Indoleamine 2,3-dioxygenase 1 (IDO1), promoting immune escape of tumors, is a therapeutic target for the cancer immunotherapy. A number of IDO1 inhibitors have been identified, but only limited structural biology studies of IDO1 inhibitors are available to provide insights on the binding mechanism of IDO1. In this study, we present the structure of IDO1 in complex with 24, a NLG919 analogue with potent activity. The complex structure revealed the imidazole nitrogen atom of 24 to coordinate with the heme iron, and the imidazoleisoindole core situated in pocket A with the 1-cyclohexylethanol moiety extended to pocket B to interact with the surrounding residues. Most interestingly, 24 formed an extensive hydrogen bond network with IDO1, which is a distinct feature of IDO1/24 complex structure and is not observed in the other IDO1 complex structures. Further structure-activity relationship, UV spectra, and structural biology studies of several analogues of 24 demonstrated that extensive hydrophobic interactions and the unique hydrogen bonding network contribute to the great potency of imidazoleisoindole derivatives. These results are expected to facilitate the structure-based drug design of new IDO inhibitors.

Keywords:Heterometallic complexes / Metal-metal interactions / Mixed-valent compounds / Electronic structure / Singlemolecule conductanceThe study of metal string complexes with 1D transition-metal frameworks began in the early 1990s. As these complexes provide great insights into metal-metal multiple bonds and may have potential applications as molecular wires, this field of research has grown in the past 20 years. As such, the electronic structures of the simplest trinuclear complexes, the supporting ligand systems, and the single-molecular conduc-

The variation of the instantaneous frequencies of bridges under moving vehicles is a problem not well studied in the literature. A theoretical framework is presented for the problem, considering the variation in frequencies for both the bridge and moving vehicle. First, the equations of motion are written for the two sub-systems. By solving the eigenvalue problem, analytical solutions in closed-form are derived from the frequencies of the vehicle and bridge that are coupled with each other. Based on this, the variation pattern, range, and dominating factors involved are studied, along with the special cases of moving mass and moving load. The results reveal that, if a moving vehicle is to be used as a tool for measuring the bridge frequencies or for detecting the bridge damages, the frequency variation caused by moving vehicles should be taken into account. Such an effect will be crucial when the vehicle mass is not negligible compared with the bridge mass or when the resonance condition is approached.

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The transcription of rice plastid psbD-psbC genes encoding photosystem II reaction center protein D2 and chlorophyll alpha-binding protein CP43 is closely regulated by light. To elucidate the sequence requirement for the light-responsive promoter of psbD-psbC operon, transcriptional analysis of the rice promoter was performed with deleted mutants and site-directed mutants in vitro. Deletion of -546 approximately -100 upstream sequences resulted in 4- to 5-fold decrease in the transcription rate. Further deletion of -99 approximately -40 conserved region of repeated sequences resulted in 2-fold decrease in the transcription rate. The core light-responsive promoter requires "-10" element but not "-35" element for accurate initiation of basal transcription. No downstream promoter element was found in the +4 approximately +111 region. The competitive gel-retardation experiments revealed the presence of DNA-binding protein in the rice chloroplasts, which interacts specifically with the -60 approximately -37 repeated sequences. Southwestern blot analysis further demonstrated that the binding factor is composed of 36-kDa polypeptide(s).

This study proposes an EOQ inventory mathematical model for deteriorating items with exponentially decreasing demand. In the model, the shortages are allowed and partially backordered. The backlogging rate is variable and dependent on the waiting time for the next replenishment. Further, we show that the minimized objective cost function is jointly convex and derive the optimal solution. A numerical example is presented to illustrate the model and the sensitivity analysis is also studied

A combined experimental and theoretical electron density study of the shortest trichromium metal wire, Cr3(dpa)4Cl2·(C2H5OC2H5)(x)(CH2Cl2)(1-x) (1, dpa = bis(2-pyridyl)amido), is reported. High resolution X-ray diffraction data has been collected both at 100 K using a conventional X-ray source (DS1) and at 15 K using a synchrotron X-ray source (DS2). The linear chromium string is terminated by Cl(-) ions at both ends, and each Cr atom is also coordinated by four N atoms from bridging dpa ligands. The two Cr-Cr bond distances are unequal at 100 K (with d(Cr1-Cr2) being 0.029 Å shorter than d(Cr2-Cr3)) but at 15 K they are almost equal (0.002 Å difference). Analysis of the slightly elongated thermal ellipsoids of the Cr2 atom suggests that it is not due to disorder, but the presence of a shallow potential energy surface. Laplacian maps clearly show local valence shell charge concentration (VSCC) in the electron density along the bisector of the equatorial Cr-N bonds. Integration over the atomic basins indicates that Cr2 has smaller atomic charge and volume than Cr1 and Cr3. The topological characterization of the Cr-Cr bonds indicates partly covalent characters with electron density at the bond critical point of ∼0.3 e Å(-3) and negative total energy density. The delocalization index of Cr-Cr is 0.8 for Cr1-Cr2 and 0.08 for Cr1-Cr3. Second-order perturbation analysis shows high stabilization energy of the Cr-Cr bonds (E(2) ∼ 190 kcal mol(-1)). Delocalization indices and source function and natural bond orbital analyses are all indicative of localized Cr-Cr bonding interactions.

The heterotrimetallic complexes [FeMFe(dpa) Cl ] (M=Ni (1), Pd (2), and Pt (3); dpa =dipyridylamido) featuring two high-spin iron centers linked by Group 10 metals were synthesized and their physical properties were investigated. Oxidation of 1-3 with suitable oxidants in CH Cl solution yielded the mixed-valent species [1] -[3] . The solution properties of [1] -[3] were characterized by H NMR and UV/Vis/NIR spectroscopy as well as spectroelectrochemisty. The mixed-valent states of [1] -[3] obtained by electrochemical or chemical oxidation are classified as class II valence delocalization. The solid-state structures of 1-3, [1] , [3] , and [1] were determined by single-crystal X-ray diffraction analysis, exhibiting a linear metal framework with an approximate D symmetry. The spin states and magnetic properties were studied by using SQUID magnetometry, EPR and Mössbauer spectroscopy, and DFT calculations. Antiferromagnetic interactions between terminal high-spin iron centers are present within [1] -[3] and the |J| values increase with the central metal ion changing from Ni to Pt. The DFT calculations reproduce the antiferromagnetic coupling and ascribe it to a σ-type exchange pathway. The substitution of the central metal not only influences the spin-spin interactions but also the degree of electronic delocalization between the terminal iron sites along the Fe-M-Fe chains.