The Lsm Proteins: Ring Architectures for RNA Capture

20 page(s

Towards Interpretable Machine Learning for Automated Damage Detection Based on Ultrasonic Guided Waves

Data-driven analysis for damage assessment has a large potential in structural health monitoring (SHM) systems, where sensors are permanently attached to the structure, enabling continuous and frequent measurements. In this contribution, we propose a machine learning (ML) approach for automated damage detection, based on an ML toolbox for industrial condition monitoring. The toolbox combines multiple complementary algorithms for feature extraction and selection and automatically chooses the best combination of methods for the dataset at hand. Here, this toolbox is applied to a guided wave-based SHM dataset for varying temperatures and damage locations, which is freely available on the Open Guided Waves platform. A classification rate of 96.2% is achieved, demonstrating reliable and automated damage detection. Moreover, the ability of the ML model to identify a damaged structure at untrained damage locations and temperatures is demonstrated

A Live Zebrafish-Based Screening System for Human Nuclear Receptor Ligand and Cofactor Discovery

Nuclear receptors (NRs) belong to a superfamily of transcription factors that regulate numerous homeostatic, metabolic and reproductive processes. Taken together with their modulation by small lipophilic molecules, they also represent an important and successful class of drug targets. Although many NRs have been targeted successfully, the majority have not, and one third are still orphans. Here we report the development of an in vivo GFP-based reporter system suitable for monitoring NR activities in all cells and tissues using live zebrafish (Danio rerio). The human NR fusion proteins used also contain a new affinity tag cassette allowing the purification of receptors with bound molecules from responsive tissues. We show that these constructs 1) respond as expected to endogenous zebrafish hormones and cofactors, 2) facilitate efficient receptor and cofactor purification, 3) respond robustly to NR hormones and drugs and 4) yield readily quantifiable signals. Transgenic lines representing the majority of human NRs have been established and are available for the investigation of tissue- and isoform-specific ligands and cofactors

Определение объема вычислительных экспериментов при решении задач оптимизационного синтеза динамических систем методом ПЛП-поиска

Даются рекомендации по выбору необходимого числа машинных экспериментов при решении конкретных задач исследования и оптимального проектирования методом ПЛП-поиска, позволяющего осуществлять глобальный квазиравномерный просмотр заданной области варьируемых параметров и применить формальные оценки из математической статистики.Recommendations about the choice of necessary number of machine experiments at the solution of specific objectives of a research and optimum design are made by method of the PLP-search allowing to carry out global quasi uniform viewing of the set area of the varied parameters and to apply formal estimates from mathematical statistics

Transport of Streptococcus pneumoniae Capsular Polysaccharide in MHC Class II Tubules

Bacterial capsular polysaccharides are virulence factors and are considered T cell–independent antigens. However, the capsular polysaccharide Sp1 from Streptococcus pneumoniae serotype 1 has been shown to activate CD4(+) T cells in a major histocompatibility complex (MHC) class II–dependent manner. The mechanism of carbohydrate presentation to CD4(+) T cells is unknown. We show in live murine dendritic cells (DCs) that Sp1 translocates from lysosomal compartments to the plasma membrane in MHCII-positive tubules. Sp1 cell surface presentation results in reduction of self-peptide presentation without alteration of the MHCII self peptide repertoire. In DM-deficient mice, retrograde transport of Sp1/MHCII complexes resulting in T cell–dependent immune responses to the polysaccharide in vitro and in vivo is significantly reduced. The results demonstrate the capacity of a bacterial capsular polysaccharide antigen to use DC tubules as a vehicle for its transport as an MHCII/saccharide complex to the cell surface for the induction of T cell activation. Furthermore, retrograde transport requires the functional role of DM in self peptide–carbohydrate exchange. These observations open new opportunities for the design of vaccines against microbial encapsulated pathogens

Mechanistic insights into an engineered riboswitch: a switching element which confers riboswitch activity

While many different RNA aptamers have been identified that bind to a plethora of small molecules only very few are capable of acting as engineered riboswitches. Even for aptamers binding the same ligand large differences in their regulatory potential were observed. We address here the molecular basis for these differences by using a set of unrelated neomycin-binding aptamers. UV melting analyses showed that regulating aptamers are thermally stabilized to a significantly higher degree upon ligand binding than inactive ones. Regulating aptamers show high ligand-binding affinity in the low nanomolar range which is necessary but not sufficient for regulation. NMR data showed that a destabilized, open ground state accompanied by extensive structural changes upon ligand binding is important for regulation. In contrast, inactive aptamers are already pre-formed in the absence of the ligand. By a combination of genetic, biochemical and structural analyses, we identified a switching element responsible for destabilizing the ligand free state without compromising the bound form. Our results explain for the first time the molecular mechanism of an engineered riboswitch

Selective inhibition of IL-6 trans-signaling by a miniaturized, optimized chimeric soluble gp130 inhibits TH17 cell expansion

The cytokine interleukin-6 (IL-6) signals through three mechanisms called classic signaling, trans-signaling, and trans-presentation. IL-6 trans-signaling is distinctly mediated through a soluble form of its transmembrane receptor IL-6R (sIL-6R) and the coreceptor gp130 and is implicated in multiple autoimmune diseases. Although a soluble form of gp130 (sgp130) inhibits only IL-6 trans-signaling, it also blocks an analogous trans-signaling mechanism of IL-11 and its soluble receptor sIL-11R. Here, we report miniaturized chimeric soluble gp130 variants that efficiently trap IL-6:sIL-6R but not IL-11:sIL-11R complexes. We designed a novel IL-6 trans-signaling trap by fusing a miniaturized sgp130 variant to an IL-6:sIL-6R complex–binding nanobody and the Fc portion of immunoglobulin G (IgG). This trap, called cs-130Fc, exhibited improved inhibition of as well as increased selectivity for IL-6 trans-signaling compared to the conventional fusion protein sgp130Fc. We introduced affinity-enhancing mutations in cs-130Fc and sgp130Fc that further improved selectivity toward IL-6 trans-signaling. Moreover, cs-130Fc efficiently inhibited the expansion of T helper 17 (TH17) cells in cultures of mouse CD4+ T cells treated with IL-6:sIL-6R. Thus, these variants may provide or lead to the development of more precisely targeted therapeutics for inflammatory disorders associated with IL-6 trans-signaling

Evidence of Υ(1S)→J/ψ+χc1\Upsilon(1S) \to J/\psi+\chi_{c1} and search for double-charmonium production in Υ(1S)\Upsilon(1S) and Υ(2S)\Upsilon(2S) decays

Using data samples of $102\times10^6$ $\Upsilon(1S)$ and $158\times10^6$ $\Upsilon(2S)$ events collected with the Belle detector, a first experimental search has been made for double-charmonium production in the exclusive decays $\Upsilon(1S,2S)\rightarrow J/\psi(\psi')+X$, where $X=\eta_c$, $\chi_{cJ} (J=~0,~1,~2)$, $\eta_c(2S)$, $X(3940)$, and $X(4160)$. No significant signal is observed in the spectra of the mass recoiling against the reconstructed $J/\psi$ or $\psi'$ except for the evidence of $\chi_{c1}$ production with a significance of $4.6\sigma$ for $\Upsilon(1S)\rightarrow J/\psi+\chi_{c1}$. The measured branching fraction \BR(\Upsilon(1S)\rightarrow J/\psi+\chi_{c1}) is $(3.90\pm1.21(\rm stat.)\pm0.23 (\rm syst.))\times10^{-6}$. The $90\%$ confidence level upper limits on the branching fractions of the other modes having a significance of less than $3\sigma$ are determined. These results are consistent with theoretical calculations using the nonrelativistic QCD factorization approach.Comment: 12 pages, 4 figures, 1 table. The fit range was extended to include X(4160) signal according to referee's suggestions. Other results unchanged. Paper was accepted for publication as a regular article in Physical Review

Cytokeratin 8/18 expression indicates a poor prognosis in squamous cell carcinomas of the oral cavity

BACKGROUND: Intermediary filaments are involved in cell motility and cancer progression. In a variety of organs, the expression of distinct intermediary filaments are associated with patient prognosis. In this study, we seeked to define the prognostic potential of cytokeratin and vimentin expression patterns in squamous cell carcinomas (SCC's) of the oral cavity. METHODS: 308 patients with histologically proven and surgically treated squamous cell carcinomas of the oral cavity were investigated for the immunohistochemical expression of a variety of intermediary filaments including high- and low-molecular weight cytokeratins (Ck's), such as Ck 5/6, Ck 8/18, Ck 1, CK 10, Ck 14, Ck 19 and vimentin, using the tissue microarray technique. Correlations between clinical features and the expression of Cytokeratins and vimentin were evaluated statistically by Kaplan-Meier curves and multivariate Cox regression analysis. RESULTS: The expression of Ck 8/18 and Ck 19 were overall significantly correlated with a poor clinical prognosis (Ck 8/18 p = 0.04; Ck19 p < 0.01). These findings could also be reproduced for Ck 8/18 in primary nodal-negative SCC's and held true in multivariate-analysis. No significant correlation with patient prognosis could be found for the expression of the other cytokeratins and for vimentin. CONCLUSION: The expression of Ck 8/18 in SCC's of the oral cavity is an independent prognostic marker and indicates a decreased overall and progression free survival. These results provide an extended knowledge about the role of intermediary filament expression patterns in SCC's