Lojasiewicz exponent of families of ideals, Rees mixed multiplicities and Newton filtrations

We give an expression for the {\L}ojasiewicz exponent of a wide class of n-tuples of ideals $(I_1,..., I_n)$ in \O_n using the information given by a fixed Newton filtration. In order to obtain this expression we consider a reformulation of {\L}ojasiewicz exponents in terms of Rees mixed multiplicities. As a consequence, we obtain a wide class of semi-weighted homogeneous functions $(\mathbb{C}^n,0)\to (\mathbb{C},0)$ for which the {\L}ojasiewicz of its gradient map $\nabla f$ attains the maximum possible value.Comment: 25 pages. Updated with minor change

N-Methylimidazole Promotes The Reaction Of Homophthalic Anhydride With Imines

The addition of N-methylimidazole (NMI) to the reaction of homophthalic anhydride with imines such as pyridine-3-carboxaldehyde-N-trifluoroethylimine (9) reduces the amount of elimination byproduct and improves the yield of the formal cycloadduct, tetrahydroisoquinolonic carboxylate 10. Carboxanilides of such compounds are of interest as potential antimalarial agents. A mechanism that rationalizes the role of NMI is proposed, and a gram-scale procedure for the synthesis and resolution of 10 is also described

Structure of capital and the cost of debt in meat procesing industry in Poland

Optymalizacja struktury kapitału wciąż stanowi ważne zagadnienie w świecie finansów. Próby stworzenia kompleksowego i transparentnego modelu ekonometrycznego umożliwiającego zwiększanie wartości przedsiębiorstwa przy jednoczesnej optymalizacji kosztu kapitału oraz budowa teorii go objaśniającej trwają nieprzerwanie od połowy XX wieku. Oszacowany w niniejszym opracowaniu model ekonometryczny, objaśniający koszt kapitału obcego na skutek zmian w strukturze kapitałowej badanych przedsiębiorstw branży mięsnej, przeszedł poprawnie weryfikację statystyczną i logiczną, co pozwala na jego dalszą weryfikację na podmiotach spoza próby badawczej oraz implementację do profesjonalnej analizy finansowej.The problem of optimizing the structure of capital is still an unsolved mystery in the financial world. Attempts to create a comprehensive and transparent econometric model allows increasing the enterprise's value while optimizing the cost of capital and the construction of explanatory theory it lasts continuously since the middle of last century. An econometric model estimated in this research explaining the cost of debt due to changes in the capital structure of the surveyed companies in the meat procesing pased correctly statistical and logical verification, which allows for its further verification to entities outside of the research sample and implementation for profesional financial analysis. Built model does not ignore the addition of changes in the parameters of the market economy, which significantly increases its value

A common druggable signature of oncogenic c-Myc, mutant KRAS and mutant p53 reveals functional redundancy and competition among oncogenes in cancer

The major driver oncogenes MYC, mutant KRAS, and mutant TP53 often coexist and cooperate to promote human neoplasia, which results in anticancer therapeutic opportunities within their downstream molecular programs. However, little research has been conducted on whether redundancy and competition among oncogenes affect their programs and ability to drive neoplasia. By CRISPR-Cas9-mediated downregulation we evaluated the downstream proteomics and transcriptomics programs of MYC, mutant KRAS, and mutant TP53 in a panel of cell lines with either one or three of these oncogenes activated, in cancers of the lung, colon and pancreas. Using RNAi screening of the commonly activated molecular programs, we found a signature of three proteins - RUVBL1, HSPA9, and XPO1, which could be efficiently targeted by novel drug combinations in the studied cancer types. Interestingly, the signature was controlled by the oncoproteins in a redundant or competitive manner rather than by cooperation. Each oncoprotein individually upregulated the target genes, while upon oncogene co-expression each target was controlled preferably by a dominant oncoprotein which reduced the influence of the others. This interplay was mediated by redundant routes of target gene activation - as in the case of mutant KRAS signaling to c-Jun/GLI2 transcription factors bypassing c-Myc activation, and by competition - as in the case of mutant p53 and c-Myc competing for binding to target promoters. The global transcriptomics data from the cell lines and patient samples indicate that the redundancy and competition of oncogenic programs are broad phenomena, that may constitute even a majority of the genes dependent on oncoproteins, as shown for mutant p53 in colon and lung cancer cell lines. Nevertheless, we demonstrated that redundant oncogene programs harbor targets for efficient anticancer drug combinations, bypassing the limitations for direct oncoprotein inhibition

The molecular network of the proteasome machinery inhibition response is orchestrated by HSP70, revealing vulnerabilities in cancer cells

Proteasome machinery is amajor proteostasis control system in human cells, actively compensated upon its inhibition. To understand this compensation, we compared global protein landscapes upon the proteasome inhibition with carfilzomib, in normal fibroblasts, cells of multiple myeloma, and cancers of lung, colon, and pancreas. Molecular chaperones, autophagy, and endocytosis-related proteins are the most prominent vulnerabilities in combination with carfilzomib, while targeting of the HSP70 family chaperones HSPA1A/B most specifically sensitizes cancer cells to the proteasome inhibition. This suggests a central role of HSP70 in the suppression of the proteasome downregulation, allowing to identify pathways impinging on HSP70 upon the proteasome inhibition. HSPA1A/B indeed controls proteasome-inhibition-induced autophagy, unfolded protein response, and endocytic flux, and directly chaperones the proteasome machinery. However, it does not control the NRF1/2-driven proteasome subunit transcriptional bounce-back. Consequently, targeting of NRF1 proves effective in decreasing the viability of cancer cells with the inhibited proteasome and HSP70