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| Open AccessATPase activity of DFCP1 controls selective autophagy
The endoplasmic reticulum protein DFCP1 is found on omegasomes implicated in autophagosome biogenesis, but its function has remained unknown. Here, Nähse et al. show that DFCP1 is an ATPase that mediates selective autophagy by promoting constriction of large omegasomes.
- Viola Nähse
- , Camilla Raiborg
- & Harald Stenmark
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Article
| Open AccessStructural insight into the human SID1 transmembrane family member 2 reveals its lipid hydrolytic activity
The SID-1 family is a putative channel/transporter for transporting nucleic acids. Here, Qian et al. report the dimeric structure of human SIDT2 suggesting that it may act as a transporter but not a channel. In addition, it has a ceramidase activity.
- Dandan Qian
- , Ye Cong
- & Deshun Gong
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Article
| Open AccessCeramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis
The SPT-ORMDL complex is tightly regulated by cellular sphingolipid levels, but the sphingolipid sensing mechanism is unknown. Here, the authors elucidate the molecular basis of ceramide sensing by the human SPTORMDL complex for establishing sphingolipid homeostasis.
- Tian Xie
- , Peng Liu
- & Xin Gong
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Article
| Open AccessSubstrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A
Molecular mechanisms of MFSD2A-mediated lysolipid transport into the brain has been elusive. Here, using molecular dynamics, the authors uncover how initial stages of transport cycle are enabled by substrate-induced conformational changes in MFSD2A.
- Shana Bergman
- , Rosemary J. Cater
- & George Khelashvili
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Article
| Open AccessStructural mechanism of intracellular autoregulation of zinc uptake in ZIP transporters
Zinc uptake and regulation are vital in all life forms. Here, authors describe a dimer of a ZIP-family zinc transporter in an inward-facing, inhibited conformation. A built-in zinc sensor is proposed to sense the intracellular zinc content to autoregulate zinc uptake across membranes.
- Changxu Pang
- , Jin Chai
- & Qun Liu
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Article
| Open AccessA 2.2 Å cryoEM structure of a quinol-dependent NO Reductase shows close similarity to respiratory oxidases
Quinol-dependent nitric oxide reductases, unique to bacteria, are considered members of respiratory heme copper oxidases. A 2.2 Å cryoEM structure of qNOR is reported shedding light on key aspects of enzyme mechanism including quinol binding and pathways for electron, substrate, and proton transport.
- Alex J. Flynn
- , Svetlana V. Antonyuk
- & S. Samar Hasnain
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Article
| Open AccessAsymmetric pendrin homodimer reveals its molecular mechanism as anion exchanger
Pendrin SLC26A4 plays an important role for anion balance. Here, authors resolve cryo-EM structures of pendrin performing co-incident uptake and secretion of anions, providing a structural basis of this anion exchange mechanism.
- Qianying Liu
- , Xiang Zhang
- & Zhenguo Chen
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Article
| Open AccessStructures of human SGLT in the occluded state reveal conformational changes during sugar transport
SGLT plays key roles in sugar uptake and reabsorption. Here the authors provided the cryo-EM structures of human SGLT1 and SGLT2 in the substrate-bound occluded state, uncovering the conformational changes of SGLT during sugar transport.
- Wenhao Cui
- , Yange Niu
- & Lei Chen
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Article
| Open AccessStructural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein
The authors report the structure of human oncochannel TRPV6 in complex with the plant derived phytoestrogen genistein. The structure provides insights into genistein binding in the channel pore, and how it acts as blocker and gating modifier, suggesting a mechanism of inhibition that can be explored for the structure-based drug design.
- Arthur Neuberger
- , Yury A. Trofimov
- & Alexander I. Sobolevsky
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Article
| Open AccessConfinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling
EGFR is a receptor that is upregulated in many cancers, but the mechanisms that control EGFR function are incompletely understood. Here the authors used single particle tracking to identify a role for tetraspanin CD81 in EGFR ligand binding, mobility, and signaling.
- Michael G. Sugiyama
- , Aidan I. Brown
- & Costin N. Antonescu
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Article
| Open AccessLipid flipping in the omega-3 fatty-acid transporter
Lipid flipping across membrane leaflets are vital yet enigmatic biological processes. Here, five cryo-EM structures provide snapshots to delineate a mechanism of omega-3 fatty acid flipping across the blood brain barrier.
- Chi Nguyen
- , Hsiang-Ting Lei
- & Tamir Gonen
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Article
| Open AccessSymport and antiport mechanisms of human glutamate transporters
Ion gradients power the neurotransmitter transport by brain glutamate transporters. Here, the authors report cryo-EM structures of the EAAT3 transporter isoform with and without the ions and the neurotransmitter, revealing the coupling mechanisms.
- Biao Qiu
- & Olga Boudker
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Article
| Open AccessPain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function
Voltage-gated sodium channels function as multiprotein signaling complexes. Here, authors show that the dispanin TMEM233 is essential for activity of stinging nettle toxins and that co-expression of TMEM233 modulates the gating properties of NaV1.7.
- Sina Jami
- , Jennifer R. Deuis
- & Irina Vetter
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Article
| Open AccessStructure and mechanism of the alkane-oxidizing enzyme AlkB
Alkane monooxygenase (AlkB) plays a key role in the global carbon cycle and remediation of oil spills. Here, the authors report the cryo-EM structure of AlkB to provide insight into the catalytic mechanism and substrate selectivity.
- Xue Guo
- , Jianxiu Zhang
- & Liang Feng
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Article
| Open AccessCryo-EM structures of mitochondrial ABC transporter ABCB10 in apo and biliverdin-bound form
ABCB10 is a mitochondrial biliverdin exporter. Here, authors report the cryo-EM structures of ABCB10 apo and biliverdin-bound forms, revealing a cholesterol binding site that promotes the ATPase activity and thermostability of ABCB10.
- Sheng Cao
- , Yihu Yang
- & Zhuqing Ouyang
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Article
| Open AccessConformational cycle of human polyamine transporter ATP13A2
ATP13A2 is a lysosomal polyamine transporter, mutated in several diseases including juvenile-onset Parkinson’s disease. Here, the authors report structures of human ATP13A2 in six distinct intermediate states, illustrating most of its conformational cycle.
- Jianqiang Mu
- , Chenyang Xue
- & Zhongmin Liu
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Article
| Open AccessSingle-molecule fingerprinting of protein-drug interaction using a funneled biological nanopore
Efficient screening of protein-drug interactions (PDIs) has been impeded by the limitations of current biophysical approaches. Here, the authors present a funneled YaxAB nanopore sensor which allows label-free, single-molecule detection of proteins and PDIs.
- Ki-Baek Jeong
- , Minju Ryu
- & Seung-Wook Chi
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| Open AccessStructure and mechanism of oxalate transporter OxlT in an oxalate-degrading bacterium in the gut microbiota
In our gut, oxalate-degrading bacteria absorb oxalate, a causative substance for kidney stone formation, and reduce our health risk. In this work, the authors report the structure of the oxalate transporter responsible for this process and how the protein works.
- Titouan Jaunet-Lahary
- , Tatsuro Shimamura
- & Atsuko Yamashita
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Article
| Open AccessThe structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2
Cells maintain a narrow physiological pH by exchanging intracellular bicarbonate for extracellular chloride. Here, authors determine the cryo-EM structures of human anion exchanger 2 (AE2) in five major operating states and one transitional state, to collectively demonstrate the process of pH-balancing.
- Qing Zhang
- , Liyan Jian
- & Yu Cao
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Article
| Open AccessMutation in glutamate transporter homologue GltTk provides insights into pathologic mechanism of episodic ataxia 6
Episodic ataxias (EAs) are rare neurological conditions that cause motor impairment. Here the authors investigated the molecular mechanism of such a pathological condition caused by a mutation of a conserved proline into arginine residue.
- Emanuela Colucci
- , Zaid R. Anshari
- & Albert Guskov
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Article
| Open AccessA generalizable nanopore sensor for highly specific protein detection at single-molecule precision
Sensitive and accurate approaches for protein detection have many potential applications. Here the authors show how engineered protein nanopore sensors, consisting of a monobody fused to a single-polypeptide nanopore, can be used for highly specific detection of proteins in complex biofluids.
- Mohammad Ahmad
- , Jeung-Hoi Ha
- & Liviu Movileanu
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Article
| Open AccessThe architecture of transmembrane and cytoplasmic juxtamembrane regions of Toll-like receptors
Toll-like receptors (TLRs) play a key role in the innate immune system. Here, Kornilov et al. resolve the 3D structures of the membrane-associated parts of four TLRs to reveal properties of the juxta-membrane domain.
- F. D. Kornilov
- , A. V. Shabalkina
- & K. S. Mineev
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Article
| Open AccessStructural basis of vitamin C recognition and transport by mammalian SVCT1 transporter
Sodium-dependent vitamin C transporters are responsible for vitamin C uptake and tissue distribution in mammals. Here, authors present cryo-EM structures of mouse SVCT1 in both the apo and substrate-bound states, revealing the structural basis of substrate recognition and transport.
- Mingxing Wang
- , Jin He
- & Ji She
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Article
| Open AccessCryo-EM structures of human Cx36/GJD2 neuronal gap junction channel
Connexin 36 (Cx36) gap junction channel is responsible for signal transmission in electrical synapses. Here, the authors determine cryo-EM structures of Cx36, providing insights into a potential role of lipids in the channel gating.
- Seu-Na Lee
- , Hwa-Jin Cho
- & Hyung Ho Lee
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Article
| Open AccessCell surface protein aggregation triggers endocytosis to maintain plasma membrane proteostasis
How cells respond to denaturation of extracellular protein domains remained largely unknown. Here, authors describe an aggregation-dependent endocytosis pathway, facilitating uptake and degradation of antibody- and stress-induced protein aggregates.
- David Paul
- , Omer Stern
- & Harvey McMahon
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Article
| Open AccessStructure and mechanism of a tripartite ATP-independent periplasmic TRAP transporter
Bacteria and archaea use tripartite ATP-independent periplasmic (TRAP) transporters to import essential nutrients. Davies et al. report a high resolution structure of a TRAP and show that it uses an ‘elevator-with-an operator’ mechanism.
- James S. Davies
- , Michael J. Currie
- & Renwick C. J. Dobson
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Article
| Open AccessConformational changes in the human Cx43/GJA1 gap junction channel visualized using cryo-EM
Gap junction intercellular channels (GJIChs) facilitate direct communication between adjacent cells. Here, authors provide high-resolution information on dynamic structural changes in Cx43 GJICh that are necessary to understand the gating mechanism.
- Hyuk-Joon Lee
- , Hyung Jin Cha
- & Jae-Sung Woo
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Article
| Open AccessThe cytoplasmic synthesis and coupled membrane translocation of eukaryotic polyphosphate by signal-activated VTC complex
The VTC complex generate eukaryotic polyphosphate (polyP). Authors here reveal how the signal-activated VTC synthesize cytosolic polyP and transport polyP across vacuolar membrane into the lumen, by using cryo-EM, in-cell NMR, and smFRET analyses.
- Zeyuan Guan
- , Juan Chen
- & Zhu Liu
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Article
| Open AccessCryo-EM structures of orphan GPR21 signaling complexes
In this work, the authors report Cryo-EM structures of the signaling complexes of human GPR21, an orphan GPCR and a potential metabolic disease target, and reveal unique receptor activation conformation when bound to downstream signaling proteins in the absence of any ligand.
- Xi Lin
- , Bo Chen
- & Fei Xu
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Article
| Open AccessActivating alternative transport modes in a multidrug resistance efflux pump to confer chemical susceptibility
Antibiotic resistance through multidrug efflux is a major hurdle in antibiotic development. Here, authors experimentally demonstrate that EmrE, a small multidrug resistance efflux pump from E. coli, can confer resistance or susceptibility depending on the small molecule substrate.
- Peyton J. Spreacker
- , Nathan E. Thomas
- & Katherine A. Henzler-Wildman
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Article
| Open AccessIdentifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases
Antimicrobial resistance to currently available antibiotics requires innovation of antibiotics. Here, the authors identify a critical inhibitory site in an energy-producing enzyme, which can lead to rational design of antibiotics.
- Yuya Nishida
- , Sachiko Yanagisawa
- & Yasunori Shintani
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Article
| Open AccessBackbone amides are determinants of Cl− selectivity in CLC ion channels
CLC-type channels selectively transport Cl− across biological membranes, but it is unclear how discrimination between anions is maintained. Here, authors use a combination of non-natural amino acid substitutions, electrophysiology, and molecular dynamics simulations to determine Cl− specificity within this family of ion channels.
- Lilia Leisle
- , Kin Lam
- & Alessio Accardi
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Article
| Open AccessStructures of the R-type human Cav2.3 channel reveal conformational crosstalk of the intracellular segments
Voltage-gated Ca2+ channel subtype Cav2.3 represents a potential drug target for neurological diseases. Here, authors report cryo-EM structures of Cav2.3 and its mutant to reveal the crosstalk of intracellular segments, which may facilitate future drug discovery.
- Xia Yao
- , Yan Wang
- & Nieng Yan
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Article
| Open AccessStructural basis for lipid and copper regulation of the ABC transporter MsbA
The bacterial ABC transporter MsbA is essential for lipopolysaccharide biogenesis. Here, the authors apply native mass spectrometry, X-ray crystallography, cryo-EM and biochemical approaches to characterize the structural basis and functional roles of MsbA binding to copper and specific lipids.
- Jixing Lyu
- , Chang Liu
- & Arthur Laganowsky
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Article
| Open AccessGating and ion selectivity of Channelrhodopsins are critical for photo-activated orientation of Chlamydomonas as shown by in vivo point mutation
Channelrhodopsin photoreceptors are responsible for phototaxis in C. reinhardtii. Here, authors introduce point mutations in the channel which modify photocycle kinetics and ion selectivity, resulting in a deeper understanding of phototaxis in low light conditions.
- Olga Baidukova
- , Johannes Oppermann
- & Peter Hegemann
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Article
| Open AccessUptake mechanism of iron-phytosiderophore from the soil based on the structure of yellow stripe transporter
Iron is an essential mineral in plant physiology. YS1 transporter imports iron–phytosiderophore complex (Fe(III)–DMA) from the soil. Here, the authors describe the cryo-EM structures of barley YS1 in complex with substrate, and a synthetic substrate analog.
- Atsushi Yamagata
- , Yoshiko Murata
- & Mikako Shirouzu
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Article
| Open AccessStructural basis for mechanotransduction in a potassium-dependent mechanosensitive ion channel
Mechanosensitive ion channels mediate biological force sensation, but the underlying mechanism remains poorly understood. Here, authors present the structural basis of mechanotransduction in an ion channel revealed by cryo-electron microscopy.
- Jonathan Mount
- , Grigory Maksaev
- & Peng Yuan
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Article
| Open AccessStructural basis of organic cation transporter-3 inhibition
The current work reports the structure of the human organic cation transporter 3 (OCT3 / SLC22A3) and provides the structural basis of its inhibition by two specific inhibitors, decynium-22 and corticosterone.
- Basavraj Khanppnavar
- , Julian Maier
- & Harald H. Sitte
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Article
| Open AccessStructural insights into light-driven anion pumping in cyanobacteria
Here, the authors present four high-resolution structures of SyHR protein from cyanobacterial anion pumps family: chloride and sulfate bound forms and two active state structures. These structures provide insights into the molecular mechanisms of SyHR and cyanobacterial anion pumps in general.
- R. Astashkin
- , K. Kovalev
- & V. Gordeliy
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Article
| Open AccessStructural mechanism of SGLT1 inhibitors
SGLT1 is essential for glucose, galactose and water uptake from the intestine, and its inhibitors have broad therapeutic potential. Here, the authors describe the cryo-EM structure of human SGLT1 in complex with an inhibitor.
- Yange Niu
- , Wenhao Cui
- & Lei Chen
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Article
| Open AccessStructures of the CcmABCD heme release complex at multiple states
Bacterial ABC transporter complex CcmABCD, a part of cytochrome c maturation system, transfers heme from one binding partner (CcmC) to another (CcmE). Here authors describe high resolution cryo-EM structures of CcmABCD in multiple states and propose a hypothetic model of heme trafficking, heme transfer and release of holoCcmE.
- Jiao Li
- , Wan Zheng
- & Jiapeng Zhu
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Article
| Open AccessA slit-diaphragm-associated protein network for dynamic control of renal filtration
The slit-diaphragm is a cellular junction that is crucial for blood filtration in the kidney. Kocylowski et al. show that the junction-spanning components are embedded in a protein network for dynamic control of filtration; network disturbance leads to severe filtration defects with proteinuria.
- Maciej K. Kocylowski
- , Hande Aypek
- & Florian Grahammer
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Article
| Open AccessCrystal structure of the Na+/H+ antiporter NhaA at active pH reveals the mechanistic basis for pH sensing
By determining the crystal structure of the Na + /H + antiporter NhaA at active pH, the authors show how substrate accessibility to the ion-binding site can be controlled by pH sensitive switch located on the cytoplasmic surface.
- Iven Winkelmann
- , Povilas Uzdavinys
- & David Drew
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Article
| Open AccessMolecular basis for isoform-selective inhibition of presenilin-1 by MRK-560
Presenilin isoforms (PS1 and PS2) containing γ-secretase show contrasting sensitivity to MRK-560. Here, the authors determined cryo-EM structures of PS1/PS2-complexes treated with MRK-560 and identified key residues responsible for the isoform-dependent selectivity.
- Xuefei Guo
- , Yumeng Wang
- & Yigong Shi
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Article
| Open AccessIn vitro assembly, positioning and contraction of a division ring in minimal cells
Constructing a minimal protein machinery for self-division of membrane compartments is a major goal of bottom-up synthetic biology. Here, authors achieved the assembly, placement and onset of contraction of a minimal division ring in lipid vesicles.
- Shunshi Kohyama
- , Adrián Merino-Salomón
- & Petra Schwille
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Article
| Open AccessThe lysosomal transporter TAPL has a dual role as peptide translocator and phosphatidylserine floppase
In this work, the authors report an ATP-dependent phosphatidylserine floppase activity for the lysosomal ATP-binding cassette transporter TAPL. In addition, they report the cryo-EM structures of mouse TAPL complexed with (i) phospholipid, (ii) cholesteryl hemisuccinate (CHS) and 9-mer peptide, and (iii) ADP·BeF3. Together, their results suggest that TAPL uses different mechanisms to function as a peptide translocase and a phosphatidylserine floppase.
- Jun Gyou Park
- , Songwon Kim
- & Mi Sun Jin
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Article
| Open AccessStructural basis for the activity regulation of a potassium channel AKT1 from Arabidopsis
Arabidopsis thaliana potassium channel AKT1 is responsible for primary K + uptake from soil, which is functionally activated through phosphorylation and negatively regulated by an α-subunit AtKC1. Here, the authors report the structures of AKT1 at different states, revealing a 2- fold to 4-fold symmetry switch at cytoplasmic domain associated with AKT1 activity regulation.
- Yaming Lu
- , Miao Yu
- & Guanghui Yang
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Article
| Open AccessThe AAA+ ATPase RavA and its binding partner ViaA modulate E. coli aminoglycoside sensitivity through interaction with the inner membrane
Membrane lipid composition is a key factor for bacterial stress adaptation. Here, authors show that ViaA and AAA+ ATPase RavA, alter lipid composition and modulate E. coli aminoglycoside sensitivity.
- Jan Felix
- , Ladislav Bumba
- & Irina Gutsche
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Article
| Open AccessStructural basis for gating mechanism of the human sodium-potassium pump
Through cryo-EM analysis, here authors reveal conformational rearrangements that are critical for the gating mechanism of the human alpha3 Na+/K+−ATPase
- Phong T. Nguyen
- , Christine Deisl
- & Beth Levine