Uncovering a CF3 Effect on X-ray Absorption Energies of [Cu(CF3 )4 ]- and Related Copper Compounds by Using Resonant Diffraction Anomalous Fine Structure (DAFS) Measurements.

Understanding the electronic structures of high-valent metal complexes aids the advancement of metal-catalyzed cross coupling methodologies. A prototypical complex with formally high valency is [Cu(CF3 )4 ]- (1), which has a formal Cu(III) oxidation state but whose physical analysis has led some to a Cu(I) assignment in an inverted ligand field model. Recent examinations of 1 by X-ray spectroscopies have led previous authors to contradictory conclusions, motivating the re-examination of its X-ray absorption profile here by a complementary method, resonant diffraction anomalous fine structure (DAFS). From analysis of DAFS measurements for a series of seven mononuclear Cu complexes including 1, here it is shown that there is a systematic trifluoromethyl effect on X-ray absorption that blue shifts the resonant Cu K-edge energy by 2-3 eV per CF3 , completely accounting for observed changes in DAFS profiles between formally Cu(III) complexes like 1 and formally Cu(I) complexes like (Ph3 P)3 CuCF3 (3). Thus, in agreement with the inverted ligand field model, the data presented herein imply that 1 is best described as containing a Cu(I) ion with dn count approaching 10.

Peanut protein acts as a TH2 adjuvant by inducing RALDH2 in human antigen-presenting cells.

BACKGROUND: Peanut is a potent inducer of proallergenic TH2 responses in susceptible individuals. Antigen-presenting cells (APCs) including dendritic cells and monocytes instruct naive T cells to differentiate into various effector cells, determining immune responses such as allergy and tolerance. OBJECTIVE: We sought to detect peanut protein (PN)-induced changes in gene expression in human myeloid dendritic cells (mDCs) and monocytes, identify signaling receptors that mediate these changes, and assess how PN-induced genes in mDCs impact their ability to promote T-cell differentiation. METHODS: mDCs, monocytes, and naive CD4+ T cells were isolated from blood bank donors and peanut-allergic patients. APCs were incubated with PN and other stimulants, and gene expression was measured using microarray and RT quantitative PCR. To assess T-cell differentiation, mDCs were cocultured with naive TH cells. RESULTS: PN induced a unique gene expression profile in mDCs, including the gene that encodes retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in the retinoic acid (RA)-producing pathway. Stimulation of mDCs with PN also induced a 7-fold increase in the enzymatic activity of RALDH2. Blocking antibodies against Toll-like receptor (TLR)1/TLR2, as well as small interfering RNA targeting TLR1/TLR2, reduced the expression of RALDH2 in PN-stimulated APCs by 70%. Naive TH cells cocultured with PN-stimulated mDCs showed an RA-dependent 4-fold increase in production of IL-5 and expression of integrin α4ß7. CONCLUSIONS: PN induces RALDH2 in human APCs by signaling through the TLR1/TLR2 heterodimer. This leads to production of RA, which acts on TH cells to induce IL-5 and gut-homing integrin. RALDH2 induction by PN in APCs and RA-promoted TH2 differentiation could be an important factor determining allergic responses to peanut.

Probing the electronic and mechanistic roles of the µ4-sulfur atom in a synthetic CuZ model system.

Nitrous oxide (N2O) contributes significantly to ozone layer depletion and is a potent greenhouse agent, motivating interest in the chemical details of biological N2O fixation by nitrous oxide reductase (N2OR) during bacterial denitrification. In this study, we report a combined experimental/computational study of a synthetic [4Cu:1S] cluster supported by N-donor ligands that can be considered the closest structural and functional mimic of the CuZ catalytic site in N2OR reported to date. Quantitative N2 measurements during synthetic N2O reduction were used to determine reaction stoichiometry, which in turn was used as the basis for density functional theory (DFT) modeling of hypothetical reaction intermediates. The mechanism for N2O reduction emerging from this computational modeling involves cooperative activation of N2O across a Cu/S cluster edge. Direct interaction of the µ4-S ligand with the N2O substrate during coordination and N-O bond cleavage represents an unconventional mechanistic paradigm to be considered for the chemistry of CuZ and related metal-sulfur clusters. Consistent with hypothetical participation of the µ4-S unit in two-electron reduction of N2O, Cu K-edge and S K-edge X-ray absorption spectroscopy (XAS) reveal a high degree of participation by the µ4-S in redox changes, with approximately 21% S 3p contribution to the redox-active molecular orbital in the highly covalent [4Cu:1S] core, compared to approximately 14% Cu 3d contribution per copper. The XAS data included in this study represent the first spectroscopic interrogation of multiple redox levels of a [4Cu:1S] cluster and show high fidelity to the biological CuZ site.

Speaker-normalized sound representations in the human auditory cortex.

The acoustic dimensions that distinguish speech sounds (like the vowel differences in "boot" and "boat") also differentiate speakers' voices. Therefore, listeners must normalize across speakers without losing linguistic information. Past behavioral work suggests an important role for auditory contrast enhancement in normalization: preceding context affects listeners' perception of subsequent speech sounds. Here, using intracranial electrocorticography in humans, we investigate whether and how such context effects arise in auditory cortex. Participants identified speech sounds that were preceded by phrases from two different speakers whose voices differed along the same acoustic dimension as target words (the lowest resonance of the vocal tract). In every participant, target vowels evoke a speaker-dependent neural response that is consistent with the listener's perception, and which follows from a contrast enhancement model. Auditory cortex processing thus displays a critical feature of normalization, allowing listeners to extract meaningful content from the voices of diverse speakers.

Cu-Catalyzed Hydroxymethylation of Unactivated Alkyl Iodides with CO To Provide One-Carbon-Extended Alcohols.

We have developed a reductive carbonylation method by which unactivated alkyl iodides can be hydroxymethylated to provide one-carbon-extended alcohol products under Cu-catalyzed conditions. The method is tolerant of alkyl ß-hydrogen atoms, is robust towards a wide variety of functional groups, and was applied to primary, secondary, and tertiary alkyl iodide substrates. Mechanistic experiments indicate that the transformation proceeds by atom-transfer carbonylation (ATC) of the alkyl iodide followed in tandem by two CuH-mediated reductions in rapid succession. This radical mechanism renders the Cu-catalyzed system complementary to precious-metal-catalyzed reductive carbonylation reactions.

Diverse bimetallic mechanisms emerging from transition metal Lewis acid/base pairs: development of co-catalysis with metal carbenes and metal carbonyl anions.

The rational development of catalytic reactions involving cooperative behavior between two catalytic reactive sites represents a frontier area of research from which novel reactivity and selectivity patterns emerge. Within this context, this Feature highlights the development of a cooperative system involving transition metal Lewis acid/base pairs. Bimetallic systems consisting of copper carbene Lewis acids and metal carbonyl anion Lewis bases, (NHC)Cu-[MCO], are easily synthesized from readily available organometallic building blocks (NHC = N-heterocyclic carbene; [MCO]- = metal carbonyl anion, e.g. [FeCp(CO)2]-, [Mn(CO)5]-, etc.). Stoichiometric reactivity studies indicate that the dative Cu←M bonds in these systems are labile towards heterolysis under mild conditions, thus providing in situ access both to polar metal-metal bonds and to "frustrated" transition metal Lewis acid/base pairs as dictated by reaction conditions. Catalytic transformations ranging from C-C and C-B coupling reactions to hydrogenation and other reductions have been developed from both manifolds: bimetallic catalysis involving (a) binuclear intermediates engaging in cooperative bond activation and formation, and (b) orthogonal mononuclear intermediates that operate in either tandem or co-dependent manners. Preliminary indications point to the future emergence of novel reactivity and selectivity patterns as these new motifs undergo continued development, and additionally demonstrate that the relative matching of two reactive sites provides a method for controlling catalytic behavior. Collectively, these results highlight the fundamental importance of exploring unconventional catalytic paradigms.

Probing the electronic structures of [Cu2(mu-XR2)]n+ diamond cores as a function of the bridging X atom (X = N or P) and charge (n = 0, 1, 2).

A series of dicopper diamond core complexes that can be isolated in three different oxidation states ([Cu2(mu-XR2)]n+, where n = 0, 1, 2 and X = N or P) is described. Of particular interest is the relative degree of oxidation of the respective copper centers and the bridging XR2 units, upon successive oxidations. These dicopper complexes feature terminal phosphine and either bridging amido or phosphido donors, and as such their metal-ligand bonds are highly covalent. Cu K-edge, Cu L-edge, and P K-edge spectroscopies, in combination with solid-state X-ray structures and DFT calculations, provides a complementary electronic structure picture for the entire set of complexes that tracks the involvement of a majority of ligand-based redox chemistry. The electronic structure picture that emerges for these inorganic dicopper diamond cores shares similarities with the Cu2(mu-SR)2 CuA sites of cytochrome c oxidases and nitrous oxide reductases.

Neurodevelopmental outcome and growth at 18 to 22 months' corrected age in extremely low birth weight infants treated with early erythropoietin and iron.

BACKGROUND: Clinical trials evaluating the use of erythropoietin (Epo) have demonstrated a limited reduction in transfusions; however, long-term developmental follow-up data are scarce. OBJECTIVE: We compared anthropometric measurements, postdischarge events, need for transfusions, and developmental outcomes at 18 to 22 months' corrected age in extremely low birth weight (ELBW) infants treated with early Epo and supplemental iron therapy with that of placebo/control infants treated with supplemental iron alone. METHODS: The National Institute of Child Health and Human Development Neonatal Research Network completed a randomized, controlled trial of early Epo and iron therapy in preterm infants < or =1250 g. A total of 172 ELBW (< or =1000-g birth weight) infants were enrolled (87 Epo and 85 placebo/control). Of the 72 Epo-treated and 70 placebo/control ELBW infants surviving to discharge, follow-up data (growth, development, rehospitalization, transfusions) at 18 to 22 months' corrected age were collected on 51 of 72 Epo-treated infants (71%) and 51 of 70 placebo/controls (73%) by certified examiners masked to the treatment group. Statistical significance was determined using chi2 analysis. RESULTS: There were no significant differences between treatment groups in weight or length or in the percentage of infants weighing <10th percentile either at the time of discharge or at follow-up, and no difference was found in the mean head circumference between groups. A similar percentage of infants in each group was rehospitalized (38% Epo and 35% placebo/control) for similar reasons. There were no differences between groups with respect to the percentage of infants with Bayley-II Mental Developmental Index <70 (34% Epo and 36% placebo/control), blindness (0% Epo and 2% placebo/control), deafness or hearing loss requiring amplification (2% Epo and 2% placebo/control), moderate to severe cerebral palsy (16% Epo and 18% placebo/control) or the percentage of infants with any of the above-described neurodevelopmental impairments (42% Epo and 44% placebo/control). CONCLUSIONS: Treatment of ELBW infants with early Epo and iron does not significantly influence anthropometric measurements, need for rehospitalization, transfusions after discharge, or developmental outcome at 18 to 22 months' corrected age.

Special feeds for special infants: 2. Feeding the preterm baby.

Individual babies may differ considerably in the way in which feeds can be introduced, the problems they encounter while this is going on, their final feed requirements and the need for supplementation. Sucking and swallowing reflexes are poorly developed before 32-34 weeks' gestation. Respiratory illness is probably the main reason for delay in the start of milk feeding. Immediate aims are to prevent hypoglycaemia and provide normal fluid requirements, if necessary by IV infusion or tube feeding. Preterm babies have large energy requirements. The mother's breast milk is the best milk with which to begin feeding. If a formula milk is given, it should be a preterm, low birth weight formula which supplies extra energy, protein and minerals, not a standard formula intended for babies at term.

Absorption of calcium and magnesium from fortified human milk by very low birth weight infants.

Absorption of calcium and magnesium endogenous to human milk, as well as calcium and magnesium added as an exogenous supplement to human milk, was determined in 9 very low birth wt infants. Human milk, intrinsically labeled with stable isotopic tracers of calcium and magnesium, was prepared by administering isotopic tracers intravenously to a lactating woman. Different isotopic tracers, which were representative of calcium and magnesium in the supplement (Enfamil Human Milk Fortifier, Mead Johnson Nutritional Div.), were added to the intrinsically labeled milk. The fortified milk, which was labeled with two calcium tracers and two magnesium tracers, was given orally to the test subjects in a single feeding. True absorption of calcium and magnesium was determined from differences between the doses of tracer ingested and the quantities of tracer excreted in the feces. Stable isotopic tracers were quantified by fast atom bombardment mass spectrometry. These results demonstrate that the fractional absorptions of calcium in the human milk and the added mineral supplement are 80 and 82%, respectively. A total of 89% magnesium endogenous to human milk and 86% of magnesium derived from the mineral supplement was absorbed by the VLBW infants.

Serum vitamin E levels in the very low birth weight infant during oral supplementation.

A prospective study was initiated to monitor serum tocopherol levels in all infants admitted to Indiana University Medical Center with birth weights less than 1,500 g. These infants routinely receive 100 mg/kg/d of oral vitamin E (Aquasol E tocopherol acetate) every six hours. Levels are determined weekly or semiweekly using a modification of the fluorometric method of Hanson and Warwick. Vitamin E dosage is adjusted regularly to achieve levels greater than or equal to 3.5 mg/dL. During the 6 months of this study, a total of 76 patients had 567 serum measurements. Of these, 220 levels (38%) were greater than or equal to 3.5 mg/dL, 71 (13%) were greater than or equal to 5.5 mg/dL, and 15 (2.7%) were greater than 8 mg/dL. Serum tocopherol levels often (1) remained greater than or equal to 3.5 mg/dL for several days after oral supplementation was discontinued or (2) again became greater than or equal to 3.5 mg/dL on a reduced dosage of 25 to 50 mg/kg/d. These data indicate that infants weighing less than 1,500 g at birth who are receiving oral vitamin E supplementation at 100 mg/kg/d will have varied serum levels with a significant percentage exceeding 3.5 mg/dL.

Nitrogen sources for parenteral nutrition in the newborn infant.

Protein requirements for the preterm and term infant have been determined by a variety of methods. The parenteral protein needs of the very low birth weight infant are around 3 gm/kg/day and of the term infant approximately 2.2 gm/kg/day for maintenance of normal growth. These values are averages and may need to be modified for individuals depending upon a variety of potentially complicating factors. In this regard, many neonatologists recommend the provision of a maximum of 2 to 2.5 gm/kg/day of protein to newborns under most clinical situations. Whereas excessive administration of protein may result in adverse consequences, the tolerance of young infants to infusion of amino acid solutions is not well defined. Based upon animal studies of fetal amino acid utilization, the preterm infant may be capable of appropriately modifying its supply of amino acids over a relatively broad concentration range. It would appear that the supply of individual amino acids is adequately met by a number of amino acid solutions. The newer preparations appear to be more ideally suited to the special needs of the very low birth weight.

Role of dietary iron and fat on vitamin E deficiency anemia of infancy.

Thirty-five infants weighing less than 1500 g at birth were fed four commercial formulas (A-D) varying in polyunsaturated fatty acid composition (32 per cent linoleic acid in A and B and 12 per cent linoleic acid in C and D) and in iron content (smaller than 1.0 in A and B; 12 to 12 mg per liter in B and D). Infants receiving formula B showed significantly lower hemoglobins (p smaller than 0.01) and higher reticulocyte counts (p smaller than 0.005) than infants fed the other three formulas. Infants receiving the two formulas with higher concentrations of unsaturated fatty acids (A and B) showed significantly greater hydrogen-peroxide-induced hemolysis (p smaller than 0.001) than those given diets containing lower amounts. Infants in groups A and B also had lower serum tocopherol concentrations. Infant red-cell membranes are altered by the increased amounts of polyunsaturated fatty acids and iron in the diet. It appears that the development of vitamin E deficiency anemia occurs in infants receiving iron supplementation.