Revealing the excited-state dynamics of cytidine and the role of excited-state proton transfer process.

The high photostability of DNAs and RNAs is inextricably related to the photochemical and photophysical properties of their building blocks, nucleobases and nucleosides, which can dissipate the absorbed UV light energy in a harmless manner. The deactivation mechanism of the nucleosides, especially the decay pathways of cytidine (Cyd), has been a matter of intense debate. In the current study, we employ high-level electronic structure calculations combined with excited state non-adiabatic dynamic simulations to provide a clear picture of the excited state deactivation of Cyd in both gas phase and aqueous solution. In both environments, a barrierless decay path driven by the ring-puckering motion and a relaxation channel with a small energy barrier driven by the elongation motion of CO bond are assigned to <200 fs and sub-picosecond decay time component, respectively. The presence of ribose group has a subtle effect on the dynamic behavior of Cyd in gas phase as the ribose-to-base hydrogen/proton transfer process is energetically inaccessible with a sizable energy barrier of about 1.4 eV. However, this energy barrier is significantly reduced in water, especially when an explicit water molecule is present. Therefore, we argue that the long-lived decay channel found in aqueous solution could be assigned to the Cyd-water intermolecular hydrogen/proton transfer process. The present study postulates a novel scenario toward deep understanding the intrinsic photostability of DNAs and RNAs and provides solid evidence to disclose the long history debate of cytidine excited-state decay mechanism, especially for the assignment of experimentally observed time components.

Rectified Bloch oscillations in dynamically modulated waveguide arrays.

We study the dynamics of excitations in dynamically modulated waveguide arrays with an external spatial linear potential. Longitudinally periodic modulation may cause a significant change in the width of the quasi-energy band and leads to the dynamical band suppression with a linear dispersion relation. This substantially affects the Bloch oscillation dynamics. Novel dynamical phenomena with no analogue in ordinary discrete waveguides, named rectified Bloch oscillations, are highlighted. Due to the interplay between directional coupling between adjacent waveguides and diffraction suppression by the introduced onsite energy difference, at odd times of half Bloch oscillations period, the new submodes are continuously excited along two opposite rectification directions and experience same oscillation evolution, and eventually lead to the formation of a diamondlike intensity network. Both the amplitude and direction of the rectified Bloch oscillations strongly depend on the coupling strength. When coupling strength passes the critical value at which dynamical band suppression with a linear dispersion relation occurs, the direction of Bloch oscillations is inverted.

Photonic Hooks Generated by a Concave Micro-Cylinder Based on Structure-Constrained Functions.

Owing to its crooked trajectory and small full width at half-maximum, photonic hook (PH) has attracted wide attention since its inception and experimental confirmation. However, the present generation and regulation of PH are mostly dependent on the breaking of the symmetry of the system composed of the incident light and the regular structure particles, which inevitably limits the research of PH. In this work, the PH of the irregular particles is demonstrated with the help of a structure-constrained function (SCF). By varying the coefficients of the function, characteristic parameters of the PH, such as the bending angle, the effective length and the bending direction, can be effectively modulated. Meanwhile, high-quality PHs with a bending angle of up to 46∘ and an effective length of up to 11.90λ, as well as PHs with three bends, can be obtained using this method. The formation mechanism of the PH is revealed by simulating the distribution of the field intensity with the finite element method and analyzing with ray optics. This is the first time that we introduce a function into the investigation of PH, paving a new way for a more interesting exploration of PH.

Optical trapping force and torque on spheroidal Rayleigh particles with arbitrary spatial orientations.

We investigate the spatial orientation dependence of optical trapping forces and intrinsic torques exerted on spheroidal Rayleigh particles under irradiation of highly focused linearly and circularly polarized beams. It is revealed that the maximal trapping forces and torques strongly depend on the orientation of the spheroid, and the spheroidal particle is driven to be stably trapped at the beam focus with its major axis perpendicular to the optical axis. For a linearly polarized trapping beam, the optical torque is always perpendicular to the plane containing the major axis and the polarization direction of the incident beam. Therefore, the spheroid tends to rotate its major axis along with the polarization direction. However, for a circularly polarized trapping beam, the optical torque is always perpendicular to the plane containing the major axis and the optical axis. What is different from the linear polarization case is that the spheroid tends to have the major axis parallel to the projection of the major axis in the transverse plane. The optical torque in the circular polarization case is half of that in the linear polarization case. These optical trapping properties may be exploited in practical optical manipulation, especially for the nonspherical particle's trapping.

Experimental demonstration of 3D accelerating beam arrays.

Accelerating beams have attracted much attention in the frontiers of optical physics and technology owing to their unique propagation dynamics of nondiffracting, self-healing, and freely accelerating along curved trajectories. Such behaviors essentially arise from the particular phase factor occurring in their spatial frequency spectrum, e.g., the cubic phase associated to the spectrum of Airy beam. In this paper, we theoretically and experimentally demonstrate a sort of accelerating beam arrays, which are composed of spatially separated accelerating beams. By superimposing kinoforms of multifocal patterns into the spatial frequency spectrum of accelerating beams, different types of beam arrays, e.g., Airy beam arrays and two-main-lobe accelerating beam arrays, are generated and measured by scanning a reflection mirror near the focal region along the optical axis. The 3D intensity patterns reconstructed from the experimental data present good agreement with the theoretical counterparts. The combination of accelerating beams with optical beam arrays proposed here may find potential applications in various fields such as optical microscopes, optical micromachining, optical trapping, and so on.

Phase stitching and error correction in aperture synthesis for generalized phase-shifting interferometry.

An accurate aperture synthesis method in generalized phase-shifting interferometry is suggested to improve the quality of the reconstructed object wavefront by stitching both the phase and the real amplitude of the object wave on the recording plane. Since the phase distribution affects the reconstruction of the original object wavefront, phase stitching is also important in aperture synthesis. Double correlations are used to find the proper relative locations and correct the phase error of subwavefronts on the recording plane. By using phase correction, the phase distributions of subwavefronts are combined perfectly. Corresponding optical experimental results have verified the effectiveness of this method, which can stitch not only the real amplitudes but also the phases of the complex amplitudes of the object wave on the recording plane and improve the quality of the reconstructed object image.

High-precision phase-shifting interferometry with spherical wavefront reference.

An advanced phase-shifting interferometry approach with a spherical wavefront reference is proposed to improve the quality of the holographic image by avoiding errors caused by noncollimated reference and lowering the resolution of the recording device. By considering not only the real amplitude but also the phase distribution of a spherical wavefront reference, a singular object-wave reconstruction formula is deduced. The suggested method here can work without using the collimator in the reference wave and can then remove all the errors incurred by it. Computer simulations demonstrate that this technique is more convenient in the recording process and can improve the precision of the reconstructed wavefront by more than one order of magnitude after considering the real reference amplitude. Optical experiment results show the feasibility and effectiveness of this method.

Donor-acceptor compound based on rhodanineacetic acid-pyrene derivative: red-light emitting fluorescent organic nanoparticles.

A donor-acceptor compound based on Rhodanineacetic acid-pyrene derivative (RAAP), which emits weak yellow-green fluorescence in the methanol solution, was investigated. RAAP nanoparticles with a mean diameter of 50-60 nm were prepared by a simple reprecipitation method without surfactants. The observation of RAAP nanoparticles were undertaken through SEM and TEM method. The emission spectra of RAAP nanoparticles are red-shifted (Δ λ(em) = 86 nm) to red region and the intensity is 40-fold higher than that in the methanol solution. Both the J-aggregation and aggregation-induced intramolecular planarization are considered to be the probable mechanism of strong emission for RAAP nanoparticles. The excellent sensibility toward organic vapor which profits from its fluorescence switching behavior is well demonstrated by vapor experiment.

2-Hy-droxy-ethanaminium 2,4-dinitro-phenolate hemihydrate.

In the title salt, C(2)H(8)NO(+)·C(6)H(3)N(2)O(5) (-)·0.5H(2)O, the anions, cations and water mol-ecules are linked via N-H⋯O and O-H⋯O hydrogen bonds, forming a three-dimensionl network.

Further structure-activity studies of lactam derivatives of MT-II and SHU-9119: their activity and selectivity at human melanocortin receptors 3, 4, and 5.

Recently we have demonstrated that replacing His(6) by constrained amino acids(2) in the well-known antagonist SHU-9119 resulted in potent and selective antagonist ligands especially at the hMC3R and hMC5 receptors. With the aim to further explore position 6 in the sequence of SHU-9119 and MT-II, we have designed, synthesized, and pharmacologically characterized a series of peptide analogues of MT-II and SHU-9119 at the human melanocortin receptors subtypes MC3R, MC4R and MC5R. All these peptides were modified at position 6 with constrained amino acids which are commercially available. In this study, we have identified new selective ligands for the hMC4R, and an antagonist for the hMC3/hMC4 receptors. Additionally, we have discovered an interesting new selective antagonist at the hMC3R, Ac-Nle-c[Asp-betaAla-DNal(2')-Arg-Trp-Lys]-NH(2) (2, PG-106) which represents an important tool in further biological investigations of the hMC3R. PG-106 will be useful in further efforts to differentiate the substructural features responsible for selectivity at the hMC3R, hMC4R, and hMC5R.

The expansion coefficients of arbitrary shaped beam in oblique illumination.

In generalized Lorenz-Mie theories, (GLMTs), the most difficult task concerns the description of the illuminating beam. We provide an approach for expansions of the incident arbitrary shaped beam in spherical and spheroidal coordinates in the general case of oblique illumination. The representations for shaped beam coefficients are derived by using addition theorem for spherical vector wave functions under coordinate rotations. For the special cases of the particle center located on shaped beam axis and plane wave, the simplified expressions are given. The convergence of the beam shape coefficients is discussed.

De novo design, synthesis, and pharmacology of alpha-melanocyte stimulating hormone analogues derived from somatostatin by a hybrid approach.

A number of alpha-melanotropin (alpha-MSH) analogues have been designed de novo, synthesized, and bioassayed at different melanocortin receptors from frog skin (fMC1R) and mouse/rat (mMC1R, rMC3R, mMC4R, and mMC5R). These ligands were designed from somatostatin by a hybrid approach, which utilizes a modified cyclic structure (H-d-Phe-c[Cys---Cys]-Thr-NH(2)) related to somatostatin analogues (e.g. sandostatin) acting at somatostatin receptors, CTAP which binds specifically to micro opioid receptors, and the core pharmacophore of alpha-MSH (His-Phe-Arg-Trp). Ligands designed were H-d-Phe-c[XXX-YYY-ZZZ-Arg-Trp-AAA]-Thr-NH(2) [XXX and AAA = Cys, d-Cys, Hcy, Pen, d-Pen; YYY = His, His(1'-Me), His(3'-Me); ZZZ = Phe and side chain halogen substituted Phe, d-Phe, d-Nal(1'), and d-Nal(2')]. The compounds showed a wide range of bioactivities at the frog skin MC1R; e.g. H-d-Phe-c[Hcy-His-d-Phe-Arg-Trp-Cys]-Thr-NH(2) (6, EC(50) = 0.30 nM) and H-d-Phe-c[Cys-His-d-Phe-Arg-Trp-d-Cys]-Thr-NH(2) (8, EC(50) = 0.10 nM). In addition, when a lactam bridge was used as in H-d-Phe-c[Asp-His-d-Phe-Arg-Trp-Lys]-Thr-NH(2) (7, EC(50) = 0.10 nM), the analogue obtained is as potent as alpha-MSH in the frog skin MC1R assay. Interestingly, switching the bridge of 6 to give H-d-Phe-c[Cys-His-d-Phe-Arg-Trp-Hcy]-Thr-NH(2) (5, EC(50) = 1000 nM) led to a 3000-fold decrease in agonist activity. An increase in steric size in the side chain of d-Phe(7) reduced the bioactivity significantly. For example, H-d-Phe-c[Cys-His-d-Nal(1')-Arg-Trp-d-Cys]-Thr-NH(2) (24) is 2000-fold less active than 9. On the other hand, H-d-Phe-c[Cys-His-d-Phe(p-I)-Arg-Trp-d-Cys]-Thr-NH(2) (23) lost all agonist activity and became a weak antagonist (IC(50) = 1 x 10(-5) M). Furthermore, the modified CTAP analogues with a d-Trp at position 7 all showed weak antagonist activities (EC(50) = 10(-6) to 10(-7) M). Compounds bioassayed at mouse/rat MCRs displayed intriguing results. Most of them are potent at all four receptors tested (mMC1R, rMC3R, mMC4R, and mMC5R) with poor selectivities. However, two of the ligands, H-d-Phe-c[Cys-His-d-Phe-Arg-Trp-Pen]-Thr-NH(2) (9, EC(50) = 6.9 x 10(-9) M, 6.4 x 10(-8) M, 2.0 x 10(-8) M, and 1.4 x 10(-10) M at mMC1R, rMC3R, mMC4R, and mMC5R, respectively) and H-d-Phe-c[Cys-His(3'-Me)-d-Phe-Arg-Trp-Cys]-Thr-NH(2) (16, EC(50) = 3.5 x 10(-8) M, 3.1 x 10(-8) M, 8.8 x 10(-9) M, and 5.5 x 10(-10) M at mMC1R, rMC3R, mMC4R, and mMC5R, respectively) showed significant selectivities for the mMC5R. Worthy of mention is that neither of these two ligands is potent in the frog skin MC1R assay (EC(50) = 10(-7) M for 9 and EC(50) = 10(-5) M for 16). These results clearly demonstrated that binding behaviors in rodent MCRs are quite different from those in the classical frog skin (R pipiens) assay.

Exploring the stereostructural requirements of peptide ligands for the melanocortin receptors.

The melanotropin peptides alpha-MSH, gamma-MSH, and beta-MSH are believed to be the natural ligands for the four melanocortin receptors, MC1R, MC3R, MC4R, and MC5R. However, these peptides generally have low selectivity for these receptors. We report on some approaches to the development of selective agonists and antagonists peptide ligands for these receptors.

MT-II induces penile erection via brain and spinal mechanisms.

alpha-Melanocyte-stimulating hormone induces penile erection via melanocortin (MC) receptors in areas surrounding the third ventricle, but spinal and peripheral mechanisms have not been demonstrated. We used pharmacological strategies to localize the site of the proerectile action of the melanocortin receptor agonist MT-II. We administered MT-II intracerebroventribularly (i.c.v.), intrathecally (i.th.), and intravenously (i.v.) and scored penile erection and yawning for 90 min in awake male rats. In some animals i.c.v. or i.th. SHU-9119 was injected 10 minutes before i.c.v. and i.th. MT-II to confirm the MC receptor action of the agonist and to distinguish spinal from supraspinal effects. To exclude a site of action in the penis, we recorded intracorporal pressure responses to intracavernosal injection of MT-II in the anesthetized rat. MT-II induced penile erections in a dose-dependent fashion, with optimal response at 1 microg for both i.c.v. and i.th. routes. Supraspinal MT-II-induced erections were completely suppressed by 1 microg SHU-9119 i.c.v. Yawning was observed with i.c.v. and i.v. MT-II, whereas spinal injection did not produce this behavior. SHU-9119 blocked the erectile responses to i.th. MT-II when injected i.th. but not i.c.v. Intracavernosal MT-II neither increased intracorporal pressure nor augmented neurostimulated erectile responses. The lumbosacral spinal cord contains MC receptors that can initiate penile erection independent of higher centers. We confirmed the supraspinal proerectile action of MT-II. These results provide insight into the central melanocortinergic pathways that mediate penile erection and may allow for more efficacious melanotropin-based therapy for erectile dysfunction.

Solution structures of cyclic melanocortin agonists and antagonists by NMR.

The melanocortin receptors are involved in many physiological functions, including pigmentation, sexual function, feeding behavior, and energy homeostasis, making them potential targets for drugs to treat obesity, sexual dysfunction, etc. Understanding the conformational basis of the receptor-ligand interactions is crucial to the design of potent and selective ligands for these receptors. The solution structures of the cyclic melanocortin agonists, partial agonist, and antagonists MTII, VJH085, SHU9119, MK5, and MK9 were determined by two-dimensional nuclear magnetic resonance (2D NMR) spectroscopy at pH 4.5 and 25 degrees C in water (90% H(2)O/10% D(2)O). The overall backbone structures of these cyclic alpha-melanocyte-stimulating hormone (alpha-MSH) analogues around the message sequence (His(6)-D-Phe(7)/D-Nal(2')(7)-Arg(8)-Trp(9)) were similar and reasonably well defined. beta-Turns spanning His(6) and D-Phe(7)/D-Nal(2')(7) were identified in all analogues, and an amphiphilic molecular surface was obtained for the message sequence residues in most structures within the NMR ensembles. The beta-turn, which most closely resembles a type II beta-turn, leads to stacking between the aromatic rings of His(6) and D-Phe(7) in MTII and VJH085. However, no aromatic stacking between His(6) and D-Nal(2')(7) was found in structures of the D-Nal(2')(7)-containing analogues. The difference in the side-chain dispositions of His(6) and D-Nal(2')(7) may be responsible for the reduced potency or antagonist activity of the D-Nal(2')(7)-containing analogues. In addition, our results suggest that the side-chain orientations may also modulate the receptor selectivity. The information found in this study will be useful for the further design of ligands for melanocortin receptors.

Novel cyclic templates of alpha-MSH give highly selective and potent antagonists/agonists for human melanocortin-3/4 receptors.

In an effort to develop highly selective and potent agonists and/or antagonists for the hMC3 and hMC4 receptors, a new approach involving the use of linker arms and a backbone to side chain cyclization strategy was employed. Three key analogues were identified to have the required selectivity and potency at the hMC3 or hMC4 receptors, implicated to play pivotal roles in energy homeostasis and other biological effects. The novel cyclic peptide (O)C-CH(2)-CH(2)-C(O)-c-[His(6)-D-Phe(7)-Arg(8)-Trp(9)-Lys(10)]-NH(2) (1) was found to be a highly selective and potent agonist of the hMC4 receptor. Structure-activity studies have shown that replacing the succinyl linker arm of 1 by an o-phthalic acid group and substituting a D-Nal(2')(7) residue in place of D-Phe(7) results in a potent antagonist 7 at the hMC4 receptor. Furthermore, increasing the 23-membered lactam ring of 1 by one carbon atom (succinyl --> glutaric acid linker) gives a highly selective and potent antagonist 9 for the hMC3 receptor. Analogues 1, 7, and 9 therefore represent the first examples of a class of cyclic melanotropin ligands with high selectivity and defined biological activities at the physiologically important hMC3 and hMC4 receptors.

Design and synthesis of highly potent and selective melanotropin analogues of SHU9119 modified at position 6.

The melanocortin receptors are involved in several important physiological functions. The potent and enzymatically stable analogues MT-II (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH(2)) and SHU9119 (Ac-Nle-c[Asp-His-DNal(2')-Arg-Trp-Lys]-NH(2)) are important ligands of these receptors but are relatively nonselective. To differentiate between the physiological functions of these receptors, agonists, and antagonists with improved receptor selectivities are needed. We report here analogues of the well-characterized antagonist SHU9119 in which we replaced His(6) with conformationally constrained amino acids. By this structure-activity study we discovered two important compounds, PG-901 (Ac-Nle(4)-c[Asp(5)-Pro(6)-DNal(2')(7)-Arg(8)-Trp(9)-Lys(10)]-NH(2)) and PG-911 (Ac-Nle(4)-c[Asp(5)-Hyp(6)-DNal(2')(7)-Arg(8)-Trp(9)-Lys(10)]-NH(2)), characterized to be full agonists at the hMC5R (EC(50) = 0.072 nM and 0.031 nM, respectively), but full antagonists at the hMC3R and the hMC4R. We also demonstrated that the relative stereochemistry of the amino acid at the 6-position is critical for activity, and could play an important role in potency as well as in selectivity for the melanocortin receptors.