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We report a minimalist gaseous sulfonyl-chloride-derived reagent for multicomponent bioconjugation with amine, phenol, or aniline reagents to afford urea or carbamate products. With the utilization of a gas-phase reagent for a reaction mediated by metal ions, a variety of biologically relevant molecules, such as saccharide, poly(ethylene glycol), fluorophore, and affinity tag, can be efficiently cross-linked to the N terminus or lysine side-chain amines on natural polypeptides or proteins. 

Peptide cyclization has dramatic effects on a variety of important properties, enhancing metabolic stability, limiting conformational flexibility, and altering cellular entry and intracellular localization. The hydrophilic, polyfunctional nature of peptides creates chemoselectivity challenges in macrocyclization, especially for natural sequences without biorthogonal handles. Herein, we describe a gaseous sulfonyl chloride derived reagent that achieves amine–amine, amine–phenol, and amine–aniline crosslinking through a minimalist linchpin strategy that affords macrocyclic urea or carbamate products. The cyclization reaction is metal‐mediated and involves a novel application of sulfine species that remains unexplored in aqueous or biological contexts. The aqueous method delivers unique cyclic or bicyclic topologies directly from a variety of natural bioactive peptides without the need for protecting‐group strategies.

 

We investigate learning the equilibria in non-stationary multi-agent systems and address the challenges that differentiate multi-agent learning from single-agent learning. Specifically, we focus on games with bandit feedback, where testing an equilibrium can result in substantial regret even when the gap to be tested is small, and the existence of multiple optimal solutions (equilibria) in stationary games poses extra challenges. To overcome these obstacles, we propose a versatile black-box approach applicable to a broad spectrum of problems, such as general-sum games, potential games, and Markov games, when equipped with appropriate learning and testing oracles for stationary environments. Our algorithms can achieve O(∆^1/4 T^3/4) regret when the degree of nonstationarity, as measured by total variation ∆, is known, and O(∆^1/5 T^4/5) regret when ∆ is unknown, where T is the number of rounds. Meanwhile, our algorithm inherits the favorable dependence on number of agents from the oracles. As a side contribution that may be independent of interest, we show how to test for various types of equilibria by a black-box reduction to single-agent learning, which includes Nash equilibria, correlated equilibria, and coarse correlated equilibria. 

Purpose: Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) ‘primes’ PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them, and devise approaches to stratify SHHi-responsive tumors non-invasively based on clinically-quantifiable parameters. Experimental design: Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intra-tumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key ‘nodes’ responsible for EMT induction. Results: multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Non-responding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect. Conclusion: This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification.

 

Rock-physics models for carbonate reservoirs assume that the mineral elastic moduli are known variables. A review of publications reveals a range of values for calcite that are out of date and misleading. We present a robust compilation for future investigations. We subsequently discuss the application of calcite elastic moduli for rock-physics modeling and interpretation of wireline data through a case study data set from an offshore Canada carbonate reservoir. The data set exhibits an offset between the zero-porosity intercept and the calcite elastic moduli values. Our experience indicates that this phenomenon is present in many wireline data sets from carbonate reservoirs around the world. We demonstrate that the data can be reconciled to the mineral elastic moduli through the interpretation of microcracks in the formation (defined by a crack density of 0.06). Understanding the microcrack effect in relatively low-porosity formations is important for the correct calibration of pore microstructure parameters and for fluid-substitution calculations. Results in the case study data set show a relatively high sensitivity to changes in fluid saturation. The sensitivity can be reduced through the use of effective mineral elastic moduli that are derived from the data. We justify the effective mineral elastic moduli as a representation of the mineral moduli plus microcracks. The effective mineral elastic moduli are proposed as a relatively simple method to constrain the fluid substitution calculations in low-porosity formations where microcracks are present.