Pharmacological levels of withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells

Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer

The marine protected area planning process in Washington state: Recommendations for increased effectiveness

In Washington State, the Department of Natural Resources (WA DNR) is responsible for managing state-owned aquatic lands. Aquatic reserves are one of many Marine Protected Area (MPA) designations in WA State that aim to protect sensitive aquatic and ecological habitat. We analyzed the designation and early planning processes of WA State aquatic reserves, identified gaps in the processes, and recommend action to improve the WA State aquatic reserve early planning approach. (PDF contains 4 pages

The Defense Of Oral Interaction In The Midst Of Whatsapp Use In The Learning Environment

This research aimed to explain the defense of oral interactions in the presence of information and communication technologies such as WhatsApp (WA) as well as to explore some of the positive contributions of WA used in building the Real Life Communication, especially in the learning environment. By applying the Exploratory design, this research involved 4 participants from various educational backgrounds as a purposively selected data source indicated as WA users at once. Data were collected through Focus Group Discussion, Interview, and Observation and analyzed by several stages i.e. data reduction, displaying data, categorizing, and verifying and concluding. The results showed that oral interactions can decrease both in the language community and learning environment as the dominant use of WA that is not wise. Nevertheless, the use of WA applications also had some positive contributions in building a real relationship. Finally, the assumption that the negative impact of using the WA application should be able to change the mindset and positive attitude of the scholars in initiating and defending an oral interaction in the learning environment

Error Analysis and Correction for Weighted A*'s Suboptimality (Extended Version)

Weighted A* (wA*) is a widely used algorithm for rapidly, but suboptimally, solving planning and search problems. The cost of the solution it produces is guaranteed to be at most W times the optimal solution cost, where W is the weight wA* uses in prioritizing open nodes. W is therefore a suboptimality bound for the solution produced by wA*. There is broad consensus that this bound is not very accurate, that the actual suboptimality of wA*'s solution is often much less than W times optimal. However, there is very little published evidence supporting that view, and no existing explanation of why W is a poor bound. This paper fills in these gaps in the literature. We begin with a large-scale experiment demonstrating that, across a wide variety of domains and heuristics for those domains, W is indeed very often far from the true suboptimality of wA*'s solution. We then analytically identify the potential sources of error. Finally, we present a practical method for correcting for two of these sources of error and experimentally show that the correction frequently eliminates much of the error.Comment: Published as a short paper in the 12th Annual Symposium on Combinatorial Search, SoCS 201

Highlights of The Concept of Islamic Education Majid 'Irsan Al-Kilani

This article tries to reveal the concept of Islamic Education Majid Irsan al-Kilani, namely through the analysis of the five papers he is closely linked to education, among other things: 1) Ahdaf alTarbiyah al-Islamiyya fi Tarbiyah al-Fard wa Ikhraj al-Umma wa Tan-Miyah al-Ukhuwwah al-Insaniyyah (Vision-Mission of the Islamic Education in Teaching Personal, cadres of the People and Develop Fraternity Human Brotherhood), 2) philosophy of al-MT al-Islamiyya: Dirasah Muqāranah Baina philosophy of alTarbiyahal-Islamiyya wa al-philosophy al-Tarbawiyyah al-Mu'ashirah (Philosophy of Islamic Education: A Comparative Study of Islamic Education Philosophy and Contemporary Educational Philosophy), 3) al-Fikr alTarbawi'indaIbn Taimiyyah (Islamic Educational Thought Perspective of Ibnu Taimiyyah), 4) Hakadza zahara Jil Shalah al-Din wa Hakadza 'Adat al-Quds (Emerging Shalahudin Generation and the return of al-Aqsa), 5) Tathawwur understand al-Nazhariyyat al-Tarbawiyyah al-Islamiyya (History conception of Educational Islamic epistimologi)

Degree of Sequentiality of Weighted Automata

Weighted automata (WA) are an important formalism to describe quantitative properties. Obtaining equivalent deterministic machines is a longstanding research problem. In this paper we consider WA with a set semantics, meaning that the semantics is given by the set of weights of accepting runs. We focus on multi-sequential WA that are defined as finite unions of sequential WA. The problem we address is to minimize the size of this union. We call this minimum the degree of sequentiality of (the relation realized by) the WA. For a given positive integer k, we provide multiple characterizations of relations realized by a union of k sequential WA over an infinitary finitely generated group: a Lipschitz-like machine independent property, a pattern on the automaton (a new twinning property) and a subclass of cost register automata. When possible, we effectively translate a WA into an equivalent union of k sequential WA. We also provide a decision procedure for our twinning property for commutative computable groups thus allowing to compute the degree of sequentiality. Last, we show that these results also hold for word transducers and that the associated decision problem is PSPACE -complete

Improving fertiliser management: redefining the relationship between soil tests and crop responses for wheat in WA

Most soils in Western Australia (WA) are highly weathered with very low levels of phosphorus. WA soils initially contained adequate indigenous soil potassium for cropping but removal of potassium over time in harvested grain has gradually resulted in the some soils becoming potassium-deficient for grain production. Fertiliser costs represent a significant part of the variable costs of growing crops in WA. Chen et al. (2009) identified the need for updated soil test interpretations due to substantial changes in farming systems, fertiliser practices and crop yield potential. The aims of this study were (1) to compile experimental data containing the standard soil test measurements and observed wheat crop yield responses for both nil and fertilised treatments across different soil types and seasons from published or unpublished sources, and (2) to critically analyse soil test-crop response relationships to derive better critical soil test values in soils and environments suitable for wheat grain production in WA

Qi-Wa, a problem that has plagued Chinese scrolls for millenniums

Qi-Wa refers to the up curl on the lengths of handscrolls and hanging scrolls, which has troubled Chinese artisans and emperors for as long as the art of painting and calligraphy exists. This warp is unwelcomed not only for aesthetic reasons, but its potential damage to the fiber and ink. Although it is generally treated as a part of the cockling and curling due to climate, mounting procedures, and conservation conditions, we emphasize that the intrinsic curvature incurred from the storage is in fact the main cause of Qi-Wa. The Qi-Wa height is determined by experiments to obey scaling relations with the length, width, curvature, and thickness of the scroll, which are supported by Molecular Dynamics Simulation and theoretic derivations. This understanding helps us come up with plausible remedies to mitigate Qi-Wa. All proposals are tested on real mounted paper and in simulations. Due to the general nature of this warp, we believe the lessons learnt from studying ancient Chinese scrolls can be applied to modern technologies such as the development of flexible electronic paper and computer screen.Comment: 5 pages and 5 figure

On a Conjecture of Rapoport and Zink

In their book Rapoport and Zink constructed rigid analytic period spaces $F^{wa}$ for Fontaine's filtered isocrystals, and period morphisms from PEL moduli spaces of $p$-divisible groups to some of these period spaces. They conjectured the existence of an \'etale bijective morphism $F^a \to F^{wa}$ of rigid analytic spaces and of a universal local system of $Q_p$-vector spaces on $F^a$. For Hodge-Tate weights $n-1$ and $n$ we construct in this article an intrinsic Berkovich open subspace $F^0$ of $F^{wa}$ and the universal local system on $F^0$. We conjecture that the rigid-analytic space associated with $F^0$ is the maximal possible $F^a$, and that $F^0$ is connected. We give evidence for these conjectures and we show that for those period spaces possessing PEL period morphisms, $F^0$ equals the image of the period morphism. Then our local system is the rational Tate module of the universal $p$-divisible group and enjoys additional functoriality properties. We show that only in exceptional cases $F^0$ equals all of $F^{wa}$ and when the Shimura group is $GL_n$ we determine all these cases.Comment: v2: 48 pages; many new results added, v3: final version that will appear in Inventiones Mathematica