Despite intense interests in developing blood measurements of Alzheimer's disease (AD), the progress has been confounded by limited sensitivity and poor correlation to brain pathology. Here, we present a dedicated analytical platform for measuring different populations of circulating amyloid β (Aβ) proteins - exosome-bound vs. unbound - directly from blood. The technology, termed amplified plasmonic exosome (APEX), leverages in situ enzymatic conversion of localized optical deposits and double-layered plasmonic nanostructures to enable sensitive, multiplexed population analysis. It demonstrates superior sensitivity (~200 exosomes), and enables diverse target co-localization in exosomes. Employing the platform, we find that prefibrillar Aβ aggregates preferentially bind with exosomes. We thus define a population of Aβ as exosome-bound (Aβ42+ CD63+) and measure its abundance directly from AD and control blood samples. As compared to the unbound or total circulating Aβ, the exosome-bound Aβ measurement could better reflect PET imaging of brain amyloid plaques and differentiate various clinical groups.

Adventitious roots (ARs) are roots that are generated from nonrooting tissues. ARs are usually produced both during normal development and in response to stress conditions, such as flooding, nutrient deprivation, heavy metal stress and wounding. The ability of plants to form ARs is a key trait that enables plant propagation, especially for most tree species.

Background: As a central signaling molecule, cyclic diguanylate (c-di-GMP) is found to regulate various bacterial phenotypes, especially those involved in pathogen infection and drug resistance. Noticeably, many microbes have up to dozens of proteins that are involved in c-di-GMP metabolism. This apparent redundancy and the relevant functional specificity have become the focus of research. While a number of these proteins have been identified and investigated, the functions of PA0847, a PAS and GGDEF domain-containing protein from Pseudomonas aeruginosa PAO1, remain unclear. Materials and methods: In the current study, microbiology, biochemistry and structural biology methods were applied to characterize the gene/protein of PA0847. Results: We showed that PA0847 affects bacterial motility but not biofilm formation. We recorded the phenotypic influences of amino acids and compounds, and found that PA0847 is involved in response to various environmental nutrients and factors, suggesting its possible role in sensing environmental cues. Both in-vitro and in-vivo studies showed that PA0847 is an active diguanylate cyclase (DGC), whose activity depends on the neighboring PAS domain. Interestingly, PA0847 demonstrates no significant product inhibition, though the key residues of two I-sites for c-di-GMP binding are conserved in its GGDEF domain. A local structural change imposed by an adjacent tyrosine residue was identified, which indicates the structural and functional diversities of the GGDEF family proteins. Conclusion: Our data provide evidence for understanding the signaling mechanism of the unique c-di-GMP metabolizing protein PA0847.

To explore the regulation of PLA2G7 silencing on myocardial fibrosis in mice with coronary atherosclerosis, we established model of atherosclerosis using ApoE knockout mice, and set up a normal group. The successfully modeled mice were assigned into the following three groups: PLA2G7 silencing (shRNA) group, negative control (NC) group and blank group. Peripheral blood and myocardial tissue of each group of mice were harvested. The expressions of serum total cholesterol, triglyceride, low density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in mice were determine using Elisa, and the atherosclerosis index was calculated. The pathological changes of myocardial tissue were observed after HE staining. The collagen volume fraction in myocardium was determined with the use of Masson staining. The expression of PLA2G7 in myocardial tissue as well as myocardial fibrosis markers C-reactive protein, interleukin-6 and intercellular adhesion molecule-1 in each group were detected by qRT-PCR and Western blot. The area of thoracic aorta injury was detected after oil red O staining. Compared with the normal group, the levels of total cholesterol, triglyceride and LDL-C were increased, HDL-C levels were decreased, and atherosclerosis index was increased in the PLA2G7 shRNA group, NC group and blank group (all P < 0.05). The pathological state of myocardial tissue in the other three groups (except for the normal group) was obvious, but the PLA2G7 shRNA group showed certain improvement as compared with the blank group and the NC group (all P < 0.05). Compared with the NC group, the PLA2G7 shRNA group had significantly decreased collagen volume fraction, myocardial fibrosis and area of thoracic aorta injury (all P < 0.05). In conclusion, PLA2G7 silencing can improve the myocardial fibrosis in mice with coronary atherosclerosis, and PLA2G7 is expected to be a potential target for coronary atherosclerosis.

In this study, the protective effects of 3,4-dihydroxyphenyl lactic acid (DLA) on blood-brain barrier (BBB) injury following subarachnoid hemorrhage (SAH) has been explored.

Atherosclerotic plaque rupture is the main cause of acute coronary syndrome (ACS). Angiotensin II (Ang II) and macrophage apoptosis are involved in the pathogenesis of atherosclerosis. However, the underlying mechanisms remain unclear. We aimed to address the role of monocyte chemotactic protein-induced protein 1 (MCPIP1) in Ang II-induced macrophage apoptosis and vulnerable plaque formation. In mouse peritoneal macrophages, Ang II promoted endoplasmic reticulum (ER) stress-dependent macrophage apoptosis. Ang II markedly upregulated the expression of MCPIP1 via activating p38 mitogen-activated protein kinase (p38 MAPK). Treatment with MCPIP1 shRNA downregulated ER stress-related proteins and decreased macrophage apoptosis induced by Ang II. Ang II also activated the AMP-activated protein kinase (AMPK) signaling in macrophages. Inhibition of AMPK reduced macrophage apoptosis by inhibiting the p38 MAPK/MCPIP1/ER stress pathway. Furthermore, blocking the Ang II type 1 receptor (AT1R) with losartan effectively inhibited Ang II-induced macrophage apoptosis and AMPK/p38 MAPK/MCPIP1/ER pathway activation. In the atherosclerotic vulnerable plaque model in mice, losartan inhibited the progression of atherosclerosis and transformed vulnerable plaque into a more stable phenotype. Moreover, losartan markedly decreased the number of CD68+TUNEL+, CD68+MCPIP1+, CD68+p-eIF2α+ and CD68+CHOP+ cells in the lesion area. Taken together, Ang II promotes macrophage apoptosis via the AMPK/p38 MAPK/MCPIP1/ER stress pathway in macrophages via its receptor AT1R, which may contribute to vulnerable plaque formation. Our study clarifies a novel regulatory role of MCPIP1 in Ang II-induced macrophage apoptosis and plaque instability, providing a potential therapeutic target for prevention of ACS.

Brachial-ankle pulse wave velocity (baPWV), as a marker of arterial stiffness, has been demonstrated to be associated with blood pressure (BP) and onset of hypertension. However, little information is available on the associations between baPWV and BP indices [systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), mean arterial pressure (MAP)] in treated hypertensive patients. We aimed to assess the associations between BP indices and baPWV. In this cross-sectional study, 14,598 hypertensive patients from China Stroke Primary Prevention Trial (CSPPT) at the exit visit of the trial were analyzed. Elevated baPWV was defined as ≥18.3 m/s. Multivariate linear and logistic regression analyses were performed to evaluate the associations of BP indices with baPWV and elevated baPWV. Moreover, the smooth curve fitting (penalized spline method) was conducted. Multivariate linear regression analyses showed that continuous SBP, DBP, PP and MAP were independently and positively associated with baPWV (β = 0.081, 0.084, 0.078 and 0.115, respectively, all P < 0.001). Compared with controlled SBP group (<140 mm Hg), uncontrolled SBP (≥140 mm Hg) was significantly associated with higher baPWV [β = 2.234, 95% confidence interval (CI): 2.137-2.332]. Similarly, compared with controlled DBP group (<90 mm Hg), uncontrolled DBP (≥90 mm Hg) was significantly associated with higher baPWV (β = 1.466, 95%CI: 1.341-1.590). Multiple logistic analyses also showed that SBP, DBP, PP and MAP were significantly and positively associated with elevated baPWV (OR = 1.056, 1.049, 1.052, and 1.075, respectively, all P < 0.001). The fully-adjusted smooth curve fitting presented a linear association between BP indices with baPWV. In conclusion, among treated hypertensive patients, SBP, DBP, PP and MAP levels were independently and positively associated with baPWV and elevated baPWV, suggesting that baPWV might be a way to predict uncontrolled BP.

We introduced a novel micro/nanofluidic chip platform (MNCP), which is based on an isothermal nucleic acid amplification method. This study aimed to evaluate the MNCP method for influenza A and B viruses detecting and subtyping using throat swab samples from patients with influenza-like illness (ILI). A total of 266 throat swab samples from 266 non-repeated patients with ILI were tested for influenza A and B viruses using three methods, MNCP, a rapid influenza diagnostic test (RIDT), and real-time reverse transcription polymerase chain reaction (rRT-PCR). The results of MNCP were compared to those obtained by rRT-PCR and RIDT and the performance of MNCP was further evaluated. Compared with rRT-PCR results, the rates of sensitivity, specificity, overall concordance, and the kappa value of MNCP were 98.89%, 96.97%, 97.65%, and 0.95 for influenza A virus; 94.95%, 99.38%, 97.68%, and 0.95 for influenza B virus, respectively. Subtypes of influenza A viruses, e.g., A(H1N1)pdm09, A(H3N2), and A(not subtyped), and influenza B viruses could be distinguished in one MNCP assay within 1 h. Compared with rRT-PCR and MNCP, RIDT showed poor clinical sensitivity for influenza virus detection. This study showed MNCP is rapid, sensitive and versatile detecting system with potential for clinical application in pathogen diagnosis for patients with ILI.

Early brain injury (EBI) refers to the direct injury to the brain during the first 72 h after subarachnoid hemorrhage (SAH), which is one of the major causes for the poor clinical outcome after SAH. In this study, we investigated the effect and the related mechanism of Salvinorin A (SA), a selective kappa opioid receptor agonist, on EBI after SAH. SA was administered by intraperitoneal injection at 24 h, 48 h and 72 h after SAH. The volume of lateral ventricle was measured by magnetic resonance imaging (MRI). The neuronal morphological changes and the apoptotic level in CA1 area of hippocampus were observed by Nissl and TUNEL staining respectively. Protein expression of p-PI3K, p-Akt, p-IKKα/β, p-NF-κB, FoxO1, Bim, Bax and Cleaved-caspase-3 was measured to explore the potential mechanism. We found that SA alleviated the neuronal morphological changes and apoptosis in CA1 area of hippocampus. The mechanism might be related to the increased protein expression of p-PI3K/p-Akt, which accompanied by decreased expression of p-IKKα/β, p-NF-κB, FoxO1, Bim, Bax and Cleaved-caspase-3 in the hippocampus. Thus, therapeutic interventions of SA targeting the PI3K/Akt pathway might be a novel approach to ameliorate EBI via reducing the apoptosis and inflammation after SAH.

Retinal vein occlusion (RVO) is the second most common retinal vascular disorder that affected 16.4 million people worldwide in 2008. The last decade has seen new epidemiological data on RVO, enabling us to provide a contemporary estimation of RVO epidemiology.

Studies on the Bin-Amphiphysin-Rvs (BAR) domain have advanced a fundamental understanding of how proteins deform membrane. We previously showed that a BAR domain in tandem with a Pleckstrin Homology (PH domain) underlies the assembly of ACAP1 (Arfgap with Coil-coil, Ankryin repeat, and PH domain I) into an unusual lattice structure that also uncovers a new paradigm for how a BAR protein deforms membrane. Here, we initially pursued computation-based refinement of the ACAP1 lattice to identify its critical protein contacts. Simulation studies then revealed how ACAP1, which dimerizes into a symmetrical structure in solution, is recruited asymmetrically to the membrane through dynamic behavior. We also pursued electron microscopy (EM)-based structural studies, which shed further insight into the dynamic nature of the ACAP1 lattice assembly. As ACAP1 is an unconventional BAR protein, our findings broaden the understanding of the mechanistic spectrum by which proteins assemble into higher-ordered structures to achieve membrane deformation.

Mitochondrial dysfunction is considered as a key mediator in the pathogenesis of diabetic nephropathy (DN). Therapeutic strategies targeting mitochondrial dysfunction hold considerable promise for the treatment of DN. In this study, we investigated the role of progranulin (PGRN), a secreted glycoprotein, in mediating mitochondrial homeostasis and its therapeutic potential in DN. We found that the level of PGRN was significantly reduced in the kidney from STZ-induced diabetic mice and patients with biopsy-proven DN compared with healthy controls. In DN model, PGRN-deficient mice aggravated podocyte injury and proteinuria versus wild-type mice. Functionally, PGRN deficiency exacerbated mitochondrial damage and dysfunction in podocytes from diabetic mice. In vitro, treatment with recombinant human PGRN (rPGRN) attenuated high glucose-induced mitochondrial dysfunction in podocytes accompanied by enhanced mitochondrial biogenesis and mitophagy. Inhibition of mitophagy disturbed the protective effects of PGRN in high glucose-induced podocytotoxicity. Mechanistically, we demonstrated that PGRN maintained mitochondrial homeostasis via PGRN-Sirt1-PGC-1α/FoxO1 signaling-mediated mitochondrial biogenesis and mitophagy. Finally, we provided direct evidence for therapeutic potential of PGRN in mice with DN. This study provides new insights into the novel role of PGRN in maintaining mitochondrial homeostasis, suggesting that PGRN may be an innovative therapeutic strategy for treating patients with DN.

Changes in soil bacterial communities, which are crucial for the assessment of ecological restoration in Chinese plantations, have never been studied in the "Three North Shelterbelt" project in the semi-arid areas. We used high-throughput sequencing of the 16S rDNA gene to investigate the soil bacterial community diversity, structure, and functional characteristics in three plantation forests, including Populus × canadensis Moench (PC), Pinus sylvestris var. mongolica (PS), and Pinus tabuliformis (PT). In addition, soil environment factors were measured. There were distinct differences in soil characteristics among different plantation forests. Compared to PS and PT, PC had a higher soil pH, dissolved organic carbon (DOC), and available P, as well as a lower C/N ratio. Furthermore, afforestation with different tree species significantly altered the abundance of Proteobacteria, and Chloroflexi in the soil, and its influence on the bacterial diversity indices. The bacterial community compositions and functional groups related to C and N cycling from PS, and PT were grouped tightly, indicating that the soil bacterial phylogenetic distance of PS and PT were closer than that between PS plus PT and PC. Our results implied that the soil characteristics, as well as the diversity, compositions and functions related to C and N cycling of soil bacterial community obviously differed from the following afforestation, especially between PC and PS plus PT, which in turn enormously established the correlation between the soil microbial community characteristics and the afforestation tree species.

Staphylococcus phages of the Myoviridae family have a wide host range and potential applications in phage therapy. In this report, safety assessments of these phages were conducted based on their complete genome sequences. The complete genomes of Staphylococcus phages of the Myoviridae family were analyzed, and the Open Reading Frame (ORFs) were compared with a pool of virulence and antibiotic resistance genes using the BLAST algorithm. In addition, the lifestyle of the phages (virulent or temperate) was also confirmed using PHACTS. The results showed that all phages were lytic and did not contain resistance or virulence genes based on bioinformatic analyses, excluding the possibility that they could be vectors for the dissemination of these undesirable genes. These findings suggest that the phages are safe at the genome level. The SceD-like transglycosylase, which is a biomarker for vancomycin-intermediate strains, was widely distributed in the phage genomes. Approximately 70% of the ORFs encoded in the phage genomes have unknown functions; therefore, their roles in the antibiotic resistance and virulence of Staphylococcus aureus are still unknown and require consideration before use in phage therapy.

Tumor necrosis factor (TNF)-α-inducing protein (Tipα) is a newly identified carcinogenic factor secreted by Helicobacter pylori (H. pylori). Although it has been proved that Tipα is a strong inducer of epithelial-mesenchymal transition (EMT), a crucial process of migration, the exact molecular mechanism is unknown. Current evidence indicates that the oncogenic transcription factor signal transducers and activators of transcription 3 (STAT3) is inappropriately activated in multiple malignancies, including gastric cancer. In this study, we showed that Tipα significantly down-regulated the expression of EMT-related markers E-cadherin as well as up-regulated N-cadherin and vimentin in SGC7901 cells, with typical morphological changes of EMT. Tipα also promoted proliferation and migration of SGC7901 cells. Furthermore, Tipα activated interleukin-6 (IL-6)/STAT3 signaling pathway in SGC7901 cells. The effects of Tipα treatment observed was abolished when we block IL-6/STAT3 signaling pathway. Altogether, our data demonstrated that Tipα may accelerate tumor aggressiveness in gastric cancer by promoting EMT through activation of IL-6/STAT3 pathway.

The Amur ide (Leuciscus waleckii) is a cyprinid fish that is widely distributed in Northeast Asia. The Lake Dali Nur population inhabits one of the most extreme aquatic environments on Earth, with an alkalinity up to 50 mmol/L (pH 9.6), thus providing an exceptional model with which to characterize the mechanisms of genomic evolution underlying adaptation to extreme environments. Here, we developed the reference genome assembly for L. waleckii from Lake Dali Nur. Intriguingly, we identified unusual expanded long terminal repeats (LTRs) with higher nucleotide substitution rates than in many other teleosts, suggesting their more recent insertion into the L. waleckii genome. We also identified expansions in genes encoding egg coat proteins and natriuretic peptide receptors, possibly underlying the adaptation to extreme environmental stress. We further sequenced the genomes of 10 additional individuals from freshwater and 18 from Lake Dali Nur populations, and we detected a total of 7.6 million SNPs from both populations. In a genome scan and comparison of these two populations, we identified a set of genomic regions under selective sweeps that harbor genes involved in ion homoeostasis, acid-base regulation, unfolded protein response, reactive oxygen species elimination, and urea excretion. Our findings provide comprehensive insight into the genomic mechanisms of teleost fish that underlie their adaptation to extreme alkaline environments.

To compare clinical parameters and the tear levels of inflammatory cytokines between pterygium surgery using sutures or fibrin glue.

Epstein-Barr virus (EBV) is an important DNA virus which establishes latent infection in human malignancies. Expression of EBV-encoded genes in the associated tumors is strongly modulated by promoter CpG methylation of EBV genome. This study aimed to explore the methylation status of the promoters of EBV BamHI-A rightward frame 1 (BARF1) and BamHI-H rightward open reading frame 1 (BHRF1) and their influence on transcriptional expression, to further understand the roles of BARF1 and BHRF1 in the occurrence of EBV-associated cancer. We evaluated the methylation status of BARF1 and BHRF1 promoters in 43 EBV-associated gastric carcinoma (EBVaGC) tissues and EBV-positive cell lines. Their expressions were evaluated by real-time quantitative PCR. We found that the promoters of BARF1 and BHRF1 were methylated by varying degrees in different EBV-positive cell lines and were almost hypermethylated in all EBVaGC tissues. The methylation status of BARF1 and BHRF1 promoters were significantly reduced by 5-Aza-CdR along with the increasing gene expressions. Hypermethylation of Ap and Hp mediates the frequent silencing of BARF1 and BHRF1 in EBV-associated tumors, which could be reactivated by a demethylation agent, suggesting that promoter demethylation and activation is important for BARF1 and BHRF1 transcription and their further action.

Serotonin receptor 5-HT6 is involved in cognition and Alzheimer's disease (AD) development. However, the mechanism of 5-HT6 in AD pathology is not clear.

Moyamoya disease (MMD) is the most common pediatric cerebrovascular disease in Eastern Asian countries but the etiology is not well understood. Circular RNAs (circRNAs) have been implicated in various biological processes, but their role in the development of MMD remains unclear. To address this issue, we carried out a comparative circRNA microarray analysis of blood samples obtained from patients with MMD and healthy subjects and identified 146 circRNAs that were differentially expressed between the two groups. Of these, 29 were upregulated and 117 were downregulated in patients as compared to controls (fold change ≥2.0 and P<0.05). The microarray results were validated by quantitative reverse-transcription PCR. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed that the differentially expressed circRNAs were primarily involved in angiogenesis, metabolism, and immune responses in MMD. In addition, the mitogen-activated protein kinase signaling pathway was found to be the core regulatory pathway associated with disease pathogenesis. These results indicate that specific circRNAs are aberrantly expressed in MMD and are potential therapeutic targets for its treatment.