Efficient Two-Dimensional Direction Finding via Auxiliary-Variable Manifold Separation Technique for Arbitrary Array Structure

A polynomial rooting direction of arrival (DOA) algorithm for multiple plane waves incident on an arbitrary array structure that combines the multipolynomial resultants and matrix computations is proposed in this paper. Firstly, a new auxiliary-variable manifold separation technique (AV-MST) is used to model the steering vector of arbitrary array structure as the product of a sampling matrix (dependent only on the array structure) and two Vandermonde-structured wavefield coefficient vectors (dependent on the wavefield). Then the propagator operator is calculated and used to form a system of bivariate polynomial equations. Finally, the automatically paired azimuth and elevation estimates are derived by polynomial rooting. The presented algorithm employs the concept of auxiliary-variable manifold separation technique which requires no sector by sector array interpolation and thus does not suffer from any mapping errors. In addition, the new algorithm does not need any eigenvalue decomposition of the covariance matrix and exhausted search over the two-dimensional parameter space. Moreover, the algorithm gives automatically paired estimates, thus avoiding the complex pairing procedure. Therefore, the proposed algorithm shows low computational complexity and high robustness performance. Simulation results are shown to validate the effectiveness of the proposed method

Lactobacillus rhamnosus GR-1 Ameliorates Escherichia coli-Induced Activation of NLRP3 and NLRC4 Inflammasomes With Differential Requirement for ASC

Escherichia coli is a common cause of mastitis in dairy cows. The adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) synergizes with caspase-1 to regulate inflammasome activation during pathogen infection. Here, the ASC gene was knocked out in bovine mammary epithelial (MAC-T) cells using clustered, regularly interspaced, short palindromic repeat (CRISPR)/CRISPR-associated (Cas)-9 technology. MAC-T cells were pre-incubated with and without Lactobacillus rhamnosus GR-1 and then exposed to E. coli. Western blot analysis demonstrated increased expression of NLRP3 and NLRC4 following E. coli infection, but this increase was attenuated by pre-incubation with L. rhamnosus GR-1, regardless of ASC knockout. Western blot and immunofluorescence analyses revealed that pre-incubation with L. rhamnosus GR-1 decreased E. coli-induced caspase-1 activation at 6 h after E. coli infection, as also observed in ASC-knockout MAC-T cells. The E. coli-induced increase in caspase-4 mRNA expression was inhibited by pre-incubation with L. rhamnosus GR-1. ASC knockout diminished, but did not completely prevent, increased production of IL-1β and IL-18 and cell pyroptosis associated with E. coli infection, whereas pre-incubation with L. rhamnosus GR-1 inhibited this increase. Our data indicate that L. rhamnosus GR-1 suppresses activation of ASC-dependent NLRP3 and NLRC4 inflammasomes and production of downstream IL-lβ and IL-18 during E. coli infection. L. rhamnosus GR-1 also inhibited E. coli-induced cell pyroptosis, in part through attenuation of NLRC4 and non-canonical caspase-4 activation independently of ASC

Antitumor Agents 259. Design, Syntheses, and Structure−Activity Relationship Study of Desmosdumotin C Analogs

Desmosdumotin C (1) and its analogs previously showed potent, selective in vitro anticancer activity. To explore structure-activity-relationships of 1 and further increase potency and selectivity, fifteen novel analogs (7–15 and 21–26) were synthesized, and evaluated for cytotoxity against several human tumor cell lines, as well as inhibition of human endothelial (HUVEC) replication. 4-Bromo-3′,3′,5′-tripropyl analog 26 showed significant cytotoxity against A549, A431, 1A9, and HCT-8 with ED50 values of 1.0, 1.2, 0.9, and 1.3 μg/mL respectively. Compound 26 also strongly inhibited the growth of matched tumor cells, KB-VIN and its parent cell KB. Furthermore, analogs 13 and 21 were over fivefold more potent against KB-VIN than KB. Bromination of ring-B and tripropyl functionalization of ring-A enhanced activity, while alkylation of ring-B promoted KB-VIN/KB selectivity. 2-Furyl analog 16 showed selective activity against HUVEC, suggesting that it may have potential as a new prototype for angiogenesis inhibition

The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk

AbstractBackgroundLarge cohort studies provide conflicting evidence regarding the potential for oral macrolide antibiotics to increase the risk of serious cardiac events.ObjectivesThis study performed a meta-analysis to examine the link between macrolides and risk of sudden cardiac death (SCD) or ventricular tachyarrhythmias (VTA), cardiovascular death, and death from any cause.MethodsWe performed a search of published reports by using MEDLINE (January 1, 1966, to April 30, 2015) and EMBASE (January 1, 1980, to April 30, 2015) with no restrictions. Studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of interest were included.ResultsThirty-three studies involving 20,779,963 participants were identified. Patients taking macrolides, compared with those who took no macrolides, experienced an increased risk of developing SCD or VTA (RR: 2.42; 95% CI: 1.61 to 3.63), SCD (RR: 2.52; 95% CI: 1.91 to 3.31), and cardiovascular death (RR: 1.31; 95% CI: 1.06 to 1.62). No association was found between macrolides use and all-cause death or any cardiovascular events. The RRs associated with SCD or VTA were 3.40 for azithromycin, 2.16 for clarithromycin, and 3.61 for erythromycin, respectively. RRs for cardiovascular death were 1.54 for azithromycin and 1.48 for clarithromycin. No association was noted between roxithromycin and adverse cardiac outcomes. Treatment with macrolides is associated with an absolute risk increase of 118.1 additional SCDs or VTA, and 38.2 additional cardiovascular deaths per 1 million treatment courses.ConclusionsAdministration of macrolide antibiotics is associated with increased risk for SCD or VTA and cardiovascular death but not increased all-cause mortality

Multi-omics analysis reveals a molecular landscape of the early recurrence and early metastasis in pan-cancer

Cancer remains a formidable challenge in medicine due to its propensity for recurrence and metastasis, which can result in unfavorable treatment outcomes. This challenge is particularly acute for early-stage patients, who may experience recurrence and metastasis without timely detection. Here, we first analyzed the differences in clinical characteristics among the primary tumor, recurrent tumor, and metastatic tumor in different stages of cancer, which may be caused by the molecular level. Moreover, the importance of predicting early cancer recurrence and metastasis is emphasized by survival analyses. Next, we used a multi-omics approach to identify key molecular changes associated with early cancer recurrence and metastasis and discovered that early metastasis in cancer demonstrated a high degree of genomic and cellular heterogeneity. We performed statistical comparisons for each level of omics data including gene expression, mutation, copy number variation, immune cell infiltration, and cell status. Then, various analytical techniques, such as proportional hazard model and Fisher’s exact test, were used to identify specific genes or immune characteristics associated with early cancer recurrence and metastasis. For example, we observed that the overexpression of BPIFB1 and high initial B-cell infiltration levels are linked to early cancer recurrence, while the overexpression or amplification of ANKRD22 and LIPM, mutation of IGHA1 and MUC16, high fibroblast infiltration level, M1 polarization of macrophages, cellular status of DNA repair are all linked to early cancer metastasis. These findings have led us to construct classifiers, and the average area under the curve (AUC) of these classifiers was greater than 0.75 in The Cancer Genome Atlas (TCGA) cancer patients, confirming that the features we identified could be biomarkers for predicting recurrence and metastasis of early cancer. Finally, we identified specific early sensitive targets for targeted therapy and immune checkpoint inhibitor therapy. Once the biomarkers we identified changed, treatment-sensitive targets can be treated accordingly. Our study has comprehensively characterized the multi-omics characteristics and identified a panel of biomarkers of early cancer recurrence and metastasis. Overall, it provides a valuable resource for cancer recurrence and metastasis research and improves our understanding of the underlying mechanisms driving early cancer recurrence and metastasis

Structural and Functional Diversity of Acidic Scorpion Potassium Channel Toxins

Background: Although the basic scorpion K + channel toxins (KTxs) are well-known pharmacological tools and potential drug candidates, characterization the acidic KTxs still has the great significance for their potential selectivity towards different K + channel subtypes. Unfortunately, research on the acidic KTxs has been ignored for several years and progressed slowly. Principal Findings: Here, we describe the identification of nine new acidic KTxs by cDNA cloning and bioinformatic analyses. Seven of these toxins belong to three new a-KTx subfamilies (a-KTx28, a-KTx29, and a-KTx30), and two are new members of the known k-KTx2 subfamily. ImKTx104 containing three disulfide bridges, the first member of the a-KTx28 subfamily, has a low sequence homology with other known KTxs, and its NMR structure suggests ImKTx104 adopts a modified cystine-stabilized a-helix-loop-b-sheet (CS-a/b) fold motif that has no apparent a-helixs and b-sheets, but still stabilized by three disulfide bridges. These newly described acidic KTxs exhibit differential pharmacological effects on potassium channels. Acidic scorpion toxin ImKTx104 was the first peptide inhibitor found to affect KCNQ1 channel, which is insensitive to the basic KTxs and is strongly associated with human cardiac abnormalities. ImKTx104 selectively inhibited KCNQ1 channel with a Kd of 11.69 mM, but was less effective against the basic KTxs-sensitive potassium channels. In addition to the ImKTx104 toxin, HeTx204 peptide, containing a cystine-stabilized a-helix-loop-helix (CS-a/a) fold scaffold motif

Synthesis and applications of porous non-silica metal oxide submicrospheres

© 2016 Royal Society of Chemistry. Nowadays the development of submicroscale products of specific size and morphology that feature a high surface area to volume ratio, well-developed and accessible porosity for adsorbates and reactants, and are non-toxic, biocompatible, thermally stable and suitable as synergetic supports for precious metal catalysts is of great importance for many advanced applications. Complex porous non-silica metal oxide submicrospheres constitute an important class of materials that fulfill all these qualities and in addition, they are relatively easy to synthesize. This review presents a comprehensive appraisal of the methods used for the synthesis of a wide range of porous non-silica metal oxide particles of spherical morphology such as porous solid spheres, core-shell and yolk-shell particles as well as single-shell and multi-shell particles. In particular, hydrothermal and low temperature solution precipitation methods, which both include various structure developing strategies such as hard templating, soft templating, hydrolysis, or those taking advantage of Ostwald ripening and the Kirkendall effect, are reviewed. In addition, a critical assessment of the effects of different experimental parameters such as reaction time, reaction temperature, calcination, pH and the type of reactants and solvents on the structure of the final products is presented. Finally, the practical usefulness of complex porous non-silica metal oxide submicrospheres in sensing, catalysis, biomedical, environmental and energy-related applications is presented

Вихретоковый анизотропный термоэлектрический первичный преобразователь лучистого потока

Представлена оригинальная конструкция первичного преобразователя лучистого потока, который может служить основой для создания приемника неселективного излучения с повышенной чувствительностью

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases