Dynamic interactions of a conserved enterotoxigenic Escherichia coli adhesin with intestinal mucins govern epithelium engagement and toxin delivery

At present, there is no vaccine for enterotoxigenic Escherichia coli (ETEC), an important cause of diarrheal illness. Nevertheless, recent microbial pathogenesis studies have identified a number of molecules produced by ETEC that contribute to its virulence and are novel antigenic targets to complement canonical vaccine approaches. EtpA is a secreted two-partner adhesin that is conserved within the ETEC pathovar. EtpA interacts with the tips of ETEC flagella to promote bacterial adhesion, toxin delivery, and intestinal colonization by forming molecular bridges between the bacteria and the epithelial surface. However, the nature of EtpA interactions with the intestinal epithelium remains poorly defined. Here, we demonstrate that EtpA interacts with glycans presented by transmembrane and secreted intestinal mucins at epithelial surfaces to facilitate pathogen-host interactions that culminate in toxin delivery. Moreover, we found that a major effector molecule of ETEC, the heat-labile enterotoxin (LT), may enhance these interactions by stimulating the production of the gel-forming mucin MUC2. Our studies suggest, however, that EtpA participates in complex and dynamic interactions between ETEC and the gastrointestinal mucosae in which host glycoproteins promote bacterial attachment while simultaneously limiting the epithelial engagement required for effective toxin delivery. Collectively, these data provide additional insight into the intricate nature of ETEC interactions with the intestinal epithelium that have potential implications for rational approaches to vaccine design

Probability weighted four-point arc imaging algorithm for time-reversed lamb wave damage detection

Damage imaging based on scattering signals of ultrasonic Lamb waves in plate structure is considered as one of the most effective ways for structural health monitoring area. To improve location accuracy and reduce the impact of artifacts, a probability weighted four-point arc imaging algorithm for time reversal Lamb wave damage detection is proposed in this paper. By taking the defect as a secondary wave source, the four-point arc positioning method is used to calculate the propagation time of the signal from transducer to defect. And the amplitude of damage signal corresponding to the time of flight is used for imaging. In order to eliminate the artifacts, a damage probability weighting is combined with four-point circular arc imaging algorithm. The effectiveness of the proposed method is experimentally verified in aluminum plate. Experimental results indicate that damage location accuracy and imaging quality has been improved in both single-flaw and double-flaw samples compared with conventional delay-and-sum method

A modified damage index probability imaging algorithm based on delay-and-sum imaging for synthesizing time-reversed Lamb waves

Imaging for damage in plate structure by Lamb waves is one of the most effective methods in the field of structural health monitoring. In order to improve the accuracy of damage localization, a novel method is proposed to modify damage exponent probability imaging algorithm based on delay-and-sum imaging by using time reversal Lamb waves. A new probability distribution function is introduced to improve the damage index probability method and is combined with delay-and-sum method for damage localization. Experimental results on aluminum plate show that the hybrid algorithm achieves better accuracy of damage location and imaging quality than the conventional delay-and-sum method

Patterns of MicroRNA Expression in Normal and Early Alzheimer\u27s Disease Human Temporal Cortex: White Matter versus Gray Matter

MicroRNA (miRNA) expression was assessed in human cerebral cortical gray matter (GM) and white matter (WM) in order to provide the first insights into the difference between GM and WM miRNA repertoires across a range of Alzheimer\u27s disease (AD) pathology. RNA was isolated separately from GM and WM portions of superior and middle temporal cerebral cortex (N = 10 elderly females, postmortem interval \u3c 4 h). miRNA profiling experiments were performed using state-of-the-art Exiqon© LNA-microarrays. A subset of miRNAs that appeared to be strongly expressed according to the microarrays did not appear to be conventional miRNAs according to Northern blot analyses. Some well-characterized miRNAs were substantially enriched in WM as expected. However, most of the miRNA expression variability that correlated with the presence of early AD-related pathology was seen in GM. We confirm that downregulation of a set of miRNAs in GM (including several miR-15/107 genes and miR-29 paralogs) correlated strongly with the density of diffuse amyloid plaques detected in adjacent tissue. A few miRNAs were differentially expressed in WM, including miR-212 that is downregulated in AD and miR-424 which is upregulated in AD. The expression of certain miRNAs correlates with other miRNAs across different cases, and particular subsets of miRNAs are coordinately expressed in relation to AD-related pathology. These data support the hypothesis that patterns of miRNA expression in cortical GM may contribute to AD pathogenetically, because the aggregate change in miRNA expression observed early in the disease would be predicted to cause profound changes in gene expression

Damage detection of composite plate based on an improved DAS algorithm by time difference due to anisotropy

This paper proposes a damage detection method based on an improved DAS imaging algorithm by introducing time difference due to anisotropy of composite material. First, the finite element characteristic frequency method is used to obtain the dispersion curve of the composite plate, and the validity of the dispersion curve is verified. Next, the average phase velocity of the Lamb wave at mixed modes in the composite plate is obtained by two-dimensional Fourier transform (2-D FFT). The mixed modal group velocity is calculated according to the corresponding phase velocity, the mean change rate of the phase velocity and the dispersion curve obtained by simulation. The time difference due to anisotropy of composite material is investigated, and the damage location is estimated by the delay-and-sum (DAS) imaging algorithm. Experiments on carbon fiber multilayer composite plates verify the effectiveness of the proposed method

The Expression of MicroRNA miR-107 Decreases Early in Alzheimer\u27s Disease and May Accelerate Disease Progression through Regulation of β-Site Amyloid Precursor Protein-Cleaving Enzyme 1

MicroRNAs (miRNAs) are small regulatory RNAs that participate in posttranscriptional gene regulation in a sequence-specific manner. However, little is understood about the role(s) of miRNAs in Alzheimer\u27s disease (AD). We used miRNA expression microarrays on RNA extracted from human brain tissue from the University of Kentucky Alzheimer\u27s Disease Center Brain Bank with near-optimal clinicopathological correlation. Cases were separated into four groups: elderly nondemented with negligible AD-type pathology, nondemented with incipient AD pathology, mild cognitive impairment (MCI) with moderate AD pathology, and AD. Among the AD-related miRNA expression changes, miR-107 was exceptional because miR-107 levels decreased significantly even in patients with the earliest stages of pathology. In situ hybridization with cross-comparison to neuropathology demonstrated that particular cerebral cortical laminas involved by AD pathology exhibit diminished neuronal miR-107 expression. Computational analysis predicted that the 3′-untranslated region (UTR) of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) mRNA is targeted multiply by miR-107. From the same RNA material analyzed on miRNA microarrays, mRNA expression profiling was performed using Affymetrix Exon Array microarrays on nondemented, MCI, and AD patients. BACE1 mRNA levels tended to increase as miR-107 levels decreased in the progression of AD. Cell culture reporter assays performed with a subset of the predicted miR-107 binding sites indicate the presence of at least one physiological miR-107 miRNA recognition sequence in the 3′-UTR of BACE1 mRNA. Together, the coordinated application of miRNA profiling, Affymetrix microarrays, new bioinformatics predictions, in situ hybridization, and biochemical validation indicate that miR-107 may be involved in accelerated disease progression through regulation of BACE1

Yeast-produced subunit protein vaccine elicits broadly neutralizing antibodies that protect mice against Zika virus lethal infection

International audienceZika virus (ZIKV) infection is a serious public health concern due to its ability to induce neurological defects and its potential for rapid transmission at a global scale. However, no vaccine is currently available to prevent ZIKV infection. Here, we report the development of a yeast-derived subunit protein vaccine for ZIKV. The envelope protein domain III (EDIII) of ZIKV was produced as a secretory protein in the yeast Pichia pastoris. The yeast-derived EDIII could inhibit ZIKV infection in vitro in a dose-dependent manner, suggesting that it had acquired an appropriate conformation to bind to cellular receptors of ZIKV. Immunization with recombinant EDIII protein effectively induced antigen-specific binding antibodies and cellular immune responses. The resulting anti-EDIII sera could efficiently neutralize ZIKV representative strains from both Asian and African lineages. Passive transfer with the anti-EDIII neutralizing sera could confer protection against lethal ZIKV challenge in mice. Importantly, we found that purified anti-EDIII antibodies did not cross-react with closely related dengue virus (DENV) and therefore did not enhance DENV infection. Collectively, our results demonstrate that yeast-produced EDIII is a safe and effective ZIKV vaccine candidate

Novel Human \u3cem\u3eABCC9/SUR2\u3c/em\u3e Brain-Expressed Transcripts and an eQTL Relevant to Hippocampal Sclerosis of Aging

ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging. The main goals of this study were 1 \u3e to detect the ABCC9 variants and define the specific 3′ untranslated region (3′UTR) for each variant in human brain, and 2 \u3e to determine whether a polymorphism (rs704180) associated with risk for hippocampal sclerosis of aging pathology is also associated with variation in ABCC9 transcript expression and/or splicing. Rapid amplification of ABCC9 cDNA ends (3′RACE) provided evidence of novel 3′ UTR portions of ABCC9 in human brain. In silico and experimental studies were performed focusing on the single nucleotide polymorphism, rs704180. Analyses from multiple databases, focusing on rs704180 only, indicated that this risk allele is a local expression quantitative trait locus (eQTL). Analyses of RNA from human brains showed increased ABCC9 transcript levels in individuals with the risk genotype, corresponding with enrichment for a shorter 3′ UTR which may be more stable than variants with the longer 3′ UTR. MicroRNA transfection experiments yielded results compatible with the hypothesis that miR‐30c causes down‐regulation of SUR2 transcripts with the longer 3′ UTR. Thus we report evidence of complex ABCC9 genetic regulation in brain, which may be of direct relevance to human disease