Development of a high-resolution typing method for SLA-3, swine MHC class I antigen 3.

We developed a high-resolution and comprehensive typing method for swine leukocyte antigen 3 (SLA-3), an MHC class I gene, employing locus-specific genomic PCR followed by subsequent direct sequencing. A total of 292 individuals from nine pure, one cross-breed and six cell lines were successfully typed. A total of 21 SLA-3 alleles were identified, of which four were found to be novel alleles. However, the allelic diversity of SLA-3 was lower than that of previously reported class I genes, SLA-1 and -2. More SLA-3 alleles were observed in the Landrace and Yorkshire breeds than the other breeds. SLA-3*04:01 was identified in seven out of nine breeds and was the most widely distributed allele across all breeds. Therefore, the typing method reported in this study completes our efforts to develop high-resolution typing methods for major SLA molecules, facilitating the combined analysis of major SLA genes from field samples, which is important to understand the relationship between the adaptive immune responses against pathogens and the immunogenetic makeup of an individual.

Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.

BACKGROUND: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. PATIENTS AND METHODS: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. RESULTS: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. CONCLUSION: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

Bioinspired Catecholic Primers for Rigid and Ductile Dental Resin Composites.

In the construction of dental restorative polymer composite materials, surface priming on mineral fillers is essential to improve the mechanical performance of the composites. Here we present bioinspired catechol-functionalized primers for a tougher dental resin composite containing glass fillers. The catecholic primers with different polymerizable end groups were designed and then coated on glass surfaces using a simple drop-casting or dip-coating process. The surface binding ability and possible cross-linking (coupling or chemical bridging between the glass substrate and the dental resin) of the catecholic bifunctional primers were evaluated using atomic force microscopy, contact angle measurements, and the knife shear bonding test and compared to a state-of-the-art silane-based coupling agent. Various mechanical tests including shrinkage and compression tests of the dental resin composites were also conducted. Compression tests of the composites containing the catecholic primed fillers exhibited enhanced mechanical properties, owing to the bidentate hydrogen bonding of catechol moieties to the oxide mineral surface. Furthermore, the superior biocompatibility of the primed surface was confirmed via cell attachment assay, thus providing applicability of catecholic primers for practical dental and biomedical applications.

Toughening elastomers using mussel-inspired iron-catechol complexes.

Materials often exhibit a trade-off between stiffness and extensibility; for example, strengthening elastomers by increasing their cross-link density leads to embrittlement and decreased toughness. Inspired by cuticles of marine mussel byssi, we circumvent this inherent trade-off by incorporating sacrificial, reversible iron-catechol cross-links into a dry, loosely cross-linked epoxy network. The iron-containing network exhibits two to three orders of magnitude increases in stiffness, tensile strength, and tensile toughness compared to its iron-free precursor while gaining recoverable hysteretic energy dissipation and maintaining its original extensibility. Compared to previous realizations of this chemistry in hydrogels, the dry nature of the network enables larger property enhancement owing to the cooperative effects of both the increased cross-link density given by the reversible iron-catecholate complexes and the chain-restricting ionomeric nanodomains that they form.

Significant Performance Enhancement of Polymer Resins by Bioinspired Dynamic Bonding.

Marine mussels use catechol-rich interfacial mussel foot proteins (mfps) as primers that attach to mineral surfaces via hydrogen, metal coordination, electrostatic, ionic, or hydrophobic bonds, creating a secondary surface that promotes bonding to the bulk mfps. Inspired by this biological adhesive primer, it is shown that a ≈1 nm thick catecholic single-molecule priming layer increases the adhesion strength of crosslinked polymethacrylate resin on mineral surfaces by up to an order of magnitude when compared with conventional primers such as noncatecholic silane- and phosphate-based grafts. Molecular dynamics simulations confirm that catechol groups anchor to a variety of mineral surfaces and shed light on the binding mode of each molecule. Here, a ≈50% toughness enhancement is achieved in a stiff load-bearing polymer network, demonstrating the utility of mussel-inspired bonding for processing a wide range of polymeric interfaces, including structural, load-bearing materials.

Perspectives on Mussel-Inspired Wet Adhesion.

Nature employs sophisticated control of a structure's properties at multiple length scales to achieve its wet adhesion. However, the translation of such structures has very often been missing in biomimetic adhesives; in turn, their performance is significantly limited as compared to that of biological adhesion, e.g., from mussels. In this Perspective, we overview the major breakthroughs in this field, highlighting the recent advances that demonstrate that holistic multiscale translation is essential to biomimetic design. We argue that the multiscale coordination of numerous key elements in the natural adhesive system is essential to replicate the strong, instant, and durable wet adhesion of the marine sessile organism.

Molecularly Smooth Self-Assembled Monolayer for High-Mobility Organic Field-Effect Transistors.

Despite the need for molecularly smooth self-assembled monolayers (SAMs) on silicon dioxide surfaces (the most common dielectric surface), current techniques are limited to nonideal silane grafting. Here, we show unique bioinspired zwitterionic molecules forming a molecularly smooth and uniformly thin SAM in "water" in <1 min on various dielectric surfaces, which enables a dip-coating process that is essential for organic electronics to become reality. This monomolecular layer leads to high mobility of organic field-effect transistors (OFETs) based on various organic semiconductors and source/drain electrodes. A combination of experimental and computational techniques confirms strong adsorption (Wad > 20 mJ m-2), uniform thickness (∼0.5 or ∼1 nm) and orientation (all catechol head groups facing the oxide surface) of the "monomolecular" layers. This robust (strong adsorption), rapid, and green SAM represents a promising advancement toward the next generation of nanofabrication compared to the current nonuniform and inconsistent polysiloxane-based SAM involving toxic chemicals, long processing time (>10 h), or heat (>80 °C).

Attosecond nanoscale near-field sampling.

The promise of ultrafast light-field-driven electronic nanocircuits has stimulated the development of the new research field of attosecond nanophysics. An essential prerequisite for advancing this new area is the ability to characterize optical near fields from light interaction with nanostructures, with sub-cycle resolution. Here we experimentally demonstrate attosecond near-field retrieval for a tapered gold nanowire. By comparison of the results to those obtained from noble gas experiments and trajectory simulations, the spectral response of the nanotaper near field arising from laser excitation can be extracted.

Marine Bioinspired Underwater Contact Adhesion.

Marine mussels and barnacles are sessile biofouling organisms that adhere to a number of surfaces in wet environments and maintain remarkably strong bonds. Previous synthetic approaches to mimic biological wet adhesive properties have focused mainly on the catechol moiety, present in mussel foot proteins (mfps), and especially rich in the interfacial mfps, for example, mfp-3 and -5, found at the interface between the mussel plaque and substrate. Barnacles, however, do not use Dopa for their wet adhesion, but are instead rich in noncatecholic aromatic residues. Due to this anomaly, we were intrigued to study the initial contact adhesion properties of copolymerized acrylate films containing the key functionalities of barnacle cement proteins and interfacial mfps, for example, aromatic (catecholic or noncatecholic), cationic, anionic, and nonpolar residues. The initial wet contact adhesion of the copolymers was measured using a probe tack testing apparatus with a flat-punch contact geometry. The wet contact adhesion of an optimized, bioinspired copolymer film was ∼15.0 N/cm(2) in deionized water and ∼9.0 N/cm(2) in artificial seawater, up to 150 times greater than commercial pressure-sensitive adhesive (PSA) tapes (∼0.1 N/cm(2)). Furthermore, maximum wet contact adhesion was obtained at ∼pH 7, suggesting viability for biomedical applications.

Optimization of a nanotip on a surface for the ultrafast probing of propagating surface plasmons.

We theoretically analyze a method for characterizing propagating surface plasmon polaritons (SPPs) on a thin gold film. The SPPs are excited by few-cycle near-infrared pulses using Kretschmann coupling, and a nanotip is used as a local field sensor. This geometry removes the influence of the incident excitation laser from the near fields, and enhances the plasmon electric field strength. Using finite-difference-time-domain studies we show that the geometry can be used to measure SPP waveforms as a function of propagation distance. The effects of the nanotip shape and material on the field enhancement and plasmonic response are discussed.

Underwater contact adhesion and microarchitecture in polyelectrolyte complexes actuated by solvent exchange.

Polyelectrolyte complexation is critical to the formation and properties of many biological and polymeric materials, and is typically initiated by aqueous mixing followed by fluid-fluid phase separation, such as coacervation. Yet little to nothing is known about how coacervates evolve into intricate solid microarchitectures. Inspired by the chemical features of the cement proteins of the sandcastle worm, here we report a versatile and strong wet-contact microporous adhesive resulting from polyelectrolyte complexation triggered by solvent exchange. After premixing a catechol-functionalized weak polyanion with a polycation in dimethyl sulphoxide (DMSO), the solution was applied underwater to various substrates whereupon electrostatic complexation, phase inversion, and rapid setting were simultaneously actuated by water-DMSO solvent exchange. Spatial and temporal coordination of complexation, inversion and setting fostered rapid (∼25 s) and robust underwater contact adhesion (Wad ≥ 2 J m(-2)) of complexed catecholic polyelectrolytes to all tested surfaces including plastics, glasses, metals and biological materials.

Glioma invasion mediated by the p75 neurotrophin receptor (p75(NTR)/CD271) requires regulated interaction with PDLIM1.

The invasive nature of glioblastoma renders them incurable by current therapeutic interventions. Using a novel invasive human glioma model, we previously identified the neurotrophin receptor p75(NTR) (aka CD271) as a mediator of glioma invasion. Herein, we provide evidence that preventing phosphorylation of p75(NTR) on S303 by pharmacological inhibition of PKA, or by a mutational strategy (S303G), cripples p75(NTR)-mediated glioma invasion resulting in serine phosphorylation within the C-terminal PDZ-binding motif (SPV) of p75(NTR). Consistent with this, deletion (ΔSPV) or mutation (SPM) of the PDZ motif results in abrogation of p75(NTR)-mediated invasion. Using a peptide-based strategy, we identified PDLIM1 as a novel signaling adaptor for p75(NTR) and provide the first evidence for a regulated interaction via S425 phosphorylation. Importantly, PDLIM1 was shown to interact with p75(NTR) in highly invasive patient-derived glioma stem cells/tumor-initiating cells and shRNA knockdown of PDLIM1 in vitro and in vivo results in complete ablation of p75(NTR)-mediated invasion. Collectively, these data demonstrate a requirement for a regulated interaction of p75(NTR) with PDLIM1 and suggest that targeting either the PDZ domain interactions and/or the phosphorylation of p75(NTR) by PKA could provide therapeutic strategies for patients with glioblastoma.

High-performance mussel-inspired adhesives of reduced complexity.

Despite the recent progress in and demand for wet adhesives, practical underwater adhesion remains limited or non-existent for diverse applications. Translation of mussel-inspired wet adhesion typically entails catechol functionalization of polymers and/or polyelectrolytes, and solution processing of many complex components and steps that require optimization and stabilization. Here we reduced the complexity of a wet adhesive primer to synthetic low-molecular-weight catecholic zwitterionic surfactants that show very strong adhesion (∼50 mJ m(-2)) and retain the ability to coacervate. This catecholic zwitterion adheres to diverse surfaces and self-assembles into a molecularly smooth, thin (<4 nm) and strong glue layer. The catecholic zwitterion holds particular promise as an adhesive for nanofabrication. This study significantly simplifies bio-inspired themes for wet adhesion by combining catechol with hydrophobic and electrostatic functional groups in a small molecule.

Field propagation-induced directionality of carrier-envelope phase-controlled photoemission from nanospheres.

Near-fields of non-resonantly laser-excited nanostructures enable strong localization of ultrashort light fields and have opened novel routes to fundamentally modify and control electronic strong-field processes. Harnessing spatiotemporally tunable near-fields for the steering of sub-cycle electron dynamics may enable ultrafast optoelectronic devices and unprecedented control in the generation of attosecond electron and photon pulses. Here we utilize unsupported sub-wavelength dielectric nanospheres to generate near-fields with adjustable structure and study the resulting strong-field dynamics via photoelectron imaging. We demonstrate field propagation-induced tunability of the emission direction of fast recollision electrons up to a regime, where nonlinear charge interaction effects become dominant in the acceleration process. Our analysis supports that the timing of the recollision process remains controllable with attosecond resolution by the carrier-envelope phase, indicating the possibility to expand near-field-mediated control far into the realm of high-field phenomena.

Microphase Behavior and Enhanced Wet-Cohesion of Synthetic Copolyampholytes Inspired by a Mussel Foot Protein.

Numerous attempts have been made to translate mussel adhesion to diverse synthetic platforms. However, the translation remains largely limited to the Dopa (3,4-dihydroxyphenylalanine) or catechol functionality, which continues to raise concerns about Dopa's inherent susceptibility to oxidation. Mussels have evolved adaptations to stabilize Dopa against oxidation. For example, in mussel foot protein 3 slow (mfp-3s, one of two electrophoretically distinct interfacial adhesive proteins in mussel plaques), the high proportion of hydrophobic amino acid residues in the flanking sequence around Dopa increases Dopa's oxidation potential. In this study, copolyampholytes, which combine the catechol functionality with amphiphilic and ionic features of mfp-3s, were synthesized and formulated as coacervates for adhesive deposition on surfaces. The ratio of hydrophilic/hydrophobic as well as cationic/anionic units was varied in order to enhance coacervate formation and wet adhesion properties. Aqueous solutions of two of the four mfp-3s-inspired copolymers showed coacervate-like spherical microdroplets (ϕ ≈ 1-5 µm at pH ∼4 (salt concentration ∼15 mM). The mfp-3s-mimetic copolymer was stable to oxidation, formed coacervates that spread evenly over mica, and strongly bonded to mica surfaces (pull-off strength: ∼17.0 mJ/m(2)). Increasing pH to 7 after coacervate deposition at pH 4 doubled the bonding strength to ∼32.9 mJ/m(2) without oxidative cross-linking and is about 9 times higher than native mfp-3s cohesion. This study expands the scope of translating mussel adhesion from simple Dopa-functionalization to mimicking the context of the local environment around Dopa.

Coherent electronic wave packet motion in C(60) controlled by the waveform and polarization of few-cycle laser fields.

Strong laser fields can be used to trigger an ultrafast molecular response that involves electronic excitation and ionization dynamics. Here, we report on the experimental control of the spatial localization of the electronic excitation in the C_{60} fullerene exerted by an intense few-cycle (4 fs) pulse at 720 nm. The control is achieved by tailoring the carrier-envelope phase and the polarization of the laser pulse. We find that the maxima and minima of the photoemission-asymmetry parameter along the laser-polarization axis are synchronized with the localization of the coherent electronic wave packet at around the time of ionization.

Photodamage attenuation effect by a tetraprenyltoluquinol chromane meroterpenoid isolated from Sargassum muticum.

A tetraprenyltoluquinol meroterpenoid with a chromane moiety, obtained as an epimeric mixture at C3, was isolated for the first time from the dichloromethane fraction of a methanolic extract from the brown alga Sargassum muticum. The structure has been established by means of spectral methods including NMR spectroscopy and MS and comparison with reported data. The compound showed photodamage attenuation on irradiated cells with UVA light, presented protection against intracellular ROS generation in a degree comparable to retinoic acid (9.1-20.6%) and did not display toxicity against human dermal fibroblast cells.

Rice prolamin extract ameliorates acute murine colitis by inhibiting nuclear factor-kappa B and modulating intestinal apoptosis and cell proliferation.

We investigated the impact of rice prolamin extract (RPE) on lipopolysaccharide (LPS)-induced nuclear factor (NF)-κB signalling in intestinal epithelial cells and macrophages, and determined the therapeutic efficacy of RPE in acute murine colitis. The effect of RPE on LPS-induced NF-κB signalling and proinflammatory gene expression was evaluated by reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, immunofluorescence and electrophoretic mobility shift assay (EMSA). The in-vivo efficacy of RPE was assessed in mice with 3% dextran sulphate sodium (DSS)-induced colitis. Apoptotic and cellular proliferative activities were evaluated by immunostaining with cleaved caspase-3 and proliferating cell nuclear antigen (PCNA) antibodies. RPE inhibited LPS-induced expression of monocyte chemotactic protein (MCP)-1, interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha and LPS-induced NF-κB signalling in intestinal epithelial cells and macrophages. RPE-fed, DSS-exposed mice showed less weight loss, longer colon length and lower histological score compared to control diet-fed, DSS-exposed mice. Immunostaining analysis revealed a significant decrease of cleaved caspase-3 positive cells in RPE-fed, DSS-exposed mice compared to DSS-exposed mice. Also, the number of PCNA-positive cells within intact colonic crypts decreased significantly in RPE-fed, DSS-exposed mice compared to control diet-fed, DSS-exposed mice. DSS-induced NF-κB signalling was inhibited by RPE. RPE ameliorates intestinal inflammation by inhibiting NF-κB activation and modulating intestinal apoptosis and cell proliferation in an acute murine colitis.

Surface-initiated self-healing of polymers in aqueous media.

Polymeric materials that intrinsically heal at damage sites under wet or moist conditions are urgently needed for biomedical and environmental applications. Although hydrogels with self-mending properties have been engineered by means of mussel-inspired metal-chelating catechol-functionalized polymer networks, biological self-healing in wet conditions, as occurs in self-assembled holdfast proteins in mussels and other marine organisms, is generally thought to involve more than reversible metal chelates. Here we demonstrate self-mending in metal-free water of synthetic polyacrylate and polymethacrylate materials that are surface-functionalized with mussel-inspired catechols. Wet self-mending of scission in these polymers is initiated and accelerated by hydrogen bonding between interfacial catechol moieties, and consolidated by the recruitment of other non-covalent interactions contributed by subsurface moieties. The repaired and pristine samples show similar mechanical properties, suggesting that the triggering of complete self-healing is enabled underwater by the formation of extensive catechol-mediated interfacial hydrogen bonds.