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Monoacylglycerol lipase (MAGL) is one of the key enzymes in the endocannabinoid system. Inhibition of MAGL has been proposed as an attractive approach for the treatment of various diseases. In this study, we designed and successfully synthesized two series of piperazinyl pyrrolidin-2-one derivatives as novel reversible MAGL inhibitors. (

In the field of Dirac materials, spin-orbit coupling (SOC) is usually considered disruptive, since it may lift degeneracies that are not protected by high-symmetry elements. Nonsymmorphic symmetries force degenerate points in the band structure at high-symmetry points that are not disrupted by SOC. The degeneracy is, however, often protected along whole high-symmetry lines or faces resulting in highly anisotropic crossings or nodal lines, which can considerably limit the region, in which the bands are linearly dispersed. It has been theoretically suggested that SOC could circumvent this problem. Here, we show experimentally that SOC can lift the extended protection in nonsymmorphic square-net compounds. We compare ZrSiS and CeSbTe , two materials with drastically different SOC, to show the effect of SOC on the band structure by means of angle-resolved photoemission spectroscopy and density functional theory calculations.

Genetic, preclinical and clinical data link Parkinson's disease and Gaucher's disease and provide a rational entry point to disease modification therapy via enhancement of β-Glucocerebrosidase (GCase) activity. We discovered a new class of pyrrolo[2,3-b]pyrazine activators effecting both Vmax and Km. They bind to human GCase and increase substrate metabolism in the lysosome in a cellular assay. We obtained the first crystal structure for an activator and identified a novel non-inhibitory binding mode at the interface of a dimer, rationalizing the observed structure-activity relationship (SAR). The compound binds GCase inducing formation of a dimeric state at both endoplasmic reticulum (ER) and lysosomal pHs, as confirmed by analytical ultracentrifugation. Importantly, the pyrrolo[2,3-b]pyrazines have central nervous system (CNS) drug-like properties. Our findings are important for future drug discovery efforts in the field of GCase activation and provide a deeper mechanistic understanding of the requirements for enzymatic activation, pointing to the relevance of dimerization.

Principles that predict reactions or properties of materials define the discipline of chemistry. In this work we derive chemical rules, based on atomic distances and chemical bond character, which predict topological materials in compounds that feature the structural motif of a square-net. Using these rules we identify over 300 potential new topological materials. We show that simple chemical heuristics can be a powerful tool to characterize topological matter. In contrast to previous database-driven materials categorization our approach allows us to identify candidates that are alloys, solid-solutions, or compounds with statistical vacancies. While previous material searches relied on density functional theory, our approach is not limited by this method and could also be used to discover magnetic and statistically-disordered topological semimetals., Comment: 30 pages, 8 figures

We introduce a van der Waals material that exhibits a very high electronic mobility and antiferromagnetism and can be exfoliated., Van der Waals (vdW) materials with magnetic order have been heavily pursued for fundamental physics as well as for device design. Despite the rapid advances, so far, they are mainly insulating or semiconducting, and none of them has a high electronic mobility—a property that is rare in layered vdW materials in general. The realization of a high-mobility vdW material that also exhibits magnetic order would open the possibility for novel magnetic twistronic or spintronic devices. Here, we report very high carrier mobility in the layered vdW antiferromagnet GdTe3. The electron mobility is beyond 60,000 cm2 V−1 s−1, which is the highest among all known layered magnetic materials, to the best of our knowledge. Among all known vdW materials, the mobility of bulk GdTe3 is comparable to that of black phosphorus. By mechanical exfoliation, we further demonstrate that GdTe3 can be exfoliated to ultrathin flakes of three monolayers.

Transition-metal chalcogenides are a promising family of materials for applications as photocathodes in photoelectrochemical (PEC) H2 generation. A long-standing challenge for chalcopyrite semiconductors is characterizing their electronic structure, both experimentally and theoretically, because of their relatively high-energy band gaps and spin-orbit coupling (SOC), respectively. In this work, we present single crystals of CuInTe2, whose relatively small optically measured band gap of 0.9 ± 0.03 eV enables electronic structure characterization by angle-resolved photoelectron spectroscopy (ARPES) in conjunction with first-principles calculations incorporating SOC. ARPES measurements reveal bands that are steeply dispersed in energy with a band velocity of 2.5-5.4 × 105 m/s, almost 50% of the extremely conductive material graphene. Additionally, CuInTe2 single crystals are fabricated into electrodes to experimentally determine the valence band edge energy and confirm the thermodynamic suitability of CuInTe2 for water redox chemistry. The electronic structure characterization and band edge position presented in this work provide kinetic and thermodynamic factors that support CuInTe2 as a strong candidate for water reduction.

We study the electronic structure of the nodal line semimetal ZrSiTe both experimentally and theoretically. We find two different surface states in ZrSiTe—topological drumhead surface states and trivial floating band surface states, which can be easily distinguished in ARPES experiments. Using the spectra of Wilson loops, we show that a nontrivial Berry phase that exists in a confined region within the Brillouin zone gives rise to the topological drumhead-type surface states. The Z_{2} structure of the Berry phase induces a Z_{2} “modular arithmetic” of the surface states, allowing surface states derived from different nodal lines to hybridize and gap out, which can be probed by a set of Wilson loops. Our findings are confirmed by ab initio calculations and angle-resolved photoemission experiments, which are in excellent agreement with each other and the topological analysis. This work is the first complete characterization of topological surface states in the family of square-net-based nodal line semimetals, and thus it fundamentally increases the understanding of the topological nature of this growing class of topological semimetals.

New developments in the field of topological matter are often driven by materials discovery, including novel topological insulators, Dirac semimetals and Weyl semimetals. In the last few years, large efforts have been performed to classify all known inorganic materials with respect to their topology. Unfortunately, a large number of topological materials suffer from non-ideal band structures. For example, topological bands are frequently convoluted with trivial ones, and band structure features of interest can appear far below the Fermi level. This leaves just a handful of materials that are intensively studied. Finding strategies to design new topological materials is a solution. Here we introduce a new mechanism that is based on charge density waves and non-symmorphic symmetry to design an idealized Dirac semimetal. We then show experimentally that the antiferromagnetic compound GdSb$_{0.46}$Te$_{1.48}$ is a nearly ideal Dirac semimetal based on the proposed mechanism, meaning that most interfering bands at the Fermi level are suppressed. Its highly unusual transport behavior points to a thus far unknown regime, in which Dirac carriers with Fermi energy very close to the node seem to gradually localize in the presence of lattice and magnetic disorder.

By establishing magnetic order in a square lattice compound, we introduce the first magnetic “new fermion.”, Recent interest in topological semimetals has led to the proposal of many new topological phases that can be realized in real materials. Next to Dirac and Weyl systems, these include more exotic phases based on manifold band degeneracies in the bulk electronic structure. The exotic states in topological semimetals are usually protected by some sort of crystal symmetry, and the introduction of magnetic order can influence these states by breaking time-reversal symmetry. We show that we can realize a rich variety of different topological semimetal states in a single material, CeSbTe. This compound can exhibit different types of magnetic order that can be accessed easily by applying a small field. Therefore, it allows for tuning the electronic structure and can drive it through a manifold of topologically distinct phases, such as the first nonsymmorphic magnetic topological phase with an eightfold band crossing at a high-symmetry point. Our experimental results are backed by a full magnetic group theory analysis and ab initio calculations. This discovery introduces a realistic and promising platform for studying the interplay of magnetism and topology. We also show that we can generally expand the numbers of space groups that allow for high-order band degeneracies by introducing antiferromagnetic order.

In this chapter, we will start by introducing some basic concepts of solid-state chemistry and how they can help us identify new topological materials. We give a short overview of common crystal growth methods and the most significant characterization techniques available to identify topological properties. Finally, we summarize this knowledge in a step-by-step procedure that will guide us from the idea to a real compound. The aim of this chapter is to give physics students a guide for implementing simple chemical principles in their search for new topological materials, as well as giving a basic introduction to the steps necessary to experimentally verify the electronic structure of a material.

The human protease family HtrA is responsible for preventing protein misfolding and mislocalization, and a key player in several cellular processes. Among these, HtrA1 is implicated in several cancers, cerebrovascular disease and age-related macular degeneration. HtrA1 activation, although very relevant for drug-targeting this protease, remains poorly characterized. Our work provides a mechanistic step-by-step description of HtrA1 activation and regulation. We report that the HtrA1 trimer is regulated by an allosteric mechanism by which monomers relay the activation signal to each other, in a PDZ-domain independent fashion. Notably, we show that inhibitor binding is precluded if HtrA1 monomers cannot communicate with each other. Our study establishes how HtrA1 oligomerization plays a fundamental role in proteolytic activity. Moreover, it offers a structural explanation for HtrA1-defective pathologies as well as mechanistic insights into the degradation of complex extracellular fibrils such as tubulin, amyloid beta and tau that belong to the repertoire of HtrA1.HighlightsMonomeric HtrA1 is activated by a gating mechanism.Trimeric HtrA1 is regulated by PDZ-independent allosteric monomer cross-talk.HtrA1 oligomerization is key for proteolytic activity.Substrate-binding is precluded if monomers cannot communicate with each other.

Layered heavy-metal square-lattice compounds have recently emerged as potential Dirac fermion materials due to bonding within those sublattices. We report quantum transport and spectroscopic data on the layered Sb square-lattice material LaCuSb$_{2}$. Linearly dispersing band crossings, necessary to generate Dirac fermions, are experimentally observed in the electronic band structure observed using angle-resolved photoemission spectroscopy (ARPES), along with a quasi-two-dimensional Fermi surface. Weak antilocalization that arises from two-dimensional transport is observed in the magnetoresistance, as well as regions of linear dependence, both of which are indicative of topologically non-trivial effects. Measurements of the Shubnikov-de Haas (SdH) quantum oscillations show low effective mass electrons on the order of 0.065$m_{e}$, further confirming the presence of Dirac fermions in this material.

In this work, we present a model of the surface states of nonsymmorphic semimetals. These are derived from surface mass terms that lift the high degeneracy imposed in the band structure by the nonsymmorphic bulk symmetries. Reflecting the reduced symmetry at the surface, the bulk bands are strongly modified. This leads to the creation of two-dimensional floating bands, which are distinct from Shockley states, quantum well states or topologically protected surface states. We focus on the layered semimetal ZrSiS to clarify the origin of its surface states. We demonstrate an excellent agreement between DFT calculations and ARPES measurements and present an effective four-band model in which similar surface bands appear. Finally, we emphasize the role of the surface chemical potential by comparing the surface density of states in samples with and without potassium coating. Our findings can be extended to related compounds and generalized to other crystals with nonsymmorphic symmetries., Comment: 8 pages, 5 figures

Materials harbouring exotic quasiparticles, such as massless Dirac and Weyl fermions, have garnered much attention from physics and material science communities due to their exceptional physical properties such as ultra-high mobility and extremely large magnetoresistances. Here, we show that the highly stable, non-toxic and earth-abundant material, ZrSiS, has an electronic band structure that hosts several Dirac cones that form a Fermi surface with a diamond-shaped line of Dirac nodes. We also show that the square Si lattice in ZrSiS is an excellent template for realizing new types of two-dimensional Dirac cones recently predicted by Young and Kane. Finally, we find that the energy range of the linearly dispersed bands is as high as 2 eV above and below the Fermi level; much larger than of other known Dirac materials. This makes ZrSiS a very promising candidate to study Dirac electrons, as well as the properties of lines of Dirac nodes., The family of topological materials has been growing rapidly but most members bare limitations hindering the study of exotic behaviour of topological particles. Here, Schoop et al. report a Fermi surface with a diamond-shaped line of Dirac nodes in ZrSiS, providing a promising candidate for studying two-dimensional Dirac fermions.

Multiparallel and combinatorial syntheses have enabled chemists to produce a vast number of chemical compounds for hit- and lead-finding campaigns. For high-throughput screening (HTS), these compound collections are typically dissolved in dimethylsulfoxid (DMSO) and stored at temperatures ranging from —80 °C to room temperature (RT). Having compounds readily available as DMSO solutions greatly facilitates HTS. However, there are a number of stability and solubility issues associated with compounds stored as DMSO solutions.1–8 To ensure compound integrity for a long period of time, we have developed a simple dry compound storage concept called DotFoil, from where compounds can be redissolved in a fast, reliable, and easy way and directly used in conventional 96- or 384-well plate based HTS (1536-well format is not supported at this time). Our results indicate that compounds are more stable if stored as dry film on DotFoils, compared to storage as DMSO solutions at +4 °C or RT. Redissolving the dry film of ...

Solutions of the poly(propylene imine) dendrimers DAB-dendr-(PA)32 and DAB-dendr-(PA)64 in methanol are investigated with small angle neutron scattering over the range of dendrimer mass fraction 0....

Small-angle neutron scattering was used to measure the size and shape of arborescent graft polymers as a function of generation in solution. The radius of gyration of arborescent graft polymers was found to be almost independent of temperature in both deuterated cyclohexane (above the cloud point) and deuterated toluene. For dilute deuterated cyclohexane solutions the optically measured cloud point was found to be 15 ± 1 °C. Two peaks were observed in the SANS data for the phase-separated (below the cloud point) deuterated cyclohexane solutions of the largest polymers (generation 3). The first peak (at smaller scattering vector) is attributed to the interference between molecules while the second peak arises from the single particle form factor which was also observed at temperatures above the cloud point. In deuterated cyclohexane the position of the form factor peak was constant at temperatures above 15 °C. In the phase-separated deuterated cyclohexane solutions the form factor peak shifted to higher q,...

The spatial distribution of the terminal groups of poly(amido amine) dendrimers have been determined experimentally by small-angle neutron scattering with deuterium labeling and scattering contrast variation. The radius of gyration of deuterated terminal units of generation 7 dendrimers is 39.3 ± 1.0 A. This is significantly larger than the radius of gyration of the whole dendrimer, which is 34.4 ± 0.2 A. These data indicate that dendrimers have terminal groups that are concentrated near the periphery. These results are inconsistent with many computer simulations and some molecular models.

The average dimensions of poly(amido amine) (PAMAM) dendrimers of generations G5 and G8 are studied by small-angle neutron scattering (SANS) as a function of solvents of differing quality, the composition of mixtures of a good solvent and a nonsolvent, and temperature. The radius of gyration, Rg, of the G8 dendrimer decreases for the series of solvents D(CD2)mOD (with m = 0, 1, 2, 4) by approximately 10% from m = 0 to m = 4 with decreasing solvent quality. The average segment density in solution is calculated for G5 and G8. The size of PAMAM dendrimers, as reflected by Rg, is not influenced by the composition of mixtures of methyl alcohol/acetone in the full range of solubility of the dendrimers. In the temperature range −10 °C ≤ T ≤ 50 °C, the dimensions of the G8 and G5 dendrimer are constant, within ≈5% of each other.

Cholangiocarcinoma (CC), the most common biliary tract malignancy, is frequently seen in advanced unresectable stages and is typically localized extrahepatically. Early diagnosis is unusual because of nonspecific symptoms. Painless jaundice is usually the first sign of tumor.We present a patient with a CC (Klatskin tumor) with a complete biliary drainage by an aberrant bile duct without jaundice.A 67-year-old woman presented with persisting elevation of liver parameters. Diagnostic tests showed a Klatskin tumor type II. A curative right hepatic trisegmentectomy was performed after liver volume augmentation by preoperative vein embolization.A direct drainage of the right posterior bile duct into the common bile duct as an aberrant hepatic duct is a rare variation and is present in less than 5% of the population. In case of persistently perturbed liver function tests, an aberrant bile duct can cover up severe intrahepatic cholestasis and even obscure the diagnosis of a Klatskin tumor. Up to now it has not been described in the literature.

It has been suggested that the liver traps and deletes activated and potentially harmful T cells, especially of the CD8(+) subset, providing mechanisms to limit systemic immune responses. It is unknown whether this also applies to CD4(+) T cells. In this study, we show that activated stages of CD4(+) T cells were trapped in the liver on intraportal injection. Intravital microscopy showed an immediate adhesion of activated CD4(+) T cells within periportal sinusoids after intraportal injection. Furthermore, we detected high frequencies of interferon gamma (IFN-gamma)-- (Th1) and interleukin 4 (IL-4)-- (Th2) synthesizing effector cells in the liver. Transfer experiments were performed to identify those phenotypes showing specific retention in the liver. Our data show that effector stages and activated cells in general are more efficiently recruited into the liver than resting CD4(+) T cells, similar to what has previously been shown for CD45RB(low) memory cells. In addition, we observed a certain preference for Th1-polarized cells to be trapped by the liver. However, the actual cytokine-producing cells did not specifically enrich among the total population. In conclusion, these data indicate that the liver acts as a filter for activated and memory/effector cells. Cells trapped in the liver might subsequently undergo modulatory influences exerted by the postulated specific microenvironment of the liver.