Orbital forcing of climate 1.4 billion years ago
Shuichang Zhang, Xiaomei Wang, Emma U. Hammarlund, Huajian Wang, M. Mafalda Costa, Christian J. Bjerrum, James N. Connelly, Baomin Zhang, Lizeng Bian, and Donald E. Canfield
There is a wealth of evidence pointing to dramatic short-term climate change on Earth over the last few million years. Much of this climate change is driven by variations of Earth’s orbit around the Sun with characteristic frequencies known as Milankovitch cycles. Robust evidence for orbitally driven climate change, however, becomes rare as one descends deep into Earth time. We studied an exceptional record of climate change as recorded in 1.4-billion-year-old marine sediments from North China (pp. E1406–E1413). This record documents regular changes in subtropical/tropical Hadley Cell dynamics. These changes in dynamics controlled wind strength, rainfall, and ocean circulation, translated into cyclic variations in sediment geochemistry, much like the orbital control on climate today and in the recent past.
Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4
Peder Cedervall, Ann Aulabaugh, Kieran F. Geoghegan, Thomas J. McLellan, and Jayvardhan Pandit
Phosphodiesterase 4 (PDE4) is an essential contributor to intracellular signaling and an important drug target. We have used protein engineering, biochemistry, and X-ray crystallography to elucidate how its conserved N-terminal regions regulate its activity. Our results (pp. E1414–E1422) show that a helical segment in the regulatory domain of one subunit crosses over to occlude the catalytic site of the other subunit of the homodimer. The structure suggests a strategy for the design of inhibitors that target specific splice variants of this enzyme. By mapping onto our structure all the mutations in PDE4D that underlie the rare human genetic disorder of acrodysostosis, we present a rationale for why they could lead to a dysregulation of PDE4D activity.
Endocytic proteins drive vesicle growth via instability in high membrane tension environment
Nikhil Walani, Jennifer Torres, and Ashutosh Agrawal
Biological cells are engaged in an incessant uptake of macromolecules for nutrition and inter- and intracellular communication; this entails significant local bending of the plasma membrane and formation of cargo-carrying vesicles executed by a designated set of membrane-deforming proteins. The energetic cost incurred in forming vesicles is directly related to the stressed state of the membrane and, hence, that of the cell. In this study (pp. E1423–E1432), we reveal a protein-induced “snap-through instability” that offsets tension and drives vesicle growth during clathrin-mediated endocytosis, the main pathway for the transport of macromolecules into cells. Because these proteins (actin and BAR proteins) are involved in other interfacial rearrangements in cells, the predicted instability could be at play in cells at-large.
Differential fates of biomolecules delivered to target cells via extracellular vesicles
Masamitsu Kanada, Michael H. Bachmann, Jonathan W. Hardy, Daniel Omar Frimannson, Laura Bronsart, Andrew Wang, Matthew D. Sylvester, Tobi L. Schmidt, Roger L. Kaspar, Manish J. Butte, A. C. Matin, and Christopher H. Contag
Extracellular vesicle (EV)-mediated transfer of macromolecules may play a key role in cellular communication and may have utility in directed molecular therapies. In addition, the EV packaged biomolecules in serum may have potential for diagnosing cancer and determining its likelihood of metastasis. EVs are heterogeneous and there are many outstanding questions associated with biogenesis, uptake, and the fate of transferred molecules in recipient cells. In fact, the function, characterization, and even the nomenclature of EVs are being refined. Here (pp. E1433–E1442) we aimed to improve the functional characterization of EVs, and observed that only microvesicles (MVs), but not exosomes, can functionally transfer loaded reporter molecules to recipient cells, largely by delivering plasmid DNA. Our data show that exosomes and MVs are structurally and functionally distinct.
A TOCA/CDC-42/PAR/WAVE functional module required for retrograde endocytic recycling
Zhiyong Bai and Barth D. Grant
Endosomes are membrane-bound organelles that are required for the sorting of membrane-associated proteins and lipids. Once integral membrane proteins reach the endosomal system they can be sent to the lysosome for degradation, recycled to the plasma membrane, or recycled to the Golgi apparatus. Here (pp. E1443–E1452) we provide insight into the molecules that mediate a poorly understood route to the Golgi from recycling endosomes. The mediators of this transport step that we identified include the membrane-binding and -bending TOCA proteins, the small GTPase CDC-42, associated polarity proteins PAR-6 and PKC-3/atypical protein kinase C, and the WAVE actin nucleation complex. Many transmembrane proteins likely use this same transport mechanism.
Sponge grade body fossil with cellular resolution dating 60 Myr before the Cambrian
Zongjun Yin, Maoyan Zhu, Eric H. Davidson, David J. Bottjer, Fangchen Zhao, and Paul Tafforeau
Phylogenomic extrapolations indicate the last common ancestor of sponges and eumetazoans existed deep in the Cryogenian, perhaps 200 million years (Myr) before the Cambrian (541 Ma). This inference implies a long Precambrian history of animals phylogenetically allied with sponges. However, there is yet little unequivocal paleontological evidence of Precambrian sponges. Here, we present a newly discovered 600-Myr-old fossil preserved at cellular resolution, displaying multiple poriferan features. The animal was covered with a dense layer of flattened cells resembling sponge pinacocytes, displaying a hollow tubular structure with apparent water inflow and outflow orifices. Although requiring additional specimens of similar form for confirmation, this finding is consistent with phylogenomic inference, and implies the presence of eumetazoan ancestors by 60 Myr before the Cambrian (pp. E1453–E1460).
L-selectin shedding is activated specifically within transmigrating pseudopods of monocytes to regulate cell polarity in vitro
Karolina Rzeniewicz, Abigail Newe, Angela Rey Gallardo, Jessica Davies, Mark R. Holt, Ashish Patel, Guillaume T. Charras, Brian Stramer, Chris Molenaar, Thomas F. Tedder, Maddy Parsons, and Aleksandar Ivetic
During an inflammatory response, L-selectin, an immune cell-specific adhesion molecule, guides monocytes from the bloodstream toward the surrounding extravascular environment (termed “transmigration”). We show, under conditions that mimic blood flow, that L-selectin is proteolytically cleaved (or shed) exclusively within leading migratory fronts (pseudopods) of actively transmigrating monocytes. Calmodulin/L-selectin interaction, which acts to block shedding, is lost through Ser phosphorylation of the L-selectin cytoplasmic tail, occurring specifically within transmigrating pseudopods. Blocking L-selectin shedding specifically during transmigration increases pseudopod numbers, leading to defective front/back polarity that is essential for migration. These findings (pp. E1461–E1470) are the first to report, to our knowledge, an extended role for L-selectin in regulating morphological changes in leukocytes that are required for migration.
Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs
Vincent Jacques, Anthony W. Czarnik, Thomas M. Judge, Lex H. T. Van der Ploeg, and Sheila H. DeWitt
Despite dramatically improved therapeutic properties of single enantiomer drugs over the racemic mixtures, numerous drugs and drug candidates are still being developed and sold as racemates, including the class of immunomodulatory drugs derived from thalidomide. The chiral center of these thalidomide analogs is chemically unstable, resulting in interconversion of the enantiomers both in vitro and in vivo. Through stabilization of the chiral center with deuterium, we show for the first time, to our knowledge, that the in vitro antiinflammatory and in vivo antitumorigenic activities of a thalidomide analog currently in clinical development (CC-122) are caused exclusively by one enantiomer. Our findings (pp. E1471–E1479) enable the development of improved thalidomide analogs as therapeutics following stated regulatory guidance for the development of single enantiomers.
Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4+ T cells, and disease progression
Daniel T. Claiborne, Jessica L. Prince, Eileen Scully, Gladys Macharia, Luca Micci, Benton Lawson, Jakub Kopycinski, Martin J. Deymier, Thomas H. Vanderford, Krystelle Nganou-Makamdop, Zachary Ende, Kelsie Brooks, Jianming Tang, Tianwei Yu, Shabir Lakhi, William Kilembe, Guido Silvestri, Daniel Douek, Paul A. Goepfert, Matthew A. Price, Susan A. Allen, Mirko Paiardini, Marcus Altfeld, Jill Gilmour, and Eric Hunter
HIV infection is associated with elevated inflammation and aberrant cellular immune activation. Indeed, the activation status of an HIV-infected individual is often more predictive of disease trajectory than viral load. Here (pp. E1480–E1489), we highlight the importance of the replicative fitness of the transmitted viral variant in driving an early inflammatory state, characterized by T-cell activation and immune dysfunction. This impact on T-cell homeostasis is independent of protective host immune response genes and viral load. Highly replicating transmitted variants were also significantly more efficient at infecting memory CD4+ T cells, a population important for maintaining the latent viral reservoir. Together, these data provide a mechanism whereby viral replicative fitness acts as a major determinant of disease progression and persistence.
Plant-derived antifungal agent poacic acid targets β-1,3-glucan
Jeff S. Piotrowski, Hiroki Okada, Fachuang Lu, Sheena C. Li, Li Hinchman, Ashish Ranjan, Damon L. Smith, Alan J. Higbee, Arne Ulbrich, Joshua J. Coon, Raamesh Deshpande, Yury V. Bukhman, Sean McIlwain, Irene M. Ong, Chad L. Myers, Charles Boone, Robert Landick, John Ralph, Mehdi Kabbage, and Yoshikazu Ohya
The search for new antifungal compounds is struggling to keep pace with emerging fungicide resistance. Through chemoprospecting of an untapped reservoir of inhibitory compounds, lignocellulosic hydrolysates, we have identified a previously undescribed antifungal agent, poacic acid. Using both chemical genomics and morphological analysis together for the first time, to our knowledge, we identified the cellular target of poacic acid as β-1,3-glucan. Through its action on the glucan layer of fungal cell walls, poacic acid is a natural antifungal agent against economically significant fungi and oomycete plant pathogens. This work (pp. E1490–E1497) highlights the chemical diversity within lignocellulosic hydrolysates as a source of potentially valuable chemicals.
Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area
Sabine Krabbe, Johanna Duda, Julia Schiemann, Christina Poetschke, Gaby Schneider, Eric R. Kandel, Birgit Liss, Jochen Roeper, and Eleanor H. Simpson
Patients with schizophrenia suffer from cognitive and negative deficits that are largely resistant to current therapeutic strategies. Here, using a genetic mouse model that displays phenotypes similar to these cognitive and negative symptoms, we found that increased postsynaptic D2 receptor (D2R) activity in the striatum leads to changes in the firing pattern of presynaptic dopamine (DA) neurons of the midbrain. These alterations occur in the ventral tegmental area (VTA) of the midbrain, but not in the substantia nigra, suggesting that DA pathways may be differently regulated by striatal D2R hyperactivity. The changes in neuron firing patterns were accompanied by a reduction in NMDA receptor subunits selectively in dopaminergic VTA neurons, providing a potential new target for the treatment of schizophrenia symptoms (pp. E1498–E1506).