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Cellular behavior is frequently influenced by the cell’s history, indicating that single cells may memorize past events. We report that budding yeast permanently escape pheromone-induced cell-cycle arrest when experiencing a deceptive mating attempt, i.e., not reaching their putative partner within reasonable time. This acquired behavior depends on super-assembly and inactivation of the G1/S inhibitor...
Parkinson’s disease (PD) is characterized by loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). An association has been reported between PD and exposure to mitochondrial toxins, including environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patient-derived stem cell model of PD allowing comparison of A53T α-synuclein (α-syn) mutant cells and...
The final cleavage event that terminates cell division, abscission of the small, dense intercellular bridge, has been particularly challenging to resolve. Here, we describe imaging innovations that helped answer long-standing questions about the mechanism of abscission. We further explain how computational modeling of high-resolution data was employed to test hypotheses and generate additional insights...
Glucocorticoids, which have been implied in mood modulation, display robust diurnal oscillations in the blood. But does their circadian rhythm regulate mood swings? Ikeda et al. now identify a paracrine signaling pathway in the adrenal cortex that potentiates the daily amplitude of plasma glucocorticoids and renders female mice braver.
Molecular determinants regulating the activation of class B G-protein-coupled receptors (GPCRs) by native peptide agonists are largely unknown. We have investigated here the interaction between the corticotropin releasing factor receptor type 1 (CRF1R) and its native 40-mer peptide ligand Urocortin-I directly in mammalian cells. By incorporating unnatural amino acid photochemical and new click-chemical...
Bacteria that cause disease rely on their ability to counteract and overcome host defenses. Here, we present a genome-scale study of Mycobacterium tuberculosis (Mtb) that uncovers the bacterial determinants of surviving host immunity, sets of genes we term “counteractomes.” Through this analysis, we found that CD4 T cells attempt to contain Mtb growth by starving it of tryptophan—a mechanism that...
The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here, we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug-resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable...
IFN-γ-activated macrophages attempt to limit pathogen growth through tryptophan starvation. Zhang et al. demonstrate that Mycobacterium tuberculosis responds to this threat by synthesizing its own tryptophan. Genetic and chemical inhibition of this pathway reduces mycobacterial survival, revealing a new immune-dependent drug target for tuberculosis.
Mouse models for cancer are revealing novel cancer-promoting roles for autophagy. Autophagy promotes tumor growth by suppressing the p53 response, maintaining mitochondrial function, sustaining metabolic homeostasis and survival in stress, and preventing diversion of tumor progression to benign oncocytomas.
Circulating glucocorticoid levels oscillate with a robust circadian rhythm, yet the physiological relevance of this rhythmicity remains unclear. Here, we show that modulation of circadian glucocorticoid oscillation by enhancing its amplitude leads to anxiolytic-like behavior. We observed that mice with adrenal subcapsular cell hyperplasia (SCH), a common histological change in the adrenals, are less...
N 6 -methyladenosine (m 6 A) is the most ubiquitous mRNA base modification, but little is known about its precise location, temporal dynamics, and regulation. Here, we generated genomic maps of m 6 A sites in meiotic yeast transcripts at nearly single-nucleotide resolution, identifying 1,308 putatively methylated sites within 1,183 transcripts. We validated eight out of eight...
The spliceosome, an assembly of snRNAs and proteins, catalyzes the removal of introns from premessenger RNAs. A new study identifies specific phosphates in the U2-U6 snRNA complex that position two catalytic metals. Remarkably, these correspond precisely to metal-binding phosphates in a homologous structure of Group II self-splicing introns, long proposed to be the ribozyme progenitor of spliceosome.
The nuclear pore complex (NPC) is a fundamental component of all eukaryotic cells that facilitates nucleocytoplasmic exchange of macromolecules. It is assembled from multiple copies of about 30 nucleoporins. Due to its size and complex composition, determining the structure of the NPC is an enormous challenge, and the overall architecture of the NPC scaffold remains elusive. In this study, we have...
Modeling symptoms of mental illness, in all their complexity, represents an unusually challenging task even by the standards of modern science. Some symptoms, in particular, receive less attention due to their difficult translation into measurable phenotypes in model organisms. However, recent studies are now providing insights into the less understood facets of this diverse range of disorders.
The 2013 Nobel Prize in Physiology or Medicine has been awarded to James Rothman, Randy Schekman, and Thomas Südhof “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells”. I present a personal view of the membrane trafficking field, highlighting the contributions of these three Nobel laureates in a historical context.
The cyanobacterial circadian clock generates genome-wide transcriptional oscillations and regulates cell division, but the underlying mechanisms are not well understood. Here, we show that the response regulator RpaA serves as the master regulator of these clock outputs. Deletion of rpaA abrogates gene expression rhythms globally and arrests cells in a dawn-like expression state. Although rpaA deletion...
Enzymatic cleavage of transmembrane anchors to release proteins from the membrane controls diverse signaling pathways and is implicated in more than a dozen diseases. How catalysis works within the viscous, water-excluding, two-dimensional membrane is unknown. We developed an inducible reconstitution system to interrogate rhomboid proteolysis quantitatively within the membrane in real time. Remarkably,...
The 2013 Nobel Prize in Chemistry has been awarded to Martin Karplus, Michael Levitt, and Arieh Warshel for “development of multiscale models for complex chemical systems.” The honored work from the 1970s has provided a foundation for the widespread activities today in modeling organic and biomolecular systems.
Long recognized to be potent suppressors of immune responses, Foxp3 + CD4 + regulatory T (Treg) cells are being rediscovered as regulators of nonimmunological processes. We describe a phenotypically and functionally distinct population of Treg cells that rapidly accumulated in the acutely injured skeletal muscle of mice, just as invading myeloid-lineage cells switched from a proinflammatory...
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