Wardsinclair5697

Our work opens up the opportunity to study the interaction between two well-known localization-delocalization mechanisms in correlation physics, i.e., Kondo vs Mott, which can be important for a fundamental understanding of 4f-electron systems.Survival depends on a balance between seeking rewards and avoiding potential threats, but the neural circuits that regulate this motivational conflict remain largely unknown. Using an approach-food vs. avoid-predator threat conflict test in rats, we identified a subpopulation of neurons in the anterior portion of the paraventricular thalamic nucleus (aPVT) which express corticotrophin-releasing factor (CRF) and are preferentially recruited during conflict. Inactivation of aPVTCRF neurons during conflict biases animal's response toward food, whereas activation of these cells recapitulates the food-seeking suppression observed during conflict. aPVTCRF neurons project densely to the nucleus accumbens (NAc), and activity in this pathway reduces food seeking and increases avoidance. In addition, we identified the ventromedial hypothalamus (VMH) as a critical input to aPVTCRF neurons, and demonstrated that VMH-aPVT neurons mediate defensive behaviors exclusively during conflict. Together, our findings describe a hypothalamic-thalamostriatal circuit that suppresses reward-seeking behavior under the competing demands of avoiding threats.Autologous epidermal cultures restore a functional epidermis on burned patients. Transgenic epidermal grafts do so also in genetic skin diseases such as Junctional Epidermolysis Bullosa. Clinical success strictly requires an adequate number of epidermal stem cells, detected as holoclone-forming cells, which can be only partially distinguished from the other clonogenic keratinocytes and cannot be prospectively isolated. Here we report that single-cell transcriptome analysis of primary human epidermal cultures identifies categories of genes clearly distinguishing the different keratinocyte clonal types, which are hierarchically organized along a continuous, mainly linear trajectory showing that stem cells sequentially generate progenitors producing terminally differentiated cells. Holoclone-forming cells display stem cell hallmarks as genes regulating DNA repair, chromosome segregation, spindle organization and telomerase activity. Finally, we identify FOXM1 as a YAP-dependent key regulator of epidermal stem cells. These findings improve criteria for measuring stem cells in epidermal cultures, which is an essential feature of the graft.Catalytic kinetic resolution of amines represents a longstanding challenge in chemical synthesis. Here, we described a kinetic resolution of secondary amines through oxygenation to produce enantiopure hydroxylamines involving N-O bond formation. The economic and practical titanium-catalyzed asymmetric oxygenation with environmentally benign hydrogen peroxide as oxidant is applicable to a range of racemic indolines with multiple stereocenters and diverse substituent patterns in high efficiency with efficient chemoselectivity and enantio-discrimination. Late-stage asymmetric oxygenation of bioactive molecules that are otherwise difficult to synthesize was also explored.Haematopoietic stem cells (HSCs) tightly regulate their quiescence, proliferation, and differentiation to generate blood cells during the entire lifetime. The mechanisms by which these critical activities are balanced are still unclear. Here, we report that Macrophage-Erythroblast Attacher (MAEA, also known as EMP), a receptor thus far only identified in erythroblastic island, is a membrane-associated E3 ubiquitin ligase subunit essential for HSC maintenance and lymphoid potential. Maea is highly expressed in HSCs and its deletion in mice severely impairs HSC quiescence and leads to a lethal myeloproliferative syndrome. Mechanistically, we have found that the surface expression of several haematopoietic cytokine receptors (e.g. MPL, FLT3) is stabilised in the absence of Maea, thereby prolonging their intracellular signalling. This is associated with impaired autophagy flux in HSCs but not in mature haematopoietic cells. Administration of receptor kinase inhibitor or autophagy-inducing compounds rescues the functional defects of Maea-deficient HSCs. Our results suggest that MAEA provides E3 ubiquitin ligase activity, guarding HSC function by restricting cytokine receptor signalling via autophagy.The discovery of interaction-driven insulating and superconducting phases in moiré van der Waals heterostructures has sparked considerable interest in understanding the novel correlated physics of these systems. While a significant number of studies have focused on twisted bilayer graphene, correlated insulating states and a superconductivity-like transition up to 12 K have been reported in recent transport measurements of twisted double bilayer graphene. Here we present a scanning tunneling microscopy and spectroscopy study of gate-tunable twisted double bilayer graphene devices. We observe splitting of the van Hove singularity peak by ~20 meV at half-filling of the conduction flat band, with a corresponding reduction of the local density of states at the Fermi level. By mapping the tunneling differential conductance we show that this correlated system exhibits energetically split states that are spatially delocalized throughout the different regions in the moiré unit cell, inconsistent with order originating solely from onsite Coulomb repulsion within strongly-localized orbitals. We have performed self-consistent Hartree-Fock calculations that suggest exchange-driven spontaneous symmetry breaking in the degenerate conduction flat band is the origin of the observed correlated state. Our results provide new insight into the nature of electron-electron interactions in twisted double bilayer graphene and related moiré systems.The lysosomal degradation pathway of macroautophagy (herein referred to as autophagy) plays a crucial role in cellular physiology by regulating the removal of unwanted cargoes such as protein aggregates and damaged organelles. Over the last five decades, significant progress has been made in understanding the molecular mechanisms that regulate autophagy and its roles in human physiology and diseases. These advances, together with discoveries in human genetics linking autophagy-related gene mutations to specific diseases, provide a better understanding of the mechanisms by which autophagy-dependent pathways can be potentially targeted for treating human diseases. Lusutrombopag order Here, we review mutations that have been identified in genes involved in autophagy and their associations with neurodegenerative diseases.