1,475 Projects, page 1 of 295
Sleep is vital and universal, but its biological function remains unknown. This project will seek to understand why we need to sleep by studying how the brain responds to sleep loss. My previous work in Drosophila showed that rising sleep pressure activates two dozen sleep-inducing neurons in the dorsal fan-shaped body (dFB) of the central complex. Sleep need is encoded in the electrical excitability of these neurons, which fluctuates because two potassium conductances, voltage-gated Shaker and the leak channel Sandman, are modulated antagonistically. As a consequence, dFB neurons are electrically silent during waking and persistently active during sleep. The key open question addressed in this project is the nature of the molecular changes that drive dFB neurons into the electrically active state. My preliminary data point to two dFB-intrinsic transducers of sleep pressure. First, the Shaker β subunit Hyperkinetic responds via a bound nicotinamide cofactor to oxidative by-products of mitochondrial electron transport, revealing a potential connection between energy metabolism, oxidative stress, and sleep, three processes implicated independently in lifespan, aging, and disease. To strengthen this connection, we will monitor sleep and the biophysics of dFB neurons after perturbing mitochondrial respiration or cellular redox chemistry and vice versa. Second, Rho GTPases relay currently unknown signals to the machinery responsible for the regulated endocytosis of Sandman, whose extraction from the plasma membrane is a prerequisite for switching the sleep-promoting activity of dFB neurons on. To identify these signals, we will investigate cell-autonomous, synaptic, and non-synaptic mechanisms of GTPase control. Because clear parallels exist between dFB neurons and sleep-active neurons in the mammalian hypothalamus, mechanistic insights that can currently be gained only in Drosophila are expected to have broad validity for understanding sleep and its disruptions.
Driven by public outrage at bank bailouts during the financial crisis, many governments have since then tried to rewrite the rules governing finance. Yet the anger provoked by the bailouts has not subsided. In Europe and in North America, citizen fury against bankers continues to structure battles over financial regulation. It also affects broader perceptions of fairness in the political system and feeds anti-elite populism. Scholars of political economy have chronicled the clashes between states and large banks, and scholars of political behaviour have noted the failings of governments to respond to the will of democratic majorities. No one has explored the feedback loops between policies regulating banks, the public anger towards banking elites, and media discussions of finance. BANK-LASH fills this gap, using a cutting-edge, high-risk research design comprising three work packages to link policy outcomes with public opinion and media coverage. BANK-LASH 1will collect the first cross-nationally comparable data on public attitudes towards finance, including a series of innovative survey experiments that assess how different media frames affect emotions and preferences. BANK-LASH 2 will use supervised machine learning to measure the overall media environment of these countries for the last decade, assessing how much different national media systems discuss finance and how different national media systems frame the discussion of banking regulation. BANK-LASH 3 links the micro-level study of attitudes and macro-level media coverage with episodes of policy intervention in each country in order to determine when democracies have imposed significant new regulation on their banks. By harnessing these different intellectual tools within a single study, BANK-LASH brings together the concerns of political economy, behavioral research and policy studies to untangle the relationship between banks, public policy, and anti-elite sentiment in the wake of the financial crisis.
Despite intense research activity, most new superconductors are discovered by chance, rather than by deliberate design. Consequently, they have limited tunability, which has plagued progress towards a room-temperature demonstration. In particular, electron interactions are extremely challenging to tune, but are assumed to be vital in most high-temperature superconductors. Here I introduce a new paradigm for the bottom-up fabrication of custom-designed superconductors, called interacting quantum metamaterials. These metamaterials are precisely constructed, one atom at a time, using a scanning tunneling microscope. They inherit tunable, strong electron interactions from their unique substrate: a topological Kondo insulator (TKI). A TKI substrate neatly overcomes the two impediments for interacting quantum metamaterials: it hosts quasiparticles that move slow enough to interact with one another, and it is a true topological bulk insulator, which electrically confines these quasiparticles to the surface, where they are easily accessed and manipulated. By rearranging surface atoms, I will create metamaterial geometries that localize these novel TKI surface quasiparticles in order to mimic the parent state of many high-temperature superconductors, a Mott-like insulator. Then, I will adjust the electron concentration by tip-induced electrostatic gating and behold the onset of superconductivity in a fully tunable experimental platform. These results will open a new path to room-temperature superconductors, leading to highly efficient power transmission and storage, which can reduce CO2 emissions and slow climate change.
Blood vessels form a versatile transport network and provide inductive signals called angiocrine factors to regulate tissue-specific functions. Blood vessels in bone are heterogeneous with distinct capillary subtypes that exhibit remarkable alterations with age. Bone is the most prevalent site of metastasis, and ageing is linked to the reactivation of dormant tumor cells (dorTCs) and metastatic relapse. Bone remodeling processes are also associated with metastatic relapse. Here, I will define the role of distinct vascular niches in regulating the fate of DTCs in bone. Finally, I will unravel the age-related angiocrine factors and identify key angiocrine signals that drive the reactivation of dorTCs. I will employ a powerful combination of advanced 3D, intravital, and whole body imaging, cell specific-inducible mouse genetics, transcriptional profiling and bioinformatics in an unprecedented manner to achieve my goals. New cutting-edge techniques such as advanced 3D and 4D bone imaging are important aspects of my proposal. I will also define the role of highly promising novel candidate age-related angiocrine signals with sophisticated inducible endothelial-specific humanised mouse models. My work will break new ground by unraveling a repertoire of age-related angiocrine factors and will contribute to a wider scientific community in bone, blood, and age-related diseases. This interdisciplinary work at the frontiers of bone, cancer and vascular biology will provide the first conceptual link between vascular ageing and bone metastasis and will contribute towards the development of therapeutic strategies for targeting DTCs in bone.