Ab initio molecular dynamics of solvation effects on reactivity at electrified interfaces
Jeffrey A. Herron, Yoshitada Morikawa, and Manos Mavrikakis
Low-temperature fuel cells are efficient energy conversion devices that face a number of hurdles toward commercialization, including difficulties in storing hydrogen. Methanol represents a liquid-phase fuel alternative to hydrogen, yet the high cost of Pt-based catalysts limits fuel cells’ economic viability. Toward improved, lower-cost catalyst design, a fundamental understanding of the methanol electrooxidation reaction mechanism is necessary. Density functional theory calculations have become invaluable in elucidating these reaction mechanisms, although the complex reaction environment including solvation of a charged electrode has been a challenge to model. Using ab initio molecular dynamics, via the Blue Moon Ensemble, we have investigated methanol electrooxidation on a solvated and charged Pt(111) surface to understand the effect of solvation and charge on the reaction energetics. (See pp. E4937–E4945.)
Quantum spin dynamics with pairwise-tunable, long-range interactions
C.-L. Hung, Alejandro González-Tudela, J. Ignacio Cirac, and H. J. Kimble
Cold atoms trapped along a photonic crystal waveguide can be used to simulate long-range quantum magnetism with pairwise-tunable spin–spin interactions mediated by guided virtual photons in a photonic band gap. Using a two-photon Raman addressing scheme, the proposed atom-nanophotonic system can achieve arbitrary and dynamic control on the strength, phase, and length scale of spin interactions. This promises new avenues for engineering a large class of spin Hamiltonians, including those exhibiting topological order or frustrated long-range magnetism. (See pp. E4946–E4955.)
Kinetic and thermodynamic framework for P4-P6 RNA reveals tertiary motif modularity and modulation of the folding preferred pathway
Namita Bisaria, Max Greenfeld, Charles Limouse, Dmitri S. Pavlichin, Hideo Mabuchi, and Daniel Herschlag
Many biological processes, including splicing, translation, and genome maintenance, require structured RNAs to fold into complex three-dimensional shapes. Our current understanding of these processes is based on distilling principles from descriptive folding studies. Moving toward predictive models will require coupling observed structural changes with kinetic and thermodynamic measurements. We have dissected P4-P6 RNA folding through distinct structural states and measured the rate and equilibrium constants for transitions between these states. Common kinetics found for RNA tertiary elements embedded in different structural contexts may help develop predictive folding models. Also, our results suggest that RNA folding may be well described by a model analogous to the diffusion-collision model for protein folding. (See pp. E4956–E4965.)
Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis
Wan Seok Yang, Katherine J. Kim, Michael M. Gaschler, Milesh Patel, Mikhail S. Shchepinov, and Brent R. Stockwell
Ferroptosis is a regulated form of cell death induced by loss of glutathione peroxidase 4 (GPX4) phospholipid peroxidase activity and lethal accumulation of reactive oxygen species. Small-molecule inhibitors of GPX4 induce ferroptosis; however, the interaction between these inhibitors and GPX4 has remained elusive, as has the identity of the reactive oxygen species that drive execution of ferroptosis. We identified here a ligand-binding site on GPX4 and determined the specific lipids oxidized during ferroptosis. We further identified two key drivers of lipid peroxidation during ferroptosis: lipoxygenases and phosphorylase kinase G2. These findings reveal a previously enigmatic mechanism of ferroptotic lipid peroxide generation and suggest new strategies for pharmacological control of ferroptosis and diseases associated with this mode of cell death. (See pp. E4966–E4975.)
Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril
Marielle Aulikki Wälti, Francesco Ravotti, Hiromi Arai, Charles G. Glabe, Joseph S. Wall, Anja Böckmann, Peter Güntert, Beat H. Meier, and Roland Riek
Alzheimer’s disease is the most prevalent neurodegenerative disease still with no known cure. The disease is characterized by the development of extracellular plaques and intracellular neurofibrillary tangles. The senile plaques consist mainly of the peptide amyloid-β (Aβ) in aggregated form, called amyloid fibrils. It is believed that the Aβ amyloid fibrils play an important role in disease progression and cell-to-cell transmissibility, and small Aβ oligomers are often assumed to be the most neurotoxic species. Here, we determined the 3D structure of a disease-relevant Aβ(1–42) fibril polymorph combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, forming a double-horseshoe–like cross–β-sheet entity with maximally buried hydrophobic side chains. (See pp. E4976–E4984.)
Role of kinesin-1–based microtubule sliding in Drosophila nervous system development
Michael Winding, Michael T. Kelliher, Wen Lu, Jill Wildonger, and Vladimir I. Gelfand
We previously demonstrated that the microtubule (MT) motor protein kinesin-1 slides and transports MTs themselves in addition to its established role in organelle transport. However, the physiological importance of MT sliding has not been determined. Here, we identified the mechanism of kinesin-1–based MT sliding and generated a sliding-deficient Drosophila mutant. Additionally, we generated a chimeric motor that actively slides MTs but cannot transport organelles. Using these tools, we demonstrated that MT sliding is an essential biological process, with key roles in both axon and dendrite outgrowth. Because the C-terminal MT-binding site of kinesin-1, which is essential for sliding, is highly conserved in vertebrates and invertebrates, we postulate that MT sliding is important for nervous system development in many organisms. (See pp. E4985–E4994.)
Microtubule–microtubule sliding by kinesin-1 is essential for normal cytoplasmic streaming in Drosophila oocytes
Wen Lu, Michael Winding, Margot Lakonishok, Jill Wildonger, and Vladimir I. Gelfand
Generation of mechanical forces by molecular motors is essential for development. Previously, we showed that the microtubule motor kinesin-1 generates forces by sliding microtubules against each other. Here, we show that microtubule sliding by kinesin-1 is important for normal oocyte cytoplasmic rotation, a process required for efficient localization of mRNAs and proteins during oogenesis. Using recently developed imaging technologies (Maple3 photoconversion and SunTag), we discover a previously uncharacterized population of extremely stable microtubules immobilized at the oocyte cortex and demonstrate that free microtubules move against cortically anchored microtubules, generating forces that contribute to cytoplasmic streaming. Because kinesin-1–based sliding is highly conserved from Drosophila to humans, we propose that microtubule sliding is also important for cellular force generation in higher organisms. (See pp. E4995–E5004.)
miR-579-3p controls melanoma progression and resistance to target therapy
Luigi Fattore, Rita Mancini, Mario Acunzo, Giulia Romano, Alessandro Laganà, Maria Elena Pisanu, Debora Malpicci, Gabriele Madonna, Domenico Mallardo, Marilena Capone, Franco Fulciniti, Luca Mazzucchelli, Gerardo Botti, Carlo M. Croce, Paolo Antonio Ascierto, and Gennaro Ciliberto
In this paper we identify a previously poorly characterized miRNA, namely miR-579-3p, as a master regulator of melanoma progression and drug resistance. Our results underscore the complexity of adaptive mechanisms that help the establishment of resistance to target therapies and the necessity to identify them to develop more effective combination therapies. (See pp. E5005–E5013.)
Alternative haplotypes of antigen processing genes in zebrafish diverged early in vertebrate evolution
Sean C. McConnell, Kyle M. Hernandez, Dustin J. Wcisel, Ross N. Kettleborough, Derek L. Stemple, Jeffrey A. Yoder, Jorge Andrade, and Jill L. O. de Jong
Antigen presentation genes are exceptionally polymorphic, enhancing immune defense. Polymorphism within additional components of the MHC pathway, particularly the antigen processing genes, may also shape immune responses. Using transcriptome, exome, and whole-genome sequencing to examine immune gene variation in zebrafish, we uncovered several antigen processing genes not found in the reference genome clustered within a deeply divergent haplotype of the core MHC locus. Our data provide evidence that these previously undescribed antigen processing genes retain ancient alternative sequence lineages, likely derived during the formation of the adaptive immune system, and represent the most divergent collection of antigen processing and presentation genes yet identified. These findings offer insights into the evolution of vertebrate adaptive immunity. (See pp. E5014–E5023.)
Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence
Priyanka L. Patel, Anitha Suram, Neena Mirani, Oliver Bischof, and Utz Herbig
Normal cells respond to oncogenic signals by activating cellular senescence, a state of irreversible/permanent growth arrest that prevents cells from undergoing further cell divisions. Although this oncogene-induced senescence (OIS) is considered a critical tumor-suppressive mechanism, the irreversible nature of OIS remains controversial. In this study, we demonstrate that OIS is not always stable. After a prolonged period in senescence, cells can re-enter the cell-division cycle with epigenetic changes that facilitate cell transformation. Escape from OIS was promoted by derepression of hTERT gene expression, an enzyme that provides cellular immortality and is activated in >90% of human cancers. (See pp. E5024–E5033.)
Gram-negative trimeric porins have specific LPS binding sites that are essential for porin biogenesis
Wanatchaporn Arunmanee, Monisha Pathania, Alexandra S. Solovyova, Anton P. Le Brun, Helen Ridley, Arnaud Baslé, Bert van den Berg, and Jeremy H. Lakey
Specific and functional interactions between membrane lipids and proteins are increasingly evident across biology. The outer membrane (OM) of gram-negative bacteria such as Escherichia coli is a selective barrier formed by complex lipids (lipopolysaccharides; LPSs) and outer-membrane proteins. The high stability and low permeability of the OM are critical to bacterial growth and pathogenesis. Here, using biochemical and structural techniques, we reveal specific LPS binding sites on OM porin proteins that allow them to stabilize, rather than disrupt, the ordered network of LPS molecules. Furthermore, we demonstrate that one such site is essential for porin assembly in the OM. (See pp. E5034–E5043.)
Salmonella Typhimurium utilizes a T6SS-mediated antibacterial weapon to establish in the host gut
Thibault G. Sana, Nicolas Flaugnatti, Kyler A. Lugo, Lilian H. Lam, Amanda Jacobson, Virginie Baylot, Eric Durand, Laure Journet, Eric Cascales, and Denise M. Monack
Gram-negative bacteria use the type VI secretion system (T6SS) to deliver effectors into adjacent cells. Salmonella Typhimurium is an enteric pathogen that causes disease in millions of individuals each year. Its ability to infect the mammalian gut is a key factor that contributes to its virulence and transmission to new hosts. However, many of the details on how Salmonella successfully colonizes the gut and persists among members of the gut microbiota remain to be deciphered. In this work, we provide evidence that Salmonella uses an antibacterial weapon, the type VI secretion system, to establish infection in the gut. In addition, our results suggest that S. Typhimurium selectively targets specific members of the microbiota to invade the gastrointestinal tract. (See pp. E5044–E5051.)
FtsEX acts on FtsA to regulate divisome assembly and activity
Shishen Du, Sebastien Pichoff, and Joe Lutkenhaus
Understanding divisome assembly and activation has become the focus of research on bacterial cytokinesis. However, very little is known about how this process is regulated. Here, we find that FtsEX (an ATP-binding cassette transporter-like complex) acts on the bacterial actin homolog FtsA to regulate divisome assembly and function in Escherichia coli. Our results suggest that FtsEX antagonizes FtsA polymerization to promote divisome assembly and continual ATP hydrolysis by FtsEX is needed for the divisome to synthesize septal peptidoglycan. Because FtsEX is also required for cell wall hydrolysis at the septum, our study indicates that FtsEX couples cell wall synthesis and hydrolysis at the septum by acting through FtsA. Our study also implies that unpolymerized FtsA is favored for division and FtsW plays a critical role in divisome activation. (See pp. E5052–E5061.)
Climate influence on Vibrio and associated human diseases during the past half-century in the coastal North Atlantic
Luigi Vezzulli, Chiara Grande, Philip C. Reid, Pierre Hélaouët, Martin Edwards, Manfred G. Höfle, Ingrid Brettar, Rita R. Colwell, and Carla Pruzzo
Long-term ecological and paleontological data analyses indicate climate change is having an impact on marine eukaryotic communities. However, little is known about effects of global warming on marine prokaryotes, which are, by far, the largest living biomass in world oceans. Here, we report, for the first time to our knowledge, that a warming trend in sea surface temperature is strongly associated with spread of vibrios, an important group of marine prokaryotes, and emergence of human diseases caused by these pathogens. Our results are based on formalin-preserved plankton samples collected in the past half-century from the temperate North Atlantic. (See pp. E5062–E5071.)
Functional neuroanatomy of intuitive physical inference
Jason Fischer, John G. Mikhael, Joshua B. Tenenbaum, and Nancy Kanwisher
Perceiving the physical structure of the world and predicting how physical events will unfold over time are central to our daily lives. Recent behavioral and computational research has suggested that our physical intuitions may be supported by a “physics engine” in the brain akin to the physical simulation engines built into video games. However, to date, there has been almost no investigation of the brain areas involved in intuitive physical inference. Here, using fMRI, we show that a variety of physical inference tasks as well as simply viewing physically rich scenes engage a common brain network in frontal and parietal cortices. These findings open the door to the cognitive neuroscientific study of physical inference in the human brain. (See pp. E5072–E5081.)
Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.
Dan Luo, Roberta Callari, Britta Hamberger, Sileshi Gizachew Wubshet, Morten T. Nielsen, Johan Andersen-Ranberg, Björn M. Hallström, Federico Cozzi, Harald Heider, Birger Lindberg Møller, Dan Staerk, and Björn Hamberger
Ingenol mebutate is a diterpene ester with a highly complex macrocyclic structure that has been approved for the treatment of actinic keratosis, a precondition of skin cancer. The current production of ingenol mebutate through plant extraction or chemical synthesis is inefficient and costly. Here, we describe the discovery of a biosynthetic route in Euphorbia lathyris L. (caper spurge) in which regio-specific oxidation of casbene is followed by an unconventional cyclization to yield jolkinol C, a probable key intermediate in the biosynthesis of macrocyclic diterpenes, including ingenol mebutate. These results can facilitate the biotechnological production of this high-value pharmaceutical and discovery of new biosynthetic intermediates with important bioactivities. (See pp. E5082–E5089.)