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Using the density functional theory, [(N2)RuIIL5]n+ species are studied in silico. The properties of the Ru-N2 bond are derived, including σ-donation, π-back donation, Ru-N and N-N bond lengths and bond orders, net charges and NN stretching frequencies, and so forth. These data are correlated using the ligand electrochemical parameter (EL) theory, whereby the availability of electrons in the [RuL5]n+ fragment is defined by its electron richness, which is the sum of the EL parameters, ΣEL(L5). The objective is to better understand the binding of the N2 ligand, leading to a molecular design whereby a specific species is constructed to have a desired property, for example, a particular bond length or charge. We supply cubic expressions linking ΣEL(L5) with these many metrics, allowing researchers to predict metric values of their own systems. The extended charge decomposition analysis is used. For the given target, N2, σ-bonding does not vary greatly with the nature of ligand L, and π-back donation is the dominant property deciding the magnitudes of the various metrics. The EL parameter provides the path to design the desired species. This contribution is devoted to dinitrogen, but the method is expected to be general for any ligand, including polydentate ligands.
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Ligand electrochemical parameters, EL , more commonly known as Lever parameters, have played a major research role in understanding redox processes involved in inorganic electrochemistry, enzymatic reactions, catalysis, solar cells, biochemistry, and materials science. Despite their broad usefulness, Lever parameters are not well understood at a first-principles level. Using density functional theory, we demonstrate in this contribution that a ligand's Lever parameter is fundamentally related to the ligand's ability to alter the eigenvalue of the electroactive spin-orbital in an octahedral transition metal complex. Our analysis furthers a first-principles understanding of the nature of Lever parameters.
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The drug development pipeline is severely limited by a lack of reliable tools for prediction of human clinical safety and efficacy profiles for compounds at the pre-clinical stage. Here we present the design and implementation of a platform technology comprising multiple human cell-based tissue models in a portable and reconfigurable format that supports individual organ function and crosstalk for periods of up to several weeks. Organ perfusion and crosstalk are enabled by a precision flow control technology based on electromagnetic actuators embedded in an arrayed format on a microfluidic platform. We demonstrate two parallel circuits of connected airway and liver modules on a platform containing 62 electromagnetic microactuators, with precise and controlled flow rates as well as functional biological metrics over a two week time course. Technical advancements enabled by this platform include the use of non-sorptive construction materials, enhanced scalability, portability, flow control, and usability relative to conventional flow control modes (such as capillary action, pressure heads, or pneumatic air lines), and a reconfigurable and modular organ model format with common fluidic port architecture. We demonstrate stable biological function for multiple pairs of airway-liver models for periods of 2 weeks in the platform, with precise control over fluid levels, temperature, flow rate and oxygenation in order to support relevant use cases involving drug toxicity, efficacy testing, and organ-organ interaction.
Assuntos
Microfluídica/métodos , Brônquios/citologia , Células Cultivadas , Técnicas de Cocultura , Citocromo P-450 CYP3A/metabolismo , Descoberta de Drogas , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Campos Magnéticos , Microfluídica/instrumentação , Microscopia de FluorescênciaRESUMO
The photochemical and photophysical properties of the cis-[Ru(II)(α-diimine)2(4-APy)2](2+) complexes, where α-diimine = 1,10-phenanthroline (phen) and 4-APy = 4-aminopyridine I, 4,7-diphenyl-1,10-phenanthroline (Ph2phen) II, 2,2'-bipyridine (bpy) III, and 4,4'-dimethyl-2,2'-bipyridine (Me2bpy) IV, are reported. The four complexes were characterized using high-performance liquid chromatography, (1)H NMR, UV-visible, emission, and transient absorption spectroscopy. Upon photolysis in acetonitrile solution these complexes undergo 4-APy dissociation to give the monoacetonitrile complex (for II, III, and IV) or the bis(acetonitrile) complex (for I). A fairly wide range of excitation wavelengths (from 420 to 580 nm) were employed to explore the photophysics of these systems. Quantum yields and transient spectra are provided. Density functional theory (DFT) and time-dependent DFT analysis of singlet and triplet excited states facilitated our understanding of the photochemical behavior. A detailed assessment of the geometric and electronic structures of the lowest energy spin triplet charge transfer state ((3)MLCT) and spin triplet metal centered state ((3)MC) (dπ â σ* transitions) for species I-IV is presented. A second, previously unobserved, and nondissociative, (3)MC state is identified and is likely involved in the primary step of photodissociation. This new (3)MC state may indeed play a major role in many other photodissociation processes.
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The electronic structures of (LX)2Ru(Vd)Ru(LX)2 complexes (Vd = 1,5-diisopropyl-3-(4,6-dimethyl-2-pyrimidinyl)-6-oxoverdazyl radical; LX = acac (acetylacetonate) or hfac (hexafluoroacetylacetonate)) in multiple charge states have been investigated experimentally and computationally. The main focus was to probe the consequences of the interplay between the ruthenium ions and the redox-active verdazyl ligand for possible mixed-valent behavior. Cyclic voltammetry studies reveal one reversible reduction and one reversible oxidation process for both complexes; in addition the acac-based derivative possesses a second reversible oxidation. Analysis of a collection of experimental (X-ray structures, EPR, electronic spectra) and computational (TD-DFT (PCM)) data reveal that the ruthenium ancillary ligands (acac vs hfac) have dramatic consequences for the electronic structures of the complexes in all charge states studied. In the hfac series, the neutral complex is best regarded as a binuclear Ru(II) species bridged by a neutral radical ligand. Reduction to give the anionic complex takes place on the verdazyl ligand, whereas oxidation to the cation (a closed shell species) is shared between Vd and ruthenium. For the acac-based complexes, the neutral species is most accurately represented as a Ru(II)/Ru(III) mixed valent complex containing a bridging verdazyl anion, though some bis(Ru(II))-neutral radical character remains. The monocation complex contains a significant contribution from a "broken symmetry" singlet diradical structure, best represented as a bis-Ru(III) system with an anionic ligand, with significant spin coupling of the two Ru(III) centers via the Vd(-1) ligand (calculated J = -218 cm(-1)). The dication, a spin doublet, consists of two Ru(III) ions linked (and antiferromagnetically coupled) to the neutral radical ligand. Computed net σ- and π-back-donation, spin densities, and orbital populations are provided. Time dependent DFT is used to predict the optical spectra and assign experimental data.
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Nine [Ru(Tp)(dppe)L] complexes, where Tp is hydrotris(pyrazol-1-yl)borate, dppe is ethylenebis(diphenylphosphine), and L is (4-nitrophenyl)cyanamide (NO(2)pcyd(-)), (2-chlorophenyl)cyanamide (2-Clpcyd(-)), (3-chlorophenyl)cyanamide (3-Clpcyd(-)), (2,4-dichlorophenyl)cyanamide (2,4-Cl(2)pcyd(-)), (2,3-dichlorophenyl)cyanamide (2,3-Cl(2)pcyd(-)), (2,5-dichlorophenyl)cyanamide (2,5-Cl(2)pcyd(-)), (2,4,5-trichlorophenyl)cyanamide (2,4,5-Cl(3)pcyd(-)), (2,3,5,6-tetrachlorophenyl)cyanamide (2,3,5,6-Cl(4)pcyd(-)), and (pentachlorophenyl)cyanamide (Cl(5)pcyd(-)), and the dinuclear complex [{Ru(Tp)(dppe)}(2)(µ-adpc)], where adpc(2-) is azo-4,4-diphenylcyanamide, have been prepared and characterized. The crystal structures of [Ru(Tp)(dppe)(Cl(5)pcyd)] and [{Ru(Tp)(dppe)}(2)(µ-adpc)] reveal the Ru(II) ion to occupy a pseudooctahedral coordination sphere in which the cyanamide ligand coordinates to Ru(II) by its terminal nitrogen atom. For both complexes, the cyanamide ligands are planar, indicating significant π mixing between the cyanamide and phenyl moieties as well as the azo group in the case of adpc(2-). The optical spectra of the nominally ruthenium(III) species [Ru(Tp)(dppe)L](+) were obtained through spectroelectrochemistry measurements and showed an intense near-IR absorption band. Time-dependent density functional theory calculations of these species revealed that oxidation of the ruthenium(II) species led to species where partial oxidation of the cyanamide ligand had occurred, indicative of noninnocent character for these ligands. The spin densities reveal that while the 3-Clpycd species has substantial Ru(II)(3-Clpycd(0)) character, the Cl(5)pycd species is a much more localized ruthenium(III) complex of the Cl(5)pycd monoanion. Some bond order and charge distribution data are derived for these ruthenium(III) species. The near-IR band is assigned as a quite complex mixture of d-d, 4d(π) to L(NCN) MLCT, and L(NCN) to Ru 4d LMCT with even a scorpionate ligand component. Spectroelectrochemistry was also performed on [{Ru(Tp)(dppe)}(2)(µ-adpc)] to generate the mixed-valence state. The intense intervalence transition that is observed in the near-IR is very similar to that previously reported for [{Ru(trpy)(bpy)}(2)(µ-adpc)](2+), where trpy is 2,2':6',2"-terpyridine and bpy is 2,2'-bipyridine, and by analogy identifies [{Ru(Tp)(dppe)}(2)(µ-adpc)](+) as a delocalized mixed-valence complex.
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Cianamida/química , Compostos Organometálicos/química , Rutênio/química , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese químicaRESUMO
The complex Ru(II)(NH(3))(2)(o-benzoquinonediimine)Cl(2) undergoes a reversible apparent acid/base reaction, although it has no obvious basic lone pairs. The reaction is a proton-assisted disproportionation yielding an oxidant ([Ru(III)(NH(3))(2)(o-benzoquinonediimine)Cl(2)](+)) and a reductant ([Ru(III)(NH(3))(2)(o-phenylenediamine)Cl(2)](+)). These species were characterized by electrochemistry, ultraviolet-visible light (UV-vis), vibrational (infrared (IR) and Raman), mass and electron paramagnetic resonance (EPR) spectroscopy, and X-ray structural analysis. The reaction is shown to be downhill from an isodesmic calculation. Three different isosbestic interconversions of the parent and product species are demonstrated. The electronic structures of these species were analyzed, and their optical spectra assigned, using density functional theory (DFT) and time-dependent DFT. This disproportionation of a noninnocent ligand complex may be relevant to the application of noninnocent ligands in organometallic catalysis and in the biological milieu.
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Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Oxidantes/síntese química , Prótons , Substâncias Redutoras/síntese química , Rutênio/química , Cristalografia por Raios X , Espectroscopia de Ressonância de Spin Eletrônica , Ligantes , Modelos Moleculares , Oxidantes/química , Teoria Quântica , Substâncias Redutoras/químicaRESUMO
AIM: To compare the accuracy of positron emission tomography (PET) using (18)F-FDG (Fluorodeoxyglucose) PET with (111)In-labelled leucocytes scintigraphy (LS) in patients with fever of unknown origin (FUO). METHODS: Twenty-three consecutive patients with FUO were prospectively studied using whole-body LS and PET. Performance of the two modalities for identifying a cause of FUO was evaluated. Final diagnosis was based on biopsy, microbiological tests, clinical and imaging follow-up. RESULTS: Abnormal tracer uptake was seen in 3/23(13%) and 14/23(61%) patients on LS and PET respectively, suggesting a higher sensitivity (p < 0.01) for the latter. All LS positive cases were identified on PET and confirmed as infection. The causes of FUO in the other PET positive patients were: infection (n = 3), vasculitis (n = 3), non-infectious inflammatory conditions (n = 2) and cancer (n = 1). No specific diagnosis was reached in 2 patients. Of 13 patients without a definite diagnosis following PET and LS, 10 made a spontaneous recovery during the follow-up period and no definite cause for FUO was found on investigation. Still's disease, Polymyalgia rheumatica and Chronic fatigue syndrome/Myalgic encephalomyelitis were diagnosed in the remaining three patients during follow-up. The results thus showed an overall sensitivity of 86% for PET and 20% for LS (p < 0.01). The overall specificity for FDG PET was 78% as against 100% for LS. PET had a PPV of 86% and a NPV of 78% whereas LS had a PPV of 100% and a NPV of 40%. CONCLUSION: PET has a higher sensitivity than LS in identifying the aetiology of FUO. PET/PET-CT, where available, should be used as the non-invasive investigation of choice in the assessment of patients with FUO.
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Febre de Causa Desconhecida/diagnóstico , Fluordesoxiglucose F18/administração & dosagem , Radioisótopos de Índio/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Cintilografia/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Parvovirus , Estudos Prospectivos , Sensibilidade e Especificidade , Coloração e Rotulagem/métodosRESUMO
The title compound, {[CoBr(2)(C(5)H(4)N(2)O(2))(H(2)O)]·H(2)O}(n), is a one-dimensional coordination polymer which crystallizes as a monohydrate. The asymmetric unit contains one Co(II) atom in a distorted octa-hedral geometry, forming a chain parallel to [010] with the pyrazine carb-oxy-lic acid ligands coordinating on one side in a bidentate fashion through one N and one O atom, and in a monodentate fashion through a N atom, with N atoms trans, and with both ligands lying in the same plane. The bromide atoms are cis to each other, while a water mol-ecule occupies the final octa-hedral coordination site. The chains are linked together though an O-Hâ¯Br hydrogen bonding network, and are further stabilized by an O-Hâ¯Br and O-Hâ¯O hydrogen-bonding framework with the solvent water mol-ecule.
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The electronic structures of (Vd)Ru(LX)(2) complexes (Vd = 1,5-diisopropyl-3-(2-pyridyl)-6-oxoverdazyl radical; LX = acac or hfac) as neutral, cationic, and anionic species have been investigated experimentally and computationally to probe the interplay between the ruthenium ion and the redox-active verdazyl ligand. The cationic complexes were prepared by oxidation of the corresponding neutral species with silver(I) salts. The hfac-based anionic complex was synthesized by reduction of the neutral species with cobaltocene, but the anionic acac analogue could not be prepared. Experimental (X-ray structures, electronic spectra) and computational (TD-DFT (PCM)) studies reveal that the expression of redox activity of the ligand and metal moieties is highly sensitive to the nature of the ancillary ligands on ruthenium. In the hfac series, the cationic, neutral, and anionic complexes can, respectively, be adequately described as Ru(II) complexes of a coordinated verdazyl cation, neutral radical, and anion. However, the more electron-donating acac coligands facilitate a stronger interaction between ruthenium and verdazyl via Ru(d) to Vd(π*) backbonding which is dependent on the overall charge of the complex and has the net effect of creating a high degree of metal-ligand covalency. Studies on the two cationic complexes reveal further distinctions between the acac- and hfac-containing systems: whereas the former has a significant open-shell singlet contribution to the complex ground state, this open-shell formulation is a minor component of the latter.
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BACKGROUND: Vertebral osteomyelitis (VO) is associated with considerable morbidity and its incidence seems to be increasing. Haematogenous spread is an important aetiological factor. AIM: The objective was to describe a series of patients with VO and to search for a relationship between preceding bacteraemia and subsequent VO with the same pathogen. DESIGN AND METHODS: A retrospective study of all treated cases of VO in a tertiary hospital over a 10-year period. RESULTS: There were 129 cases of VO (involving 125 patients) that received antimicrobial treatment. Eighty-three (66%) were male and the mean age was 59.5 years (range 1 month to 87 years). The vertebral level involved was lumbar in 66 (53%) cases and thoracic in 35 (28%) cases. Seventy-four cases (59%) had a microbiologically confirmed aetiology. The diagnostic yield from procedures was 46 and 36% from blood culture and bone biopsy, respectively. Staphylococcus aureus was the most common pathogen [38 of 74 (51%) cases]. Nine of 38 (24%) cases of Staphylococcus aureus VO had a preceding bacteraemia with the same pathogen in the previous year. CONCLUSION: Staphylococcus aureus is an important pathogen causing bacteraemia with the ability to cause metastatic complications including VO. The high proportion of cases developing VO following a documented bacteraemia, sometimes many months previously, reinforce the importance of adequate aggressive treatment for bacteraemia. VO must be considered in all patients presenting with back pain up to a year after bacteraemia. Previous bacteraemias with relevant pathogens can help guide antibiotic treatment at presentation of VO and if biopsy cannot be obtained.
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Bacteriemia/microbiologia , Osteomielite/microbiologia , Doenças da Coluna Vertebral/microbiologia , Infecções Estafilocócicas/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Osteomielite/epidemiologia , Estudos Retrospectivos , Doenças da Coluna Vertebral/epidemiologia , Doenças da Coluna Vertebral/etiologia , Staphylococcus aureus/isolamento & purificação , Adulto JovemRESUMO
Spectroscopic, structural, and computational studies of verdazyl radical-ruthenium complexes reveal the verdazyl to be a redox-active and non-innocent ligand. The ensuing delocalization of charge is highly sensitive to the nature of the beta-diketonate co-ligands.
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Elétrons , Compostos Heterocíclicos/síntese química , Cetonas/química , Compostos Organometálicos/síntese química , Rutênio/química , Simulação por Computador , Cristalografia por Raios X , Radicais Livres/síntese química , Radicais Livres/química , Compostos Heterocíclicos/química , Ligantes , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/química , OxirreduçãoRESUMO
We surveyed the HIV-positive population attending a major teaching hospital sited outwith a major conurbation. Eighty-five percent of homosexually acquired infections were contracted within the UK and 91% of heterosexually acquired infections were contracted outside of the UK. A strikingly wide range of nationalities (45) and countries of origin of infection were represented within a relatively small patient population. Most patients were non-UK-born immigrants. A high proportion of illegal immigrants were identified within which there was a high proportion lost to follow-up. This degree of ethnic diversity and domiciliary instability is rarely a feature of non-HIV populations in this setting and imposes additional demands on delivery of care and health-care planning.
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Etnicidade , Infecções por HIV/epidemiologia , Adolescente , Adulto , Emigrantes e Imigrantes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Adulto JovemRESUMO
Rev remains a hot topic. In this review, we revisit the insights that have been gained into the control of gene expression by the retroviral protein Rev and speculate on where current research is leading. We outline what is known about the role of Rev in translation and encapsidation and how these are linked to its more traditional role of nuclear export, underlining the multifaceted nature of this small viral protein. We discuss what more is to be learned in these fields and why continuing research on these 116 amino acids and understanding their function is still important in devising methods to combat AIDS.
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Regulação Viral da Expressão Gênica , Produtos do Gene rev/fisiologia , Interações Hospedeiro-Patógeno , Retroviridae/fisiologia , Transporte Ativo do Núcleo Celular , Humanos , Biossíntese de Proteínas , Montagem de VírusAssuntos
Quimioprevenção/economia , Quimioprevenção/métodos , Pentamidina/economia , Pentamidina/uso terapêutico , Pneumonia por Pneumocystis/tratamento farmacológico , Pneumonia por Pneumocystis/prevenção & controle , Administração por Inalação , Hospitais de Ensino , Humanos , Pentamidina/administração & dosagemRESUMO
Reaction of cis-Ru(bpy)(2)Cl(2) with 1,2-benzenedithiol afforded a monosulfhydryl-monosulfinate complex, [Ru(bpy)(2)(S.SO(2))] (1). Complex 1 readily undergoes oxidation when treated with 30% H(2)O(2) and also upon exposure to atmospheric O(2) (rapidly in bright light) to afford the disulfinate complex, [Ru(bpy)(2)(SO(2.)SO(2))] (2). Complexes 1 and 2 were studied using various analytical techniques including elemental analysis, UV-vis, mass spectroscopy, NMR, IR spectroscopy, cyclic voltammetry, X-ray crystallography (for 2). Density functional theory computation was employed with extended charge decomposition and natural population analyses. The agreement between the observed electronic spectrum and that predicted by time dependent DFT, and between the observed infrared spectrum and that predicted by DFT, is truly exceptional. These molecules are relevant to the very unusual active site in the metalloenzyme nitrile hydratase.
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The syntheses and properties are reported for five Ru(acac)2(R-bqdi) species where acac is acetylacetonate, and R-bqdi is the non-innocent ligand ortho-benzoquinonediimine substituted with R = H (1), 4,5-dimethyl (2), 4-Cl (3), or 4-NO2 (4), and N,N''-dimethylsulfonyl (5). Their identities and purities were confirmed by NMR, mass spectra, IR and analytical data. The large degree of metal-to-ligand pi-back-donation was analyzed by spectroscopic (UV/visible, IR, Raman) and electrochemical data, supported by molecular orbital composition computations using density functional theory (DFT), with the polarizable continuum model (PCM) to mimic the presence of solvent, and prediction of electronic spectra using time-dependent DFT methods. Extended charge decomposition analysis (ECDA) and natural population analysis (NPA) both produced a detailed picture of the bonding between the non-innocent bqdi ligand and the metal center, allowing correlations to be drawn between the nature of the R substituents and the quantitative extent of pi-back-donation and sigma-forward donation. In conclusion, the issue of whether these species are best regarded as Ru(II)(quinonediimine) or coupled Ru(III)(semiquinonediiminate) species is discussed.
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The title compound, C(18)H(14)Cl(2)N(2)O(4)S(2), is a diamine that is a precursor to a quinonoid bidentate redox-active ligand. The dihedral angles between the central phenyl ring and the end rings are 87.5(1) and 60.7(1)°, while the two end rings make a dihedral angle of 82.5(1)°. The crystal structure is stabilized by two weak inter-molecular N-Hâ¯O hydrogen bonds, as well as one intra-molecular C-Hâ¯O and one N-Hâ¯N hydrogen bond.
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The reaction of Mo2(SCH2CH2S)2Cp2 (1; Cp=eta-C5H5) with an excess of an alkyne in refluxing dichloromethane affords the bis(dithiolene) complexes Mo2(micro-SCR1=CR2S)2Cp2 (2a, R1=R2=CO2Me; 2b, R1=R2=Ph; 2c, R1=H, R2=CO2Me) whereas with 1 equiv of alkyne at room temperature the mixed dithiolene-dithiolate species Mo2(micro-SCR1=CR2S)(micro-SCH2CH2S)Cp2 (3a, R1=R2=CO2Me; 3b, R1=R2=Ph) are formed. The remaining dithiolate ligand in 3 can then be converted into a different dithiolene by reaction with a second alkyne. Applying this methodology, we have used bis(diphenylphosphino)acetylene to prepare the first examples of complexes containing phosphine-substituted dithiolene ligands: Mo2{micro-SC(CO2Me)=C(CO2Me)S}{micro-SC(PPh2)=C(PPh2)S}Cp2 (2g) and Mo2{micro-SC(PPh2)=C(PPh2)S}2Cp2 (2h). Tri- and tetrametallic complexes can then be assembled by coordination of these diphosphines to CpRuCl units by reaction with CpRu(PPh3)2Cl. Electrochemical studies of the Ru(II)/Ru(III) couple in Mo2{micro-SC(PPh2)=C(PPh2)S}2Cp2(RuClCp)2 (4b) reveals that the two separate ruthenium centers are oxidized electrochemically at different potentials, demonstrating communication between them through the dimolybdenum bis(dithiolene) core. Density functional theory calculations were carried out to explore the electronic structures of these species and to predict and assign their electronic spectra.
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Human immunodeficiency virus (HIV)-based vectors are being increasingly used in vitro for gene transfer and in vivo for gene therapy. The proportion of integrated retroviral vectors that are silenced or remain transcriptionally active, and the stability of gene expression in the latter remains poorly explored. To study this, T cells were infected with an HIV-1-based vector construct containing a long terminal repeat-driven reporter gene. Only a small percentage of detectable integrated vector expressed gene product. In clones derived from cells with transcriptionally active vector, gene expression was remarkably stable with more than 80% continuing to express for greater than 18 months. Failure to continue expressing the vector was associated with epigenetic changes. Our data suggest that there are two forms of vector silencing: one occurring immediately after integration affecting the majority of the vectors, and one occurring in the much longer term affecting a small minority of vectors which had previously established expression.