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In order to overcome the saturation of a single-photon avalanche diode (SPAD)-based receiver and keep the output counts at optimum level automatically, a new, to the best of our knowledge, scheme using the automatic attenuation control (AAC) technique is proposed. In the scheme, an AAC module is applied to attenuate excess incident photons. Furthermore, on the foundation of the bit error rate (BER) model of a photon-counting optical communication system, a reliable and efficient AAC algorithm is developed to compute the optimal attenuation factor. Based on the AAC algorithm, the optimal attenuation factors under different operation conditions are investigated. The results indicate that the incident optical intensity and signal-to-background ratio play an important role in determining the optimal attenuation factor. Moreover, at high incident optical intensity, the system BER utilized AAC module can be improved by 0.5 to 3 orders of magnitude. The AAC technique can effectively expand the dynamic range of the SPAD-based receiver.

Isotopic fractionation has been linked to the lattice vibrations of materials through their phonon spectra. The Lamb-Mössbauer factor (fLM) has the potential to provide information about the lattice vibrations in materials. We constrain the temperature evolution of the fLMof γ- and ε-Fe at in situ high-P-Tconditions between 1650 K and the melting point. We find that the vibrations of γ- and ε-Fe can be described using a quasiharmonic model with a pressure- and temperature-dependent Debye temperature computed from the measured fLM. From the Debye temperature, we derive the equilibrium isotopic fractionation β-factor of iron. Our results show that the quasiharmonic behavior of metallic iron would lower the value of lnβFe57/54by 0.1‰ at 1600–2800 K and 50 GPa when compared to the extrapolation of room temperature nuclear resonant inelastic X‑ray scattering data. Our study suggests that anharmonicity may be more prevalent in Fe metal than in lower mantle minerals at 2800 K and 50 GPa, a relevant condition for the core formation, and the silicate mantle may be isotopically heavy in iron.

Flavodiiron nitric oxide reductases (FNORs) carry out the reduction of nitric oxide (NO) to nitrous oxide (N2O), allowing infectious pathogens to mitigate toxic levels of NO generated in the human immune response. We previously reported the model complex [Fe2(BPMP)(OPr)(NO)2](OTf)2(1, OPr–= propionate) that contains two coplanar NO ligands and that is capable of quantitative NO reduction to N2O [White et al. J. Am. Chem. Soc.2018, 140, 2562–2574]. Here we investigate, for the first time, how a distortion of the active site affects the ability of the diiron core to mediate N2O formation. For this purpose, we prepared several analogues of 1that contain two monodentate ligands in place of the bridging carboxylate, [Fe2(BPMP)(X)2(NO)2]3+/1+(2-X; X = triflate, 1-methylimidazole, or methanol). Structural data of 2-Xshow that without the bridging carboxylate, the diiron core expands, leading to elongated (O)N–N(O) distances (from 2.80 Å in 1to 3.00–3.96 Å in 2-X) and distorted (O)N–Fe–Fe–N(O) dihedral angles (from coplanarity (5.9°) in 1to 52.9–85.1° in 2-X). Whereas 1produces quantitative amounts of N2O upon one-electron reduction, N2O production is substantially impeded in 2-X, to an initial 5–10% N2O yield. The main products after reduction are unprecedented hs-FeII/{Fe(NO)2}9/10dinitrosyl iron complexes (DNICs). Even though mononuclear DNICs are stable and do not show N–N coupling (since it is a spin-forbidden process), the hs-FeII/{Fe(NO)2}9/10DNICs obtained from 2-Xshow unexpected reactivity and produce up to quantitative N2O yields after 2 h. The implications of these results for the active site structure of FNORs are discussed.

Flavodiiron nitric oxide reductases (FNORs) are a subclass of flavodiiron proteins (FDPs) capable of preferential binding and subsequent reduction of NO to N2O. FNORs are found in certain pathogenic bacteria, equipping them with resistance to nitrosative stress, generated as a part of the immune defense in humans, and allowing them to proliferate. Here, we report the spectroscopic characterization and detailed reactivity studies of the diiron dinitrosyl model complex [Fe2(BPMP)(OPr)(NO)2](OTf)2for the FNOR active site that is capable of reducing NO to N2O [Zheng et al., J. Am. Chem. Soc.2013, 135, 4902–4905]. Using UV–vis spectroscopy, cyclic voltammetry, and spectro-electrochemistry, we show that one reductive equivalent is in fact sufficient for the quantitative generation of N2O, following a semireduced reaction mechanism. This reaction is very efficient and produces N2O with a first-order rate constant k> 102s–1. Further isotope labeling studies confirm an intramolecular N–N coupling mechanism, consistent with the rapid time scale of the reduction and a very low barrier for N–N bond formation. Accordingly, the reaction proceeds at −80 °C, allowing for the direct observation of the mixed-valent product of the reaction. At higher temperatures, the initial reaction product is unstable and decays, ultimately generating the diferrous complex [Fe2(BPMP)(OPr)2](OTf) and an unidentified ferric product. These results combined offer deep insight into the mechanism of NO reduction by the relevant model complex [Fe2(BPMP)(OPr)(NO)2]2+and provide direct evidence that the semireduced mechanism would constitute a highly efficient pathway to accomplish NO reduction to N2O in FNORs and in synthetic catalysts.

The transition toward a carbon-neutral society based on renewable energies goes hand in hand with the availability of energy-efficient technologies. Magnetocaloric cooling is a very promising refrigeration technology to fulfill this role regarding cryogenic gas liquefaction. However, the current reliance on highly resource critical, heavy rare-earth-based compounds as magnetocaloric material makes global usage unsustainable. Here, we aim to mitigate this limitation through the utilization of a multicaloric cooling concept, which uses the external stimuli of isotropic pressure and magnetic field to tailor and induce magnetostructural phase transitions associated with large caloric effects. In this study, La0.7Ce0.3Fe11.6Si1.4is used as a nontoxic, low-cost, low-criticality multiferroic material to explore the potential, challenges, and peculiarities of multicaloric cryocooling, achieving maximum isothermal entropy changes up to −28 J (kg K)−1in the temperature range from 190 K down to 30 K. Thus, the multicaloric cooling approach offers an additional degree of freedom to tailor the phase transition properties and may lead to energy-efficient and environmentally friendly gas liquefaction based on designed-for-purpose, noncritical multiferroic materials.

We previously reported the synthesis and preliminary characterization of a unique series of low-spin (ls) {FeNO}8–10complexes supported by an ambiphilic trisphosphineborane ligand, [Fe(TPB)(NO)]+/0/−. Herein, we use advanced spectroscopic techniques and density functional theory (DFT) calculations to extract detailed information as to how the bonding changes across the redox series. We find that, in spite of the highly reduced nature of these complexes, they feature an NO+ligand throughout with strong Fe−NO π-backbonding and essentially closed-shell electronic structures of their FeNO units. This is enabled by an Fe−B interaction that is present throughout the series. In particular, the most reduced [Fe(TPB)(NO)]−complex, an example of a ls-{FeNO}10species, features a true reverse dative Fe → B bond where the Fe center acts as a strong Lewis-base. Hence, this complex is in fact electronically similar to the ls-{FeNO}8system, with two additional electrons “stored” on site in an Fe−B single bond. The outlier in this series is the ls-{FeNO}9complex, due to spin polarization (quantified by pulse EPR spectroscopy), which weakens the Fe−NO bond. These data are further contextualized by comparison with a related N2complex, [Fe(TPB)(N2)]−, which is a key intermediate in Fe(TPB)-catalyzed N2fixation. Our present study finds that the Fe → B interaction is key for storing the electrons needed to achieve a highly reduced state in these systems, and highlights the pitfalls associated with using geometric parameters to try to evaluate reverse dative interactions, a finding with broader implications to the study of transition metal complexes with boratrane and related ligands.

High-valent nonheme FeIV–oxido species are key intermediates in biological oxidation, and their properties are proposed to be influenced by the unique microenvironments present in protein active sites. Microenvironments are regulated by noncovalent interactions, such as hydrogen bonds (H-bonds) and electrostatic interactions; however, there is little quantitative information about how these interactions affect crucial properties of high valent metal–oxido complexes. To address this knowledge gap, we introduced a series of FeIV–oxido complexes that have the same S = 2 spin ground state as those found in nature and then systematically probed the effects of noncovalent interactions on their electronic, structural, and vibrational properties. The key design feature that provides access to these complexes is the new tripodal ligand [poat]3–, which contains phosphinic amido groups. An important structural aspect of [FeIVpoat(O)]−is the inclusion of an auxiliary site capable of binding a Lewis acid (LAII); we used this unique feature to further modulate the electrostatic environment around the Fe–oxido unit. Experimentally, studies confirmed that H-bonds and LAIIs can interact directly with the oxido ligand in FeIV–oxido complexes, which weakens the Fe═O bond and has an impact on the electronic structure. We found that relatively large vibrational changes in the Fe–oxido unit correlate with small structural changes that could be difficult to measure, especially within a protein active site. Our work demonstrates the important role of noncovalent interactions on the properties of metal complexes, and that these interactions need to be considered when developing effective oxidants.

The iron(II)-nitroxyl complex [Fe(NO)(L3)](1) (with L3–= a hindered hydrotris(pyrazolyl)borate ligand), a high-spin (hs)-{FeNO}8complex in the Enemark–Feltham notation, is surprisingly stable and is the first of its kind that could be structurally characterized. We further studied this compound using a variety of spectroscopic methods. These results indicate a hs iron(II) center with a bound 3NO–ligand where the spins are antiferromagnetic coupled (St= 1). Vibrational data show that this complex has a very strong Fe−NO bond. DFT calculations support this result and link it to very strong π-donation from the 3NO–ligand to the iron(II) center. Furthermore, a very unusual equilibrium between the hs-{FeNO}8complex and a dinitrosyl iron complex (DNIC) of {Fe(NO)2}9type is observed. The O2reactivity of the complex is finally reported.

The intermediacy of metal–NNH2complexes has been implicated in the catalytic cycles of several examples of transition-metal-mediated nitrogen (N2) fixation. In this context, we have shown that triphosphine-supported Fe(N2) complexes can be reduced and protonated at the distal N atom to yield Fe(NNH2) complexes over an array of charge and oxidation states. Upon exposure to further H+/e–equivalents, these species either continue down a distal-type Chatt pathway to yield a terminal iron(IV) nitride or instead follow a distal-to-alternating pathway resulting in N–H bond formation at the proximal N atom. To understand the origin of this divergent selectivity, herein we synthesize and elucidate the electronic structures of a redox series of Fe(NNMe2) complexes, which serve as spectroscopic models for their reactive protonated congeners. Using a combination of spectroscopies, in concert with density functional theory and correlated ab initio calculations, we evidence one-electron redox noninnocence of the “NNMe2” moiety. Specifically, although two closed-shell configurations of the “NNR2” ligand have been commonly considered in the literature—isodiazene and hydrazido(2−)—we provide evidence suggesting that, in their reduced forms, the present iron complexes are best viewed in terms of an open-shell [NNR2]•–ligand coupled antiferromagnetically to the Fe center. This one-electron redox noninnocence resembles that of the classically noninnocent ligand NO and may have mechanistic implications for selectivity in N2fixation activity.

Fungal denitrification plays a crucial role in the nitrogen cycle and contributes to the total N2O emission from agricultural soils. Here, cytochrome P450 NO reductase (P450nor) reduces two NO to N2O using a single heme site. Despite much research, the exact nature of the critical “Intermediate I” responsible for the key N–N coupling step in P450nor is unknown. This species likely corresponds to a Fe-NHOH-type intermediate with an unknown electronic structure. Here we report a new strategy to generate a model system for this intermediate, starting from the iron(III) methylhydroxylamide complex [Fe(3,5-Me-BAFP)(NHOMe)] (1), which was fully characterized by 1H NMR, UV–vis, electron paramagnetic resonance, and vibrational spectroscopy (rRaman and NRVS). Our data show that 1is a high-spin ferric complex with an N-bound hydroxylamide ligand that is strongly coordinated (Fe–N distance, 1.918 Å; Fe-NHOMe stretch, 558 cm–1). Simple one-electron oxidation of 1at −80 °C then cleanly generates the first model system for Intermediate I, [Fe(3,5-Me-BAFP)(NHOMe)]+(1+). UV–vis, resonance Raman, and Mössbauer spectroscopies, in comparison to the chloro analogue [Fe(3,5-Me-BAFP)(Cl)]+, demonstrate that 1+is best described as an FeIII-(NHOMe)•complex with a bound NHOMe radical. Further reactivity studies show that 1+is highly reactive toward NO, a reaction that likely proceeds via N–N bond formation, following a radical–radical-type coupling mechanism. Our results therefore provide experimental evidence, for the first time, that an FeIII-(NHOMe)•electronic structure is indeed a reasonable electronic description for Intermediate I and that this electronic structure is advantageous for P450nor catalysis because it can greatly facilitate N–N bond formation and, ultimately, N2O generation.

The extradiol dioxygenases are a large subclass of mononuclear nonheme Fe enzymes that catalyze the oxidative cleavage of catechols distal to their OH groups. These enzymes are important in bioremediation, and there has been significant interest in understanding how they activate O2. The extradiol dioxygenase homoprotocatechuate 2,3-dioxygenase (HPCD) provides an opportunity to study this process, as two O2intermediates have been trapped and crystallographically defined using the slow substrate 4-nitrocatechol (4NC): a side-on Fe–O2–4NC species and a Fe–O2–4NC peroxy bridged species. Also with 4NC, two solution intermediates have been trapped in the H200N variant, where H200 provides a second-sphere hydrogen bond in the wild-type enzyme. While the electronic structure of these solution intermediates has been defined previously as FeIII-superoxo-catecholate and FeIII-peroxy-semiquinone, their geometric structures are unknown. Nuclear resonance vibrational spectroscopy (NRVS) is an important tool for structural definition of nonheme Fe–O2intermediates, as all normal modes with Fe displacement have intensity in the NRVS spectrum. In this study, NRVS is used to define the geometric structure of the H200N–4NC solution intermediates in HPCD as an end-on FeIII-superoxo-catecholate and an end-on FeIII-hydroperoxo-semiquinone. Parallel calculations are performed to define the electronic structures and protonation states of the crystallographically defined wild-type HPCD–4NC intermediates, where the side-on intermediate is found to be a FeIII-hydroperoxo-semiquinone. The assignment of this crystallographic intermediate is validated by correlation to the NRVS data through computational removal of H200. While the side-on hydroperoxo semiquinone intermediate is computationally found to be nonreactive in peroxide bridge formation, it is isoenergetic with a superoxo catecholate species that is competent in performing this reaction. This study provides insight into the relative reactivities of FeIII-superoxo and FeIII-hydroperoxo intermediates in nonheme Fe enzymes and into the role H200 plays in facilitating extradiol catalysis.

Heme and non-heme iron–nitrosyl complexes are important intermediates in biology. While there are numerous examples of low-spin heme iron–nitrosyl complexes in different oxidation states, much less is known about high-spin (hs) non-heme iron–nitrosyls in oxidation states other than the formally ferrous NO adducts ({FeNO}7in the Enemark–Feltham notation). In this study, we present a complete series of hs-{FeNO}6–8complexes using the TMG3tren coligand. Redox transformations from the hs-{FeNO}7complex [Fe(TMG3tren)(NO)]2+to its {FeNO}6and {FeNO}8analogs do not alter the coordination environment of the iron center, allowing for detailed comparisons between these species. Here, we present new MCD, NRVS, XANES/EXAFS, and Mössbauer data, demonstrating that these redox transformations are metal based, which allows us to access hs-Fe(II)–NO–, Fe(III)–NO–, and Fe(IV)–NO–complexes. Vibrational data, analyzed by NCA, directly quantify changes in Fe–NO bonding along this series. Optical data allow for the identification of a “spectator” charge-transfer transition that, together with Mössbauer and XAS data, directly monitors the electronic changes of the Fe center. Using EXAFS, we are also able to provide structural data for all complexes. The magnetic properties of the complexes are further analyzed (from magnetic Mössbauer). The properties of our hs-{FeNO}6–8complexes are then contrasted to corresponding, low-spin iron–nitrosyl complexes where redox transformations are generally NO centered. The hs-{FeNO}8complex can further be protonated by weak acids, and the product of this reaction is characterized. Taken together, these results provide unprecedented insight into the properties of biologically relevant non-heme iron–nitrosyl complexes in three relevant oxidation states.

In order to detect weak light from background radiation, utilizing an array of Geiger-mode avalanche photodiodes (GM-APDs) as a detector in the receiver is researched. First, the principle of a GM-APD operated in gated mode is analyzed. Based on the Poisson random process of arrival of photons, the trigger probability of a single GM-APD has been computed. Then, according to the trigger probability, a new bit error rate (BER) model of a photon-counting array receiver system is built, and the expression of BER is derived based on the quantum efficiency, signal photons, background photons, dark carriers, and the number of GM-APDs in array. Using the BER expression, the error performance of a new photon-counting array receiver system can be predicted rapidly. Furthermore, the error performance of a system based on an array of GM-APDs is investigated. The simulation results indicated that maintaining the ratio of signal photons and background photons above 1 is necessary for system operation. When background noise is limited to the acceptable range, maintaining a certain scale of GM-APDs (above 20) in array can greatly reduce the demand of transmitting power. Compared with achieving target BERs of 10^−6 and 10^−9, preserving a BER of 10^−3 and making use of error correction coding can further improve the receiving sensitivity to 5–8 dB.

Compared to well studied diatomic ligands (NO, CN–, CO), the axial bonds of carbene hemes is much less known although its significance in biological chemistry. The unusually large quadrupole splitting (ΔEQ= +2.2 mm·s–1) and asymmetric parameter (η = 0.9) of the five-coordinate heme carbene [Fe(TTP)(CCl2)], which is the largest among all known low spin ferrohemes, has driven investigations by means of Mössbauer effect Nuclear Resonance Vibrational Spectroscopy (NRVS). Three distinct measurements on one single crystal (two in-plane and one out-of-plane) have demonstrated comprehensive vibrational structures including stretch (429) and bending modes (472 cm–1) of the axial Fe–CCl2, and revealed iron vibrational anisotropy in three orthogonal directions for the first time. Frontier orbital analysis especially comparisons with diatomic analogues (NO, CN–, CO) suggest that CCl2, similar to NO, has led to strong but anisotropic π bonding in a ligand-based “4C”-coordinate which induced the vibrational anisotropies and very large Mössbauer parameters. This is contrasted to CN–and CO complexes which possess a porphyrin-based “4N”-coordinate electronic and vibrational structures due to inherent on-axis linear ligation.

The transport of hydrogen into Earth's deep interior may have an impact on lower mantle dynamics as well as on the seismic signature of subducted material. Due to the stability of the hydrous phases δ‐AlOOH (delta phase), MgSiO2(OH)2(phase H), and ε‐FeOOH at high temperatures and pressures, their solid solutions may transport significant amounts of hydrogen as deep as the core‐mantle boundary. We have constrained the equation of state, including the effects of a spin crossover in the Fe3+atoms, of (Al, Fe)‐phase H: Al0.84Fe3+0.07Mg0.02Si0.06OOH, using powder X‐ray diffraction measurements to 125 GPa, supported by synchrotron Mössbauer spectroscopy measurements on (Al, Fe)‐phase H and δ‐(Al, Fe)OOH. The changes in spin state of Fe3+in (Al, Fe)‐phase H results in a significant decrease in bulk sound velocity and occurs over a different pressure range (48–62 GPa) compared with δ‐(Al, Fe)OOH (32–40 GPa). Changes in axial compressibilities indicate a decrease in the compressibility of hydrogen bonds in (Al, Fe)‐phase H near 30 GPa, which may be associated with hydrogen bond symmetrization. The formation of (Al, Fe)‐phase H in subducted oceanic crust may contribute to scattering of seismic waves in the mid‐lower mantle (∼1,100–1,550 km). Accumulation of 1–4 wt.% (Al, Fe)‐phase H could reproduce some of the seismic signatures of large, low seismic‐velocity provinces. Our results suggest that changes in the electronic structure of phases in the (δ‐AlOOH)‐(MgSiO2(OH)2)‐(ε‐FeOOH) solid solution are sensitive to composition and that the presence of these phases in subducted oceanic crust could be seismically detectable throughout the lower mantle. Hydrogen can be transported into the interior of the Earth by phases which contain hydrogen in their crystal structure. Interpretation of measured seismic velocities relies on understanding the elastic properties of minerals, including their equation of state. In this study, we use X‐ray diffraction and Mössbauer spectroscopy to constrain the equation of state for a particular hydrous phase known as (Al, Fe)‐phase H and understand pressure‐induced related effects due to changes in the electronic structure of Fe atoms. Our results imply that only a small amount of this phase needs to be transported to the deep mantle to reproduce observed seismic velocities at the edges of large structures known as low seismic‐velocity provinces. The presence of (Al, Fe)‐phase H in subducted oceanic crust may also contribute to the scattering of seismic waves in shallower regions of Earth's interior. The equation of state of (Al, Fe)‐phase H (Al0.84Fe3+0.07Mg0.02Si0.06OOH) is constrained by powder X‐ray diffraction to 125 GPaThe equation of state and synchrotron Mössbauer spectroscopy measurements reveal a spin crossover of Fe3+in (Al, Fe)‐phase H (48–63 GPa)Accumulation of 1–4 wt. % (Al, Fe)‐phase H may explain seismic velocities at edges of large, low seismic velocity provinces The equation of state of (Al, Fe)‐phase H (Al0.84Fe3+0.07Mg0.02Si0.06OOH) is constrained by powder X‐ray diffraction to 125 GPa The equation of state and synchrotron Mössbauer spectroscopy measurements reveal a spin crossover of Fe3+in (Al, Fe)‐phase H (48–63 GPa) Accumulation of 1–4 wt. % (Al, Fe)‐phase H may explain seismic velocities at edges of large, low seismic velocity provinces

We have determined a convenient method for the bulk synthesis of high-purity ferric heme-nitrosyl complexes ({FeNO}6in the Enemark–Feltham notation); this method is based on the chemical or electrochemical oxidation of corresponding {FeNO}7precursors. We used this method to obtain the five- and six-coordinate complexes [Fe(TPP)(NO)]+(TPP2–= tetraphenylporphyrin dianion) and [Fe(TPP)(NO)(MI)]+(MI = 1-methylimidazole) and demonstrate that these complexes are stable in solution in the absence of excess NO gas. This is in stark contrast to the often-cited instability of such {FeNO}6model complexes in the literature, which is likely due to the common presence of halide impurities (although other impurities could certainly also play a role). This is avoided in our approach for the synthesis of {FeNO}6complexes via oxidation of pure {FeNO}7precursors. On the basis of these results, {FeNO}6complexes in proteins do not show an increased stability toward NO loss compared to model complexes. We also prepared the halide-coordinated complexes [Fe(TPP)(NO)(X)] (X = Cl–, Br–), which correspond to the elusive, key reactive intermediate in the so-called autoreduction reaction, which is frequently used to prepare {FeNO}7complexes from ferric precursors. All of the complexes were characterized using X-ray crystallography, UV–vis, IR, and nuclear resonance vibrational spectroscopy (NRVS). On the basis of the vibrational data, further insight into the electronic structure of these {FeNO}6complexes, in particular with respect to the role of the axial ligand transto NO, is obtained.

Optically controlled beamforming technology has attracted a lot of research interest for its unique advantages and application in phased array antennas (PAAs). In this paper, a novel scheme of an optically controlled beamforming system based on an array of chirped microwave signal generators is proposed. In the proposed system, an array of photonic microwave delay line filters (PMDLFs) with quadratic phase response is configured, and chirped microwave signals, which are then applied to the antennas, are generated by processing a chirped-free Gaussian pulse by those filters, and the relative delay among those chirped microwave signals can be controlled by tuning the optical carriers’ wavelength in each path. Therefore, the system can realize optically controlled beamforming by successfully combining photonic generation of a chirped microwave signal with optical true time delay (OTTD). As the PMDLFs’ frequency response can be flexibly varied, the generated microwave signal waveforms can be adjustable to suit the needs of different applications. A theoretical analysis of the proposed beamforming system is carried out and its feasibility is verified by numerical simulations.

As an element ubiquitous in the Solar system, the isotopic composition of iron exhibits rich variations in different planetary reservoirs. Such variations reflect the diverse range of differentiation and evolution processes experienced by their parent bodies. A key in deciphering iron isotope variations among planetary samples is to understand how iron isotopes fractionate during core formation. Here we report new Nuclear Resonant Inelastic X‐ray Scattering experiments on silicate glasses of bulk silicate Earth compositions to measure their force constants at high pressures of up to 30 GPa. The force constant results are subsequently used to constrain iron isotope fractionation during core formation on terrestrial planets. Using a model that integrates temperature, pressure, core composition, and redox state of the silicate mantle, we show that core formation might lead to an isotopically light mantle for small planetary bodies but a heavy one for Earth‐sized terrestrial planets. Planetary formation and differentiation are fundamental processes that physically and chemically shaped terrestrial planets. As a major element ubiquitous in terrestrial planets, the isotopic ratios of Fe are found to vary among different planetary reservoirs, reflecting the formation and differentiation processes that occurred on their parent bodies. Deciphering the information behind these variations require experimental and theoretical constraints on how the isotopic ratios of Fe evolve during different planetary processes. Here, we present a systematic model on how Fe isotopes behave during planetary core formation based on high pressure experiments. We show that Fe isotope fractionation between the mantle and core of terrestrial bodies depends strongly on the planet size. We constrained the Fe isotope fractionation factor for the silicate mantle up to 30 GPa using a bulk silicate Earth compositionWe present a holistic Fe isotope fractionation model for core formation considering pressure, temperature, composition, and redox stateOur model shows that core formation can cause the mantle of small planetary bodies to be light in Fe isotopes, but heavy for that of Earth We constrained the Fe isotope fractionation factor for the silicate mantle up to 30 GPa using a bulk silicate Earth composition We present a holistic Fe isotope fractionation model for core formation considering pressure, temperature, composition, and redox state Our model shows that core formation can cause the mantle of small planetary bodies to be light in Fe isotopes, but heavy for that of Earth

Dinitrosyl iron complexes (DNICs) are among the most abundant NO-derived cellular species. Monomeric DNICs can exist in the {Fe(NO)2}9or {Fe(NO)2}10oxidation state (in the Enemark–Feltham notation). However, experimental studies of analogous DNICs in both oxidation states are rare, which prevents a thorough understanding of the differences in the electronic structures of these species. Here, the {Fe(NO)2}9DNIC [Fe(dmp)(NO)2](OTf) (1; dmp = 2,9-dimethyl-1,10-phenanthroline) is synthesized from a ferrous precursor via an unusual pathway, involving disproportionation of an {FeNO}7complex to yield the {Fe(NO)2}9DNIC and a ferric species, which is subsequently reduced by NO gas to generate a ferrous complex that re-enters the reaction cycle. In contrast to most {Fe(NO)2}9DNICs with neutral N-donor ligands, 1exhibits high solution stability and can be characterized structurally and spectroscopically. Reduction of 1yields the corresponding {Fe(NO)2}10DNIC [Fe(dmp)(NO)2] (2). The Mössbauer isomer shift of 2is 0.08 mm/s smaller than that of 1, which indicates that the iron center is slightly more oxidized in the reduced complex. The nuclear resonance vibrational spectra (NRVS) of 1and 2are distinct and provide direct experimental insight into differences in bonding in these complexes. In particular, the symmetric out-of-plane Fe–N–O bending mode is shifted to higher energy by 188 cm–1in 2in comparison to 1. Using quantum chemistry centered normal coordinate analysis (QCC-NCA), this is shown to arise from an increase in Fe–NO bond order and a stiffening of the Fe(NO)2unit upon reduction of 1to 2. DFT calculations demonstrate that the changes in bonding arise from an iron-centered reduction which leads to a distinct increase in Fe–NO π-back-bonding in {Fe(NO)2}10DNICs in comparison to the corresponding {Fe(NO)2}9complexes, in agreement with all experimental findings. Finally, the implications of the electronic structure of DNICs for their reactivity are discussed, especially with respect to N–N bond formation in NO reductases.

Iron-bearing periclase is thought to represent a significant fraction of Earth’s lower mantle. However, the concentration of iron in (Mg,Fe)O is not well constrained at all mantle depths. Therefore, understanding the effect of iron on the density and elastic properties of this phase plays a major role in interpreting seismically observed complexity in the deep Earth. Here we examine the high-pressure behavior of polycrystalline (Mg,Fe)O containing 48 mol% FeO, loaded hydrostatically with neon as a pressure medium. Using X-ray diffraction and synchrotron Mössbauer spectroscopy, we measure the equation of state to about 83 GPa and hyperfine parameters to 107 GPa at 300 K. A gradual volume drop corresponding to a high-spin (HS) to low-spin (LS) crossover is observed between ~45 and 83 GPa with a volume drop of 1.85% at 68.8(2.7) GPa, the calculated spin transition pressure. Using a newly formulated spin crossover equation of state, the resulting zero-pressure isothermal bulk modulus K0T,HSfor the HS state is 160(2) GPa with a K0T,HS′$K_{0{\rm{T,HS}}}^\prime $of 4.12(14) and a V0,HSof 77.29(0) Å3. For the LS state, the K0T,LSis 173(13) GPa with a K0T,LS′$K_{0{\rm{T,LS}}}^\prime $fixed to 4 and a V0,LSof 73.64(94) Å3. To confirm that the observed volume drop is due to a spin crossover, the quadrupole splitting (QS) and isomer shift (IS) are determined as a function of pressure. At low pressures, the Mössbauer spectra are well explained with two Fe2+-like sites. At pressure between 44 and 84, two additional Fe2+-like sites with a QS of 0 are required, indicative of low-spin iron. Above 84 GPa, two low-spin Fe2+-like sites with increasing weight fraction explain the data well, signifying the completion of the spin crossover. To systematically compare the effect of iron on the equation of state parameters for (Mg,Fe)O, a spin crossover equation of state was fitted to the pressure-volume data of previous measurements. Our results show that K0,HSis insensitive to iron concentration between 10 to 60 mol% FeO, while the spin transition pressure and width generally increases from about 50–80 and 2–25 GPa, respectively. A key implication is that iron-rich (Mg,Fe)O at the core-mantle boundary would likely contain a significant fraction of high-spin (less dense) iron, contributing a positive buoyancy to promote observable topographic relief in tomographic images of the lowermost mantle.

Iron alloyed with Ni and Si has been suggested to be a major component of the Earth's inner core. High‐pressure results on the combined alloying effects of Ni and Si on seismic parameters of iron are thus essential for establishing satisfactory geophysical and geochemical models of the region. Here we have investigated the compressional (VP) and shear (Vs) wave velocity‐density (ρ) relations, Poisson's ratio (ν), and seismic heterogeneity ratios (dlnρ/dlnVP, dlnρ/dlnVS, and dlnVP/dlnVS) of hcp‐Fe and hcp‐Fe86.8Ni8.6Si4.6alloy up to 206 GPa and 136 GPa, respectively, using multiple complementary techniques. Compared with the literature velocity values for hcp‐Fe and Fe‐Ni‐Si alloys, our results show that the combined addition of 9.0 wt % Ni and 2.3 wt % Si slightly increases the VPbut significantly decreases the VSof hcp‐Fe at a given density relevant to the inner core. Such distinct alloying effects on velocities of hcp‐Fe produce a high νof about 0.40 for the alloy at inner core densities, which is approximately 20% higher than that for hcp‐Fe. Analysis of the literature high P‐Tresults on VPand VSof Fe alloyed with light elements shows that high temperature can further enhance the νof hcp‐Fe alloyed with Ni and Si. Most significantly, the derived seismic heterogeneity ratios of this hcp alloy present a better match with global seismic observations. Our results provide a multifactored geophysical constraint on the compositional model of the inner core which is consistent with silicon being a major light element alloyed with Fe and 5 wt % Ni. Sound velocity of hcp‐Fe and Fe‐Ni‐Si alloy measured up to 2 Mbar in a diamond anvil cellFe‐rich Fe‐Ni‐Si alloy in the hcp phase displays a relatively high Poisson's ratioThe multifactored constraint implies that hcp Fe‐Ni‐Si alloy can be abundant in the inner core

Ubc13 is an E2 ubiquitin conjugating enzyme that functions in nuclear DNA damage signaling and cytoplasmic NF-κB signaling. Here, we present the structures of complexes of Ubc13 with two inhibitors, NSC697923 and BAY 11-7082, which inhibit DNA damage and NF-κB signaling in human cells. NSC697923 and BAY 11-7082 both inhibit Ubc13 by covalent adduct formation through a Michael addition at the Ubc13 active site cysteine. The resulting adducts of both compounds exploit a binding groove unique to Ubc13. We developed a Ubc13 mutant which resists NSC697923 inhibition and, using this mutant, we show that the inhibition of cellular DNA damage and NF-κB signaling by NSC697923 is largely due to specific Ubc13 inhibition. We propose that unique structural features near the Ubc13 active site could provide a basis for the rational development and design of specific Ubc13 inhibitors.

High-pressure synchrotron Mössbauer (SMS) and X-ray emission (XES) spectroscopic measurements were conducted to investigate the spin and valence states of iron in (Al,Fe)-bearing magnesium silicate glass (Mg0.79Fe0.10Al0.10Si0.96O3) up to 126 GPa and 300 K. By analyzing the Fe Kβ emission spectra using the integrated relative difference (IRD) method, which accounts for the spectral broadening effects, the derived total spin momentum (S) of the iron in the glass shows no observable changes with pressure within the experimental uncertainties. A two-doublet fitting model representing two diverse local iron atomic environments was used to satisfactorily simulate the high-pressure SMS spectra of iron in the glass. The doublet with an averaged quadrupole splitting (QS) value of 1.94(±0.25) mm/s and chemical shift (CS) of 1.02(±0.25) mm/s at ambient conditions was assigned to be high-spin Fe2+, whereas the second doublet with QS = 0.83(±0.25) mm/s and CS = 0.49(±0.25) mm/s was assigned to be high-spin Fe3+. Increasing pressure continuously elevates the QS of Fe2+from ~2 mm/s at ambient pressure to 3.5 mm/s at 126 GPa, while Fe3+ only exhibits a slight increase in the QS to 1.34(±0.25) mm/s. Comparing with previous experimental and theoretical studies on the local geometries and hyperfine parameters of silicate glasses and minerals, we conclude that the occurrence of the extremely high QS of Fe2+in our glass above ~40-50 GPa can be associated with the enhanced density and diverse distortions and geometries of the local Fe2+environments. Our combined XES and SMS results show that both Fe2+and Fe3+ions in Al-bearing silicate remain in the high-spin state, rather than undergoing a spin-pairing transition as proposed previously. Assuming that the silicate glass results can be used as an analog for understanding silicate melts, our results here indicate that iron ions likely experience significant changes in the local environments yet remain overall in the high-spin state in silicate melts at the extreme pressure and temperature conditions of the deep mantle.

AbstractHigh-pressure synchrotron Mössbauer (SMS) and X-ray emission (XES) spectroscopic measurements were conducted to investigate the spin and valence states of iron in (Al,Fe)-bearing magnesium silicate glass (Mg0.79Fe0.10Al0.10Si0.96O3) up to 126 GPa and 300 K. By analyzing the Fe Kß emission spectra using the integrated relative difference (IRD) method, which accounts for the spectral broadening effects, the derived total spin momentum (S) of the iron in the glass shows no observable changes with pressure within the experimental uncertainties. A two-doublet fitting model representing two diverse local iron atomic environments was used to satisfactorily simulate the high-pressure SMS spectra of iron in the glass. The doublet with an averaged quadrupole splitting (QS) value of 1.94(±0.25) mm/s and chemical shift (CS) of 1.02(±0.25) mm/s at ambient conditions was assigned to be high-spin Fe2+, whereas the second doublet with QS = 0.83(±0.25) mm/s and CS = 0.49(±0.25) mm/s was assigned to be high-spin Fe3+. Increasing pressure continuously elevates the QS of Fe2+from ~2 mm/s at ambient pressure to 3.5 mm/s at 126 GPa, while Fe3+ only exhibits a slight increase in the QS to 1.34(±0.25) mm/s. Comparing with previous experimental and theoretical studies on the local geometries and hyperfine parameters of silicate glasses and minerals, we conclude that the occurrence of the extremely high QS of Fe2+in our glass above ~40-50 GPa can be associated with the enhanced density and diverse distortions and geometries of the local Fe2+environments. Our combined XES and SMS results show that both Fe2+and Fe3+ions in Al-bearing silicate remain in the high-spin state, rather than undergoing a spin-pairing transition as proposed previously. Assuming that the silicate glass results can be used as an analog for understanding silicate melts, our results here indicate that iron ions likely experience significant changes in the local environments yet remain overall in the high-spin state in silicate melts at the extreme pressure and temperature conditions of the deep mantle.

Flavodiiron nitric oxide reductases (FNORs), found in pathogenic bacteria, are capable of reducing nitric oxide (NO) to nitrous oxide (N2O) to detoxify NO released by the human immune system. Previously, we reported the first FNOR model system that mediates direct NO reduction (Dong, H. T.; J. Am. Chem. Soc.2018, 140, 13429−13440), but no intermediate of the reaction could be characterized. Here, we present a new set of model complexes that, depending on the ligand substitution, can either mediate direct NO reduction or stabilize a highly activated high-spin (hs) {FeNO}7complex, the first intermediate of the reaction. The precursors, [{FeII(MPA-(RPhO)2)}2] (1, R = H and 2, R = tBu, Me), were prepared first and fully characterized. Complex 1(without steric protection) directly reduces NO to N2O almost quantitatively, which constitutes only the second example of this reaction in model systems. Contrarily, the reaction of sterically protected 2with NO forms the stable mononitrosyl complex 3, which shows one of the lowest N–O stretching frequencies (1689 cm–1) observed so far for a mononuclear hs-{FeNO}7complex. This study confirms that an N–O stretch ≤1700 cm–1represents the appropriate level of activation of the FeNO unit to enable direct NO reduction. The higher activation level of these hs-{FeNO}7complexes required for NO reduction compared to those formed in FNORs emphasizes the importance of hydrogen bonding residues in the active sites of FNORs to activate the bound NO ligands for direct N–N coupling and N2O formation. The implications of these results for FNORs are further discussed.

Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, remains a partially curable disease. Genetic alterations affecting components of NF-κB signaling pathways occur frequently in DLBCL. Almost all activated B cell–like (ABC) DLBCL, which is the least curable group among the 3 major subtypes of this malignancy, and a substantial fraction of germinal center B cell–like (GCB) DLBCL exhibit constitutive NF-κB pathway activity. It has been demonstrated that ABC-DLBCL cells require such activity for proliferation and survival. Therefore, inhibition of NF-κB activation in DLBCL may provide an efficient and targeted therapy. In screening for small-molecule compounds that may inhibit NF-κB activation in DLBCL cells, we identified a compound, NSC697923, which inhibits the activity of the ubiquitin-conjugating (E2) enzyme Ubc13-Uev1A. NSC697923 impedes the formation of the Ubc13 and ubiquitin thioester conjugate and suppresses constitutive NF-κB activity in ABC-DLBCL cells. Importantly, NSC697923 inhibits the proliferation and survival of ABC-DLBCL cells and GCB-DLBCL cells, suggesting the Ubc13-Uev1A may be crucial for DLBCL growth. Consistently, knockdown of Ubc13 expression also inhibited DLBCL cell survival. The results of the present study indicate that Ubc13-Uev1A may represent a potential therapeutic target in DLBCL. In addition, compound NSC697923 may be exploited for the development of DLBCL therapeutic agents.

Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, remains a partially curable disease. Genetic alterations affecting components of NF-κB signaling pathways occur frequently in DLBCL. Almost all activated B cell–like (ABC) DLBCL, which is the least curable group among the 3 major subtypes of this malignancy, and a substantial fraction of germinal center B cell–like (GCB) DLBCL exhibit constitutive NF-κB pathway activity. It has been demonstrated that ABC-DLBCL cells require such activity for proliferation and survival. Therefore, inhibition of NF-κB activation in DLBCL may provide an efficient and targeted therapy. In screening for small-molecule compounds that may inhibit NF-κB activation in DLBCL cells, we identified a compound, NSC697923, which inhibits the activity of the ubiquitin-conjugating (E2) enzyme Ubc13-Uev1A. NSC697923 impedes the formation of the Ubc13 and ubiquitin thioester conjugate and suppresses constitutive NF-κB activity in ABC-DLBCL cells. Importantly, NSC697923 inhibits the proliferation and survival of ABC-DLBCL cells and GCB-DLBCL cells, suggesting the Ubc13-Uev1A may be crucial for DLBCL growth. Consistently, knockdown of Ubc13 expression also inhibited DLBCL cell survival. The results of the present study indicate that Ubc13-Uev1A may represent a potential therapeutic target in DLBCL. In addition, compound NSC697923 may be exploited for the development of DLBCL therapeutic agents.

We report our studies of the vibrational dynamics of iron for three imidazole‐ligated oxyheme derivatives that mimic the active sites of histidine‐ligated heme proteins complexed with dioxygen. The experimental vibrational data are obtained from nuclear resonance vibrational spectroscopy (NRVS) measurements conducted on both powder samples and oriented single crystals, and which includes several in‐plane (ip) and out‐of‐plane (oop) measurements. Vibrational spectral assignments have been made through a combination of the oriented sample spectra and predictions based on density functional theory (DFT) calculations. The two Fe–O2modes that have been previously observed by resonance Raman spectroscopy in heme proteins are clearly shown to be very strongly mixed and are not simply either a bending or stretching mode. In addition, a third Fe–O2mode, not previously reported, has been identified. The long‐sought Fe–Im stretch, not observed in resonance Raman spectra, has been identified and compared with the frequencies observed for the analogous CO and NO species. The studies also suggest that the in‐plane iron motion is anisotropic and is controlled by the orientation of the Fe–O2group and not sensitive to the in‐plane FeNpbonds and/or imidazole orientations.

Dissecting the barrier: The nuclear resonance vibrational spectrum of the S=2 [(TMG3tren)FeIVO] complex revealed features indicative of an axial “steric wall” that contributes to the overall reaction barrier. DFT calculations show that both S=2 (axial attack) and S=1 (equatorial attack) surfaces possess steric contributions to their barriers, and estimates of these steric effects result in comparable intrinsic barriers for both spin surfaces (see picture).

Eine axiale „sterische Wand“, die zur Gesamtreaktionsbarriere beiträgt, wird aus dem NMR‐Spektrum des S=2‐Komplexes [(TMG3tren)FeIVO] deutlich. DFT‐Rechnungen zeigen, dass sowohl die S=2‐ (axialer Angriff) als auch die S=1‐Flächen (äquatorialer Angriff) sterische Beiträge zu ihren Barrieren haben; Abschätzungen dieser sterischen Effekte ergeben vergleichbare intrinsische Barrieren für beide Spinflächen (siehe Bild).

No Abstract

Sondierung der Lage: Eine resonanzschwingungsspektroskopische Einkristallstudie lieferte detaillierte Informationen zu den In‐Plane‐Schwingungen eines Nitrosyl‐Eisenporphyrinats, [Fe(oep)(NO)] (siehe Bild; oep=Octaethylporphyrin). Der axiale Nitrosyl‐Ligand bestimmt die Richtung der In‐Plane‐Bewegung des Eisenzentrums.

The electronic spin state of Fe2+in ferropericlase, (Mg0.75Fe0.25)O, transitions from a high-spin (spin unpaired) to low-spin (spin paired) state within the Earth’s mid-lower mantle region. To better understand the local electronic environment of high-spin Fe2+ions in ferropericlase near the transition, we obtained synchrotron Mössbauer spectra (SMS) of (Mg0.75,Fe0.25)O in externally heated and laser-heated diamond anvil cells at relevant high pressures and temperatures. Results show that the quadrupole splitting (QS) of the dominant high-spin Fe2+site decreases with increasing temperature at static high pressure. The QS values at constant pressure are fitted to a temperature-dependent Boltzmann distribution model, which permits estimation of the crystal-field splitting energy (Δ3) between the dxyand dxzor dzyorbitals of the t2gstates in a distorted octahedral Fe2+site. The derived Δ3increases from approximately 36 meV at 1 GPa to 95 meV at 40 GPa, revealing that both high pressure and high temperature have significant effects on the 3d electronic shells of Fe2+in ferropericlase. The SMS spectra collected from the laser-heated diamond cells within the time window of 146 ns also indicate that QS significantly decreases at very high temperatures. A larger splitting of the energy levels at high temperatures and pressures should broaden the spin crossover in ferropericlase because the degeneracy of energy levels is partially lifted. Our results provide information on the hyperfine parameters and crystal-field splitting energy of high-spin Fe2+in ferropericlase at high pressures and temperatures, relevant to the electronic structure of iron in oxides in the deep lower mantle.

Conformational flexibility is essential to the functional behavior of proteins. We use an effective force constant introduced by Zaccai, the resilience, to quantify this flexibility. Site-selective experimental and computational methods allow us to determine the resilience of heme protein active sites. The vibrational density of states of the heme Fe determined using nuclear resonance vibrational spectroscopy provides a direct experimental measure of the resilience of the Fe environment, which we compare quantitatively with values derived from the temperature dependence of atomic mean-squared displacements in molecular dynamics simulations. Vibrational normal modes in the THz frequency range dominate the resilience. Both experimental and computational methods find a higher resilience for cytochrome cthan for myoglobin, which we attribute to the increased number of covalent links to the peptide in the former protein. For myoglobin, the resilience of the iron environment is larger than the average resilience previously determined for hydrogen sites using neutron scattering. Experimental results suggest a slightly reduced resilience for cytochrome cupon oxidation, although the change is smaller than reported in previous Mössbauer investigations on a bacterial cytochrome c, and is not reproduced by the simulations. Oxidation state also has no significant influence on the compressibility calculated for cyt c, although a slightly larger compressibility is predicted for myoglobin.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and the most common type of non-Hodgkin lymphoma. Despite recent advances in treatment, less than 50% of the patients are cured with current multiagent chemotherapy. Abnormal NF-κB activity not only contributes to tumor development but also renders cancer cells resistant to chemotherapeutic agents. Identifying and targeting signaling molecules that control NF-κB activation in cancer cells may thus yield more effective therapy for DLBCL. Here, we show that while overexpression of protein kinase C–associated kinase (PKK) activates NF-κB signaling in DLBCL cells, suppression of PKK expression inhibits NF-κB activity in these cells. In addition, we show that NF-κB activation induced by B cell–activating factor of tumor necrosis factor family (BAFF) in DLBCL cells requires PKK. Importantly, we show that knockdown of PKK impairs the survival of DLBCL cells in vitro and inhibits tumor growth of xenografted DLBCL cells in mice. Suppression of PKK expression also sensitizes DLBCL cells to treatment with chemotherapeutic agents. Together, these results indicate that PKK plays a pivotal role in the survival of human DLBCL cells and represents a potential target for DLBCL therapy.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and the most common type of non-Hodgkin lymphoma. Despite recent advances in treatment, less than 50% of the patients are cured with current multiagent chemotherapy. Abnormal NF-κB activity not only contributes to tumor development but also renders cancer cells resistant to chemotherapeutic agents. Identifying and targeting signaling molecules that control NF-κB activation in cancer cells may thus yield more effective therapy for DLBCL. Here, we show that while overexpression of protein kinase C–associated kinase (PKK) activates NF-κB signaling in DLBCL cells, suppression of PKK expression inhibits NF-κB activity in these cells. In addition, we show that NF-κB activation induced by B cell–activating factor of tumor necrosis factor family (BAFF) in DLBCL cells requires PKK. Importantly, we show that knockdown of PKK impairs the survival of DLBCL cells in vitro and inhibits tumor growth of xenografted DLBCL cells in mice. Suppression of PKK expression also sensitizes DLBCL cells to treatment with chemotherapeutic agents. Together, these results indicate that PKK plays a pivotal role in the survival of human DLBCL cells and represents a potential target for DLBCL therapy.

We use nuclear resonance vibrational spectroscopy and computational predictions based on density functional theory (DFT) to explore the vibrational dynamics of 57Fe in porphyrins that mimic the active sites of histidine-ligated heme proteins complexed with carbon monoxide. Nuclear resonance vibrational spectroscopy yields the complete vibrational spectrum of a Mössbauer isotope, and provides a valuable probe that is not only selective for protein active sites but quantifies the mean-squared amplitude and direction of the motion of the probe nucleus, in addition to vibrational frequencies. Quantitative comparison of the experimental results with DFT calculations provides a detailed, rigorous test of the vibrational predictions, which in turn provide a reliable description of the observed vibrational features. In addition to the well-studied stretching vibration of the Fe-CO bond, vibrations involving the Fe-imidazole bond, and the Fe-Npyr bonds to the pyrrole nitrogens of the porphyrin contribute prominently to the observed experimental signal. All of these frequencies show structural sensitivity to the corresponding bond lengths, but previous studies have failed to identify the latter vibrations, presumably because the coupling to the electronic excitation is too small in resonance Raman measurements. We also observe the FeCO bending vibrations, which are not Raman active for these unhindered model compounds. The observed Fe amplitude is strongly inconsistent with three-body oscillator descriptions of the FeCO fragment, but agrees quantitatively with DFT predictions. Over the past decade, quantum chemical calculations have suggested revised estimates of the importance of steric distortion of the bound CO in preventing poisoning of heme proteins by carbon monoxide. Quantitative agreement with the predicted frequency, amplitude, and direction of Fe motion for the FeCO bending vibrations provides direct experimental support for the quantum chemical description of the energetics of the FeCO unit.

Anti-HER2 antibody trastuzumab (Herceptin®) has been used effectively to treat patients with breast cancer that overexpresses HER2. We have demonstrated that p27Kip1 upregulation is one of the key events that cause G1 arrest upon trastuzumab treatment. Here, we have examined the effect of trastuzumab on CDK2, Rb, E2F1, NPAT, histone H4, and their associated signaling pathway. Results showed that trastuzumab was able to dramatically inhibit the kinase activity and expression of CDK2, whereas the kinase activity and expression of CDK4 were not affected by trastuzumab treatment. Unlike the p27Kip1 upregulation that occurs primarily through post-translational mechanisms, CDK2 was mainly downregulated at a transcriptional level as shown by Northern blotting and real-time RT-PCR analyses. Trastuzumab decreased the kinase activity of cyclin E (because of CDK2 inhibition) although it had little effect on cyclin E protein level. Overexpression of wild-type cyclin E or its lower molecular weight forms did not influence the response to trastuzumab. Levels and activities of CDK6, cyclin A, and cyclin D1 were all suppressed by trastuzumab. As a result, Rb phosphorylations that associates with CDK2, cyclin E, CDK6, cyclin A, or cyclin D1 were substantially inhibited by trastuzumab. Trastuzumab decreased the DNA-binding activity of E2F1. Trastuzumab decreased the level of NPAT protein. Trastuzumab decreased the level of histone H4 mRNA. Blockade of PI3K pathway with LY294002 produced similar effects to trastuzumab treatment. Taken together, these results demonstrated that anti-HER2antibody trastuzumab inhibits CDK2, Rb phosphorylation, E2F1 activity, NPAT, and histone H4 via PI3K signaling pathway, which are essential to both DNA and histone synthesis during the progression of G1 phase to S phase of the cell cycle.