX) is loaded in the nanopump by intercalation in the DNA helix. Under NIR light, the UCNPs emit both UV and visible photons to fuel the continuous photoisomerization of azo, which acts as an impeller pump to trigger cyclic DNA hybridization and dehybridization for controllable DOX release. In a relatively short period, this system demonstrates 86.7 % DOX release. By assembling HIV-1 TAT peptide and hyaluronic acid on the system, targeting of the cancer-cell nucleus is achieved for perinuclear aggregation of DOX and enhanced anticancer therapy. This highly effective drug delivery nanopump could contribute to chemotherapy development.

Rolling Bearing Fault Diagnosis Based on Optimal Notch Filter and Enhanced Singular Value Decomposition.

The impulsive fault feature signal of rolling bearings at the early failure stage is easily contaminated by the fundamental frequency (i.e., the rotation frequency of the shaft) signal and background noise. To address this problem, this paper puts forward a rolling bearing weak fault diagnosis method with the combination of optimal notch filter and enhanced singular value decomposition. Firstly, in order to eliminate the interference of the fundamental frequency signal, the original signal was processed by the notch filter with the fundamental frequency as the center frequency and with a varying bandwidth to get a series of corresponding notch filter signals. Secondly, the Teager energy entropy index was adopted to adaptively determine the optimal bandwidth to complete the optimal notch filter analysis on the raw vibration signal and obtain the corresponding optimal notch filter signal. Thirdly, an enhanced singular value decomposition de-nosing method was employed to de-noise the optimal notch filter signal. Finally, the envelope spectrum analysis was conducted on the de-noised signal to extract the fault characteristic frequencies. The effectiveness of the presented method was demonstrated via simulation and experiment verifications. In addition, the minimum entropy deconvolution, Kurtogram and Infogram methods were employed for comparisons to show the advantages of the presented method.

Highly Efficient Artificial Light-Harvesting Systems Constructed in Aqueous Solution Based on Supramolecular Self-Assembly.

Highly efficient light-harvesting systems were successfully fabricated in aqueous solution based on the supramolecular self-assembly of a water-soluble pillar[6]arene (WP6), a salicylaldehyde azine derivative (G), and two different fluorescence dyes, Nile Red (NiR) or Eosin Y (ESY). The WP6-G supramolecular assembly exhibits remarkably improved aggregation-induced emission enhancement and acts as a donor for the artificial light-harvesting system, and NiR or ESY, which are loaded within the WP6-G assembly, act as acceptors. An efficient energy-transfer process takes place from the WP6-G assembly not only to NiR but also to ESY for these two different systems. Furthermore, both of the WP6-G-NiR and WP6-G-ESY systems show an ultrahigh antenna effect at a high donor/acceptor ratio.

Enhanced Sensitivity of Cancer Stem Cells to Chemotherapy Using Functionalized Mesoporous Silica Nanoparticles.

Cancer stem cells (CSCs) are responsible for cancer drug resistance with high expression of ABCG2, which pumps the internalized chemotherapeutic out to escape drug-induced cytotoxicity. Here, we established a functionalized mesoporous silica nanoparticle (MSN) system to deliver shABCG2 and doxorubicin (Dox) synergistically. With excellent cell uptake and endosomal escape capacities, the dual-delivery carriers internalized shABCG2 and Dox into CSCs efficiently. ABCG2 depletion increased intracellular and intranuclear Dox enrichment, drove vigorous Dox-induced cell death, and impaired the self-renewal of CSCs. Additionally, the nanoparticles eliminated tumors efficiently and reduced tumor initiation by CSCs in vivo, with negligible side effects. Our findings suggest that well-designed delivery systems for conventional chemotherapeutic agents are promising for CSC therapy.

Enhanced shRNA delivery and ABCG2 silencing by charge-reversible layered nanocarriers.

Polycationic vectors have been used to deliver short hairpin RNAs (shRNAs) to knock-down genes for cancer therapies, but their inefficiency in lysosomal escape and shRNA release causes their low gene transcription efficiency. Herein, a three-layered polyethyleneimine (PEI)-coated gold nanocomplex interlaid with a pH-responsive charge-reversible chitosan-aconitic anhydride (CS-Aco) is constructed: a Au-PEI/CS-Aco/PEI/shRNA nanoparticle. The negatively charged CS-Aco hydrolyzes into positively charged CS in lysosomes, causing the nanocomposite to disassemble. The released Au-PEI nanoparticles efficiently rupture the lysosomes and thus release the PEI/shRNA polyplexes into cytoplasm, where they quickly disassociate because the PEI chains are short (1.2 kDa). As a consequence, the nanocomplexes display higher shRNA delivery efficiency than the 25 kDa PEI, and efficiently deliver shABCG2 to tumors and markedly silence ABCG2 expression, which sensitizes HepG2 cells to the drugs with minimal toxicity.

[Study on Archaeological Lime Powders from Taosi and Yinxu Sites by FTIR].

Archaeological lime powders samples from Taosi and Yinxu sites, natural limestone and experimentally prepared lime mortar were investigated by means of Fourier transform infrared spectrometry (FTIR) to identify the raw material of lime powders from Taosi and Yinxu sites. Results show that ν2/ν4 ratio of calcite resulted from carbonation reaction of man-made lime is around 6.31, which is higher than that of calcite in natural limestone and reflects the difference in the disorder of calcite crystal structure among the natural limestone and prepared lime mortar. With additional grinding, the values of v2 and ν4 in natural limestone and prepared lime mortar decrease. Meanwhile, the trend lines of ν2 versus ν4 for calcite in experimentally prepared lime mortar have a steeper slope when compared to calcite in natural limestone. These imply that ν2/ν4 ratio and the slope of the trend lines of ν2 versus ν4 can be used to determine the archaeological man-made lime. Based on the experiment results, it is possible that the archaeological lime powder from Taosi and Yinxu sites was prepared using man-made lime and the ancient Chinese have mastered the calcining technology of man-made lime in the late Neolithic period about 4 300 years ago.

Plasma-resistivity-induced strong damping of the kinetic resistive wall mode.

An energy-principle-based dispersion relation is derived for the resistive wall mode, which incorporates both the drift kinetic resonance between the mode and energetic particles and the resistive layer physics. The equivalence between the energy-principle approach and the resistive layer matching approach is first demonstrated for the resistive plasma resistive wall mode. As a key new result, it is found that the resistive wall mode, coupled to the favorable average curvature stabilization inside the resistive layer (as well as the toroidal plasma flow), can be substantially more stable than that predicted by drift kinetic theory with fast ion stabilization, but with the ideal fluid assumption. Since the layer stabilization becomes stronger with decreasing plasma resistivity, this regime is favorable for reactor scale, high-temperature fusion devices.

Correction: Enhanced DNA release from disulfide-containing layered nanocomplexes by heparin-electrostatic competition.

Correction for 'Enhanced DNA release from disulfide-containing layered nanocomplexes by heparin-electrostatic competition' by Zhenzhen Chen et al., J. Mater. Chem. B, 2015, 3, 225-237, https://doi.org/10.1039/c4tb01113a.