Members of the Opioid Receptor (OR) family of G protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system where they play key roles in nociception and analgesia. Unlike the classical ORs, δ–OR, κ–OR,1 and μ-OR,2 which were delineated by pharmacological criteria in the 1970’s and 1980’s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, aka ORL-1) was discovered relatively recently via molecular cloning and characterization of an orphan GPCR3. Despite its high sequence similarity (~60%) with ORs, NOP has a strikingly distinct pharmacology4,5. Despite high sequence similarity with classical opioid G protein-coupled receptor subtypes, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) has a distinct biological and pharmacological role, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands. This study reports the crystal structure of human NOP solved in complex with the peptide mimetic antagonist Banyu Compound-24 (C-24), revealing atomic details of ligand-receptor recognition and selectivity. C-24 mimics the first four N-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to binding of these peptides. The X-ray structure also reveals substantial conformational differences in the pocket regions between NOP and the “classical” opioid receptors κ (Ref. 1) and μ (Ref. 2), which are likely due to a small number of residues that vary between the two receptors. The NOP/C-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.

When a powerful femtosecond laser pulse propagates in an optical medium, self-focusing occurs. Normally, it is the most powerful part (slice) of the pulse that self-focuses first during its propagation. Self-focusing is balanced by the creation of plasma in the self-focal volume, which defocuses the pulse. This balance leads to a limitation of the peak intensity (intensity clamping). The series of self-foci from different slices of the front part of the pulse give rise to the perception of a so-called filament. The back part of the pulse undergoes self-phase modulation and self-steepening resulting in a strong spectral broadening. The final pulse is a white-light laser pulse (supercontinuum). The physics of such (long distance) filamentation and the self-transformation process are reviewed both in air and in condensed matters. The self-transformation leads to a shorter pulse and is currently being studied for efficient pulse compression to the single and (or) few-cycle level. The efficient generation of a third harmonic in the filament is due to a new phenomenon called self-phase locking. The potential applications in atmospheric sensing and lightning control will be briefly discussed. The capability of melting glass leading to index change will be underlined. The paper will end with an outlook into the future of the field. PACS Nos.: 42.65, 42.65Jx, 42.25, 42.79Qx

Genetic studies aimed at understanding the molecular basis of complex human phenotypes require the genotyping of many thousands of single-nucleotide polymorphisms (SNPs) across large numbers of individuals. Public efforts have so far identified over two million common human SNPs; however, the scoring of these SNPs is labor-intensive and requires a substantial amount of automation. Here we describe a simple but effective approach, termed whole-genome sampling analysis (WGSA), for genotyping thousands of SNPs simultaneously in a complex DNA sample without locus-specific primers or automation. Our method amplifies highly reproducible fractions of the genome across multiple DNA samples and calls genotypes at >99% accuracy. We rapidly genotyped 14,548 SNPs in three different human populations and identified a subset of them with significant allele frequency differences between groups. We also determined the ancestral allele for 8,386 SNPs by genotyping chimpanzee and gorilla DNA. WGSA is highly scaleable and enables the creation of ultrahigh density SNP maps for use in genetic studies.

Background: Bone marrow-derived mesenchymal stem cells (BMSCs) are a widely researched adult stem cell population capable of differentiation into various lineages. Because many promising applications of tissue engineering require cell expansion following harvest and involve the treatment of diseases and conditions found in an aging population, the effect of donor age and ex vivo handling must be understood in order to develop clinical techniques and therapeutics based on these cells. Furthermore, there currently exists little understanding as to how these two factors may be influenced by one another.

A talin intermolecular interaction autoinhibits its own activation and regulates β3-integrin binding. When bound, β3-integrin undergoes structural alterations that prevent its β and α subunits from associating, maintaining β3-integrin's clustering capability.

Two-dimensional transition-metal dichalcogenides (TMDCs) exhibit extraordinary nonlinearities and direct bandgaps at K (K') valleys. Those valleys could be optically manipulated through the plasmon-valley-exciton coupling, for example, with spin-dependent photoluminescence. However, the weak coherence between the pumping and emission due to intervalley scattering poses formidable challenges in exploring the valley-contrasting physics and applications. Here we show that a synthetic metasurface entangling the phase and spin of light can simultaneously enhance and manipulate the nonlinear valley-locked chiral emission in monolayer tungsten disulfide (WS 2) at room temperature. The second-harmonic valley photons, accessed and coherently pumped by the light with spin-related geometric phase imparted by Au-metasurface, are separated and routed to predetermined directions in free space. Besides, the nonlinear photons with the same spin of incident light can be steered into any predefined direction thanks to the nonlinear optical selection rule of WS 2 in our synthetic metasurface. Our synthetic TMDCs-metasurface interface may facilitate advanced roomtemperature and free-space nonlinear, quantum and valleytronic nanodevices.

The terahertz region is a special region of the electromagnetic spectrum that incorporates the advantages of both microwaves and infrared light waves. In the past decade, metamaterials with effective medium parameters or gradient phases have been studied to control terahertz waves and realize functional devices. Here, we present a new approach to manipulate terahertz waves by using coding metasurfaces that are composed of digital coding elements. We propose a general coding unit based on a Minkowski closed-loop particle that is capable of generating 1-bit coding (with two phase states of 0 and 1806), 2-bit coding (with four phase states of 0, 906, 1806, and 2706), and multi-bit coding elements in the terahertz frequencies by using different geometric scales. We show that multi-bit coding metasurfaces have strong abilities to control terahertz waves by designing-specific coding sequences. As an application, we demonstrate a new scattering strategy of terahertz waves-broadband and wide-angle diffusion-using a 2-bit coding metasurface with a special coding design and verify it by both numerical simulations and experiments. The presented method opens a new route to reducing the scattering of terahertz waves.

ObjectiveThe lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC.DesignApplying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2554 Chinese subjects: 1204 patients with HCC, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC) and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularisation for feature selection.ResultsThe 5hmC-Seal data from patients with HCC showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer staging system from non-HCC (validation set: area under curve (AUC)=88.4%; (95% CI 85.8% to 91.1%)), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumours (eg, ≤2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC=84.6%; (95% CI 80.6% to 88.7%)), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (eg, smoking/alcohol intake history).ConclusionWe have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals.