Convenient analysis of protein modification by chemical blotting with fluorogenic “click” reagents

Direct visualization of bioorthogonal alkyne or azide handles using fluorogenic azide–alkyne cycloaddition conducted on the surface of a blot membrane. The method eliminates the need for separation steps to remove excess small molecule reagents before attachment of antigen molecules or other visualization handles, and is especially useful for the analysis of peptides and small proteins. A variety of potential fluorogenic reagents are assessed, and sensitivity (<0.1 picomole) similar to current commercially available fluorescence imaging methods is possible

Luminogenic iridium azide complexes

The synthesis and characterization of luminogenic, bioorthogonal iridium probes is described. These probes exhibit long photoluminescence lifetimes amenable to time-resolved applications. A simple, modular synthesis via 5-azidophenanthroline allows structural variation and allows optimization of cell labeling

Small molecule conjugates with dimetal species for protein inhibition

Methods for targeting a protein by providing an inhibitor covalently linked to a rhodium(II) complex, introducing the inhibitor to the target protein and allowing the inhibitor and protein to interact. The rhodium(II) complex covalently linked to the inhibitor binds the target protein both inorganically and organically and forms stabilizing secondary contacts between the rhodium(II) complex and the protein

Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors

Src-family kinases (SFKs) play important roles in human biology and are key drug targets as well. However, achieving selective inhibition of individual Src-family kinases is challenging due to the high similarity within the protein family. We describe rhodium(II) conjugates that deliver both potent and selective inhibition of Src-family SH3 domains. Rhodium(II) conjugates offer dramatic affinity enhancements due to interactions with specific and unique Lewis-basic histidine residues near the SH3 binding interface, allowing predictable, structure-guided inhibition of SH3 targets that are recalcitrant to traditional inhibitors. In one example, a simple metallopeptide binds the Lyn SH3 domain with 6 nM affinity and exhibits functional activation of Lyn kinase under biologically relevant concentrations (EC50 ∼ 200 nM)

An efficient and principled method for detecting communities in networks

A fundamental problem in the analysis of network data is the detection of network communities, groups of densely interconnected nodes, which may be overlapping or disjoint. Here we describe a method for finding overlapping communities based on a principled statistical approach using generative network models. We show how the method can be implemented using a fast, closed-form expectation-maximization algorithm that allows us to analyze networks of millions of nodes in reasonable running times. We test the method both on real-world networks and on synthetic benchmarks and find that it gives results competitive with previous methods. We also show that the same approach can be used to extract nonoverlapping community divisions via a relaxation method, and demonstrate that the algorithm is competitively fast and accurate for the nonoverlapping problem.Comment: 14 pages, 5 figures, 1 tabl

Rhodium(II) Proximity-Labeling Identifies a Novel Target Site on STAT3 for Inhibitors with Potent Anti-Leukemia Activity

Nearly 40 % of children with acute myeloid leukemia (AML) suffer relapse arising from chemoresistance, often involving upregulation of the oncoprotein STAT3 (signal transducer and activator of transcription 3). Herein, rhodium(II)-catalyzed, proximity-driven modification identifies the STAT3 coiled-coil domain (CCD) as a novel ligand-binding site, and we describe a new naphthalene sulfonamide inhibitor that targets the CCD, blocks STAT3 function, and halts its disease-promoting effects in vitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML

Spin and Rotations in Galois Field Quantum Mechanics

We discuss the properties of Galois Field Quantum Mechanics constructed on a vector space over the finite Galois field GF(q). In particular, we look at 2-level systems analogous to spin, and discuss how SO(3) rotations could be embodied in such a system. We also consider two-particle `spin' correlations and show that the Clauser-Horne-Shimony-Holt (CHSH) inequality is nonetheless not violated in this model.Comment: 21 pages, 11 pdf figures, LaTeX. Uses iopart.cls. Revised introduction. Additional reference

Identifying Overlapping and Hierarchical Thematic Structures in Networks of Scholarly Papers: A Comparison of Three Approaches

We implemented three recently proposed approaches to the identification of overlapping and hierarchical substructures in graphs and applied the corresponding algorithms to a network of 492 information-science papers coupled via their cited sources. The thematic substructures obtained and overlaps produced by the three hierarchical cluster algorithms were compared to a content-based categorisation, which we based on the interpretation of titles and keywords. We defined sets of papers dealing with three topics located on different levels of aggregation: h-index, webometrics, and bibliometrics. We identified these topics with branches in the dendrograms produced by the three cluster algorithms and compared the overlapping topics they detected with one another and with the three pre-defined paper sets. We discuss the advantages and drawbacks of applying the three approaches to paper networks in research fields.Comment: 18 pages, 9 figure

Stoichiometric Shifts in Soil C:N:P Promote Bacterial Taxa Dominance, Maintain Biodiversity, and Deconstruct Community Assemblages

Imbalances in C:N:P supply ratios may cause bacterial resource limitations and constrain biogeochemical processes, but the importance of shifts in soil stoichiometry are complicated by the nearly limitless interactions between an immensely rich species pool and a multiple chemical resource forms. To more clearly identify the impact of soil C:N:P on bacteria, we evaluated the cumulative effects of single and coupled long-term nutrient additions (i.e., C as mannitol, N as equal concentrations NH4+ and NO3−, and P as Na3PO4) and water on communities in an Antarctic polar desert, Taylor Valley. Untreated soils possessed relatively low bacterial diversity, simplified organic C sources due to the absence of plants, limited inorganic N, and excess soil P potentially attenuating links between C:N:P. After 6 years of adding resources, an alleviation of C and N colimitation allowed one rare Micrococcaceae, an Arthrobacter species, to dominate, comprising 47% of the total community abundance and elevating soil respiration by 136% relative to untreated soils. The addition of N alone reduced C:N ratios, elevated bacterial richness and diversity, and allowed rare taxa relying on ammonium and nitrite for metabolism to become more abundant [e.g., nitrite oxidizing Nitrospira species (Nitrosomonadaceae), denitrifiers utilizing nitrite (Gemmatimonadaceae) and members of Rhodobacteraceae with a high affinity for ammonium]. Based on community co-occurrence networks, lower C:P ratios in soils following P and CP additions created more diffuse and less connected communities by disrupting 73% of species interactions and selecting for taxa potentially exploiting abundant P. Unlike amended nutrients, water additions alone elicited no lasting impact on communities. Our results suggest that as soils become nutrient rich a wide array of outcomes are possible from species dominance and the deconstruction of species interconnectedness to the maintenance of biodiversity