Structural Insights into Notum Covalent Inhibition

The carboxylesterase Notum hydrolyzes a palmitoleate moiety from Wingless/Integrated(Wnt) ligands and deactivates Wnt signaling. Notum inhibitors can restore Wnt signaling which may be of therapeutic benefit for pathologies such as osteoporosis and Alzheimer’s disease. We report the identification of a novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4-oxobutanoate esters. High-resolution crystal structures of the Notum inhibitor complexes reveal a common covalent adduct formed between the nucleophile serine-232 and hydrolyzed butyric esters. The covalent interaction in solution was confirmed by mass spectrometry analysis. Inhibitory potencies vary depending on the warheads used. Mechanistically, the resulting acyl-enzyme intermediate carbonyl atom is positioned at an unfavorable angle for the approach of the active site water, which, combined with strong hydrophobic interactions with the enzyme pocket residues, hinders the intermediate from being further processed and results in covalent inhibition. These insights into Notum catalytic inhibition may guide development of more potent Notum inhibitors

Relation of substance use disorders to mortality, accident and emergency department attendances, and hospital admissions: A 13-year population-based cohort study in Hong Kong

BACKGROUND: The impact of substance use disorders (SUD) in an Asian population has not been fully explored. We aimed to assess the risk of mortality, accident and emergency (A&E) department attendances, and hospital admissions associated with SUD in a population-based cohort study. METHOD: Patients diagnosed with SUD in public A&E departments from 2004 to 2016 (N = 8,423) were identified in the Clinical Database Analysis and Reporting System of the Hong Kong Hospital Authority and 1:1 matched to patients without SUD by propensity score (N = 6,074 in each group). Relative risks of mortality, A&E attendances and hospital admissions were assessed using Cox regression and Hurdle negative binomial regression. RESULTS: Patients with SUD had higher mortality (hazard ratio=1.43; 95% confidence interval [CI]=1.26-1.62) and more often died from poisoning or toxicity and injuries. The odds ratio (OR) for A&E attendances and all-cause hospital admissions associated with SUD were 2.80 (95% CI=2.58-3.04) and 3.54 (95% CI=3.26-3.83), respectively. The impact of SUD on the above outcomes was greatest among school-aged individuals (≤ 21 years) and decreased with age. The relative risk of mental disorder-related hospital admissions was much higher than that for infections, respiratory diseases, and cardiovascular diseases. In patients with SUD, ketamine and amphetamine use were associated with increased A&E attendances than opioid use. CONCLUSIONS: SUD was associated with increased mortality, A&E attendances and hospital admissions, especially in school-aged individuals. Our findings suggest prioritising early treatment and preventive interventions for school-aged individuals and focusing on the management of comorbid mental disorders and the use of ketamine and amphetamine

Radial Growth of Qilian Juniper on the Northeast Tibetan Plateau and Potential Climate Associations

There is controversy regarding the limiting climatic factor for tree radial growth at the alpine treeline on the northeastern Tibetan Plateau. In this study, we collected 594 increment cores from 331 trees, grouped within four altitude belts spanning the range 3550 to 4020 m.a.s.l. on a single hillside. We have developed four equivalent ring-width chronologies and shown that there are no significant differences in their growth-climate responses during 1956 to 2011 or in their longer-term growth patterns during the period AD 1110–2011. The main climate influence on radial growth is shown to be precipitation variability. Missing ring analysis shows that tree radial growth at the uppermost treeline location is more sensitive to climate variation than that at other elevations, and poor tree radial growth is particularly linked to the occurrence of serious drought events. Hence water limitation, rather than temperature stress, plays the pivotal role in controlling the radial growth of Sabina przewalskii Kom. at the treeline in this region. This finding contradicts any generalisation that tree-ring chronologies from high-elevation treeline environments are mostly indicators of temperature changes

Electric Field Control of Spin Transport

Spintronics is an approach to electronics in which the spin of the electrons is exploited to control the electric resistance R of devices. One basic building block is the spin-valve, which is formed if two ferromagnetic electrodes are separated by a thin tunneling barrier. In such devices, R depends on the orientation of the magnetisation of the electrodes. It is usually larger in the antiparallel than in the parallel configuration. The relative difference of R, the so-called magneto-resistance (MR), is then positive. Common devices, such as the giant magneto-resistance sensor used in reading heads of hard disks, are based on this phenomenon. The MR may become anomalous (negative), if the transmission probability of electrons through the device is spin or energy dependent. This offers a route to the realisation of gate-tunable MR devices, because transmission probabilities can readily be tuned in many devices with an electrical gate signal. Such devices have, however, been elusive so far. We report here on a pronounced gate-field controlled MR in devices made from carbon nanotubes with ferromagnetic contacts. Both the amplitude and the sign of the MR are tunable with the gate voltage in a predictable manner. We emphasise that this spin-field effect is not restricted to carbon nanotubes but constitutes a generic effect which can in principle be exploited in all resonant tunneling devices.Comment: 22 pages, 5 figure

Pleiotropic functions of the tumor- and metastasis-suppressing Matrix Metalloproteinase-8 in mammary cancer in MMTV-PyMT transgenic mice

Matrix metalloproteinase-8 (MMP-8; neutrophil collagenase) is an important regulator of innate immunity which has onco-suppressive actions in numerous tumor types

Tuning a Circular p-n Junction in Graphene from Quantum Confinement to Optical Guiding

The motion of massless Dirac-electrons in graphene mimics the propagation of photons. This makes it possible to control the charge-carriers with components based on geometrical-optics and has led to proposals for an all-graphene electron-optics platform. An open question arising from the possibility of reducing the component-size to the nanometer-scale is how to access and understand the transition from optical-transport to quantum-confinement. Here we report on the realization of a circular p-n junction that can be continuously tuned from the nanometer-scale, where quantum effects are dominant, to the micrometer scale where optical-guiding takes over. We find that in the nanometer-scale junction electrons are trapped in states that resemble atomic-collapse at a supercritical charge. As the junction-size increases, the transition to optical-guiding is signaled by the emergence of whispering-gallery modes and Fabry-Perot interference. The creation of tunable junctions that straddle the crossover between quantum-confinement and optical-guiding, paves the way to novel design-architectures for controlling electronic transport.Comment: 16 pages, 4 figure

Realization of a Tunable Artificial Atom at a Supercritically Charged Vacancy in Graphene

The remarkable electronic properties of graphene have fueled the vision of a graphene-based platform for lighter, faster and smarter electronics and computing applications. One of the challenges is to devise ways to tailor its electronic properties and to control its charge carriers. Here we show that a single atom vacancy in graphene can stably host a local charge and that this charge can be gradually built up by applying voltage pulses with the tip of a scanning tunneling microscope (STM). The response of the conduction electrons in graphene to the local charge is monitored with scanning tunneling and Landau level spectroscopy, and compared to numerical simulations. As the charge is increased, its interaction with the conduction electrons undergoes a transition into a supercritical regime 6-11 where itinerant electrons are trapped in a sequence of quasi-bound states which resemble an artificial atom. The quasi-bound electron states are detected by a strong enhancement of the density of states (DOS) within a disc centered on the vacancy site which is surrounded by halo of hole states. We further show that the quasi-bound states at the vacancy site are gate tunable and that the trapping mechanism can be turned on and off, providing a new mechanism to control and guide electrons in grapheneComment: 18 pages and 5 figures plus 14 pages and 15 figures of supplementary information. Nature Physics advance online publication, Feb 22 (2016

Robust isothermal electric switching of interface magnetization: A route to voltage-controlled spintronics

Roughness-insensitive and electrically controllable magnetization at the (0001) surface of antiferromagnetic chromia is observed using magnetometry and spin-resolved photoemission measurements and explained by the interplay of surface termination and magnetic ordering. Further, this surface in placed in proximity with a ferromagnetic Co/Pd multilayer film. Exchange coupling across the interface between chromia and Co/Pd induces an electrically controllable exchange bias in the Co/Pd film, which enables a reversible isothermal (at room temperature) shift of the global magnetic hysteresis loop of the Co/Pd film along the magnetic field axis between negative and positive values. These results reveal the potential of magnetoelectric chromia for spintronic applications requiring non-volatile electric control of magnetization.Comment: Single PDF file: 27 pages, 6 figures; version of 12/30/09; submitted to Nature Material

PhOTO Zebrafish: A Transgenic Resource for In Vivo Lineage Tracing during Development and Regeneration

Background: Elucidating the complex cell dynamics (divisions, movement, morphological changes, etc.) underlying embryonic development and adult tissue regeneration requires an efficient means to track cells with high fidelity in space and time. To satisfy this criterion, we developed a transgenic zebrafish line, called PhOTO, that allows photoconvertible optical tracking of nuclear and membrane dynamics in vivo. Methodology: PhOTO zebrafish ubiquitously express targeted blue fluorescent protein (FP) Cerulean and photoconvertible FP Dendra2 fusions, allowing for instantaneous, precise targeting and tracking of any number of cells using Dendra2 photoconversion while simultaneously monitoring global cell behavior and morphology. Expression persists through adulthood, making the PhOTO zebrafish an excellent tool for studying tissue regeneration: after tail fin amputation and photoconversion of a ~100µm stripe along the cut area, marked differences seen in how cells contribute to the new tissue give detailed insight into the dynamic process of regeneration. Photoconverted cells that contributed to the regenerate were separated into three distinct populations corresponding to the extent of cell division 7 days after amputation, and a subset of cells that divided the least were organized into an evenly spaced, linear orientation along the length of the newly regenerating fin. Conclusions/Significance: PhOTO zebrafish have wide applicability for lineage tracing at the systems-level in the early embryo as well as in the adult, making them ideal candidate tools for future research in development, traumatic injury and regeneration, cancer progression, and stem cell behavior