TY - JOUR AB - Effective design of combination therapies requires understanding the changes in cell physiology that result from drug interactions. Here, we show that the genome-wide transcriptional response to combinations of two drugs, measured at a rigorously controlled growth rate, can predict higher-order antagonism with a third drug in Saccharomyces cerevisiae. Using isogrowth profiling, over 90% of the variation in cellular response can be decomposed into three principal components (PCs) that have clear biological interpretations. We demonstrate that the third PC captures emergent transcriptional programs that are dependent on both drugs and can predict antagonism with a third drug targeting the emergent pathway. We further show that emergent gene expression patterns are most pronounced at a drug ratio where the drug interaction is strongest, providing a guideline for future measurements. Our results provide a readily applicable recipe for uncovering emergent responses in other systems and for higher-order drug combinations. A record of this paper’s transparent peer review process is included in the Supplemental Information. AU - Lukacisin, Martin AU - Bollenbach, Tobias ID - 7026 IS - 5 JF - Cell Systems SN - 2405-4712 TI - Emergent gene expression responses to drug combinations predict higher-order drug interactions VL - 9 ER - TY - JOUR AB - We find a graph of genus 5 and its drawing on the orientable surface of genus 4 with every pair of independent edges crossing an even number of times. This shows that the strong Hanani–Tutte theorem cannot be extended to the orientable surface of genus 4. As a base step in the construction we use a counterexample to an extension of the unified Hanani–Tutte theorem on the torus. AU - Fulek, Radoslav AU - Kynčl, Jan ID - 7034 IS - 6 JF - Combinatorica SN - 0209-9683 TI - Counterexample to an extension of the Hanani-Tutte theorem on the surface of genus 4 VL - 39 ER - TY - CONF AB - Optical frequency combs (OFCs) are light sources whose spectra consists of equally spaced frequency lines in the optical domain [1]. They have great potential for improving high-capacity data transfer, all-optical atomic clocks, spectroscopy, and high-precision measurements [2]. AU - Rueda Sanchez, Alfredo R AU - Sedlmeir, Florian AU - Leuchs, Gerd AU - Kuamri, Madhuri AU - Schwefel, Harald G. L. ID - 7032 SN - 9781728104690 T2 - 2019 Conference on Lasers and Electro-Optics Europe & European Quantum Electronics Conference TI - Electro-optic frequency comb generation in lithium niobate whispering gallery mode resonators ER - TY - JOUR AB - BAX, a member of the BCL2 gene family, controls the committed step of the intrinsic apoptotic program. Mitochondrial fragmentation is a commonly observed feature of apoptosis, which occurs through the process of mitochondrial fission. BAX has consistently been associated with mitochondrial fission, yet how BAX participates in the process of mitochondrial fragmentation during apoptosis remains to be tested. Time-lapse imaging of BAX recruitment and mitochondrial fragmentation demonstrates that rapid mitochondrial fragmentation during apoptosis occurs after the complete recruitment of BAX to the mitochondrial outer membrane (MOM). The requirement of a fully functioning BAX protein for the fission process was demonstrated further in BAX/BAK-deficient HCT116 cells expressing a P168A mutant of BAX. The mutant performed fusion to restore the mitochondrial network. but was not demonstrably recruited to the MOM after apoptosis induction. Under these conditions, mitochondrial fragmentation was blocked. Additionally, we show that loss of the fission protein, dynamin-like protein 1 (DRP1), does not temporally affect the initiation time or rate of BAX recruitment, but does reduce the final level of BAX recruited to the MOM during the late phase of BAX recruitment. These correlative observations suggest a model where late-stage BAX oligomers play a functional part of the mitochondrial fragmentation machinery in apoptotic cells. AU - Maes, Margaret E AU - Grosser, J. A. AU - Fehrman, R. L. AU - Schlamp, C. L. AU - Nickells, R. W. ID - 7095 JF - Scientific Reports TI - Completion of BAX recruitment correlates with mitochondrial fission during apoptosis VL - 9 ER - TY - JOUR AB - Early endosomes, also called sorting endosomes, are known to mature into late endosomesvia the Rab5-mediated endolysosomal trafficking pathway. Thus, early endosome existence isthought to be maintained by the continual fusion of transport vesicles from the plasmamembrane and thetrans-Golgi network (TGN). Here we show instead that endocytosis isdispensable and post-Golgi vesicle transport is crucial for the formation of endosomes andthe subsequent endolysosomal traffic regulated by yeast Rab5 Vps21p. Fittingly, all threeproteins required for endosomal nucleotide exchange on Vps21p arefirst recruited to theTGN before transport to the endosome, namely the GEF Vps9p and the epsin-relatedadaptors Ent3/5p. The TGN recruitment of these components is distinctly controlled, withVps9p appearing to require the Arf1p GTPase, and the Rab11s, Ypt31p/32p. These resultsprovide a different view of endosome formation and identify the TGN as a critical location forregulating progress through the endolysosomal trafficking pathway. AU - Nagano, Makoto AU - Toshima, Junko Y. AU - Siekhaus, Daria E AU - Toshima, Jiro ID - 7097 IS - 1 JF - Communications Biology SN - 2399-3642 TI - Rab5-mediated endosome formation is regulated at the trans-Golgi network VL - 2 ER -