@article{7708, abstract = {We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case–control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case–control status in the Netherlands sample (area under the curve, AUC = 0.65, CI95% = [0.62–0.68], p = 8.3 × 10−22). The maximum AUC achieved was 0.69 (CI95% = [0.66–0.71], p = 4.3 × 10−34) when cell-type proportion was included in the predictor.}, author = {Nabais, Marta F. and Lin, Tian and Benyamin, Beben and Williams, Kelly L. and Garton, Fleur C. and Vinkhuyzen, Anna A. E. and Zhang, Futao and Vallerga, Costanza L. and Restuadi, Restuadi and Freydenzon, Anna and Zwamborn, Ramona A. J. and Hop, Paul J. and Robinson, Matthew Richard and Gratten, Jacob and Visscher, Peter M. and Hannon, Eilis and Mill, Jonathan and Brown, Matthew A. and Laing, Nigel G. and Mather, Karen A. and Sachdev, Perminder S. and Ngo, Shyuan T. and Steyn, Frederik J. and Wallace, Leanne and Henders, Anjali K. and Needham, Merrilee and Veldink, Jan H. and Mathers, Susan and Nicholson, Garth and Rowe, Dominic B. and Henderson, Robert D. and McCombe, Pamela A. and Pamphlett, Roger and Yang, Jian and Blair, Ian P. and McRae, Allan F. and Wray, Naomi R.}, issn = {2056-7944}, journal = {npj Genomic Medicine}, publisher = {Springer Nature}, title = {{Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis}}, doi = {10.1038/s41525-020-0118-3}, volume = {5}, year = {2020}, } @article{7778, abstract = {Recent advances in synthetic posttranslational protein circuits are substantially impacting the landscape of cellular engineering and offer several advantages compared to traditional gene circuits. However, engineering dynamic phenomena such as oscillations in protein-level circuits remains an outstanding challenge. Few examples of biological posttranslational oscillators are known, necessitating theoretical progress to determine realizable oscillators. We construct mathematical models for two posttranslational oscillators, using few components that interact only through reversible binding and phosphorylation/dephosphorylation reactions. Our designed oscillators rely on the self-assembly of two protein species into multimeric functional enzymes that respectively inhibit and enhance this self-assembly. We limit our analysis to within experimental constraints, finding (i) significant portions of the restricted parameter space yielding oscillations and (ii) that oscillation periods can be tuned by several orders of magnitude using recent advances in computational protein design. Our work paves the way for the rational design and realization of protein-based dynamic systems.}, author = {Kimchi, Ofer and Goodrich, Carl Peter and Courbet, Alexis and Curatolo, Agnese I. and Woodall, Nicholas B. and Baker, David and Brenner, Michael P.}, journal = {Science Advances}, number = {51}, title = {{Self-assembly-based posttranslational protein oscillators}}, doi = {10.1126/sciadv.abc1939}, volume = {6}, year = {2020}, } @article{7788, abstract = {Mutations in NDUFS4, which encodes an accessory subunit of mitochondrial oxidative phosphorylation (OXPHOS) complex I (CI), induce Leigh syndrome (LS). LS is a poorly understood pediatric disorder featuring brain-specific anomalies and early death. To study the LS pathomechanism, we here compared OXPHOS proteomes between various Ndufs4−/− mouse tissues. Ndufs4−/− animals displayed significantly lower CI subunit levels in brain/diaphragm relative to other tissues (liver/heart/kidney/skeletal muscle), whereas other OXPHOS subunit levels were not reduced. Absence of NDUFS4 induced near complete absence of the NDUFA12 accessory subunit, a 50% reduction in other CI subunit levels, and an increase in specific CI assembly factors. Among the latter, NDUFAF2 was most highly increased. Regarding NDUFS4, NDUFA12 and NDUFAF2, identical results were obtained in Ndufs4−/− mouse embryonic fibroblasts (MEFs) and NDUFS4-mutated LS patient cells. Ndufs4−/− MEFs contained active CI in situ but blue-native-PAGE highlighted that NDUFAF2 attached to an inactive CI subcomplex (CI-830) and inactive assemblies of higher MW. In NDUFA12-mutated LS patient cells, NDUFA12 absence did not reduce NDUFS4 levels but triggered NDUFAF2 association to active CI. BN-PAGE revealed no such association in LS patient fibroblasts with mutations in other CI subunit-encoding genes where NDUFAF2 was attached to CI-830 (NDUFS1, NDUFV1 mutation) or not detected (NDUFS7 mutation). Supported by enzymological and CI in silico structural analysis, we conclude that absence of NDUFS4 induces near complete absence of NDUFA12 but not vice versa, and that NDUFAF2 stabilizes active CI in Ndufs4−/− mice and LS patient cells, perhaps in concert with mitochondrial inner membrane lipids.}, author = {Adjobo-Hermans, Merel J.W. and De Haas, Ria and Willems, Peter H.G.M. and Wojtala, Aleksandra and Van Emst-De Vries, Sjenet E. and Wagenaars, Jori A. and Van Den Brand, Mariel and Rodenburg, Richard J. and Smeitink, Jan A.M. and Nijtmans, Leo G. and Sazanov, Leonid A and Wieckowski, Mariusz R. and Koopman, Werner J.H.}, issn = {1879-2650}, journal = {Biochimica et Biophysica Acta - Bioenergetics}, number = {8}, publisher = {Elsevier}, title = {{NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2}}, doi = {10.1016/j.bbabio.2020.148213}, volume = {1861}, year = {2020}, } @article{7789, abstract = {During embryonic and postnatal development, organs and tissues grow steadily to achieve their final size at the end of puberty. However, little is known about the cellular dynamics that mediate postnatal growth. By combining in vivo clonal lineage tracing, proliferation kinetics, single-cell transcriptomics, andin vitro micro-pattern experiments, we resolved the cellular dynamics taking place during postnatal skin epidermis expansion. Our data revealed that harmonious growth is engineered by a single population of developmental progenitors presenting a fixed fate imbalance of self-renewing divisions with an ever-decreasing proliferation rate. Single-cell RNA sequencing revealed that epidermal developmental progenitors form a more uniform population compared with adult stem and progenitor cells. Finally, we found that the spatial pattern of cell division orientation is dictated locally by the underlying collagen fiber orientation. Our results uncover a simple design principle of organ growth where progenitors and differentiated cells expand in harmony with their surrounding tissues.}, author = {Dekoninck, Sophie and Hannezo, Edouard B and Sifrim, Alejandro and Miroshnikova, Yekaterina A. and Aragona, Mariaceleste and Malfait, Milan and Gargouri, Souhir and De Neunheuser, Charlotte and Dubois, Christine and Voet, Thierry and Wickström, Sara A. and Simons, Benjamin D. and Blanpain, Cédric}, issn = {1097-4172}, journal = {Cell}, number = {3}, pages = {604--620.e22}, publisher = {Elsevier}, title = {{Defining the design principles of skin epidermis postnatal growth}}, doi = {10.1016/j.cell.2020.03.015}, volume = {181}, year = {2020}, } @article{7792, abstract = {Phonon polaritons—light coupled to lattice vibrations—in polar van der Waals crystals are promising candidates for controlling the flow of energy on the nanoscale due to their strong field confinement, anisotropic propagation and ultra-long lifetime in the picosecond range1,2,3,4,5. However, the lack of tunability of their narrow and material-specific spectral range—the Reststrahlen band—severely limits their technological implementation. Here, we demonstrate that intercalation of Na atoms in the van der Waals semiconductor α-V2O5 enables a broad spectral shift of Reststrahlen bands, and that the phonon polaritons excited show ultra-low losses (lifetime of 4 ± 1 ps), similar to phonon polaritons in a non-intercalated crystal (lifetime of 6 ± 1 ps). We expect our intercalation method to be applicable to other van der Waals crystals, opening the door for the use of phonon polaritons in broad spectral bands in the mid-infrared domain.}, author = {Taboada-Gutiérrez, Javier and Álvarez-Pérez, Gonzalo and Duan, Jiahua and Ma, Weiliang and Crowley, Kyle and Prieto Gonzalez, Ivan and Bylinkin, Andrei and Autore, Marta and Volkova, Halyna and Kimura, Kenta and Kimura, Tsuyoshi and Berger, M. H. and Li, Shaojuan and Bao, Qiaoliang and Gao, Xuan P.A. and Errea, Ion and Nikitin, Alexey Y. and Hillenbrand, Rainer and Martín-Sánchez, Javier and Alonso-González, Pablo}, issn = {1476-4660}, journal = {Nature Materials}, pages = {964–968}, publisher = {Springer Nature}, title = {{Broad spectral tuning of ultra-low-loss polaritons in a van der Waals crystal by intercalation}}, doi = {10.1038/s41563-020-0665-0}, volume = {19}, year = {2020}, } @article{7793, abstract = {Hormonal signalling in animals often involves direct transcription factor-hormone interactions that modulate gene expression. In contrast, plant hormone signalling is most commonly based on de-repression via the degradation of transcriptional repressors. Recently, we uncovered a non-canonical signalling mechanism for the plant hormone auxin whereby auxin directly affects the activity of the atypical auxin response factor (ARF), ETTIN towards target genes without the requirement for protein degradation. Here we show that ETTIN directly binds auxin, leading to dissociation from co-repressor proteins of the TOPLESS/TOPLESS-RELATED family followed by histone acetylation and induction of gene expression. This mechanism is reminiscent of animal hormone signalling as it affects the activity towards regulation of target genes and provides the first example of a DNA-bound hormone receptor in plants. Whilst auxin affects canonical ARFs indirectly by facilitating degradation of Aux/IAA repressors, direct ETTIN-auxin interactions allow switching between repressive and de-repressive chromatin states in an instantly-reversible manner.}, author = {Kuhn, André and Ramans Harborough, Sigurd and McLaughlin, Heather M and Natarajan, Bhavani and Verstraeten, Inge and Friml, Jiří and Kepinski, Stefan and Østergaard, Lars}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Direct ETTIN-auxin interaction controls chromatin states in gynoecium development}}, doi = {10.7554/elife.51787}, volume = {9}, year = {2020}, } @inproceedings{7802, abstract = {The Massively Parallel Computation (MPC) model is an emerging model which distills core aspects of distributed and parallel computation. It has been developed as a tool to solve (typically graph) problems in systems where the input is distributed over many machines with limited space. Recent work has focused on the regime in which machines have sublinear (in $n$, the number of nodes in the input graph) space, with randomized algorithms presented for fundamental graph problems of Maximal Matching and Maximal Independent Set. However, there have been no prior corresponding deterministic algorithms. A major challenge underlying the sublinear space setting is that the local space of each machine might be too small to store all the edges incident to a single node. This poses a considerable obstacle compared to the classical models in which each node is assumed to know and have easy access to its incident edges. To overcome this barrier we introduce a new graph sparsification technique that deterministically computes a low-degree subgraph with additional desired properties. The degree of the nodes in this subgraph is small in the sense that the edges of each node can be now stored on a single machine. This low-degree subgraph also has the property that solving the problem on this subgraph provides \emph{significant} global progress, i.e., progress towards solving the problem for the original input graph. Using this framework to derandomize the well-known randomized algorithm of Luby [SICOMP'86], we obtain $O(\log \Delta+\log\log n)$-round deterministic MPC algorithms for solving the fundamental problems of Maximal Matching and Maximal Independent Set with $O(n^{\epsilon})$ space on each machine for any constant $\epsilon > 0$. Based on the recent work of Ghaffari et al. [FOCS'18], this additive $O(\log\log n)$ factor is conditionally essential. These algorithms can also be shown to run in $O(\log \Delta)$ rounds in the closely related model of CONGESTED CLIQUE, improving upon the state-of-the-art bound of $O(\log^2 \Delta)$ rounds by Censor-Hillel et al. [DISC'17].}, author = {Czumaj, Artur and Davies, Peter and Parter, Merav}, booktitle = {Proceedings of the 32nd ACM Symposium on Parallelism in Algorithms and Architectures (SPAA 2020)}, location = {Virtual Event, United States}, number = {7}, pages = {175--185}, publisher = {Association for Computing Machinery}, title = {{Graph sparsification for derandomizing massively parallel computation with low space}}, doi = {10.1145/3350755.3400282}, year = {2020}, } @inproceedings{7803, abstract = {We settle the complexity of the (Δ+1)-coloring and (Δ+1)-list coloring problems in the CONGESTED CLIQUE model by presenting a simple deterministic algorithm for both problems running in a constant number of rounds. This matches the complexity of the recent breakthrough randomized constant-round (Δ+1)-list coloring algorithm due to Chang et al. (PODC'19), and significantly improves upon the state-of-the-art O(logΔ)-round deterministic (Δ+1)-coloring bound of Parter (ICALP'18). A remarkable property of our algorithm is its simplicity. Whereas the state-of-the-art randomized algorithms for this problem are based on the quite involved local coloring algorithm of Chang et al. (STOC'18), our algorithm can be described in just a few lines. At a high level, it applies a careful derandomization of a recursive procedure which partitions the nodes and their respective palettes into separate bins. We show that after O(1) recursion steps, the remaining uncolored subgraph within each bin has linear size, and thus can be solved locally by collecting it to a single node. This algorithm can also be implemented in the Massively Parallel Computation (MPC) model provided that each machine has linear (in n, the number of nodes in the input graph) space. We also show an extension of our algorithm to the MPC regime in which machines have sublinear space: we present the first deterministic (Δ+1)-list coloring algorithm designed for sublinear-space MPC, which runs in O(logΔ+loglogn) rounds.}, author = {Czumaj, Artur and Davies, Peter and Parter, Merav}, booktitle = {Proceedings of the 2020 ACM Symposium on Principles of Distributed Computing}, location = {Salerno, Italy}, pages = {309--318}, publisher = {Association for Computing Machinery}, title = {{Simple, deterministic, constant-round coloring in the congested clique}}, doi = {10.1145/3382734.3405751}, year = {2020}, } @inproceedings{7806, abstract = {We consider the following decision problem EMBEDk→d in computational topology (where k ≤ d are fixed positive integers): Given a finite simplicial complex K of dimension k, does there exist a (piecewise-linear) embedding of K into ℝd? The special case EMBED1→2 is graph planarity, which is decidable in linear time, as shown by Hopcroft and Tarjan. In higher dimensions, EMBED2→3 and EMBED3→3 are known to be decidable (as well as NP-hard), and recent results of Čadek et al. in computational homotopy theory, in combination with the classical Haefliger–Weber theorem in geometric topology, imply that EMBEDk→d can be solved in polynomial time for any fixed pair (k, d) of dimensions in the so-called metastable range . Here, by contrast, we prove that EMBEDk→d is algorithmically undecidable for almost all pairs of dimensions outside the metastable range, namely for . This almost completely resolves the decidability vs. undecidability of EMBEDk→d in higher dimensions and establishes a sharp dichotomy between polynomial-time solvability and undecidability. Our result complements (and in a wide range of dimensions strengthens) earlier results of Matoušek, Tancer, and the second author, who showed that EMBEDk→d is undecidable for 4 ≤ k ϵ {d – 1, d}, and NP-hard for all remaining pairs (k, d) outside the metastable range and satisfying d ≥ 4.}, author = {Filakovský, Marek and Wagner, Uli and Zhechev, Stephan Y}, booktitle = {Proceedings of the Annual ACM-SIAM Symposium on Discrete Algorithms}, isbn = {9781611975994}, location = {Salt Lake City, UT, United States}, pages = {767--785}, publisher = {SIAM}, title = {{Embeddability of simplicial complexes is undecidable}}, doi = {10.1137/1.9781611975994.47}, volume = {2020-January}, year = {2020}, } @inproceedings{7807, abstract = {In a straight-line embedded triangulation of a point set P in the plane, removing an inner edge and—provided the resulting quadrilateral is convex—adding the other diagonal is called an edge flip. The (edge) flip graph has all triangulations as vertices, and a pair of triangulations is adjacent if they can be obtained from each other by an edge flip. The goal of this paper is to contribute to a better understanding of the flip graph, with an emphasis on its connectivity. For sets in general position, it is known that every triangulation allows at least edge flips (a tight bound) which gives the minimum degree of any flip graph for n points. We show that for every point set P in general position, the flip graph is at least -vertex connected. Somewhat more strongly, we show that the vertex connectivity equals the minimum degree occurring in the flip graph, i.e. the minimum number of flippable edges in any triangulation of P, provided P is large enough. Finally, we exhibit some of the geometry of the flip graph by showing that the flip graph can be covered by 1-skeletons of polytopes of dimension (products of associahedra). A corresponding result ((n – 3)-vertex connectedness) can be shown for the bistellar flip graph of partial triangulations, i.e. the set of all triangulations of subsets of P which contain all extreme points of P. This will be treated separately in a second part.}, author = {Wagner, Uli and Welzl, Emo}, booktitle = {Proceedings of the Annual ACM-SIAM Symposium on Discrete Algorithms}, isbn = {9781611975994}, location = {Salt Lake City, UT, United States}, pages = {2823--2841}, publisher = {SIAM}, title = {{Connectivity of triangulation flip graphs in the plane (Part I: Edge flips)}}, doi = {10.1137/1.9781611975994.172}, volume = {2020-January}, year = {2020}, } @article{7814, abstract = {Scientific research is to date largely restricted to wealthy laboratories in developed nations due to the necessity of complex and expensive equipment. This inequality limits the capacity of science to be used as a diplomatic channel. Maker movements use open-source technologies including additive manufacturing (3D printing) and laser cutting, together with low-cost computers for developing novel products. This movement is setting the groundwork for a revolution, allowing scientific equipment to be sourced at a fraction of the cost and has the potential to increase the availability of equipment for scientists around the world. Science education is increasingly recognized as another channel for science diplomacy. In this perspective, we introduce the idea that the Maker movement and open-source technologies have the potential to revolutionize science, technology, engineering and mathematics (STEM) education worldwide. We present an open-source STEM didactic tool called SCOPES (Sparking Curiosity through Open-source Platforms in Education and Science). SCOPES is self-contained, independent of local resources, and cost-effective. SCOPES can be adapted to communicate complex subjects from genetics to neurobiology, perform real-world biological experiments and explore digitized scientific samples. We envision such platforms will enhance science diplomacy by providing a means for scientists to share their findings with classrooms and for educators to incorporate didactic concepts into STEM lessons. By providing students the opportunity to design, perform, and share scientific experiments, students also experience firsthand the benefits of a multinational scientific community. We provide instructions on how to build and use SCOPES on our webpage: http://scopeseducation.org.}, author = {Beattie, Robert J and Hippenmeyer, Simon and Pauler, Florian}, issn = {2504-284X}, journal = {Frontiers in Education}, publisher = {Frontiers Media}, title = {{SCOPES: Sparking curiosity through Open-Source platforms in education and science}}, doi = {10.3389/feduc.2020.00048}, volume = {5}, year = {2020}, } @article{7847, abstract = {Water-in-salt electrolytes based on highly concentrated bis(trifluoromethyl)sulfonimide (TFSI) promise aqueous electrolytes with stabilities nearing 3 V. However, especially with an electrode approaching the cathodic (reductive) stability, cycling stability is insufficient. While stability critically relies on a solid electrolyte interphase (SEI), the mechanism behind the cathodic stability limit remains unclear. Here, we reveal two distinct reduction potentials for the chemical environments of 'free' and 'bound' water and that both contribute to SEI formation. Free-water is reduced ~1V above bound water in a hydrogen evolution reaction (HER) and responsible for SEI formation via reactive intermediates of the HER; concurrent LiTFSI precipitation/dissolution establishes a dynamic interface. The free-water population emerges, therefore, as the handle to extend the cathodic limit of aqueous electrolytes and the battery cycling stability. }, author = {Bouchal, Roza and Li, Zhujie and Bongu, Chandra and Le Vot, Steven and Berthelot, Romain and Rotenberg, Benjamin and Favier, Fréderic and Freunberger, Stefan Alexander and Salanne, Mathieu and Fontaine, Olivier}, issn = {1521-3773}, journal = {Angewandte Chemie International Edition}, number = {37}, pages = {15913--1591}, publisher = {Wiley}, title = {{Competitive salt precipitation/dissolution during free‐water reduction in water‐in‐salt electrolyte}}, doi = {10.1002/anie.202005378}, volume = {59}, year = {2020}, } @article{7864, abstract = {Purpose of review: Cancer is one of the leading causes of death and the incidence rates are constantly rising. The heterogeneity of tumors poses a big challenge for the treatment of the disease and natural antibodies additionally affect disease progression. The introduction of engineered mAbs for anticancer immunotherapies has substantially improved progression-free and overall survival of cancer patients, but little efforts have been made to exploit other antibody isotypes than IgG. Recent findings: In order to improve these therapies, ‘next-generation antibodies’ were engineered to enhance a specific feature of classical antibodies and form a group of highly effective and precise therapy compounds. Advanced antibody approaches include among others antibody-drug conjugates, glyco-engineered and Fc-engineered antibodies, antibody fragments, radioimmunotherapy compounds, bispecific antibodies and alternative (non-IgG) immunoglobulin classes, especially IgE. Summary: The current review describes solutions for the needs of next-generation antibody therapies through different approaches. Careful selection of the best-suited engineering methodology is a key factor in developing personalized, more specific and more efficient mAbs against cancer to improve the outcomes of cancer patients. We highlight here the large evidence of IgE exploiting a highly cytotoxic effector arm as potential next-generation anticancer immunotherapy.}, author = {Singer, Judit and Singer, Josef and Jensen-Jarolim, Erika}, issn = {14736322}, journal = {Current opinion in allergy and clinical immunology}, number = {3}, pages = {282--289}, publisher = {Wolters Kluwer}, title = {{Precision medicine in clinical oncology: the journey from IgG antibody to IgE}}, doi = {10.1097/ACI.0000000000000637}, volume = {20}, year = {2020}, } @article{7875, abstract = {Cells navigating through complex tissues face a fundamental challenge: while multiple protrusions explore different paths, the cell needs to avoid entanglement. How a cell surveys and then corrects its own shape is poorly understood. Here, we demonstrate that spatially distinct microtubule dynamics regulate amoeboid cell migration by locally promoting the retraction of protrusions. In migrating dendritic cells, local microtubule depolymerization within protrusions remote from the microtubule organizing center triggers actomyosin contractility controlled by RhoA and its exchange factor Lfc. Depletion of Lfc leads to aberrant myosin localization, thereby causing two effects that rate-limit locomotion: (1) impaired cell edge coordination during path finding and (2) defective adhesion resolution. Compromised shape control is particularly hindering in geometrically complex microenvironments, where it leads to entanglement and ultimately fragmentation of the cell body. We thus demonstrate that microtubules can act as a proprioceptive device: they sense cell shape and control actomyosin retraction to sustain cellular coherence.}, author = {Kopf, Aglaja and Renkawitz, Jörg and Hauschild, Robert and Girkontaite, Irute and Tedford, Kerry and Merrin, Jack and Thorn-Seshold, Oliver and Trauner, Dirk and Häcker, Hans and Fischer, Klaus Dieter and Kiermaier, Eva and Sixt, Michael K}, issn = {1540-8140}, journal = {The Journal of Cell Biology}, number = {6}, publisher = {Rockefeller University Press}, title = {{Microtubules control cellular shape and coherence in amoeboid migrating cells}}, doi = {10.1083/jcb.201907154}, volume = {219}, year = {2020}, } @article{7876, abstract = {In contrast to lymph nodes, the lymphoid regions of the spleen—the white pulp—are located deep within the organ, yielding the trafficking paths of T cells in the white pulp largely invisible. In an intravital microscopy tour de force reported in this issue of Immunity, Chauveau et al. show that T cells perform unidirectional, perivascular migration through the enigmatic marginal zone bridging channels. }, author = {Sixt, Michael K and Lämmermann, Tim}, issn = {1097-4180}, journal = {Immunity}, number = {5}, pages = {721--723}, publisher = {Elsevier}, title = {{T cells: Bridge-and-channel commute to the white pulp}}, doi = {10.1016/j.immuni.2020.04.020}, volume = {52}, year = {2020}, } @article{7880, abstract = {Following its evoked release, dopamine (DA) signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DA transporter (DAT). DAT surface availability is dynamically regulated by endocytic trafficking, and direct protein kinase C (PKC) activation acutely diminishes DAT surface expression by accelerating DAT internalization. Previous cell line studies demonstrated that PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT. However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis in DAergic terminals or whether there are region- and/or sex-dependent differences in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 controls PKC-stimulated DAT endocytosis are unknown. Here, we directly examined these important questions. Ex vivo studies revealed that PKC activation acutely decreased DAT surface expression selectively in ventral, but not dorsal, striatum. AAV-mediated, conditional Rit2 knockdown in DAergic neurons impacted baseline DAT surface:intracellular distribution in DAergic terminals from female ventral, but not dorsal, striatum. Further, Rit2 was required for PKC-stimulated DAT internalization in both male and female ventral striatum. FRET and surface pulldown studies in cell lines revealed that PKC activation drives DAT-Rit2 surface dissociation and that the DAT N terminus is required for both PKC-mediated DAT-Rit2 dissociation and DAT internalization. Finally, we found that Rit2 and Ack1 independently converge on DAT to facilitate PKC-stimulated DAT endocytosis. Together, our data provide greater insight into mechanisms that mediate PKC-regulated DAT internalization and reveal unexpected region-specific differences in PKC-stimulated DAT trafficking in bona fide DAergic terminals. }, author = {Fagan, Rita R. and Kearney, Patrick J. and Sweeney, Carolyn G. and Luethi, Dino and Schoot Uiterkamp, Florianne E and Schicker, Klaus and Alejandro, Brian S. and O'Connor, Lauren C. and Sitte, Harald H. and Melikian, Haley E.}, issn = {1083-351X}, journal = {Journal of Biological Chemistry}, number = {16}, pages = {5229--5244}, publisher = {ASBMB Publications}, title = {{Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact}}, doi = {10.1074/jbc.RA120.012628}, volume = {295}, year = {2020}, } @article{7908, abstract = {Volatile anesthetics are widely used for surgery, but neuronal mechanisms of anesthesia remain unidentified. At the calyx of Held in brainstem slices from rats of either sex, isoflurane at clinical doses attenuated EPSCs by decreasing the release probability and the number of readily releasable vesicles. In presynaptic recordings of Ca2+ currents and exocytic capacitance changes, isoflurane attenuated exocytosis by inhibiting Ca2+ currents evoked by a short presynaptic depolarization, whereas it inhibited exocytosis evoked by a prolonged depolarization via directly blocking exocytic machinery downstream of Ca2+ influx. Since the length of presynaptic depolarization can simulate the frequency of synaptic inputs, isoflurane anesthesia is likely mediated by distinct dual mechanisms, depending on input frequencies. In simultaneous presynaptic and postsynaptic action potential recordings, isoflurane impaired the fidelity of repetitive spike transmission, more strongly at higher frequencies. Furthermore, in the cerebrum of adult mice, isoflurane inhibited monosynaptic corticocortical spike transmission, preferentially at a higher frequency. We conclude that dual presynaptic mechanisms operate for the anesthetic action of isoflurane, of which direct inhibition of exocytic machinery plays a low-pass filtering role in spike transmission at central excitatory synapses.}, author = {Wang, Han Ying and Eguchi, Kohgaku and Yamashita, Takayuki and Takahashi, Tomoyuki}, issn = {1529-2401}, journal = {Journal of Neuroscience}, number = {21}, pages = {4103--4115}, publisher = {Society for Neuroscience}, title = {{Frequency-dependent block of excitatory neurotransmission by isoflurane via dual presynaptic mechanisms}}, doi = {10.1523/JNEUROSCI.2946-19.2020}, volume = {40}, year = {2020}, } @article{7919, abstract = {We explore the time evolution of two impurities in a trapped one-dimensional Bose gas that follows a change of the boson-impurity interaction. We study the induced impurity-impurity interactions and their effect on the quench dynamics. In particular, we report on the size of the impurity cloud, the impurity-impurity entanglement, and the impurity-impurity correlation function. The presented numerical simulations are based upon the variational multilayer multiconfiguration time-dependent Hartree method for bosons. To analyze and quantify induced impurity-impurity correlations, we employ an effective two-body Hamiltonian with a contact interaction. We show that the effective model consistent with the mean-field attraction of two heavy impurities explains qualitatively our results for weak interactions. Our findings suggest that the quench dynamics in cold-atom systems can be a tool for studying impurity-impurity correlations.}, author = {Mistakidis, S. I. and Volosniev, Artem and Schmelcher, P.}, issn = {2643-1564}, journal = {Physical Review Research}, publisher = {American Physical Society}, title = {{Induced correlations between impurities in a one-dimensional quenched Bose gas}}, doi = {10.1103/physrevresearch.2.023154}, volume = {2}, year = {2020}, } @article{7940, abstract = {We prove that the Yangian associated to an untwisted symmetric affine Kac–Moody Lie algebra is isomorphic to the Drinfeld double of a shuffle algebra. The latter is constructed in [YZ14] as an algebraic formalism of cohomological Hall algebras. As a consequence, we obtain the Poincare–Birkhoff–Witt (PBW) theorem for this class of affine Yangians. Another independent proof of the PBW theorem is given recently by Guay, Regelskis, and Wendlandt [GRW18].}, author = {Yang, Yaping and Zhao, Gufang}, issn = {1531-586X}, journal = {Transformation Groups}, pages = {1371--1385}, publisher = {Springer Nature}, title = {{The PBW theorem for affine Yangians}}, doi = {10.1007/s00031-020-09572-6}, volume = {25}, year = {2020}, } @article{7942, abstract = {An understanding of the missing antinodal electronic excitations in the pseudogap state is essential for uncovering the physics of the underdoped cuprate high-temperature superconductors1,2,3,4,5,6. The majority of high-temperature experiments performed thus far, however, have been unable to discern whether the antinodal states are rendered unobservable due to their damping or whether they vanish due to their gapping7,8,9,10,11,12,13,14,15,16,17,18. Here, we distinguish between these two scenarios by using quantum oscillations to examine whether the small Fermi surface pocket, found to occupy only 2% of the Brillouin zone in the underdoped cuprates19,20,21,22,23,24, exists in isolation against a majority of completely gapped density of states spanning the antinodes, or whether it is thermodynamically coupled to a background of ungapped antinodal states. We find that quantum oscillations associated with the small Fermi surface pocket exhibit a signature sawtooth waveform characteristic of an isolated two-dimensional Fermi surface pocket25,26,27,28,29,30,31,32. This finding reveals that the antinodal states are destroyed by a hard gap that extends over the majority of the Brillouin zone, placing strong constraints on a drastic underlying origin of quasiparticle disappearance over almost the entire Brillouin zone in the pseudogap regime7,8,9,10,11,12,13,14,15,16,17,18.}, author = {Hartstein, Máté and Hsu, Yu Te and Modic, Kimberly A and Porras, Juan and Loew, Toshinao and Tacon, Matthieu Le and Zuo, Huakun and Wang, Jinhua and Zhu, Zengwei and Chan, Mun K. and Mcdonald, Ross D. and Lonzarich, Gilbert G. and Keimer, Bernhard and Sebastian, Suchitra E. and Harrison, Neil}, issn = {1745-2481}, journal = {Nature Physics}, pages = {841--847}, publisher = {Springer Nature}, title = {{Hard antinodal gap revealed by quantum oscillations in the pseudogap regime of underdoped high-Tc superconductors}}, doi = {10.1038/s41567-020-0910-0}, volume = {16}, year = {2020}, }