A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

SET-Induced Biaryl Cross-Coupling: An S_RN1 Reaction

The SET-induced biaryl cross-coupling reaction is established as the first example of a Grignard S_RN1 reaction. The reaction is examined within the mechanistic framework of dissociative electron transfer in the presence of a Lewis acid. DFT calculations show that the reaction proceeds through a radical intermediate in the form of an Mg ion-radical cage, which eludes detection in trapping experiments by reacting quickly to form an MgPh₂ radical anion intermediate. A new mechanism is proposed

Factors Impacting the Mechanism of the Mono-N-Protected Amino Acid Ligand-Assisted and Directing-Group-Mediated C–H Activation Catalyzed by Pd(II) Complex

We computationally studied the roles of the (a) protecting group (PG), (b) side chain (R), and (c) length of amino acid backbone of the mono-N-protected amino acid (MPAA) ligand as well as (d) the nature of the substrate (DG-SUB) and directing group (DG) on the following elementary steps of the “N–H bond cleavage and subsequent C–H bond activation” mechanism for [MPAA]–Pd­(II)-catalyzed C–H activation: (i) formation of the prereaction complex, [MPAA]–Pd­(II)–[DG-SUB], with a weakly coordinated monoanionic amino acid ligand; (ii) N–H bond cleavage and formation of the catalytically active intermediate, [MPAA′]–Pd­(II)–[DG-SUB], with a bidentately coordinated dianionic amino acid ligand, and (iii) C–H bond activation in [MPAA′]–Pd­(II)–[DG-SUB] occurring via the concerted metalation/deprotonation pathways A (outer-sphere) and B (inner-sphere). For the prereaction complex, we find that weak coordination of the MPAA ligand to Pd­(II) is affected by (a) the strong electron-withdrawing ability of the PG, (b) longer amino acid backbone, and (c) a strong Pd-DG interaction. For the N–H bond-cleavage step, we find that facile N–H cleavage is affected by (a) the strong electron-withdrawing ability of the PG, (b) the existence of stabilizing noncovalent interactions, and (c) a weak Pd–DG interaction. For the C–H activation step, we report that (a) the increase in the electron-withdrawing ability of the PG stabilizes both pathways A and B, whereas proton affinity of the PG impacts only pathway B; (b) the geometrical features of the substrate–ligand motif in [MPAA′]–Pd­(II)–[DG-SUB] and the existence of stabilizing noncovalent interactions can alter the reaction mechanism; and (c) the enantioselectivity of the reaction is reported to be controlled by either steric congestion around the substrate (in pathway A) or cooperative ligand-substrate geometrical constraints (in pathway B)

The Increasingly Complex Mechanism of HMG-CoA Reductase

HMG-CoA reductase (HMGR) is the target of statins, cholesterol-lowering drugs prescribed to millions of patients worldwide. More recent research indicates that HMGR could be a useful target in the development of antimicrobial agents. Over the last seven decades, researchers have proposed a series of increasingly complex reaction mechanisms for this biomedically important enzyme.The maturation of the mechanistic proposals for HMGR have paralleled advances in a diverse set of research areas, such as molecular biology and computational chemistry. Thus, the development of the HMGR mechanism provides a useful case study for following the advances in state-of-the-art methods in enzyme mechanism research. Similarly, the questions raised by these mechanism proposals reflect the limitations of the methods used to develop them.The mechanism of HMGR, a four-electron oxidoreductase, is unique and far more complex than originally thought. The reaction contains multiple chemical steps, coupled to large-scale domain motions of the homodimeric enzyme. The first proposals for the HMGR mechanism were based on kinetic and labeling experiments, drawing analogies to the mechanism of known dehydrogenases. Advances in molecular biology and bioinformatics enabled researchers to use site-directed mutagenesis experiments and protein sequencing to identify catalytically important glutamate, aspartate, and histidine residues. These studies, in turn, have generated new and more complicated mechanistic proposals.With the development of protein crystallography, researchers solved HMGR crystal structures to reveal an unexpected lysine residue at the center of the active site. The many crystal structures of HMGR led to increasingly complex mechanistic proposals, but the inherent limitations of the protein crystallography left a number of questions unresolved. For example, the protonation state of the glutamate residue within the active site cannot be clearly determined from the crystal structure. The differing protonation state of this residue leads to different proposed mechanisms for the enzyme.As computational analysis of large biomolecules has become more feasible, the application of methods such as hybrid quantum mechanics/molecular mechanics (QM/MM) calculations to the HMGR mechanism have led to the most detailed mechanistic proposal yet. As these methodologies continue to improve, they prove to be very powerful for the study of enzyme mechanisms in conjunction with protein crystallography. Nevertheless, even the most current mechanistic proposal for HMGR remains incomplete due to limitations of the current computational methodologies. Thus, HMGR serves as a model for how the combination of increasingly sophisticated experimental and computational methods can elucidate very complex enzyme mechanisms

Generality and Strength of Transition Metal β‑Effects

Using computation, we examine the generality and strength of β-effects from transition metal centers on β-elimination. In particular, we find that a β-Pd­(II) substituent imparts over twice the stabilization to a carbocation as a Si substituent, representative of the well-known β-silicon effect. We established efficient and practical computational parameters to investigate the σσ conjugation in an experimentally relevant system: <i>N</i>,<i>N</i>-picolinamide vinyl metalacycles with β-substituents that can undergo elimination. We have found that the β-Pd effect depends on the nature of the C_β substituent (X): This effect is negligible for X = H, Me, OH, and F, but is significant for X = Cl, Br, and I. We have also extended these studies to the β-effect in <i>N</i>,<i>N</i>-picolinamide vinyl metalacycles with β-substituents of other transition metalsFe­(II), Ru­(II), Os­(II), Co­(III), Rh­(III), Ir­(III), Ni­(II), Pd­(II), Pt­(II), Cu­(III), Ag­(III), and Au­(III). We found that the electronegativity of the metals correlates reasonably well with the relative β-effects, with first-row transition metals exerting the strongest influence. Overall, it is our anticipation that a more profound appreciation of transition metal β-effects will facilitate the design of novel reactions, including new variants of transition metal catalyzed C–H functionalization

The Increasingly Complex Mechanism of HMG-CoA Reductase

HMG-CoA reductase (HMGR) is the target of statins, cholesterol-lowering drugs prescribed to millions of patients worldwide. More recent research indicates that HMGR could be a useful target in the development of antimicrobial agents. Over the last seven decades, researchers have proposed a series of increasingly complex reaction mechanisms for this biomedically important enzyme.The maturation of the mechanistic proposals for HMGR have paralleled advances in a diverse set of research areas, such as molecular biology and computational chemistry. Thus, the development of the HMGR mechanism provides a useful case study for following the advances in state-of-the-art methods in enzyme mechanism research. Similarly, the questions raised by these mechanism proposals reflect the limitations of the methods used to develop them.The mechanism of HMGR, a four-electron oxidoreductase, is unique and far more complex than originally thought. The reaction contains multiple chemical steps, coupled to large-scale domain motions of the homodimeric enzyme. The first proposals for the HMGR mechanism were based on kinetic and labeling experiments, drawing analogies to the mechanism of known dehydrogenases. Advances in molecular biology and bioinformatics enabled researchers to use site-directed mutagenesis experiments and protein sequencing to identify catalytically important glutamate, aspartate, and histidine residues. These studies, in turn, have generated new and more complicated mechanistic proposals.With the development of protein crystallography, researchers solved HMGR crystal structures to reveal an unexpected lysine residue at the center of the active site. The many crystal structures of HMGR led to increasingly complex mechanistic proposals, but the inherent limitations of the protein crystallography left a number of questions unresolved. For example, the protonation state of the glutamate residue within the active site cannot be clearly determined from the crystal structure. The differing protonation state of this residue leads to different proposed mechanisms for the enzyme.As computational analysis of large biomolecules has become more feasible, the application of methods such as hybrid quantum mechanics/molecular mechanics (QM/MM) calculations to the HMGR mechanism have led to the most detailed mechanistic proposal yet. As these methodologies continue to improve, they prove to be very powerful for the study of enzyme mechanisms in conjunction with protein crystallography. Nevertheless, even the most current mechanistic proposal for HMGR remains incomplete due to limitations of the current computational methodologies. Thus, HMGR serves as a model for how the combination of increasingly sophisticated experimental and computational methods can elucidate very complex enzyme mechanisms

Generality and Strength of Transition Metal β‑Effects

Using computation, we examine the generality and strength of β-effects from transition metal centers on β-elimination. In particular, we find that a β-Pd­(II) substituent imparts over twice the stabilization to a carbocation as a Si substituent, representative of the well-known β-silicon effect. We established efficient and practical computational parameters to investigate the σσ conjugation in an experimentally relevant system: <i>N</i>,<i>N</i>-picolinamide vinyl metalacycles with β-substituents that can undergo elimination. We have found that the β-Pd effect depends on the nature of the C_β substituent (X): This effect is negligible for X = H, Me, OH, and F, but is significant for X = Cl, Br, and I. We have also extended these studies to the β-effect in <i>N</i>,<i>N</i>-picolinamide vinyl metalacycles with β-substituents of other transition metalsFe­(II), Ru­(II), Os­(II), Co­(III), Rh­(III), Ir­(III), Ni­(II), Pd­(II), Pt­(II), Cu­(III), Ag­(III), and Au­(III). We found that the electronegativity of the metals correlates reasonably well with the relative β-effects, with first-row transition metals exerting the strongest influence. Overall, it is our anticipation that a more profound appreciation of transition metal β-effects will facilitate the design of novel reactions, including new variants of transition metal catalyzed C–H functionalization

Ten Questions Concerning the Implications of Carpet on Indoor Chemistry and Microbiology

Carpet and rugs currently represent about half of the United States flooring market and offer many benefits as a flooring type. How carpets influence our exposure to both microorganisms and chemicals in indoor environments has important health implications but is not well understood. The goal of this manuscript is to consolidate what is known about how carpet impacts indoor chemistry and microbiology, as well as to identify the important research gaps that remain. After describing the current use of carpet indoors, questions focus on five specific areas: 1) indoor chemistry, 2) indoor microbiology, 3) resuspension and exposure, 4) current practices and future needs, and 5) sustainability. Overall, it is clear that carpet can influence our exposures to particles and volatile compounds in the indoor environment by acting as a direct source, as a reservoir of environmental contaminants, and as a surface supporting chemical and biological transformations. However, the health implications of these processes are not well known, nor how cleaning practices could be optimized to minimize potential negative impacts. Current standards and recommendations focus largely on carpets as a primary source of chemicals and on limiting moisture that would support microbial growth. Future research should consider enhancing knowledge related to the impact of carpet in the indoor environment and how we might improve the design and maintenance of this common material to reduce our exposure to harmful contaminants while retaining the benefits to consumers

Mechanism of Permanganate-Promoted Dihydroxylation of Complex Diketopiperazines: Critical Roles of Counter-cation and Ion-Pairing

The mechanism of permanganate-mediated dual C-H oxidation of complex diketopiperazines has been examined with density functional theory computations. The products of these oxidations are enabling intermediates in the synthesis of structurally diverse ETP natural products. We evaluated, for the first time, the impact of ion-pairing and aggregation states of the permanganate ion and counter-cations, such as bis(pyridine)-silver(I) (Ag[superscript +]) and tetra-n-butylammonium (TBA[superscript +]), on the C-H oxidation mechanism. The C-H abstraction occurs through an open shell singlet species, as noted previously, followed by O-rebound and a competing OH-rebound pathway. The second C-H oxidation proceeds with a second equivalent of oxidant with lower free energy barriers than the first C-H oxidation due to directing effects and the generation of a more reactive oxidant species after the first C-H oxidation. The success and efficiency of the second C-H oxidation are found to be critically dependent on the presence of an ion-paired oxidant. We used the developed mechanistic knowledge to rationalize an experimentally observed oxidation pattern for C[superscript 3]-indole-substituted diketopiperazine (+)-5 under optimal oxidation conditions: namely, the formation of diol (-)-6 as a single diastereomer and lack of the ketone products. We proposed two factors that may impede the ketone formation: (i) the conformational flexibility of the diketopiperazine ring, and (ii) hindrance of this site, making it less accessible to the ion-paired oxidant species. Keywords: oxidation reactions; free energy; oxidation; quantum mechanics; transition metalsNational Institute of General Medical Sciences (U.S.) (Award GM089732