Drugs that mirror the cellular effects of starvation mimics are considered promising therapeutics for common metabolic disorders, such as obesity, liver steatosis, and for ageing. Starvation, or caloric restriction, is known to activate the transcription factor EB (TFEB), a master regulator of lipid metabolism and lysosomal biogenesis and function. Here, we report a nanotechnology-enabled high-throughput screen to identify small-molecule agonists of TFEB and discover three novel compounds that promote autophagolysosomal activity. The three lead compounds include the clinically approved drug, digoxin; the marine-derived natural product, ikarugamycin; and the synthetic compound, alexidine dihydrochloride, which is known to act on a mitochondrial target. Mode of action studies reveal that these compounds activate TFEB via three distinct Ca2+-dependent mechanisms. Formulation of these compounds in liver-tropic biodegradable, biocompatible nanoparticles confers hepatoprotection against diet-induced steatosis in murine models and extends lifespan of Caenorhabditis elegans. These results support the therapeutic potential of small-molecule TFEB activators for the treatment of metabolic and age-related disorders.

We study the ground-state phase diagram of two-component fermions loaded in a ladder-like lattice at half filling in the presence of spin-orbit coupling. For repulsive fermions with unidirectional spin-orbit coupling along the legs we identify a Néel state which is separated from rung-singlet and ferromagnetic states by Ising phase transition lines. These lines cross for maximal spin-orbit coupling and a direct Gaussian phase transition between rung-singlet and ferro phases is realized. For the case of Rashba-like spin-orbit coupling, besides the rung singlet phases two distinct striped ferromagnetic phases are formed. In case of attractive fermions with spin-orbit coupling at half-filling for decoupled chains we identify a dimerized state that separates a singlet superconductor and a ferromagnetic states.

We investigate transient spin-dependent thermoelectric signatures in a single-molecule magnet under the effect of a time-dependent voltage pulse. We model the system using nonequilibrium Green's functions and a generalized spin equation of motion incorporating the dynamic electronic structure of the molecule. We show that the generated heat current in the system is due to both charge and spin contributions, related to the Peltier and the spin-dependent Peltier effect. There is also a clear signature in the heat current due to the spin dynamics of the single-molecule and a possibility to control the spin-dependent heat currents by bias, tunneling coupling and exchange interaction. A reversal of the net heat transfer in the molecule is found for increasing bias voltage due to the local Zeeman split and we can correlate the net heat transfer with the local anisotropies and dynamic exchange fields in the system.

Under the influence of an external magnetic field and spin-changing collisions, the band insulator state of one-dimensional s-wave repulsively interacting four-component fermions at half-filling transforms into Mott insulator states with a spontaneously doubled unit cell: a dimerized state for shallow lattices and a Néel state for deep lattices via an intermediate topological state. These Mott insulator phases could be of special interest for experiments as they can be reached starting from band insulator state and changing magnetic field adiabatically. [3,4]. At sufficiently low temperatures the MI phase should acquire a magnetic Néel (antiferromagnetic) ordering. Still it has not been resolved [5]; the main obstacle is the absence of efficient cooling methods in the presence of an optical lattice [6].By increasing the number of components above two, an interesting possibility of hosting exotic ground states like 2D spin liquids [7,8] or 1D topological states [9,10] emerges. A novel ingredient in multicomponent alkali-metal gases, different from the two-component case, is the presence of spin-changing collisions: two interacting atoms cannot only exchange their initial internal hyperfine states, but they can also change them to new values. The spin-changing collisions open a fascinating prospect to arrive at unconventional MI ground states of multicomponent Fermi gases starting from the band insulator (BI) state made of only two components having vanishing entropy per particle. For fermions due to the Pauli principle the minimal number of components required for BI to MI transformation is four.In this work we present the ground-state phases of fourcomponent alkali-metal fermions at half-filling obtained by nonperturbative analytical and numerical tools, particularly tailored for studying 1D systems. We identify various MI phases: Dimer and Néel states spontaneously break discrete lattice translational symmetry and are characterized by doubly degenerate ground state in thermodynamic limit and local order parameters; whereas singlet and a topological Haldane phase do not break any microscopic symmetry and are characterized by unique ground state and nonlocal parity and string orders, respectively. Even though these different MI phases are manifested below the ultralow temperatures, typical to the superexchange scale, the fact that one can start from the BI state and by adiabatically changing the magnetic field enter into these nontrivial states, makes the system of half-filled four-component alkali-metal fermions a particularly attractive candidate to resolve ground-state spin order in experiments on ultracold lattice gases. Note that the spin-changing collision processes, crucial for BI to MI transformations, are maximally pronounced at half-filling.Our main result, the ground-state phase diagram of four components of 40 K atoms, is presented in Fig. 1. Most importantly all states can be explored just by changing the lattice depth and strength of the external magnetic field without the need to modify the natura...

In the embryo development problem for the Drosophila melanogaster, a set of molecules known as mor-phogens are responsible for the embryo segmentation. These morphogens are encoded by different genes, including the GAP genes, maternal coordination genes and pair-rule genes. One of the maternal coordination genes encodes the Bicoid morphogen, which is the responsible for the development of the Drosophila embryo at the anterior part and for the control and regulation of the GAP genes in segmentation of the early development of the Drosophila melanogaster. The work presented in this document, reports a methodology that tends to integrate mechanistic and data driven based models, aiming at making inference over the mRNA Bicoid from gene expression data at the protein level for the Bicoid morphogen. The fundamental contribution of this work is the description of the concentration gradient of the Bicoid morphogen in the continuous spatio-temporal domain as well as the output regression (gene expression at protein level) using a Gaussian process described by a mechanistically inspired covariance function. Regression results and metrics computed for the Bicoid protein expression both in the temporal and spatial domains, showed outstanding performance with respect to reported experiments from previous studies. In this paper, a correlation coefficient of r = 0.9758 against a correlation coefficient of r = 0.9086 is being reported, as well as a SMSE of 0.0303±0.1512 against a SMSE of 0.1106±0.5090 and finally reporting a MSLL of -1.7036 ± 1.3472 against -1.0151±1.7669.