Tracking solvents in the skin through atomically resolved measurements of molecular mobility in intact stratum corneum
Quoc Dat Pham, Daniel Topgaard, and Emma Sparr
Our skin is regularly exposed to solvents in cosmetics, washing and sanitary agents, and drug formulations. The uptake of solvents into the skin may change essential properties of the skin, for example, its protective barrier function, as well as its flexibility and softness. Herein different solvents relevant to skin formulations and sanitary products were added to samples of intact stratum corneum (SC), which is the outer layer of the skin. The solvent molecules can be tracked inside SC, showing reduced mobility. Furthermore, the solvents induce fluidity in SC components. These changes depend on solvent identity and concentration and on SC hydration conditions. Changes in SC components can be related to changes in macroscopic properties of SC, including skin barrier function. (See pp. E112–E121.)
Climate change damages to Alaska public infrastructure and the economics of proactive adaptation
April M. Melvin, Peter Larsen, Brent Boehlert, James E. Neumann, Paul Chinowsky, Xavier Espinet, Jeremy Martinich, Matthew S. Baumann, Lisa Rennels, Alexandra Bothner, Dmitry J. Nicolsky, and Sergey S. Marchenko
Climate change in Alaska is causing widespread environmental change that is damaging critical infrastructure. As climate change continues, infrastructure may become more vulnerable to damage, increasing risks to residents and resulting in large economic impacts. We quantified the potential economic damages to Alaska public infrastructure resulting from climate-driven changes in flooding, precipitation, near-surface permafrost thaw, and freeze–thaw cycles using high and low future climate scenarios. Additionally, we estimated coastal erosion losses for villages known to be at risk. Our findings suggest that the largest climate damages will result from flooding of roads followed by substantial near-surface permafrost thaw-related damage to buildings. Proactive adaptation efforts as well as global action to reduce greenhouse gas emissions could considerably reduce these damages. (See pp. E122–E131.)
Ohr plays a central role in bacterial responses against fatty acid hydroperoxides and peroxynitrite
Thiago G. P. Alegria, Diogo A. Meireles, José R. R. Cussiol, Martín Hugo, Madia Trujillo, Marcos Antonio de Oliveira, Sayuri Miyamoto, Raphael F. Queiroz, Napoleão Fonseca Valadares, Richard C. Garratt, Rafael Radi, Paolo Di Mascio, Ohara Augusto, and Luis E. S. Netto
Hydroperoxides play central roles in cell signaling. Hydroperoxides of arachidonic acid are mediators of inflammatory processes in mammals, whereas hydroperoxides of linoleic acid play equivalent roles in plants. Peroxynitrite is also involved in host–pathogen interactions, and hydroperoxide levels must therefore be strictly controlled by host-derived thiol-dependent peroxidases. Organic hydroperoxide resistance (Ohr) enzymes, which are present in many bacteria, display unique biochemical properties, reducing fatty acid hydroperoxides and peroxynitrite with extraordinary efficiency. Furthermore, Ohr (but not other thiol-dependent peroxidases) is involved in the Pseudomonas aeruginosa response to fatty acid hydroperoxides and to peroxynitrite, although the latter is more complex, probably depending on other enzymes. Therefore, Ohr plays central roles in the bacterial response to two hydroperoxides that are at the host–pathogen interface. (See pp. E132–E141.)
Uhrf1 controls the self-renewal versus differentiation of hematopoietic stem cells by epigenetically regulating the cell-division modes
Jingyao Zhao, Xufeng Chen, Guangrong Song, Jiali Zhang, Haifeng Liu, and Xiaolong Liu
Hematopoietic stem cells (HSCs) harbor the capacities of both self-renewal and differentiation to sustain life-long production of all blood cells. However, how individual HSCs accomplish the decision of self-renewal versus differentiation remains largely unknown. Here, we find that Uhrf1, a key epigenetic regulator of DNA methylation, specifically controls this critical process. In the absence of Uhrf1, HSCs undergo erythroid-biased differentiation at the expense of self-renewal capacity, leading to hematopoietic failure and lethality. Mechanistically, Uhrf1 regulates the HSC-division mode by DNA methylation-mediated repression of the expression of certain erythroid-specific genes, and thus modulates the cell fate decision of HSCs. This study provides unique insights into the relationship among Uhrf1-mediated DNA methylation, cell-division mode, and HSC fate decision. (See pp. E142–E151.)
Unrestrained AMPylation targets cytosolic chaperones and activates the heat shock response
Matthias C. Truttmann, Xu Zheng, Leo Hanke, Jadyn R. Damon, Monique Grootveld, Joanna Krakowiak, David Pincus, and Hidde L. Ploegh
The stability of the proteome is essential to cellular and organismic health and lifespan. To maintain proteostasis, cells are equipped with a network of chaperones that support folding of nascent proteins, as well as refolding of unfolded or misfolded proteins. Aging and age-associated diseases progressively increase the accumulation of misfolded, damaged, and aggregated proteins, thus taxing the chaperoning machinery to its limits. Here, we describe how AMPylation of cytosolic heat shock proteins (HSP) leads to a collapse of proteostasis, the induction of a strong heat shock response, inhibition of translation, as well as the formation of protein aggregates. AMPylation-mediated inhibition of HSP70 may represent a strategy for targeted ablation of this chaperone. (See pp. E152–E160.)
Microbial competition in porous environments can select against rapid biofilm growth
Katharine Z. Coyte, Hervé Tabuteau, Eamonn A. Gaffney, Kevin R. Foster, and William M. Durham
The overwhelming majority of bacteria live in porous environments, like soil, aquifers, and sediments, where they facilitate many important processes. Despite their importance, we understand little about how these complex environments shape the composition of the microbial communities that live within them. Here, we combine two diverse bodies of theory—fluid dynamics and game theory—to shed light on how bacteria evolve in these habitats. We show that bacteria in porous environments face a fundamental dilemma: they rely on flow for nutrients and dispersal; however, as cells grow, they tend to reduce their access to flow. A fast growing strain can, therefore, choke off its own nutrient supply, diverting it instead to competitors. In contrast with classical theory, our results suggest that cells within a biofilm can obtain a competitive advantage by growing more slowly. (See pp. E161–E170.)
Major transitions in dinoflagellate evolution unveiled by phylotranscriptomics
Jan Janouškovec, Gregory S. Gavelis, Fabien Burki, Donna Dinh, Tsvetan R. Bachvaroff, Sebastian G. Gornik, Kelley J. Bright, Behzad Imanian, Suzanne L. Strom, Charles F. Delwiche, Ross F. Waller, Robert A. Fensome, Brian S. Leander, Forest L. Rohwer, and Juan F. Saldarriaga
We created a dataset of dinoflagellate transcriptomes to resolve internal phylogenetic relationships of the group. We show that the dinoflagellate theca originated once, through a process that likely involved changes in the metabolism of cellulose, and suggest that a late origin of dinosterol in the group is at odds with dinoflagellates being the source of this important biomarker before the Mesozoic. We also show that nonphotosynthetic dinoflagellates have retained nonphotosynthetic plastids with vital metabolic functions, and propose that one of these may be the evolutionary source of dinoflagellate bioluminescence. Finally, we reconstruct major molecular and morphological transitions in dinoflagellates and highlight the role of horizontal gene transfer in the origin of their unique nuclear architecture. (See pp. E171–E180.)
Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy
Jan Broder Engler, Nina Kursawe, María Emilia Solano, Kostas Patas, Sabine Wehrmann, Nina Heckmann, Fred Lühder, Holger M. Reichardt, Petra Clara Arck, Stefan M. Gold, and Manuel A. Friese
Reproduction in placental mammals relies on potent control of the mother’s immune system to not attack the developing fetus. As a bystander effect, pregnancy also potently suppresses the activity of the autoimmune disease multiple sclerosis (MS). Here, we report that T cells are able to directly sense progesterone via their glucocorticoid receptor (GR), resulting in an enrichment of regulatory T cells (Tregs). By using an MS animal model, we found that the presence of the GR in T cells is essential to increase Tregs and confer the protective effect of pregnancy, but not for maintaining the pregnancy itself. Better understanding of this tolerogenic pathway might yield more specific therapeutic means to steer the immunological balance in transplantation, cancer, and autoimmunity. (See pp. E181–E190.)
Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy
Elisa D’Este, Dirk Kamin, Francisco Balzarotti, and Stefan W. Hell
In vertebrates, the action potential travels along myelin-coated electrically isolated axons and is regenerated at the nodes of Ranvier, which lack myelination and are characterized by a tight interaction between the axon and glial cells. Specific sets of proteins are enriched in each region of the nodes. Thanks to its subdiffraction resolution, stimulated emission depletion (STED) microscopy here uncovers the organization of 12 of these proteins at the nanoscale. The superresolved imaging reveals an extremely fine interplay and alignment of the axonal and glial cytoskeleton, with a defined ∼190-nm periodicity. Furthermore, the results point to the importance of the lateral organization of proteins at nodal gaps, an aspect that is yet unexplored. (See pp. E191–E199.)
Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease
Johnny Habchi, Sean Chia, Ryan Limbocker, Benedetta Mannini, Minkoo Ahn, Michele Perni, Oskar Hansson, Paolo Arosio, Janet R. Kumita, Pavan Kumar Challa, Samuel I. A. Cohen, Sara Linse, Christopher M. Dobson, Tuomas P. J. Knowles, and Michele Vendruscolo
The absence of fully reproducible protein aggregation assays has contributed to the systematic failures in clinical trials for Alzheimer’s disease (AD) of compounds targeting the aggregation process of the amyloid-β peptide (Aβ). To address this problem, we report the identification of a library of compounds against Aβ aggregation using a drug discovery strategy based on highly quantitative aggregation rate measurements. We then demonstrate, both in Caenorhabditis elegans and human cerebrospinal fluid, that this approach can systematically provide a rich variety of related small molecules to take forward into a drug discovery process. We therefore report an approach that should substantially help overcome the very high level of attrition associated with drug discovery programs for AD. (See pp. E200–E208.)
Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration
Yiqing Li, Lukas Andereggen, Kenya Yuki, Kumiko Omura, Yuqin Yin, Hui-Ya Gilbert, Burcu Erdogan, Maria S. Asdourian, Christine Shrock, Silmara de Lima, Ulf-Peter Apfel, Yehong Zhuo, Michal Hershfinkel, Stephen J. Lippard, Paul A. Rosenberg, and Larry Benowitz
The inability of CNS pathways to regenerate after injury can lead to devastating, life-long losses in sensory, motor, and other functions. We report that after injury to the optic nerve, a widely studied CNS pathway that normally cannot regenerate, mobile zinc (Zn2+) increases rapidly in the processes of retinal interneurons (amacrine cells) and then transfers via vesicular release to retinal ganglion cells (RGCs), the injured projection neurons. Eliminating Zn2+ leads to both persistent RGC survival and substantial axon regeneration with a broad therapeutic window. These findings show that signaling between interneurons and RGCs contributes to regulating the fate of RGCs after optic nerve injury, and that Zn2+ chelation may provide a potent therapeutic approach. (See pp. E209–E218.)
Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na+ and Mg2+ transport
Susanne Milatz, Nina Himmerkus, Vera Christine Wulfmeyer, Hoora Drewell, Kerim Mutig, Jianghui Hou, Tilman Breiderhoff, Dominik Müller, Michael Fromm, Markus Bleich, and Dorothee Günzel
The thick ascending limb (TAL) of Henle’s loop is a nephron segment that reabsorbs Na+, Ca2+, and Mg2+ via the paracellular pathway, the tight junction (TJ). TJ permeability is regulated by claudin proteins. We show that the TAL expresses claudins cldn3, cldn10b, cldn16, and cldn19 in a TJ mosaic pattern with cldn3/cldn16/cldn19 in a complex and cldn10b alone. This mutual exclusiveness is facilitated by different claudin interaction properties. TJs with cldn10b favor Na+ over Mg2+, whereas TJs with cldn3/cldn16/cldn19 prefer Mg2+ over Na+. Hence we conclude that mono- and divalent cations in the TAL take different paracellular routes, and their reabsorption can be regulated independently. This spatial separation is important for renal ion homeostasis and its discovery improves our understanding of paracellular transport organization. (See pp. E219–E227.)
Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3
Jeremy W. Linsley, I-Uen Hsu, Linda Groom, Viktor Yarotskyy, Manuela Lavorato, Eric J. Horstick, Drew Linsley, Wenjia Wang, Clara Franzini-Armstrong, Robert T. Dirksen, and John Y. Kuwada
Skeletal muscle contractions are regulated by a process called excitation–contraction (EC) coupling, and defects in it are associated with numerous human myopathies. Recently, stac3 (SH3 and cysteine-rich domain 3) was identified as a key regulator of EC coupling and a STAC3 mutation as causal for the debilitating Native American myopathy (NAM). We now show that Stac3 controls EC coupling by regulating Ca2+ channels in muscles. Both the NAM mutation and a mutation that leads to the loss of Stac3 decrease the amount, organization, stability, and voltage sensitivity of Ca2+ channels. Furthermore, we find evidence that the NAM allele of STAC3 is linked to malignant hyperthermia, a common pharmacogenic disorder. These findings define critical roles for Stac3 in muscle contraction and human disease. (See pp. E228–E236.)
Two independent S-phase checkpoints regulate appressorium-mediated plant infection by the rice blast fungus Magnaporthe oryzae
Míriam Osés-Ruiz, Wasin Sakulkoo, George R. Littlejohn, Magdalena Martin-Urdiroz, and Nicholas J. Talbot
Rice blast is a devastating fungal disease of cultivated rice, and its control is vital to ensure global food security. In an effort to understand how the rice blast fungus causes disease, we have investigated how the cell cycle controls the early stages of plant infection. The rice blast fungus develops a special cell, called an appressorium, to infect rice leaves. This structure generates enormous pressure, which the fungus applies as physical force to puncture the leaf surface. We have shown that a buildup of pressure in the appressorium is necessary to trigger an unusual cell-cycle checkpoint that is necessary for the appressorium to function properly. If this process is blocked, rice blast disease cannot occur. (See pp. E237–E244.)
Abscisic acid signaling is controlled by a BRANCHED1/HD-ZIP I cascade in Arabidopsis axillary buds
Eduardo González-Grandío, Alice Pajoro, José M. Franco-Zorrilla, Carlos Tarancón, Richard G. H. Immink, and Pilar Cubas
Shoot-branching patterns affect key aspects of plant life and are important targets for crop breeding. However, we are still ignorant of the genetic mechanisms controlling locally an important decision during branch development: whether the axillary bud grows out to give a lateral shoot or remains dormant. Here we show that the TEOSINTE BRANCHED1, CYCLOIDEA, PCF (TCP) transcriptional regulator BRANCHED1 (BRC1), which acts inside axillary buds, binds and activates three genes encoding Homeodomain leucine zipper (HD-ZIP) transcription factors. These factors, together with BRC1, trigger a cascade leading to local abscisic acid (ABA) accumulation and response, essential for bud dormancy under light-limiting conditions. This finding demonstrates a direct relationship between BRC1 and ABA signaling and places ABA downstream of BRC1 in the control of axillary bud dormancy. (See pp. E245–E254.)
Impact of mosquito gene drive on malaria elimination in a computational model with explicit spatial and temporal dynamics
Philip A. Eckhoff, Edward A. Wenger, H. Charles J. Godfray, and Austin Burt
Gene drive mosquitoes have tremendous potential to help eliminate malaria, and multiple gene drive approaches have recently shown promise in laboratory settings. These approaches include population suppression through fertility disruption, driving-Y chromosomes, and population replacement with genes that limit malaria transmission. Mathematical modeling is used to evaluate these approaches by simulating realistic field settings with seasonality to determine constraints on construct parameters and release strategies. Parameter variation from simulation baselines captures much of sub-Saharan African epidemiology and shows high potential for gene drive constructs to provide transformational tools to facilitate elimination of malaria, even in the most challenging settings. This analysis provides insights into performance characteristics necessary for each approach to succeed that can inform their further development. (See pp. E255–E264.)