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Postmating isolation is thought to be an important driver of the late stages of speciation. However, relatively little is empirically known about the process compared with other isolating mechanisms that drive the early stages of speciation, especially in non-model organisms. We characterized the genetic architecture of postmating isolation between 2 rockfishes, Sebastes schlegelii and S. trivittatus, whose reproductive isolation is complete. We examined transmission ratio distortion (TRD) patterns of genetic markers in 2 reciprocal backcross populations. Markers showing either of the 2 types of TRD was widespread across the genome, with some of the distorted markers forming extensive clusters around the recombination coldspots. These suggest that the postmating isolation effectively prevents gene flow across the genome and the recombination landscape contributes to the genetic architecture. Comparisons between 2 backcross families and 2 developmental stages showed little similarity in the distorted markers, suggesting asymmetry and stage specificity of the isolation. This may be due to hybrid incompatibility involving maternal factors or extrinsic selection. The lack of sex-ratio distortion in the mapping families suggested that Haldane’s rule in terms of hybrid inviability does not hold. Additionally, quantitative trait loci (QTL) mapping detected significant QTLs for sex and the morphological traits relevant to speciation and convergence of rockfishes, including body coloration. Genes in the melanocortin system, including agouti-signaling protein 1 (asip1) and melanocortin 1 receptor (mc1r), might underlie the horizontal and vertical color patterns on the body, respectively. These findings constitute an essential step toward a comprehensive understanding of speciation and morphological diversification of rockfishes.

A boron-catalyzed direct α-trifluoromethylthiolation of carboxylic acids was developed. Catalytically generated boron enediolates reacts with electrophilic SCF3 reagent, N-SCF3-phthalimide, to provide α-SCF3 carboxylic acids without the need of substrate pre-activation. The method is applicable to direct modification of bioactive carboxylic acids. Data science analyses provided suitable models for substrate classification as well as yield prediction.

Reductive alkynylation of aldehydes by the Umpolung approach was developed using a photoredox catalyst under blue LED irradiation. Ketyl radicals, generated by single-electron reduction of aldehydes through proton-coupled electron transfer (PCET), reacted with electrophilic alkynylsulfones. Sterically demanding bulky aldehydes reacted smoothly under the Umpolung reaction conditions. Moreover, the alkynylation proceeded chemoselectively with an aryl aldehyde group in the presence of other carbonyl groups including an aliphatic aldehyde group.

A series of neutral C,N,N Au(III) complexes were synthesized with N-(8-quinolinyl)benzamide derivatives or chiral N-[2-(1,3-oxazolin-2-yl)phenyl]benzamide derivatives. The convenient synthesis method for the amide ligands, together with their operationally simple complexation by direct C–H auration, permitted changes to both the steric and electronic properties of Au(III) complexes for promoting the catalytic three-component couplings of an aldehyde, an amine, and an alkyne.

A high-quality genome assembly is imperative to explore the evolutionary basis of characteristic attributes that define chemotype and provide essential resources for a molecular breeding strategy for enhanced production of medicinal metabolites. Here, using single-molecule high-fidelity (HiFi) sequencing reads, we report chromosome-scale genome assembly for Chinese licorice (Glycyrrhiza uralensis), a widely used herbal and natural medicine. The entire genome assembly was achieved in eight chromosomes, with contig and scaffold N50 as 36.02 and 60.2 Mb, respectively. With only 17 assembly gaps and half of the chromosomes having no or one assembly gap, the presented genome assembly is among the best plant genomes to date. Our results showed an advantage of using highly accurate long-read HiFi sequencing data for assembling a highly heterozygous genome including its complexed repeat content. Additionally, our analysis revealed that G. uralensis experienced a recent whole-genome duplication at approximately 59.02 million years ago post a gamma (γ) whole-genome triplication event, which contributed to its present chemotype features. The metabolic gene cluster analysis identified 355 gene clusters, which included the entire biosynthesis pathway of glycyrrhizin. The genome assembly and its annotations provide an essential resource for licorice improvement through molecular breeding and the discovery of valuable genes for engineering bioactive components and understanding the evolution of specialized metabolites biosynthesis.

A boron-catalyzed alpha-allylation of carboxylic acids with allylsulfones under blue LED irradiation conditions is developed. We propose that photoexcitation of catalytically generated boron enediolates induces single-electron transfer to the allylsulfones. Subsequent C-C bond formation through a radical reaction constructs sterically demanding quaternary carbon centers at the position a to the carboxy group. The p-extended ligand on the boron atom is likely the key for efficient photoexcitation of the boron enediolates.

Postmating isolation is thought to be an important driver of the late stages of speciation. However, relatively little is empirically known about the process compared to other isolating mechanisms that drive the early stages of speciation, especially in non-model organisms. We characterized the genetic architecture of postmating isolation between two rockfishes,Sebastes schlegeliiandS. trivittatus, whose reproductive isolation is complete. We examined transmission ratio distortion (TRD) patterns of genetic markers in two reciprocal backcross populations. Markers showing either of the two types of TRD was widespread across the genome, with some of the distorted markers forming extensive clusters around the recombination coldspots. These suggest that the postmating isolation effectively prevents gene flow across the genome and the recombination landscape contributes to the genetic architecture. Comparisons between two backcross families and two developmental stages showed little similarity in the distorted markers, suggesting asymmetry and stage-specificity of the isolation. This may be due to hybrid incompatibility involving maternal factors or extrinsic selection. The lack of sex-ratio distortion in the mapping families suggested that Haldane’s rule in terms of hybrid inviability does not hold. Additionally, QTL mapping detected significant QTLs for sex and the morphological traits relevant to speciation and convergence of rockfishes, including body coloration. Genes in the melanocortin system, includingagouti-signaling protein 1(asip1) andmelanocortin 1 receptor(mc1r), might underlie the horizontal and vertical color patterns on the body, respectively. These findings constitute an essential step towards a comprehensive understanding of speciation and morphological diversification of rockfishes.

Corticotropin-releasing factor (CRF), a representative stress-related neuropeptide, in the central nervous system reportedly both facilitates and suppresses the micturition, therefore, roles of central CRF in regulation of the micturition are still controversial. In this study, we investigated (1) effects of intracerebroventricularly (icv)-administered CRF on the micturition, and (2) brain CRF receptor subtypes (CRFR1/CRFR2) and glutamatergic receptors (NMDA/AMPA subtypes) involved in the CRF-induced effects in male Wistar rats under urethane anesthesia. Intercontraction intervals (ICI), and maximal voiding pressure (MVP), were evaluated by continuous cystometry 45 min before CRF administration or intracerebroventricular pretreatment with other drugs as follows and 3 h after CRF administration. Single-voided volume (Vv), post-voiding residual volume (Rv), bladder capacity (BC), and voiding efficiency (VE) were evaluated by single cystometry 60 min before CRF administration and 60-120 min after the administration. Icv-administered CRF reduced ICI, Vv, and BC without changing MVP, Rv, or VE. The CRF-induced ICI reduction was attenuated by icv-pretreated CP154526 (CRFR1 antagonist), MK-801 (NMDA receptor antagonist), and DNQX (AMPA receptor antagonist), but not by K41498 (CRFR2 antagonist). These results indicate that stimulation of brain CRFR1 can be involved in facilitation of the rat micturition via brain NMDA/AMPA receptors.

International audience; Spectroscopy of an unbound nucleus $^{17}$C was performed using the SAMURAI spectrometer at RIBF of RIKEN. Six resonances were observed for the $^{16}$C+n system with relative energies of 0.52, 0.77, 1.36, 1.91, 2.22 and 3.20 MeV. The excitation energies ($E_x$) of the observed resonances were deduced, by taking into account the states of the $^{16}$C fragments identified by coincident $\gamma $ rays, as $E_x$=(3.02), 1.51, (3.86), 2.65, (4.72) and 3.94 MeV. The orbital angular momenta of the two observed states in $^{17}$C at $E_x$=2.65 and 3.94 MeV were determined as 1 by comparing parallel momentum distributions with theoretical predictions.

AIM Brain nitric oxide (NO) have been reported in regulation of the sympatho-adrenomedullary system, which can affect voiding and storage functions. Therefore, we investigated effects of intracerebroventricularly (icv) administered 3-(4-morpholinyl)sydnonimine, hydrochloride (SIN-1) (NO donor) on the micturition reflex, focusing on their dependence on the sympatho-adrenomedullary system and on brain N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in urethane-anesthetized (0.8 g/kg, ip) male Wistar rats. METHODS Plasma noradrenaline and adrenaline were measured just before and 5 minutes after SIN-1 administration. Evaluation of urodynamic parameters was started 1 hour before SIN-1 administration or intracerebroventricular pretreatment with other drugs. RESULTS SIN-1 (100 and 250 µg/animal) elevated plasma adrenaline and reduced intercontraction interval ([ICI] values; 110.5% [SIN-1, 0 µg] and 54.9% [SIN-1, 250 µg] during 15 minutes after SIN-1 administration [P

Chemoselective reactions can contribute to streamlining synthesis of pharmaceuticals, agrochemicals, and other functional molecules by avoiding use of protecting groups. In this review, copper catalysts were demonstrated useful for developing two types of chemoselective reactions: C-C bond-forming reactions at an anomeric carbon of unprotected aldoses and difunctionalization reaction of C-C multiple bonds. The "soft" nucleophilic copper species exhibit orthogonal reactivity toward "hard" polar functional groups and preferentially react with "soft" functional groups. The catalysis also controls stereoselectivity and/or regioselectivity to provide value-added products from readily available feedstock compounds.

A chiral phenol–NHC ligand enabled the copper-catalyzed enantioselective conjugate reduction of α,β-unsaturated esters. The phenol moiety of the chiral NHC ligand played a critical role in producing the enantiomerically enriched products. The catalyst worked well for various (Z)-isomer substrates. Opposite enantiomers were obtained from (Z)- and (E)-isomers, with a higher enantiomeric excess from the (Z)-isomer.

Anti-cancer chemotherapy with good efficacy and fewer side effects is highly desirable. A drug delivery system comprising a cancer-targeting module and a cytotoxic agent connected with a cleavable linker is promising for reducing side effects. The development of a cleavable linker satisfying the requirements of both stability and cleavability, however, is difficult, especially when a carbonate moiety is used for conjugating the linker to a hydroxy group in a drug of interest. We herein report a new stable linker comprising carbamate and ester spacers, which can be introduced on a hydroxy group of a drug. This linker is more stable in aqueous neutral buffer than a corresponding carbonate-type linker, and releases a payload anti-cancer drug, SN-38, through a two-step sequence upon cathepsin B treatment. This linker may have potential use in other drug delivery systems to lower side effects by selectively transporting cytotoxic drugs to tumor cells.

The status of a project to measure spin-isospin responses of neutron drip-line nuclei using a new low-energy neutron detector, PANDORA (Particle Analyzer Neutron Detector Of Real-time Acquisition), is reported. The performance of PANDORA was characterized by the 6He(p,n)6Li reaction in inverse kinematics at the HIMAC facility in Chiba. Observation of the strong transition to the ground state in 6Li is discussed. Preliminary results of 11Li(p,n)11Be and 14Be(p,n)14B experiments in inverse kinematics at RI Beam Factory (RIBF) of RIKEN Nishina Center are also presented including the exotic decay channel of 11Be→9Li + d. Details of the experimental setup based on PANDORA and the SAMURAI large-acceptance magnetic spectrometer, as well as the combined data-acquisition system are described. The neutron-gamma discrimination capability of PANDORA was evaluated, Figure-of-Merit (FoM) values higher than those found in the literature for similar materials were derived from experimental data.

The Optimized Energy Degrading Optics (OEDO) beamline was constructed at RIBF to produce slowed-down, well-focused radioactive-isotope beams at 10–50 MeV/u, and began operation in June 2017. We examined the performance of the OEDO system by decelerating high-energy medium-mass radioactive ions. The main components of the OEDO beamline are two superconducting quadrupole triplet magnets and one radio-frequency deflector. This paper introduces the unique design of the ion optics of the beamline and describes the achieved performance of the beamline in the commissioning and following physics experiments. We will discuss the properties of energy-degraded beams produced by the OEDO beamline by comparison of simulations and the achieved performance.

We searched for the $\alpha$ condensed state in $^{13}$C by measuring the $\alpha$ inelastic scattering at $E_{\alpha} = 388$ MeV at forward angles including 0 degrees. We performed the distorted-wave Born-approximation calculation with the single-folding potential and the multipole decomposition analysis to determine the isoscalar transition strengths in $^{13}$C. We found a bump structure around $E_x = 12.5$ MeV due to the isoscalar monopole ($IS0$) transition. A peak-fit analysis suggested that this bump consisted of several $1/2^-$ states. We propose that this bump is due to the mirror state of the 13.5 MeV-state in $^{13}$N, which dominantly decays to the $\alpha$ condensed state in $^{12}$C. It was speculated that the $1/2^-$ states around $E_x = 12.5$ MeV were candidates for the $\alpha$ condensed state, but the $3\alpha + n$ orthogonality condition model suggests that the $\alpha$ condensed state is unlikely to emerge as the negative parity states. We also found two $1/2^+$ or $3/2^+$ states at $E_x = 14.5$ and 16.1 MeV excited with the isoscalar dipole ($IS1$) strengths. We suggest that the 16.1-MeV state is a possible candidate for the $\alpha$ condensed state predicted by the cluster-model calculations on the basis of the good correspondence between the experimental and calculated level structures. However, the theoretical $IS1$ transition strength for this state is significantly smaller than the measured value. Further experimental information is strongly desired to establish the $\alpha$ condensed state in $^{13}$C., Comment: 24 pages, 12 figures, published in PTEP

Asymmetric catalysis enabling divergent control of multiple stereocenters remains challenging in synthetic organic chemistry. While machine learning-based optimization of molecular catalysis is an emerging approach, data-driven catalyst design to achieve stereodivergent asymmetric synthesis producing multiple reaction outcomes, such as constitutional selectivity, diastereoselectivity, and enantioselectivity, is unprecedented. Here, we report the straightforward identification of asymmetric two-component iridium/boron hybrid catalyst systems for α-C-allylation of carboxylic acids. Structural optimization of the chiral ligands for iridium catalysts was driven by molecular field-based regression analysis with a dataset containing overall 32 molecular structures. The catalyst systems enabled selective access to all the possible isomers of chiral carboxylic acids bearing contiguous stereocenters. This stereodivergent asymmetric catalysis is applicable to late-stage structural modifications of drugs and their derivatives.

Copper(I)-catalyzed stereodivergent nucleophilic propargylation at the anomeric carbon of unprotected N-acetyl mannosamine was developed using 3-substituted allenylboronates as a nucleophile. The homopropargylic alcohol products contained two contiguous stereocenters, and two stereoisomers out of the four possible isomers were selectively obtained in a catalyst-controlled manner by applying either basic conditions: a MesCu/(R,R,R)-Ph-SKP catalyst with a B(OiPr)3 additive or acidic conditions: a CuBF4/(S,S,S)-Ph-SKP catalyst with an MeB(OiPr)2 additive. Mechanistic studies suggested the presence of distinct active nucleophilic species depending on the conditions: an allenylcopper species under the basic conditions or an allenylboronate activated by the Lewis acidic copper catalyst under the acidic conditions. The propargylation products were concisely transformed into C3-substituted sialic acids in two steps without the use of protecting groups.

Summary Chiral allenes are highly valuable as versatile synthetic intermediates and core skeletons of various functional organic molecules. Despite marked recent advances, the straightforward catalytic enantioselective synthesis of hydrocarbon allenes from readily available starting materials without relying on polar functional groups is still very challenging. Here, we report a copper(I)-catalyzed enantioselective proton migration from skipped enynes to allenes as an efficient approach in chiral allene synthesis. With catalyst loading as low as 0.5 mol %, the reaction proceeds smoothly under mild conditions without the need for additional stoichiometric reagents or generation of waste. Novel chiral ligand L6 plays a critical role in furnishing high catalyst activity, promoting regioselective protonation to produce allenes instead of conjugated enynes, and inducing axial chirality of allenes. The multiple roles of the chiral ligand are rationalized by density functional theory calculations.

In advanced cancer patients, malignant cells invade and disseminate within normal cells and develop resistance to therapy with additional genetic mutations, which makes radical cure very difficult. Precision medicine against advanced cancer is hampered by the lack of systems aimed at multiple target molecules within multiple loci. Here, we report the development of a versatile diagnostic and therapeutic system for advanced cancer, named the Cupid and Psyche system. Based on the strong non-covalent interaction of streptavidin and biotin, a low immunogenic mutated streptavidin, Cupid, and a modified artificial biotin, Psyche, have been designed. Cupid can be fused with various single-chain variable fragment antibodies and forms tetramer to recognize cancer cells precisely. Psyche can be conjugated to a wide range of diagnostic and therapeutic agents against malignant cells. The Cupid and Psyche system can be used in pre-targeting therapy as well as photo-immunotherapy effectively in animal models supporting the concept of a system for precision medicine for multiple targets within multiple loci.

The tetraneutron has attracted the attention of nuclear physicists during the past decades, but there is still no unambiguous confirmation of its existence or non-existence. A new experiment based on $$^{8}$$ He(p, 2p) $$^{7}$$ H{t+ $$^{4}n$$ } reaction, with direct detection of the four neutrons, has been carried out at RIBF, which can hopefully help to draw a definite conclusion on the tetraneutron system.

A kinematically complete quasifree (p,pn) experiment in inverse kinematics was performed to study the structure of the Borromean nucleus ^{17}B, which had long been considered to have a neutron halo. By analyzing the momentum distributions and exclusive cross sections, we obtained the spectroscopic factors for 1s_{1/2} and 0d_{5/2} orbitals, and a surprisingly small percentage of 9(2)% was determined for 1s_{1/2}. Our finding of such a small 1s_{1/2} component and the halo features reported in prior experiments can be explained by the deformed relativistic Hartree-Bogoliubov theory in continuum, revealing a definite but not dominant neutron halo in ^{17}B. The present work gives the smallest s- or p-orbital component among known nuclei exhibiting halo features and implies that the dominant occupation of s or p orbitals is not a prerequisite for the occurrence of a neutron halo.

Brain nicotinic acetylcholine receptors (nAChRs) reportedly suppress the micturition, but the mechanisms responsible for this suppression remain unclear. We previously reported that intracerebroventricularly administered (±)-epibatidine (non-selective nAChR agonist) activated the sympatho-adrenomedullary system, which can affect the micturition. Therefore, we investigated (1) whether intracerebroventricularly administered (±)-epibatidine-induced effects on the micturition were dependent on the sympatho-adrenomedullary system, and (2) brain nAChR subtypes involved in the (±)-epibatidine-induced effects in urethane-anesthetized male Wistar rats. Plasma noradrenaline and adrenaline (catecholamines) were measured just before and 5 min after (±)-epibatidine administration. Evaluation of urodynamic parameters, intercontraction intervals (ICI) and maximal voiding pressure (MVP) by cystometry was started 1 h before (±)-epibatidine administration or intracerebroventricular pretreatment with other drugs and continued 1 h after (±)-epibatidine administration. Intracerebroventricularly administered (±)-epibatidine elevated plasma catecholamines and prolonged ICI without affecting MVP, and these changes were suppressed by intracerebroventricularly pretreated mecamylamine (non-selective nAChR antagonist). Acute bilateral adrenalectomy abolished the (±)-epibatidine-induced elevation of plasma catecholamines, but had no effect on the (±)-epibatidine-induced ICI prolongation. The latter was suppressed by intracerebroventricularly pretreated methyllycaconitine (selective α7-nAChR antagonist), SR95531 (GABAA antagonist), and SCH50911 (GABAB antagonist), but not by dihydro-β-erythroidine (selective α4β2-nAChR antagonist). Intracerebroventricularly administered PHA568487 (selective α7-nAChR agonist) prolonged ICI without affecting MVP, similar to (±)-epibatidine. These results suggest that stimulation of brain α7-nAChRs suppresses the rat micturition through brain GABAA/GABAB receptors, independently of the sympatho-adrenomedullary outflow modulation.

Physics letters / B 822, 136681 (2021). doi:10.1016/j.physletb.2021.136681, Published by North-Holland Publ., Amsterdam

The formation of a dineutron in the nucleus $^{11}$Li is found to be localized to the surface region. The experiment measured the intrinsic momentum of the struck neutron in $^{11}$Li via the $(p,pn)$ knockout reaction at 246 MeV/nucleon. The correlation angle between the two neutrons is, for the first time, measured as a function of the intrinsic neutron momentum. A comparison with reaction calculations reveals the localization of the dineutron at $r\sim3.6$ fm. The results also support the density dependence of dineutron formation as deduced from Hartree-Fock-Bogoliubov calculations for nuclear matter.

We have measured the differential cross-sections and analyzing powers for ($p,2p$) reactions at an incident energy of 392 MeV on $^{12}$C, $^{16}$O, $^{40}$Ca, and $^{208}$Pb nuclei, leading to discrete states of the residual nuclei. The data are compared with two kinds of distorted-wave impulse approximation (DWIA) calculations, a standard calculation using a global optical potential and a calculation using wave functions generated in a relativistic Hartree model. The spectroscopic factors deduced from these two calculations agree with those determined in ($e,e'p$) studies mostly within 15% in the case of the lighter three target nuclei. However, those for the $^{208}$Pb target are overestimated compared with the ($e,e'p$) results. In the heavy target case, the DWIA results are very sensitive to the radius parameter of the bound-state potential and thus a careful treatment is required. Regarding the analyzing powers of the present measurement, we confirmed that the $j$-dependence is sufficient for practical spectroscopic use.

The heaviest bound isotope of boron ^{19}B has been investigated using exclusive measurements of its Coulomb dissociation, into ^{17}B and two neutrons, in collisions with Pb at 220 MeV/nucleon. Enhanced electric dipole (E1) strength is observed just above the two-neutron decay threshold with an integrated E1 strength of B(E1)=1.64±0.06(stat)±0.12(sys) e^{2} fm^{2} for relative energies below 6 MeV. This feature, known as a soft E1 excitation, provides the first firm evidence that ^{19}B has a prominent two-neutron halo. Three-body calculations that reproduce the energy spectrum indicate that the valence neutrons have a significant s-wave configuration and exhibit a dineutronlike correlation.

Detailed spectroscopy of the neutron-unbound nucleus 28 F has been performed for the first time following proton/neutron removal from 29 Ne / 29 F beams at energies around 230 MeV / nucleon . The invariant-mass spectra were reconstructed for both the 27 F ( * ) + n and 26 F ( * ) + 2 n coincidences and revealed a series of well-defined resonances. A near-threshold state was observed in both reactions and is identified as the 28 F ground state, with S n ( 28 F ) = − 199 ( 6 ) keV , while analysis of the 2 n decay channel allowed a considerably improved S n ( 27 F ) = 1620 ( 60 ) keV to be deduced. Comparison with shell-model predictions and eikonal-model reaction calculations have allowed spin-parity assignments to be proposed for some of the lower-lying levels of 28 F . Importantly, in the case of the ground state, the reconstructed 27 F + n momentum distribution following neutron removal from 29 F indicates that it arises mainly from the 1 p 3 / 2 neutron intruder configuration. This demonstrates that the island of inversion around N = 20 includes 28 F , and most probably 29 F , and suggests that 28 O is not doubly magic.

INTRODUCTION AND OBJECTIVE:In the lower urinary tract, nitric oxide (NO) is well known as a relaxation factor in the urethra. On the other hand, in the central nervous system, NO is reported to hav...

27th International Nuclear Physics Conference, INPC2019, Glasgow, United Kingdom, 29 Jul 2019 - 2 Aug 2019; Journal of physics / Conference series 1643(1), 012106 (2020). doi:10.1088/1742-6596/1643/1/012106, Published by IOP Publ., Bristol

Spectroscopy of 16B plays an essential role in understanding the halo structure in 17B, but very limited knowledge has so far been obtained. We have carried out a kinematically complete measurement on the spectroscopy of 16B by using quasi-free (p,pn) reaction on 17B. The level scheme of 16B up to 5 MeV was made clear for the first time.

7 pags., 3 figs. -- 27th International Nuclear Physics Conference (INPC2019), The tetraneutron has attracted the attention of nuclear physicists during the past decades, but there is still no unambiguous confirmation of its existence or nonexistence. A new experiment based on 8 He(p,2p)7H{t+4n} reaction, with direct detection of the four neutrons, has been carried out at RIBF, which can hopefully help to draw a definite conclusion on the tetraneutron system., We acknowledge the support of the RIBF accelerator staff and the BigRIPS team for providing the high-quality beam. Z. H. Yang acknowledges the financial support from the Foreign Postdoctoral Researcher program of RIKEN. T. Aumann acknowledges the support by DFG via SFB 1245. P. Koseoglou acknowledges the support from BMBF (NUSTAR.DA grant No.05P 15RDFN1).