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1.
Neuron ; 104(3): 544-558.e6, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31471123

RESUMO

In pursuit of food, hungry animals mobilize significant energy resources and overcome exhaustion and fear. How need and motivation control the decision to continue or change behavior is not understood. Using a single fly treadmill, we show that hungry flies persistently track a food odor and increase their effort over repeated trials in the absence of reward suggesting that need dominates negative experience. We further show that odor tracking is regulated by two mushroom body output neurons (MBONs) connecting the MB to the lateral horn. These MBONs, together with dopaminergic neurons and Dop1R2 signaling, control behavioral persistence. Conversely, an octopaminergic neuron, VPM4, which directly innervates one of the MBONs, acts as a brake on odor tracking by connecting feeding and olfaction. Together, our data suggest a function for the MB in internal state-dependent expression of behavior that can be suppressed by external inputs conveying a competing behavioral drive.


Assuntos
Comportamento Apetitivo/fisiologia , Dopamina/metabolismo , Motivação , Corpos Pedunculados/metabolismo , Neurônios/metabolismo , Octopamina/metabolismo , Animais , Comportamento Animal , Neurônios Dopaminérgicos/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Alimentos , Fome , Corpos Pedunculados/citologia , Corpos Pedunculados/fisiologia , Vias Neurais/fisiologia , Odorantes , Receptores de Dopamina D1/metabolismo , Recompensa , Olfato
2.
Thromb Haemost ; 119(4): 633-644, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30699446

RESUMO

BACKGROUND AND OBJECTIVES: The Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial reported that pharmacomechanical catheter-directed thrombolysis (PCDT) did not reduce post-thrombotic syndrome (PTS), but reduced moderate-to-severe PTS and the severity of PTS symptoms. In this analysis, we examine the effect of PCDT in patients with femoral-popliteal deep vein thrombosis (DVT) (without involvement of more proximal veins). PATIENTS AND METHODS: Within the ATTRACT trial, 300 patients had DVT involving the femoral vein without involvement of the common femoral or iliac veins and were randomized to receive PCDT with anticoagulation or anticoagulation alone (no PCDT). Patients were followed for 24 months. RESULTS: From 6 to 24 months, between the PCDT versus no PCDT arms, there was: no difference in any PTS (Villalta scale ≥ 5: risk ratio [RR] = 0.97; 95% confidence interval [CI], 0.75-1.24); moderate-or-severe PTS (Villalta scale ≥ 10: RR = 0.93; 95% CI, 0.57-1.52); severity of PTS scores; or general or disease-specific quality of life (p > 0.5 for all comparisons). From baseline to both 10 and 30 days, there was no difference in improvement of leg pain or swelling between treatment arms. From baseline to 10 days, major bleeding occurred in three versus none (p = 0.06) and any bleeding occurred in eight versus two (p = 0.032) PCDT versus no PCDT patients. Over 24 months, recurrent venous thromboembolism occurred in 16 PCDT and 12 no PCDT patients (p = 0.24). CONCLUSION: In patients with femoral-popliteal DVT, PCDT did not improve short- or long-term efficacy outcomes, but it increased bleeding. Therefore, PCDT should not be used as initial treatment of femoral-popliteal DVT. (NCT00790335).


Assuntos
Veia Femoral/fisiopatologia , Veia Poplítea/fisiopatologia , Terapia Trombolítica/métodos , Trombose Venosa/terapia , Adolescente , Adulto , Idoso , Anticoagulantes/uso terapêutico , Cateterismo , Cateterismo Periférico , Feminino , Fibrinólise , Fibrinolíticos/uso terapêutico , Hemorragia/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Síndrome Pós-Trombótica/prevenção & controle , Qualidade de Vida , Meias de Compressão , Tromboembolia , Pesquisa Translacional Biomédica , Resultado do Tratamento , Adulto Jovem
3.
Curr Biol ; 25(17): 2203-14, 2015 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-26299514

RESUMO

Animals continuously evaluate sensory information to decide on their next action. Different sensory cues, however, often demand opposing behavioral responses. How does the brain process conflicting sensory information during decision making? Here, we show that flies use neural substrates attributed to odor learning and memory, including the mushroom body (MB), for immediate sensory integration and modulation of innate behavior. Drosophila melanogaster must integrate contradictory sensory information during feeding on fermenting fruit that releases both food odor and the innately aversive odor CO2. Here, using this framework, we examine the neural basis for this integration. We have identified a local circuit consisting of specific glutamatergic output and PAM dopaminergic input neurons with overlapping innervation in the MB-ß'2 lobe region, which integrates food odor and suppresses innate avoidance. Activation of food odor-responsive dopaminergic neurons reduces innate avoidance mediated by CO2-responsive MB output neurons. We hypothesize that the MB, in addition to its long recognized role in learning and memory, serves as the insect's brain center for immediate sensory integration during instantaneous decision making.


Assuntos
Dióxido de Carbono/metabolismo , Drosophila melanogaster/fisiologia , Corpos Pedunculados/fisiologia , Odorantes , Percepção Olfatória , Animais , Neurônios Dopaminérgicos/fisiologia , Feminino , Aprendizagem , Memória
4.
J Biol Chem ; 286(37): 32628-37, 2011 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-21775430

RESUMO

The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand cross-links. At the heart of this pathway is the monoubiquitination of the FANCI-FANCD2 (ID) complex by the multiprotein "core complex" containing the E3 ubiquitin ligase FANCL. Vertebrate organisms have the eight-protein core complex, whereas invertebrates apparently do not. We report here the structure of the central domain of human FANCL in comparison with the recently solved Drosophila melanogaster FANCL. Our data represent the first structural detail into the catalytic core of the human system and reveal that the central fold of FANCL is conserved between species. However, there are macromolecular differences between the FANCL proteins that may account for the apparent distinctions in core complex requirements between the vertebrate and invertebrate FA pathways. In addition, we characterize the binding of human FANCL with its partners, Ube2t, FANCD2, and FANCI. Mutational analysis reveals which residues are required for substrate binding, and we also show the domain required for E2 binding.


Assuntos
Proteína do Grupo de Complementação L da Anemia de Fanconi/química , Anemia de Fanconi/enzimologia , Dobramento de Proteína , Animais , Drosophila melanogaster , Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/química , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Proteína do Grupo de Complementação L da Anemia de Fanconi/genética , Proteína do Grupo de Complementação L da Anemia de Fanconi/metabolismo , Humanos , Mutação , Mapeamento de Peptídeos , Ligação Proteica , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Enzimas de Conjugação de Ubiquitina/química , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo
5.
Biochemistry ; 50(12): 2061-71, 2011 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-21288003

RESUMO

Amyloid-like fibrous crystals formed by the peptide KFFEAAAKKFFE have been previously characterized and provide an ideal model system to examine the importance of specific interactions by introducing specific substitutions. We find that the removal of any phenylalanine residue completely abrogates assembly ability, while charged residues modulate interactions within the structure resulting in alternative fibrillar morphologies. X-ray fiber diffraction analysis reveals that the essential backbone packing of the peptide molecules is maintained, while small changes accommodate differences in side chain size in the variants. We conclude that even very short peptides are adaptable and add to the growing knowledge regarding amyloid polymorphisms. Additionally, this work impacts on our understanding of the importance of residue composition for amyloidogenic peptides, in particular the roles of electrostatic, aromatic, and hydrophobic interactions in amyloid assembly.


Assuntos
Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Multimerização Proteica , Eletricidade Estática , Sequência de Aminoácidos , Modelos Moleculares , Fenilalanina , Estabilidade Proteica , Estrutura Secundária de Proteína
6.
Nat Struct Mol Biol ; 17(3): 294-8, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20154706

RESUMO

The Fanconi anemia (FA) pathway is activated in response to DNA damage, leading to monoubiquitination of the substrates FANCI and FANCD2 by the FA core complex. Here we report the crystal structure of FANCL, the catalytic subunit of the FA core complex, at 3.2 A. The structure reveals an architecture fundamentally different from previous sequence-based predictions. The molecule is composed of an N-terminal E2-like fold, which we term the ELF domain, a novel double-RWD (DRWD) domain, and a C-terminal really interesting new gene (RING) domain predicted to facilitate E2 binding. Binding assays show that the DRWD domain, but not the ELF domain, is responsible for substrate binding.


Assuntos
Proteína do Grupo de Complementação L da Anemia de Fanconi/química , Proteína do Grupo de Complementação L da Anemia de Fanconi/metabolismo , Animais , Domínio Catalítico , Cristalografia por Raios X , Drosophila melanogaster/metabolismo , Proteínas de Grupos de Complementação da Anemia de Fanconi/química , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína
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