Tumor Endothelium Marker-8 Based Decoys Exhibit Superiority over Capillary Morphogenesis Protein-2 Based Decoys as Anthrax Toxin Inhibitors

Anthrax toxin is the major virulence factor produced by Bacillus anthracis. The toxin consists of three protein subunits: protective antigen (PA), lethal factor, and edema factor. Inhibition of PA binding to its receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2) can effectively block anthrax intoxication, which is particularly valuable when the toxin has already been overproduced at the late stage of anthrax infection, thus rendering antibiotics ineffectual. Receptor-like agonists, such as the mammalian cell-expressed von Willebrand factor type A (vWA) domain of CMG2 (sCMG2), have demonstrated potency against the anthrax toxin. However, the soluble vWA domain of TEM8 (sTEM8) was ruled out as an anthrax toxin inhibitor candidate due to its inferior affinity to PA. In the present study, we report that L56A, a PA-binding-affinity-elevated mutant of sTEM8, could inhibit anthrax intoxication as effectively as sCMG2 in Fisher 344 rats. Additionally, pharmacokinetics showed that L56A and sTEM8 exhibit advantages over sCMG2 with better lung-targeting and longer plasma retention time, which may contribute to their enhanced protective ability in vivo. Our results suggest that receptor decoys based on TEM8 are promising anthrax toxin inhibitors and, together with the pharmacokinetic studies in this report, may contribute to the development of novel anthrax drugs

Review of emulsified asphalt modification mechanisms and performance influencing factors

In recent years, with the improvement of the requirements of road performance, modified emulsified asphalts with better performance has gradually replaced the emulsified asphalt and become the primary material for road maintenance. This paper introduces the modified emulsified asphalt materials commonly used in pavement maintenance projects, definitions and modified mechanisms of polymerized styrene butadiene rubber (SBR) modified emulsified asphalt, styrene butadiene styrene block polymer (SBS) modified emulsified asphalt and waterborne epoxy resin (WER) modified emulsified asphalt are summarized. The analysis focused on comparing the effects of modifiers, preparation process, auxiliary additives, and other factors on the performance of modified emulsified asphalt. In this paper, it is considered that the greatest impact on the performance of emulsified asphalt is the modifier, emulsifier mainly affects the speed of breaking the emulsion, stabilizers on the basic performance of emulsified asphalt evaporative residue is small; and when the modifier is distributed in the asphalt in a network, the dosage at this time is the recommended optimum dosage. Finally, this study recommends that in the future, the polymer-asphalt compatibility can be improved through composite modification, chemical grafting and other methods to continue to develop broader applicability and better performance of modified emulsified asphalt

A review on evaluation of crack resistance of asphalt mixture by semi-circular bending test

A B S T R A C T: Although there are many kinds of fracture tests to choose from in evaluating the crack resistance of asphalt mixture, the semi-circular bending (SCB) test has attracted a lot of attention in the academic road engineering community because of its simplicity, stability, and flexibility in testing and evaluation. The SCB test has become a common method to study the cracking resistance of asphalt mixture in recent years. This paper mainly summarizes the overview of the SCB test, summarizes some research results and common characterization parameters of the SCB test method in monotone test and fatigue test in recent years, and predicts and suggests the research direction of the SCB test in the future. It is found that the research on the monotonic SCB test is more comprehensive, and the research on the SCB fatigue test needs to be further improved in the aspects of loading mode, characterization parameter selection, and so on. Researchers can flexibly adjust the geometric dimensions and the test parameters of semi-cylindrical specimens, and conduct comprehensive analysis combined with the results of numerical simulation. The crack resistance of asphalt mixture can be comprehensively evaluated by fracture energy, fracture toughness, stiffness, flexibility index and other fracture indicators, combined with the crack propagation of the specimen. The analysis of numerical simulation can confirm the test results. In order to standardize the setting of fatigue parameters for future application, it is necessary to standardize the setting of bending performance

Impaired Spatial Firing Representations of Neurons in the Medial Entorhinal Cortex of the Epileptic Rat Using Microelectrode Arrays

Epilepsy severely impairs the cognitive behavior of patients. It remains unclear whether epilepsy-induced cognitive impairment is associated with neuronal activities in the medial entorhinal cortex (MEC), a region known for its involvement in spatial cognition. To explore this neural mechanism, we recorded the spikes and local field potentials from MEC neurons in lithium–pilocarpine-induced epileptic rats using self-designed microelectrode arrays. Through the open field test, we identified spatial cells exhibiting spatially selective firing properties and assessed their spatial representations in relation to the progression of epilepsy. Meanwhile, we analyzed theta oscillations and theta modulation in both excitatory and inhibitory neurons. Furthermore, we used a novel object recognition test to evaluate changes in spatial cognitive ability of epileptic rats. After the epilepsy modeling, the spatial tuning of various types of spatial cells had suffered a rapid and pronounced damage during the latent period (1 to 5 d). Subsequently, the firing characteristics and theta oscillations were impaired. In the chronic period (>10 d), the performance in the novel object experiment deteriorated. In conclusion, our study demonstrates the detrimental effect on spatial representations and electrophysiological properties of MEC neurons in the epileptic latency, suggesting the potential use of these changes as a “functional biomarker” for predicting cognitive impairment caused by epilepsy

Distinct nuclear and cytoplasmic functions of androgen receptor cofactor p44 and association with androgen-independent prostate cancer

Androgen receptor (AR) mediates transcriptional activation of diverse target genes through interactions with various coactivators that may alter its function and help mediate the switch between prostate cell proliferation and differentiation. We recently identified p44/MEP50 as an AR coactivator and further showed that it is expressed primarily in the nucleus and cytoplasm of benign prostate epithelial and prostate cancer cells, respectively. We also showed that haploinsufficiency in p44+/− mice causes prostate epithelial cell proliferation. To establish direct cause-and-effect relationships, we have used p44 fusion proteins that are selectively expressed in the nucleus or cytoplasm of prostate cancer cells (LNCaP), along with RNAi analyses, to examine effects of p44 both in vitro and in vivo (in tumor xenografts). We show that preferential expression of p44 in the nucleus inhibits proliferation of LNCaP cells in an AR-dependent manner, whereas preferential expression of p44 in the cytoplasm enhances cell proliferation. These effects appear to be mediated, at least in part, through the regulation of distinct cell-cycle regulatory genes that include p21 (up-regulated by nuclear p44) and cyclin D2 and CDK6 (up-regulated by cytoplasmic p44). Importantly, we also demonstrate that altered p44 expression is associated with androgen-independent prostate cancer. Our results indicate that nuclear p44 and cytoplasmic p44 have distinct and opposing functions in the regulation of prostate cancer cell proliferation

Autophagy governs protumorigenic effects of mitotic slippage-induced senescence

The most commonly utilized class of chemotherapeutic agents administered as a first-line therapy are antimitotic drugs; however, their clinical success is often impeded by chemoresistance and disease relapse. Hence, a better understanding of the cellular pathways underlying escape from cell death is critical. Mitotic slippage describes the cellular process where cells exit antimitotic drug-enforced mitotic arrest and "slip" into interphase without proper chromosome segregation and cytokinesis. The current report explores the cell fate consequence following mitotic slippage and assesses a major outcome following treatment with many chemotherapies, therapy-induced senescence. It was found that cells postslippage entered senescence and could impart the senescence-associated secretory phenotype (SASP). SASP factor production elicited paracrine protumorigenic effects, such as migration, invasion, and vascularization. Both senescence and SASP factor development were found to be dependent on autophagy. Autophagy induction during mitotic slippage involved the autophagy activator AMPK and endoplasmic reticulum stress response protein PERK. Pharmacologic inhibition of autophagy or silencing of autophagy-related ATG5 led to a bypass of G1 arrest senescence, reduced SASP-associated paracrine tumorigenic effects, and increased DNA damage after S-phase entry with a concomitant increase in apoptosis. Consistent with this, the autophagy inhibitor chloroquine and microtubule-stabilizing drug paclitaxel synergistically inhibited tumor growth in mice. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment.Implications: Clinical regimens targeting senescence and SASP could provide a potential effective combinatorial strategy with antimitotic drugs.NRF (Natl Research Foundation, S’pore)MOE (Min. of Education, S’pore)Accepted versio

A Circulating miRNA Signature for Stratification of Breast Lesions among Women with Abnormal Screening Mammograms

Although mammography is the gold standard for breast cancer screening, the high rates of false-positive mammograms remain a concern. Thus, there is an unmet clinical need for a non-invasive and reliable test to differentiate between malignant and benign breast lesions in order to avoid subjecting patients with abnormal mammograms to unnecessary follow-up diagnostic procedures. Serum samples from 116 malignant breast lesions and 64 benign breast lesions were comprehensively profiled for 2,083 microRNAs (miRNAs) using next-generation sequencing. Of the 180 samples profiled, three outliers were removed based on the principal component analysis (PCA), and the remaining samples were divided into training (n = 125) and test (n = 52) sets at a 70:30 ratio for further analysis. In the training set, significantly differentially expressed miRNAs (adjusted p < 0.01) were identified after correcting for multiple testing using a false discovery rate. Subsequently, a predictive classification model using an eight-miRNA signature and a Bayesian logistic regression algorithm was developed. Based on the receiver operating characteristic (ROC) curve analysis in the test set, the model could achieve an area under the curve (AUC) of 0.9542. Together, this study demonstrates the potential use of circulating miRNAs as an adjunct test to stratify breast lesions in patients with abnormal screening mammograms