Why Party Democrats Need Popular Democracy and Popular Democrats Need Parties

Too often, popular political power-whether it is in the form of direct democracy or other more innovative forays in participatory or deliberative democracy-presents itself principally as a counterweight to the political power parties wield. Yet setting up popular democracy and \u27 party democracy in opposition to one another in the American political landscape is not only unnecessary but also pathological: this oppositional posture risks the ossification of party democracy and keeps popular democrats insulated from the substantial improvements the power of parties could bring to the polity. This Article, accordingly, seeks to enrich both party democracy and popular democracy by showing how each might draw strengths from the other, and how each needs the other to function more effectively. A new literature in political theory explores the central role of partisanship in democratic functioning, and we will deploy that theory in service of some practical applications in institutional design here. We have been involved-on the ground level-in two recent policy conversations that really would have been improved with a complementary vision of the parties and the people. We could have better exercises of party democracy and popular democracy, if only we started to see how they might be brought into pragmatic symbiosis

Proteomics of Primary Cilia by Proximity Labeling.

While cilia are recognized as important signaling organelles, the extent of ciliary functions remains unknown because of difficulties in cataloguing proteins from mammalian primary cilia. We present a method that readily captures rapid snapshots of the ciliary proteome by selectively biotinylating ciliary proteins using a cilia-targeted proximity labeling enzyme (cilia-APEX). Besides identifying known ciliary proteins, cilia-APEX uncovered several ciliary signaling molecules. The kinases PKA, AMPK, and LKB1 were validated as bona fide ciliary proteins and PKA was found to regulate Hedgehog signaling in primary cilia. Furthermore, proteomics profiling of Ift27/Bbs19 mutant cilia correctly detected BBSome accumulation inside Ift27(-/-) cilia and revealed that β-arrestin 2 and the viral receptor CAR are candidate cargoes of the BBSome. This work demonstrates that proximity labeling can be applied to proteomics of non-membrane-enclosed organelles and suggests that proteomics profiling of cilia will enable a rapid and powerful characterization of ciliopathies

Proteomics of Primary Cilia by Proximity Labeling.

While cilia are recognized as important signaling organelles, the extent of ciliary functions remains unknown because of difficulties in cataloguing proteins from mammalian primary cilia. We present a method that readily captures rapid snapshots of the ciliary proteome by selectively biotinylating ciliary proteins using a cilia-targeted proximity labeling enzyme (cilia-APEX). Besides identifying known ciliary proteins, cilia-APEX uncovered several ciliary signaling molecules. The kinases PKA, AMPK, and LKB1 were validated as bona fide ciliary proteins and PKA was found to regulate Hedgehog signaling in primary cilia. Furthermore, proteomics profiling of Ift27/Bbs19 mutant cilia correctly detected BBSome accumulation inside Ift27(-/-) cilia and revealed that β-arrestin 2 and the viral receptor CAR are candidate cargoes of the BBSome. This work demonstrates that proximity labeling can be applied to proteomics of non-membrane-enclosed organelles and suggests that proteomics profiling of cilia will enable a rapid and powerful characterization of ciliopathies

The Forebrain Thirst Circuit Drives Drinking through Negative Reinforcement

The brain transforms the need for water into the desire to drink, but how this transformation is performed remains unknown. Here we describe the motivational mechanism by which the forebrain thirst circuit drives drinking. We show that thirst-promoting subfornical organ neurons are negatively reinforcing and that this negative-valence signal is transmitted along projections to the organum vasculosum of the lamina terminalis (OVLT) and median preoptic nucleus (MnPO). We then identify molecularly defined cell types within the OVLT and MnPO that are activated by fluid imbalance and show that stimulation of these neurons is sufficient to drive drinking, cardiovascular responses, and negative reinforcement. Finally, we demonstrate that the thirst signal exits these regions through at least three parallel pathways and show that these projections dissociate the cardiovascular and behavioral responses to fluid imbalance. These findings reveal a distributed thirst circuit that motivates drinking by the common mechanism of drive reduction

Thirst neurons anticipate the homeostatic consequences of eating and drinking

Thirst motivates animals to drink in order to maintain fluid balance. Traditionally, thirst has been viewed as a homeostatic response to changes in the blood volume or tonicity(1–3). However, most drinking behavior is regulated too rapidly to be controlled by blood composition directly and instead appears to anticipate homeostatic imbalances before they arise(4–11). How this is achieved remains unknown. Here we reveal an unexpected role for the subfornical organ (SFO) in the anticipatory regulation of thirst. We show by monitoring deep-brain calcium dynamics that thirst-promoting SFO neurons respond to inputs from the oral cavity during eating and drinking, which they then integrate with information about the composition of the blood. This integration allows SFO neurons to predict how ongoing food and water consumption will alter fluid balance in the future and then adjust behavior preemptively. Complementary optogenetic manipulations show that this anticipatory modulation is necessary for drinking in multiple contexts. These findings provide a neural mechanism to explain longstanding behavioral observations, including the prevalence of drinking during meals(10,11), the rapid satiation of thirst(7–9), and the fact that oral cooling is thirst-quenching(12–14)