An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

Background: The carboxylesterase Notum has been shown to act as a key negative regulator of the Wnt signalling pathway by mediating the depalmitoleoylation of Wnt proteins. LP-922056 (1) is an orally active inhibitor of Notum. We are investigating the role of Notum in modulating Wnt signalling in the central nervous system and wished to establish if 1 would serve as a peripherally restricted control. An accessible and improved synthetic route would allow 1 to become more readily available as a chemical tool to explore the fundamental biology of Notum and build target validation to underpin new drug discovery programs. / Results: An improved, scalable synthesis of 1 is reported. Key modifications include: (1) the introduction of the C7-cyclopropyl group was most effectively achieved with a Suzuki–Miyaura cross-coupling reaction with MIDA-boronate 11 (5 → 6); and (2) C6 chlorination was performed with 1-chloro-1,2-benziodoxol-3-one (12) (6 → 7) as a mild selective electrophilic chlorination agent. This 7-step route has been reliably performed on large scale to produce multigram quantities of 1 in good efficiency and high purity. Pharmacokinetic studies in mouse showed CNS penetration of 1 is very low with brain:plasma concentration ratio of just 0.01. A small library of amides 17 were prepared from acid 1 to explore if 1 could be modified to deliver a CNS penetrant tool by capping off the acid as an amide. Although significant Notum inhibition activity could be achieved, none of these amides demonstrated the required combination of metabolic stability along with cell permeability without evidence of P-gp mediated efflux. / Conclusion: Mouse pharmacokinetic studies demonstrate that 1 is unsuitable for use in models of disease where brain penetration is an essential requirement of the compound but would be an ideal peripherally restricted control. These data will contribute to the understanding of drug levels of 1 to overlay with appropriate in vivo efficacy endpoints, i.e. the PK-PD relationship. The identification of a suitable analogue of 1 (or 17) which combines Notum inhibition with CNS penetration would be a valuable chemical probe for investigating the role of Notum in disease models

Random Walks Along the Streets and Canals in Compact Cities: Spectral analysis, Dynamical Modularity, Information, and Statistical Mechanics

Different models of random walks on the dual graphs of compact urban structures are considered. Analysis of access times between streets helps to detect the city modularity. The statistical mechanics approach to the ensembles of lazy random walkers is developed. The complexity of city modularity can be measured by an information-like parameter which plays the role of an individual fingerprint of {\it Genius loci}. Global structural properties of a city can be characterized by the thermodynamical parameters calculated in the random walks problem.Comment: 44 pages, 22 figures, 2 table

Particle production at AGS energies

The authors discuss particle production from 14.6 A{center_dot}GeV/c Si and 11.6 A{center_dot}GeV/c Au projectiles on Al and Au targets. The second-level trigger utilized by E859 allows high precision measurements of K{sup {minus}}, {bar p}, {Lambda} and {bar {Lambda}}. The {bar {Lambda}} yield is larger than expected, and a surprisingly large fraction of the {bar p}`s are observed to arise from the decay of {bar {Lambda}}

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

Forest Plant and Bird Communities in the Lau Group, Fiji

We examined species composition of forest and bird communities in relation to environmental and human disturbance gradients on Lakeba (55.9 km²), Nayau (18.4 km²), and Aiwa Levu (1.2 km²), islands in the Lau Group of Fiji, West Polynesia. The unique avifauna of West Polynesia (Fiji, Tonga, Samoa) has been subjected to prehistoric human-caused extinctions but little was previously known about this topic in the Lau Group. We expected that the degree of human disturbance would be a strong determinant of tree species composition and habitat quality for surviving landbirds, while island area would be unrelated to bird diversity.All trees > 5 cm diameter were measured and identified in 23 forest plots of 500 m² each. We recognized four forest species assemblages differentiated by composition and structure: coastal forest, dominated by widely distributed species, and three forest types with differences related more to disturbance history (stages of secondary succession following clearing or selective logging) than to environmental gradients (elevation, slope, rockiness). Our point counts (73 locations in 1 or 2 seasons) recorded 18 of the 24 species of landbirds that exist on the three islands. The relative abundance and species richness of birds were greatest in the forested habitats least disturbed by people. These differences were due mostly to increased numbers of columbid frugivores and passerine insectivores in forests on Lakeba and Aiwa Levu. Considering only forested habitats, the relative abundance and species richness of birds were greater on the small but completely forested (and uninhabited) island of Aiwa Levu than on the much larger island of Lakeba.Forest disturbance history is more important than island area in structuring both tree and landbird communities on remote Pacific islands. Even very small islands may be suitable for conservation reserves if they are protected from human disturbance

Selected Soybean Plant Introductions with Partial Resistance to \u3ci\u3eSclerotinia sclerotiorum\u3c/i\u3e

Sclerotinia stem rot, caused by Sclerotinia sclerotiorum, is a major soybean (Glycine max) disease in north-central regions of the United States and throughout the world. Current sources of resistance to Sclerotinia stem rot express partial resistance, and are limited in number within soybean germ plasm. A total of 6,520 maturity group (MG) 0 to IV plant introductions (PIs) were evaluated for Sclerotinia stem rot resistance in the United States and Canada in small plots or in the greenhouse from 1995 to 1997. Selected PIs with the most resistance were evaluated for resistance in the United States and Canada in replicated large plots from 1998 to 2000. The PIs in the MG I to III tests in Urbana, IL were evaluated for agronomic traits from 1998 to 2000. The selected PIs also were evaluated with an excised leaf inoculation and petiole inoculation technique. After the 1995 to 1997 evaluations, all but 68 PIs were eliminated because of their susceptibility to Sclerotinia stem rot. In field tests in Urbana, higher disease severity in selected MG I to III PIs was significantly (P \u3c 0.05) associated with taller plant heights and greater canopy closure. All other agronomic traits evaluated were not associated or were inconsistently associated with disease severity. MG I to III PIs 153.282, 189.931, 196.157, 398.637, 417.201, 423.818, and 561.331 had high levels of resistance and had canopies similar to the resistant checks. The resistance ratings from the petiole inoculation technique had a high and significant (P \u3c 0.01) correlation with disease severity in the MG I and II field tests. The partially resistant PIs identified in this study can be valuable in incorporating Sclerotinia stem rot resistance into elite germ plasm

The Charge Form Factor of the Neutron at Low Momentum Transfer from the 2H⃗(e⃗,e′n)p^{2}\vec{\rm H}(\vec{\rm e},{\rm e}'{\rm n}){\rm p} Reaction

We report new measurements of the neutron charge form factor at low momentum transfer using quasielastic electrodisintegration of the deuteron. Longitudinally polarized electrons at an energy of 850 MeV were scattered from an isotopically pure, highly polarized deuterium gas target. The scattered electrons and coincident neutrons were measured by the Bates Large Acceptance Spectrometer Toroid (BLAST) detector. The neutron form factor ratio $G^{n}_{E}/G^{n}_{M}$ was extracted from the beam-target vector asymmetry $A_{ed}^{V}$ at four-momentum transfers $Q^{2}=0.14$, 0.20, 0.29 and 0.42 (GeV/c)$^{2}$.Comment: 5 pages, 3 figures, submitted to Phys. Rev. Let

Pseudorapidity and centrality dependence of the collective flow of charged particles in Au+Au collisions at sqrt{s_NN} = 130 GeV

This paper describes the measurement of collective flow for charged particles in Au+Au collisions at sqrt{s_NN}} = 130 GeV using the PHOBOS detector at the Relativistic Heavy Ion Collider (RHIC). An azimuthal anisotropy is observed in the charged particle hit distribution in the PHOBOS multiplicity detector. This anisotropy is presented over a wide range of pseudorapidity (eta) for the first time at this energy. The size of the anisotropy (v_{2}) is thought to probe the degree of equilibration achieved in these collisions. The result here,averaged over momenta and particle species, is observed to reach 7% for peripheral collisions at mid-rapidity, falling off with centrality and increasing |eta|. Data are presented as a function of centrality for |eta|<1.0 and as a function of eta, averaged over centrality, in the angular region -5.0<eta<5.3. These results call into question the common assumption of longitudinal boost invariance over a large region of rapidity in RHIC collisions.Comment: 5 pages, 4 figures, submitted to Physical Review Letter