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Law LMJ, Razooky BS, Li MMH, You S, Jurado A, Rice CM, MacDonald MR
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ZAP's stress granule localization is correlated with its antiviral activity and induced by virus replication

PLOS PATHOGENS 2019 MAY; 15(5):? Article e1007798
Cellular antiviral programs encode molecules capable of targeting multiple steps in the virus lifecycle. Zinc-finger antiviral protein (ZAP) is a central and general regulator of antiviral activity that targets pathogen mRNA stability and translation. ZAP is diffusely cytoplasmic, but upon infection ZAP is targeted to particular cytoplasmic structures, termed stress granules (SGs). However, it remains unclear if ZAP's antiviral activity correlates with SG localization, and what molecular cues are required to induce this localization event. Here, we use Sindbis virus (SINV) as a model infection and find that ZAP's localization to SGs can be transient. Sometimes no apparent viral infection follows ZAP SG localization but ZAP SG localization always precedes accumulation of SINV non-structural protein, suggesting virus replication processes trigger SG formation and ZAP recruitment. Data from single-molecule RNA FISH corroborates this finding as the majority of cells with ZAP localization in SGs contain low levels of viral RNA. Furthermore, ZAP recruitment to SGs occurred in ZAP-expressing cells when co-cultured with cells replicating full-length SINV, but not when co-cultured with cells replicating a SINV replicon. ZAP recruitment to SGs is functionally important as a panel of alanine ZAP mutants indicate that the anti-SINV activity is correlated with ZAP's ability to localize to SGs. As ZAP is a central component of the cellular antiviral programs, these data provide further evidence that SGs are an important cytoplasmic antiviral hub. These findings provide insight into how antiviral components are regulated upon virus infection to inhibit virus spread.
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Ignatenko M, Mccoll N, Regnard S, Saltzberg D, Schnaible C, Valuev V, Bouvier E, Burt K, Clare R, Ellison J, Gary JW, Shirazi SMAG, Hanson G, Karapostoli G, Kennedy E, Lacroix F, Long OR, Negrete MO, Paneva MI, Si W, Wang L, Wei H, Wimpenny S, Yates BR, Branson JG, Cittolin S, Derdzinski M, Gerosa R, Gilbert D, Hashemi B, Holzner A, Klein D, Kole G, Krutelyov V, Letts J, Masciovecchio M, Olivito D, Padhi S, Pieri M, Sani M, Sharma V, Simon S, Tadel M, Vartak A, Wasserbaech S, Wood J, Wurthwein F, Yagil A, Della Porta GZ, Amin N, Bhandari R, Bradmiller-Feld J, Campagnari C, Citron M, Dishaw A, Dutta V, Sevilla MF, Gouskos L, Heller R, Incandela J, Ovcharova A, Qu H, Richman J, Stuart D, Suarez I, Yoo J, Anderson D, Bornheim A, Bunn J, Lawhorn JM, Newman HB, Nguyen TQ, Pena C, Spiropulu M, Vlimant JR, Wilkinson R, Xie S, Zhang Z, Zhu RY, Andrews MB, Ferguson T, Mudholkar T, Paulini M, Russ J, Sun M, Vogel H, Vorobiev I, Weinberg M, Cumalat JP, Ford WT, Jensen F, Johnson A, Krohn M, Leontsinis S, Macdonald E, Mulholland T, Stenson K, Ulmer KA, Wagner SR, Alexander J, Chaves J, Cheng Y, Chu J, Datta A, Dittmer S, Mcdermott K, Mirman N, Patterson JR, Quach D, Rinkevicius A, Ryd A, Skinnari L, Soffi L, Tan SM, Tao Z, Thom J, Tucker J, Wittich P, Zientek M, Abdullin S, Albrow M, Alyari M, Apollinari G, Apresyan A, Apyan A, Banerjee S, Bauerdick LAT, Beretvas A, Berryhill J, Bhat PC, Bolla G, Burkett K, Butler JN, Canepa A, Cerati GB, Cheung HWK, Chlebana F, Cremonesi M, Duarte J, Elvira VD, Freeman J, Gecse Z, Gottschalk E, Gray L, Green D, Grunendahl S, Gutsche O, Hanlon J, Harris RM, Hasegawa S, Hirschauer J, Hu Z, Jayatilaka B, Jindariani S, Johnson M, Joshi U, Klima B, Kreis B, Lammel S, Lincoln D, Lipton R, Liu M, Liu T, De Sa RL, Lykken J, Maeshima K, Magini N, Marraffino JM, Mason D, McBride P, Merkel P, Mrenna S, Nahn S, O'Dell V, Pedro K, Prokofyev O, Rakness G, Ristori L, Savoy-Navarro A, Schneider B, Sexton-Kennedy E, Soha A, Spalding WJ, Spiegel L, Stoynev S, Strait J, Strobbe N, Taylor L, Tkaczyk S, Tran NV, Uplegger L, Vaandering EW, Vernieri C, Verzocchi M, Vidal R, Wang M, Weber HA, Whitbeck A, Wu W, Acosta D, Avery P, Bortignon P, Bourilkov D, Brinkerhoff A, Carnes A, Carver M, Curry D, Field RD, Furic IK, Gleyzer SV, Joshi BM, Konigsberg J, Korytov A, Kotov K, Ma P, Matchev K, Mei H, Mitselmakher G, Shi K, Sperka D, Terentyev N, Thomas L, Wang J, Wang S, Yelton J, Joshi YR, Linn S, Markowitz P, Rodriguez JL, Ackert A, Adams T, Askew A, Hagopian S, Hagopian V, Johnson KF, Kolberg T, Martinez G, Perry T, Prosper H, Saha A, Santra A, Sharma V, Yohay R, Baarmand MM, Bhopatkar V, Colafranceschi S, Hohlmann M, Noonan D, Roy T, Yumiceva F, Adams MR, Apanasevich L, Berry D, Betts RR, Cavanaugh R, Chen X, Evdokimov O, Gerber CE, Hangal DA, Hofman DJ, Jung K, Kamin J, Gonzalez IDS, Tonjes MB, Varelas N, Wang H, Wu Z, Zhang J, Bilki B, Clarida W, Dilsiz K, Durgut S, Gandrajula RP, Haytmyradov M, Khristenko V, Merlo JP, Mermerkaya H, Mestvirishvili A, Moeller A, Nachtman J, Ogul H, Onel Y, Ozok F, Penzo A, Snyder C, Tiras E, Wetzel J, Yi K, Blumenfeld B, Cocoros A, Eminizer N, Fehling D, Feng L, Gritsan AV, Maksimovic P, Roskes J, Sarica U, Swartz M, Xiao M, You C, Al-bataineh A, Baringer P, Bean A, Boren S, Bowen J, Castle J, Khalil S, Kropivnitskaya A, Majumder D, Mcbrayer W, Murray M, Rogan C, Royon C, Sanders S, Schmitz E, Takaki JDT, Wang Q, Ivanov A, Kaadze K, Maravin Y, Mohammadi A, Saini LK, Skhirtladze N, Rebassoo F, Wright D, Baden A, Baron O, Belloni A, Eno SC, Feng Y, Ferraioli C, Hadley NJ, Jabeen S, Jeng GY, Kellogg RG, Kunkle J, Mignerey AC, Ricci-Tam F, Shin YH, Skuja A, Tonwar SC, Abercrombie D, Allen B, Azzolini V, Barbieri R, Baty A, Bauer G, Bi R, Brandt S, Busza W, Cali IA, D'Alfonso M, Demiragli Z, Ceballos GG, Goncharov M, Harris P, Hsu D, Hu M, Iiyama Y, Innocenti GM, Klute M, Kovalskyi D, Lee YJ, Levin A, Luckey PD, Maier B, Marini AC, Mcginn C, Mironov C, Narayanan S, Niu X, Paus C, Roland C, Roland G, Salfeld-Nebgen J, Stephans GSF, Sumorok K, Tatar K, Velicanu D, Wang J, Wang TW, Wyslouch B, Benvenuti AC, Chatterjee RM, Evans A, Hansen P, Kalafut S, Kubota Y, Lesko Z, Mans J, Nourbakhsh S, Ruckstuhl N, Rusack R, Turkewitz J, Wadud MA, Acosta JG, Oliveros S, Avdeeva E, Bloom K, Claes DR, Fangmeier C, Golf F, Suarez RG, Kamalieddin R, Kravchenko I, Monroy J, Siado JE, Snow GR, Stieger B, Dolen J, Godshalk A, Harrington C, Iashvili I, Nguyen D, Parker A, Rappoccio S, Roozbahani B, Alverson G, Barberis E, Freer C, Hortiangtham A, Massironi A, Morse DM, Orimoto T, De Lima RT, Wamorkar T, Wang B, Wisecarver A, Wood D, Bhattacharya S, Charaf O, Hahn KA, Mucia N, Odell N, Schmitt MH, Sung K, Trovato M, Velasco M, Bucci R, Dev N, Hildreth M, Anampa KH, Jessop C, Karmgard DJ, Kellams N, Lannon K, Li W, Loukas N, Marinelli N, Meng F, Mueller C, Musienko Y, Planer M, Reinsvold A, Ruchti R, Siddireddy P, Smith G, Taroni S, Wayne M, Wightman A, Wolf M, Woodard A, Alimena J, Antonelli L, Bylsma B, Durkin LS, Flowers S, Francis B, Hart A, Hill C, Ji W, Ling TY, Luo W, Winer BL, Wulsin HW, Cooperstein S, Driga O, Elmer P, Hardenbrook J, Hebda P, Higginbotham S, Kalogeropoulos A, Lange D, Luo J, Marlow D, Mei K, Ojalvo I, Olsen J, Palmer C, Piroue P, Stickland D, Tully C, Malik S, Norberg S, Barker A, Barnes VE, Das S, Gutay L, Jones M, Jung AW, Khatiwada A, Miller DH, Neumeister N, Peng CC, Qiu H, Schulte JF, Sun J, Wang F, Xiao R, Xie W, Cheng T, Parashar N, Chen Z, Ecklund KM, Freed S, Geurts FJM, Guilbaud M, Kilpatrick M, Li W, Michlin B, Padley BP, Roberts J, Rorie J, Shi W, Tu Z, Zabel J, Zhang A, Bodek A, de Barbaro P, Demina R, Duh YT, Ferbel T, Galanti M, Garcia-Bellido A, Han J, Hindrichs O, Khukhunaishvili A, Lo KH, Tan P, Verzetti M, Ciesielski R, Goulianos K, Mesropian C, Agapitos A, Chou JP, Gershtein Y, Espinosa TAG, Halkiadakis E, Heindl M, Hughes E, Kaplan S, Elayavalli RK, Kyriacou S, Lath A, Montalvo R, Nash K, Osherson M, Saka H, Salur S, Schnetzer S, Sheffield D, Somalwar S, Stone R, Thomas S, Thomassen P, Walker M, Delannoy AG, Heideman J, Riley G, Rose K, Spanier S, Thapa K, Bouhali O, Hernandez AC, Celik A, Dalchenko M, De Mattia M, Delgado A, Dildick S, Eusebi R, Gilmore J, Huang T, Kamon T, Mueller R, Pakhotin Y, Patel R, Perloff A, Pernie L, Rathjens D, Safonov A, Tatarinov A, Akchurin N, Damgov J, De Guio F, Dudero PR, Faulkner J, Gurpinar E, Kunori S, Lamichhane K, Lee SW, Mengke T, Muthumuni S, Peltola T, Undleeb S, Volobouev I, Wang Z, Greene S, Gurrola A, Janjam R, Johns W, Maguire C, Melo A, Ni H, Padeken K, Sheldon P, Tuo S, Velkovska J, Xu Q, Arenton MW, Barria P, Cox B, Hirosky R, Joyce M, Ledovskoy A, Li H, Neu C, Sinthuprasith T, Wang Y, Wolfe E, Xia F, Harr R, Karchin PE, Poudyal N, Sturdy J, Thapa P, Zaleski S, Brodski M, Buchanan J, Caillol C, Carlsmith D, Dasu S, Dodd L, Duric S, Gomber B, Grothe M, Herndon M, Herve A, Hussain U, Klabbers P, Lanaro A, Levine A, Long K, Loveless R, Rekovic V, Ruggles T, Savin A, Smith N, Smith WH, Woods N
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Combined measurements of Higgs boson couplings in proton- proton collisions at v s=13TeV

EUROPEAN PHYSICAL JOURNAL C 2019 MAY 20; 79(5):? Article 421
Combined measurements of the production and decay rates of the Higgs boson, as well as its couplings to vector bosons and fermions, are presented. The analysis uses the LHC proton-proton collision data set recorded with the CMS detector in 2016 at fb-1. The combination is based on analyses targeting the five main Higgs boson production mechanisms (gluon fusion, vector boson fusion, and associated production with a W or Z boson, or a top quark-antiquark pair) and the following decay modes: H, ZZ, WW, , bb, and . Searches for invisible Higgs boson decays are also considered. The best-fit ratio of the signal yield to the standard model expectation is measured to be =1.17 +/- 0.10, assuming a Higgs boson mass of 125.09. Additional results are given for various assumptions on the scaling behavior of the production and decay modes, including generic parametrizations based on ratios of cross sections and branching fractions or couplings. The results are compatible with the standard model predictions in all parametrizations considered. In addition, constraints are placed on various two Higgs doublet models.
Reich B, Zhou Y, Goldstein E, Srivats SS, Contoreggi NH, Kogan JF, McEwen BS, Kreek MJ, Milner TA, Gray JD
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Chronic immobilization stress primes the hippocampal opioid system for oxycodone-associated learning in female but not male rats

SYNAPSE 2019 MAY; 73(5):? Article e22088
In adult female, but not male, Sprague Dawley rats, chronic immobilization stress (CIS) increases mossy fiber (MF) Leu-Enkephalin levels and redistributes delta- and mu-opioid receptors (DORs and MORs) in hippocampal CA3 pyramidal cells and GABAergic interneurons to promote excitation and learning processes following subsequent opioid exposure. Here, we demonstrate that CIS females, but not males, acquire conditioned place preference (CPP) to oxycodone and that CIS "primes" the hippocampal opioid system in females for oxycodone-associated learning. In CA3b, oxycodone-injected (Oxy) CIS females relative to saline-injected (Sal) CIS females exhibited an increase in the cytoplasmic and total densities of DORs in pyramidal cell dendrites so that they were similar to Sal- and Oxy-CIS males. Consistent with our earlier studies, Sal- and Oxy-CIS females but not CIS males had elevated DOR densities in MF-CA3 dendritic spines, which we have previously shown are important for opioid-mediated long-term potentiation. In the dentate gyrus, Oxy-CIS females had more DOR-labeled interneurons than Sal-CIS females. Moreover, Sal- and Oxy-CIS females compared to both groups of CIS males had elevated levels of DORs and MORs in GABAergic interneuron dendrites, suggesting capacity for greater synthesis or storage of these receptors in circuits important for opioid-mediated disinhibition. However, more plasmalemmal MORs were on large parvalbumin-containing dendrites of Oxy-CIS males compared to Sal-CIS males, suggesting a limited ability for increased granule cell disinhibition. These results suggest that low levels of DORs in MF-CA3 synapses and hilar GABAergic interneurons may contribute to the attenuation of oxycodone CPP in males exposed to CIS.
Farber G, Parks MM, Guahmich NL, Zhang Y, Monette S, Blanchard SC, Di Lorenzo A, Blobel CP
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ADAM10 controls the differentiation of the coronary arterial endothelium

ANGIOGENESIS 2019 MAY; 22(2):237-250
The coronary vasculature is crucial for normal heart function, yet much remains to be learned about its development, especially the maturation of coronary arterial endothelium. Here, we show that endothelial inactivation of ADAM10, a key regulator of Notch signaling, leads to defects in coronary arterial differentiation, as evidenced by dysregulated genes related to Notch signaling and arterial identity. Moreover, transcriptome analysis indicated reduced EGFR signaling in A10EC coronary endothelium. Further analysis revealed that A10EC mice have enlarged dysfunctional hearts with abnormal myocardial compaction, and increased expression of venous and immature endothelium markers. These findings provide the first evidence for a potential role for endothelial ADAM10 in cardioprotective homeostatic EGFR signaling and implicate ADAM10/Notch signaling in coronary arterial cell specification, which is vital for normal heart development and function. The ADAM10/Notch signaling pathway thus emerges as a potential therapeutic target for improving the regenerative capacity and maturation of the coronary vasculature.
Ersching J, Victora GD
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Ebola from Bedside to Bench

CELL 2019 MAY 30; 177(6):1370-1372
A longitudinal study by Davis et al. followed the evolution of antibody responses in four survivors of the 2014 Ebola outbreak treated in the United States and provides insight into the emergence of neutralizing antibodies long after convalescence.
Pfaff D, Tabansky I, Haubensak W
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Tinbergen's challenge for the neuroscience of behavior

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2019 MAY 14; 116(20):9704-9710
Nobel laureate Nikolaas Tinbergen provided clear criteria for declaring a neuroscience problem solved, criteria which despite the passage of more than 50 years and vastly expanded neuroscience tool kits remain applicable today. Tinbergen said for neuroscientists to claim that a behavior is understood, they must correspondingly understand its (i) development and its (ii) mechanisms and its (iii) function and its (iv) evolution. Now, all four of these domains represent hotbeds of current experimental work, each using arrays of new techniques which overlap only partly. Thus, as new methodologies come online, from single-nerve-cell RNA sequencing, for example, to smart FISH, large-scale calcium imaging from cortex and deep brain structures, computational ethology, and so on, one person, however smart, cannot master everything. Our response to the likely "fracturing" of neuroscience recognizes the value of ever larger consortia. This response suggests new kinds of problems for (i) funding and (ii) the fair distribution of credit, especially for younger scientists.
Bartsch TF, Hengel FE, Oswald A, Dionne G, Chipendo IV, Mangat SS, El Shatanofy M, Shapiro L, Muller U, Hudspeth AJ
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Elasticity of individual protocadherin 15 molecules implicates tip links as the gating springs for hearing

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2019 MAY 28; 116(22):11048-11056
Hair cells, the sensory receptors of the inner ear, respond to mechanical forces originating from sounds and accelerations. An essential feature of each hair cell is an array of filamentous tip links, consisting of the proteins protocadherin 15 (PCDH15) and cadherin 23 (CDH23), whose tension is thought to directly gate the cell's transduction channels. These links are considered far too stiff to represent the gating springs that convert hair bundle displacement into forces capable of opening the channels, and no mechanism has been suggested through which tip-link stiffness could be varied to accommodate hair cells of distinct frequency sensitivity in different receptor organs and animals. Consequently, the gating spring's identity and mechanism of operation remain central questions in sensory neuroscience. Using a high-precision optical trap, we show that an individual monomer of PCDH15 acts as an entropic spring that is much softer than its enthalpic stiffness alone would suggest. This low stiffness implies that the protein is a significant part of the gating spring that controls a hair cell's transduction channels. The tip link's entropic nature then allows for stiffness control through modulation of its tension. We find that a PCDH15 molecule is unstable under tension and exhibits a rich variety of reversible unfolding events that are augmented when the Ca2+ concentration is reduced to physiological levels. Therefore, tip link tension and Ca2+ concentration are likely parameters through which nature tunes a gating spring's mechanical properties.
Zhang Y, Jang Y, Lee JE, Ahn J, Xu LX, Holden MR, Cornett EM, Krajewski K, Klein BJ, Wang SP, Dou YL, Roeder RG, Strahl BD, Rothbart SB, Shi XB, Ge K, Kutateladze TG
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Selective binding of the PHD6 finger of MLL4 to histone H4K16ac links MLL4 and MOF

NATURE COMMUNICATIONS 2019 MAY 24; 10(?):? Article 2314
Histone methyltransferase MLL4 is centrally involved in transcriptional regulation and is often mutated in human diseases, including cancer and developmental disorders. MLL4 contains a catalytic SET domain that mono-methylates histone H3K4 and seven PHD fingers of unclear function. Here, we identify the PHD6 finger of MLL4 (MLL4-PHD6) as a selective reader of the epigenetic modification H4K16ac. The solution NMR structure of MLL4-PHD6 in complex with a H4K16ac peptide along with binding and mutational analyses reveal unique mechanistic features underlying recognition of H4K16ac. Genomic studies show that one third of MLL4 chromatin binding sites overlap with H4K16ac-enriched regions in vivo and that MLL4 occupancy in a set of genomic targets depends on the acetyltransferase activity of MOF, a H4K16ac-specific acetyltransferase. The recognition of H4K16ac is conserved in the PHD7 finger of paralogous MLL3. Together, our findings reveal a previously uncharacterized acetyllysine reader and suggest that selective targeting of H4K16ac by MLL4 provides a direct functional link between MLL4, MOF and H4K16 acetylation.
Calenda G, Frank I, Arrode-Bruses G, Pegu A, Wang KY, Arthos J, Cicala C, Rogers KA, Shirreff L, Grasperge B, Blanchard JL, Maldonado S, Roberts K, Gettie A, Villinger F, Fauci AS, Mascola JR, Martinelli E
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Delayed vaginal SHIV infection in VRC01 and anti-alpha 4 beta 7 treated rhesus macaques

PLOS PATHOGENS 2019 MAY; 15(5):? Article e1007776
VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-alpha(4)beta(7) mAb (Rh-alpha(4)beta(7)) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4(+) T cells. To investigate the impact of combining VRC01 and Rh-alpha(4)beta(7) on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-alpha(4)beta(7) or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID50) of SHIVAD8-EO. The combination Rh-alpha(4)beta(7)-VRC01 significantly delayed SHIVAD8-EO vaginal infection. Following infection, VRC01-Rh-alpha(4)beta(7)-treated macaques maintained higher CD4(+) T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-alpha(4)beta(7)-treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIVAD8-EO envelope in the VRC01-Rh-alpha(4)beta(7) group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-alpha(4)beta(7) delayed infection, altered antiviral immune responses and minimized CD4(+) T cell loss. Further exploration of the effect of combining bNAbs with Rh-alpha(4)beta(7) on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies.
Dennis EJ, Goldman OV, Vosshall LB
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Aedes aegypti Mosquitoes Use Their Legs to Sense DEET on Contact

CURRENT BIOLOGY 2019 MAY 6; 29(9):1551-1556.e5
DEET (N, N-diethyl-meta-toluamide) is the most effective and widely used insect repellent, but its mechanism of action is both complex and controversial [1]. DEET acts on insect smell [2-6] and taste [7-11], and its olfactory mode of action requires the odorant coreceptor orco [2, 3, 6]. We previously observed that orco mutant female Aedes aegypti mosquitoes are strongly attracted to humans even in the presence of DEET, but they are rapidly repelled after contacting DEET-treated skin [6]. DEET inhibits food ingestion by Drosophila melanogaster flies, and this repellency is mediated by bitter taste neurons in the proboscis [9]. Similar neurons were identified in the mosquito proboscis, leading to the hypothesis that DEET repels on contact by activating an aversive bitter taste pathway [10]. To understand the basis of DEET contact chemorepellency, we carried out behavioral experiments and discovered that DEET acts by three distinct mechanisms: smell, ingestion, and contact. Like bitter tastants, DEET is a feeding deterrent when ingested, but its bitterness per se does not fully explain DEET contact chemorepellency. Mosquitoes blood fed on human arms treated with high concentrations of bitters, but rapidly avoided DEET-treated skin and did not blood feed. Insects detect tastants both through their proboscis and legs. We show that DEET contact chemorepellency is mediated exclusively by the tarsal segments of the legs and not the proboscis. This work establishes mosquito legs as the behaviorally relevant contact sensors of DEET. These results will inform the search for molecular mechanisms mediating DEET contact chemorepellency and novel contact-based insect repellents.