Effect of electron count and chemical complexity in the Ta-Nb-Hf-Zr-Ti high-entropy alloy superconductor
Fabian von Rohr, Michał J. Winiarski, Jing Tao, Tomasz Klimczuk, and Robert Joseph Cava
High-entropy alloys are a new class of materials that consist of several principal elements arranged on simple lattices. These structures are stabilized by the high configurational entropy of the random mixing of the elements. Here, we show that the properties of a superconducting high-entropy alloy are strongly related to the electron count and that the superconducting transition temperatures of these alloys fall between those of analogous crystalline and amorphous materials. We find that despite the large degree of randomness and disorder in these alloys, the superconducting properties are nevertheless strongly dependent on the chemical composition and complexity. We argue that high-entropy alloys are excellent model systems for understanding how superconductivity and other collective quantum states evolve from crystals to amorphous solids. (See pp. E7144–E7150.)
Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop
Haoqing Wang, Alexander A. Cohen, Rachel P. Galimidi, Harry B. Gristick, Grant J. Jensen, and Pamela J. Bjorkman
The HIV-1 envelope (Env) glycoprotein exists in multiple conformations on virion surfaces. Although the closed Env state is well characterized, less is known about open Env conformations stabilized by host receptor (CD4) binding. We solved an 8.9-Å structure of a partially open CD4-bound Env trimer by single particle cryo-EM. In the CD4-bound Env, the gp120 V1V2 loops were displaced by ∼40 Å from their positions at the trimer apex. The displaced V1V2 loops were at the sides of the open trimer in positions adjacent to, and interacting with, the three bound CD4s. These results are relevant to understanding CD4-induced conformational changes leading to coreceptor binding and fusion, and HIV-1 Env conformational dynamics, and describe a target structure relevant to drug design and vaccine efforts. (See pp. E7151–E7158.)
Mapping intracellular mechanics on micropatterned substrates
Kalpana Mandal, Atef Asnacios, Bruno Goud, and Jean-Baptiste Manneville
Cell mechanics is crucial for many, if not all, cell functions. Although mechanics at the scale of the whole cell is extensively documented, there are only few methods to measure intracellular mechanics at the local scale. Here, we develop a technique that allows us (i) to map the spatial variations of intracellular mechanical parameters; (ii) to study how the actin and microtubule cytoskeleton, intracellular membranes, and ATP-dependent active forces contribute to intracellular mechanics; and (iii) to differentiate normal and cancer cells. Because intracellular mechanical maps can detect subtle differences in the spatial distribution of mechanical parameters even in the absence of any change in their average values, our approach could provide a diagnostic and prognostic tool for cancers. (See pp. E7159–E7168.)
Recognition of the 3′ splice site RNA by the U2AF heterodimer involves a dynamic population shift
Lena Voith von Voithenberg, Carolina Sánchez-Rico, Hyun-Seo Kang, Tobias Madl, Katia Zanier, Anders Barth, Lisa R. Warner, Michael Sattler, and Don C. Lamb
The splicing of human pre-mRNAs is tightly controlled and regulated during the assembly of the spliceosome onto pre-mRNA introns. Recognition of regulatory RNA sequence motifs by splicing factors is an essential early step during spliceosome assembly. We combine single-pair FRET and NMR to show that the recognition of the 3′ splice site in pre-mRNA introns by the essential heterodimeric splicing factor U2 auxiliary factor (U2AF) involves conformational dynamics and population shifts of its RNA binding domains between open and closed conformations. Unexpectedly, the small subunit U2AF35 facilitates the recognition of weak splice sites by a population shift of the RNA binding domains of U2AF65 toward the open conformation. Notably, disease-linked mutations in U2AF65 do not affect RNA or U2AF35 binding. (See pp. E7169–E7175.)
Mechanism of microtubule lumen entry for the α-tubulin acetyltransferase enzyme αTAT1
Courtney Coombes, Ami Yamamoto, Mark McClellan, Taylor A. Reid, Melissa Plooster, G. W. Gant Luxton, Joshua Alper, Jonathon Howard, and Melissa K. Gardner
αTAT1 is an enzyme that acetylates microtubules inside of cells, and acetylation is an important posttranslational microtubule modification. However, microtubules are long tubes, and the acetylation site for αTAT1 is on the inside of this tube. We investigated how αTAT1 enters the microtubule and moves around to access its acetylation sites once inside. We found that αTAT1 enters microtubules through its ends but does not move efficiently inside of the microtubule. However, a lowered affinity allows the enzyme to move more efficiently and leads to longer stretches of acetylation. Therefore, acetylation of microtubules could be controlled in the cell by modulating the affinity of αTAT1 for its acetylation site or increasing the number of microtubule ends. (See pp. E7176–E7184.)
Transport efficiency of membrane-anchored kinesin-1 motors depends on motor density and diffusivity
Rahul Grover, Janine Fischer, Friedrich W. Schwarz, Wilhelm J. Walter, Petra Schwille, and Stefan Diez
Molecular motors, such as kinesin-1, are essential molecules involved in active intracellular transport. Current mechanistic insights on transport by motors are mainly based on in vitro studies where the motors are bound to rigid substrates. However, when transporting membranous cargo under physiological conditions, multiple motors are often only loosely coupled via a lipid bilayer. In this study, we investigate how the motors’ transport efficiency is affected when bound to a lipid bilayer. In our reconstituted gliding motility assays, we show that membrane-anchored motors exhibit reduced transport efficiency due to slippage in the lipid bilayer. Notably, the efficiency increases at higher motor density and reduced membrane diffusivity, providing cells with an additional means of regulating the efficiency of cargo transport. (See pp. E7185–E7193.)
Critical role of ATP-induced ATP release for Ca2+ signaling in nonsensory cell networks of the developing cochlea
Federico Ceriani, Tullio Pozzan, and Fabio Mammano
This study dissects the mechanisms underlying the occurrence of ATP- and inositol 1,4,5-trisphosphate (IP3)-dependent intracellular cytosolic free calcium concentration [Ca2+]c oscillations and intercellular Ca2+ waves in the syncytium formed by nonsensory cells in the postnatal mouse cochlea. The findings are significant with regard to development of the cochlear sensory epithelium, injury signaling in the cochlea, and pathophysiology around connexinopathies that dominate prelingual deafness. On a broader frame, this work provides an accurate, quantitative description of the mode of propagation of extracellular ATP-mediated paracrine signaling in epithelial cells. Critically, the modeling brings together a synthesis of quantitative data on the key elements concerning the signaling molecules (ATP and IP3) and propagation mechanisms from a broad range of prior work. (See pp. E7194–E7201.)
Divergence of ectodermal and mesodermal gene regulatory network linkages in early development of sea urchins
Eric M. Erkenbrack
Sea urchins (echinoids) consist of two subclasses, cidaroids and euechinoids. Research on gene regulatory networks (GRNs) in the early development of three euechinoids indicates that little appreciable change has occurred to their linkages since they diverged ∼90 million years ago (mya). I asked whether this conservation extends to all echinoids. I systematically analyzed the spatiotemporal expression and function of regulatory genes segregating euechinoid ectoderm and mesoderm in a cidaroid. I report marked divergence of GRN architecture in early embryonic specification of the oral–aboral axis in echinoids. Although I found evidence for diverged regulation of both mesodermal and ectodermal genes, comparative analyses indicated that, since these two clades diverged 268 mya, mesodermal GRNs have undergone significantly more alterations than ectodermal GRNs. (See pp. E7202–E7211.)
HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia
Damayanti Chakraborty, Wei Cui, Gracy X. Rosario, Regan L. Scott, Pramod Dhakal, Stephen J. Renaud, Makoto Tachibana, M. A. Karim Rumi, Clifford W. Mason, Adam J. Krieg, and Michael J. Soares
The hemochorial placenta is a dynamic structure endowed with responsibilities controlling the extraction of maternal resources, ensuring fetal development and preserving maternal health. A healthy placenta exhibits plasticity and can adapt to environmental challenges. Such adaptations can be executed through instructive actions on trophoblast stem cells, influencing their abilities to expand and differentiate into specialized cells that accommodate the challenge. Hypoxia, when appropriately timed, promotes invasive trophoblast-directed uterine spiral artery remodeling. Hypoxia activates hypoxia inducible factor-dependent expression of lysine demethylase 3A, modifying the histone landscape on key target genes, including matrix metallopeptidase 12, which acts to facilitate trophoblast invasion and uterine vascular remodeling. Plasticity and adaptations at the maternal–fetal interface safeguard placental development and the healthy progression of pregnancy. (See pp. E7212–E7221.)
Optimal stomatal behavior with competition for water and risk of hydraulic impairment
Adam Wolf, William R. L. Anderegg, and Stephen W. Pacala
Plants lose water and take up carbon through stomata, whose behavior has major influences on global carbon and water fluxes. Yet both competition for water and the potential fitness costs of hydraulic damage during water stress could alter how stomata behave. Here, we add variable xylem conductivity to water and carbon costs of low-xylem water potentials to the classic stomatal optimization and a pure carbon-maximization optimization. We show that both optimizations can reproduce known stomatal responses to environmental conditions but that the pure carbon-maximization optimization is also consistent with competition for water. We describe a new measure—the marginal xylem tension efficiency—that can be used to test stomatal optimizations. (See pp. E7222–E7230.)
PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection
Christian J. Maine, John R. Teijaro, Kristi Marquardt, and Linda A. Sherman
Some viruses, including lymphocytic choriomeningitis virus clone 13, shut down the ability of CD4 T lymphocytes to produce IL-2, a cytokine required for the survival and function of T lymphocytes. This shutdown contributes to exhaustion of CD4 and CD8 T lymphocytes and chronic viral infection of the host. The underlying mechanism responsible for the loss of cytokine production by CD4 T cells remains poorly understood. We demonstrate that the expression of a protein tyrosine phosphatase, PTPN22, contributes to chronic viral infection. PTPN22 increases the production of IFN-β following infection, resulting in increased expression of the cAMP response element modulator (CREM) in CD4 T lymphocytes. CREM prevents production of IL-2, thereby contributing to T-cell exhaustion and chronic viral infection. (See pp. E7231–E7239.)
Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells
Shu Wang, Jose Campos, Marilena Gallotta, Mei Gong, Chad Crain, Edwina Naik, Robert L. Coffman, and Cristiana Guiducci
Recent data suggest that patients harboring immunologically incompetent tumors fail to respond to programmed death 1 (PD-1) blockade. We have developed a mouse tumor model that mimics resistance found in human tumors, and we show that intratumoral injections of a high IFN-inducing CpG oligonucleotide, SD-101, can rapidly lead to durable rejection of anti–PD-1 nonresponder tumors and generate systemic immunity to untreated distant-site tumors. The change in tumor microenvironment caused by SD-101 leads to rapid T-cell infiltration and generation of multifunctional CD8+ T cells. These studies provide significant insights into the synergy between PD-1 blockade and local TLR9 activation and provide the experimental support for clinical studies of combination therapy with PD-1 blockade and intratumoral SD-101. (See pp. E7240–E7249.)
Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations
José Rivera-Torres, Conrado J. Calvo, Anna Llach, Gabriela Guzmán-Martínez, Ricardo Caballero, Cristina González-Gómez, Luis J. Jiménez-Borreguero, Juan A. Guadix, Fernando G. Osorio, Carlos López-Otín, Adela Herraiz-Martínez, Nuria Cabello, Alex Vallmitjana, Raul Benítez, Leslie B. Gordon, José Jalife, José M. Pérez-Pomares, Juan Tamargo, Eva Delpón, Leif Hove-Madsen, David Filgueiras-Rama, and Vicente Andrés
Defective prelamin A processing causes cardiovascular alterations and premature death in Hutchinson–Gilford progeria syndrome (HGPS) patients and also occurs during physiological aging. We found overt repolarization abnormalities in HGPS patients at advanced disease stages. Similar alterations were present in progeroid Zmpste24−/− mice, which had cardiomyocytes that exhibited prolonged calcium transient duration and reduced sarcoplasmic reticulum calcium loading capacity and release, consistent with absence of isoproterenol-induced ventricular arrhythmias. Zmpste24−/− mice developed age-dependent bradycardia and PQ interval/QRS complex prolongation, likely contributing to premature death. These defects correlated with mislocalization of connexin43, which was also noted in heart tissue from HGPS patients. These results reveal molecular alterations that might cause cardiac rhythm alterations and premature death in HGPS. (See pp. E7250–E7259.)
Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma
Lixin Rui, Amanda C. Drennan, Michele Ceribelli, Fen Zhu, George W. Wright, Da Wei Huang, Wenming Xiao, Yangguang Li, Kreg M. Grindle, Li Lu, Daniel J. Hodson, Arthur L. Shaffer, Hong Zhao, Weihong Xu, Yandan Yang, and Louis M. Staudt
Autocrine cytokine signaling in cancer can activate members of the Janus kinase (JAK) family, which are generally thought to act by phosphorylating STAT family transcription factors. We report here that JAK1 mediates autocrine IL-6 and IL-10 cytokine signaling in activated B-cell–like (ABC) diffuse large B-cell lymphoma (DLBCL) by a noncanonical epigenetic regulatory mechanism involving phosphorylation of histone H3 on tyrosine 41. We have identified target genes that are activated in ABC DLBCL by this epigenetic mechanism. Knowledge of these epigenetic targets led to our demonstration that JAK1 inhibitors synergize with inhibitors of active B cell receptor signaling in ABC DLBCL, suggesting a new therapeutic strategy for this subtype of DLBCL, which is the most difficult to cure with current therapy. (See pp. E7260–E7267.)
DNA-relay mechanism is sufficient to explain ParA-dependent intracellular transport and patterning of single and multiple cargos
Ivan V. Surovtsev, Manuel Campos, and Christine Jacobs-Wagner
Although intracellular patterning is crucial for cell function, the mechanisms by which spatial patterns arise often remain elusive. Here, we investigate the mechanism of intracellular patterning by the broadly conserved bacterial ParA/B systems, which drive the transport and partitioning of cellular cargos such as plasmids. We show that a simple model that considers only the known biochemical properties of the ParA and ParB proteins and the stochastic dynamics of chromosomal loci observed in vivo explains the spontaneous formation of propagating protein gradients, cargo oscillations, and equidistant patterns that are characteristic of ParA/B systems. Our study shows that stochastic processes and directionally random forces alone—without cytoskeletal elements or motor proteins—can result in directed motion and complex spatial patterning. (See pp. E7268–E7276.)
Mapping human temporal and parietal neuronal population activity and functional coupling during mathematical cognition
Amy L. Daitch, Brett L. Foster, Jessica Schrouff, Vinitha Rangarajan, Itır Kaşikçi, Sandra Gattas, and Josef Parvizi
Humans have the unique ability to perform exact mental arithmetic, which derives from the association of symbols (e.g., “3”) with discrete quantities. Using direct intracranial recordings, we measured electrophysiological activity from neuronal populations in the lateral parietal cortex (LPC) and ventral temporal cortex (VTC) that are known to be important for numerical processing as subjects performed various experiments. We observed functional heterogeneity within each region at the millimeter and millisecond scales and report empirical evidence of functional coupling between the LPC and VTC during mathematical cognition. Our results suggest the presence of an anatomically selective numerical cognition system that engages discrete neuronal populations of the ventral temporal and lateral parietal regions in different time windows of numerical processing. (See pp. E7277–E7286.)
Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome
Abhishek Banerjee, Rajeev V. Rikhye, Vincent Breton-Provencher, Xin Tang, Chenchen Li, Keji Li, Caroline A. Runyan, Zhanyan Fu, Rudolf Jaenisch, and Mriganka Sur
Understanding neurophysiological correlates of neurodevelopmental disorders is one of the pressing challenges of neuroscience. By analyzing a mouse model of Rett syndrome (RTT), we show that cortical pyramidal neurons in methyl-CpG binding protein 2 (MeCP2) mutant mice have reduced excitatory as well as inhibitory synaptic drive. Thus, neuronal response reliability and selectivity, features that arise from excitatory/inhibitory processing circuits within cortex, are reduced. MeCP2 deletion crucially regulates inhibition via two complementary mechanisms: reducing responses of parvalbumin-expressing (PV+) inhibitory neurons and altering the polarity of GABAergic inhibition in pyramidal neurons. Treating mutant mice with recombinant human insulin-like growth factor-1 (rhIGF1) restores GABAergic polarity along with PV+ and pyramidal neuron responses, thus providing a mechanistic basis of action of rhIGF1 in RTT. (See pp. E7287–E7296.)
FEF inactivation with improved optogenetic methods
Leah Acker, Erica N. Pino, Edward S. Boyden, and Robert Desimone
The frontal eye field (FEF) is critical for making eye movements to remembered locations. FEF neurons increase their firing rate in response to seeing a target, to remembering the target location during a delay period, and to planning eye movements to the location. Conventional tools do not allow us to determine what aspects of FEF neuronal activity (i.e., visual, delay, motor) are critical for memory-guided eye movements, so we developed optogenetic tools to inactivate FEF neurons during each task epoch individually. We found that all aspects of FEF firing contribute to behavior. Further, we present tools that inactivate large enough brain volumes for optogenetics to be widely used in primate neuroscience and, potentially, human medicine. (See pp. E7297–E7306.)
E3 ubiquitin ligase SP1 regulates peroxisome biogenesis in Arabidopsis
Ronghui Pan, John Satkovich, and Jianping Hu
Peroxisomes are eukaryotic organelles crucial for development. Peroxisomal matrix proteins are imported by the peroxisome import machinery composed of peroxins (PEX proteins), but how the function of these PEX proteins is regulated is largely unknown. We discovered in Arabidopsis that the ubiquitin–proteasome system regulates peroxisome protein import via an E3 ubiquitin ligase, SP1 (suppressor of ppi1 locus1), which targets PEX13 and possibly several other components of the peroxisome matrix protein import machinery for degradation. Our data demonstrate that the same E3 ubiquitin ligase can be shared by metabolically linked peroxisomes and chloroplasts to promote the destabilization of distinct components of the two import machineries, suggesting that the ubiquitin–proteasome system may represent an important regulatory mechanism coordinating the biogenesis of functionally associated organelles. (See pp. E7307–E7316.)
Genetic architecture of nonadditive inheritance in Arabidopsis thaliana hybrids
Danelle K. Seymour, Eunyoung Chae, Dominik G. Grimm, Carmen Martín Pizarro, Anette Habring-Müller, François Vasseur, Barbara Rakitsch, Karsten M. Borgwardt, Daniel Koenig, and Detlef Weigel
Hybrid progeny of inbred parents are often more fit than their parents. Such hybrid vigor, or heterosis, is the focus of many plant breeding programs, and the rewards are evident. Hybrid maize has for many decades accounted for the majority of seed planted each year in North America and Europe. Despite the prevalence of this phenomenon and its agricultural importance, the genetic basis of heterotic traits is still unclear. We have used a large collection of first-generation hybrids in Arabidopsis thaliana to characterize the genetics of heterosis in this model plant. We have identified loci that contribute substantially to hybrid vigor and show that a subset of these exhibits classical dominance, an important finding with direct implications for crop improvement. (See pp. E7317–E7326.)
Practice improves peri-saccadic shape judgment but does not diminish target mislocalization
Yuval Porat and Ehud Zohary
Visual sensitivity is markedly reduced during saccades, and peri-saccadic stimuli are misperceived as being closer to the saccade target. We show here that peri-saccadic shape discrimination improves significantly with practice. Unlike classical training paradigms that lead to better performance despite external masking, this perceptual learning occurs in the presence of natural, self-induced masking due to the eye movement (i.e., saccadic suppression). Improvement is generalized across saccade direction and stimulus location but is specific to the stimulus type and task. In contrast, stimulus mislocalization remains as pronounced. Thus, the representation of stimulus position probably involves an obligatory process triggered by the upcoming saccade. The results point to a dissociation between shape and location representations of peri-saccadic stimuli. (See pp. E7327–E7336.)
Neural correlates of specific musical anhedonia
Noelia Martínez-Molina, Ernest Mas-Herrero, Antoni Rodríguez-Fornells, Robert J. Zatorre, and Josep Marco-Pallarés
This study provides direct evidence supporting the model of reward–auditory cortex interaction as underlying musical pleasure: People who do not experience that pleasure have selectively reduced responses in that system. People who are especially sensitive to musical reward conversely seem to show an enhanced interaction. Our paper offers insights into the neurobiological basis of music-induced pleasure that could also provide the basis for thinking more broadly about other types of aesthetic rewards. Our results also provide an important step toward the understanding of how music may have acquired reward value through evolution. (See pp. E7337–E7345.)