Loss Of Ligand Research Articles

Calcium catalyzed enantioselective intramolecular alkene hydroamination with chiral C2-symmetric bis-amide ligands.

The chiral building block (R)-(+)-2,2'-diamino-1,1'-binaphthyl, (R)-BINAM, which is often used as backbone in privileged enantioselective catalysts, was converted to a series of N-substituted proligands R1-H2 (R = CH2tBu, C(H)Ph2, PPh2, dibenzosuberane, 8-quinoline). After double deprotonation with strong Mg or Ca bases, a series of alkaline earth (Ae) metal catalysts R1-Ae·(THF)n was obtained. Crystal structures of these C2-symmetric catalysts have been analyzed by quadrant models which show that the ligands with C(H)Ph2, dibenzosuberane and 8-quinoline substituents should give the best steric discrimination for the enantioselective intramolecular alkene hydroamination (IAH) of the aminoalkenes H2C[double bond, length as m-dash]CHCH2CR'2CH2NH2 (CR'2 = CPh2, CCy or CMe2). The dianionic R12- ligand in R1-Ae·(THF)n functions as reagent that deprotonates the aminoalkene substrate, while the monoanionic (R1-H)- ligand formed in this reaction functions as a chiral spectator ligand that controls the enantioselectivity of the ring closure reaction. Depending on the substituent R in the BINAM ligand, full cyclization of aminoalkenes to chiral pyrrolidine products as fast as 5 minutes was observed. Product analysis furnished enantioselectivities up to 57% ee, which marks the highest enantioselectivity reported for Ca catalyzed IAH. Higher selectivities are impeded by double protonation of the R12- ligand leading to complete loss of chiral information in the catalytically active species.

Nitride protonation and NH3 binding versus N-H bond cleavage in uranium nitrides.

The conversion of metal nitrides to NH3 is an essential step in dinitrogen fixation, but there is limited knowledge of the reactivity of nitrides with protons (H+). Herein, we report comparative studies for the reactions of H+ and NH3 with uranium nitrides, containing different types of ancillary ligands. We show that the differences in ancillary ligands, leads to dramatically different reactivity. The nitride group, in nitride-bridged cationic and anionic diuranium(iv) complexes supported by –N(SiMe3)2 ligands, is resistant toward protonation by weak acids, while stronger acids result in ligand loss by protonolysis. Moreover, the basic –N(SiMe3)2 ligands promote the N–H heterolytic bond cleavage of NH3, yielding a “naked” diuranium complex containing three bridging ligands, a nitride (N3−) and two NH2 ligands. Conversely, in the nitride-bridged diuranium(iv) complex supported by –OSi(OtBu)3 ligands, the nitride group is easily protonated to afford NH3, which binds the U(iv) ion strongly, resulting in a mononuclear U–NH3 complex, where NH3 can be displaced by addition of strong acids. Furthermore, the U–OSi(OtBu)3 bonds were found to be stable, even in the presence of stronger acids, such as NH4BPh4, therefore indicating that –OSi(OtBu)3 supporting ligands are well suited to be used when acidic conditions are required, such as in the H+/e− mediated catalytic conversion of N2 to NH3.

Primary and Secondary Loss of CO and NO Ligands in the Ultraviolet Photodissociation of the Heteroleptic Co(CO)3NO Complex.

The photodissociation dynamics of the heteroleptic Co(CO)3NO complex were investigated in the metal-to-carbonyl (CO) ligand charge-transfer band to compare the reactivity of the CO and nitrosyl (NO) ligands. The final state distributions of both the CO and NO fragments were measured using resonance-enhanced multiphoton ionization (REMPI) spectroscopy and velocity-map ion-imaging. The primary CO photofragment was differentiated from the secondary fragments of the subsequent unimolecular decomposition of coordinatively unsaturated intermediates by comparing the momentum distributions. The internal energy of the Co(CO)2NO intermediate was sufficiently high (≥348 kJ/mol) to be generated in the electronic excited state, indicating the occurrence of the primary CO elimination on an excited state. The NO fragments exhibited two velocity components. The analysis of the final state distributions suggested that the higher- and lower-kinetic-energy components originated from the direct primary elimination and sequential elimination, respectively. The direct photoelimination through a transiently bent ligand conformation was illustrated on the basis of a two-dimensional REMPI approach and time-dependent density functional theory calculations. The present results of both ligands demonstrate the correlation between elimination mechanisms and possible ligand conformations in the electronic excited state.

Rictor Is a Novel Regulator of TRAF6/TRAF3 in Osteoclasts.

Tumor necrosis factor receptor-associated factors (TRAFs) are crucial for receptor activator of nuclear factor-κB (RANK) activation in osteoclasts. However, the upstream mechanisms of TRAF members in the osteoclastic lineage remain largely unknown. Here, we demonstrated that Rictor, a key component of mechanistic target of rapamycin complex 2 (mTORC2), was crucial for TRAF6/TRAF3 expression in osteoclasts. Our ex vivo and in vivo studies showed that Rictor ablation from the osteoclastic lineage reduced osteoclast numbers and increased bone mass in mice. Mechanistically, we found that Rictor ablation restricted osteoclast formation, which disrupted TRAF6 stability and caused autophagy block in a manner distinct from mTORC1, resulting in reduced TRAF3 degradation. Boosting TRAF6 expression or knockdown of TRAF3 levels in Rictor-deficient cells could both overcome the defect. Moreover, Rictor could interact with TRAF6 upon RANK ligand (RANKL) stimulation and loss of Rictor impaired TRAF6 stability and promoted its ubiquitinated degradation. These findings established an innovative link between Rictor, TRAF protein levels, and autophagic block. More importantly, mTOR complexes in the osteoclastic lineage are likely switches for coordinating TRAF6 and TRAF3 protein levels, and Rictor may function as an essential upstream regulator of TRAF6/TRAF3 that is partially independent of mTORC1 activity. Inhibitors targeting Rictor may therefore be valuable for preventing or treating osteoclast-related diseases. © 2021 American Society for Bone and Mineral Research (ASBMR).

(Invited) Magnetic Relaxation Nanoparticle Biosensor for Dosimetric, Longitudinal Biochemical Monitoring In Vivo

Introduction: Harnessing the diversity of sensing platforms for applications in complex environments has been an ongoing challenge in biosensing. Most techniques exhibit limitations ranging from biocompatibility, sensitivity, and signal transduction through opaque media, to longevity under non-laboratory conditions. Through multidisciplinary advances in nanoscience and medical devices, we have developed an implant for the measurement of biomarkers using a magnetic particle assay platform1,2. Exposure to target induces a switch from a dispersed to an assembled state with a corresponding change in magnetic relaxation properties allowing for robust contrast. Current applications focus on diagnostics in chronic cardiac disease and spikes in biomarker presence frequently missed by serial sampling. We address design parameters for sensing functionality, tunability, and degradation to lay the groundwork for multi-month implantation in vivo. Materials and Methods: Particle core materials provided magnetic contrast while biological functionality was tuned by surface ligands for affinity toward multivalent targets (Figure 1a). Polyclonal antibodies were conjugated to superparamagnetic iron oxide nanoparticles (20-50 nm) by maleimide-thiol chemistry. Proton Magnetic Relaxation measurements were acquired on a custom-made, single-sided, inhomogeneous field relaxometer (0.43 Tesla, 25°C, NMR MOUSE) fitted with a programmable robotic scanning stage3. A Carr-Purcell-Meiboom-Gill pulse sequence was used: TE = 0.035 ms, 5454 echoes, 15 scans, TR = 6 s. Relaxation times were determined by single exponential fit to echo peak intensities with a custom MATLAB script. Delrin diffusion devices were filled with particle colloidal suspension and sealed with 30 nm pore polycarbonate semi-permeable membranes via double-sided, pressure-sensitive adhesive (Figure 1b). Devices were exposed to target while sensor response was read every 90-120 minutes for up to 48 hrs. Degradation was measured by quantitating loss of ligand from the surface (ELISA) and changes in sensor performance after elevated temperature storage (37°C) for up to 12 weeks. Results and Discussion: Ligand valency was tuned over an order of magnitude (4-40 Antibodies/Particle) by varying bioconjugation strategies and reagents. Conjugation stability under standard storage conditions indicated a lifetime >5 months by isolating free from bound protein by centrifugation. A maximum 1% of conjugated ligand was released, minimally decreasing valency and sensor functionality. Assay performance showed prozone agglutination behavior with quantitative exposure ranging from 50-2000 ng/mL of target and contrast in <2 hrs. Device dosimeter performance was validated for a cardiac Myoglobin model. Saturation was tuned from 4 to 12 μg/mL*hrs corresponding with 8 to >24 hrs of continuous biomarker elevation at 0-500 ng/mL. 4 hr equilibration and irreversible dosimeter signal stability post-exposure for >12 hrs was also observed (Figure 1c). Biochemical and aggregation performance degradation parameters were evaluated. Over 6.5 weeks of elevated temperature storage, 1.8% of the conjugated antibody was unbound. Sensor longitudinal performance on exposure to target over 12 weeks of incubation showed a monotonically decreasing response magnitude and rate (Figure 1d). Exponential fit to sensor response decay curve predicts a 29 week “switch” (on/off) sensor lifetime for an infarction model (500 ng/mL Myo). These results indicate our sensor can be derivatized for a cardiac biomarker with usable sensitivity and saturation dosimeter response corresponding to elevations expected in a Myocardial Infarction (MI). Device performance can be tuned by matching sensor characteristics with the physiological range of target sensitivity and saturation desired. By tuning bioconjugation strategies we enhanced the performance of the biosensor by an order of magnitude over prior studies. Sensor lifetime and nanostructure degradation studies have shown the limiting performance factor is not the loss of ligand from the surface of the particles but rather the loss of binding activity as seen in elevated temperature experiments. Conclusions: This implant has the potential to broaden diagnostics in personalized medicine by addressing the hurdles of longevity and robust sensor signal stability in complex environments. In situ diagnostics offer continuous sentineling of critical biomarkers, providing a deeper understanding of local biology in dynamic, heterogeneous systems. This monitoring provides valuable timescale data to clinicians with insight into their patients’ lab results for early intervention and data collection throughout treatment. This implant has the capacity to bridge the gap between lab and clinical grade sensors, significantly improving interventional medicine by leveraging the robust and tunable nature of magnetic relaxation particle assays.

A Combined Spectroscopic and Protein Crystallography Study Reveals Protein Interactions of RhI(NHC) Complexes at the Molecular Level.

While most Rh-N-heterocyclic carbene (NHC) complexes currently investigated in anticancer research contain a Rh(III) metal center, an increasing amount of research is focusing on the cytotoxic activity and mode of action of square-planar [RhCl(COD)(NHC)] (where COD = 1,5-cyclooctadiene) which contains a Rh(I) center. The enzyme thioredoxin reductase (TrxR) and the protein albumin have been proposed as potential targets, but the molecular processes taking place upon protein interaction remain elusive. Herein, we report the preparation of peptide-conjugated and its nonconjugated parent [RhCl(COD)(NHC)] complexes, an in-depth investigation of both their stability in solution, and a crystallographic study of protein interaction. The organorhodium compounds showed a rapid loss of the COD ligand and slow loss of the NHC ligand in aqueous solution. These ligand exchange reactions were reflected in studies on the interaction with hen egg white lysozyme (HEWL) as a model protein in single-crystal X-ray crystallographic investigations. Upon treatment of HEWL with an amino acid functionalized [RhCl(COD)(NHC)] complex, two distinct rhodium adducts were found initially after 7 d of incubation at His15 and after 4 weeks also at Lys33. In both cases, the COD and chlorido ligands had been substituted with aqua and/or hydroxido ligands. While the histidine (His) adduct also indicated a loss of the NHC ligand, the lysine (Lys) adduct retained the NHC core derived from the amino acid l-histidine. In either case, an octahedral coordination environment of the metal center indicates oxidation to Rh(III). This investigation gives the first insight on the interaction of Rh(I)(NHC) complexes and proteins at the molecular level.

Designing New Metal Chalcogenide Nanoclusters through Atom‐by‐Atom Substitution

Atom-by-atom substitution is a promising strategy for designing new cluster-based materials, which has been used to generate new gold- and silver-containing clusters. Here, the first study focused on atom-by-atom substitution of Fe and Ni to the core of a well-defined cobalt sulfide superatom [Co6 S8 L6 ]+ ligated with triethylphosphine (L = PEt3 ) to produce [Co5 MS8 L6 ]+ (M = Fe, Ni) is reported. Electrospray ionization mass spectrometry confirms the substitution of 1-6 Fe atoms with the single Fe-substituted cluster being the dominant species. The Fe-substituted clusters oxidize in solution to generate dicationic species. In contrast, only a single Ni-substituted cluster is observed, which remains stable as a singly charged species. Collision-induced dissociation experiments indicate the reduced stability of the [Co5 FeS8 L6 ]+ toward ligand loss in comparison with the unsubstituted and Ni-substituted counterparts. Density functional theory calculations provide insights into the effect of metal atom substitution on the stability and electronic structures of the clusters. The results indicate that Fe and Ni have a different impact on the electronic structure, optical, and magnetic properties, as well as ligand-core interaction of [Co6 S8 L6 ]. This study extends the atom-by-atom substitution strategy to the metal chalcogenide superatoms providing a direct path toward designing novel atomically precise core-tailored superatoms.

Charge-State-Dependent Fragmentation of [2.2]Based Metallosupramolecular Cyclic Helicates in the Gas Phase.

A detailed mass-spectrometric study provides insight into the gas-phase fragmentation pathways of a cyclic helicate selectively built from four iron(II) centers and six [2.2]cyclophane-based ligands through the subcomponent self-assembly approach. The charge state of the precursor ion, i. e., the number of triflate anions accompanying the metallo-supramolecular core, has a strong influence on the observed fragmentations. The triply charged ion shows loss of a neutral ligand whereas ions of higher charge fragment by up to three different charge-separating pathways to minimize the charge density of the ions. Additional subsequent fragmentations of highly charged fragment ions include redox processes as well as splitting of the unusual paracyclophane backbone.

Flavone as a novel matrix for the matrix-assisted laser desorption/ionisation analysis of lanthanide and transition metal salts.

The mass spectral analysis of metal salts, especially lanthanide and transition metal salts, can be challenging. Although getting information on the metal present is usually straightforward, obtaining information on the correct oxidation state and anion composition is challenging. Many ionisation techniques have some redox component to the ionisation process, which commonly results in changing the oxidation state of the metal and the associated loss of ligand and anion information. We present here a simple method for negative ion matrix-assisted laser desorption/ionisation mass spectrometry using the non-acidic flavonoid flavone as a novel matrix. This results in reliable information on the oxidation state of the metal as spectra are dominated by anion adduct ions with very little (typically no) redox processes occurring.

Abstract 480: Molecular mechanism of action of photoimmunotherapy with antibody-IR700 dye conjugates

Abstract INTRODUCTION: Cancer cell-targeted photoimmunotherapy (PIT) is a platform technology under development for the treatment of various cancers. PIT is a drug and device combination that utilizes an antibody conjugated to the IR700 (IRDye 700DX®) light-excitable dye, which upon antigen binding and illumination with non-thermal red light, leads to necrotic cell death. The objective of these studies was to characterize the molecular pharmacology and the underlying mechanism of action of PIT. METHODS: In vitro PIT studies using human and mouse cancer cells were performed to evaluate conjugate (antibody + dye) binding, dose response and light dosimetry response. Mouse xenograft experiments assessed necrotic markers in tumor tissue and surrounding normal tissue post-PIT treatment. Oxidative damage to lipids was detected with a reporter dye. Mass spectrometry analysis was performed to assess protein oxidation, crosslinking and axial ligand dissociation from the dye. RESULTS: Binding of the conjugate to the target cancer cells was required for PIT treatment to induce cell death as measured by antibody competition studies, however, internalization of the conjugate was not required for cytotoxic effects. Administration of non-thermal red light to the target cells bound with the conjugate led to morphologic changes and membrane disruption within minutes, and necrotic cell death was observed in a conjugate- and light-dose dependent manner. Requirement of conjugate binding to the cancer antigen provided high level of tumor specificity as demonstrated by lack of damage to normal surrounding tissue after PIT treatment. Light excitation of the conjugate generated 1O2 with high quantum yield. In vitro PIT treatment led to cell membrane lipid peroxidation, mediated by 1O2 as shown by abrogation with sodium azide, a selective 1O2 quencher. In addition, protein oxidation, cross-linking and aggregation of the conjugate was observed. In low oxygen concentrations and in the presence of ascorbate, photo-induced dissociation of axial ligands from the dye was detected. CONCLUSIONS: These studies suggest the molecular mechanism of action of PIT includes generation of 1O2 that leads to lipid peroxidation and cell membrane disruption. Additional mechanisms may include protein oxidation and non-oxygen dependent mechanisms such as axial ligand loss of the IR700 dye. These results describe a biophysical process that damages and disrupts the cell membrane integrity resulting in necrotic cell death and immunogenic cell death. Citation Format: Roger Heim, Lew Makings, Torsten Wiemann, Anthony Manibusan, Miguel Garcia-Guzman. Molecular mechanism of action of photoimmunotherapy with antibody-IR700 dye conjugates [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 480.

Using electrospray ionization-tandem mass spectrometry to explore formation and gas-phase chemistry of silver nanoclusters generated from the reaction of silver salts with NaBH4 in the presence of bis(diphenylarsino)methane.

Electrospray ionization-mass spectrometry (ESI-MS) of mixtures of AgBF4 or AgNO3 with the capping ligand bis(diphenylarsino)methane ((Ph2 As)2 CH2 = dpam) in a solution of acetonitrile revealed the formation of the following cations: [Ag(CH3 CN)(dpam)]+ , [Ag(dpam)2 ]+ , [Ag2 (Cl)(dpam)2 ]+ , and [Ag3 (Cl)2 (dpam)3 ]+ . Addition of NaBH4 to these solutions results in the formation of the cluster cations [Ag2 (BH4 )(dpam)2 ]+ , [Ag2 (BH4 )(dpam)3 ]+ , [Ag3 (H)(BH4 )(dpam)3 ]+ , [Ag3 (BH4 )2 (dpam)3 ]+ , [Ag3 (H)(Cl)(dpam)3 ]+ , and [Ag3 (I)(BH4 )(dpam)3 ]+ , as established by ESI-MS. Use of NaBD4 confirmed that borohydride is the source of the hydride in these clusters. An Orbitrap Fusion LUMOS mass spectrometer was used to explore the gas-phase unimolecular chemistry of selected clusters via multistage mass spectrometry (MSn ) experiments employing low-energy collision-induced dissociation (CID) and high-energy collision-induced dissociation (HCD) experiments. The borohydride containing clusters fragment via two competing pathways: (i) ligand loss and (ii) B-H bond activation involving BH3 loss. Density functional theory (DFT) calculations were used to calculate the energetics of the optimized structures for all precursor ions, fragment ions, and neutrals and to estimate the reaction endothermicities. Generally, there is reasonable agreement between the most abundant product ion formed and the predicted endothermicity of the associated reaction channel. The DFT calculations predicted that the novel dimer [Ag2 (BH4 )(dpam)2 ]+ has a paddlewheel structure in which the dpam and BH4 - ligands bridge both silver centers.

Hydrogen bonding influences collision-induced dissociation of Na+ -bound guanine tetrads.

Na+ -bound guanine (G)-tetrads possess square planar structures formed solely by noncovalent interactions including multiple hydrogen bonds. Unlike G-tetrads facilitated by other alkali metal ions, an intriguing behavior in collision-induced dissociation (CID) has been observed in Na+ -bound G-tetrads, which features a preferential, simultaneous loss of two G ligands in the low energy regime. To understand this unique behavior, we investigated the CID of Na+ -bound G-tetrads with mixed ligands of G and 9-methylguanine (9mG), [Na·Gm ·9mGn ]+ (m + n = 4), and [Li·9mG4 ]+ for comparison. In the CID experiments, the simultaneous losses of two ligands were by far more pronounced than the loss of a single ligand for all five Na+ -bound G-tetrads. However, it appeared that the CID of [Li·9mG4 ]+ prefers to lose single ligands sequentially. An analysis of the fragment abundances suggested that the generation of Na+ -bound dimeric fragments might have occurred with two adjacent ligands. This theoretical study predicted for [Li·9mG4 ]+ that the loss of a single ligand is more energetically favorable than the production of neutral hydrogen-bonded fragments by 35.5 kJ/mol (ΔG). This contradicts our previous calculations for [Na·9mG4 ]+ that a neutral loss of hydrogen-bonded dimers provides the lowest energy product state of Na+ -bound dimeric fragments, which is lower than that of Na+ -bound trimeric fragments by 15.6 kJ/mol. From the results, this comparative study suggests that the pronounced generation of Na+ -bound dimeric fragments in CID of the G-tetrads is likely promoted by the dissociation pathway associated with neutral loss of hydrogen-bonded dimers. It thus demonstrates that multiple hydrogen bonding participating in formation of Na+ -bound G-tetrads may also strongly influence the fate of dissociating complexes of G-tetrads.

Resistance of KIR Ligand-Missing Leukocytes to NK Cells In Vivo in Patients with Acquired Aplastic Anemia.

The loss of killer cell Ig-like receptor ligands (KIR-Ls) due to the copy number-neutral loss of heterozygosity of chromosome 6p (6pLOH) in leukocytes of patients with acquired aplastic anemia (AA) may alter the susceptibility of the affected leukocytes to NK cell killing in vivo. We studied 408 AA patients, including 261 who were heterozygous for KIR-Ls, namely C1/C2 or Bw6/Bw4, for the presence of KIR-L-missing [KIR-L(-)] leukocytes. KIR-L(-) leukocytes were found in 14 (5.4%, C1 [n = 4], C2 [n = 3], and Bw4 [n = 7]) of the 261 patients, in whom corresponding KIR(+) licensed NK cells were detected. The incidence of 6pLOH in the 261 patients (18.0%) was comparable to that in 147 patients (13.6%) who were homozygous for KIR-L genes. The percentages of HLA-lacking granulocytes (0.8-50.3%, median 15.2%) in the total granulocytes of the patients with KIR-L(-) cells were significantly lower than those (1.2-99.4%, median 55.4%) in patients without KIR-L(-) cells. KIR2DS1 and KIR3DS1 were only possessed by three of the 14 patients, two of whom had C2/C2 leukocytes after losing C1 alleles. The expression of the KIR3DS1 ligand HLA-F was selectively lost on KIR-L(-) primitive hematopoietic stem cells derived from 6pLOH(+) induced pluripotent stem cells in one of the KIR3DS1(+) patients. These findings suggest that human NK cells are able to suppress the expansion of KIR-L(-) leukocytes but are unable to eliminate them partly due to the lack of activating KIRs on NK cells and the low HLA-F expression level on hematopoietic stem cells in AA patients.

Iron(II) Spin Crossover Complexes Based on a Redox Active Equatorial Schiff-Base-Like Ligand.

In this work, two iron(II) coordination compounds with a N2O2 coordinating Schiff base-like ligand bearing a redox active tetrathiafulvalene (TTF) unit and pyridine or trans-1,2-bis(4-pyridylethylene) as an axial ligand are synthesized. Crystals suitable for single X-ray structure analysis were obtained for the new ligand. The complexes were characterized by magnetic susceptibility measurements, T-dependent UV-vis spectroscopy, and cyclic voltammetry. Both complexes display spin transition behavior below room temperature with T1/2 values of 146 and 156 K. The mononuclear iron(II) complex [FeTTFL(py)2] is relatively stable up to 400 K compared to similar complexes, showing no loss of axial ligands upon heating. Temperature dependent Mössbauer spectroscopy was conducted for the coordination polymer {[FeTTFL(bpee)]}n to get more information regarding the origin of the stepwise spin crossover (SCO) behavior observed in the magnetic measurements. The change of the spin state is accompanied by a change of the optical properties, which can be monitored by VT-UV-vis spectroscopy for the mononuclear complex and has been analyzed in theoretical studies. The redox behavior of the iron(II) complexes reveals three reversible redox steps which are located at the iron center and at the TTF unit of the ligand. Oxidation of the TTF unit induces characteristic changes in the UV-vis spectrum that can be followed by spectroelectrochemical UV-vis spectroscopy. Addressing the potential of the iron-centered redox process results in similar changes in the UV-vis spectrum, which indicates an electronic coupling of the redox active unit with the metal center under certain circumstances.

Thermal properties of molybdenum hexacarbonyl: Kinetic and thermodynamic studies

The thermal analysis of molybdenum hexacarbonyl has been performed under helium stream (2 K min−1) between room temperature and (1100 ± 2) K. According to mass spectrometry results, the organometallic sublimates between (330.4 ± 0.1) K and (339.7 ± 0.1) K, and the sublimation enthalpy, determined at two particular temperatures (ΔsubH(298.15 K) = (73.66 ± 0.02) kJ mol−1), is similar to the activation energy. As a matter of fact, the sublimation of Mo(CO)6(cr) follows a perfect-zero order reaction kinetic (Ea = (73.49 ± 0.10) kJ mol−1 and the pre-exponential factor is (8.33 ± 0.33) × 108s−1). Furthermore, using Langmuir equation and thermogravimetry data, we were able to determine the vaporization constant (α) (=8.95 × 10−5 ± 1.45 × 10−7), the constant k (=80735 J0.5 mol−0.5 K−0.5) as well as ΔsubH(298.15 K) (equal to (75.91 ± 0.37) kJ mol−1). In the presence of ZSM-5 zeolite, the temperatures of Mo(CO)6(cr) decarbonylation, Ea and ΔsubH values were succinctly determined. Interestingly, the loss of the first CO ligand in Mo(CO)6(cr) occurred between (480 ± 0.1) K and (532 ± 0.1) K.

Computational Study of an Iron(II) Polypyridine Electrocatalyst for CO2 Reduction: Key Roles for Intramolecular Interactions in CO2 Binding and Proton Transfer

A solar-driven conversion of CO2 into fuels by artificial photosynthesis would not only mitigate the greenhouse effect but also provide an alternative to obtain fuels in a renewable fashion. To this end, the new iron polypyridine catalyst [Fe(bpyNHEtPY2Me)L2]2+ (L = H2O, CH3CN) was recently developed for the electrochemical reduction of CO2 to CO. In this study, we performed density functional theory (DFT) electronic structure calculations to shed light on a possible pathway for CO2 reduction and the origin of the selectivity between CO2 reduction versus the hydrogen evolution reaction. The metal center remains Lewis acidic throughout the reduction process due to ligand loss and mainly ligand-based reduction stabilized by antiferromagnetic coupling to a high-spin Fe(II) center. This results in a high barrier for hydride formation but a facile addition and activation of CO2 via an η2 coordination and stabilizing hydrogen bonding by the amine group. The second unoccupied equatorial coordination site opens up the possibility for an intramolecular protonation with a coordinated water ligand. This facilitates protonation because not only CO2 but also the proton source H2O is activated and properly aligned for a proton transfer due to the Fe-OH2 bond; consequently, both protonation steps are facile. The moderate ligand field allows a rapid ligand exchange for a second intramolecular protonation step and facilitates an exergonic CO release. The lower selectivity of the related [Fe(bpyOHPY2Me)L2]2+ complex can be related to its more acidic second coordination sphere, which enables an intramolecular proton transfer that is kinetically competitive with CO2 addition.

Targeted Myoglobin Delivery as a Strategy for Enhancing the Sensitivity of Hypoxic Cancer Cells to Radiation.

SummaryThe effectiveness of cancer radiotherapy is frequently hindered by the hypoxia of the tumor microenvironment. Direct delivery of oxygen to hypoxic tumor tissues is an attractive strategy to overcome this hypoxia-associated radioresistance. Herein, we report the generation of submicron-sized particles comprising myoglobin fused to the crystal-forming domain of Cry3Aa protein for the targeted delivery of oxygen to cancer cells. We demonstrate that myoglobin-containing particles were successfully produced in Bacillus thuringiensis with the assistance of the Cry3Aa domain I. Furthermore, these particles could be genetically modified to incorporate the cell penetrating peptide TAT and cell targeting peptide A549.1, resulting in particles that exhibited improved cellular uptake and targeting toward A549 cells. Notably, these myoglobin-containing particles increased the intracellular oxygen levels of A549 cells and thereby sensitized them to radiation. These findings suggest that the targeted delivery of O2-bound myoglobin could be an effective approach to enhance the efficacy of radiotherapy.

Glycan Remodelling Controls Germinal Centre B cell Responses

Abstract Germinal centre (GC) B cells are routinely identified through distinct changes on their surface carbohydrates, called glycans; yet, whether these modifications play an essential role in GC reaction remain unknown. One striking change relates to the monosaccharide sialic acid. In mice, this change is mediated through downregulation of an enzyme called Cmah. As a consequence, GC B cells lose the preferred ligand for CD22, a member of the sialic acid-binding immunoglobulin-type lectins (Siglecs) and a co-inhibitory receptor of the B cell antigen receptor. Since CD22 regulates B cell function, we hypothesize that this specific glycan remodelling on B cells control the GC reaction by modulating the activity of CD22. To test our hypothesis, we developed a mouse model that constitutively expresses Cmah in B cells. Following immunization, we find that sustained expression of Cmah in B cells results in impaired generation of antigen-specific GC B cells. More significantly, this observed defect is dependent on CD22, highlighting that coordinated loss of preferred ligands for CD22 on B cells plays a critical function in the GC. Furthermore, antibody affinity maturation is significantly impaired in immunized mice harbouring B cells which lack either CD22 or its cis glycan ligands, further supporting the role of CD22 and its glycan ligands in the GC. Ongoing efforts are focused on defining the GC-specific nature of these observations and examining potential mechanism related to BCR signalling, GC B cell survival and exit to plasma cells, and B-T cell interactions.

Niobium and tantalum in hydrothermal fluids: Thermodynamic description of hydroxide and hydroxofluoride complexes

Available experimental data on the solubility of β -Nb2O5 and β -Ta2O5 in the Nb–O–H–F and Ta–O–H–F systems were critically evaluated, and the thermodynamic properties of hydroxide and hydroxofluoride complexes were estimated in a wide range of temperatures (0–600 °C) and pressures (1–3000 bar). In near neutral pH solutions, the solubility of the oxides is governed by uncharged aqueous hydroxides, Nb(OH)5 and Ta(OH)5, and is rather low even at high temperatures (1–9 ppm for Nb and 0.1–0.9 ppm for Ta at 600 °C, 1000 bar). In acid HF bearing solutions, the solubility is governed by Nb(OH)2F3 and Ta(OH)2F3 complexes and increases sharply with increasing HF molality: at mHF = 0.1 mol·kg−1, 600 °C and 1000 bar, the Nb and Ta concentrations reach 80 and 30 ppm respectively. In alkaline fluoride bearing solutions, the HNbO3F− and HTaO3F− - oxyfluoride anions control the solubility of the oxides. The temperature and pressure dependences of the oxides solubility governed by these fluoride complexes are rather weak; therefore, the neutralization of acid fluoride solution and the loss of fluoride ligand during fluid evolution can be the main factors of Nb and Ta deposition.

Elucidating the stability of ligand-protected Au nanoclusters under electrochemical reduction of CO2

Ligand-protected gold nanoclusters are a novel class of particles that have attracted great interest in the field of catalysis due to their atomically-precise structure, high surface-to-volume ratio, and unique electronic properties. In particular, the anionic thiolate-protected Au25 nanocluster (NC), [Au25(SR)18]1−, with partially lost ligands, has been demonstrated to act as an active catalyst for the electrochemical reduction of CO2. However, the stability of this and other thiolate-protected NCs after partial ligand removal remains elusive. Using density functional theory (DFT) calculations and the recently developed thermodynamic stability model, we investigate the stability of [Au25(SR)18]1−, [Au18(SR)14]0, [Au23(SR)16]1−, and [Au28(SR)20]0 with ligand loss. Additionally, we examine the stability of the partially protected NCs upon adsorption of CO2 reduction reaction intermediates (i.e. H, CO, and COOH) on the different active sites generated after ligand removal. Our results reveal that the partially protected Au25 NC shows the highest stability compared to the other partially protected NCs in the presence of electrochemical reduction intermediates. We find that the presence of the COOH intermediate on the generated active sites stabilizes the Au25 NC almost as well as the removed ligands. Moreover, time-dependent DFT calculations and UV–Vis/Raman experiments suggest that the most probable ligand removal mode under electrochemical conditions is the one that generates S active sites, in agreement with the DFT ligand removal thermodynamic analysis. Importantly, this study demonstrates the robustness of the Au25 NC and offers a novel way to address stability of ligand protected NCs during electrocatalytic reaction conditions.