Cells respond to environmental fluctuations by regulating multiple transcriptional programs. This response can be studied by measuring the effect of environmental changes on the transcriptome or the proteome of the cell at the end of the response. However, the dynamics of the response reflect the working of the regulatory mechanisms in action. Here, we utilized a fluorescent stress reporter gene to track the dynamics of protein production in yeast responding to environmental stress. The response is modulated by changes in both the duration and rate of transcription. We probed the underlying molecular pathways controlling these two dimensions using a library of ~1,600 single‐ and double‐mutant strains. Dissection of the effects of these mutants and the interactions between them identified distinct modulators of response duration and response rate. Using a combination of mRNA ‐seq and live‐cell microscopy, we uncover mechanisms by which Msn2/4, Mck1, Msn5, and the cAMP / PKA pathway modulate the response of a large module of stress‐induced genes in two discrete regulatory phases. Our results and analysis show that transcriptional stress response is regulated by multiple mechanisms that overlap in time and cellular location.
Die 0x0-iminiumsalze I l a -e und 13a -e werden durch Oximierung der w-Chlorketone 9a -e iiber die cyclischen Oximether 10a -e bzw. die cyclischen Imin-oxide 12a -e und deren anschlienende Alkylierung mit ,,Meerweinsalr" hergestellt. Die Deprotonierungsreaktionen von 11 a -e sowie 13a-e fiihren uber die regioselektiv hergesiellten Zwischenprodukte 14a-e bzw. 17a-e zu den a,p-ungesattigten lminen 15a -e und den cyclischen lminen 18a -e. Synthesis and Thermolysis of 0-Alkyl-N-vinylhydroxylamine DerivativesOxoiminium salts l l a -e and 13a-e have been prepared from the o-chloroketones 9 a -e by oximation via the cyclic oxime ethers 10a-e and the cyclic imine oxides 12a-e, followed by alkylation with ,,Meerwein salt". The deprotonation reaction of 11 a -e and 13a -e yields, uiu the regioselectively prepared intermediates 14a -e and 17a -e, the a$-unsaturated imines 15a -e and the cyclic imines 18a-e, respectively.In Fortfuhrung unserer Untersuchungen uber 0x0-iminiumsalze') bemiihten wir uns urn die Synthese sowie die chemischen Anwendungsm6glichkeiten der bisher nur wenig untersuchten N-Vinyl-O-alkylhydroxylamine2'.
Novel methods are described for the preparation of alkyldimethylamine cyanoboranes and β-hydroxylalkyldimethylamine cyanoboranes by C-lithiation of trimethylamine cyanoboranes followed by reaction with alkyl halides, aldehydes, and ketones. Lithiation of the monobromo derivatives of amine cyanoboranes led to the synthesis of the first examples of diborane derivatives of amine cyanoboranes. Bromo derivatives of amine cyanoboranes and amine carboxyboranes have been synthesized by new simple and efficient methods. Amine fluorocyanoboranes and amine fluorocarboxyboranes, new classes of compounds, have been prepared from the bromo precursors by fluorine/bromine exchange using fluorinating reagents such as AgF and Et3N.3HF. Eight different derivatives of oxazaborolidines were synthesized and evaluated for their affect on Streptococcus mutans viability, adhesion, and biofilm formation using 3[H]-thymidine labeled bacteria, and fluorescent stained bacteria. This is the first reported antibacterial activity of this class of compounds. The minimal inhibitory concentration (MIC) values ranged from 0.26 to 10 mM. Structure-activity relationship was observed. The B-butyl moiety of the oxazaborolidines contributed an anti-adhesion effect for all derivatives, while its effect diminished when the boron atom was incorporated in a fused heterocyclic ring. The B-phenyl group induced bacterial adhesion in all tested compounds. In a separate study for boronated saccahrides and enzymatic inhibition, the complex formation between N-butylboronic acid and a series of monosaccharides was investigated by 1H, 13C, and 11B NMR spectroscopy and gas chromatography-mass spectrometry (GC-MS). Then, a series of boronic acid compounds with protease inhibition properties were prepared. The effect of added mono-, di-, and polysaccharides on the inhibitory activity of these compounds was studied. Potassium organotrifluoroborates were found to be reversible competitive inhibitors of α-chymotrypsin and trypsin. Based on 19F NMR, it was speculated that they inactivate the enzymes as a result of the formation of hydrogen bonds between fluorine atoms of the inhibitors and the serine protease.
A series of new amine cyanoborane derivatives were synthesized and exhibited antifungal activity. A long alkyl chain attached to the nitrogen of the amine cyanoboranes and carboxyboranes enhances antifungal activity. An enhanced activity was also obtained upon the halogenation of the amine cyanoboranes as well as in the presence of C=C double bond at the end of the N-alkyl group. The lead compounds were dimethylundecylamine cyanoborane (C11H23N(CH3)2BH2CN), 9, and its dibromo derivative dimethylundecylamine dibromocyanoborane (C11H23N(CH3)2BBr2CN), 11. The MIC values for the lead compounds against the most important human pathogenic fungi ranged from 16.25 to 32.5 micromol/L and from 10.05 to 79 micromol/L, respectively. Both compounds were found to be relatively safe in intravenous injections to mice, (MTD = 121.9 and 73.1 micromol/kg, respectively) and active against strains that are resistant to fluconazole (a conventional antifungal medicine). These data indicate their potential to become antifungal agents.
We have developed a new method for the preparation of esters of trimethylamine−dibromocarboxyborane (Me3N·BBr2COOR), from trimethylamine−carboxyborane, in a one-pot reaction. The reaction involves the treatment of trimethylamine−carboxyborane with 2.5 equiv of Br2 in the appropriate alcohol for 4 h at 0 °C, for compounds 1−5 (R = Me, Et, n-Pr, CH2CH2Cl, CH2CF3), and 5 equiv of Br2 for 8 h under the same conditions, for compounds 6−8 (R = n-Bu, i-Bu, i-Pe). Compounds 1−5 were obtained in high purity and in essentially quantitative yields (∼99%). Compounds 6−8 were purified from traces of monobromo product and the alcohol by column chromatography. Molecular structures for the compounds 2, 6, and 7 were determined by X-ray crystallography.
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