Orthogonal biofunctionalization of magnetic nanoparticles via ``clickable'' poly(ethylene glycol) silanes: a ``universal ligand'' strategy to design stealth and target-specific nanocarriers

The present work demonstrates a novel strategy to synthesize orthogonally bio-engineered magnetonanohybrids (MNPs) through the design of versatile, biocompatible linkers whose structure includes: (i) a robust anchor to bind with metal-oxide surfaces; (ii) tailored surface groups to act as spacers and (iii) a general method to implement orthogonal functionalizations of the substrate via ``click chemistry''. Ligands that possess the synthetic generality of features (i)-(iii) are categorized as ``universal ligands''. Herein, we report the synthesis of a novel, azido-terminated poly(ethylene glycol) (PEG) silane that can easily self-assemble on MNPs through hetero-condensation between surface hydroxyl groups and the silane end of the ligand, and simultaneously provide multiple clickable sites for high density, chemoselective bio-conjugation. To establish the universal-ligand-strategy, we clicked alkyl-functionalized folate onto the surface of PEGylated MNPs. By further integrating a near-infrared fluorescent (NIRF) marker (Alexa-Fluor 647) with MNPs, we demonstrated their folate-receptor mediated internalization inside cancer cells and subsequent translocation into lysosomes and mitochondria. Ex vivo NIRF imaging established that the azido-PEG-silane developed in course of the study can effectively reduce the sequestration of MNPs by macrophage organs (viz. liver and spleen). These folate-PEG-MNPs were not only stealth and noncytotoxic but their dual optical and magnetic properties aided in tracking their whereabouts through combined magnetic resonance and optical imaging. Together, these results provided a strong motivation for the future use of the ``universal ligand'' strategy towards development of ``smart'' nanohybrids for theragnostic applications.

Truthful multi-armed bandit mechanisms for multi-slot sponsored search auctions

In pay-per-click sponsored search auctions which are currently extensively used by search engines, the auction for a keyword involves a certain number of advertisers (say k) competing for available slots (say m) to display their advertisements (ads for short). A sponsored search auction for a keyword is typically conducted for a number of rounds (say T). There are click probabilities mu(ij) associated with each agent slot pair (agent i and slot j). The search engine would like to maximize the social welfare of the advertisers, that is, the sum of values of the advertisers for the keyword. However, the search engine does not know the true values advertisers have for a click to their respective advertisements and also does not know the click probabilities. A key problem for the search engine therefore is to learn these click probabilities during the initial rounds of the auction and also to ensure that the auction mechanism is truthful. Mechanisms for addressing such learning and incentives issues have recently been introduced. These mechanisms, due to their connection to the multi-armed bandit problem, are aptly referred to as multi-armed bandit (MAB) mechanisms. When m = 1, exact characterizations for truthful MAB mechanisms are available in the literature. Recent work has focused on the more realistic but non-trivial general case when m > 1 and a few promising results have started appearing. In this article, we consider this general case when m > 1 and prove several interesting results. Our contributions include: (1) When, mu(ij)s are unconstrained, we prove that any truthful mechanism must satisfy strong pointwise monotonicity and show that the regret will be Theta T7) for such mechanisms. (2) When the clicks on the ads follow a certain click precedence property, we show that weak pointwise monotonicity is necessary for MAB mechanisms to be truthful. (3) If the search engine has a certain coarse pre-estimate of mu(ij) values and wishes to update them during the course of the T rounds, we show that weak pointwise monotonicity and type-I separatedness are necessary while weak pointwise monotonicity and type-II separatedness are sufficient conditions for the MAB mechanisms to be truthful. (4) If the click probabilities are separable into agent-specific and slot-specific terms, we provide a characterization of MAB mechanisms that are truthful in expectation.

Self-Adapting Peripherally Heterofunctionalized Hyperbranched Polymers: Formation of Janus and Tripodal Structures

A peripherally clickable hyperbranched polyester carrying numerous propargyl terminal groups was prepared by a simple melt transesterification polycondensation of a suitably designed AB(2) monomer; this clickable hyperscaffold was then transformed into a variety of different derivatives by using the Cu-catalyzed azide-yne click reaction. Functionalization of the periphery with equimolar quantities of mutually immiscible segments, such as hydrocarbon, fluorocarbon, and PEG, yielded frustrated molecular systems that readapt and form structures wherein the immiscible segments appear to self-segregate to generate either Janus structures (when two immiscible segments are present) or tripodal structures (when three immiscible segments are present). Evidence for such self-segregation was obtained from a variety of studies, such as differential scanning calorimetry, Langmuir isotherms, AFM imaging, and small-angle X-ray scattering measurements. Crystallization of one or more of the peripheral segments reinforced this self-segregation; the weight-fraction-normalized enthalpies of melting associated with the different domains revealed a competition between the segments to optimize their crystalline organization. When one or more of the segments are amorphous, the remaining segments crystallize more effectively and consequently exhibit a higher melting enthalpy. AFM images of monolayers, transferred from the Langmuir trough, revealed that the thickness matches the expected values; furthermore, contact angle measurements clearly demonstrated that the monolayer films are fairly hydrophobic, and in the case of the tripodal hybramers, the presence of domains of hydrocarbon and fluorocarbon appears to impart nanoscale chemical heterogeneity that is reflected in the strong hysteresis in the advancing and receding contact angles.

Single-step synthesis of internally functionalizable hyperbranched polyethers

Radical catalyzed thiol-ene reaction has become a useful alternative to the Huisgen-type azide-yne click reaction as it helps expand the variability in reaction conditions as well as the range of clickable entities. In this study, the direct generation of a hyperbranched polyether (HBPE) having decyl units at the periphery and a pendant allyl group on every repeat unit of the polymer backbone is described; the allyl groups serve as a reactive handle for postpolymerization modifications and permits the generation of a variety of internally functionalized HBPEs. In this design, the AB(2) monomer carries two decylbenzyl ether units (B-functionality), an aliphatic OH (A-functionality) and a pendant allyl group within the spacer segment; polymerization of the monomer readily occurs at 150 degrees C via melt transetherification process by continuous removal of 1-decanol under reduced pressure. The resulting HBPE has a hydrophobic periphery due to the presence of numerous decyl chains, while the allyl groups that remain unaffected during the melt polymerization provides an opportunity to install a variety of functional groups within the interior; thiol-ene click reaction with two different thiols, namely 3-mercaptopropionic acid and mercaptosuccinic acid, generated interesting amphiphilic structures. Preliminary field emission scanning electron microscope (FESEM) and Atomic Force Microscopy (AFM) imaging studies reveal the formation of fairly uniform spherical aggregates in water with sizes ranging from 200 to 400 nm; this suggests that these amphiphilic HBPs is able to reconfigure to generate jellyfish-like conformations that subsequently aggregate in an alkaline medium. The internal allyl functional groups were also used to generate intramolecularly core-crosslinked HBPEs, by the use of dithiol crosslinkers; gel permeation chromatography traces provided clear evidence for reduction in the size after crosslinking. In summary, we have developed a simple route to prepare core-clickable HBPEs and have demonstrated the quantitative reaction of the allyl groups present within the interior of the polymers; such HB polymeric systems that carry numerous functional groups within the core could have interesting applications in analyte sequestration and possibly sensing, especially from organic media. (c) 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 4125-4135

Pattern-growth based frequent serial episode discovery

Frequent episode discovery is a popular framework for pattern discovery from sequential data. It has found many applications in domains like alarm management in telecommunication networks, fault analysis in the manufacturing plants, predicting user behavior in web click streams and so on. In this paper, we address the discovery of serial episodes. In the episodes context, there have been multiple ways to quantify the frequency of an episode. Most of the current algorithms for episode discovery under various frequencies are apriori-based level-wise methods. These methods essentially perform a breadth-first search of the pattern space. However currently there are no depth-first based methods of pattern discovery in the frequent episode framework under many of the frequency definitions. In this paper, we try to bridge this gap. We provide new depth-first based algorithms for serial episode discovery under non-overlapped and total frequencies. Under non-overlapped frequency, we present algorithms that can take care of span constraint and gap constraint on episode occurrences. Under total frequency we present an algorithm that can handle span constraint. We provide proofs of correctness for the proposed algorithms. We demonstrate the effectiveness of the proposed algorithms by extensive simulations. We also give detailed run-time comparisons with the existing apriori-based methods and illustrate scenarios under which the proposed pattern-growth algorithms perform better than their apriori counterparts. (C) 2013 Elsevier B.V. All rights reserved.

Ring opening of activated cyclopropanes with NIS/NaN3: synthesis of C-1 linked pseudodisaccharides

NIS/NaN3 mediated ring opening of various donor-acceptor cyclopropanes has been investigated. The study shows the necessity of the donor oxygen lone pair in such ring opening reactions. This methodology has been utilized in the synthesis of C-1 linked pseudodisaccharides through the use of click chemistry. (C) 2013 Elsevier Ltd. All rights reserved.