Crossover From Individual to Collective Magnetism in Dense Nanoparticle Systems: Local Anisotropy Versus Dipolar Interactions.

Dense systems of magnetic nanoparticles may exhibit dipolar collective behavior. However, two fundamental questions remain unsolved: i) whether the transition temperature may be affected by the particle anisotropy or it is essentially determined by the intensity of the interparticle dipolar interactions, and ii) what is the minimum ratio of dipole-dipole interaction (Edd ) to nanoparticle anisotropy (Kef V, anisotropy⋅volume) energies necessary to crossover from individual to collective behavior. A series of particle assemblies with similarly intense dipolar interactions but widely varying anisotropy is studied. The Kef  is tuned through different degrees of cobalt-doping in maghemite nanoparticles, resulting in a variation of nearly an order of magnitude. All the bare particle compacts display collective behavior, except the one made with the highest anisotropy particles, which presents "marginal" features. Thus, a threshold of Kef V/Edd  ≈ 130 to suppress collective behavior is derived, in good agreement with Monte Carlo simulations. This translates into a crossover value of ≈1.7 for the easily accessible parameter TMAX (interacting)/TMAX (non-interacting) (ratio of the peak temperatures of the zero-field-cooled magnetization curves of interacting and dilute particle systems), which is successfully tested against the literature to predict the individual-like/collective behavior of any given interacting particle assembly comprising relatively uniform particles.

Peptide-Peptide Co-Assembly: A Design Strategy for Functional Detection of C-peptide, A Biomarker of Diabetic Neuropathy.

Diabetes-related neuropathy is a debilitating condition that may be averted if it can be detected early. One possible way this can be achieved at low cost is to utilise peptides to detect C-peptide, a biomarker of diabetic neuropathy. This depends on peptide-peptide co-assembly, which is currently in a nascent stage of intense study. Instead, we propose a bead-based triple-overlay combinatorial strategy that can preserve inter-residue information during the screening process for a suitable complementary peptide to co-assemble with C-peptide. The screening process commenced with a pentapeptide general library, which revealed histidine to be an essential residue. Further screening with seven tetrapeptide focused libraries led to a table of self-consistent peptide sequences that included tryptophan and lysine at high frequencies. Three complementary nonapeptides (9mer com-peptides), wpkkhfwgq (Trp-D), kwkkhfwgq (Lys-D), and KWKKHFWGQ (Lys-L) (as a negative control) were picked from this table for co-assembly studies with C-peptide. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) and circular dichroism (CD) spectroscopies were utilized to study inter-peptide interactions and changes in secondary structures respectively. ATR-FTIR studies showed that there is indeed inter-peptide interaction between C-peptide and the tryptophan residues of the 9mer com-peptides. CD studies of unaggregated and colloidal C-peptide with the 9mer com-peptides suggest that the extent of co-assembly of C-peptide with Trp-D is greatest, followed by Lys-D and Lys-L. These results are promising and indicate that the presented strategy is viable for designing and evaluating longer complementary peptides, as well as complementary peptides for co-assembly with other polypeptides of interest and importance. We discuss the possibility of designing complementary peptides to inhibit toxic amyloidosis with this approach.

Molecular Swings as Highly Active Ion Transporters.

Ions are transported across membrane mostly via carrier or channel mechanisms. Herein, a unique class of molecular-machine-inspired membrane transporters, termed molecular swings is reported that utilize a previously unexplored swing mechanism for promoting ion transport in a highly efficient manner. In particular, the molecular swing, which carries a 15-crown-5 unit as the ion-binding and transporting unit, exhibits extremely high ion-transport activities with EC50 values of 46 nm (a channel:lipid molar ratio of 1:4800 or 0.021 mol % relative to lipid) and 110 nm for K+ and Na+ ions, respectively. Remarkably, such ion transport activities remain high in a cholesterol-rich environment, with EC50 values of 130 (0.045 mol % relative to lipid/cholesterol) and 326 nm for K+ and Na+ ions, respectively.

The interplay between single particle anisotropy and interparticle interactions in ensembles of magnetic nanoparticles.

This paper aims to analyze the competition of single particle anisotropy and interparticle interactions in nanoparticle ensembles using a random anisotropy model. The model is first applied to ideal systems of non-interacting and strongly dipolar interacting ensembles of maghemite nanoparticles. The investigation is then extended to more complex systems of pure cobalt ferrite CoFe2O4 (CFO) and mixed cobalt-nickel ferrite (Co,Ni)Fe2O4 (CNFO) nanoparticles. Both samples were synthetized by the polyol process and exhibit the same particle size (DTEM ≈ 5 nm), but with different interparticle interaction strengths and single particle anisotropy. The implementation of the random anisotropy model allows investigation of the influence of single particle anisotropy and interparticle interactions, and sheds light on their complex interplay as well as on their individual contribution. This analysis is of fundamental importance in order to understand the physics of these systems and to develop technological applications based on concentrated magnetic nanoparticles, where single and collective behaviors coexist.

An efficient strategy to enhance binding affinity and specificity of a known isozyme inhibitor.

The binding profile of a known inhibitor, benzenesulfonamide, against a family of carbonic anhydrase isozymes was efficiently enhanced via high-throughput screening of customized combinatorial one-bead-one-compound peptide libraries modified with the inhibitor molecule. The screening of the conjugate libraries recognized subtle variations in the microenvironments of the target enzyme and thus facilitated the identification of short peptide sequences that bind selectively to a close proximity of the active site. The identified peptide portions contributed significantly to the overall binding of the conjugate peptides with greatly enhanced affinity as well as improved specificity towards the target isozyme. The interactions between the inhibitors and the isozymes were validated by surface plasmon resonance (SPR), pull-down assay and enzymatic activity measurement. This high-throughput approach proved useful and efficient to enhance the binding profile of known inhibitors and may apply to developing effective inhibitors for a wide range of isozyme families.

Recyclable Photo-Thermal Nano-Aggregates of Magnetic Nanoparticle Conjugated Gold Nanorods for Effective Pathogenic Bacteria Lysis.

We describe the nucleophilic hybridization technique for fabricating magnetic nanoparticle (MNP) around gold nanorod (AuNR) for desired photo-thermal lysis on pathogenic bacteria. From the electromagnetic energy conversion into heat to the surrounding medium, a significant and quicker temperature rise was noted after light absorption on nanohybrids, at a controlled laser light output and optimum nanoparticle concentration. We observed a similar photo-thermal pattern for more than three times for the same material up on repeated magnetic separation. Regardless of the cell wall nature, superior pathogenic cell lysis has been observed for the bacteria suspensions of individual and mixed samples of Salmonella typhi (S.typhi) and Bacillus subtilis (B.subtilis) by the photo-heated nanoparticles. The synthesis of short gold nanorod, conjugation with magnetic nanoparticle and its subsequent laser exposure provides a rapid and reiterated photo-thermal effect with enhanced magnetic separation for efficient bactericidal application in water samples. Resultant novel properties of the nano-aggregates makes them a candidate to be used for a rapid, effective, and re-iterated photo-thermal agent against a wide variety of pathogens to attain microbe free water.

Elucidating pH-dependent collagen triple helix formation through interstrand hydroxyproline-glutamic acid interactions.

Here, we describe systematic explorations into the molecular basis underlying hydroxyproline-mediated interstrand interactions on the triple-helical stability of collagen-mimetic peptides containing glutamic acid residues. Our studies reveal that the triple-helical stability of these peptides relies on the existence of interstrand interactions between hydroxyprolines and glutamic acid residues that are pH dependent. These unique interactions have been used to engineer collagen peptides that form triple helices on demand through pH control.

Size-dependent surface effects in maghemite nanoparticles and its impact on interparticle interactions in dense assemblies.

The question of the dominant interparticle magnetic interaction type in random closely packed assemblies of different diameter (6.2-11.5 nm) bare maghemite nanoparticles (NPs) is addressed. Single-particle magnetic properties such as particle anisotropy and exchange bias field are first of all studied in dilute (reference) systems of these same NPs, where interparticle interactions are neglible. Substantial surface spin disorder is revealed in all particles except the smallest, viz. for diameters d = 8-11.5 nm but not for d = 6.2-6.3 nm. X-ray diffraction analysis points to a crystallographic origin of this effect. The study of closely packed assemblies of the d ≥ 8 nm particles observes collective (superspin) freezing that clearly appears to be governed by interparticle dipole interactions. However, the dense assemblies of the smallest particles exhibit freezing temperatures that are higher than expected from a simple (dipole) extrapolation of the corresponding temperatures found in the d ≥ 8 nm assemblies. It is suggested that the nature of the dominant interparticle interaction in these smaller particle assemblies is superexchange, whereby the lack of significant surface spin disorder allows this mechanism to become important at the level of interacting superspins.

Highly selective macrocycle formations by metathesis catalysts fixated in nanopores.

Ruthenium-based metathesis catalysts immobilized on mesocellular siliceous foam (MCF) bearing large nanopores proved highly efficient and selective for macrocyclic ring-closing metathesis (RCM). Kinetic studies revealed that the homogeneous counterpart exhibited far higher activity that accounted for more oligomerization pathways and resulted in less macrocyclization products. Meanwhile, the immobilized catalysts showed lower conversion rates leading to higher yields of macrocyclic products in a given reaction time, with conversion rates and yields dependent upon pore size, catalyst loading density, and linker length. The macrocycle formations via RCM were accelerated by increasing the pore size and decreasing the catalyst loading density while retaining the comparably high yield. The catalysts immobilized on MCF, of which silica surface is rigid and pores are relatively large, showed high conversion rates and yields compared with an analogue immobilized on TentaGel resins, of which backbone becomes flexible upon swelling in the reaction medium. It is noteworthy that the selectivity for the macrocyclic RCM can be significantly improved by tuning the catalyst initiation rates via immobilization onto the support materials in which well-defined three-dimentional network of large nanopores are deployed.

Magnetic nanoparticles entrapped in siliceous mesocellular foam: a new catalyst support.

γ-Fe(2)O(3) nanoparticles were formed inside the cage-like pores of mesocellular foam (MCF). These magnetic nanoparticles showed a uniform size distribution that could be easily controlled by the MCF pore size, as well as by the hydrocarbon chain length used for MCF surface modification. Throughout the entrapment process, the pore structure and surface area of the MCF remained intact. The resulting magnetic MCF facilitated the immobilization of biocatalysts, homogeneous catalysts, and nanoclusters. Moreover, the MCF allowed for facile catalyst recovery by using a simple magnet. The supported catalysts exhibited excellent catalytic efficiencies that were comparable to their homogeneous counterparts.

Potentials of Neuropeptides as Therapeutic Agents for Neurological Diseases.

Despite recent leaps in modern medicine, progress in the treatment of neurological diseases remains slow. The near impermeable blood-brain barrier (BBB) that prevents the entry of therapeutics into the brain, and the complexity of neurological processes, limits the specificity of potential therapeutics. Moreover, a lack of etiological understanding and the irreversible nature of neurological conditions have resulted in low tolerability and high failure rates towards existing small molecule-based treatments. Neuropeptides, which are small proteinaceous molecules produced by the body, either in the nervous system or the peripheral organs, modulate neurological function. Although peptide-based therapeutics originated from the treatment of metabolic diseases in the 1920s, the adoption and development of peptide drugs for neurological conditions are relatively recent. In this review, we examine the natural roles of neuropeptides in the modulation of neurological function and the development of neurological disorders. Furthermore, we highlight the potential of these proteinaceous molecules in filling gaps in current therapeutics.

Iterative in situ click chemistry assembles a branched capture agent and allosteric inhibitor for Akt1.

We describe the use of iterative in situ click chemistry to design an Akt-specific branched peptide triligand that is a drop-in replacement for monoclonal antibodies in multiple biochemical assays. Each peptide module in the branched structure makes unique contributions to affinity and/or specificity resulting in a 200 nM affinity ligand that efficiently immunoprecipitates Akt from cancer cell lysates and labels Akt in fixed cells. Our use of a small molecule to preinhibit Akt prior to screening resulted in low micromolar inhibitory potency and an allosteric mode of inhibition, which is evidenced through a series of competitive enzyme kinetic assays. To demonstrate the efficiency and selectivity of the protein-templated in situ click reaction, we developed a novel QPCR-based methodology that enabled a quantitative assessment of its yield. These results point to the potential for iterative in situ click chemistry to generate potent, synthetically accessible antibody replacements with novel inhibitory properties.

Accurate MALDI-TOF/TOF sequencing of one-bead-one-compound peptide libraries with application to the identification of multiligand protein affinity agents using in situ click chemistry screening.

Combinatorial one-bead-one-compound (OBOC) peptide libraries are widely used for affinity screening, and the sequencing of peptides from hit beads is a key step in the process. For rapid sequencing, CNBr cleavage of the peptides from the beads, followed by de novo sequencing by MALDI-TOF/TOF, is explored. We report on a semiautomated sequencing algorithm and validate it through comparison against Edman degradation sequencing. The initial 44% sequencing success rate of the standard de novo sequencing software was improved to nearly 100%. The sequencing algorithm incorporates existing knowledge of amino acid chemistry and a new strategy for differentiating isobaric amino acids. We tested the algorithm by using MALDI-TOF/TOF to identify a peptide biligand affinity agent against the protein bovine carbonic anhydrase II, starting from comprehensive one-bead-one-compound peptide libraries comprised of non-natural and artificial amino acid components and using the strategy of in situ click/OBOC library screening.

Directing GDNF-mediated neuronal signaling with proactively programmable cell-surface saccharide-free glycosaminoglycan mimetics.

A significant barrier to harnessing the power of cell-surface glycosaminoglycans (GAGs) to modulate glial cell-line-derived neurotrophic factor (GDNF) signaling is the difficulty in accessing key GAG structures involved. Here, we report tailored GDNF signaling using synthetic polyproline-based GAG mimetics (PGMs). PGMs deliver the much needed proactive programmability for GDNF recognition and effectively modulate GDNF-mediated neuronal processes in a cellular context.

Silica-supported catalysts for ring-closing metathesis: effects of linker group and microenvironment on recyclability.

The interesting effects of the linker and microenvironment on the recyclability of well-defined silica-supported catalysts were examined, which demonstrated the excellent activity and reusability for the ring-closing metathesis (RCM) of a number of substrates.

A Review of Resveratrol as a Potent Chemoprotective and Synergistic Agent in Cancer Chemotherapy.

Background: Cancer has become a major disease endangering human health around the world. Conventional chemotherapy suffers from many side effects including pain, cardiotoxicity, hepatotoxicity, and renal toxicity. This review aims to describe a natural product of resveratrol as a chemoprotective and synergistic agent in the modulation of cancer chemotherapy. Methods: The publications were identified by comprehensive searching of SciFinder, PubMed, Web of Science, and our own reference library. Search terms included combinations of "resveratrol," "cancer," "natural products," "chemotherapy," and "side effects." Selection of material focused on resveratrol reducing the side effects on cancer chemotherapy. Results: Thirty one references were referred in this review to outline resveratrol as a potent chemoprotective and synergistic agent in cancer chemotherapy, including 22 papers for describing the chemoprotective effects, and 9 papers for illustrating the synergistic effects. Conclusion: This study provides a systematic summary of resveratrol serving as a potent chemoprotective and synergistic agent to reduce the associated-side effects and enhance the therapeutic outcomes in cancer chemotherapy. Further studies in terms of resveratrol on a large amount of preclinical tests and clinical trials are highly demanded.

Facile saccharide-free mimetics that recapitulate key features of glycosaminoglycan sulfation patterns.

Controlling glycosaminoglycan (GAG) activity to exploit its immense potential in biology ultimately requires facile manipulation of sulfation patterns associated with GAGs. However, satisfying this requirement in full remains challenging, given that synthesis of GAGs is technically arduous while convenient GAG mimetics often produce sulfation patterns that are uncharacteristic of GAGs. To overcome this, we develop saccharide-free polyproline-based GAG mimetics (PGMs) that can be facilely assembled via amide coupling chemistry. Molecular dynamics simulations show that PGMs recapitulate key GAG structural features (i.e. ∼9 Å-sized repeating units, periodicity and helicity) and as with GAGs, can be tuned to introduce systematic variations in sulfate clustering and spacing. Functionally, a variety of PGMs control various GAG activities (concerning P-selectin, neurotrophic factors and heparinase) and exhibit GAG-like characteristics such as progressive modulation, comparable effectiveness with heparins, need for different sequences to suit different activities and the presence of a "minimal bioactive length". Furthermore, PGMs produce consistent effects in vivo and successfully provide therapeutic benefits over cancer metastasis. Taken together with their high level of biosafety, PGMs answer the long-standing need for an effective and practicable strategy to manipulate GAG-appropriate sulfation patterns and exploit GAG activity in medicine and biotechnology.

A Versatile Microarray Immobilization Strategy Based on a Biorthogonal Reaction Between Tetrazine and Trans-Cyclooctene.

Given its increasing importance in transforming biomedical research in recent years, microarray technology has become highly popular as a powerful screening platform in detecting biomolecule interactions, discovering new inhibitors, and identifying biomarkers as well as diagnosing disease. The success of microarray technology in various biological applications is highly dependent on the accessibility, the functionality, and the density of the surface bound biomolecules. Therefore, compound immobilization represents a critical step for the successful implementation of microarray screening. Herein we describe a fast and site-specific microarray immobilization approach by using trans-cyclooctene-tetrazine ligation. This approach not only ensures fast immobilization and uniform display of biomolecules, but also allows the optimum orientation of biomolecules after immobilization. All these excellent properties facilitate subsequent interactions of the biomolecules and their interacting partners during the screening process. We envision that the immobilization strategy described here can find useful applications in many other microarray related studies.

Recent Advances in Synthesis and Identification of Cyclic Peptides for Bioapplications.

Cyclic peptides, owing to their good stability, high resistance to exo- and to some extent endo-peptidases, enhanced binding affinity and selectivity towards target biomolecules, are actively investigated as biochemical tools and therapeutic agents. In this review, we discuss various commonly utilized synthetic strategies for cyclic peptides and peptoids (peptidomimetics), their important screening methods to identify the bioactive cyclic peptides and peptoids such as combinatorial beadbased peptide library, phage display, mRNA display etc. and recent advances in their applications as bioactive compounds. Lastly, we also make a summary and provide an outlook of the research area.

Integration of Novel Materials and Advanced Genomic Technologies into New Vaccine Design.

Designing new vaccines is one of the most challenging tasks for public health to prevent both infectious and chronic diseases. Even though many research scientists have spent great efforts in improving the specificity, sensitivity and safety of current available vaccines, there are still much space on how to effectively combine different biomaterials and technologies to design universal or personalized vaccines. Traditionally, vaccines were made based on empirical approaches designed to mimic immunity induced by natural infection. Either live attenuated or killed whole microorganisms were used as vaccines. With the development of biomaterial science, DNA/RNA, recombinant vector, adjuvant and nanoparticles greatly expand the category of vaccines. More importantly, with the tremendous advances of new technologies including genomics, proteomics and immunomics, the paradigm of vaccine design has shifted from microbiological to sequence-based approaches. This ever-growing large amount of genomic data and new genomic approaches such as comparative genomics, reverse vaccinology and pan-genomics, will play critical roles in novel vaccine design and enable development of more effective vaccines to cure and control both chronic and infectious diseases. In this review, we summarize current various vaccine materials, advanced technologies and combinational strategies to integrate biomaterials and advanced technologies for vaccine design, which we hope will provide some very useful guidelines and perspectives for the vaccine design.